Low-Fat or Low-Carb?

Image: Flickr – malias
There has long been debate about the relative merits of a low-carbohydrate diet, as popularised by Atkins, compared to the more traditional low-fat approach to weight loss. A low-carbohydrate diet has also been anecdotally associated with adverse effects on health.

A newly published clinical study, led by researchers at the Center for Obesity Research and Education at Temple University, Philadelphia, has now shown remarkably little difference between the two regimes. The study followed over 300 subjects randomly assigned to either diet over a two year period and, importantly, combined the diets with comprehensive behavioural treatment.

In the low-carb group, carbohydrate intake was limited to 20 g/d for 3 months in the form of low–glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants were allowed to increase their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. The low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d) with less than 30% of the calories derived from fat. For the behavioural treatment, each participant attended group sessions weekly for the first 20 weeks of the study, every other week for the next 20 weeks, and once every other month for the remainder of the study. In each session, participants discussed topics such as goal setting, self-monitoring, and limiting triggers to overeating.

Although attrition was high at 2 years, there were no differences in weight, body composition, or bone mineral density between the groups at any time point. Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol (“good” cholesterol) levels at all time points, increasing by approximately 23% at 2 years, suggesting that a low-carb diet may have some cardiovascular benefit.

Gary Foster, Director of Temple’s Center for Obesity Research and Education and lead author of the study said:

When comparing these two popular weight loss plans, none of the existing research had included a comprehensive, long-term, behavioural support component. This research tells us that people wanting to manage their weight need to be less concerned with which diet they choose, and more concerned with incorporating behavioural changes into their plan.

The study is published in Annals of Internal Medicine.

HCV NS5A Inhibitor Shows Early Promise in Clinic

Crystal structure of the N-terminal zinc-binding domain of HCV NS5A (PDB ID=1ZH1), the proposed target of BMS-790052 (inset)
Hepatitis C virus (HCV) is a leading cause of liver disease and the current ‘standard of care’ treatment, a combination of pegylated interferon-α and ribavirin, is expensive, can cause serious side effects and is only effective for some patients. There are at least 6 known HCV genotypes, with several subtypes and quasispecies within each genotype and these all respond differently to treatment – the combination of pegylated interferon-α and ribavirin is able to clear the virus from about half of patients infected with genotype 1 HCV. In the search for more effective treatments, a number of groups are developing compounds that specifically target HCV. Inhibitors of the viral NS3 serine protease and the NS5B4 RNA-dependent RNA polymerase have already entered the clinic and researchers at Bristol-Myers Squibb have now reported that a compound with a new mechanism of action, BMS-790052, led to dramatic reductions in viral load and produced few side effects in a phase I clinical study. BMS-790052 targets NS5A, an HCV non-structural protein that possesses no enzymatic activity and is thought to regulate viral replication and host cell interactions. The compound, which was identified using a chemical genetics strategy, is active at picomolar concentrations in vitro towards replicons expressing a broad range of HCV genotypes and acts additively to synergistically with interferon and other small molecule antiviral compounds.

The study, which is published in the journal Nature, provides the first clinical evidence that targeting NS5A may be an effective strategy for treating patients who are chronically infected with HCV. Future treatments for HCV infection may involve ‘cocktails’ of drugs that target specific stages in the viral lifecycle, just as HIV infection is managed now, although whether it will be possible to drop interferon from HCV treatment combinations remains to be seen.

Promise on the Horizon for Huntington’s

Image: Flickr – Dominic’s pics
Results from a phase II trial of the experimental drug Dimebon (latrepirdine) in people with Huntington’s disease have provided indications that it may improve cognition. The drug, being developed by Medivation, Inc., is also in Phase III trials for Alzheimer’s disease. In July 2009, Medivation and Pfizer, Inc. launched a Phase III clinical trial (HORIZON) of the drug for Huntington’s disease.

Huntington’s disease is a progressive neurodegenerative disorder that impacts movement, behaviour and cognition, generally resulting in death within 20 years of the disease’s onset. The disease steadily erodes memory and ability to think and learn. Over time, this cognitive impairment contributes to the loss of the ability to work and perform the activities of daily life. There are no treatments current available that effectively alter the course of the disease or improve cognition.

We have previously reported on the potential for Dimebon in Alzheimer’s disease (July 2008, July 2009), where the ability of the drug to stabilise and/or enhance mitochondrial function is believed to be of benefit. Mitochondria are also thought to play a role in the development of Huntington’s disease, suggesting that Dimebon could also have utility in this condition.

