Researchers identify severe side effects of Clozapine drug

Clozapine (CLZ) is a "gold standard" drug for managing treatment-resistant schizophrenia (TRS), who do not respond adequately to first-line antipsychotics.

Despite its efficacy with TRS, the use of CLZ is significantly restricted by severe side effects, such as Clozapine-induced agranulocytosis (CIA) or Clozapine-induced granulocytopenia (CIG), which are rare (CIA: 1% and CIG: 3%) but potentially life-threatening.

Ryota Hashimoto, an associate professor at Osaka University, Nakao Iwata, a professor at Fujita Health University, and Taisei Mushiroda, a group director at RIKEN conducted a genome-wide pharmacogenomic analysis and detected a significant association of HLA-B*59:01 with CIA/CIG (CIAG).

HLA-B*59:01 is one of the alleles of HLA-B gene, which is involved in recognition of 'self' and 'non-self' and induction of immune response. HLA- B*59:01 may be clinically useful as a marker to prioritize the CIG patients who have low risk to develop CIA, by accumulating scientific grounds through prospective clinical studies based on this group's research results. The analysis of functions of HLA-B*59:01 is also essential for the clarification of mechanism for CIAG.

Researchers identify severe side effects of Clozapine drug: Clozapine (CLZ) is a 'gold standard' drug for managing treatment-resistant schizophrenia (TRS), who do not respond adequately to first-line antipsychotics.

Epilepsy drug exposure does not increase newborn orofacial cleft risk

In continuation of my update on  lamotrigine

Pregnant women with epilepsy should not rule out continuing lamotrigine therapy due to concerns that exposure could increase the risk of orofacial clefts (OCs) in their babies, say investigators.

Their findings indicate that the excess risk of OC is less than one in every 550 babies exposed to lamotrigine and therefore they do not support the sixfold increased risk suggested by the North American antiepileptic drug registry in 2006, a signal that led to warnings of the risk being added to patient information.

Helen Dolk (Ulster University, UK) and team looked at data from 21 EUROCAT congenital anomaly registries on more than 10 million births spanning 16 years, including from 2006 onwards when lamotrigine exposure was nearly three times more prevalent.

Congenital anomalies were identified in 226,806 babies and within this group 147 with nonchromosomal anomalies had been exposed to lamotrigine within the first trimester of pregnancy.

Exposure to lamotrigine monotherapy was not associated with a significant increase in the incidence of any OC, isolated OCor cleft palate specifically, with odds ratios of 1.31, 1.45 and 1.69.

"Our estimate of the risk of OC relative to other anomalies is nonsignificant with an upper confidence limit of 2.3", reports the team in Neurology.

They add: "Our results concur with other studies published since the original signal, which do not find a large excess of OC or cleft palate."

They suggest that the difference compared with the North American findings may be due to use of a larger baseline population risk of OC of 1.4 per 1000, compared with 1.1 per 1000.

"The size of the original OC signal may also have been a chance finding, or exacerbated by coexposures", the researchers suggest.

Dolk and colleagues also studied the risk of club foot among the sample, having found a significant excess in a previous study. While the current data gave a significant 83% increased risk with lamotrigine exposure, data from an independent study population of 6.3 million births mainly from 2006 on wards found no increased risk.

Epilepsy drug exposure does not increase newborn orofacial cleft risk: Pregnant women with epilepsy should not rule out continuing lamotrigine therapy due to concerns that exposure could increase the risk of orofacial clefts in their babies, say investigators.

Losmapimod drug fails to meet primary endpoint in clinical trial

Patients taking losmapimod, an anti-inflammatory drug currently being developed, for 12 weeks following a heart attack did not show improvements in the trial's primary endpoint, the rate of cardiovascular death, subsequent heart attack or urgent coronary revascularization, which includes placement of a stent or coronary artery bypass surgery, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

The findings are from the initial phase of a losmapimod trial involving 3,500 patients. Because the trial failed to meet its primary endpoint, study authors said the second phase trial involving 22,000 patients will not go forward. However, in a finding that could warrant further study, the trial offers some evidence that the drug may benefit a subset of patients experiencing the most severe form of heart attack, ST-segment elevation myocardial infarction, or STEMI.

