Drug Discovery Opinion

Onchoceriasis – also known as river blindness – is the world’s second leading infectious cause of blindness. The disease is caused by the nematode, Onchocerca volvulus, and is transmitted to humans through the bite of a blackfly. Once inside the body, the female worm produces thousands of larval worms (microfilariae) which migrate to the skin and eyes. When the microfilariae die, they cause intense itching and a strong immune response that can destroy nearby tissue, leading eventually to blindness and disfiguring skin lesions. Control programmes have involved the use of larvicides to reduce blackfly populations and the use of ivermectin to treat infected people and limit the spread of disease. Ivermectin is most effective against the larval stage of the worm and is believed to kill the parasites by activating glutamate-gated chloride channels which are specific to invertebrates.

A team led by researchers at the Scripps Institute has now focused on a new way to kill the parasite. The protective outer cuticle of the worms is made of chitin and two classes of enzymes – chitin synthases and chitinases – are known to be critical for chitin formation and remodelling. One chitinase, OvCHT1, is expressed only in the infective third-stage larvae and is believed to be involved in development and host transmission. The team screened a small library of compounds for activity against OvCHT1 and found that closantel was able to inhibit the enzyme. When closantel was tested on cultured third-stage larvae, the compound prevented the larvae from moulting and developing into adult worms. Since the mechanism of action of closantel is completely different to that of ivermectin, it – or other chitinase inhibitors – could potentially be used to treat ivermectin-resistant worms. Closantel is a broad-spectrum anti-parasitic agent currently used in some countries in veterinary medicine.

The study is published in the Proceedings of the National Academy of Sciences.

In 2008, researchers led by a team at Columbia University showed that, by turning on or off production of serotonin in the gut, they could control bone formation. Serotonin signals to cells in the skeleton to slow production of new bone and, by turning off the intestine’s release of serotonin, the team was able to prevent osteoporosis in mice undergoing menopause. The team have now shown that daily oral administration of LP-533401 for 6 weeks is effective both prophylactically and therapeutically against osteoporosis in ovariectomized mice.

LP-533401 inhibits tryptophan hydroxylase-1 (TPH-1), the first enzyme in gut-derived serotonin biosynthesis. TPH-1 is mostly expressed in peripheral tissues such as the gut, whilst TPH-2 is the major isoform in the central nervous system. Although LP-533401 inhibits human TPH-1 and TPH-2 with similar potency (K_i ~ 0.7µM) in vitro, it selectively lowers serotonin levels in the gut whilst leaving levels in the brain unchanged, likely because the compound does not cross the blood-brain barrier. LP-533401 and an ethyl ester pro-drug were originally developed to treat gastrointestinal diseases such as irritable bowel syndrome and to reduce chemotherapy-induced vomiting and nausea.

Although much work will need to be done before trials can be carried out in patients, the present study, which is published in Nature Medicine, demonstrates that pharmacological inhibition of synthesis of gut-derived serotonin could become a new anabolic treatment for osteoporosis. Most osteoporosis drugs only prevent the breakdown of old bone and are not able to stimulate the growth of new bone.

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.”

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.

Chikungunya is a viral disease spread by mosquitoes which causes fever and severe joint pain – the name derives from a verb meaning ‘to become contorted’ and describes the appearance of sufferers bent with pain. Chikungunya is an alphavirus of the family Togaviridae and is usually spread by Aedes aegypti mosquitoes. In 2005-2006, however, a point mutation in one of the viral envelope genes facilitated transmission by Aedes albopictus (tiger mosquito), increasing the risk of outbreaks in areas where the Asian tiger mosquito is present. In the coming years, expansion of the ranges of mosquitoes and changes in insect vectors could increase the spread of Chikungunya virus and other arboviruses.

There is no cure for Chikungunya and treatment is focussed on relieving symptoms. There is also no commercially available vaccine but researchers in the US have now developed an experimental vaccine using non-infectious virus-like particles (VLPs). Selective expression of viral structural proteins produced VLPs that resemble replication-competent alphaviruses and immunization with these VLPs led to neutralizing antibodies against envelope proteins from alternative Chikungunya strains. Rhesus macaques produced high-titre neutralizing antibodies that protected against viremia after high-dose challenge. When the monkey antibodies were transferred into immunodeficient mice, they protected against subsequent lethal viral challenge, indicating a humoral mechanism of protection. VLPs could potentially be developed to offer protection from other alphaviruses such as O’nyong’nyong virus, Ross River virus and Barmah Forest virus. Virus-like particle based-vaccines against human papillomavirus and hepatitis B virus have already been approved by the Food and Drug Administration.

The study is published in the journal Nature Medicine.