Karl Kieburtz, M.D., University of Rochester Medical Center neurologist and lead investigator on the Horizon trial, said:

“This is the first clinical trial that has focused on what is perhaps the most disabling aspect of the disease. While more investigation needs to be done, these results are encouraging and show, for the first time, a statistically significant benefit in terms of improved cognitive function in patients with Huntington’s disease.”

dimebon (latrepirdine) structure
Dimebon (latrepirdine)
In the phase II study, the impact of the drug on 91 patients over a 90 day period was assessed. Half were given the drug and the other half a placebo. The patients were then evaluated using a cognitive tool called the Mini-Mental State Examination. This test – which is used by clinicians to evaluate the stage and severity of dementia and Alzheimer’s disease – consists of questions used to evaluate an individual’s orientation, memory, and ability to follow commands. The researchers found that the drug on average improved the scores of people taking the drug compared to those who received the placebo. Although the treatment had no significant impact on the Unified Huntington’s Disease Rating Scale (UHDRS) or the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog), the results support further investigation in Huntington’s disease.

Results of the study are published in the Archives of Neurology.

New Clinical Trial Platform at Medpedia

red and blue pills
Image: Flickr – Frank Jakobi
Launched in 2009, the Medpedia Project aims to evolve a model for sharing and advancing knowledge in health and medicine. It provides a free online collaborative platform, allowing healthcare professionals to contribute to the growing knowledge base. As well as building a medical encyclopedia, professionals and non-professionals can share information about conditions, treatments, lifestyle choices, etc. Other parts of the Medpedia platform include Medpedia Answers for asking and answering medical and health questions; Medpedia Alerts for displaying real-time medical and health news alerts; and Medpedia News & Analysis for sharing medical news and analysis. The latter includes syndicated articles from blogs such as this one.

Now Medpedia has announced the launch of their clinical trial platform, which updates every 24 hours from data at ClinicalTrials.gov. Search results provide details on a trial’s purpose, who may participate, locations, and contact information from a database of around 80,000 registered trials. Whilst these data are accessible via other sources, including ClinicalTrials.gov itself, the new platform allows content to be “pushed” or fed automatically to appropriate contexts. Trial information can show up alongside a Medpedia article covering the same condition, in a personalized feed of someone interested in that condition, or in a patient community related to that condition.

Dr. David L. Katz MD, MPH, Director of the Prevention Research Center at Yale University School of Medicine, said:

“Clinical trials are among the most important of tools for advancing biomedical knowledge, and improving the human condition. But for this to happen, the trials must successfully recruit their participants, and awareness of the trials must be effectively disseminated. All too often, these requirements are rate limiting. In its customarily user-friendly manner, Medpedia is helping to resolve this problem with its clinical trial finder. This tool should serve doctors and patients alike, helping to get important trials done, and helping to spread the word about important findings as they come in.”

This free resource is available now on Medpedia at www.medpedia.com/clinical-trials. All we need now is an easy way to find trial results!

Antidepressants May Have Benefit in Post-Stroke Therapy

rubic cube
Image: Flickr – Steve Rhodes
Stroke continues to be a major health issue and is a significant cause of death and disability. The recent introduction of clot-dissolving therapies has had a significant impact on survival, although the narrow window of opportunity for successful treatment remains a challenge. For those surviving stroke, the period immediately following is critical for recovery of physical and cognitive abilities. There has therefore been much interest in treatments that will aid the spontaneous recovery of function observed in the first few months following a stroke.

escitalopram structure
Researchers at Carver College of Medicine and College of Public Health (Ms Acion), University of Iowa, Iowa City, have now reported results from a clinical trial with escitalopram, a selective serotonin-reuptake inhibitor (SSRI) antidepressant. The team hypothesised that treatment with antidepressants may be beneficial because of their ability to stimulate production of compounds essential for nerve growth.

In the randomised trial, 43 patients were assigned to take 5 to 10 milligrams of escitalopram daily, 45 to take placebo daily and 41 to participate in a problem-solving therapy program developed for patients with depression. After 12 weeks of treatment, patients taking escitalopram had higher scores on neuropsychological tests assessing overall cognitive function, specifically on those measuring verbal and visual memory. The beneficial effect of escitalopram on cognitive recovery was independent of its effect on depressive symptoms and was not influenced by stroke type or mechanism of ischemic stroke. In addition, escitalopram was well tolerated and the frequency of adverse effects similar to those of patients receiving placebo.

The authors of the study, published in the February issue of Archives of General Psychiatry, suggest that the utility of antidepressant therapy in post-stroke recovery warrants further investigation.

