Dark Chocolate improves vision with 2 hours

Dark Chocolate improves vision with 2 hours

 

Contrast sensitivity and visual acuity were significantly higher 2 hours after consumption of a dark chocolate bar compared with a milk chocolate bar, but the duration of these effects and their influence in real-world performance await further testing.

Rabin JC, Karunathilake N, Patrizi K. Effects of Milk vs Dark Chocolate Consumption on Visual Acuity and Contrast Sensitivity Within 2 HoursA Randomized Clinical Trial. JAMA Ophthalmol. Published online April 26, 2018. doi:10.1001/jamaophthalmol.2018.0978

FDA often ignored or just not there for many drug approvals and trials

Study examines FDA influence on design of pivotal drug studies

An examination of the potential interaction between pharmaceutical companies and the U.S. Food and Drug Administration (FDA) to discuss future studies finds that one-quarter of recent new drug approvals occurred without any meeting, and when such meetings occurred, pharmaceutical companies did not comply with one-quarter of the recommendations made by the FDA regarding study design or primary outcome, according to a study in the November 26 issue of JAMA.

To enhance protocol quality, federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication. These meetings often generate FDA recommendations for improving research, although companies are not bound to follow them, according to background information in the article.

Steven Woloshin, M.D., M.S., of the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, N.H., and colleagues reviewed and analyzed approximated 200 FDA documents (memos; meeting minutes; filing checklists; and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012. The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality. Continue reading “FDA often ignored or just not there for many drug approvals and trials”

The European Union will make review of clinical trials for drugs ” absolutely impossible “

2014-05-27

Just look, but don’t touch: EMA terms of use for clinical study data are impracticable

Data are only allowed to be viewed on screen / Pre-censorship by drug manufacturers

The European Medicines Agency (EMA) receives comprehensive clinical study data from drug manufacturers. These data form the basis for the decision on the approval of new drugs. To make this information available to researchers and decision-makers, EMA issued a draft policy in 2013 for the publication of clinical study data, in which extensive data transparency was planned. Continue reading “The European Union will make review of clinical trials for drugs ” absolutely impossible “”

Discrepancies between trial results reported on clinical trial registry and in journals ( nearly all had discrepancies )

– nearly all had at least 1 discrepancy in the study group

– Our findings raise questions about accuracy of both ClinicalTrials.gov and publications, as each source’s reported results at times disagreed with the other.

Shhh...Can you keep a secret?

During a one year period, among clinical trials published in high-impact journals that reported results on a public clinical trial registry (ClinicalTrials.gov), nearly all had at least 1 discrepancy in the study group, intervention, or results reported between the 2 sources, including discrepancies in the designated primary end points for the studies, according to a study in the March 12 issue of JAMA.

The 2007 Food and Drug Administration (FDA) Amendments Act expanded requirements for ClinicalTrials.gov, mandating results reporting within 12 months of trial completion for all FDA-regulated medical products. “To our knowledge, no studies have examined reporting and accuracy of trial results information. Accordingly, we compared trial information and results reported on ClinicalTrials.gov with corresponding peer-reviewed publications,” write Jessica E. Becker, A.B., of the Yale University School of Medicine, New Haven, Conn., and colleagues. Continue reading “Discrepancies between trial results reported on clinical trial registry and in journals ( nearly all had discrepancies )”

Ghostwritten articles overstate benefits of ( Prempro ) hormone replacement therapy and downplay harms

Public release date: 7-Sep-2010 HRR-Re-Posted at Request

analyzed dozens of ghostwritten reviews and commentaries published in medical journals and journal supplements that were used to promote unproven benefits and downplay harms of Prempro

The analysis revealed that DesignWrite was paid US$25,000 to ghostwrite articles reporting clinical trials, including four manuscripts on the HOPE trials of low-dose Prempro

– DesignWrite was also assigned to write 20 review articles about the drug, for which they were paid US$20,000 each.

The first academic analysis of the 1500 documents unsealed in recent litigation against the pharmaceutical giant Wyeth (now part of Pfizer) reveals unprecedented insights into how pharmaceutical companies use ghostwriters to insert marketing messages into articles published in medical journals. Dr. Adriane Fugh-Berman, associate professor in the Department of Physiology at Georgetown University Medical Center in Washington DC, analyzed dozens of ghostwritten reviews and commentaries published in medical journals and journal supplements that were used to promote unproven benefits and downplay harms of Prempro—a brand of menopausal hormone therapy (HT)—and to cast competing therapies in a negative light. These articles were widely circulated to drug reps and doctors to disseminate the company’s marketing messages. The analysis appears in this week’s PLoS Medicine. Continue reading “Ghostwritten articles overstate benefits of ( Prempro ) hormone replacement therapy and downplay harms”

Pharmaceuticals: A market for producing ‘lemons’ and serious harm

EEV: Re-Post Request

Public release date: 17-Aug-2010

– they spend two to three times more on marketing than on research to persuade doctors to prescribe these new drugs
– Doctors may get misleading information and then misinform patients about the risks of a new drug. It’s really a two-tier market for lemons.”
Three reasons why the pharmaceutical market produces “lemons” are: Having companies in charge of testing new drugs, providing firewalls of legal protection behind which information about harms or effectiveness can be hidden, and the relatively low bar set for drug efficacy in order for a new drug to be approved
Drugs Addiction and Pharma
Drugs Addiction and Pharma (Photo credit: DES Daughter)

Incentives and protections for industry encourage development of many drugs with few new benefits over existing pharmaceuticals, but with risk of serious harm to users Continue reading “Pharmaceuticals: A market for producing ‘lemons’ and serious harm”

Doctors Group Sues FDA, Saying Drug Does More Harm Than Good

roflumilast, a drug used to treat chronic obstructive pulmonary disease

English: Logo of the .
English: Logo of the . (Photo credit: Wikipedia)
 

By ELIZABETH WARMERDAM

 

LOS ANGELES (CN) – A physicians group sued the U.S. FDA, seeking revocation of FDA approval of roflumilast, a drug used to treat chronic obstructive pulmonary disease. Continue reading “Doctors Group Sues FDA, Saying Drug Does More Harm Than Good”

Results from many large clinical trials are never published

Contact: Tom Hughes tahughes@unch.unc.edu 919-966-6047 University of North Carolina Health Care

Non-publication is more common among industry-funded trials, study finds

CHAPEL HILL, N.C. – A new analysis of 585 large, randomized clinical trials registered with ClinicalTrials.gov finds that 29 percent have not been published in scientific journals. In addition, nearly 78 percent of the unpublished trials had no results available on the website, either.

As a result, nearly 300,000 people who were enrolled in the 171 unpublished trials “were exposed to the risks of trial participation without the societal benefits which accompany the dissemination of trial results,” said Christopher W. Jones, MD, a former resident physician at University of North Carolina School of Medicine who is now an attending physician at Cooper Medical School of Rowan University in Camden, N.J. and lead author of the study published in the Oct. 29, 2013 issue of the British Medical Journal.

Continue reading “Results from many large clinical trials are never published”

Widow Says Death Spurred Employer Profits: Claims Bristol-Myers Squibb had a $6 million life insurance policy on her husband

By LORRAINE BAILEY

 

CHICAGO (CN) – After her husband died, Bristol-Myers Squibb slipped up and accidentally informed his widow that it had taken out a $6 million life insurance policy on the rank-and-file worker, without an insurable interest in him and without telling him or his family about it, the widow claims in court.

Gigi Simmons, administrator of her late husband’s estate, filed a class action against Bristol-Myers Squibb and an “as-yet unknown insurance company,” in Federal Court.

After Bruce Simmons died in 2012, his widow sought financing for his funeral, and provided a third-party financier documents detailing the life-insurance policy Bruce had purchased through his former employer, Bristol-Myers Squibb.

“Bristol-Myers’ benefits department would not verify the coverage when it was contacted by the third-party financier,” the widow says in the complaint.

But when funeral home owner Sam Rawls contacted the drug company, “an employee of the Bristol-Myers’ benefits department told Mr. Rawls that there was a $6,000,000 policy on Mr. Simmons’ life,” the lawsuit states. “Astonished at the amount of the coverage, Mr. Rawls began to question the Bristol-Myers employee about the policy. The employee refused to give Mr. Rawls any additional information and said she probably ‘was not supposed to have said anything about it.’

Continue reading “Widow Says Death Spurred Employer Profits: Claims Bristol-Myers Squibb had a $6 million life insurance policy on her husband”

Unpublished trial data ‘violates an ethical obligation’ to study participants, say researchers / 1 in 3 large clinicals not Published

Contact: Stephanie Burns
sburns@bmj.com
44-020-738-36920
BMJ-British Medical Journal

 

Study finds almost 1 in 3 large clinical trials still not published 5 years after completion

Almost one in three (29%) large clinical trials remain unpublished five years after completion. And of these, 78% have no results publicly available, finds a study published on bmj.com today.

This means that an estimated 250,000 people have been exposed to the risks of trial participation without the societal benefits that accompany the dissemination of their results, say the authors.

They argue that this “violates an ethical obligation that investigators have towards study participants” and call for additional safeguards “to ensure timely public dissemination of trial data.”

Randomized clinical trials are a critical means of advancing medical knowledge. They depend on the willingness of people to expose themselves to risks, but the ethical justification for these risks is that society will eventually benefit from the knowledge gained from the trial.

But when trial data remain unpublished, the societal benefit that may have motivated someone to enrol in a study remains unrealized.

US law requires that many trials involving human participants be registered – and their results posted – on the largest clinical trial website ClinicalTrials.gov. But evidence suggests that this legislation has been largely ignored.

So a team of US-based researchers set out to estimate the frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database.

They searched scientific literature databases and identified 585 trials with at least 500 participants that were registered with ClinicalTrials.gov and completed prior to January 2009. The average time between study completion and the final literature search (November 2012) was 60 months for unpublished trials.

Registry entries for unpublished trials were then reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.

Of 585 registered trials, 171 (29%) remained unpublished. Of these, 133 (78%) had no results available in ClinicalTrials.gov. Non-publication was more common among trials that received industry funding (32%) than those that did not (18%).

“Our results add to existing work by showing that non-publication is an important problem even among large randomized trials,” say the authors. Furthermore, the sponsors and investigators of these unpublished trials infrequently utilize the ClinicalTrials.gov results database.

The lack of availability of results from these trials “contributes to publication bias and also constitutes a failure to honor the ethical contract that is the basis for exposing study participants to the risks inherent in trial participation,” they add. “Additional safeguards are needed to ensure timely public dissemination of trial data,” they conclude.

Current study shows: Important information on effects and side effects of drugs is missing in most publications

IQWiG: Reliable assessment of drugs is only possible on the basis of clinical study reports (CSRs)

In 2012 researchers from the German Institute for Quality and Efficiency in Health Care (IQWiG) presented a study in the BMJ analysing information sources used in 16 health technology assessment (HTA) reports of drugs (“benefit assessments”). This study clearly demonstrated that publicly available sources, such as scientific journals and entries posted in trial registries (“registry reports”), contained far less information on methods and outcomes of clinical trials than non-public CSRs prepared by pharmaceutical companies.

In a second article published today in PLOS Medicine, the IQWiG researchers now show that if, instead of only assessing selected outcomes as in the first study, all patient-relevant outcomes of the clinical trials are assessed, the information deficit in the publicly available sources is even greater.

Data analysed for more than 1000 outcomes

All HTA reports of drugs completed by IQWiG between 2006 and 2011 also formed the basis for the new study. The authors included those trials from the HTA reports for which the pharmaceutical companies had provided complete CSRs to IQWiG. Publicly available information in scientific journals and trial registries was available for 86 out of 101 of these trials, so that the information provided in all 3 sources could be compared. The trials contained data on more than 1000 patient-relevant outcomes such as mortality or disease symptoms.

Huge difference in the information provided

IQWiG assessed whether the results on the patient-relevant outcomes in the trials were “completely” or “incompletely” reported. The difference in the information provided was immense: Whereas 86% of all outcomes were fully reported in unpublished CSRs, the corresponding number was only 39% for combined publicly available sources. Likewise, negative effects on patients (“harm outcomes”) such as serious adverse events or treatment discontinuations were reported far less often in the publicly available sources (27 to 72% versus 84 to 92%, depending on the harm outcome investigated).

Make CSRs publicly accessible

Beate Wieseler, Head of the Drug Assessment Department, comments on this first comprehensive quantification of the information gain through full CSRs: “The publicly available journal articles and registry entries thus report less than half of outcomes of clinical trials comprehensively. At the same time, with CSRs documents are available that provide complete information on methods and outcomes. The consequence can only be: all CSRs must be made publicly accessible. One should note that IQWiG is already in a privileged position due to its legal remit to conduct benefit assessments. Other researchers and physicians wishing to be fully informed about the advantages and disadvantages of an intervention have even more difficulties in gaining access to data.

Although the proportion of clinical trials published as scientific articles or registry reports has increased in the past few years, this is unfortunately not accompanied by more complete reporting of patient-relevant outcomes. Large information gaps still remain and we cannot even guess how large these gaps are in other types of drug trials or in trials of non-drug interventions.”

Need for legislation

Beate Wieseler further points out: “The plan by the European Medicines Agency (EMA) to make all clinical trial data submitted for marketing authorization publicly available from January 2014 onwards can therefore only be a first step. A central repository is required, also including data from older trials, as such trials investigate drugs widely used in current medical practice. These data would probably shed a totally new light on several drugs and their position in their therapeutic area. However, a voluntary commitment by the pharmaceutical industry, which would like to decide on a case-by-case basis which data it discloses, is insufficient. We are hoping for legislation and continue to support the All Trials Campaign (see below) so that the problem stays on the agenda.”

Drugs now to be approved based on a educated guess that it will help the patient, not necessarily improved survival

U.S. drugmakers cheer ‘speed lane’ for breakthrough therapies

Source: Reuters – Wed, 24 Jul 2013 11:53 PM

Author: Reuters

By Toni Clarke

WASHINGTON, July 24 (Reuters) – A new regulatory pathway could shave years off the traditional drug approval process in the United States, according to some companies whose drugs have been given “breakthrough therapy” designation by the U.S. Food and Drug Administration.

Speaking at a briefing in Washington to raise awareness of the drug review process, Dr. Jay Siegel, head of global regulatory affairs at Johnson & Johnson, said he expects two years to be knocked off the time it would typically take the FDA to review ibrutinib, the company’s experimental cancer drug.

To be granted breakthrough designation, an experimental drug must show early indication of clinical improvement over existing therapies, even if the clinical trial is small. It might apply, for example, to a new type of cancer drug that shows strong early promise.

J&J’s ibrutinib, which it is developing with Pharmacyclics Inc, would be the first in a class of oral medicines that block a protein known as Bruton’s tyrosine kinase. It is being developed for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and for patients with mantle cell lymphoma, both cancers of the blood.

Dr. Jeffrey Leiden, the chief executive of Vertex Pharmaceuticals Inc, who also spoke at the briefing and whose cystic fibrosis drug Kalydeco was approved under the designation, said his company’s experience working with the FDA was dramatically different from the normal drug approval process.

Under breakthrough designation, he said, “everything is on the table” for discussion in order to move the process along as quickly as possible. Communications that might typically take weeks and months, under the breakthrough pathway take minutes.

“We pick up the phone and talk in real time,” Leiden said. “It makes the process immeasurably smoother.”

The breakthrough pathway was spearheaded by Friends of Cancer Research, a patient advocacy organization. It received bipartisan support in Congress and was signed into law in July 2012. As of July 12, the FDA had received 67 requests for breakthrough designation. It had granted 24 and denied 18.

Dr. Janet Woodcock, director of the FDA’s drugs division, said during the discussion that the breakthrough pathway was designed to accommodate new science, particularly targeted therapies that may work in people with certain genetic mutations. She noted that just because the review process is speeded up there is no guarantee of approval.

In the 1990s, she said, the agency was not seeing drugs whose promise could be detected in early clinical trials.

“We didn’t see these therapies in Phase I or II where you said ‘bingo,’ you’ve got a likely winner,” she said.

Still, there are challenges associated with speeding up a drug’s development timeline. For one thing, other nations might not be willing to approve the products based on the FDA’s more flexible clinical trial standards under the breakthrough designation.

“Our hope is that foreign regulators will catch up,” Siegel said.

Moreover, he said, it is not clear that insurers will pay for drugs if the data do not show improved survival or other clear benefit they are used to seeing when drugs are approved. One task, he said is to figure out “how to bring payors on board.”

The panelists did not discuss what happens once a drug reaches the market under the breakthrough designation.

Under a separate pathway known as “accelerated approval” drugs may be approved based on a so-called surrogate endpoint – a measure, such as tumor shrinkage – that might reasonably be expected to confer a clinical benefit such as improved survival.

Companies that win approval for a product under the accelerated approval process are required subsequently to prove through further clinical trials that the surrogate measure does in fact correlate with improved survival or a reduction in disease symptoms.

“A discussion on this topic is reckless if it doesn’t discuss the next stage after the drug reaches the market,” said Sidney Wolfe, co-founder and senior adviser to Public Citizen’s Health Research Group, a watchdog organization that has frequently criticized the FDA for approving, or failing to withdraw, drugs it considers unsafe.

Woodcock said the FDA is now working to develop a mechanism to speed the development of breakthrough diagnostics that can be used in conjunction with new drugs to help identify which patients will respond to a particular therapy.

http://www.trust.org/item/20130724235354-sr8za/?source=hpbreaking

Wanted: Students to take cocaine – University asks for volunteers to take drugs for study

The email specifies that potential participants must be: ‘Fit and well, have no past medical history and not be users of recreational drugs’

Rob Williams

Friday, 22 February 2013

A prestigious London university has asked for volunteers to take part in an experiment where they will be required to take cocaine.

An email sent by a professor at King’s College London asks for ‘healthy male volunteers, 25 – 40 years of age, to take part in a clinical study involving nasal administration of cocaine.’

