Diabetic retinopathy – damage to blood vessels in the retina – is the most common diabetic eye disease and is a leading cause of vision loss and blindness in those of working age. Increased retinal vascular permeability is characteristic of diabetic retinopathy and can lead to diabetic macular oedema. Hypertension is a major risk factor for diabetic retinopathy and contributes to a variety of other retinal diseases in the absence of diabetes mellitus. Involvement of both the renin-angiotensin system and the kallikrein-kinin system in diabetic retinopathy has been suggested, and there is evidence indicating that angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce the risk of disease progression, both in the presence and absence of hypertension. Using a specific inhibitor, ASP-440, scientists from the Joslin Diabetes Center and ActiveSite Pharmaceuticals have now demonstrated that inhibition of the protease, plasma kallikrein, may provide a new therapeutic approach for the treatment of diabetic retinopathy.

Plasma kallikrein levels were found to be increased in the retina of rats with hypertension induced by angiotensin II, and the animals also showed increased retinal vascular permeability. Treatment with the angiotensin II receptor antagonist, candesartan, reduced retinal vascular permeability stimulated by angiotensin II by almost 80%. Continuous systemic administration of ASP-440 via a subcutaneous pump decreased hypertension-induced retinal vascular permeability by a similar amount, suggesting that systemic inhibition of plasma kallikrein may provide a new approach for treating blood-retinal barrier dysfunction caused by high blood pressure.

The study is published in full in the February 1^st edition of the journal Hypertension.

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Myriad Pharmaceuticals recently announced the acquisition, from Panacos Pharmaceuticals, of bevirimat, a novel HIV-1 maturation inhibitor.

Bevirimat is a derivative of betulinic acid, a triterpenoid isolated from the leaves of the Chinese herb, Syzygium claviflorum, which was found to have potent inhibitory activity against HIV-1. Bevirimat shows potent in vitro activity against a broad range of HIV-1 strains, including isolates that are resistant to drugs currently approved for the treatment of HIV-1: protease inhibitor-resistant HIV-1 strains appear to be especially sensitive to bevirimat. Like HIV-1 protease inhibitors, bevirimat interferes with proteolytic processing of the newly translated viral polyprotein, Gag. One of the last steps in viral maturation is cleavage at the capsid-SP1 junction, and bevirimat is believed to prevent cleavage by binding to the Gag polyprotein at this site. Release of SP1 is essential for proper capsid condensation and function: preventing release of SP1 results in non-infectious virions containing abnormal, unstable cores. Bevirimat-resistant strains of HIV-1 can be generated in vitro, but arise more slowly in strains resistant to protease inhibitors than in wild-type strains. Mutations conferring resistance to bevirimat occur at or near the capsid-SP1 cleavage site.

Clinical studies have shown that bevirimat is well tolerated and have demonstrated significant and clinically relevant reductions in viral load in a subset of patients. Studies have suggested that clinical resistance to bevirimat does not develop rapidly, possibly because of selective pressure to maintain the highly conserved capsid-SP1 cleavage sequence. There may also be a greater hurdle to development of bevirimat resistance in strains of virus that are resistant to protease inhibitors, suggesting that patients with such viruses may be especially likely to benefit from treatment with maturation inhibitors such as bevirimat.

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Blockade of the transient receptor potential vanilloid channel, TRPV1, which is widely expressed in both central and peripheral nervous tissue, has been considered by many groups to be an attractive approach to pain relief. The receptor is activated by a number of endogenous and exogenous stimuli including the endocannabinoid, anandamide; capsaicin, the ‘hot’ component of chilli peppers; low pH; and heat. The sensitivity of TRPV1 to heat has suggested a role in maintenance of body temperature, and clinical trials of at least one TRPV1 antagonist were stopped because of unacceptable levels of hyperthermia.

A new study published in the January 19^th Online First edition of the journal Cancer Research now suggests a link between TRPV1 and the development of cancer. The authors show that TRPV1 interacts with epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is overexpressed in many human epithelial cancers. Interaction of TRPV1 with EGFR was found to recruit the ubiquitin ligase, Cbl, leading to ubiquitylation and lysosomal degradation of EGFR.

In a further set of experiments, the authors showed that mouse epidermal cells over-expressing TRPV1 were significantly less likely to undergo malignant transformation when stimulated with EGFR, either with or without a tumour promoter. TRPV1 was next shown to be expressed in the skin of wild type mice but not TRPV1 knock-out mice; the knock-out mice also had elevated levels of EGFR protein in the skin. When exposed to the tumour initiator, 7,12-dimethylbenz[a]anthracene (DMBA) and the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), almost all TRPV1 knock-out mice developed larger and more numerous tumours than age- and sex-matched wild type animals. Pretreatment of all mice with the EGFR antagonist, AG1478, significantly suppressed tumour formation, but the effect was much greater in the TRPV1 knock-out animals.