COX-2 Inhibitor Slows Basal Cell Carcinoma

Image: Flickr - RBerteig
Image: Flickr - RBerteig
Researchers in the US have shown that the COX-2 inhibitor, celecoxib, can slow the development of basal cell carcinoma. Although celecoxib was known to inhibit the development of squamous cell carcinoma in mice, and epidemiological studies had suggested a protective role in people, little was known about its efficacy in preventing the more common basal cell carcinoma. In mice with a genetic mutation similar to that which occurs in Gorin syndrome – a genetic condition which predisposes to basal cell carcinoma – deletion of the COX-1 or COX-2 gene reduced the microscopic tumour burden by 75% when the mice were exposed to ionising radiation. Treatment with celecoxib reduced the tumour burden by 35%. The overall size of the tumours was also shown to be doubled in mice engineered to overexpress COX-2.

In a planned 3-year, double-blinded, randomised clinical trial in 60 patients with Gorin syndrome, a trend towards reduced basal cell carcinoma burden was seen in all subjects receiving oral celecoxib (200mg bid). If only patients with less severe disease (less than 15 lesions at study entry) were included in the analysis, celecoxib significantly reduced basal cell carcinoma number and burden: subjects receiving placebo had a 50% increase in burden per year whereas subjects in the celecoxib group had a 20% increase. The study began recruiting in 2001 and was discontinued in 2004 when rofecoxib was withdrawn from the market amidst concerns about an association between long-term treatment with COX-2 inhibitors and increased incidence of heart attack and stroke. At that time, most patients had received celecoxib for 2 years and none had suffered cardiovascular side effects as a result of participation in the trial. Although safety concerns appear to preclude oral dosing, the researchers hope that topical application of celecoxib could provide safer, yet still effective, protection against basal cell carcinoma.

The study is published in the January issue of Cancer Prevention Research.

Epidemiological studies have also linked COX-2 inhibitor use to reduced incidence of other cancers, including colorectal cancer and breast cancer. Inhibition of the COX-2 pathway has been shown to reduce cancer cell proliferation, increase apoptosis and reduce angiogenesis, as well as modifying the immune response.

GlyT-1 Inhibitor Helps Negative Symptoms of Schizophrenia

Image: Flickr - Mark Cummins
Last week, Roche reported data from a 320 patient phase II proof-of-concept study with its first-in-class investigational glycine transporter-1 (GlyT-1) inhibitor, RG1678. Dysfunction of neurotransmission at the NMDA-type glutamate receptor has been implicated in the pathophysiology of schizophrenia, suggesting that enhancement of receptor function may be effective in treating schizophrenia; GlyT-1 inhibitors increase glycine levels and hence NMDA signalling.

Schizophrenia is a chronic, severe and disabling mental health problem that is found all over the world, affecting roughly one per cent of the population. Although men and women are equally affected, men tend to experience symptoms at a slightly earlier age than women, often in their late teens. The symptoms of schizophrenia can be broadly classified as positive, negative or cognitive. Positive symptoms are psychotic behaviours including hallucinations, particularly hearing voices; delusions, or false yet strongly held personal beliefs; and disorders of thinking. Negative symptoms, which are harder to recognise and can be mistaken for depression, include blunted emotions; lack of motivation; an inability to take an interest in, or enjoy, life; and poor social functioning. Cognitive symptoms include problems with working memory and trouble focusing or paying attention.

Antipsychotic medications, which have been available since the mid-1950s and work primarily by suppressing dopamine activity, are the current mainstay of treatment for schizophrenia. These are generally able to reduce hallucinations and delusions and allow patients to function more effectively and appropriately. They are, however, less helpful with negative symptoms such as reduced motivation and emotional expressiveness, which for many patients contribute more to poor quality of life and functional disability than do positive symptoms.

Possible structure of RG1678, taken from this patent.
Possible structure of RG1678, taken from this patent.
When given as an add-on treatment to patients who were stable on antipsychotic therapy and suffered mainly from negative or disorganised thought symptoms, RG1678 was well tolerated at all doses tested and was able to improve negative symptoms and patients’ personal and social performance, reaching statistical significance on primary and secondary endpoints. The company believes that RG1678, which is being co-developed globally with Chugai, has the potential to enable patients to better establish social relationships and participate in functional activities, reducing the burden for caregivers and patients alike.

It May be New – But is It Better?

apothecaryThis is not a question that the FDA normally asks before approving a new drug, but researchers at Stanford University Medical School have called for a change in labelling to include information about how effective the new drug is compared with existing treatments. And, if this information is not available, the researchers believe that the label should clearly say so. With the exception of situations where it would be unethical to withhold active treatment from one study group, as in the case of cancer patients or those with HIV/AIDS, the FDA requires only that a drug should be deemed safe and effective in order to receive marketing approval. In many cases, ‘efficacy’ is determined solely on the basis of superiority to placebo.