"Overall the results were neutral, showing no evidence of efficacy in our primary analysis," said Michelle O'Donoghue, M.D., a cardiologist and investigator in the TIMI Study Group at Brigham and Women's Hospital and the study's lead author. "We did, however, see intriguing signals toward there potentially being some efficacy in ST-elevation myocardial infarction patients. But because that signal was only within a smaller subgroup, we would need to validate those findings in a new study in order to confirm such an effect."

Although inflammation is a natural part of the body's response to injury, in some cases it can cause more harm than good. Inflammation is thought to increase cardiovascular risk after a heart attack by affecting the healing of heart muscle tissue, increasing the formation of plaque in the arteries and raising the likelihood that plaque will dislodge and cause another heart attack.

Losmapimod drug fails to meet primary endpoint in clinical trial

Liraglutide drug makes highly desirable foods less appealing to people

In continuation of my update on Liraglutide

Understanding the motivations that drive humans to eat is an important consideration in the development of weight loss therapies. Now a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) helps explain how the diabetes and weight loss drug liraglutide acts on brain receptors to make enticing foods seems less desirable. The findings were recently presented at ENDO 2016, the annual meeting of the Endocrine Society, and will appear in the May issue of the journal Diabetologia.

"We know that everything that controls our body weight and metabolism is integrated by the brain," said senior author Christos S. Mantzoros, MD, Director of the Human Nutrition Unit in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. "This includes both internal stimuli such as hormones and stress, and external stimuli, such as the smell and appearance of enticing foods."

The Mantzoros laboratory has been studying the differences in the brain activity of individuals who are overweight and individuals of normal weight when they are exposed to desirable foods. These differences are quantified through computer-based neurocognitive testing, as well as imaging tests using fMRI (functional magnetic resonance imaging) to observe alterations in the activity of specific brain areas.

In this new work, the researchers examined the glucagon-like peptide (GLP) hormone, which is secreted by the gastrointestinal tract to regulate metabolism. They also examined the drug liraglutide, which is an analog, or mimicker, of the GLP hormone.

Liraglutide prolongs the action of GLP-1 receptors (protein molecules that respond to the GLP hormone's signal) and is known to work through the digestive tract and the pancreas. Previous animal studies had shown that GLP-1 may also act on the brain, but this had not been confirmed in humans.

Liraglutide drug makes highly desirable foods less appealing to people: Understanding the motivations that drive humans to eat is an important consideration in the development of weight loss therapies. Now a study led by researchers at Beth Israel Deaconess Medical Center helps explain how the diabetes and weight loss drug liraglutide acts on brain receptors to make enticing foods seems less desirable.

Investigational drug abaloparatide-SC may help increase bone mineral density in postmenopausal women

 

The investigational drug abaloparatide-SC (subcutaneous) may help increase bone mineral density in postmenopausal women and reduce their risk of fracture, new industry-sponsored research suggests. The results of the subgroup analysis within the ACTIVE clinical trial will be presented Friday, April 1, at ENDO 2016, the annual meeting of the Endocrine Society in Boston.

"Abaloparatide-SC increased bone mineral density and reduced the risk of vertebral and nonvertebral fractures consistently in postmenopausal women with osteoporosis regardless of their baseline patient characteristics, including age, bone mineral density, and whether or not they had prior fractures," said lead study author Felicia Cosman, MD, endocrinologist and osteoporosis specialist at Helen Hayes Hospital in West Haverstraw, New York, and professor of clinical medicine at Columbia University in New York City.

"If approved by the Food and Drug Administration (FDA), abaloparatide-SC may have the potential to reduce the risk of fractures in postmenopausal women with osteoporosis across a broad range of patient characteristics," said Cosman, who is also a consultant to Radius Health, Inc., in Waltham, Massachusetts.

The researchers investigated patients enrolled in the randomized, double-blind, multinational phase 3 ACTIVE trial to evaluate the efficacy and safety of 80 micrograms of abaloparatide-SC in preventing fractures in otherwise healthy, ambulatory, postmenopausal women with osteoporosis. Overall, 2,463 patient between 49 and 86 years of age were randomized to take one of three medications for 18 months: 80 micrograms of abaloparatide-SC, 20 micrograms of subcutaneous teriparatide (an FDA-approved prescription drug known to increase bone density and strength), or placebo.

Investigational drug abaloparatide-SC may help increase bone mineral density in postmenopausal women

Evolocumab could be more effective than ezetimibe in lowering cholesterol in statin-intolerant patients

 

Ezetimibe                                                                                                           atorvastatin

In the first major trial of its kind, Cleveland Clinic researchers used a blinded rechallenge with atorvastatin or placebo to objectively confirm the presence of muscle-related symptoms in patients with a history of intolerance to multiple statins and found that evolocumab (a PCSK9 inhibitor) was a more effective option to lower cholesterol than ezetimibe in these patients.