The lifecycle of all Plasmodium species is complex and involves a round of replication in host erythrocytes. The clinical manifestations of malaria are linked to this stage in the lifecycle and are associated with rupture of the infected erythrocytes. During this growth phase, the parasite enters the erythrocyte and then releases several hundred effector proteins into the cytoplasm. These key virulence proteins provide a suitable environment for multiplication and allow the parasite to evade the host immune system. Proteins destined for export contain a conserved pentameric motif known as PEXEL and, when this is cleaved in the endoplasmic reticulum, the protein can be transported into the host cell. Two independent studies by scientists in the US and Australia have now shown that the protease responsible for cleaving the PEXEL motif is the aspartyl protease, plasmepsin V. Cleavage reveals an export signal at the amino terminus of the cargo protein which is then transported into the host cell cytoplasm, likely through a channel in the parasite’s outer membrane. Since export of the effector proteins is essential for the erythrocytic stage of the plasmodium life-cycle, drugs that block plasmepsin V should provide an effective treatment for malaria.

Both studies are published in the journal Nature (Australian study; US study).

The presence of multiple redundant and compensatory pathways controlling energy homeostasis has, so far, limited the effectiveness of anti-obesity treatments and suggests that combination therapy may be the best approach for treating the worldwide obesity epidemic. Writing in the journal Cell Metabolism, researchers at Merck have now demonstrated a role for the orphan bombesin receptor subtype 3 (BRS-3) in controlling energy balance.

Using a selective BRS-3 agonist (Bag-1) and antagonist (Bantag-1), the team have established a role for BRS-3 in the regulation of food intake, metabolic rate, and body weight. Intracerebroventricular infusion of the peptide Bantag-1 led to higher food intake and a progressive increase in adipose mass and body weight whereas oral administration of Bag-1 increased metabolic rate and reduced food intake, adipose weight, and body weight. Prolonged high levels of brain receptor occupancy by agonist increased weight loss, suggesting a lack of tachyphylaxis.

As well as suggesting a potential new target for the treatment of obesity, the discovery of selective BRS-3 agonists and antagonists will allow investigation of the mechanisms by which BRS-3 regulates energy metabolism as well as exploration of other aspects of BRS-3 biology.

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!

Although a variety of broad-spectrum antibiotics have been developed, broad-spectrum antiviral agents have proved more difficult to identify. Effective treatments have been developed for individual viruses such as HIV, herpes viruses and influenza viruses – and vaccines have also been developed against papilloma viruses and herpes viruses – but there is a need for small molecules that are able to treat a range of viral infections and could also be used against newly emerging viruses.

Researchers led by a team at UCLA have now identified a compound, LJ-001, that can treat a range of enveloped viruses. The team screened a library of around 30,000 compounds against Nipah virus, a pathogen that was first identified in 1998 and causes severe disease in both animals and humans. Further tests showed that LJ-001 was also effective against other enveloped viruses including Ebola virus, HIV, hepatitis C virus, West Nile virus, Rift Valley fever virus, yellow fever virus and influenza A virus, but had no effect against non-enveloped viruses. The compound interacts with the viral lipid envelope and inhibits viral entry at a step after virus binding but before virus–cell fusion.

Although LJ-001 also binds to cellular membranes, the team believe that its low toxicity can be attributed to the fact that metabolically active cells are able to repair their membranes whilst static viruses are not. LJ-001showed no overt toxicity at effective anti-viral concentrations in either in vitro or in vivo studies, and pretreatment of mice with LJ-001 prevented virus-induced mortality from Ebola and Rift Valley fever viruses.

The study is published in Proceedings of the National Academy of Sciences.

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.

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.

An aortic aneurysm is a bulge in the aorta, the largest blood vessel in the body, which results from weakening of the artery wall. The majority of these occur in the portion of the aorta that passes through the abdomen and are referred to as abdominal aortic aneurysms (AAA). AAA is something of a stealth disease, since it is generally asymptomatic and may only be diagnosed at a routine physical examination or following X-ray. Over time the aneurysm may expand, with an increased risk of rupturing. Unfortunately, the rapid blood loss following aneurysm rupture is frequently fatal and accounts for at least 15,000 deaths in the US annually.

The only treatment for AAA currently available is surgical intervention. Early diagnosis is followed by monitoring the size of the aneurysm until the risk of rupture exceeds the risk of surgery. However, scientists at Providence Heart + Lung Institute at St. Paul’s Hospital and the University of British Columbia (UBC) have now raised the possibility of pharmacological intervention. Using experimental models of AAA, the team have found a role for the protein-degrading enzyme Granzyme B (GMZB).

GMZB is a serine protease expressed by a variety of immune cells and is responsible for destroying unwanted tissue, such as virally-infected cells. This role is supported by the pore-forming protein, perforin, which delivers GMZB to the intracellular compartment. The UBC research has shown that GMZB, which is abundantly expressed in aneurysms from human and animal model AAA, also plays a role in the pathogenesis of AAA. Further, the experimental data suggest that this is a perforin-independent mechanism involving extracellular matrix degradation and subsequent loss of vessel wall integrity. The results suggest that an inhibitor of GMZB may provide a therapeutic option in the treatment of AAA.

The study is published in the American Journal of Pathology.