Dr. Schally, who is also professor of medicine in the Division of Hematology-Oncology at the Sylvester Comprehensive Cancer Center, has been a world leader in the study of hormone-related cancers. Last year, he and his colleagues showed that a splice variant (SV1) of a hormone receptor stimulated breast cancer cells in the laboratory. SV1 is a hormone growth factor receptor which responds to growth hormone-releasing hormone (GHRH). GHRH normally binds to receptors in the pituitary gland, stimulating the release of growth hormone, which induces normal tissue growth.

However, GHRH also acts as a growth factor in various tumors. Dr. Schally and Dr. Barabutis previously demonstrated that GHRH is a growth factor for prostate, lung, breast and other cancers. GHRH antagonists, which Dr. Schally has been developing for 15 years, block the action of GHRH, and thereby strongly inhibit the growth of cancer.

“The influence of GHRH antagonists on oxidative stress” says Dr. Schally, “has not been investigated before and it is critical that we learn their effect on the development and progression of cancer.” In this study, he worked with Dr. Barabutis to test the antioxidant activity of GHRH antagonists on the LNCaP human prostate cancer cell line.

Oxidants, which are harmful, are generated from our own bodies and some external sources through our lives. As we get older, oxidants build up because the body’s defense system isn’t able to protect as well. Oxidative stress, or the accumulation of oxidants in the body, contributes to the process of aging and the development of cancer.

Dr. Schally and Dr. Barabutis tested antagonistic analogues of GHRH, synthesized by Dr. Schally’s team, Martha Zarandi, Ph.D., D.Sc., visiting assistant professor of pathology, Jozsef L. Varga, Ph.D., research associate professor of medicine, and Ren-Zhi Cai, Ph.D., visiting associate professor of pathology. Dr. Schally and Dr. Barabutis discovered that GHRH antagonists inhibited the growth of LNCaP prostate cancer cells by reducing the amount of free radicals in the cells. This is the first demonstration that GHRH antagonists possess antioxidant activity. “This discovery further elucidates the mechanism of action of these compounds that we are developing into a new therapy for cancer” says Dr. Schally, who is a world leader in targeting hormone-related cancers.

Besides providing novel approaches to cancer treatment, this discovery could have other potential therapeutic applications. Increased oxidative stress is involved in the pathogenesis of diabetes and its major complications including retinopathy, neuropathy and nephropathy as well as in development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) and Huntington’s disease. “We think these compounds could be used not only as anti-cancer drugs but also to treat other diseases related to increased oxidative stress” says Dr. Schally.

Next, Dr. Schally and Dr. Barabutis plan to conduct various tests in-vivo on brain tissue of rats and human neural cell lines, to determine if GHRH antagonists have the same antioxidative effects on neural tissues. They will also examine the effects of GHRH antagonists on neuronal cultures in an endeavor to develop a new therapy for neurodegenerative diseases. This project is already leading to extensive national/international collaboration.

Lisa Worley
Office of Communications
University of Miami Miller School of Medicine
http://www.med.miami.edu

University of California, Santa Barbara psychologists Brain J. Spiering and F. Gregory Ashby wanted to pinpoint the best strategies for learning new information. In their study, a group of volunteers were taught a new task in which they had to categorize items. The volunteers were trained to complete the task by one of three methods - starting with easy problems, starting with harder problems then moving on to easier examples or being shown examples in random order.

The results, published in Psychological Science, a journal of the Association for Psychological Science, showed that the effects of the different training methods depended on the type of categories that the participants were learning. When the categories could be easily described (i.e. was the line horizontal or vertical?), all three of the training procedures were equally effective. However, when the categories could not be described easily, starting with the harder problems then moving to easier ones produced the best results. The volunteers in the easy-to-hard group were able to come up with simple rules and category descriptions which worked for the easy problems, but were not applicable to more complicated problems. As a result, these participants ended up doing poorly on the task because they were unable to think abstractly to solve the problem. On the other hand, the participants who began with harder problems very quickly stopped trying to come up ways to describe the categories and thought about the problems in a more abstract way; this strategy helped them to perform well throughout the task.

