Novel antibiotics to overcome antibacterial resistance

Small and innovative pharmaceutical companies, with products in early stages of development, presented some of their novel approaches and antimicrobial therapies under development during a dedicated session at the annual congress (ECCMID) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in Amsterdam.

Dr. Ursula Theuretzbacher, the founder of the Centre for Anti-Infective Agents in Vienna, led the session, which gave an overview of the research and development programmes that are driving innovation in this critical space.

At a time of transition with big pharma continuing to move away from the development of antibacterial treatments, these small biotechnology companies and start-ups are rising to the challenge and filling the gap through the discovery and development of novel therapies.

Dr. Ursula Theuretzbacher remarked: “we are pleased to see a number of highly promising antibacterial drugs of a new class and or a new mode of action now in the research or close to the preclinical phase. To aid the development of more drug candidates, crucial to increasing the chances of a sufficient number reaching the clinical stage, innovative researchers in small companies or universities are pursuing a range of non-traditional approaches in addition to classical ones.

New approaches highlighted at pipeline corner fall into three key categories: targeted therapies, adjunctive therapies and potentiators.

• Targeted therapies - traditional antibiotics and antibodies that are active against a single pathogen, especially Staphylococcus aureus or Pseudomonas aeruginosa
• Adjunctive therapies – including drugs that target virulence factors, biofilm formation, immune system stimulation, modifying the microbiome, and phages. All such approaches require an active antibiotic
• Potentiators – an adjuvant drug, such as beta-lactamase-inhibitors or efflux pump inhibitors, improve the activity of an antibiotic by inhibiting resistance determinants, either facilitating the penetration or changing the sensitivity of the bacterial cell

Spero, Cidara and Melinta Therapeutics attend from the USA and Vitas Pharma from India. European biotechnology companies making presentations included Discuva, Bioversys and Morphochem. In addition, a publicly funded research institution, the German Centre for Infection Research, was also a key feature at the 2016 pipeline corner.    

Novel antibiotics to overcome antibacterial resistance: Small and innovative pharmaceutical companies, with products in early stages of development, presented some of their novel approaches and antimicrobial therapies under development during a dedicated session at the annual congress (ECCMID) of the European Society of Clinical Microbiology and Infectious Diseases(ESCMID) in Amsterdam.

Substances from tequila plant may help treat osteoporosis

Mexican scientist identified substances from the plant that enhance absorption of calcium in the body.

Apart from being the raw material for making a very traditional drink in Mexico, the blue variety of the Agave tequilana has substances capable of improving the absorption of calcium and magnesium, essential minerals to maintain bone health. This has been demonstrated by research conducted at the Center for Research and Advanced Studies (Cinvestav) in center Mexico.

Dr. Mercedes López, leader of the project, states that "the consumption of fructans contained in the agave, in collaboration with adequate intestinal micriobiota, promotes the formation of new bone, even with the presence of osteoporosis."

To reach this conclusion, the research team conducted various experiments with animal models. The procedure consisted of removing the ovaries from female mice in order to induce osteoporosis. The next step was to administer agave fructans and eight weeks later a femur sample was taken to measure the absorption of minerals and osteocalcin, protein that indicates the production of new bone.

"It was found that mice that consumed this fructans synthesized nearly 50 percent more of such protein, in addition that the diameter of their bones was higher compared with the subjects which were not supplied with derivatives of the agave" she reports.

This substances reach the large intestine intact and interact with the microbiota living there to become short-chain fatty acids. These catch minerals available in the tract and help to transport them through the cells.

"This way, we have a second chance to take advantage of the nutrients that were no longer available to the body. However, it is very important that people have a healthy intestinal microbiome, because only then it is possible that bacteria ferment fructans to transform them into fatty acids, "says Dr. Lopez.

The results provide the possibility of developing an alternative in the treatment of osteoporosis, a disease that, according to the latest statistics from the International Osteoporosis Foundation, affects 200 million of people worldwide, which means that one of every five fractures, in the population with more than 50 years of age, is related to the disease.

