Drug Discovery Opinion

Seasonal affective disorder (SAD) is thought to be caused primarily by reduced levels of daylight that occur during the winter months. For more than 20 years, bright white light therapy has been used to treat SAD, although this is not effective for all sufferers. Improved ways to use light therapy focusing on timing and exposure have been described in the November issue of the Harvard Mental Health Letter.

The researchers report that remission from SAD is more likely if light therapy is precisely timed to coincide with the patient’s melatonin rhythms. ‘Dawn stimulation’, in which a preset light turns on before the patient wakes and gradually increases in intensity was found to be effective in a small study group. It was also found that cells in the retina are especially sensitive to blue light, suggesting that this wavelength may have a more powerful effect on circadian rhythms.

Another study, published in Journal of Affective Disorders suggests that a recently discovered mutation in melanopsin, a photo-pigment in the eye, may make SAD patients less sensitive to light. Melanopsin is a light-sensitive protein that is not involved with vision, but is linked to many non-visual responses such as control of circadian rhythms and hormones, and regulation of alertness and sleep. Understanding the basis for reduced responsiveness to light in people who suffer from SAD may help to improve treatments.

Bookmark It

Hide Sites

Melioidosis is an infectious disease caused by the bacterium, Burkholderia pseudomallei which is found in soil and water. The disease is endemic in parts of south east Asia and northern Australia, and affects other species such as goats, sheep and horses as well as humans. The route of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei. The most severe form of the disease is melioidosis septic shock, and mortality remains high despite antibiotic treatment.

A recent report in the journal PLoS elucidates the pathways which confer susceptibility to disease. The research focused on Toll-like receptors (TLRs), which have a central role in the recognition of pathogens and the initiation of the innate immune response. Specifically, the new study looked at the effect of two important adaptor proteins involved in TLR signalling and, using experiments in mice, found that MyD88 but not TRIF is important for host defense against B. pseudomallei.

The authors had previously shown that, although both TLR2 and TLR4 contribute to cellular responsiveness to B. pseudomallei in vitro, only TLR2 knockout mice were protected against B. pseudomallei induced mortality. Together, the data indicate that MyD88 deficiency results in a strongly impaired resistance to melioidosis despite an interruption of harmful TLR2 signalling.

Bookmark It

Hide Sites

It has been estimated that most people lose between 35% and 45% of skeletal muscle in the 6 decades between the ages of 20 and 80. This progressive loss of muscle is known as sarcopenia and, combined with osteoporosis, is responsible for the loss of strength, increasing frailty, and loss of independence seen in many elderly people.

Along with lack of regular exercise, declining levels of growth hormone are thought to be linked to muscle loss. A new study published in Annals of Internal Medicine describes the effect of the orally active ghrelin agonist, MK-677, in healthy adults aged 60-81 years.

Daily dosing with 25mg MK-677 was generally well tolerated and increased levels of growth hormone and insulin-like growth factor-1 to those of healthy young adults. Over 1 year, mean fat-free mass declined in the placebo group, but increased by 20% in the MK-677 treated group. MK-677 induced a transient increase in appetite; body weight increased by 2.7 kg in the MK-677 treated group, but by only 0.8 kg in the placebo treated group. Overall, treatment with MK-677 had a positive effect on three factors that contribute to loss of muscle mass: reduced growth hormone levels, loss of fat-free mass, and inadequate food intake. The increase in lean mass seen with MK-677 therapy did not translate into enhanced strength or function, but the researchers say that “the study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty”.

Bookmark It

Hide Sites

Bacterial resistance to available antibiotics is becoming an increasing problem; methicillin-resistant Staphylococcus aureus (MRSA), which is broadly resistant to penicillins and cephalosporins, is a particular problem in hospital settings.

A recent report in the journal Science describes new compounds effective against MRSA. The compounds target FtsZ, a bacterial homologue of mammalian β-tubulin, which is essential for bacterial cell division. One of the compounds, PC190723, has been shown to have potent in vitro bactericidal activity against staphylococci, including MRSA, and also to cure mice infected with a lethal dose of MRSA.

The binding site for PC190723 has been mapped to a region of FtsZ that is analogous to the paclitaxel -binding site of tubulin. The activity of PC190723 further validates FtsZ as an antibacterial target, and provides the basis for optimisation to provide new treatments for MRSA.

Bookmark It

Hide Sites

Escherichia coli (E.coli) are bacteria commonly found in the gut of both people and animals. Although many types of E. coli are harmless, infection with Shiga-toxigenic strains of E. coli such as E. coli O111 and E. coli O157 can cause bloody diarrhoea. Infection with Shiga-toxigenic E. Coli can also sometimes lead to haemolytic uraemic syndrome, a condition characterised by kidney failure, bleeding and anaemia which can sometimes be fatal. Infection usually results from consuming contaminated food or water or from contact with infected animals or people.

A letter published online on 29 October in the journal Nature, describes how subtilase cytotoxin, an AB5 type toxin produced by Shiga-toxigenic E. coli, preferentially targets cells expressing glycans terminating in N-glycolylneuraminic acid (Neu5Gc). What is remarkable is that humans are not able to produce Neu5Gc, and so should be resistant to the effects of the toxin. It now seems that red meat and dairy products contain high levels of Neu5Gc which is absorbed into human tissues, including the surface of cells lining the intestines and blood vessels. This means that food contaminated with Shiga-toxigenic E. Coli strains can also provide a ready source of the molecular target for the toxin.

The research emphasizes the need to eat only well cooked meat and pasteurized dairy products, since both processes destroy any contaminating bacteria.