These findings have important implications for teachers and educators and suggest that materials should be presented to students in a specific order, depending on what is being taught.

Notes:

Psychological Science is ranked among the top 10 general psychology journals for impact by the Institute for Scientific Information. For a copy of the article “Initial Training With Difficult Items Facilitates Information Integration, but Not Rule-Based Category Learning” and access to other Psychological Science research findings, please contact Barbara Isanski

The study, “The Clinical Time-Course of Experimental Autoimmune Uveoretinitis Using Topical Endoscopic Fundal Imaging with Histologic and Cellular Infiltrate Correlation,” was published in the Association for Research in Vision and Ophthalmology journal Investigative Ophthalmology and Visual Science (Invest. Ophthalmol. Vis. Sci. 2008 49: 5458-5465).

It featured the use of Topical Endoscopic Fundal Imaging (TEFI), a technique that uses an endoscope with parallel illumination and observation channels connected to a digital camera. TEFI was developed by Michel Paques, et al (see Invest. Ophthalmol. Vis. Sci. 2007 48: 2769-2774).

David Copland, BSc, MSc, and the team from the University of Bristol’s Academic Unit of Ophthalmology monitored changes in the mice retina over time without distress to the animals or the need for anesthesia.

“TEFI enhances our monitoring of clinical disease in a rapid and non-invasive fashion,” the researchers reported. “It will aid in the design of experimental protocols according to clinical observations.”

The study focused on a condition similar to human posterior uveitis, which can be difficult to monitor using present techniques. TEFI allowed the researchers to see changes to the eye that were previously undetectable.

The researchers wrote that TEFI can help monitor the effects of new ocular therapies, as well as invasive procedures such as intravitreal or sub-retinal injections.

Though the method will be a helpful resource to improving detection, Copland’s team said the technology should be used in conjunction with existing techniques for monitoring the progression of eye diseases.

“Combined TEFI and histological methods enable the observation of clinical features and severity of disease, but information regarding the dynamics, phenotype, function and quantity of cellular traffic through the eye is only provided through detailed analysis of cell populations present in the eye at various stages of disease progression.”

Notes:

ARVO is the largest eye and vision research organization in the world. Members include more than 12,500 eye and vision researchers from over 73 countries. The Association encourages and assists research, training, publication and dissemination of knowledge in vision and ophthalmology. For more information, visit http://www.arvo.org

Many developing regions have experienced high economic growth in recent years. Between 2005 - 2007, developing countries in Asia grew at an annual average rate of nine percent, while African economies grew at six percent. In 2008, however, with the onset of the food and financial crises, that robust growth has tapered off.

“The current crises are likely to have strong and long-lasting effects on emerging economies and the people most in need,” said Joachim von Braun, director general of IFPRI. “The unfolding global financial crisis and economic slowdown have eased some pressure on food prices, but they also significantly reduce the income-earning opportunities for poor people. Even before the world food crisis, the poorest of the poor were struggling to survive. Poor people spend 50 to 70 percent of their income on food and have little capacity to adapt as prices rise and wages for unskilled labor fail to adjust accordingly. The financial crunch lowers the real wages of poor workers, and leads to rising unemployment.

“The financial crunch has also constrained the availability of capital at a time when greater investment in agriculture is urgently needed,” von Braun continued.

IFPRI developed projections to track changes in the production and consumption of major food commodities between 2005 and 2020 if there is a world recession that reduces economic growth between two to three percent (depending on the region). In this scenario, the projections assume that agricultural investment and productivity also decline, in line with the reduced economic growth.

Compared to a baseline scenario in which high economic growth continues and productivity and investments in agriculture are maintained, IFPRI finds that the cumulative effect of reduced growth, investment, and productivity would lead to increases in the prices of basic staples. By 2020, rice prices would rise by 13 percent, wheat by 15 percent, and maize by 27 percent, compared to the baseline scenario, and 16 million more children would be malnourished.