The double-blinded, placebo-controlled clinical trial was designed with two stages:

• In Phase A, patients were assigned to two groups. Each group was treated for 10 weeks with atorvastatin or placebo in a blinded fashion, then crossed over to the alternate therapy for another 10 weeks. Patients were asked to report any muscle pain or weakness.
• Patients who reported intolerable muscle symptoms on atorvastatin, but not placebo, moved to Phase B. In this 24-week phase, patients with confirmed statin intolerance were administered two alternative non-statin therapies, ezetimibe vs. evolocumab.
• The research is being presented at the American College of Cardiology's 65th Annual Scientific Session and simultaneously published online in the Journal of the American Medical Association.
  "Statin intolerance has been a very challenging clinical problem," said Steven Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. "The study showed that PCSK9 inhibitors can significantly lower cholesterol in patients with documented statin intolerance, providing an effective treatment for these difficult to manage patients."
  The GAUSS-3 trial enrolled 511 patients with very high levels of LDL cholesterol - averaging more than 210 mg/dL ¬¬- and with a history of muscle-related statin intolerance. More than 80% of participants had previously reported intolerance to three or more statins. The study showed that 42.6 percent of these patients reported muscle pain or weakness on atorvastatin, but not placebo, and 26.5 percent on the placebo, but not atorvastatin.

Evolocumab could be more effective than ezetimibe in lowering cholesterol in statin-intolerant patients

Inhalable form of Ambrisentan drug could offer faster-acting treatment option for pulmonary edema

In a new study, researchers show an aerosolized, inhalable form of the drug Ambrisentan could offer a faster-acting treatment option for pulmonary edema, a life-threatening condition in which fluid accumulates in the lungs. Pulmonary edema is a significant risk for anyone spending time at high altitudes, and also affects people with chronic conditions including congestive heart failure and sickle cell anemia.

High altitude pulmonary edema, or HAPE, results when exposure to reduced oxygen levels causes the arteries in the lungs to constrict, which in turn causes blood pressure within the lungs to rise. Unchecked, this process leads to the rapid accumulation of fluid in the lungs, further reducing a person's ability to get oxygen and causing severe physical impairment.

Currently, Ambrisentan is available only in pill form and takes time to provide relief. The new study, conducted in rats, showed that delivering the drug via an inhaler achieved the same effect with just one-fifth of the typical oral dose.

"This mode of delivery gets the drug directly to the site of the problem—the lungs—providing relief much faster than the oral treatment," said Scott Ferguson, Ph.D. a postdoctoral researcher at the University of Colorado, Denver Anschutz Medical Center, who conducted the research. "Additionally, it requires a much lower dose, likely lowering the incidence of side effects and the cost of treatment."

Ferguson will present this research at the American Physiological Society Annual Meeting during Experimental Biology 2016.

Inhalable form of Ambrisentan drug could offer faster-acting treatment option for pulmonary edema

Adding liraglutide to diet and exercise plan may help people lose weight, reduce diabetes risk

In continuation of my update on liraglutide

For people with prediabetes who are overweight or obese, adding 3.0 mg of liraglutide for three years to a diet and exercise plan may lead to major health improvements, new industry-sponsored research suggests. The results will be presented Monday, April 4, at ENDO 2016, the annual meeting of the Endocrine Society, in Boston.

"Treatment with subcutaneous liraglutide 3.0 mg for three years, combined with a reduced-calorie diet and increased physical activity, can help people to not only lose weight, but also reduce the risk of Type 2 diabetes and improve cardiometabolic risk factors, which may ultimately reduce the risk of cardiovascular disease - the number one cause of death globally," said lead study author Ken Fujioka, MD, director of nutrition and metabolic research, and director for weight management at Scripps Research Institute in La Jolla, California.

"Type 2 diabetes is a major cause of death in the US. Both obesity, a chronic disease with serious health consequences, and prediabetes, typically defined as blood glucose concentrations that are higher than normal but lower than diabetes thresholds, increase the risk of developing Type 2 diabetes," Fujioka said. "For people with overweight or obesity and prediabetes, losing between 5 and 10 percent of their body weight can reduce their risk of Type 2 diabetes and other obesity-related health consequences."