The email, which was sent on Thursday afternoon to hundreds of postgraduate and undergraduate students at the university, is in seven sections, each titled with a question.

Under the section, ‘What will happen?’, the email states: ‘After cocaine administration, repeated biological samples (blood, urine, hair, sweat, oral fluid) will be taken to compare and investigate how cocaine and its metabolites are spread through the human body.’

The email, which was first reported on the Huffington Post website this morning, specifies that potential participants must be: ‘Fit and well, have no past medical history and not be users of recreational drugs.

According to the university the project has been approved by London Westminster Research Ethics Committee and “contributes to the College’s role in conducting research, and teaching research methods”.

A spokesperson for Kings College London said today: “This is an important scientific study to investigate how cocaine and its metabolites are spread through the human body. All the relevant ethical approvals were received for this study. The study will be conducted under the highest level of medical supervision in a dedicated clinical research suite.”

The Email:

HEALTHY VOLUNTEERS NEEDED

Who are we looking for?

Healthy male volunteers, 25 – 40 years of age, to take part in a clinical study involving nasal administration of cocaine. Medical and dental students will not be enrolled to this study.

What will happen?

After cocaine administration, repeated biological samples (blood, urine, hair, sweat, oral fluid) will be taken to compare and investigate how cocaine and its metabolites are spread through the human body.

What are the requirements?

Potential participants must be fit and well, have no past medical history and not be users of recreational drugs. They must be happy not to cut or dye their hair for 120 days during the study follow up period.

How long will it take?

During the first visit we will check your suitability for the study. The second visit (main experiment) will be around thirty days later and will take most of the day. We would then like to see you 5 more times over a 90 day period so that some repeat biological samples can be taken.

Will you benefit from taking part in this study?

There is no direct benefit from taking part. Reasonable financial compensation will be made for your time, effort and expenses incurred from completing the study.

Who is overseeing the study?

The study will be supervised by the Clinical Toxicology department from St Thomas’ Hospital, London. The research team includes a medical doctor (registrar or consultant) who will be present at all times.

What now?

All participant information will be anonymised and held confidentially. All participant information will be anonymised and held confidentially. If you are interested in taking part and would like to find more information please primarily address any enquires to the Chief Scientific Officer) at [email address deleted] were  you will be provided with a full participant information sheet.

http://www.independent.co.uk/student/news/wanted-students-to-take-cocaine–university-asks-for-volunteers-to-take-drugs-for-study-8506701.html#

 

Liver cancer survival time tripled by virus: JX-594

The virus used in the vaccine that helped eradicate smallpox is now working its magic on liver cancer. A genetically engineered version of the vaccinia virus has trebled the average survival time of people with a severe form of liver cancer, with only mild, flu-like side effects.Thirty people with hepatocellular carcinoma received three doses of the modified virus – code-named JX-594 – directly into their liver tumour over one month. Half the volunteers received a low dose of the virus, the other half a high dose. Members of the low and high-dose groups subsequently survived for, on average, 6.7 and 14.1 months respectively. By contrast, trials several years ago showed that sorafenib, the best existing medication for this cancer, prolonged life by only three months.

Two of the patients on the highest viral dose were still alive more than two years after the treatment. “It’s a very substantial survival benefit,” says Laurent Fischer, president of Jennerex, the company in San Francisco developing the treatment under the trade name Pexa-Vec.

Besides shrinking the primary tumour, the virus was able to spread to and shrink any secondary tumours outside the liver. “Some tumours disappeared completely, and most showed partial destruction on MRI scans,” says David Kirn, head of the study at Jennerex. Moreover, the destruction was equally dramatic in the primary and secondary tumours.

“This clinical trial is an exciting step forward to help find a new way of treating cancers,” says Alan Melcher of the University of Leeds, UK, who was not involved in the study. “It helps demonstrate the cancer-fighting potential of viruses, which have relatively few side effects compared with traditional chemo or radiotherapy,” he says. “If it proves effective in larger trials, it could be available to patients within five years.”

The fact that the virus appears able to spread to secondary tumours suggests that simply injecting the virus into the bloodstream may be effective. A trial to compare this treatment with injecting the virus directly into a tumour is under way.

Targeted at cancer

The virus has had a gene coding for an enzyme called thymidine kinase snipped out. The enzyme enables the virus to recognise and infect dividing cells. By removing the gene, the virus’s developers have reduced the likelihood of healthy dividing cells being infected.

Instead, the virus exclusively attacks cancerous tissue, by targeting two genes that have increased activity in tumour cells. One genes is associated with an epidermal growth factor receptor, which stimulates the cancer to grow. The other is associated with a vascular endothelial growth factor, which enables the cancer to recruit its own blood supply. The virus reduces the activity of both genes, causing the infected cancer cell to wither and die.

What’s more, the virus carries extra genes to prod the body’s own immune system into action against the cancer. One produces granulocyte colony stimulating factor, a protein that encourages production of extra white blood cells at sites of infection. The other produces a protein not naturally found in humans, called Lac-Z, that earmarks infected cells for destruction.

Fischer says that to date, more than 200 people have received the virus, which has also shown promise against other types of cancer, including those of the kidney and skin. But he warns that not everyone sees a benefit. “We know why patients respond, but not why they don’t,” he says.

Journal reference: Nature Medicine, DOI: 10.1038/nm.3089

http://www.newscientist.com/article/dn23154-liver-cancer-survival-time-tripled-by-virus.html

 

New evidence on how compound found in red wine can help prevent cancer

Contact: Hannah Tucker hct16@le.ac.uk 01-162-522-415 University of Leicester

International conference at the University of Leicester will show how resveratrol can prevent cancer, heart disease and diabetes

University of Leicester scientists will present groundbreaking new evidence about how a chemical found in red wine can help prevent cancer on Wednesday, December 5.

Experts from around the world are set to attend Resveratrol 2012, a major conference at the University which will assess the latest advances in the study of resveratrol – a compound found in the skins of red grapes.

The conference will feature new findings based on the last two years of research, which show how the chemical can help prevent cancer, heart disease and diabetes.

The event follows the first international conference on resveratrol, held in 2010 in Denmark, and evidence from more than ten clinical trials held since will be presented and discussed.

Although the potential health benefits of resveratrol have been known for some time, it has not yet been proven that resveratrol can be effective in humans and the best dose to give remains unknown – meaning that its widespread use cannot safely be recommended at the moment.

Researchers at the University of Leicester have been researching the levels of resveratrol which can be beneficial in preventing cancer.

Using laboratory models, they have found that a daily amount of resveratrol equivalent to two glasses of wine can halve the rate of bowel tumors.

Professor Karen Brown, a member of the University’s Cancer Biomarkers and Prevention Group and one of the organisers of Resveratrol 2012, said: “This is the second conference that brings together all the world experts in resveratrol. We have got a fantastic line up covering cancer, heart disease, diabetes, neurological diseases and life extension.

“At the University of Leicester, we want to see how resveratrol might work to prevent cancer in humans. Having shown in our lab experiments that it can reduce tumour development we are now concentrating on identifying the mechanisms of how resveratrol works in human cells.”

The Leicester researchers now hope to take their findings from the lab to the next stage by carrying out clinical trials to find the optimum level of resveratrol in humans.

Professor Brown added: “A lot of people take resveratrol as a supplement, but at the moment we don’t know how it works or on whom it can work until we have more information – we don’t even know the best dose you should take. It has been shown that high doses of resveratrol may potentially interfere with other medication. With all the exciting new studies that are being done – especially the clinical trials – I hope we’ll have a clearer picture in the next few years.”

The conference will include more than 65 lectures, presentations and posters by different researchers from all over the world.

As well as offering opportunities for knowledge sharing and networking, the conference will produce a selection of reports with the latest update on global resveratrol research, as well as the next set of recommendations for the coming year’s scientific research and the use of resveratrol.

###

The conference will be held at the University’s Stamford Court, Manor Road, Oadby, from December 5 to 7.

Study shows how dietary supplement may block cancer cells

2010 study posted for filing

 

Contact: Darrell E. Ward Darrell.Ward@osumc.edu 614-293-3737 Ohio State University Medical Center

COLUMBUS, Ohio – Researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) have discovered how a substance that is produced when eating broccoli and Brussels sprouts can block the proliferation of cancer cells.

Compelling evidence indicates that the substance, indole-3-carbinol (I3C), may have anticancer effects and other health benefits, the researchers say. These findings show how I3C affects cancer cells and normal cells.

The laboratory and animal study discovered a connection between I3C and a molecule called Cdc25A, which is essential for cell division and proliferation. The research showed that I3C causes the destruction of that molecule and thereby blocks the growth of breast cancer cells.

The study was published online June 29 in the journal Cancer Prevention Research.

“Cdc25A is present at abnormally high levels in about half of breast cancer cases, and it is associated with a poor prognosis,” says study leader Xianghong Zou, assistant professor of pathology at the Ohio State University Medical Center.

The molecule also occurs at abnormally high levels in cancers of the breast, prostate, liver, esophagus, endometrium and colon, and in non-Hodgkin lymphoma, and in other diseases such as Alzheimer’s disease, he noted.

“For this reason, a number of anti-Cdc25 agents have been identified, but they have not been successful for cancer prevention or treatment due to concerns about their safety or efficacy,” says Zou, who is also a member of the OSUCCC-James Molecular Carcinogenesis and Chemoprevention program.

“I3C can have striking effects on cancer cells,” he explains, “and a better understanding of this mechanism may lead to the use of this dietary supplement as an effective and safe strategy for treating a variety of cancers and other human diseases associated with the overexpression of Cdc25A,” Zou says.

For this study, Zou and his colleagues exposed three breast cancer cell lines to I3C. These experiments revealed that the substance caused the destruction of Cdc25A. They also pinpointed a specific location on that molecule that made it susceptible to I3C, showing that if that location is altered (because of a gene mutation), I3C no longer causes the molecule’s destruction.

Last, the investigators tested the effectiveness of I3C in breast tumors in a mouse model. When the substance was given orally to the mice, it reduced tumor size by up to 65 percent. They also showed that I3C had no affect on breast-cell tumors in which the Cdc25A molecule had a mutation in that key location.

Release all Tamiflu data as promised, argue researchers

Contact: Emma Dickinson edickinson@bmjgroup.com 44-020-738-36529 BMJ-British Medical Journal

Company plans to set up review board, but researchers want it to keep its promise

The latest correspondence is posted online today as part of the BMJ‘s open data campaign, aimed at persuading Roche to honour the promise it made almost three years ago to make key Tamiflu trial data available for independent scrutiny.

Last week, Donald MacLean, Life Cycle Leader for Tamiflu, wrote to Professor Chris Del Mar in his capacity as coordinating editor of the Cochrane Acute Respiratory Infections Group, concerning “our debate on Tamiflu data.”

The Cochrane researchers say they object to Roche’s suggestion that there is a debate on Tamiflu data. “There is no debate nor can there be any debate about the data whilst you do not honour your promise,” they say. “The only reason we keep asking Roche to keep its promise, rather than simply getting the data from the European Medicines Agency directly, is because Roche has not supplied all of the data to the European regulator.”

Roche’s letter also mentions “disagreements” over the type of analyses the Cochrane team wish to do, but the researchers point out that their methods and analyses have been public for nearly two years and “follow Cochrane procedure” and state that they are not aware of any specific concerns from Roche.

Roche’s letter goes on to say that, in order to reach “an amicable resolution” Roche plans to set up “a multi-party advisory board to review the totality of Tamiflu data” …. which they believe is “a sensible, fair and transparent way of addressing this public debate.”

But the Cochrane team argue that Roche’s offer is merely a belated attempt at turning the clock back, and call on the company to expand its data sharing pledges “to become compatible with current regulatory norms.”

They say: “The European Medicines Agency and the EU Ombudsman have made abundantly clear that there is no reason for anonymised clinical data to be withheld from public scrutiny once a marketing authorisation has been obtained for a pharmaceutical.  Why should Roche not – at the minimum – meet this standard?”

In summary, they say, “we ask to you to honour your promise of three years ago and make public full clinical study reports in your possession.”

###

Green tea extract appears to keep cancer in check in majority of CLL patients

2010 study posted for filing

Contact: Karl Oestreich newsbureau@mayo.edu 507-284-5005 Mayo Clinic

Mayo Clinic has conducted the first clinical studies of tea extract in cancer patients

CHICAGO — ASCO Abstract Number: 6522 (http://abstract.asco.org/AbstView_74_47574.html). An extract of green tea appears to have clinical activity with low toxicity in chronic lymphocytic leukemia (CLL) patients who used it in a phase II clinical trial, say researchers at Mayo Clinic.

The findings, to be presented Monday, June 7, during the annual meeting of the American Society of Clinical Oncology (http://www.asco.org/) (ASCO), are the latest in a series of Mayo studies to show promise for use of the chemical epigallocatechin gallate (EGCG) — the major component of green tea — in reducing the number of leukemia cells in patients with CLL. Mayo first tested EGCG in a variety of laboratory assays about eight years ago, and it was found to reduce the survival of CLL leukemic cells. This laboratory finding was followed by a successful phase I clinical trial — the first time green tea extract had been studied in CLL patients.

“Although only a comparative phase III trial can determine whether EGCG can delay progression of CLL, the benefits we have seen in most CLL patients who use the chemical suggest that it has modest clinical activity and may be useful for stabilizing this form of leukemia, potentially slowing it down,” says Tait Shanafelt, M.D. (http://www.mayoclinic.org/bio/12787116.html), a Mayo Clinic hematologist (http://www.mayoclinic.org/hematology-rst/) and lead author of the study.

“These studies advance the notion that a nutraceutical like EGCG can and should be studied as cancer preventives,” says Neil Kay, M.D. (http://www.mayoclinic.org/bio/13445391.html), a hematology researcher whose laboratory first tested the green tea extract in leukemic blood cells from CLL patients. “Using nontoxic chemicals to push back cancer growth to delay the need for toxic therapies is a worthy goal in oncology research — particularly for forms of cancer initially managed by observation such as CLL.”

Drs. Shanafelt and Kay caution that EGCG is not a substitute for chemotherapy. All of the patients Mayo tested with EGCG were early stage, asymptomatic CLL patients who would not otherwise be treated until their disease progressed. The extract was supplied by the National Cancer Institute (http://www.nci.nih.gov/ )(NCI) and Polyphenon E International for these initial clinical trials.

CLL is a blood cancer that is a hybrid between leukemia and lymphoma. Progression of the disease is measured by the quantity of leukemia cells in the blood and bone marrow as well as enlargement of lymph nodes due to infiltration by the leukemia cells. In the phase I study, published in May 2009 in the Journal of Clinical Oncology, researchers found that the blood lymphocyte (leukemia cell) count was reduced in one-third of participants, and that the majority of patients who entered the study with enlarged lymph nodes due to involvement by CLL saw a 50 percent or greater reduction in their lymph node size.

Using the highest dose tested in the phase I study, the researchers launched their phase II clinical trial in an additional 36 patients. The results presented at the ASCO meeting evaluate the effects in these 36 patients as well as the six patients from the phase I trial treated at the same dose (total 42 patients). Results from 41 patients who have completed the study show that 31 percent of patients had a 20 percent or greater sustained reduction in blood leukemia count, and 69 percent of patients with enlarged lymph nodes saw a reduction of node size of 50 percent or greater.

In all, 69 percent of CLL patients had a biological response to EGCG as evidenced by a 20 percent or greater sustained reduction in blood lymphocyte count and/or a 50 percent or greater reduction in lymph node size, the researchers say.

Because EGCG was being studied in patients who did not otherwise need treatment, the researchers took a rigorous approach toward studying side effects. Most clinical trials of therapeutic agents only report grade 3 and higher side effects, but the researchers looked at and reported grade 1 and grade 2 as well. While a number of patients had transient grade 1 or 2 side effects, only three of 42 experienced a grade 3 side effect during their six months of treatment.

“All in all, the treatment was well tolerated with very mild side effects in most patients,” Dr. Shanafelt says.

The researchers say that the prior publications on the effects of EGCG on CLL leukemia cells in the laboratory and the data from the published phase I study have been widely disseminated via the Internet by patient advocacy groups. Based on information from patients and colleagues throughout the country, the Mayo researchers have become aware that many CLL patients nationwide have started to use EGCG supplements, which are readily available over the counter.

“Without a phase III clinical trial, we cannot make a recommendation that EGCG be used by CLL patients, but those who want to take supplements should consult with their oncologists and need to receive appropriate monitoring using laboratory tests,” Dr. Kay says.

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The study was funded by grants from the NCI, the Mayo Comprehensive Cancer Center (http://mayoresearch.mayo.edu/mayo/research/cancercenter/index.cfm), and from donors and patient advocacy foundations. The authors declare no conflicts of interest.

About Mayo Clinic

For more than 100 years, millions of people from all walks of life have found answers at Mayo Clinic. These patients tell us they leave Mayo Clinic with peace of mind knowing they received care from the world’s leading experts. Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. At Mayo Clinic, a team of specialists is assembled to take the time to listen, understand and care for patients’ health issues and concerns. These teams draw from more than 3,700 physicians and scientists and 50,100 allied staff that work at Mayo Clinic’s campuses in Minnesota, Florida, and Arizona; and community-based providers in more than 70 locations in southern Minnesota, western Wisconsin and northeast Iowa. These locations treat more than half a million people each year.  To best serve patients, Mayo Clinic works with many insurance companies, does not require a physician referral in most cases and is an in-network provider for millions of people. To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. For information about research and education, visit www.mayo.edu. MayoClinic.com (www.mayoclinic.com) is available as a resource for your general health information.

VIDEO ALERT: Additional audio and video resources, including excerpts from an interview with Dr. Tait Shanafelt is available on the Mayo Clinic News Blog (http://newsblog.mayoclinic.org/2010/06/04/green-tea-extract-appears-to-keep-cancer-in-check-in-majority-of-cll-patients/).