“When economic growth declines, investment in agriculture is typically cut back and that hurts production in the long-run,” said Mark Rosegrant, director of Environment and Production Technology at IFPRI. “However, if developing countries and investors can maintain agricultural productivity and investments under a recession, these dire consequences can be avoided. We need more public spending in R&D, irrigation, and productive services in developing country agriculture, now.”

In an alternative scenario, the research finds that if economic growth is reduced, but investment in agriculture and productivity are maintained, grain would be much more affordable, per capita calorie consumption would be much higher, and there would be significantly fewer malnourished children.

“More effort is needed to successfully resolve the food price crisis, build resistance to future challenges, and reduce poverty and hunger,” von Braun commented. “IFPRI recommends three priorities for action: (1) promote pro-poor agricultural growth, (2) reduce market volatility, and (3) expand social safety nets and child nutrition programs.

“Ultimately, our measure of success should not be defined by the price of food, but by the provision of adequate healthy food for all,” he said.

Notes:

The International Food Policy Research Institute (IFPRI) seeks sustainable solutions for ending hunger and poverty. IFPRI is one of 15 centers supported by the Consultative Group on International Agricultural Research, an alliance of 64 governments, private foundations, and international and regional organizations. Please visit our website

So far, the only way to eliminate the pathogen is to spray plants with fungicides, which can be costly and can contaminate the surrounding environment.

Now Brown University chemist David Cane, working with researchers in France and Spain, has figured out how the fungus’s deadly toxin is made and how it might be disarmed naturally. In a paper published online in ACS Chemical Biology, the scientists have identified the set of genes that manufactures the toxin and in particular the central gene the fungus uses for this synthesis. They also have also shown that shutting off this gene by interrupting the fungus’s DNA completely shuts down toxin production, removing the special weapon the mold uses to kill and invade target plant cells.

“It’s a big step to being able to disarm this toxin naturally through a combination of DNA sequencing and chemistry,” said Cane, the Vernon K. Krieble Professor of Chemistry and professor of biochemistry, one of three primary authors of the paper.

The researchers, led by French scientist and paper co-author Muriel Viaud, started by determining the complete DNA sequence for Botrytis cinerea. Working with Spanish organic chemist and paper co-author Isidro Collado, the scientists focused on the chemical agent - botrydial - that gray mold uses to overwhelm host plants.

From among the roughly 9,000 genes present in gray mold, the researchers identified a cluster of five genes that is responsible for production of botrydial. They then sought to learn how this cluster manufactures the chemical agent and which of the genes was the mastermind in the production.

The culprit is an enzyme called a sesquiterpene cyclase, Cane’s laboratory found.

“The metabolic pathways for creating organic compounds typically involve gene clusters, like a package,” Cane explained. “One great advantage to our investigation is that if you find one, you look to the left or to the right, and you find the others.”

In laboratory tests, Cane and the team introduced a mutant gene that deleted the sesquiterpene cyclase, which completely abolished production of the toxin.

“This means that if you can inhibit the enzyme from this pathway, you can eliminate this toxin,” Cane said.

The team now is working on a similar procedure to tackle a strain of Botrytis cinerea that is able to produce both botrydial and a second toxin that it uses to attack its plant targets

Pseudoephedrine has been associated with deaths and adverse events in young children. However, the absolute risks of pediatric pseudoephedrine use are difficult to determine because the number of children exposed to this medication and typical patterns of use are unknown. In addition, use may be changing because of the Combat Methamphetamine Act of 2005, a law which limited availability of pseudoephedrine-containing products.

To define the frequency and patterns of use, the researchers analyzed data from 1999 through 2006 on pseudoephedrine use among 4,267 children, aged 0 to 17 years, who were enrolled in the Slone Survey, a national random-digit-dial telephone survey of medication use in the U.S.