Substances from tequila plant may help treat osteoporosis: Mexican scientist identified substances from the plant that enhance absorption of calcium in the body.

Breast cancer medication letrozole could increase ovulation in women with PCOS

In continuation of my update on Letrozole

A medicine used in breast cancer treatment is now considered the best option for treating the most common cause of infertility.

Letrozole has been found to increase ovulation in women with Polycystic Ovarian Syndrome (PCOS), a common form of ovulation dysfunction, leading to a 40 percent increase in pregnancy rates and more ovulation and live births than Clomid, the previous standard.

In breast cancer patients, Letrozole decreases the amount of estrogen, but a side effect is increased ovulation.

"We have found out that the hormonal messages affect different areas of the body in different ways," said Dr. Stephanie Estes, a board certified fertility specialist and director of the Robotic Surgery Program at Penn State Health Milton S. Hershey Medical Center.

She suggests that patients whose infertility is caused by irregular ovulation ask their providers about letrozole, since news of its effectiveness as an infertility treatment hasn't spread very quickly. "It is easy to take, has a low rate of multiple births, and fewer side effects than Clomid," Estes said.

If infertility is caused by male factors or simply unexplainable, doctors may recommend other medicines, injectables, inseminations or in-vitro fertilization (IVF), depending on the diagnosis.

"You always have to look at the underlying cause to pick which treatment is correct," Estes said.

Intra-uterine insemination (IUI) places concentrated sperm directly into the woman's uterus so it doesn't have so far to travel and thus increases chances of fertilization. With IVF, the woman's eggs are harvested and combined with sperm in an embryology laboratory and then an embryo is placed into the uterus.

"IVF is becoming more and more successful, so its availability to patients has improved," Estes said. "More states and companies are seeing the importance of family-building within the job, so now there is a lot more coverage for these treatments."

Estes said most insurance companies will cover fertility testing, even if they don't cover the treatments. "Many people just wait and hope, and their family tells them it will happen when it is supposed to happen," Estes said. "But why not come and see what the issue might be?"

Breast cancer medication letrozole could increase ovulation in women with PCOS: A medicine used in breast cancer treatment is now considered the best option for treating the most common cause of infertility.

New extended-release pills could reduce dosage frequency of some drugs

Researchers from MIT and Brigham and Women's Hospital have designed a new type of pill that, once swallowed, can attach to the lining of the gastrointestinal tract and slowly release its contents. The tablet is engineered so that one side adheres to tissue, while the other repels food and liquids that would otherwise pull it away from the attachment site.

Such extended-release pills could be used to reduce the dosage frequency of some drugs, the researchers say. For example, antibiotics that normally have to be taken two or three times a day could be given just once, making it easier for patients to stick to their dosing schedule.

"This could be adapted to many drugs. Any drug that is dosed frequently could be amenable to this kind of system," says Giovanni Traverso, a research affiliate at MIT's Koch Institute for Integrative Cancer Research, a gastroenterologist at Brigham and Women's Hospital, and one of the senior authors of a paper describing the device in the April 6 issue of the journal Advanced Healthcare Materials.

Robert Langer, the David H. Koch Institute Professor and a member of the Koch Institute, is also a senior author of the paper. The paper's lead author is Young-Ah Lucy Lee, a technical assistant at the Koch Institute.

Two faces

Over the past several decades, Langer's lab has developed many types of materials that can be implanted in the body or attached to the skin for long-term drug release. To achieve similar, long-term drug release in the gastrointestinal tract, the researchers focused on a type of material known as mucoadhesives, which can stick to the mucosal linings of organs such as the stomach.

Scientists have previously explored using this kind of material for drug delivery to the GI tract, but it has proven difficult because food and liquid in the stomach become stuck to the tablet, pulling it away from the tissue before it can deliver its entire drug payload.

"The challenge with mucoadhesives is that the GI tract is a very rough and abrasive environment," says Lee, a 2014 Wellesley College graduate who began this project as her senior thesis.

To overcome this challenge, the researchers decided to create a dual-sided device, also called a Janus device after the two-faced Roman god. One side sticks to mucosal surfaces, while the other is omniphobic, meaning that it repels everything it encounters.