Breakthrough Nanoparticle Halts Multiple Sclerosis in Mice, Offers Hope for Other Immune-Related Diseases

A biodegradable nanoparticle turns out to be the perfect vehicle to stealthily deliver an antigen that tricks the immune system into stopping its attack on myelin and halt a model of relapsing remitting multiple sclerosis (MS) in mice, researchers report. (Credit: © mgkuijpers / Fotolia)

ScienceDaily (Nov. 18, 2012) — In a breakthrough for nanotechnology and multiple sclerosis, a biodegradable nanoparticle turns out to be the perfect vehicle to stealthily deliver an antigen that tricks the immune system into stopping its attack on myelin and halt a model of relapsing remitting multiple sclerosis (MS) in mice, according to new Northwestern Medicine research.

The new nanotechnology also can be applied to a variety of immune-mediated diseases including Type 1 diabetes, food allergies and airway allergies such as asthma.

In MS, the immune system attacks the myelin membrane that insulates nerves cells in the brain, spinal cord and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness. About 80 percent of MS patients are diagnosed with the relapsing remitting form of the disease.

The Northwestern nanotechnology does not suppress the entire immune system as do current therapies for MS, which make patients more susceptible to everyday infections and higher rates of cancer. Rather, when the nanoparticles are attached to myelin antigens and injected into the mice, the immune system is reset to normal. The immune system stops recognizing myelin as an alien invader and halts its attack on it.

“This is a highly significant breakthrough in translational immunotherapy,” said Stephen Miller, a corresponding author of the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “The beauty of this new technology is it can be used in many immune-related diseases. We simply change the antigen that’s delivered.”

“The holy grail is to develop a therapy that is specific to the pathological immune response, in this case the body attacking myelin,” Miller added. “Our approach resets the immune system so it no longer attacks myelin but leaves the function of the normal immune system intact.”

The nanoparticle, made from an easily produced and already FDA-approved substance, was developed by Lonnie Shea, professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and Applied Science.

“This is a major breakthrough in nanotechnology, showing you can use it to regulate the immune system,” said Shea, also a corresponding author. The paper will be published Nov. 18 in the journal Nature Biotechnology.

Miller and Shea are also members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. In addition, Shea is a member of the Institute for BioNanotechnology in Medicine and the Chemistry of Life Processes Institute.

Clinical Trial for Ms Tests Same Approach — With Key Difference

The study’s method is the same approach now being tested in multiple sclerosis patients in a phase I/II clinical trial — with one key difference. The trial uses a patient’s own white blood cells — a costly and labor intensive procedure — to deliver the antigen. The purpose of the new study was to see if nanoparticles could be as effective as the white blood cells as delivery vehicles. They were.

The Big Nanoparticle Advantage for Immunotherapy

Nanoparticles have many advantages; they can be readily produced in a laboratory and standardized for manufacturing. They would make the potential therapy cheaper and more accessible to a general population. In addition, these nanoparticles are made of a polymer called Poly(lactide-co-glycolide) (PLG), which consists of lactic acid and glycolic acid, both natural metabolites in the human body. PLG is most commonly used for biodegradable sutures.

The fact that PLG is already FDA approved for other applications should facilitate translating the research to patients, Shea noted. Miller and Shea tested nanoparticles of various sizes and discovered that 500 nanometers was most effective at modulating the immune response.

“We administered these particles to animals who have a disease very similar to relapsing remitting multiple sclerosis and stopped it in its tracks,” Miller said. “We prevented any future relapses for up to 100 days, which is the equivalent of several years in the life of an MS patient.”

Shea and Miller also are currently testing the nanoparticles to treat Type one diabetes and airway diseases such as asthma.

Nanoparticles Fool Immune System

In the study, researchers attached myelin antigens to the nanoparticles and injected them intravenously into the mice. The particles entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. There, the particles were engulfed by macrophages, a type of immune cell, which then displayed the antigens on their cell surface. The immune system viewed the nanoparticles as ordinary dying blood cells and nothing to be concerned about. This created immune tolerance to the antigen by directly inhibiting the activity of myelin responsive T cells and by increasing the numbers of regulatory T cells which further calmed the autoimmune response.

“The key here is that this antigen/particle-based approach to induction of tolerance is selective and targeted. Unlike generalized immunosuppression, which is the current therapy used for autoimmune diseases, this new process does not shut down the whole immune system,” said Christine Kelley, National Institute of Biomedical Imaging and Bioengineering director of the division of Discovery Science and Technology at the National Institutes of Health, which supported the research. “This collaborative effort between expertise in immunology and bioengineering is a terrific example of the tremendous advances that can be made with scientifically convergent approaches to biomedical problems.”

“We are proud to share our expertise in therapeutics development with Dr. Stephen Miller’s stellar team of academic scientists,” said Scott Johnson, CEO, president and founder of the Myelin Repair Foundation. “The idea to couple antigens to nanoparticles was conceived in discussions between Dr. Miller’s laboratory, the Myelin Repair Foundation’s drug discovery advisory board and Dr. Michael Pleiss, a member of the Myelin Repair Foundation’s internal research team, and we combined our efforts to focus on patient-oriented, clinically relevant research with broad implications for all autoimmune diseases. Our unique research model is designed to foster and extract the innovation from the academic science that we fund and transition these technologies to commercialization. The overarching goal is to ensure this important therapeutic pathway has its best chance to reach patients, with MS and all autoimmune diseases.”

http://www.sciencedaily.com/releases/2012/11/121118141516.htm

Crazy in love: What happens in your brain when you really do have chemistry

By Victoria Fletcher

PUBLISHED:17:00 EST, 10  November 2012| UPDATED:17:00 EST, 10 November 2012

 

You may wonder why anyone in the throes of an  illicit affair would risk their marriage, family and career for the sake of a  what may seem like an  irrational crush.

But doctors have begun to unravel the mystery  of why love can make us giddy, irrational and even ridiculous.

Scanning technology allows neurologists to  unearth incredible images of what happens in our brains when we fall in  love.

Dumb love: When we are passionate about a person it makes parts of our brain shut down, including the ones controlling fear and judgement 

Dumb love: When we are passionate about a person it  makes parts of our brain shut down, including the ones controlling fear and  judgement

They have mapped the chemical changes that  occur and discovered the parts of the brain that activate – and more  importantly, the parts that shut down – during the heady days of  courtship.

And far from being blissful, they have  discovered how it can make us nervous and unstable.

They hope it may also one day reveal why a  few of us might overstep the mark when dealing with the object of our  affections.

THE BRAIN IN LOVE

The frontal cortex, vital to judgment, shuts  down when we fall in love. MRI scans show this de-activation occurs only when  someone is shown a photo of the person they adore, causing them to suspend all  criticism or doubt.

Semir Zeki, professor of neuro-aesthetics at  University College London, says: ‘When you look at someone you are passionate  about, some areas of the brain become active,’ he says. ‘But a large part is  de-activated, the part that plays a role in judgment.’

love

Prof Zeki believes the brain may behave in  this way for ‘higher biological purposes’ – it makes reproduction more likely.  If judgment is suspended, the most unlikely pair can get together and reproduce.  Someone in love will still be capable of making other major decisions in their  lives, from striking a business deal to choosing a new mortgage.

And this sanity makes it harder for friends  to convince them  ‘they have taken leave of their senses’ when it comes to  an ill-advised affair.

Brain scans have also shown the area of the  brain that controls fear, and another region involved in negative emotions,  close  down, explaining why people feel  so happy with the world – and  unafraid of what might go wrong – when they fall head over heels.

LOVE IS THE  DRUG

Studies have shown brain chemical dopamine is  at higher levels in those in love. Dopamine is key to our experiences of  pleasure and pain, linked to desire, addiction, euphoria, and a surge may cause  such acute feelings of reward that it makes love hard to give up.

Tests show that taking opioid drugs such as  cocaine have a similar effect on dopamine as love.

A side effect of rising dopamine levels is a  reduction in another chemical, serotonin, a key hormone in our moods and  appetite.

Scream for love: Levels of adrenaline released when frightened means that two people going through a scary experience together can fall madly in love 

Scream for love: Levels of adrenaline released when  frightened means that two people going through a scary experience together can  fall madly in love

Serotonin levels may fall in a similar way to  those seen in people with obsessive-compulsive disorder, explaining why love can  make us feel anxious and jittery.

The love chemical we are most familiar with  is adrenaline. This hormone is why our heart races, palms sweat and mouth goes  dry when we see the person we like.

The same hormone is also released when we are  frightened. This means that two people only vaguely attracted to one another can  fall madly in love if they go through an exciting or scary experience together.  It may also explain the lure of forbidden love.

OUT OF CONTROL  LOVE

Psychologists are still trying to understand  why some become dangerously obsessed and risk everything for love. Dr David Nias  is a psychologist and author on love, and a specialist in stalkers. Although an  extreme end of the ‘love spectrum’, stalkers do shed light on why people do  inconceivable things when in love.

‘The emotion of love snowballs for stalkers.  It becomes a mental disorder and leads them to be delusional. Sadly we don’t  know much more about its causes.’

But if someone gets treatment in which they  learn to think  differently and often more positively, they can recover  from their obsession and look back in amazement at how they behaved.

Dr Nias says there is a distinct personality  type involved in this one-sided love: the over-emotional and highly  imaginative.

Read more: http://www.dailymail.co.uk/health/article-2230969/Crazy-love-What-happens-brain-really-chemistry.html#ixzz2BvwJYA1d Follow us: @MailOnline on Twitter | DailyMail on Facebook

Mango effective in preventing, stopping certain colon, breast cancer cells

2010 study posted for filing

 

Contact: Kathleen Phillips ka-phillips@tamu.edu 979-845-2872 Texas A&M AgriLife Communications

COLLEGE STATION – Mango. If you know little about this fruit, understand this: It’s been found to prevent or stop certain colon and breast cancer cells in the lab.

That’s according to a new study by Texas AgriLife Research food scientists, who examined the five varieties most common in the U.S.: Kent, Francine, Ataulfo, Tommy/Atkins and Haden.

Though the mango is an ancient fruit heavily consumed in many parts of the world, little has been known about its health aspects. The National Mango Board commissioned a variety of studies with several U.S. researchers to help determine its nutritional value.

“If you look at what people currently perceive as a superfood, people think of high antioxidant capacity, and mango is not quite there,” said Dr. Susanne Talcott, who with her husband, Dr. Steve Talcott, conducted the study on cancer cells. “In comparison with antioxidants in blueberry, acai and pomegranate, it’s not even close.”

But the team checked mango against cancer cells anyway, and found it prevented or stopped cancer growth in certain breast and colon cell lines, Susanne Talcott noted.

“It has about four to five times less antioxidant capacity than an average wine grape, and it still holds up fairly well in anticancer activity. If you look at it from the physiological and nutritional standpoint, taking everything together, it would be a high-ranking super food,” she said. “It would be good to include mangoes as part of the regular diet.”

The Talcotts tested mango polyphenol extracts in vitro on colon, breast, lung, leukemia and prostate cancers. Polyphenols are natural substances in plants and are associated with a variety of compounds known to promote good health.

Mango showed some impact on lung, leukemia and prostate cancers but was most effective on the most common breast and colon cancers.

“What we found is that not all cell lines are sensitive to the same extent to an anticancer agent,” she said. “But the breast and colon cancer lines underwent apotosis, or programmed cell death. Additionally, we found that when we tested normal colon cells side by side with the colon cancer cells, that the mango polyphenolics did not harm the normal cells.”

The duo did further tests on the colon cancer lines because a mango contains both small molecules that are readily absorbed and larger molecules that would not be absorbed and thus remain present in a colon.

“We found the normal cells weren’t killed, so mango is not expected to be damaging in the body,” she said. “That is a general observation for any natural agent, that they target cancer cells and leave the healthy cells alone, in reasonable concentrations at least.”

The Talcotts evaluated polyphenolics, and more specifically gallotannins as being the class of bioactive compounds (responsible for preventing or stopping cancer cells). Tannins are polyphenols that are often bitter or drying and found in such common foods as grape seed, wine and tea.

The study found that the cell cycle, which is the division cells go through, was interrupted. This is crucial information, Suzanne Talcott said, because it indicates a possible mechanism for how the cancer cells are prevented or stopped.

“For cells that may be on the verge of mutating or being damaged, mango polyphenolics prevent this kind of damage,” she said.

The Talcotts hope to do a small clinical trial with individuals who have increased inflamation in their intestines with a higher risk for cancer.

“From there, if there is any proven efficacy, then we would do a larger trial to see if there is any clinical relevance,” she said.

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According to the National Mango Board, based in Winter Park, Fla., most mangoes consumed in the U.S. are produced in Mexico, Ecuador, Peru, Brazil, Guatemala and Haiti. Mangoes are native to southeast Asia and India and are produced in tropical climates. They were introduced to the U.S. in the late 1800s, and a few commercial acres still exist in California and Florida.

New DNA vaccine technology poised to deliver safe and cost-effective disease protection

 

Contact: Richard Harth
richard.harth@asu.edu
Arizona State University

New and increasingly sophisticated vaccines are taking aim at a broad range of disease-causing pathogens, targeting them with greater effectiveness at lower cost and with improved measures to ensure safety.

To advance this quest, a research team led by Roy Curtiss, director of the Center for Infectious Diseases and Vaccinology, and Wei Kong, a research assistant professor, at Arizona State University’s Biodesign Institute have taken a dramatic step forward, revealing the design of a universal platform for delivering highly potent DNA vaccines, by employing a cleverly re-engineered bacterium to speed delivery to host cells in the vaccine recipient.

“The technology that we’re describing in this paper can be used to develop a vaccine against any virus, any parasite, any fungus, whereas this was never possible before the development of recombinant attenuated bacterial strains like those produced in our lab,” Curtiss says.

The experimental vaccine described in the new research demonstrated complete protection from influenza in mice, but Wei Kong, the leading author of the new study stresses that the innovative technique could be applied to the rapid manufacture of effective vaccines against virtually any infectious invader at dramatically reduced cost and without risk to either those vaccinated or the wider public.

“By delivering the DNA vaccine using a recombinant attenuated bacterium, we can get 10,000-100,000 doses per liter of culture,” Kong says, an improvement of 3-4 orders of magnitude over use of the naked plasmid DNA, which must be painstakingly isolated from bacteria before injection.

The group’s research results appear in the online Early Edition (EE) of the Proceedings of the National Academy of Sciences, the week of November 5, 2012.

 

Designing a vaccine that is both safe and effective presents a kind of Catch-22 for researchers. Live pathogenic strains typically generate a robust immune response, mimicking natural infection, but many challenges exist in terms of ensuring such strains do not cause illness or escape into the environment, where they have the potential to remain viable. Killed pathogen strains or vaccines produced from pathogen subunits sacrifice some of their immunogenic effectiveness for enhanced safety, and may require subsequent booster doses to ensure continued effectiveness.

The Curtiss team has worked to combine safety and effectiveness in orally administered vaccines that can be produced at a fraction of the cost of traditional methods. To do this, they have pioneered techniques using Salmonella—the notorious agent associated with food-borne illness—as a cargo vessel to deliver a suite of disease antigens to the recipient. The result has been the development and ongoing refinement of so-called RASVs (for recombinant attenuated Salmonella vaccines), capable of provoking an intense, system-wide immune response and conferring effective immunity.

One of the key innovations developed earlier by Wei Kong and other members of the Curtiss group, is a specialized Salmonella strain that can be timed to self-destruct in the body once it has carried out its immunization duties. To create this strain, the researchers modified the bacterium in such a way that it can only survive on a non-naturally occurring form of sugar. Once the Salmonella cells exhaust their store of specialized sugar, supplied to them as part of the vaccine, they are unable to maintain the integrity of their cell walls and they essentially implode. “This crucial safety feature ensures that Salmonella are unable to persist as living organisms to survive if excreted into the environment,” says Kong.

This self-destruct feature can be fine-tuned so that the bacteria fully colonize host cells, provoking a strong response from both humoral and cell-mediated arms of the immune system. Inside host tissues, recombinant Salmonella are able to synthesize protective antigens, releasing their contents when they become unstable and lyse into the intracellular fluid or cytosol.

The group demonstrated the effectiveness of this delayed-lysis bacteria in vaccine experiments with a variety of pathogens, including influenza and mycobacteria (causative agent of tuberculosis) and an RASV vaccine developed in the Curtiss lab against infant pneumonia is currently in FDA Phase I clinical trials. This earlier work focused on producing protective protein antigens in a bacterium, which would subsequently release a bolus of these antigens when the bacterial cell lysed within host cells and tissues.

In the latest research, the group sought to turn a delayed-lysis Salmonella strain into a universal DNA vaccine delivery vehicle. DNA vaccines stimulate cellular and humoral immune responses to protein antigens through the direct introduction of genetic material, prompting host cells to manufacture specific gene products. This is a crucial advance as it allows for the production of antigens that undergo host cell modification through the addition carbohydrates—a process known as glycosylation. Such modified antigens, which occur in a broad range of pathogenic viruses, fungi and parasites require synthesis by host cells, rather than by the attenuated bacteria.

“Here, we were able to deliver a vaccine whose DNA sequence induces the immunized individual to make the protective glycoprotein the way you would during a viral infection,” Curtiss says. Previous efforts to achieve this advance for delivery of DNA vacines by bacteria date to 1995, but only now has such work come to fruition.

A number of key modifications to the delayed-lysis RASV were required for this feat, and the Kong and Curtiss team has worked intensively over the past 5 years to achieve them. A hyperinvasive form of Salmonella was constructed through recombinant DNA methods in order to maximize the vaccine vector’s ability to invade host cells and become internalized.

Following host cell uptake, Salmonella are encased in a membrane-bound endosome known as the Salmonella Containing Vacuole. The RASV was further modified to permit escape from the endosome so that the mature bacterium could spew its immunogenic contents into the host cell’s cytosol.

Finally, further revisions to the Salmonella strain were applied to diminish the pathogen’s ability to cause host cell death, which would prevent the DNA vaccine from migrating to the host cell nucleus to induce the synthesis of protective antigens necessary for the immune response.