The authors suggest that channels such as TRPV1 are able have a direct effect which is independent of their function as ion channels; the TRP family of proteins seems to show different levels of expression in cancer tissues, although whether these changes are cause or effect is not known.

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The circadian clock regulates a wide range of physiological activities and, for many years, it has been suggested that the time of day at which cancer patients receive chemotherapy or radiation therapy can influence both the effectiveness and side-effects of the treatment. A lack of understanding of the complex mechanisms underlying this effect – together with logistical considerations – has, however, prevented timing from becoming a major determinant in most treatment centres. A study from scientists at the University of North Carolina at Chapel Hill has now identified a biochemical mechanism which may explain circadian sensitivity to the anti-cancer drug cisplatin.

The results, published in the 21^st January Early Edition of PNAS, suggest that treatment with chemotherapy may be most effective at times of the day when levels of one the DNA repair enzymes are at their lowest. The enzyme is xeroderma pigmentosum A (XPA), the component of the nucleotide excision repair system that repairs bulky lesions in DNA such as those caused by cisplatin. The study showed that the activity of XPA in brain tissue from mice followed a circadian rhythm with peak levels some 5-10-fold higher than the lowest levels. It is not yet known whether the circadian levels of XPA in tumour cells or other cells of the body follow the same oscillations as those in the brain, but the study clearly suggests that circadian changes in levels of XPA should be taken into account when designing chemotherapy regimens. Studies on the effect of timing on treatment with cisplatin in rodents and human patients have so far focussed largely on reducing toxicity, and results are complicated by the fact that rodents are nocturnal. Cisplatin was generally found to be most toxic in both rodents and humans when administered soon after awakening.

The present study could also have implications for the prevention of cancer, for example by allowing people to use extra protection against the damaging effects of ultraviolet irradiation from the sun at those times of day when levels of DNA repair enzyme in the skin are at their lowest.

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Erythropoietic protoporphyria is a rare inherited condition that usually first becomes apparent in early childhood. A deficiency in the enzyme ferrochelatase causes a build-up of protoporphyrin in the skin, leading to extreme photosensitivity. Exposure to the sun – and some types of artificial light – causes an uncomfortable or painful burning sensation and the skin may become red, swollen and blistered. There is no cure for the disease and, with sun barriers and creams offering little protection against the wavelengths that cause photosensitivity, sufferers are generally advised to avoid sunlight and wear closely woven clothing to minimise exposure. A new treatment may, however, be on the way as Clinuvel has recently announced positive interim results of a phase III trial of its photoprotective drug, afamelanotide which stimulates the body’s production of melanin.

Afamelanotide is administered beneath the skin as a biodegradable implant approximately the size of a grain of rice. The interim results are based on 12 month data for 14 Swiss patients and showed that the maximum severity of phototoxic reactions for patients on the drug was significantly reduced compared with those in the placebo group. Full results for the full cohort of 101 European and Australian patients are expected in the fourth quarter of 2009. The Swiss test was carried out at a high altitude where ultraviolet irradiation is more intense and the drug provided benefit in the spring and summer months, when symptoms of the disease are normally most severe. Increased pigmentation of the skin appeared a few days after administration of afamelanotide and lasted for up to two months. Exceptionally, at the end of the study, all 14 participants requested continuation of the drug for photoprotection for the next 12 months. Afamelanotide potentially offers people with erythropoietic protoporphyria an opportunity to lead more normal lives where they don’t have to avoid the sun or stay indoors.

Another group who may benefit from treatment are organ transplant recipients for whom daily exposure to ultraviolet irradiation poses an increased risk of skin cancers because of their life-long reliance on immune-suppressing drugs. Clinuvel hopes to file for initial approval in Europe in the next 18 months.

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In men, the second (index) finger tends to be shorter (updated – thanks to Petr for pointing out the error) than the fourth (ring) finger whereas, in women, the second finger is most often the same size or slightly longer than the fourth. Studies have suggested that the 2D:4D digit ratio (ratio of length of index finger to ring finger) is influenced by prenatal exposure to androgen although ethnic origins also appear to have an effect, with higher digit ratios in more northerly populations. Many authors have suggested correlations between digit ratio and health or personality traits as well as sporting prowess, and a study published in the January 13^th issue of the journal PNAS now links 2D:4D ratio with some types of trading skills.