New extended-release pills could reduce dosage frequency of some drugs: Researchers from MIT and Brigham and Women's Hospital have designed a new type of pill that, once swallowed, can attach to the lining of the gastrointestinal tract and slowly release its contents. The tablet is engineered so that one side adheres to tissue, while the other repels food and liquids that would otherwise pull it away from the attachment site.

Compound from unique blue-green algae could be key to next anti-cancer drug

Could a slippery glob of algae hold the key to the next anti-cancer drug? According to new research into a compound produced by a unique community of blue-green algae, the answer could be yes.

The compound in question is called coibamide A, discovered eight years ago by scuba-diving scientist Kerry McPhail, Ph.D., of Oregon State University. A new study shows coibamide A has potent anti-cancer activity in mice and cell cultures that model brain tumors and triple negative breast cancer, two of the most aggressive and difficult-to-treat types of cancer.

"The chemical diversity found in nature has always been a significant source of inspiration for drug design and development, but although the medicinal properties of plants have been recognized for thousands of years, marine environments remain relatively unexplored," said Jane Ishmael, Ph.D., associate professor of pharmacology at Oregon State University and the lead author of the new study. "We think that with this compound, nature has already found a way to target some of the specific proteins that are relevant to the growth of tumors."

Ishmael will present this research at the American Society for Pharmacology and Experimental Therapeutics Annual Meeting during Experimental Biology 2016.

McPhail, who specializes in blue-green algae and dives all over the world in search of interesting species, collected the algae during a dive in Panama's Coiba National Park. It turned out to be a mash-up of at least three algal species that grow together on rocks in areas with fast-moving water. In addition to Panama, similar algal communities has been found in the Red Sea and off the coast of South Africa. Blue-green algae, or cyanobacteria, have existed for at least two billion years and are one of the oldest life forms on Earth.

After McPhail isolated coibamide A from the original algal specimen, it was run through a National Cancer Institute screening system that looks for potential anti-cancer activity across 60 different types of cancer. Coibamide A showed a pattern of activity unmatched by any other compound, suggesting it might be able to fight cancer through a mechanism of action unlike that of any existing drug.

Compound from unique blue-green algae could be key to next anti-cancer drug: Could a slippery glob of algae hold the key to the next anti-cancer drug? According to new research into a compound produced by a unique community of blue-green algae, the answer could be yes.

Entresto drug shows added benefit in symptomatic chronic heart failure

In continuation of my update on sacubitril and Valsartan   

The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function (ejection fraction). The German Institute for Quality and Efficiency in Health Care (IQWiG) now examined in an early benefit assessment whether this drug combination offers an added benefit for patients in comparison with the appropriate comparator therapy.

According to the findings, the positive effects regarding mortality, necessity of heart failure hospitalizations, and quality of life predominate. These were not put into question by a negative effect in non-severe side effects; hence overall an indication of considerable added benefit can be derived from the data.

Approval study terminated prematurely

In its dossier, the drug manufacturer used data from a randomized controlled trial, which compared sacubitril/valsartan directly with enalapril, each in combination with a beta-blocker. Since a planned interim analysis was able to show after 51 months already that fewer cardiovascular deaths occurred under sacubitril/valsartan, the study was terminated prematurely.

Fewer deaths due to cardiovascular failure

The data from the dossier showed that all-cause mortality was lower under sacubitril/valsartan than under enalapril, which was mainly caused by fewer cardiovascular deaths.

The results regarding the frequency of hospitalizations due to heart failure were also in favour of the new fixed-dose combination; however, these were limited to patients with a lower severity grade (NYHA class I and II). Finally, the data on health-related quality of life also showed an advantage of sacubitril/valsartan.

Entresto drug shows added benefit in symptomatic chronic heart failure: The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function (ejection fraction). The German Institute for Quality and Efficiency in Health Care (IQWiG) now examined in an early benefit assessment whether this drug combination offers an added benefit for patients in comparison with the appropriate comparator therapy.

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.