The authors note that their orally-administered RASV is markedly superior to earlier efforts which introduced DNA vaccines by means of intramuscular injection or gene gun. These methods fail to deliver the vaccine to both mucosal tissues and certain internal lymphoid tissues, vital to a sustained, protective immunity. “We can protect mice to doses of influenza that would be lethal were they not effectively immunized,” Curtiss says, adding that “RASV safety has been established in mice just two hours old as well as in pregnant and immunodeficient mice”.

Influenza spreads around the world in seasonal epidemics, resulting in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly deaths, rising to millions in some pandemic years. Current manufacture of influenza vaccines requires use of chick embryos or cell culture methods. Global capacity is limited, making sufficient vaccine to immunize everyone impossible. Adding to concerns about managing future naturally occurring influenza epidemics is the potential for bioterrorists to produce weaponized influenza strains created using plasmid-based reverse genetics systems. “Increasing the speed of producing a matching vaccine is key in the context of response to an influenza epidemic,” Kong says.

The ability to rapidly engineer and scale up effective vaccines for influenza and other potentially lethal pathogens will require innovative approaches to vaccine design, manufacture and application. The universal DNA vaccine platform outlined in the new study represents an important advance.

“The vast majority of viruses including influenza, measles, mumps and HIV all have glycosylated proteins. You could never deliver protective immunity using a bacterium to produce those protein antigens,” Curtiss says. “But now we have the opportunity to produce vaccines against such pathogens,” Kong says. Further, the technique permits large quantities of DNA vaccine to be produced rapidly at low cost, freeze-dried and stockpiled to be used when needed.

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Dr Roy Curtiss is also a professor in the College of Liberal Arts and Sciences, School of Life Sciences

Written by: Richard Harth
Science Writer: The Biodesign Institute
richard.harth@asu.edu

Sources:
Roy Curtiss, (480) 727-0445
Wei Kong, (480) 727-9591

Spices halt growth of breast stem cells, U-M study finds ( Curcumin, piperine )

2009 study posted for filing

Contact: Nicole Fawcett nfawcett@umich.edu 734-764-2220 University of Michigan Health System

ANN ARBOR, Mich. — A new study finds that compounds derived from the spices turmeric and pepper could help prevent breast cancer by limiting the growth of stem cells, the small number of cells that fuel a tumor’s growth.

Researchers at the University of Michigan Comprehensive Cancer Center have found that when the dietary compounds curcumin, which is derived from the Indian spice turmeric, and piperine, derived from black peppers, were applied to breast cells in culture, they decreased the number of stem cells while having no effect on normal differentiated cells.

“If we can limit the number of stem cells, we can limit the number of cells with potential to form tumors,” says lead author Madhuri Kakarala, M.D., Ph.D., R.D., clinical lecturer in internal medicine at the U-M Medical School and a research investigator at the VA Ann Arbor Healthcare System.

Cancer stem cells are the small number of cells within a tumor that fuel the tumor’s growth. Current chemotherapies do not work against these cells, which is why cancer recurs and spreads. Researchers believe that eliminating the cancer stem cells is key to controlling cancer. In addition, decreasing the number of normal stem cells – unspecialized cells that can give rise to any type of cell in that organ – can decrease the risk of cancer.

In this study, a solution of curcumin and piperine was applied to the cell cultures at the equivalent of about 20 times the potency of what could be consumed through diet. The compounds are available at this potency in a capsule form that could be taken by mouth. (Note: This work has not been tested in patients, and patients are not encouraged to add curcumin or piperine supplements to their diet at this time.)

The researchers applied a series of tests to the cells, looking at markers for breast stem cells and the effects of curcumin and piperine, both alone and combined, on the stem cell levels. They found that piperine enhanced the effects of curcumin, and that the compounds interrupted the self-renewal process that is the hallmark of cancer-initiating stem cells. At the same time, the compounds had no affect on cell differentiation, which is the normal process of cell development.

“This shows that these compounds are not toxic to normal breast tissue,” Kakarala says. “Women at high risk of breast cancer right now can choose to take the drugs tamoxifen or raloxifene for prevention, but most women won’t take these drugs because there is too much toxicity. The concept that dietary compounds can help is attractive, and curcumin and piperine appear to have very low toxicity.”

Curcumin and piperine have been explored by other researchers as a potential cancer treatment. But this paper, published online in the journal Breast Cancer Research and Treatment, is the first to suggest these dietary compounds could prevent cancer by targeting stem cells.

In addition, tamoxifen or raloxifene are designed to affect estrogen, which is a factor in most, but not all breast cancers. In fact, the aggressive tumors that tend to occur more often in women with a family history or genetic susceptibility are typically not affected by estrogen. Because curcumin and piperine limit the self renewal of stem cells, they would impact cancers that are not estrogen sensitive as well as those that are.

Researchers are planning an initial Phase I clinical trial to determine what dose of curcumin or piperine can be tolerated in people. The trial is not expected to begin accruing participants until spring.

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Breast cancer statistics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society

Additional authors: Dean Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriel Dontu and Max Wicha, all from U-M

Funding: National Institutes of Health; curcumin and piperine were donated by Sabinsa Co.

Reference: Breast Cancer Research and Treatment, DOI: 10.1007/s10549-009-0612-x

Resources: U-M Cancer AnswerLine, 800-865-1125 U-M Comprehensive Cancer Center, www.mcancer.org Cancer’s Stem Cell Revolution, www.mcancer.org/stemcells

Acetaminophen may be linked to asthma in children and adults

2009 study posted for filing
Contact: Jennifer Stawarz
847-498-8306
American College of Chest Physicians

New research shows that the widely used pain reliever acetaminophen may be associated with an increased risk of asthma and wheezing in both children and adults exposed to the drug. Researchers from the University of British Columbia, Vancouver, BC, Canada, conducted a systematic review and metaanalysis of 19 clinical studies (total subjects=425,140) that compared the risk of asthma or wheezing with acetaminophen exposure.

The analysis showed that the pooled odds ratio (odds ratio for all studies combined) for asthma among users of acetaminophen was 1.63. The risk of asthma in children who used acetaminophen in the year prior to asthma diagnosis or in the first year of life was elevated to 1.60 and 1.47, respectively.

Furthermore, results showed a slight increase in the risk of asthma and wheezing with prenatal use of acetaminophen by mothers. Researchers speculate that acetaminophen’s lack of inhibition of cyclooxygenase, the key enzyme involved in the inflammatory response of asthma, may be one explanation for the potential link between acetaminophen use and asthma.

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This study is published in the November issue of CHEST, the peer-reviewed journal of the American College of Chest Physicians.

BMJ editor urges Roche to fulfil promise to release Tamiflu trial data: Or anything that shows the drug does more good than harm.

Contact: Stephanie Burns
sburns@bmjgroup.com
44-020-738-36920
BMJ-British Medical Journal

BMJ editor urges Roche to fulfil promise to release Tamiflu trial data

Journal launches open data campaign to compel greater accountability in healthcare

In an open letter to company director, Professor Sir John Bell, she says: “Billions of pounds of public money have been spent on [Tamiflu] and yet the evidence on its effectiveness and safety remains hidden from appropriate and necessary independent scrutiny.”

The letter is published on the BMJ‘s website (bmj.com/tamiflu) alongside correspondence by the Cochrane team with Roche, the US Centres for Disease Control (CDC) and the World Health Organisation (WHO), as part of an open data campaign aimed at persuading Roche to give doctors and patients access to the full data on Tamiflu.

Dr Godlee’s letter follows recent reports that the European Medicines Agency (EMA) has initiated infringement proceedings against Roche to investigate deficiencies in safety reporting, including the processing of around 80,000 reports on suspected adverse drug reactions.

Dr Godlee is also one of 28 signaturies to a letter published in The Times today (thetimes.co.uk/letters) calling on drug companies to “come clean” and make clinical trial data for all drugs in current use available to healthcare professionals.

Pressure from politicians is also mounting. Last week, Sarah Wollaston, a GP and Conservative MP, raised the issue of missing data in Parliament, while Health Minister Norman Lamb has agreed to meet experts to discuss the issue of access to clinical trial data.

In December 2009, Roche made a public promise to release full clinical trial reports of its antiviral drug oseltamivir (Tamiflu) in response to a major investigation by the BMJ and researchers Peter Doshi and Tom Jefferson from the Cochrane Collaboration.

The investigation found no clear evidence that Tamiflu prevents complications like pneumonia in healthy people. It also raised serious concerns about access to drug data, the use of ghost writers in drug trials, and the drug approval process.

Since the investigation, some further data have been released to the Cochrane reviewers, but the full data set has still not been provided.

The Cochrane reviewers now know that there are at least 123 trials of Tamiflu and that the majority (60%) of patient data from Roche Phase 3 completed treatment trials remain unpublished. Their main concerns relate to “the likely overstating of effectiveness and the apparent under-reporting of potentially serious adverse effects.”

Meanwhile, Tamiflu has been a great commercial success for Roche and has been added to the World Health Organisation’s list of essential medicines.

In her letter, Dr Godlee appeals to Professor Bell “to bring your influence to bear on your colleagues on Roche’s board.” She adds: “In refusing to release these data of enormous public interest, you put Roche outside the circle of responsible pharmaceutical companies. Releasing the data would do a great deal to restore confidence in your company and its board of directors.”

In a response not for publication, Professor Bell said he has referred the matter to Roche and is awaiting a response.

“The open correspondence on bmj.com aims to hold specific individuals and organisations to account,” writes Dr Godlee in an accompanying editorial. “Their actions are preventing independent scrutiny of the results of clinical trials and putting patients’ lives at risk. We also hope it will contribute to a sea change in the public mood.”

A poll on bmj.com last week asked: “Who is mainly at fault for denying access to negative clinical trial results?” Of the 569 votes, 69% said pharma, 13.5% said regulators, and 9% said legislators.

The BMJ plans to launch other campaigns linked to its investigations in the future.

###

Doubts cast on credibility of some published clinical trials: “a remarkable 93 percent of 2235 so-called RCTs published in some Chinese medical journals during 1994 to 2005 was flawed”

2009 study posted for filing

Contact: Charlotte Webber charlotte.webber@biomedcentral.com 44-078-253-17342 BioMed Central

This release is available in Chinese.

Randomised Controlled Trials (RCTs) are considered the ‘gold standard’ research method for assessing new medical treatments.  But research published in BioMed Central’s open access journal Trials shows that the design of a remarkable 93 percent of 2235 so-called RCTs published in some Chinese medical journals during 1994 to 2005 was flawed, casting doubt on the reliability of research that is likely to influence medical decision-makers.

Researchers led by Taixiang Wu of the Chinese Cochrane Centre at Sichuan University, China and Ottawa Hospital Research Institute investigated clinical trials published in China between 1994 and 2005, searching the China National Knowledge Infrastructure (CNKI) electronic database for RCTs on 20 common diseases. To determine how many of these met recognised standards for randomly allocating participants to treatment groups, trained investigators interviewed the first or co-authors of 2235 trial reports by phone.

Less than seven percent of self-described RCTs published in some Chinese medical journals meet criteria for authentic randomisation. The researchers looked at both conventional and traditional Chinese medicine trials, but there was no difference between these in terms of study authenticity rates. However, all RCTs of pre-market drug clinical trial were authentic, and RCTs conducted at hospitals affiliated with medical universities were more likely to be authentic than trials conducted at lower tier level three and level two hospitals. More than half of the trials at university-affiliated hospitals met RCT criteria, which means lower-tier hospital research is the least rigorous in design terms.

“The fact that so many non-RCTs were published as RCTs reflected that peer-review needs to be improved and a Good Practice of Peer Review, including how to identify the authenticity of the study, urgently needs to be developed,” says Wu.

Misleading reporting of medical research is not unique to China. Studies labelled as RCTs are more likely to influence health policy-makers meaning falsely reported RCTs have the potential to mislead health care providers, consumers and policy-makers. The results of this study suggest authors of systematic reviews – articles that combine the results of multiple RCTs – need to be aware that RCTs in some Chinese journals may not be RCTs at all.

The approximately 1100 medical journals now active in China are rapidly increasing their output of research reports, including many identified by their authors as RCTs. But these trials present mostly positive results (they favour the treatment being investigated), which can be influenced by inadequate randomisation of patients when designing the study.

###

 

Notes to Editors

1. Randomized trials published in some Chinese journals: How many are randomized? Taixiang Wu, Youping Li, Zhaoxiang Bian, Guanjian Liu and David Moher Trials (in press)

During embargo, article available here: http://www.trialsjournal.com/imedia/1756122426222937_article.pdf?random=263457

After the embargo, article available at the journal website: http://www.trialsjournal.com/

Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central’s open access policy.

Article citation and URL available on request at press@biomedcentral.com on the day of publication.

2. This study was funded by the Chinese Medical Board of New York.

3. Trials is an open access, peer-reviewed, online journal that will encompass all aspects of the performance and findings of randomized controlled trials. Trials will experiment with, and then refine, innovative approaches to improving communication about trials. We are keen to move beyond publishing traditional trial results articles (although these will be included). We believe this represents an exciting opportunity to advance the science and reporting of trials. Prior to 2006, Trials was published as Current Controlled Trials in Cardiovascular Medicine (CCTCVM). All published CCTCVM articles are available via the Trials website and citations to CCTCVM article URLs will continue to be supported.

4. BioMed Central (http://www.biomedcentral.com/) is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector.

60th Health Research Report 07 JUL 2009 – Reconstruction

Editors Top Five:

1.Your Arteries on Wonder Bread

2.Report: Prostate cancer screening has yet to prove its worth

3. Doubts cast on credibility of some published clinical trials

4. Health food supplement may curb compulsive hair pulling

5. Acid-reducing medicines may lead to dependency

In this issue:

1.Irritability should be considered when diagnosing bipolar disorder in children

2. Kidney damage from medical imaging procedures can cause long-term health problems

3. Chemicals in common consumer products may play a role in pre-term births

4. Vitamin A derivative provides clues to better breast cancer drugs

5.Your Arteries on Wonder Bread

6. Tryptophan deficiency may underlie quinine side effects

7. Mice run faster on high-grade oil

8.Report: Prostate cancer screening has yet to prove its worth

9. Magic ingredient in breast milk protects babies’ intestines

10.K-STATE RESEARCHER STUDIES THE ANTI-CANCER CAPABILITIES OF A SPECIAL PURPLE SWEET POTATO

11.Triggering muscle development — a therapeutic cure for muscle wastage?

12.Acid-reducing medicines may lead to dependency

13.Doubts cast on credibility of some published clinical trials

14.. Caffeine reverses memory impairment in Alzheimer’s mice

15.Researchers find possible environmental causes for Alzheimer’s, diabetes

16.Muscle damage may be present in some patients taking statins

17. Health food supplement may curb compulsive hair pulling

18.Sugar substitute appears to prevent early childhood cavities

Health Research Report

60th Issue Date 07 JUL 2009

Compiled By Ralph Turchiano

www.healthresearchreport.me www.vit.bz

www.youtube.com/vhfilm www.facebook.com/engineeringevil

www.engineeringevil.com

Green tea may affect prostate cancer progression

2009 study posted for filing

Contact: Tara Yates
tara.yates@aacr.org
267-646-0558
American Association for Cancer Research

PHILADELPHIA – According to results of a study published in Cancer Prevention Research, a journal of the American Association for Cancer Research, men with prostate cancer who consumed the active compounds in green tea demonstrated a significant reduction in serum markers predictive of prostate cancer progression.

“The investigational agent used in the trial, Polyphenon E (provided by Polyphenon Pharma) may have the potential to lower the incidence and slow the progression of prostate cancer,” said James A. Cardelli, Ph.D., professor and director of basic and translational research in the Feist-Weiller Cancer Center, LSU Health Sciences Center-Shreveport.

Green tea is the second most popular drink in the world, and some epidemiological studies have shown health benefits with green tea, including a reduced incidence of prostate cancer, according to Cardelli. However, some human trials have found contradictory results. The few trials conducted to date have evaluated the clinical efficacy of green tea consumption and few studies have evaluated the change in biomarkers, which might predict disease progression.

Cardelli and colleagues conducted this open-label, single-arm, phase II clinical trial to determine the effects of short-term supplementation with green tea’s active compounds on serum biomarkers in patients with prostate cancer. The biomarkers include hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and prostate specific antigen (PSA). HGF and VEGF are good prognostic indicators of metastatic disease.

The study included 26 men, aged 41 to 72 years, diagnosed with prostate cancer and scheduled for radical prostatectomy. Patients consumed four capsules containing Polyphenon E until the day before surgery — four capsules are equivalent to about 12 cups of normally brewed concentrated green tea, according to Cardelli. The time of study for 25 of the 26 patients ranged from 12 days to 73 days, with a median time of 34.5 days.

Findings showed a significant reduction in serum levels of HGF, VEGF and PSA after treatment, with some patients demonstrating reductions in levels of greater than 30 percent, according to the researchers.

Cardelli and colleagues found that other biomarkers were also positively affected. There were only a few reported side effects associated with this study, and liver function remained normal.

Results of a recent year-long clinical trial conduced by researchers in Italy demonstrated that consumption of green tea polyphenols reduced the risk of developing prostate cancer in men with high-grade prostate intraepithelial neoplasia (HGPIN).

“These studies are just the beginning and a lot of work remains to be done, however, we think that the use of tea polyphenols alone or in combination with other compounds currently used for cancer therapy should be explored as an approach to prevent cancer progression and recurrence,” Cardelli said.

William G. Nelson, V., M.D., Ph.D., professor of oncology, urology and pharmacology at the Johns Hopkins Kimmel Cancer Center, believes the reduced serum biomarkers of prostate cancer may be attributable to some sort of benefit relating to green tea components.

“Unfortunately, this trial was not a randomized trial, which would have been needed to be more sure that the observed changes were truly attributable to the green tea components and not to some other lifestyle change (better diet, taking vitamins, etc.) men undertook in preparation for surgery,” added Nelson, who is also a senior editor for Cancer Prevention Research. However, “this trial is provocative enough to consider a more substantial randomized trial.”