The researchers found 4.9 percent of children took pseudoephedrine in a given week. Use was highest in children under two years of age (8.1 percent). Sixteen children (7.5 percent of users) took more than one pseudoephedrine-containing product within the same week, including six children under two years old. Of the pseudoephedrine products used, most were multiple-ingredient liquids (58.9 percent) and multiple-ingredient tablets (24.7 percent). Fifty-two subjects (25 percent of users) took pseudoephedrine for longer than one week, including seven children under two years of age. Perhaps reflecting reduced availability, use in 2006 (2.9 percent) was significantly lower than in 1999-2005 (5.2 percent).

Concerning patterns of use identified in the study include taking more than one pseudoephedrine-containing product at the same time and using pseudoephedrine for long periods of time. Pediatric pseudoephedrine use appears to be declining since the institution of the 2005 Combat Methamphetamine Act. “Pseudoephedrine exposure, mostly in the form of multiple-ingredient products, is common among U.S. children and needs to be monitored closely because of the potential for this medication to cause harm, particularly to children under two” said lead author Louis Vernacchio, MD, MSc, an assistant professor of epidemiology and pediatrics at Boston University School of Medicine

Men with advanced prostate cancer may receive initially effective treatment with hormonal therapies to which the majority of prostate cancers can later become resistant. This is known as hormone refractory, androgen resistant or castration (medical or surgical) resistant prostate cancer. The Phase II EPOC (Endothelin A Proof Of Concept) data published today show that HRPC patients who were asymptomatic or mildly symptomatic for pain and received ZD4054 10mg once-daily experienced a 45% reduction in the risk of death compared to placebo (HR 0.55; 80% CI 0.41, 0.73). [1]

The Phase II EPOC data show an increase in overall survival (OS) (the secondary endpoint of the study) though they do not show a statistically significant difference in Progression-Free Survival (PFS) between ZD4054 and placebo treatment arms (the primary endpoint of the study). [1]

Nick James, Professor of Clinical Oncology, Institute for Cancer Studies, Birmingham, UK, and principal investigator of the EPOC study said: “Currently, the only licensed treatment option for metastatic patients shown to improve survival in men with HRPC is docetaxel chemotherapy. These data demonstrate that ZD4054 may offer hope to men with the most severe form of prostate cancer who no longer respond to hormone therapies.”

To further evaluate the potential of ZD4054 in men with HRPC, a Phase III trial programme ENTHUSE (ENDOTHELIN A USE) is underway. The ENTHUSE programme consists of three studies. The first of these trials is aimed at investigating the efficacy of ZD4054 in metastatic HRPC, while the second will look at its role in non-metastatic HRPC patients. A third trial will study ZD4054 in combination with docetaxel chemotherapy (Taxotere TM) for the treatment of metastatic HRPC.

EPOC Phase II Clinical findings

Results from the EPOC study, which originally presented at the 14th European Congress of Clinical Oncology (ECCO, 23-27 September, Barcelona) in which all men received study treatment in addition to best supportive care (palliative measures that help control cancer symptoms and treatment side effects), suggest that patients who received ZD4054 10mg once-daily experienced a 45 per cent reduction in the risk of death compared to placebo (HR 0.55; 80% CI 0.41, 0.73). Patients who received ZD4054 15mg once-daily experienced a 35% reduction in risk of death (HR 0.65; 80% CI 0.49, 0.86), translating into an improved median OS of 23.5 months compared with 17.3 months in the placebo arm. [1]

The primary endpoint of PFS data did not show a statistically significant difference between ZD4054 and placebo treatment arms. PFS in this study was measured through clinical progression or radiological evidence of disease worsening, or worsening of disease-related pain. However, patients with metastatic HRPC can typically have multiple bone metastases, making assessments of further changes in bone metastases difficult.

Professor Nick James commented: “There is no established definition for progression in HRPC and as such it can be difficult to measure accurately; however, overall survival represents a clear endpoint in this disease stage.”