The researchers measured 2D:4D ratios in a group of male traders from the City of London engaged in “noise” or “high-frequency” trading. They found that 2D:4D not only predicted the traders’ long-term profitability, but also the number of years they remained in the business. Looking only at experienced traders, the study found that the traders with lowest 2D:4D ratios made up to six times more money over a 20 month period than those with higher ratios. The researchers suggest that prenatal exposure to testosterone, which increases a person’s sensitivity to the effects of the hormone later in life, may be linked to attributes such as confidence, risk-taking ability, and quick reactions which are important for this type of competitive, quick-fire trading.

In 2007, the researchers published a report, also in PNAS, showing that a trader’s morning testosterone level predicts his day’s profitability. The newer study suggests that the lower those traders’ 2D:4D ratios, the bigger their swing in profits between the high- and low-testosterone days. Although a testosterone rush may give an edge in situations where traders have to make snap decisions, it may not be what is needed for long-term trading.

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play essential roles in the regulation of cellular differentiation, development and metabolism. Since the introduction of the thiazolidinedione class of PPAR-γ activators in the late 1990s to treat type 2 diabetes, the use of PPAR-γ ligands to treat other conditions, including cancer, has been investigated. Researchers at the Mayo Clinic discovered that human anaplastic thyroid tumour cells treated with the PPAR-γ activator, RS5444, express a protein known as p21 that inhibits cell replication and suppresses tumour growth, but the underlying mechanism was not understood.

The group has now shown that activation of PPAR-γ with RS5444 (also known as CS-7017) turns on the RhoB tumor suppressor gene, which in turn induces p21 expression, thereby shutting down the cell cycle and blocking tumour growth. The researchers say that it is unusual for a cancer drug to be able to cause re-expression of a suppressed gene in this way, and hope that other cancers in which RhoB is deactivated, such as head and neck, brain, and lung cancers, might respond to RS5444 or to similar drugs. RS5444 is undergoing phase I/II clinical trials (in combination with paclitaxel) in patients with anaplastic thyroid cancer and phase II trials (in combination with carboplatin/paclitaxel) in patients with metastatic non-small cell lung cancer.

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Infection with hepatitis C virus (HCV) is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and cancer. Current treatments are not able to cure all of those chronically infected with the virus, and there is a real need for new therapies. An interest in novel cyclophilin inhibitors for the treatment of HCV arose out of the observation that cyclosporin-A, which is widely used in the management of liver transplant recipients, also inhibits HCV replication. Scynexis has recently released top-line results of a Phase Ib study of its non-immunosuppressive cyclophilin inhibitor, SCY-635, in adults with chronic HCV infection. The randomized, double-blind, placebo-controlled study showed that treatment with SCY-635 for 15 days was well tolerated and produced a clinically relevant reduction in plasma HCV RNA.

Cyclophilins are ubiquitously expressed proteins with peptidyl prolyl cis-trans isomerase activity that play an important role in folding and isomerisation of proteins. Although the isomerase activity of cyclophilin is critical for HCV replication, it is not completely clear which viral protein is modified by the isomerase; interactions with both the NS5B polymerase and the non-structural protein, NS5A, have been proposed. Preclinical data have suggested that viral resistance to cyclophilin inhibitors may not arise as easily as resistance to polymerase and protease inhibitors. Other cyclophilin inhibitors that are being studied for the treatment of HCV infection include NIM811 and Debio-025. Positive clinical efficacy data have been reported for Debio-025, both as monotherapy and in combination with pegylated interferon-α.

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Phenylketonuria (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 30^th 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.

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A good night’s sleep makes a big difference to how we feel, and a new US study suggests that it could also reduce our risk of catching a cold. People who sleep for fewer than seven hours a night were found to be almost three times more likely to get a cold than those who average eight or more hours a night. Having trouble falling asleep or waking up during the night increased the risk even more.

In the study, 54 out of 153 healthy men and women (average age 37) developed cold symptoms in the 5 days after nasal administration of drops containing a rhinovirus. After 28 days, blood samples were tested for antibodies to the virus and it was found that 135 people had become infected, although not all had developed a cold.

For two weeks before being exposed to the virus, the participants were asked each day about the duration and quality of their sleep. In the five days following exposure to the virus, people who had slept for fewer than seven hours each night in the previous two weeks were almost three times more likely to report symptoms than those who had slept for eight hours or more. Broken sleep was found to be even more important: those who were awake for more than 8% of sleep time were five and a half times more likely to show symptoms than those who were awake for 2% or less of the time. Interestingly, the development of cold symptoms did not correlate with how well rested the subjects felt. After taking into account a wide variety of other factors, how long – and especially how well – individuals slept were the strongest predictors of who would develop a cold. Previous research had suggested a link between sleep deprivation and impaired immune function, but this is the first study to show that sleep disturbances can affect susceptibility to cold viruses in normal healthy people. The study is published in the January 12^th edition of Archives of Internal Medicine.

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