In collaboration with Columbia University in New York City, the researchers are currently conducting a comparable trial among patients with breast cancer. They also plan to conduct further studies to identify the factors that could explain why some patients responded more dramatically to Polyphenon E than others. Cardelli suggested that additional controlled clinical trials should be done to see if combinations of different plant polyphenols were more effective than Polyphenon E alone.

“There is reasonably good evidence that many cancers are preventable, and our studies using plant-derived substances support the idea that plant compounds found in a healthy diet can play a role in preventing cancer development and progression,” said Cardelli.

 

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The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and nearly 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

Green tea extract shows promise in leukemia trials: Chronic lymphocytic leukemia 50 percent or greater decline in their lymph node size.

2009 study posted for filing

ROCHESTER, Minn. — Mayo Clinic researchers are reporting positive results in early leukemia clinical trials using the chemical epigallocatechin gallate (EGCG), an active ingredient in green tea. The trial determined that patients with chronic lymphocytic leukemia (CLL) can tolerate the chemical fairly well when high doses are administered in capsule form and that lymphocyte count was reduced in one-third of participants. The findings appear today online in the Journal of Clinical Oncology.

“We found not only that patients tolerated the green tea extract at very high doses, but that many of them saw regression to some degree of their chronic lymphocytic leukemia,” says Tait Shanafelt, M.D., Mayo Clinic hematologist and lead author of the study. “The majority of individuals who entered the study with enlarged lymph nodes saw a 50 percent or greater decline in their lymph node size.”

CLL is the most common subtype of leukemia in the United States. Currently it has no cure. Blood tests have enabled early diagnosis in many instances; however, treatment consists of watchful waiting until the disease progresses. Statistics show that about half of patients with early stage diseases have an aggressive form of CLL that leads to early death. Researchers hope that EGCG can stabilize CLL for early stage patients or perhaps improve the effectiveness of treatment when combined with other therapies.

The research has moved to the second phase of clinical testing in a follow-up trial — already fully enrolled — involving roughly the same number of patients. All will receive the highest dose administered from the previous trial.

These clinical studies are the latest steps in a multiyear bench-to-bedside project that began with tests of the green tea extract on cancer cells in the laboratory of Mayo hematologist Neil Kay, M.D., a co-author on this article. After laboratory research showed dramatic effectiveness in killing leukemia cells, the findings were applied to studies on animal tissues and then on human cells in the lab. (See “Green Tea and Leukemia” in Discovery’s Edge magazine.)

In the first clinical trial, 33 patients received variations of eight different oral doses of Polyphenon E, a proprietary compound whose primary active ingredient is EGCG. Doses ranged from 400 milligrams (mg) to 2,000 mg administered twice a day. Researchers determined that they had not reached a maximum tolerated dose, even at 2,000 mg twice per day.

###

VIDEO ALERT: Additional audio and video resources, including comments by Dr. Shanafelt describing the research, are available on the Mayo Clinic News Blog. These materials are also subject to embargo but may be accessed in advance by journalists for incorporation into stories. The password for this post is gteacll.

The study was sponsored by Mayo Clinic, the CLL Global Research Foundation, CLL Topics (including contributions by individual CLL patients) and the Commonwealth Foundation for Cancer Research. Medication for the study was provided by Polyphenon E International. Others on the research team were Timothy Call, M.D.; Clive Zent, M.D.; Betsy LaPlant; Deborah Bowen; Michelle Roos; Charla Secreto; Asish Ghosh, Ph.D.; Brian Kabat; Diane Jelinek, Ph.D.; and Charles Erlichman, M.D., all of Mayo Clinic; and Mao-Jung Lee, Ph.D., and Chung Yang, Ph.D., both of Rutgers University.

About Mayo Clinic

Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. Doctors from every medical specialty work together to care for patients, joined by common systems and a philosophy of “the needs of the patient come first.” More than 3,300 physicians, scientists and researchers and 46,000 allied health staff work at Mayo Clinic, which has sites in Rochester, Minn., Jacksonville, Fla., and Scottsdale/Phoenix, Ariz. Collectively, the three locations treat more than half a million people each year. To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories. For more on Mayo Clinic research, go to www.mayo.edu.

 

Why Antidepressants Don’t Live Up to the Hype

2009 report posted for filing

By John Cloud Wednesday, May 06, 2009

 

In the ’90s, Americans grew fond of the idea that you can fix depression simply by taking a pill – most famously fluoxetine (better known as Prozac), though fluoxetine is just one of at least seven selective serotonin reuptake inhibitors (SSRIs) that have been prescribed to treat hundreds of millions of people around the world.

 

 

But in the past few years, researchers have challenged the effectiveness of Prozac and other SSRIs in several studies. For instance, a review published in the Journal of Affective Disorders in February attributed 68% of the benefit from antidepressants to the placebo effect. Likewise, a paper published in PLoS Medicine a year earlier suggested that widely used SSRIs, including Prozac, Effexor and Paxil, offer no clinically significant benefit over placebos for patients with moderate or severe depression. Meanwhile, pharmaceutical companies maintain that their research shows that SSRIs are powerful weapons against depression. (Here’s a helpful blog post that summarizes the debate.)

 

 

Now a major new study suggests that both critics and proponents might be right about SSRIs: the drugs can work, but they appear to work best for only a subset of depressed patients – those with a limited range of psychological problems. People whose depression is compounded with, say, substance abuse or a personality disorder may not get much help from SSRIs – which is unfortunate for the 45% to 60% of patients in the U.S. who have been diagnosed with a common mental disorder like depression and also meet the criteria for at least one other disorder, like substance abuse. (Multiple diagnoses are known in medical parlance as comorbidities.)

 

 

The new study, published online in April by the American Journal of Psychiatry, was conducted using data from a large, government-funded trial called Sequenced Treatment Alternatives to Relieve Depression, which usually goes by the moniker STAR*D. The STAR*D project, which collected data from 2001 to 2004 at 41 U.S. psychiatric facilities, was one of the most ambitious efforts ever to understand how best to treat people with major depression. STAR*D participants comprise a powerful research sample because they are highly representative of all depressed Americans. Very few depressed people were excluded from STAR*D; only women who were pregnant, those with seizure disorders and a few others with acute conditions were kept out. All other psychiatric and medical comorbidities were allowed.

 

 

The authors of the new paper, a team of 11 researchers led by University of Pittsburgh professor of epidemiology Stephen Wisniewski, were curious how the STAR*D group would compare with a typical group of patients selected for a run-of-the-mill drug-company trial for a new antidepressant – the very trials on which the Food and Drug Administration bases its decisions regarding new drug approval. Drawing on their own experiences in helping to conduct such trials, which have far more stringent inclusion criteria than the STAR*D group, Wisniewski and his team divided the STAR*D patients into two groups – an “efficacy” sample of patients who would normally be included in a typical Phase III clinical trial for a new antidepressant and a “nonefficacy” sample of patients who would normally be rejected.

 

 

Depressed STAR*D patients who were classified for inclusion had no more than one general medical condition (like, say, heart disease) and no more than one additional primary psychiatric disorder besides depression. All patients with multiple comorbidities – along with anyone whose depression had lasted more than two years – were excluded. Once the authors crunched all the numbers, they found that only 22% of STAR*D patients met entry criteria for a conventional antidepressant trial.

 

 

All the STAR*D patients were taking citalopram, an SSRI marketed in North America as Celexa. Not surprisingly, those who met standard inclusion criteria for a clinical trial had significantly better outcomes on the drug. In the efficacy group, 52% responded to Celexa vs. 40% of the nonefficacy group. Patients in the latter group also took longer to respond and had to be readmitted to psychiatric settings more often. “Thus,” the authors conclude, “current efficacy trials suggest a more optimistic outcome than is likely in practice, and the duration of adequate treatment suggested by data from efficacy trials may be too short.”

 

 

To bolster their findings, the authors cite a smaller 2002 study that arrived at similar results: in that paper, published in the American Journal of Psychiatry, Dr. Mark Zimmerman of Brown University and his colleagues found that of 315 patients with major depressive disorder who sought care, only 29, or 9.2%, met typical criteria for an efficacy trial. Similarly, psychologist Ronald Kessler of Harvard co-authored a 2003 paper in the Journal of the American Medical Association that concluded that most “real world” patients with major depression would be excluded from clinical trials because of comorbidities.

 

 

Such findings help explain why antidepressants haven’t quite lived up to their promise. But the University of Pittsburgh’s Wisniewski, the lead author of the new study, cautions against interpreting the results as an indictment against greedy drug companies eager to exclude difficult patients in order to show better results. “If the population in a [clinical] trial were more representative, that would come at a cost,” he says. Researchers expect a certain number of bad reactions during clinical trials; some of these reactions can cause serious medical problems. If patients enter a trial with multiple complications – if they are, say, not only depressed, but also cocaine-addicted, hypertensive and diabetic – you dramatically increase the chances of adverse side effects. “That’s why trials to determine efficacy are done on a relatively homogeneous population,” Wisniewski says.

 

 

That’s understandable, but the new study does shed light on the limitations of antidepressants. Conducting clinical trials with representative samples would undoubtedly be more complex – and expensive – since patients with multiple risk factors would have to be monitored more carefully. But for a future generation of antidepressants to be truly effective for most patients, more-inclusive trials may be the best answer.

 

http://www.time.com/time/health/article/0,8599,1895672,00.html

People with depression often excluded from clinical studies of antidepressants?

2009 report posted for filing

Contact: Clare Collins
CollCX@upmc.edu
412-647-3555
University of Pittsburgh Schools of the Health Sciences

Are we cherry picking participants for studies of antidepressants?

People with depression often excluded from clinical studies and tend not to fare as well as study participants

PITTSBURGH, April 28 – Findings from clinical studies used to gain Food and Drug Administration approval of common antidepressants are not applicable to most patients with depression, according to a report led by the University of Pittsburgh Graduate School of Public Health. Published in the May issue of the American Journal of Psychiatry, the study suggests only a small percentage of people with depression qualify for these studies, and those who do not qualify are often treated with the same medications but may suffer poorer clinical outcomes.

A part of the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project – the largest study of the treatment of depression conducted in the United States – researchers compared symptoms and outcomes in depressed patients who met phase III study inclusion criteria to those who did not. Phase III studies for antidepressants determine the effectiveness of the drug in comparison to a placebo. The inclusion criteria for these studies are not standardized nor subject to federal guidelines, resulting in some variation from study to study in the profile of eligible patients. Typically excluded are patients with milder forms of depression, who might be more likely to respond to a placebo drug, and those who may have chronic depression or psychiatric and medical co-morbidities – additional illnesses or conditions.

After assessing 2,855 patients treated with citalopram, a commonly prescribed selective serotonin reuptake inhibitor for mood disorders, study authors concluded that fewer than one in four, or 22.2 percent, of the patients met the usual criteria for inclusion in phase III antidepressant trials.

“Only a small percentage of depressed patients in our study would have qualified for inclusion in phase III efficacy trials of depression drugs,” said study lead author, Stephen Wisniewski, Ph.D., professor of epidemiology and co-director of the Epidemiology Data Center, University of Pittsburgh Graduate School of Public Health. “This raises major concerns about whether results from traditional phase III studies can be generalized to most people with depression, who also often suffer from anxiety, substance abuse and other medical and psychiatric problems.”

When Dr. Wisniewski and colleagues further assessed how well patients did on treatment, they found that those who met the eligibility criteria for phase III trials had better outcomes, including higher remission rates, less severe side effects and serious adverse events. The depression remission rate in the patients who met the criteria was 34.4 percent, compared to only 24.7 percent in the ineligible group. Additionally, the drug response rate also was higher in the eligible group – 51.6 percent compared to 39.1 percent of the ineligible group.

“Results from research studies suggest more optimistic outcomes than may exist for real-world patients receiving treatment for depression,” said Dr. Wisniewski. Although phase III eligibility criteria could be changed to include a broader population of patients, Dr. Wisniewski cautions that this could come at the cost of more serious side effects in patients who have co-morbidities and are generally sicker. These patients may not be able to safely tolerate the drugs being tested. Instead, he suggests medical care providers who treat patients with depression use their professional judgment by noting that most phase III findings are based on patients who may be very different than those under their care.

 

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The study was funded by the National Institute for Mental Health. Co-authors include A. John Rush, M.D., National University of Singapore; Diane Warden, Ph.D., M.B.A., and Madhukar Trivedi, M.D., University of Texas Southwestern Medical Center; Andrew Nierenberg, M.D., and Maurizio Fava, M.D., Harvard Medical School; Bradley Gaynes, M.D., M.P.H., University of North Caroline School of Medicine; James Luther, M.A., University of Pennsylvania School of Medicine; Patrick McGrath, M.D., Columbia University Medical Center; Philip Lavori, Ph.D., Stanford University School of Medicine; and Michael Thase, M.D., University of Pittsburgh School of Medicine.

Cancer institute tackles sloppy data

Funder demands better evidence for biomarkers in clinical trials.

Monya Baker

12 October 2012

Biologists combing through massive patient data sets often find potential biomarkers of certain diseases, but many of these signals turn out to be false. To weed out these useless associations, the US National Cancer Institute (NCI) yesterday released a draft list of 29 criteria, such as documenting where specimens came from and ensuring experiments can be properly replicated, that researchers must address before receiving NCI funds to run a clinical trial.

The goal of the guidelines is to divert some of the problems that arise in developing tests on the basis of ‘omics’ studies — investigations of thousands of genes, proteins and other biomolecules within patient samples. Such tests could help to predict the best treatments for patients with cancer, but evaluating them can be tricky, says Lisa McShane, a biostatistician at the NCI in Rockville, Maryland, and a co-author of the guidelines.

Problems with omics predictions captured headlines after clinical trials for cancer at Duke University in Durham, North Carolina, were halted in 2010 owing to suspicion of data alteration. More than two dozen papers were retracted in association with the scandal, and the lead investigator, Anil Potti, resigned amid an investigation of research misconduct (see ‘Cancer trial errors revealed‘).

After the investigation, the US Institute of Medicine released a report in March calling for higher standards in developing omics tests to guide treatment decisions in clinical trials (see ‘Lapses in oversight compromise omics results’). That report outlined principles for discovering, evaluating and validating omics tests, and specified that any tests used to determine a patient’s medical care within a clinical trial should first be reviewed by the US Food and Drug Administration.

The NCI guidelines address similar problems as the IOM report but are more like a how-to manual, says McShane, and they are not just a checklist — because the NCI approves and funds clinical trials, the guidelines are enforceable.

Although cases of outright misconduct are rare, many papers and protocols contain serious scientific flaws, says McShane. Intuition breaks down when so many variables are considered, she says, making researchers blind to methodological flaws.

Keith Baggerly, a bioinformatician at MD Anderson Cancer Center in Houston, Texas, who, along with McShane, helped to uncover problems in the Duke trials says that no one expected that it would be so easy to find spurious patterns in genomic data.

“Early after the genome was mapped, there was a notion we could take this wonderful data, plug it through some mathematical algorithms, and out would pop the secrets of biology. Guess what? It’s not that easy,” says Larry Kessler, who studies how research can best move into clinical practice at the University of Washington in Seattle.

One of the most egregious flaws, says McShane, is ‘resubstitution’, in which some of the data used to build a hypothesis are also used to evaluate it. “You can see that even in top journals,” says McShane. Other problems occur when researchers fail to thoroughly document where patient specimens come from or how they’ve been assayed, making it hard to replicate results.

“The guidelines are so important and necessary,” says Kessler. “A lot of experiments have not been done with the [necessary] rigour and replication.” Neither funders nor scientists get excited about replicating studies, he says, but not doing so is wasteful at best. The guidelines enforce replication at several levels, such as requiring researchers to repeat an assay on the same sample to make sure it provides consistent results, to document computer code in enough detail for someone else to reproduce an analysis, or to check that the same biomarkers are associated with the same conditions in independent data sets.

Part of the problem is cultural, says David Ransohoff, a cancer epidemiologist at the University of North Carolina in Chapel Hill, who says that the NCI guidelines are a good start. There is a big difference between assessing data for clinical research and generating hypotheses in labs. “Whatever you’re using, you have to give it a fair, blinded hypothesis test to validate it, and if you don’t, you don’t have strong enough data to be doing patient management.”

What researchers might bill as blinded is not necessarily so, says McShane. If results don’t come out as expected, researchers may tweak a model or disregard outlier data and then rerun a test without realizing that those tweaks corrupt validation studies. “People don’t realize how much bias that can introduce,” she says.

McShane says that she hopes the guidelines will protect patients and make research more efficient. “We are seeing these guidelines not as something making people’s life difficult, but something that can spare people pain,” says McShane. “So they won’t write up a bad protocol or hype a bad study.”

Journal name:
Nature
DOI:
doi:10.1038/nature.2012.11580
 

http://www.nature.com/news/cancer-institute-tackles-sloppy-data-1.11580

 

Questions of ethics and quality cloud globalization of clinical trials: Same drug in different populations could produce markedly different results

2009 study posted for filing

Contact: Michelle Gailiun
michelle.gailiun@duke.edu
919-724-5343
Duke University Medical Center

DURHAM, N.C. – Top-tier U.S.-based pharmaceutical companies are moving their clinical trials overseas at warp speed, raising questions about ethics, quality control, and even the scientific value of their findings for people back in the U.S.

Many of the trials are taking place in developing countries in Eastern Europe and Asia where study participants are often poorer and less educated than are study participants in the U.S., according to researchers at Duke Clinical Research Institute (DCRI).

“The FDA is supposed to provide oversight for such trials, but it simply wasn’t designed to handle this kind of situation,” says Kevin Schulman, M.D., the senior author of the report appearing in the New England Journal of Medicine. Schulman says the number of Food and Drug Administration investigators based outside the U.S. has grown by 15 percent every year since 2002, while the number of U.S.-based investigators has fallen just over 5 percent during the same period.