ZD4054 taken as an oral tablet was seen to be convenient and well tolerated, with a side-effect profile consistent with that seen in previous ZD4054 studies, which included headache, oedema and nasal congestion. [1] Further assessment of the safety of ZD4054 will continue throughout the ENTHUSE clinical trials.

More information on the ZD4054 ENTHUSE programme in the UK can be found on . http://www.astrazenecaclinicaltrials.com/ and http://astrazeneca.citeline.com.

Mode of action - specific ETA receptor antagonism

ZD4054 works by specifically blocking the ETA receptor. This may lead to the inhibition of multiple processes that drive tumour growth and spread, including tumour cell proliferation, tumour cell survival, angiogenesis and the formation of bone metastases. It does so without blocking the ETB receptor, which may provide beneficial biological effects in terms of encouraging apoptosis, the death of unhealthy cells.[2]

About the EPOC study

-The EPOC study is a Phase II, randomised, double-blind, placebo-controlled study of ZD4054

-A total of 312 pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer were enrolled in the study

-Participants were from Australia, Belgium, Canada, Denmark, Finland, France, Indonesia, Netherlands, Norway, Poland, Sweden, Switzerland, UK and the USA

About Prostate Cancer in the UK

Prostate cancer is the most common cancer to be found in elderly men in the UK. Over 34,000 men in the UK alone are diagnosed with prostate cancer each year and prostate cancer has overtaken lung cancer to become the most common cancer for men in the UK. Prostate cancer is the second biggest cause of death from cancer in men in the UK with around 10,000 deaths each year. More than 60 percent of cases occur in men over 70 years old and the largest number of cases is diagnosed in those aged 70-79. [3]

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world’s leading pharmaceutical companies with healthcare sales of $26.475 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4 Good Index.

References

[1] James ND, et al. Safety and Efficacy of the Specific Endothelin-A Receptor Antagonist ZD4054 in Patients with Hormone-Resistant Prostate Cancer, Eur Urol (2008), doi:10.1016/j.eururo.2008.11.002

[2] Morris, C.D. et al. Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. British Journal of Cancer. 2005: 92

[3] Cancer Research UK. http://info.cancerresearchuk.org/cancerstats/types/prostate/ accessed November 200

In the past decades, asthma rates have increased dramatically, paralleling an increase in cesarean section births. The proportion of these procedures has increased from 5% in the 1970s to more than 30% in 2000. However, studies examining the potential link between asthma and cesarean delivery have been inconclusive.

About 3,000 children were followed until the age of 8 years with regard to respiratory health, and this data was compared to the methods of birth. At age 8, 12.4% (362) had been diagnosed with asthma and thus prescribed inhaled steroids. While only 8.5% (247) of the children were born by cesarean, but these children were nearly 80% more likely to have a diagnosis of asthma, in comparison to the children delivered naturally. This association between cesarean section and asthma was strengthened by the presence of two allergic parents, indicating a hereditary predisposition to asthma. In children with two allergic parents, cesarean-born children were 200% times more likely to be asthmatic, in comparison with children without allergic parents, who were 36% more likely.

The authors suggest that this association may be linked to the development of the immune system at birth. That is, a cesarean may prevent the baby from being exposed to certain microbes earlier in life. They also suggest that their findings are quite robust given the sample size, long period of followup, and the strict definition of asthma.

They say: “The increased rate of caesarean section is partly due to maternal demand without medical reason.” The authors continue: “In this situation the mother should be informed of the risk of asthma for her child, especially when the parents have a history of allergy or asthma.”

Asthma at 8 years of age in children born by caesarean section
C Roduit, S Scholtens, J C de Jongste, A H Wijga, J Gerritsen, DS Postma, B Brunekreef, MO Hoekstra, R Aalberse, H A Smit
Online First Thorax 2008;
doi 10.1136/thx.2008.100875

As the most common congenital birth defect in male children, cryptorchidism may occur in 2-4% of all full-term male births. However, its cause is largely unknown, and the authors point out that, “although cryptorchidism is often considered a mild malformation, it can seriously affect men’s health, representing the best characterized risk factor for infertility and testicular cancer in adulthood.”