Writing in the New England Journal of Medicine, the authors suggest that including comparative efficacy information on labels would allow more informed choices by clinicians, patients and providers and also curb increases in healthcare costs. The authors cite several reasons for the current practice of carrying out placebo-controlled trials; smaller sample size, reduced cost, and lowered risk of generating unexpected unfavourable results (for example, neither active comparator found to be better than placebo). Drug development is an inherently long and risky business and, although some products represent true therapeutic breakthroughs, many offer little benefit over existing therapies. The authors argue that the current regulatory climate provides few incentives to conduct active-comparator trials and favours creation of products that differ minimally from existing therapies.

Thrombin Receptor Antagonist Meets Primary Endpoints

Results of a phase II clinical trial of a novel oral thrombin receptor antagonist (TRA) were published in the March 14th issue of The Lancet.

SCH 530348 met the study’s primary endpoints of safety and tolerability, and caused no increase in major and minor stentThrombolysis in Myocardial Infarction (TIMI)-scale bleeding when given with current standard antiplatelet therapy (aspirin and clopidogrel) for patients undergoing percutaneous coronary intervention (PCI), commonly known as balloon angioplasty, with stenting. Thrombin is a protein with key roles in blood coagulation – as well as activating platelets for aggregation, thrombin is involved in the production of fibrin, a fibrous protein involved in blood clotting and wound healing. Patients with blocked coronary arteries undergoing PCI are at risk of blood clots and are usually treated with anti-clotting drugs such as aspirin or clopidgrel. Although these drugs are effective at preventing blood clots, they increase the risk of bleeding and there is a need for safer drugs to prevent clots during PCI.

The new study, which involved over 1000 patients, was designed to evaluate the safety and efficacy of SCH 530348 in patients undergoing PCI. SCH-530348 acts as an antagonist at the thrombin receptor and reduces thrombin-induced platelet activation but doesn’t interfere with thrombin’s role in fibrin synthesis. Compared to standard-of-care treatment alone, addition of SCH 530348 led to much greater inhibition of thrombin-receptor agonist peptide (TRAP)-induced platelet aggregation in both loading and maintenance doses.

sch 530348 structureSCH 530348 is related to the natural product, himbacine, and has a complex structure with seven stereogenic centres but can be synthesised efficiently using a diastereoselective intramolecular Diels-Alder reaction which generates the core tricyclic structure. SCH 530348 is being developed by Schering-Plough for the prevention and treatment of atherothrombotic events in patients with acute coronary syndrome and in those with prior myocardial infarction or stroke, as well as in patients with existing peripheral arterial disease. SCH 530348 is currently being evaluated in two large-scale multinational, randomized, double-blind, placebo-controlled Phase III clinical trials.

rPEG-PAL is Potential Treatment for PKU

foodPhenylketonuria (PKU) is caused by a genetic deficiency in the enzyme phenylalanine hydroxylase which metabolizes dietary phenylalanine to tyrosine. When phenylalanine accumulates, it is converted to phenyl ketones, including phenylpyruvate and phenylacetate. Excess phenylalanine in the blood also saturates the large neutral amino acid transporter and depletes other large neutral amino acids in the brain, disrupting brain development and leading to mental retardation. Although there is no cure for PKU, if detected early it can be controlled by strictly limiting dietary intake of phenylalanine and supplementing intake of tyrosine. This restrictive diet essentially excludes milk and dairy products, meat, fish, chicken, eggs, beans and nuts which all contain very high levels of phenylalanine. Fruits, vegetables, breads and pastas also contain some phenylalanine and cannot be eaten freely. Soft drinks and foods containing the sweetener aspartame must also be avoided. Most experts believe that the diet should be adhered to throughout life but this can be very difficult, especially during adolescence and early adulthood.

A study published in the December 30th issue of the journal PNAS now suggests that a new treatment may allow people with PKU to eat a much less restricted diet. The study, which was carried out in a mouse model that mimics PKU, evaluated the ability of PEGylated phenylalanine ammonia lyases (PEG-PALs) from four different species to lower phenylalanine levels in both vascular space and brain tissue over a >90 day period. The most effective lyase therapeutically was one produced by the cyanobacterium, Anabaena variabilis. This lyase had the highest stability rather than the highest specific activity, indicating the importance of protein stability for in vivo efficacy. BioMarin Pharmaceutical Inc have begun a phase I clinical trial to assess the safety and tolerability of recombinant PEG-PAL in people with PKU.