Schulman and a research team led by Seth Glickman, M.D., a senior scholar at Duke’s Fuqua School of Business, used the clinicaltrials.gov registry to examine recruitment patterns in industry-sponsored Phase 3 trials in 2007. Phase 3 trials are typically the largest and most meaningful trials, often involving thousands of patients. They found that about a third of the trials (157 of 509) were being solely conducted outside the U.S. They also discovered that over half the study sites (13,521 of 24,206) lay outside U.S. borders.

Researchers also reviewed 300 articles reporting clinical trial results appearing in the New England Journal of Medicine, the Journal of the American Medical Association and the Lancet in 1995 and 2005 and found that over that decade, the number of clinical trial sites abroad doubled, while the number in the U.S and Western Europe declined.

“There are powerful forces luring clinical trials overseas, including the lower cost of doing business and access to larger study populations,” says Glickman. “The cost per participant in a clinical trial in India, for example, can be only one-tenth of what it is in the U.S.”

“But there are equally powerful forces pushing,” says Schulman, who adds that a mix of well-intentioned policy efforts is actually creating barriers to conducting research in a timely fashion in the U.S.

The authors say some of the clinical trials abroad are raising concern about aligning research to the health needs of the population under study. “It’s pretty clear that companies are testing drugs in countries where they will not be marketed or sold,” says Glickman. “This is a major ethical concern.” The researchers found plenty of examples where companies were testing drugs for conditions such as allergic rhinitis, fibromyalgia and overactive bladders in emerging markets – rather than treatments for diseases like malaria or tuberculosis that might be more prevalent there.

Glickman says social ecology and genetics may also play a role in trial outcomes, and may limit their applicability to patients who do not share such characteristics. For example, healthcare-rich economies produce patients with one set of characteristics, while participants with little access to healthcare may have quite different profiles. “It is conceivable that use of the same drug in both populations would produce markedly different results.” Likewise, genetic polymorphisms, or “signatures” in some populations can affect response to certain drugs, making it inappropriate to apply results from studies in these populations to patients who do not share those characteristics.

“Clearly, there is some benefit for everyone involved in clinical trials overseas,” says Glickman. “Generally, such trials increase local prosperity, education and access to better healthcare. And it is critical that new drugs and devices be tested in diverse populations. In order to for that to properly continue, however, we need a robust research framework that will protect trial participants and ensure that sponsors adhere to the highest ethical standards.”

The authors say a body such as the Institute of Medicine or the World Health Organization could create an international commission that would bring industry, academia, regulatory agencies and patient advocacy groups to the same table. “The future of the pharmaceutical and device industries is predicated on addressing these issues,” they write.

 

###

 

DCRI colleagues who contributed to the study include Drs. John McHutchison, Eric Peterson, Charles Cairns, Robert Harrington and Rob Califf

HHS Report Slams FDA’s Conflict of Interest Oversight: 42% were missing the required financial disclosures

2009 report posted for filing

 

By Emily P. Walker, Washington Correspondent, MedPage Today

 

WASHINGTON, Jan. 12 — The FDA fails to ensure that scientists conducting clinical trials on investigational products disclose financial conflicts of interest, found a review by the Department of Health and Human Services.

 

An analysis by the Office of Inspector General (OIG), covering all 118 marketing applications for products approved by the FDA in 2007, showed that 42% were missing the required financial disclosures on the investigators.

 

 

“Financial relationships between researchers and medical companies may compromise the safety of human subjects and the integrity of research data,” the OIG report said.

 

 

The report recommended that trial sponsors submit financial disclosures as part of the pre-trial process, rather than after the trial’s completion.

 

 

For every study submitted to the FDA as part of a marketing application, the agency’s regulations require sponsors to submit financial disclosure information on each investigator.

 

 

Sponsors have the option of not including financial information if they tried and failed to obtain it. The report found that more than one-quarter of the marketing applications used that “due diligence” exemption. Most often, the sponsors said the investigators could not be located or failed to return the financial form.

 

 

For those marketing applications that disclosed financial conflicts of interest, FDA reviewers and sponsors failed to take action to remedy the conflict in 20% of all cases, the report said.

 

 

For about one-third of all marketing applications, FDA reviewers didn’t even document that they checked the financial disclosure.

 

 

“If FDA reviewers fail to document a review, division directors may overlook disclosed financial interests and their potential impact on data integrity,” the report said.

 

 

Even when disclosure forms were filed, the number reporting potential conflicts was surprisingly low.

 

 

The OIG’s investigation revealed that among forms filed for 29,691 clinical investigators, only 206 — less than 1% — indicated at least one financial interest, contrasting sharply with independent estimates.

 

 

For example, a figure of one-quarter of academic researchers having financial ties to medical companies was published last year in the Journal of the American Medical Association, the report noted.

 

 

The OIG recommended that the FDA compile a central list of clinical investigators and their financial disclosures in order to accurately and easily look for conflicts of interest for future trials.

 

 

In addition, the FDA should check that sponsors have submitted all required attachment and financial forms along with their marketing applications, and it should update guidance on the due diligence exemption, the report said.

 

 

FDA spokeswoman Karen Riley said in a statement that the recommendations were reasonable, with one exception.

 

 

The agency opposes requiring investigator disclosures as part of the pre-trial process, she said.

 

 

“This recommendation could have the unintended effect of adding to the complexity and cost of the clinical trial enterprise with no commensurate gain in the protection of human subjects or the quality of the data,” Riley said.

 

 

She argued that a pre-trial submission requirement could create significant unnecessary paperwork, since data from a given study “may never be submitted in support of a marketing application.”

 

 

Riley said clinical investigators’ financial incentives are only one type of bias that might exist in a trial. She said it has not been established that increasing the level or frequency of disclosure “would solve a recognized problem or enhance subject protection.”

 

 

The agency takes at face value the OIG’s finding that fewer than 1% of investigators reported potential conflicts, according to Riley.

 

 

On that basis, Riley said, as well as the fact that only 8% of products entering phase I testing eventually gain final approval, “restructuring FDA’s review process to accommodate this recommendation does not seem warranted.”

 

Additional source: Office of the Inspector General in the Department of Health and Human Services

Pneumococcal vaccine does not appear to protect against pneumonia: ” a systematic review and meta-analysis, looked at 22 clinical trials, reviews and meta-analyses and more than 100,000 participants “

2009 study posted for filing

Contact: Kim Barnhardt
kim.barnhardt@cmaj.ca
613-731-8610 x2224
Canadian Medical Association Journal

Commonly used pneumococcal polysaccharide vaccines do not appear to be effective for preventing pneumonia, found a study by a team of researchers from Switzerland and the United Kingdom http://www.cmaj.ca/press/pg48.pdf.

In many industrialized countries, polysaccharide pneumococcal vaccines (PPVs) are currently recommended to help prevent pneumococcal disease in people aged 65 and over and for younger people with increased risk due to conditions like HIV. Studies have shown conflicting results regarding the efficacy of PPV.

The study, a systematic review and meta-analysis, looked at 22 clinical trials, reviews and meta-analyses and more than 100,000 participants from countries in North America as well as India, Africa, Latin America and the Caribbean. Unlike other similar studies the authors examined the reasons why different clinical trials produced different results. They found that the quality of the studies substantially affected the results. When only high quality trials were included, there was no evidence that PPVs could prevent pneumonia. The study adds to the ongoing debate around effectiveness of the vaccine.

“Policy makers may therefore wish to reconsider their current recommendations for PPV, especially where routine pneumococcal conjugate immunization has been introduced,” conclude Dr. Matthias Egger from the University of Bern, Switzerland and coauthors.

However, in a related commentary http://www.cmaj.ca/press/pg18.pdf, Dr. Ross Andrews and coauthor from the Menzies School of Health Research, Darwin, Australia state that the researchers’ conclusions exceed the evidence presented. They caution that there should be no change in vaccine policy in countries that recommend PPV to prevent invasive pneumococcal disease

LOYOLA TESTING MELANOMA TREATMENT THAT BOOSTS PATIENT’S IMMUNE SYSTEM TO FIGHT DEADLY CANCER

Contact:

Jim Ritter
Media Relations
jritter@lumc.edu
(708) 216-2445
Anne Dillon
Director, Media Relations
adillon@lumc.edu
(708) 216-8232

 

MAYWOOD, Ill. – Loyola University Medical Center has launched the first clinical trial in the Midwest of an experimental melanoma treatment that genetically engineers a patient’s immune system to fight the deadly cancer.

 

 

A batch of the immune system’s killer T cells will be removed from the patient and genetically modified in a Loyola lab. Two genes will be inserted into the T cells so that they will recognize tumor cells as abnormal.

 

 

Patients will undergo high-dose chemotherapy to kill most of their remaining T cells. This will make room for the genetically modified T cells when they are put back in the patient. The modified T cells, it is hoped, will recognize the tumor cells as abnormal and then attack and kill them.

 

 

“This clinical trial is a unique attempt to manipulate a person’s own immune system to attack their cancer in a more effective and specific manner,” said Joseph Clark, MD, one of the principal investigators of the trial.

 

 

The purpose of the Phase 1 trial is to determine the optimum dose and whether the treatment is safe. Four doses will be tested, with the highest dose consisting of about 5 billion genetically modified T cells. If Phase 1 demonstrates the treatment is safe, investigators will proceed to Phase 2, which will determine whether the treatment is effective.

 

 

Melanoma is the sixth most common cancer in Americans, and the most common fatal malignancy in young adults. Incidence is rising dramatically. About 1 in 50 people will be diagnosed with melanoma. In the 1960s, it was 1 in 600.
Surgery is highly successful if the cancer is caught early. But if the cancer has spread to other parts of the body, the five-year survival rate is only 15 to 20 percent, according to the American Cancer Society.

 

 

“This is a terrible, devastating disease,” Clark said. “It starts on the skin and can spread to just about anywhere in the body.”

 

 

The clinical trial is open to patients with metastatic melanoma who are no longer responding to standard therapy. “We need better treatments,” Clark said. “Our clinical trial is designed for patients who have no other options.”

 

 

The experimental immune system therapy was developed by Michael I. Nishimura, PhD, director of the Immunotherapeutics Program at Loyola’s Cardinal Bernardin Cancer Center. The cells will be prepared in the Robert R. McCormick Foundation Center for Cellular Therapy in the Cardinal Bernardin Cancer Center.

 

 

Nishimura is principal investigator of a five-year, $16.3 million grant from the National Cancer Institute. “Our goal is to create novel therapies for the treatment of advanced malignancies,” he said.

 

 

Additional funding for the trial comes from a National Cancer Institute grant to Lentigen Corp., which makes the vector that delivers the genes to the T cells, and from the American Recovery and Reinvestment Act (the economic stimulus bill).

 

 

Clark is a professor in the Department of Medicine, Division of Hematology/Oncology of Loyola University Stritch School of Medicine. Nishimura is a professor in the Department of Surgery and associate director of the Oncology Institute of Loyola University Chicago Stritch School of Medicine.
Other investigators in the trial are Patrick Stiff, MD, director of the Cardinal Bernardin Cancer Center; Constantine Godellas, MD; Kelli Hutchens, MD; and Caroline Le Poole, PhD.

 

 

For more information, please call (708) 327-3221.

Melatonin may save eyesight in inflammatory disease: Uveitis

2008 study posted for filing

Contact: Angela Colmone
acolmone@asip.org
301-634-7953
American Journal of Pathology

Buenos Aires, Argentina — Current research suggests that melatonin therapy may help treat uveitis, a common inflammatory eye disease. The related report by Sande et al., “Therapeutic Effect of Melatonin in Experimental Uveitis,” appears in the December issue of The American Journal of Pathology.

People with uveitis develop sudden redness and pain in their eyes, and their vision rapidly deteriorates. Untreated, uveitis can lead to permanent vision loss, accounting for an estimated 10-15% of cases of blindness in the US. Uveitis has a wide variety of causes, including eye injury, cancer, infection, and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. There is currently no optimal treatment for uveitis. Corticoid steroid eye drops are often used; however, long-term corticoid use has many negative side effects, including the possible development of glaucoma.

Researchers lead by Dr. Ruth Rosenstein of The University of Buenos Aires and The National Research Council (CONICET) hypothesized that melatonin, which regulates sleep/wake cycles and reduces jet lag, may be able to prevent the ocular inflammation in uveitis. They found in an experimental model of uveitis that levels of two factors that contribute to inflammation, TNFα and NFκB, were reduced with melatonin treatment. Importantly, melatonin treatment also decreased the appearance of clinical symptoms of uveitis such as inflammation, blood vessel expansion and cataract, and protected the blood-ocular barrier integrity.

Taken together, the data from Sande et al suggest that “melatonin, which lacks adverse collateral effects even at high doses, could be a promising resource in the management of uveitis. Alone or combined with corticosteroid therapy, the anti-inflammatory effects of melatonin may benefit patients with chronic uveitis and decrease the rate and degree of corticosteroid-induced complications.” Future studies will aim at understanding the mechanisms governing melatonin protection in the eye.

 

###

 

This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), the University of Buenos Aires, CONICET, Argentina, and the John Simon Guggenheim Memorial Foundation.

Sande PH, Fernandez DC, Aldana Marcos HJ, Chianelli MS, Aisemberg J, Silberman DM, Sáenz, DA, Rosenstein RE: Therapeutic effect of melatonin in experimental uveitis. Am J Pathol 2008 173:1702-1713

For press copies of the articles, please contact Dr. Angela Colmone at 301-634-7953 or acolmone@asip.org or the Journal Editorial Office at 301-634-7959.

For more information on Dr. Rosenstein, please contact at: ruthr@fmed.uba.ar

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

Half of trials supporting FDA applications go unpublished

2008 study posted for filing

Contact: Andrew Hyde
press@plos.org
44-122-346-3330
Public Library of Science

Over half of all supporting trials for FDA-approved drugs remained unpublished 5 years after approval, says new research published in this week’s PLoS Medicine. The most important trials determining efficacy, and those with statistically significant results and larger sample sizes, are more likely to be published.

Ida Sim and colleagues from the University of California San Francisco searched the medical literature to determine the publication status of all 909 clinical trials that supported the 90 new drug approval applications approved by the US Food and Drug Administration (FDA) between 1998 and 2000. Although 76% of the pivotal trials (typically large Phase II or III trials designed to provide evidence on the overall risks and benefits of a drug) had been published in medical journals—usually within 3 years of FDA approval—only 43% of all of the submitted trials had been published.

The researchers also found evidence of selective reporting of the results from these trials. For example, Sim and colleagues report that a pivotal trial in which a new drug works better than an old drug is more likely to be published than a trial in which the new drug does no better. This is a form of publication bias that may lead to an inappropriately favorable record in the medical literature of a drug’s true risk-benefit profile relative to other standard therapies, and can lead to preferential prescribing of newer and more-expensive treatments, say the authors.

These new results provide a baseline for monitoring the effects of the FDA Amendments Act 2007, which was introduced to improve the accuracy and completeness of drug trial reporting. Under this Act, all trials supporting FDA-approved drugs must be registered when they start and the results of all the outcomes declared at trial registration as well as specific details about the trial protocol must be publicly posted within a year of drug approval on the US National Institutes of Health clinical trials.gov site.

 

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In July the PLoS Medicine editors published an editorial discussing the FDA Amendment Act and what it means for medical journals: The PLoS Medicine Editors (2008) Next Stop, Don’t Block the Doors: Opening Up Access to Clinical Trials Results. PLoS Med 5(7): e160 doi:10.1371/journal.pmed.0050160

Citation: Lee K, Bacchetti P, Sim I (2008) Publication of clinical trials supporting successful new drug applications: A literature analysis. PLoS Med 5(9): e191. doi:10.1371/journal.pmed.0050191

IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE PUBLISHED PAPER: http://medicine.plosjournals.org/perlserv/?request=get-document&doi:10.1371/journal.pmed.0050191

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-05-09-sim.pdf

CONTACT:
Ida Sim
University of California, San Francisco
Department of Medicine and the Program in Biological and Medical Informatics,
400 Parnassus Ave., A-405
San Francisco, CA 94143-0320
United States of America
(415) 502-1954
(415) 476-7964 (fax)
ida.sim@ucsf.edu

 

Documentary Evidence Reveals Motives of Pharmaceutical “Seeding” Trials

Re-Post for filing 2008

Clinical studies that are designed by pharmaceutical companies to promote use of their drugs are called “seeding” trials. While much has been written about the marketing tactics of the pharmaceutical industry, seeding trials have not been characterized in depth. A new study finds strong documentary evidence of how a pharmaceutical company framed a marketing effort as a clinical trial. Researchers reviewed internal documents that became public during litigation against the drug manufacturer. The company’s marketing division designed the trial, and handled all collection, analysis, and dissemination of data. The company hid their motive for the trial from participants, investigators, and institutional review board members. Researchers concluded that seeding trials are harmful for three reasons: First, because the company disguises its motives, informed consent is impossible; second, good quality research is at risk when marketers – rather than scientists – design a study; and third, the scientific question posed by a seeding trial often has little merit. An accompanying editorial warns institutional research review boards to avoid approving seeding trials and physicians to avoid enrolling their patients in them

Toxic drugs, toxic system: Sociologist predicts drug disasters “Drug disasters are literally built into the current system of drug testing and approvals in the United States,”

Repost 2008

Contact: Jackie Cooper jcooper@asanet.org 202-247-9871 American Sociological Association

Study says harm from prescription drugs growing, cites fatal flaws in drug testing, approval and marketing

BOSTON — Americans are likely to be exposed to unacceptable side effects of FDA-approved drugs such as Vioxx in the future because of fatal flaws in the way new drugs are tested and marketed, according to research to be presented today at the annual meeting of the American Sociological Association (ASA).

“Drug disasters are literally built into the current system of drug testing and approvals in the United States,” said Donald Light, the sociologist who authored the study and a professor of comparative health policy at the University of Medicine and Dentistry of New Jersey. “Recent changes in the system have only increased the proportion of new drugs with serious risks.”