Adding liraglutide to diet and exercise plan may help people lose weight, reduce diabetes risk

Researchers design more effective version of FDA-approved epilepsy drug with fewer side effects

Researchers at the University of Pittsburgh School of Medicine and Arts & Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published on March 22 in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

Epilepsy, in which erratic firing of nerve signals causes seizures, affects about 1 percent of people worldwide, said senior investigator Thanos Tzounopoulos, Ph.D., Endowed Chair in Auditory Physiology, associate professor of otolaryngology and member of the Auditory Research Group, University of Pittsburgh School of Medicine. Drugs to treat the disorder primarily work by influencing the transport of sodium, potassium and chloride ions across the nerve cell membrane to try to reduce the excitability of the brain cells.

"Unfortunately, these drugs don't work well in nearly a third of patients and there is a great need for better treatments," Dr. Tzounopoulos said. "We have been able to refine an existing medication so that it acts selectively on certain nerve cell membrane transport channels, which should make it more effective."

he available drug is called retigabine, and while it has improved symptoms for some patients, it can also lead to troublesome side effects, including retinal abnormalities, urinary retention and skin discoloration. Dr. Tzounopoulos was part of a study team that evaluated an earlier modification of retigabine, dubbed SF0034, which is being further developed by SciFluor Life Sciences LLC in Cambridge, Mass.

For the current project, Dr. Tzounopoulos and Peter Wipf, Ph.D., Distinguished University Professor of Chemistry at Pitt, rationally redesigned several structural components of retigabine to further increase its potency. Retigabine works by activating all five types of potassium transport channels in the KCNQ category, but only two of the potassium channels, KCNQ2/3, are important for stabilizing the cell membrane of brain cells involved in hyperexcitability-related disorders, such as epilepsy and tinnitus, Dr. Tzounopoulos explained. The new compound, known as RL648_81 ("RL-81"), targets just those channels.

When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects.

The experimental compound could also help people with tinnitus by preventing hyper-excitation of nerve cells in auditory pathways, Dr. Tzounopoulos noted.

       

Researchers design more effective version of FDA-approved epilepsy drug with fewer side effects

NTU researchers make breakthrough to tackle growing concern of antibiotic resistance

Scientists at Nanyang Technological University, Singapore (NTU Singapore) have discovered that antibiotics can continue to be effective if bacteria's cell-to-cell communication and ability to latch on to each other are disrupted.

This research breakthrough is a major step forward in tackling the growing concern of antibiotic resistance, opening up new treatment options for doctors to help patients fight against chronic and persistent bacterial infections.

The study, led by Assistant Professor Yang Liang from the Singapore Centre for Environmental Life Sciences (SCELSE) at NTU, found that a community of bacteria, known as biofilm, can put up a strong line of defence to resist antibiotics. The NTU team has successfully demonstrated how biofilms can be disrupted to let antibiotics continue their good work.

The research was published recently in Nature Communications, a prestigious academic journal by the Nature Publishing Group.

"Many types of bacteria that used to be easily killed by antibiotics have started to develop antibiotic resistance or tolerance, either through acquiring the antibiotic resistant genes or by forming biofilms," said Asst Prof Yang, who also teaches at NTU's School of Biological Sciences.

"The US Center for Disease Control estimates that over 60 per cent of all bacterial infections are related to biofilms. Our study has shown that by disrupting the cell-to-cell communication between bacteria and their ability to latch on to each other, we can compromise the biofilms, leaving the bacteria vulnerable and easily killed by antibiotics."

Bacterial resistance to antibiotics is rapidly growing world-wide and this puts at risk the ability to treat common infections in the community and hospitals.

The World Health Organisation states on its factsheet on Antimicrobial resistance that  "without urgent, coordinated action, the world is heading towards a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill".

Associate Professor Kevin Pethe, an expert in antibiotic development and infectious diseases from NTU's Lee Kong Chian School of Medicine, said that this discovery may yield new treatment options that doctors can employ against chronic and persistent bacterial infections.

"Being able to disable biofilms and its protective benefits for the bacteria is a big step towards tackling the growing concern of antibiotic resistance," said Assoc Prof Pethe.

"While the scientific community is developing new types of antibiotics and antimicrobial treatments, this discovery may help to buy time by improving the effectiveness of older drugs."

NTU researchers make breakthrough to tackle growing concern of antibiotic resistance