To investigate the potential cause of cryptorchidism, Alberto Ferlin, Ph.D., of the University of Padova, Italy, and colleagues performed a case-control study evaluating the frequency of genetic alterations in 600 male children with and 300 male children without the disease. the children were followed up for 2 to 3 years for persistence of the malformation.

In the genetic examination, abnormalities were low even in the group of cases (2.8%), but statistically significantly higher than those of the controls. This was true in for children with persistent cryptochidism (5.3%) and bilateral cryptorchidism (8.3%) in which both testes fail to descend at once. The odds of a genetic alteration in children with persistent cryptorchidism was 17 times that of controls; the odds of a genetic alteration in children with bilateral persistent cryptorchidism was 27 times that of controls.

The types of genetic mutation were varied. In the small proportion of cases with genetic abnormalities, the most common was Klinefelter syndrome, the most common genetic cause of male infertility. Additionally, several cases had mutations in the INSL3 receptor gene, which affects descent of the testes. Genetic alterations were found exclusively in children with normal weights and gestational ages.

The authors point out the exclusive presence of Klinefelter syndrome: “We found that chromosomal aberrations represent the most frequent genetic alteration in participants with isolated cryptorchidism, particularly in those with persistent cryptorchidism (1.6 percent in the unilateral forms and 4.2 percent in the bilateral forms), and that chromosomal alterations were exclusively represented by Klinefelter syndrome.”

They continue, summarizing the results of the study: “In this study, we found genetic alterations in a small percentage of boys with cryptorchidism. We found a significant association between bilateral and persistent cryptorchidism and genetic alterations, including mutations in the INSL3 receptor gene and Klinefelter syndrome. Genetic alterations were not found in participants with low birth weight or low gestational age …”

However, the authors finally caution against strong generalization of these results, noting the limitations of their study. “Our findings have the limitations of a case-control study, and the main limitation is the small number of genetic abnormalities found. Future studies involving a higher number of participants are necessary to confirm our findings. This study should therefore be considered preliminary, and strong conclusions about association cannot be drawn,” they write.

The study was the work of Dr Aaron S Kesselheim, of Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues, and is published online in the 3rd December issue of the Journal of the American Medical Association, JAMA.

When two drugs are bioequivalent it means that to all intents and purposes after they have been given to the patient they are biologically equivalent to each other, for example the composition, rate and extent to which their active ingredients are present at the target site inside the body are so similar that you can’t tell the difference between them.

And yet there appears to be a general opinion among doctors and patients that despite the fact generic drugs are bioequivalent to brand name drugs, the brand names are clinically superior. But generic drugs are much cheaper, so Kesselheim and colleagues decided to investigate the available clinical evidence on generics versus brand names and the views of editorial writers on the subject with respect to cardiovascular treatments.

For the study, the researchers systematically searched for peer reviewed studies published between 1984 and 2008 and listed in a number of well known databases, including MEDLINE, EMBASE, and International Pharmaceutical Abstracts.

They selected those studies that compared the clinical effectiveness and safety of generic versus brand name cardiovascular drugs. In a separate exercise they also identified editorials that wrote about substituting brand names with generic versions.

Kesselheim and colleagues then used techniques commonly used in research that reviews other studies, whereby the design, setting, participants, results and funding of each study is extracted and put through a test that assesses the quality of the trial, whilst the results are pooled in such a way that they can then be viewed as if they had come from one giant trial (meta-analysis).

As a separate exercise they reviewed the editorials and classified them as negative, positive or neutral, depending on the authors’ view on generic substitution.

They found a total of 47 clinical trials covering 9 subclasses of cardiovascular drugs, and established the following results:

* 38 of the 47 (81 per cent) trials were randomized controlled trials (considered to be higher quality).

* For beta-blockers, 7 out of 7 randomized controlled trials (100 per cent) found generics to be clinically equivalent to brand names.