According to a 1999 report for the Institute of Medicine, adverse drug reactions (ADRs) are the fourth leading cause of death in the United States and more than two million serious reactions occur every year. ADRs can occur for a number of reasons, including improper prescribed dosage, drug abuse and drug interactions.

Light’s analysis identifies the organizational foundations of patient risk from prescription drugs and suggests institutional reforms to help avoid or reduce future drug disasters.

According to Light, rather than using current approved drugs as benchmarks of efficacy, the existing testing system evaluates the effectiveness of new drugs based on their effects compared to placebos. Systematic reviews indicate that one in seven new drugs is superior to existing drugs, but two in every seven new drugs result in side effects serious enough for action by the U.S. Food and Drug Administration (FDA), including black box warnings, adverse reaction warnings, or even withdrawal of the drug.

Based on this system, Light asserts that new drugs are twice as likely to harm patients as to provide them with benefits superior to existing drugs.

Light’s analysis suggests another flaw lies within the design of clinical trials. He contends that pharmaceutical companies frequently design their trails to minimize evidence of toxic side effects. To do so, they sample from a healthier population atypical of patients who will actually take the drug, excluding people who are older, poorer or who have multiple health problems. Trials are run long enough to pick up main effects but not to detect some long term side effects. Approvals are based on these data; so drugs with harmful effects sometimes get through.

“Based on our current system, the designation of ‘safe and effective’ on today’s new drugs could be replaced with, ‘apparently safe based on incomplete information, and more effective than a placebo,'” Light said.

With regard to government oversight, Light cites serious under-funding of the FDA, which creates a dependency on the pharmaceutical industry—the industry FDA regulates—to pay its staff. In return for drug company funding, Light says, the industry expects faster reviews, but faster reviews potentially fail to identify serious long-term side effects.

“Speed-up reviews for safety have more than tripled the number of ‘black box warnings’ of side effects or withdrawals after drugs are on the market,” Light said. “Despite recent reforms to strengthen the FDA’s role in protecting the public from harmful drugs, the harm-benefit ratio is worsening due to these reviews and relaxed rules that allow companies to promote drugs for unapproved uses.”

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The paper, “Institutional Foundations of the Vioxx Disaster,” will be presented on Sunday, Aug. 3, at 2:30 p.m. in the Sheraton Boston at the American Sociological Association’s 103rd annual meeting. Light will identify eight institutional foundations for future drug disasters, and will suggest multiple reforms to improve the U.S. drug approval system.

Contact Jackie Cooper at jcooper@asanet.org or (202) 247-9871 for more information on Light’s presentation. During the annual meeting (July 31 to Aug. 4), ASA’s Public Information Office staff can be reached in the press room, located in the Sheraton Boston’s Exeter AB room, at (617) 351-6853, (617) 351-6854 or (301) 509-0906 (cell).

About the American Sociological Association

The American Sociological Association (www.asanet.org), founded in 1905, is a non-profit membership association dedicated to serving sociologists in their work, advancing sociology as a science and profession, and promoting the contributions to and use of sociology by society.

Pain drug can kill resistant tuberculosis: Researchers claim may never be tested in TB clinical trials.

Public release date: 10-Sep-2012
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Contact: Lauren Woods
law2014@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College

Researchers find low cost drug wipes out drug resistant TB, but worry it may not reach patients in need

NEW YORK (September 10, 2012) — An off-patent anti-inflammatory drug that costs around two cents for a daily dose in developing countries has been found by researchers at Weill Cornell Medical College to kill both replicating and non-replicating drug resistant tuberculosis in the laboratory — a feat few currently approved TB drugs can do, and resistance to those is spreading.

Their findings, published online by the journal PNAS, point to a potential new therapy for the more than 500,000 people worldwide whose TB has become resistant to standard drug treatments. But the researchers worry that the effective drug, oxyphenbutazone, may never be tested in TB clinical trials.

Weill Cornell’s Dr. Carl Nathan and his research team found what they call the “completely surprising” ability of oxyphenbutazone to kill drug resistant TB after testing thousands of approved drugs against the bacteria. This repurposing of agents already on the market can lead to quicker testing for new uses.

“This agent might help save lives if there was a way to test it in TB patients,” says Dr. Nathan. Oxyphenbutazone went on the market as a patented drug for arthritis-like pain in the early 1950s, and lost its patent and market dominance by the 1970s.

“It is difficult today to launch clinical studies on a medication that is so outdated in the United States, that it is mainly used here in veterinary medicine to ease pain,” says the study’s senior author, Dr. Nathan, chairman of the Department of Microbiology and Immunology, the R.A. Rees Pritchett Professor of Microbiology, and the director of The Abby and Howard Milstein Program in the Chemical Biology of Infectious Disease at Weill Cornell. “No drug firm will pay for clinical trials if they don’t expect to make a profit on the agent. And that would be the case for an off-patent drug that people can buy over the counter for pain in most of the world.”

He adds that oxyphenbutazone, best known under the trademark name of Tandearil, does have some established toxicities, “and is not a drug you should take for aches and pains if a safer alternative is available.” But the drug’s major toxicities appear to be less frequent than the major side-effects of the drug regimens that are currently used to treat TB, he says.

Treating the TB that Hides

Mycobacterium tuberculosis is unusual among disease-causing bacteria in that it naturally infects just humans. One-third of the world’s population is infected with TB, but the bacteria typically remain dormant in a person with a healthy immune system.

Nonetheless, TB becomes active in enough people that it is the leading cause of death in humans from a bacterial infection. It is difficult to treat, and the bacteria can become resistant to therapy. TB treatment in a drug-sensitive patient takes six months, using a combination of agents. If the TB is sensitive to these first-line agents and the therapy is completed with full-strength, non-counterfeit drugs, up to 95 percent of patients can be cured.

However, if a patient’s TB becomes resistant to these drugs, second-line agents are administered every day for two years or more. “These second-line drugs are often toxic and expensive, and are not readily available in developing countries, where most of the infections occur,” Dr. Nathan says. Mortality in drug resistant TB patients can be as high as 80 percent.

A major issue in treating TB is that the bacteria can “hide out” in the body in a non-replicating form, even when a TB patient is undergoing treatment.

To find agents that could attack non-replicating TB, Dr. Nathan’s research team first identified four conditions that keep bacteria in that state within the human body: low oxygen, mild acidity, a fat instead of sugar to eat and a small amount of the natural defense molecule nitric oxide.

The research team replicated those conditions in the test tube and then methodically tested the effectiveness of thousands of agents against the bacteria. After testing 5,600 drugs, researchers found oxyphenbutazone.

Researchers then delved into the mechanism by which oxyphenbutazone kills TB and found that the conditions that allow the bacterium to remain dormant modify the drug to the point that it starts reacting against both non-replicating and replicating TB. “When this happens, TB can’t defend itself and dies,” Dr. Nathan says.

But the researchers were unable to test oxyphenbutazone in mice, because the animals metabolize the drug to an inactive form far faster than humans.

“This makes testing the drug for TB use in humans problematic since the FDA requires preclinical animal testing studies for safety and efficacy,” Dr. Nathan says. “Yet there is a long track record of oxyphenbutazone’s relatively safe use in hundreds of thousands of people over decades.”

Dr. Nathan and his team are continuing their research, testing hundreds of thousands of compounds for their action against TB. His team has already found another approved drug, nitazoxanide, to be effective against the bacteria, publishing his findings in 2009.

Nitazoxanide, a drug with an excellent safety record, is still on patent for use against some infections caused by other microbes. Discussions have been held about testing it in TB, Dr. Nathan says, but have stalled because of the same problem as oxyphenbutazone. The drug is metabolized so quickly in mice that it cannot be tested against experimental TB in that species.

For both oxyphenbutazone and nitazoxanide, Dr. Nathan argues that the requirement for testing in animals with experimental TB should be waived, because these agents work against TB in the test tube, have already been used with relative safety in people and might address an urgent need for treatment of a contagious disease with high mortality and few other treatment options.

###

This research was supported by the Tuberculosis Drug Accelerator Program of the Bill and Melinda Gates Foundation and the Abby and Howard P. Milstein Program in Chemical Biology of Infectious Disease.

Co-authors of the study include: Dr. Ben Gold, Dr. Maneesh Pingle, Julia Roberts, Dr. Mark Rundell, Dr. Thulasi Warrier, Dr. Aditya Venugopal, Dr. Crystal Darby, Xiuju Jiang, Dr. J. David Warren, Amy Cunningham-Bussel, Poonam Rath, Tamutenda Chidawanyika, Dr. Selin Somersan and Dr. W. Clay Bracken from Weill Cornell; Dr. Steven J. Brickner of S. J. Brickner Consulting; Dr. Ouathek Ouerfelli and Dr. Nilesh Shah from Memorial Sloan–Kettering Cancer Center; Dr. Eric L. Nuermberger from Johns Hopkins Hospital; and Dr. Joseph Fernandez, Ronald Realubit, Dr. J. Fraser Glickman, and Dr. Haiteng Deng from The Rockefeller University.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

Mushroom-Derived Compound Lengthens Survival in Dogs With Cancer, Study Suggests: Yunzhi mushroom

ScienceDaily (Sep. 10, 2012) — Dogs with hemangiosarcoma that were treated with a compound derived from the Coriolus versicolor mushroom had the longest survival times ever reported for dogs with the disease. These promising findings offer hope that the compound may one day offer cancer patients — human and canine alike — a viable alternative or complementary treatment to traditional chemotherapies.

The study was conducted by two University of Pennsylvania School of Veterinary Medicine faculty. Dorothy Cimino Brown is professor and chair of the Department of Clinical Studies and director of the Veterinary Clinical Investigation Center. Jennifer Reetz is an attending radiologist in the Department of Clinical Studies. They published their findings in an open-access article in the journal Evidence-Based Complementary and Alternative Medicine.

The Coriolus versicolor mushroom, known commonly as the Yunzhi mushroom, has been used in traditional Chinese medicine for more than 2,000 years. The compound in the mushroom that is believed to have immune-boosting properties is polysaccharopeptide, or PSP. In the last two decades, some studies have suggested that PSP also has a tumor-fighting effect.

“There have been a series of studies looking at groups of people with cancer,” Cimino Brown said. “The issue with those studies is that they weren’t necessarily measuring what most people would think is the most clinically important result, which is, do people taking PSP live longer?”

To address this critical question, Cimino Brown and Reetz pursued a study in dogs with naturally occurring hemangiosarcoma, an aggressive, invasive cancer that arises from the blood cells and typically affects the spleen. It commonly strikes golden retrievers and German shepherds.

Fifteen dogs that had been diagnosed with hemangiosarcoma participated in the trial. Divided into three groups of five, each group received a different dose — 25, 50 or 100 mg/kg/day — of I’m-Yunity, a formulation of PSP that has been tested for consistency and good manufacturing processes.

The owners were instructed to give their dog capsules of I’m-Yunity, compounded by Penn pharmacists, daily. Each month, the owners brought their dogs to Penn’s Ryan Veterinary Hospital for follow-up visits. There, the researchers took blood samples and conducted ultrasounds to determine the extent that tumors developed or grew and spread in the dogs’ bodies.

Based on the ultimate endpoints — how quickly the tumors progressed and how long the dogs actually lived — the results of the researchers’ trial suggest that the I’m-Yunity was effectively fighting the tumors.

“We were shocked,” Cimino Brown said. “Prior to this, the longest reported median survival time of dogs with hemangiosarcoma of the spleen that underwent no further treatment was 86 days. We had dogs that lived beyond a year with nothing other than this mushroom as treatment.”

There were not statistically significant differences in survival between the three dosage groups, though the median survival time was highest in the 100 mg group, at 199 days, eclipsing the previously reported median survival time.

The results were so surprising, in fact, that the researchers asked Penn Vet pathologists to recheck the dogs’ tissue biopsies to make sure that the dogs really had the disease.

“They reread the samples and said, yes, it’s really hemangiosarcoma,” Cimino Brown said.

Chemotherapy is available for treating hemangiosarcoma, but many owners opt not to pursue that treatment once their dog is diagnosed.

“It doesn’t hugely increase survival, it’s expensive and it means a lot of back and forth to the vet for the dog,” Cimino Brown said. “So you have to figure in quality of life.”

While I’m-Yunity is not inexpensive, if proven effective, it would offer owners a way of extending their pet’s life without regular trips to the vet. As an added benefit, Cimino Brown and Reetz have found no evidence of adverse effects from the PSP treatment.

The researchers are now getting ready to pursue further trials of I’m-Yunity in dogs with hemangiosarcoma to confirm and refine their results. One trial will compare I’m-Yunity to a placebo for those owners who opt not to pursue chemotherapy in their pet and another will compare the compound to standard-of-care chemotherapy.

Depending on those results, veterinarians could eventually prescribe the compound for treating hemangiosarcoma, and perhaps other cancers, in dogs. The company that manufacturers I’m-Yunity may also pursue large-scale clinical trials in humans.

“Although hemangiosarcoma is a very sad and devastating disease,” Cimino Brown said, “in the long term, if we prove that this works, this treatment can be a really nice alternative for owners to have increased quality time with their pet at the end of its life.”

The study was funded by a grant from Chinese Medicine Holdings LTD

Green tea extract ‘eradicates cancer tumours’

Powerful new anti-cancer drugs based on green tea could soon be developed   after scientists found an extract from the beverage could make almost half   of tumours vanish.

By , Medical Correspondent 6:05PM BST 21 Aug 2012

The University of Strathclyde team made 40 per cent of human skin cancer   tumours disappear using the compound, in a laboratory study.

Green tea has long been suspected of having anti-cancer properties and the   extract, called epigallocatechin gallate, has been investigated before.

However, this is the first time researchers have managed to make it effective   at shrinking tumours.

Previous attempts to capitalise on its cancer-fighting properties have failed   because scientists used intravenous drips, which failed to deliver enough of   the extract to the tumours themselves.

So, the Strathclyde team devised a “targeted delivery system”, piggy-backing   the extract on proteins that carry iron molecules, which cancer tumours   Hoover up.

The lab test on one type of human skin cancer showed 40 per cent of tumours   disappeared after a month of treatment, while an additional 30 per cent   shrank.

Dr Christine Dufès, a senior lecturer at the Strathclyde Institute of Pharmacy   and Biomedical Sciences, who led the research, said: “These are very   encouraging results which we hope could pave the way for new and effective   cancer treatments.

“When we used our method, the green tea extract reduced the size of many of   the tumours every day, in some cases removing them altogether.

“By contrast, the extract had no effect at all when it was delivered by other   means, as every one of these tumours continued to grow.

“This research could open doors to new treatments for what is still one of the   biggest killer diseases in many countries.”

She added: “I was expecting good results, but not as strong as these.”

Dr Dufès said population studies had previously indicated that green tea had   anti-cancer properties, and scientists had since identified the active   compound as epigallocatechin gallate.

But the Strathclyde researchers were the first to delivery it in high enough   doses to tumours to have an effect.

She explained: “The problems with this extract is that when it’s administered   intravenously, it goes everywhere in the body, so when it gets to the   tumours it’s too diluted.

“With the targeted delivery system, it’s taken straight to the tumours without   any effect on normal tissue.”

Cancer scientists are increasingly using targeted delivery to improve results,   relying on the many different ‘receptors’ that tumours have for different   biological substances.

In this instance, the scientists used the fact that tumours have receptors for   transferrin, a plasma protein which transports iron through the blood.

The results have been published in the journal Nanomedicine.

The “ultimate objective” was a clinical trial in humans – but Dr Dufès said   that was some way off.

http://www.telegraph.co.uk/health/healthnews/9490733/Green-tea-extract-eradicates-cancer-tumours.html

In the laboratory, green tea proves a powerful medicine against severe sepsis

 

 

MANHASSET, NY – A major component of green tea could prove the perfect elixir for severe sepsis, an abnormal immune system response to a bacterial infection. In a new laboratory study, Haichao Wang, PhD, of The Feinstein Institute for Medical Research, and his colleagues have been studying the therapeutic powers of dozens of Chinese herbal compounds in reversing a fatal immune response that kills 225,000 Americans every year. They found that an ingredient in green tea rescued mice from lethal sepsis – and the findings could pave the way to clinical trials in patients.

 

Scientists worldwide have been stumped by sepsis. Even with the most advanced medical techniques available, half of those who develop sepsis die of the massive assault on the body. Several laboratories at the Feinstein Institute are working on sepsis – both on the basic biological level and in patients.

 

In the latest study, Dr. Wang’s group gave a substance in green tea called EGCG to mice in the throes of severe sepsis. The dose was equivalent to 10 cups in a human. Survival jumped from 53 percent in those who didn’t receive the green tea substance to 82 percent in those who did. “Clinically, even if we could save five percent of patients, that would be huge,” said Dr. Wang. “In this study, we saved 25 percent more animals with the green tea.” He said that the green tea component, EGCG, is readily available.

 

There have been more than 100 papers focusing on this natural substance and its anti-cancer benefits. “This compound prevents HMGB1 from being released by immune cells and it also prevents it from activating immune cells to produce more cytokines,” he said. Cytokines are produced by immune cells and act as weapons to defend the body against invaders. “We are hoping to stimulate future interest in clinical studies,” said Dr. Wang, who worked on the study in collaboration with Wei Li, PhD, Andrew Sama, MD, chairman of emergency medicine at North Shore University Hospital, and other Feinstein investigators.

* Reposted for Filing

St. Jude develops vaccine against potential pandemic influenza virus H5N1 using reverse genetics (Using H1N1, requested repost 2003)

Contact: Bonnie Cameron bonnie.cameron@stjude.org 901-495-4815 St. Jude Children’s Research Hospital

Special modification of reverse genetics created at St. Jude allowed vaccine to be custom-made within weeks of emergence of virus

(MEMPHIS, TENN.–April 2, 2003) Scientists at St. Jude Children’s Research Hospital announced today the development of a vaccine against H5N1, a new lethal influenza virus that triggered the World Health Organization (WHO) to declare a pandemic alert in February 2003.