Bookmark It

Hide Sites

P2X₇ receptors are cation-permeable, ATP-gated ion channels found on cells of immunological origin, including peripheral macrophages and glial cells in the CNS. Studies in P2X₇ receptor knockout mice have suggested a specific role in inflammatory and neuropathic pain states, and there has been considerable interest in developing P2X₇ receptor-selective antagonists for the treatment of inflammatory conditions and pain.

A report in the Oct 22 early edition of PNAS, however, suggests that direct blocking of P2X₇ receptors may not be the best strategy for reducing pain or lessening neuronal degeneration. The report shows that P2X₇ receptors in satellite cells play a crucial role in maintaining proper P2X₃ receptor expression in dorsal root ganglia. Reducing P2X₇ receptor expression using siRNA, or blocking P2X₇ receptor activity by antagonists, was found to cause up-regulation of P2X₃ receptors, leading to increased activity of sensory neurons responding to painful stimuli and evoking abnormal nociceptive behaviours in rats.

Bookmark It

Hide Sites

Paclitaxel is highly effective for the treatment of cancers of the lung, ovary, breast, and head and neck. The efficacy of paclitaxel in treating malignant gliomas (cancers of the brain and spine) and brain metastases, however, is severely compromised by the relative inability of the drug to cross the blood-brain barrier. Cancers of the brain are very difficult to treat, and the prognosis for patients is generally poor. A new drug delivery system has been developed to increase the effectiveness of paclitaxel in treating brain tumours. Three paclitaxel molecules were joined by a cleavable succinyl ester linkage to a brain peptide vector, Angiopep, to provide a paclitaxel-Angiopep conjugate named ANG1005. ANG1005 enters the brain to a much greater extent than paclitaxel, and leads to a significant increase in survival of mice with intracerebral implantation of U87 MG glioblastoma cells.

Preliminary data have recently been released showing that initial doses of ANG1005 are safe and well tolerated in brain cancer patients. Two parallel phase I/II studies are being carried out, one in patients with recurrent glioblastoma and the other in patients with brain metastases. ANG1005 is administered by intravenous infusion for 1 hour every 21 days. The studies aim to determine safety, tolerability and maximum tolerated dose, as well as giving preliminary pharmacokinetic and efficacy data. Both studies involve around 30 patients and top-line data are expected by the end of 2008.

The Angiopep vector system may provide a way of effectively transporting other drugs, including antibodies, siRNA, peptides and small molecules, across the blood-brain barrier to improve the treatment of a variety of CNS disorders.

Bookmark It

Hide Sites

Multiple sclerosis (MS) is an auto-immune disease in which the myelin sheaths surrounding nerve fibres are destroyed. The disease affects millions of people worldwide and can lead to loss of sight and mobility as well as depression, fatigue and problems with cognition. There is currently no cure, and few truly effective treatments.

A study published in the New England Journal of Medicine describes the results of a randomized, blinded, phase II clinical trial examining the effects of alemtuzumab in patients with previously untreated, early, relapsing-remitting multiple sclerosis. Alemtuzumab is a humanized monoclonal antibody that targets the CD52 receptor on lymphocytes and monocytes and is prescribed for the treatment of chronic lymphocytic leukemia and T-cell lymphoma. Patients with scores of 3.0 or less on the Expanded Disability Status Scale and disease duration of 3 years or less were assigned to receive either subcutaneous interferon β-1a, (44 µg) three times per week, or annual intravenous cycles of alemtuzumab (either 12 mg or 24 mg per day) for 36 months. Interferon β-1a is one of the most effective licensed therapies for similar cases of MS. Alemtuzumab therapy was suspended in September 2005 after immune thrombocytopenic purpura developed in three patients, one of whom died. Treatment with interferon β-1a continued for the full duration of the study.

Alemtuzumab treatment was found to significantly reduce the rate of sustained accumulation of disability by 71% and the annualized rate of relapse by 74% compared with interferon β-1a treatment. Importantly, the mean disability score on a 10-point scale improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the interferon β-1a group. The lesion burden was also reduced in the alemtuzumab group compared with the interferon β-1a group and, from month 12 to month 36, brain volume increased in the alemtuzumab group but decreased in the interferon β-1a group.

The incidence of side effects was somewhat higher in the alemtuzumab group compared with the interferon β-1a group. Adverse events included thyroid disorders (23% vs 3%), immune thrombocytopenic purpura (3% vs 1%) and infections (66% vs 47%). There were no significant differences in outcomes between the 12-mg dose and the 24-mg dose of alemtuzumab.

Bookmark It

Hide Sites

The concept of gaseous molecules as signalling messengers began to emerge in the 1980s with the discovery of endothelial derived relaxing factor, later identified as the gas, nitric oxide. Carbon monoxide and, more recently, hydrogen sulphide have also emerged as important modulators of signal transduction. Hydrogen sulphide is better known as a highly toxic gas with the unforgettable odour of rotten eggs. The beneficial effects of dietary garlic on blood pressure and the vasculature have been shown to be mediated largely by the conversion of garlic-derived polysulphides into hydrogen sulphide by red blood cells. Production of hydrogen sulphide has been attributed to two enzymes in the cysteine biosynthesis pathway, cystathionine β-synthase and cystathionine γ-lyase.

A study published in the journal Science now shows that genetically modified mice lacking cystathionine γ-lyase have reduced levels of hydrogen sulphide in the serum, heart, aorta, and other tissues. The mice showed pronounced hypertension and diminished endothelium-dependent vasorelaxation, providing the first direct evidence that hydrogen sulphide is a physiological vasodilator and regulator of blood pressure.

Hydrogen sulphide has also been shown to cause a drastic reduction in metabolic demand which may provide benefit in the treatment of myocardial ischaemia and reperfusion.

Bookmark It

Hide Sites