* For diuretics, the figure was 10 out of 11 (91 per cent).

* For calcium channel blockers it was 5 out of 7 (71 per cent).

* For antiplatelet agents it was 3 of 3 (100 per cent).

* For statins it was 2 out of 2 (100 per cent).

* For angiotensin-converting enzyme inhibitors it was 1 out of 1 (100 per cent).

* And for alpha-blockers, 1 out 1 randomized controlled trial (100 per cent) found generics to be clinically equivalent to brand names.

* In drugs that have a narrow therapeutic index (where you have to be really careful to give the right dose so as not to injure the patient), clinical equivalence was found in 1 out of 1 randomized controlled trial (100 per cent) for class 1 antiarrhythmic agents, and in 5 out of 5 (100 per cent) for warfarin.

* Pooling the results of all the trials gave a total of 837 participants and an aggregate effect size of -0.03 (95 per cent confidence interval of -0.15 to 0.08), meaning that across the studies as a whole, there was no statistically significant evidence that brand names were superior to generic drugs.

Reviewing the material from 43 editorials, the researchers found that:

* 23 of them (53 per cent), expressed a negative view about whether generic drugs could replace or be used instead of brand names.

* This compared with 12 (28 per cent) that encouraged substitution.

* The other 8 editorials did not reach a conclusion on interchangeability.

* Among editorials covering narrow therapeutic index drugs, 12 (67 per cent) expressed a negative view compared with 4 (22 per cent) in favour generic substitution.

Kesselheim and colleagues concluded that:

“Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.”

They wrote that the rising cost of prescription drugs is a critical policy issue: it strains the budgets of patients and insurance providers, and leads to poorer health as it works against helping everyone to make sure patients can complete their medication schedules.

“The primary drivers of elevated drug costs are brand-name drugs, which are sold at high prices during a period of patent protection and market exclusivity after approval by the Food and Drug Administration (FDA),” they added.

The idea of generics is to help people afford drugs, and these become available after the brand names have had their period of being the only ones on the market, the so called exclusivity period. Many doctors and payers encourage this.

However, some patients and doctors have been concerned that the generic versions may not be as effective. As Kesselheim and colleagues explained:

“Brand-name manufacturers have suggested that generic drugs may be less effective and safe than their brand-name counterparts. Anecdotes have appeared in the lay press raising doubts about the efficacy and safety of certain generic drugs.”

Kesselheim and colleagues suggested that one explanation for the discordance between the clinical evidence and the opinion expressed by experts in the editorials could be that:

“Commentaries may be more likely to highlight physicians’ concerns based on anecdotal experience or other nonclinical trial settings.”

Another explanation they suggested was that the:

“Conclusions may be skewed by financial relationships of editorialists with brand-name pharmaceutical companies, which are not always disclosed.”

Nearly half the trials (23 out of 47) and nearly all the editorials and commentaries they reviewed did not reveal where the funding came from, noted Kesselheim and colleagues, who also wrote that:

“We identified numerous studies that evaluated differences in clinical outcomes with generic and brand-name medications. Our results suggest that it is reasonable for physicians and patients to rely on FDA bioequivalence rating as a proxy for clinical equivalence among a number of important cardiovascular drugs, even in higher-risk contexts such as the NTI drug warfarin.”

“These findings also support the use of formulary designs aimed at stimulating appropriate generic drug use. To limit unfounded distrust of generic medications, popular media and scientific journals could choose to be more selective about publishing perspective pieces based on anecdotal evidence of diminished clinical efficacy or greater risk of adverse effects with generic medications. Such publications may enhance barriers to appropriate generic drug use that increase unnecessary spending without improving clinical outcomes,” they added.

“Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease: A Systematic Review and Meta- analysis.”
Aaron S. Kesselheim; Alexander S. Misono; Joy L. Lee; Margaret R. Stedman; M. Alan Brookhart; Niteesh K. Choudhry; William H. Shrank.
JAMA. Vol 300, No 21, pp 2514-2526, December 3, 2008