The virus appeared in birds in Hong Kong late last year and subsequently killed one of two infected people with rapidly progressive pneumonia in the past month.  St. Jude developed the vaccine in only four weeks from the time it received the H5N1 sample from colleagues in Hong Kong.

The announcement comes at a time when a second, as-yet-unidentified virus, has taken several lives around the world. The unknown virus, which causes severe acute respiratory syndrome (SARS), appears to have originated at the same time and in the same place as the new “flu.”

The development of the initial (“seed”) batch of H5N1 vaccine is significant because humans do not have a natural immunity to the virus, according to Robert Webster, Ph.D., a member of the Department of Infectious Diseases at St. Jude. Rather, humans appear to become infected through contact with chickens and other birds. In the past the virus killed only the chickens it infected. But the new variant of H5N1 also killed many kinds of wild birds, which is unusual.

If H5N1 acquires the ability to pass from human to human, there would be the potential for concern similar to that for SARS, according to Webster.

“It’s likely there were two things that prevented the 1997 poultry influenza outbreak in Hong Kong from becoming more deadly–its inability to spread from human to human and the slaughter of more than 1.5 million chickens and other birds in the open-air markets of Hong Kong, which eliminated the source of the virus,” Webster said. “In fact, the sudden appearance of SARS in the same region of the world is just another warning that the large populations of people and poultry in this region are a potential source of viruses.”

Webster is the director of the WHO’s U.S. Collaborating Center at St. Jude that studies animal influenza viruses. It is the only WHO laboratory that focuses on the transmission of animal viruses to humans.

Webster’s laboratory has sent the seed H5N1 vaccine to the Centers for Disease Control in Atlanta and the World Influenza Center in London for further testing, in preparation for initial Phase I and Phase II trials in humans.  “It’s important to move right along with these trials in case the virus begins spreading from person to person,” Webster says. Led by Richard Webby, Ph.D., and Daniel Perez, Ph.D., the St. Jude laboratory team successfully modified a technique called reverse genetics to permit them to develop the H5N1 vaccine so quickly. Using the samples of H5N1 obtained from Hong Kong, Webby mixed two genes from H5N1 with six genes from a second virus (A/PR8/34)[H1N1]). H1N1 is a rapidly growing “master” strain of virus commonly used to make vaccines.

The genes from flu viruses produce proteins called HA and NA, which are on the surface of the virus, in full “view” of the immune system. Webby took the modified gene for HA and the NA from H5N1 and mixed them inside a cell with six genes from H1N1. The HA gene was modified to abolish its ability to cause disease and therefore made it safer to use in the vaccine.

The genes mixed together, and the resulting vaccine virus produced in the cell thus carried HA and NA from H5N1. But because of the alterations to the HA, and the rest of the genes being derived from H1N1, the new virus vaccine cannot cause disease. Rather, it can only stimulate the immune system to respond to H5N1.

“The St. Jude vaccine is like a gun without ammunition,” said Elaine Tuomanen, M.D., director of the St. Jude Department of Infectious Diseases. “The vaccine looks deadly enough for its HA and NA proteins to alert the immune system. But in reality, it’s carrying blanks that can’t cause disease.”

Key to the quick success in developing the vaccine was the on-campus availability of GMP (Good Manufacturing Practices) facilities, which are equivalent in quality to those used by pharmaceutical companies to make biological agents such as vaccines. In addition, the centralization of genetic analysis and other molecular biology work, performed in the Hartwell Center for Bioinformatics and Biotechnology at St. Jude, greatly accelerated the process of building the vaccine components.

“We’ve been lucky twice with H5N1–once in 1997 and once so far during this current outbreak–in not experiencing human-to-human transmission,” Webster says. “But the mixing bowl in Hong Kong is still stirring up new variations of familiar viruses. Although we just made a vaccine against one of that mixing bowl’s nasty viral brews, SARS shows us there’s always another threat down the road.”

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St. Jude Children’s Research Hospital St. Jude Children’s Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital’s work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children’s Research Hospital. Families without insurance are never asked to pay. For more information, please visit http://www.stjude.org.

Long-term methadone treatment can affect nerve cells in brain

Long-term methadone treatment can cause changes in the brain, according to recent studies from the Norwegian Institute of Public Health. The results show that treatment may affect the nerve cells in the brain. The studies follow on from previous studies where methadone was seen to affect cognitive functioning, such as learning and memory.

 

Since it is difficult to perform controlled studies of methadone patients and unethical to attempt in healthy volunteers, rats were used in the studies. Previous research has shown that methadone can affect cognitive functioning in both humans and experimental animals.

Sharp decrease in key signaling molecule

Rats were given a daily dose of methadone for three weeks. Once treatment was completed, brain areas which are central for learning and memory were removed and examined for possible neurobiological changes or damage.
In one study, on the day after the last exposure to methadone, there was a significant reduction (around 70 per cent) in the level of a signal molecule which is important in learning and memory, in both the hippocampus and in the frontal area of the brain. This reduction supports findings from a previous study (Andersen et al., 2011) where impaired attention in rats was found at the same time. At this time, methadone is no longer present in the brain. This indicates that methadone can lead to cellular changes that affect cognitive functioning after the drug has left the body, which may be cause for concern.

No effect on cell generation

The second study, a joint project with Southwestern University in Texas, investigated whether methadone affects the formation of nerve cells in the hippocampus. Previous research has shown that new nerve cells are generated in the hippocampus in both adult humans and rats, and that this formation is probably important for learning and memory. Furthermore, it has been shown that other opiates such as morphine and heroin can inhibit this formation. It was therefore reasonable to assume that methadone, which is also an opiate, would have the same effect.
However, the researchers did not find any change in the generation of new nerve cells after long-term methadone treatment. If the same is true in humans, this is probably more positive for methadone patients than continuing with heroin. However, the researchers do not know what effect methadone has on nerve cells that have previously been exposed to heroin.

Large gaps in knowledge

Since the mid-1960s, methadone has been used to treat heroin addiction. This is considered to be a successful treatment but, despite extensive and prolonged use, little is known about possible side effects. There are large knowledge gaps in this field.
Our studies show that prolonged methadone treatment can affect the nerve cells, and thus behaviour, but the results are not always as expected. Many more pre-clinical and clinical studies are needed to understand methadone’s effect on the brain, how this can result in altered cognitive function, and, if so, how long these changes last. Knowledge of this is important – both for the individual methadone patient and the outcome of treatment.

References

  • Andersen JM, Klykken C, Mørland J. (2012) Long-term methadone treatment reduces phosphorylation of CaMKII in rat brain. J Pharm Pharmacol. 64(6):843-7.
  • Sankararaman A, Masiulis I, Richardson DR, Andersen JM, Mørland J, Eisch AJ. (2012) Methadone does not alter key parameters of adult hippocampal neurogenesis in the heroin-naïve rat. Neurosci Lett. 516(1):99-104.

Broccoli derivative shows promise at stopping even worst cancers

Vegetables that prevent may ultimately cure some cancers

COLLEGE STATION – Broccoli, cabbage, turnips and mustard greens. A dose a day keeps most cancers away.

But for those who develop cancer, the same vegetables may ultimately produce the cure. Research at the Texas Agricultural Experiment Station has led to a patent for a new use for derivatives of DIM, or diindolylmethane, a natural compound derived from certain vegetables, to treat cancer.

“We took advantage of a natural chemical, that research has shown will prevent cancer, and developed several more analogs,” said Dr. Steve Safe, an Experiment Station chemist who has been studying cancer for about 10 years.

Safe’s patent has been picked up by Plantacor, a new biotech company headquartered in College Station, and is expected to enter clinical trials soon in collaboration with M.D. Anderson in Houston.

DIM already is commercially available as a natural supplement for cancer prevention and for treating estrogen-related health issues.

“DIM is a potent substance,” Safe said. “But we made it even more potent against various tumors.”

The first development in this research using chemically altered DIM from broccoli came when the growth of breast cancer cells was inhibited in laboratory studies. Subsequent research showed these compounds also inhibited growth of pancreatic, colon, bladder and ovarian cancer cells in culture, Safe said. Limited trials on lab mice and rats have produced the similar results, he noted. 

Safe said the research began by considering compounds that protect a person from developing cancer. Journal articles of other researchers are stacked on Safe’s expansive desk, extolling the scientific evidence that cruciferous vegetables prevent cancer.

His team wondered whether the similar compounds could be developed for treatment of cancer. They looked at the mechanism – how the compounds block cancer cell growth – and found that they target PPAR gamma, a protein that is highly active in fat cells. However, this same PPAR gamma is over-expressed in many tumors and tumor cells and is a potential target for new drugs, he said.

Safe’s lab chemically modified “natural” DIM to give a series of compounds that target the PPAR gamma and stop the growth of cancer.

“One of the best parts is that this treatment appears to have minimal or no side effects, in the mice trials; it just stops tumor growth,” he said. “The hope now is that the patented chemicals can be developed into useful drugs for clinical trials and then be used for cancer treatment.

“It looks promising in cancer cells and animals at this time. We need future studies in humans to see if it is beneficial with people as well,” he added.

###

Additional photos: http://agnews.tamu.edu/dailynews/stories/HEAL/photos/Dec2403a.htm

A video that can be linked on web sites also is available athttp://agnews.tamu.edu/dailynews/stories/HEAL/video/Dec2403a.mov or http://agnews.tamu.edu/dailynews/stories/HEAL/video/Dec2403a.rm

A related story about growing cruciferous plants in the garden is at http://agnews.tamu.edu/dailynews/stories/HEAL/Dec2403a.htm

*Resposted at request

Drug company funding of drug trials greatly influences outcome – 35x Better Outcome if Funded by the Drug Company

Contact: Wallace Ravven wravven@pubaff.ucsf.edu 415-476-2557 University of California – San Francisco

Drug company funding of drug trials greatly influences outcome

In head-to-head trials of two drugs, the one deemed better appears to depend largely on who is funding the study, according to an analysis of nearly 200 statin-drug comparisons carried out between 1999 and 2005.

UCSF researchers examined 192 published results of trials comparing one cholesterol-lowering statin drug to another, or to a non-statin drug.

Their findings found that two links stood out. If the reported results favored the test drug, the trial was about 20 times more likely to be funded by the maker of the statin rather than the comparison drug company.  Even more striking, they say, if the conclusions or interpretation of the drug trial – which reflect the impressions of the trial investigators — favored the test drug, the trial was about 35 times more likely to be funded by the maker of that drug rather than the comparison drug.

The results of the new analysis are reported in the June 7 online edition of the journal “PLos Medicine.”

“Many people are concerned about the growing proportion of drug trials funded by the drug’s manufacturers,” says Lisa Bero, PhD, UCSF professor of clinical pharmacy and health policy studies. “Results of drug trials affect what drugs are covered by medical plans, and so what drugs physicians will prescribe. If drug trial outcomes are largely determined by who pays for the trial, we don’t really know what the best drug is.” Bero is senior author on the PLoS paper.

The UCSF study examined the links between reported outcomes of the statin trials and many factors, including study design, sample size, thoroughness and type of analysis, as well as funding source. They examined only published randomized controlled trials. The trials involved seven different statins overall, all studied in head-to-head drug comparisons.

The analysis found that about half of the trials were funded by industry, and about a third did not disclose any funding source. Among those declaring industry funding, about one fifth explained the role of the sponsor, such as data analysis, or writing and preparing the manuscript. Trials with no disclosed funding sources were less likely to have conclusions favoring the test drug, compared to trials with industry funding, the researchers report.

The researchers note that a number of factors can result in the drug trial results favoring the trial drug’s sponsor. Drug companies could selectively fund trials on drugs that are likely to produce a statistically significant result, the researchers explain.  This can be accomplished, they say, by selecting non-equivalent doses of drugs for testing.  Also, sponsors may choose not to report results that don’t favor the drugs they sell. Or, they may report positive results in more than one journal, skewing the number of positive articles about their drug.

In addition, almost half of the trials lacked adequate blinding – assuring that study scientists don’t know which drug the patients were taking until the end of the trial. Blinding is considered of paramount importance in clinical trials. The researchers found that those studies with adequate blinding were less likely to report results favoring the test drug.  This finding was independent of who funded the study – in other words, funding source was a stronger predictor of outcome than blinding, but both had independent effects on outcome.

The most important weakness found in most of the trials was a lack of clinical measures of outcome, such as heart attacks or mortality — considered better indicators in trial design than less direct measures such as lipid levels.

“The lack of true clinical outcome measures in these direct head-to-head comparisons of drugs is disappointing because the studies don’t give us the best information we need to choose one statin over another,” Bero says.

The analysis is one of the first large studies examining the influence of funding source on the outcomes of head-to-head drug comparisons, rather than comparing the effectiveness of one statin with no drug at all. The market for statins is competitive, so it is important to have valid information to choose one statin versus another, Bero explained.  For policy makers, the relevant choice is not to select a statin versus a placebo, but to select one statin compared to another.

The study also differed from most other assessments of influences on drug trials by examining 11 different factors, and how they may interact to affect trial results. Most previous studies examined the link of results to one factor alone, such as funding source. But this analysis adjusted for “confounders” – study aspects that can influence the results, such as study design, including randomization, blinding, sample size, even choice of comparison drug in the study.

Inclusion of the confounders still pointed to industry sponsorship as the most influential factor related to positive results and conclusions.

The study examined trials by all funding sources, as well as a subset of studies that were only industry funded.  Favorable results and conclusions were associated not so much with industry sponsorship, but with the specific company that funded the study, Bero points out.

“The data available on choosing between statins based on head-to-head drug comparisons appears to be influenced by financial conflicts of interest,” Bero concludes.  “So decision makers — those choosing drugs for a formulary or insurance plan — should be skeptical about these kinds of trials. We need to know if a newer, more expensive drug is really better compared to older, less expensive drugs.”

###

Co-authors of the study are Peter Bacchetti, PhD, professor of epidemiology, and Kirby Lee, PharmD, assistant professor of clinical pharmacy, both of UCSF; and Fieke Oostvogel, University of Leiden, Netherlands.

The research was funded by a California Tobacco Related Disease Research Program grant.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.

Requested Repost 11 JUN 2007

Vitamin B3 reduces Alzheimer’s symptoms, lesions

Reposting Breakthroughs as current, to respark attention (From 2008)

UC Irvine starts clinical trial on nicotinamide effect in Alzheimer’s patients

Irvine, Calif. — An over-the-counter vitamin in high doses prevented memory loss in mice with Alzheimer’s disease, and UC Irvine scientists now are conducting a clinical trial to determine its effect in humans.

Nicotinamide, a form of vitamin B3, lowered levels of a protein called phosphorylated tau that leads to the development of tangles, one of two brain lesions associated with Alzheimer’s disease. The vitamin also strengthened scaffolding along which information travels in brain cells, helping to keep neurons alive and further preventing symptoms in mice genetically wired to develop Alzheimer’s.

“Nicotinamide has a very robust effect on neurons,” said Kim Green, UCI scientist and lead author of the study. “Nicotinamide prevents loss of cognition in mice with Alzheimer’s disease, and the beauty of it is we already are moving forward with a clinical trial.”

The study appears online Nov. 5 in the Journal of Neuroscience.

Nicotinamide is a water-soluble vitamin sold in health food stores. It generally is safe but can be toxic in very high doses. Clinical trials have shown it benefits people with diabetes complications and has anti-inflammatory properties that may help people with skin conditions.

Nicotinamide belongs to a class of compounds called HDAC inhibitors, which have been shown to protect the central nervous system in rodent models of Parkinson’s and Huntington’s diseases and amyotrophic lateral sclerosis. Clinical trials are underway to learn whether HDAC inhibitors help ALS and Huntington’s patients.

In the nicotinamide study, Green and his colleague, Frank LaFerla, added the vitamin to drinking water fed to mice. They tested the rodents’ short-term and long-term memory over time using water-maze and object-recognition tasks and found that treated Alzheimer’s mice performed at the same level as normal mice, while untreated Alzheimer’s mice experienced memory loss.

The nicotinamide, in fact, slightly enhanced cognitive abilities in normal mice. “This suggests that not only is it good for Alzheimer’s disease, but if normal people take it, some aspects of their memory might improve,” said LaFerla, UCI neurobiology and behavior professor.

Scientists also found that the nicotinamide-treated animals had dramatically lower levels of the tau protein that leads to the Alzheimer’s tangle lesion. The vitamin did not affect levels of the protein beta amyloid, which clumps in the brain to form plaques, the second type of Alzheimer’s lesion.

Nicotinamide, they found, led to an increase in proteins that strengthen microtubules, the scaffolding within brain cells along which information travels. When this scaffolding breaks down, the brain cells can die. Neuronal death leads to dementia experienced by Alzheimer’s patients.

“Microtubules are like highways inside cells. What we’re doing with nicotinamide is making a wider, more stable highway,” Green said. “In Alzheimer’s disease, this highway breaks down. We are preventing that from happening.”

###

LaFerla and Green are affiliated with the Institute for Brain Aging and Dementia, which is conducting the clinical trial with funding from the Alzheimer’s Association.

The institute seeks volunteers who have been diagnosed with Alzheimer’s, are 50 or older, and have a friend or relative who can accompany them to clinic visits and answer questions. Study participants will take the vitamin supplement or a placebo twice daily for 24 weeks, with seven visits to the UCI clinic.

For more information on the clinical trial, contact Beatriz Yanez at 949-824-5733.

UCI scientists Joan Steffan, Hilda Martinez-Coria, Xuemin Sun, Steven Schreiber and Leslie Thompson also worked on the study, which was supported in part by the Alzheimer’s Drug Discovery Foundation and the National Institutes of Health.

About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 27,000 undergraduate and graduate students and nearly 2,000 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.6 billion. For more UCI news, visit www.today.uci.edu.

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UCI maintains an online directory of faculty available as experts to the media. To access, visit www.today.uci.edu/experts.  For UCI breaking news, visit www.zotwire.uci.edu.