Rare antibiotic compound detected in fungi for first time

In continuation of my update on valproic acid

Besides mushrooms such as truffles or morels, also many yeast and mould fungi, as well as other filamentous fungi belong to the Ascomycota phylum. They produce metabolic products which can act as natural antibiotics to combat bacteria and other pathogens. Penicillin, one of the oldest antibiotic agents, is probably the best known example. Since then, fungi have been regarded as a promising biological source of antibiotic compounds. Researchers expect that there is also remedy for resistant pathogens among these metabolites.

It depends on the stimulus

However, agents like penicillin are only produced when necessary, not permanently. "Fungi can even deactivate the respective parts of their genome if a metabolite is not needed anymore. These compounds can't be detected any longer and are classified as cryptic compounds," explained Christoph Zutz from the Institute for Milk Hygiene, Milk Technology and Food Science of the Vetmeduni Vienna.

The right stimulus can reinduce the production of antibiotic compounds. The researchers used valproic acid which can induce the activation of such deactivated genes in fungi. In the fungus Doratomyces microsporus, valproic acid even induced the production of several antimicrobial compounds.

 1.valproic acid  

2. cyclo-(L-proline-L-methionine)

Rare compound detected in fungi for the first time

The gained metabolites were effective against a "normal", as well as resistantStaphylococcus aureus pathogens. The team succeeded in filtering out the six most active compounds from all metabolites. These six compounds have been regarded as "cryptic" so far. One compound, cyclo-(L-proline-L-methionine) or cPM, could be detected even for the first time in a fungus. The only source of this compound so far has been a bacterium living in an Antarctic sponge.

Boosting effect as an asset in the fight against resistance

The as yet "cryptic" compound cPM has a special function. It boosts the activity of other antimicrobial compounds. The team assumes that particularly this boosting effect constitutes the effect these compounds have on the tested pathogens.

Therefore, the researchers went a step further and tested the newly detected compound cPM together with ampicillin in two ampicillin-resistant bacteria. The combination has proved successful. "The resistance was demonstrably reduced, even at a lower dose of ampicillin than usually," said co-author and corresponding group leader Kathrin Rychli.

New research platform is looking at the big picture

The team is now going to search for novel antibiotic compounds from other microorganisms by applying similar methods. The new research platform "Bioactive Microbial Metabolites" (BiMM) in Tulln (Lower Austria) provides the facility. BiMM represents the detection of bioactive compounds - metabolites - in microorganisms. "Valproic acid is not the only way to gain active compounds from fungi or other microorganisms. You can also make bacteria and fungi grow together. This also leads to a natural stimulus," explained Joseph Strauss from the University of Natural Resources and Life Sciences, Vienna, who heads the platform. For this purpose, researchers from the University of Veterinary Medicine, Vienna and the University of Natural Resources and Life Sciences, Vienna founded this new research core facility.

Christoph Zutz identified a significant advantage of this inter-university research platform. "Unlike industrial enterprises, we investigate all promising metabolites in microorganisms, not only single chemical compounds. Thus, we consider known and cryptic compounds in our analyses."

Ref : http://www.vetmeduni.ac.at/en/infoservice/news/detail/artikel/2016/07/15/fungi/

Antipsychotic drug could help reduce nausea and vomiting caused by chemotherapy

In continuation of my update on Olanzapine

A drug that blocks neurotransmitters could reduce nausea and vomiting caused by chemotherapy, research co-authored by a Sanford Health physician and published in theNew England Journal of Medicine finds.

Sanford oncologist and cancer researcher Steven Powell, M.D., was among a team of researchers who discovered that the drug olanzapine, which is FDA approved for use as an antipsychotic agent, significantly improved nausea prevention in patients who were receiving chemotherapy for cancer treatment. The drug blocks neurotransmitters involved with nausea and vomiting.

"We've long known the nausea and vomiting that come along with chemotherapy are a major problem and affect the quality of life of our patients," said Powell. "The findings of this study, fortunately, provide physicians with a tool to better address the needs of those they are treating for cancer."

Researchers noted that within the first day after treatment, 74 percent of study participants experienced no nausea or vomiting when their chemotherapy was paired with olanzapine. When a placebo was used instead of olanzapine, that figure dropped to 45 percent. This benefit continued for five days after chemotherapy treatment for many patients.

Ref : http://www.sanfordhealth.org/newsroom/2016/07/sanford-physician-assists-in-developing-new-treatment

Antipsychotic drug could help reduce nausea and vomiting caused by chemotherapy

Virgin olive oil helps in preventing and treating hypertension

Oleic acid plus a constellation of minor constituents as a natural antihypertensive.

Consumption of virgin olive oil is good for you, but why? Scientific evidence on this issue has been accumulating for a quarter century. Epidemiological, clinical, and animal studies support that the consumption of virgin olive oil, instead of other sources of dietary fats, has antihypertensive effects.

What contains does virgin olive oil contain that makes it so healthy? Virgin olive oil is an oily fruit whose composition includes large quantities of oleic acid (a monounsaturated fatty acid) and also a variety of compounds present in lower quantities, named minor constituents, such as hydrocarbons, phytosterols, triterpenic compounds, and phenolic compounds. Both oleic acid and these minor constituents confer unique bioactive properties to virgin olive oil.

How do its components protect from hypertension? They influence on factors associated with the pathophysiology of hypertension such as vascular contractibility and protect from heart and kidney cellular loss and functionality, leading to a reduction of blood pressure.

Is it a miraculous ingredient? No, it is just a food. Virgin olive oil helps in preventing and treating hypertension but its full power arises as part of the Mediterranean diet in a global strategy for a healthy and long-lasting life.

Metallic molecule offers real-time monitoring of amyloid plaques in patients with Alzheimer's

  

A metallic molecule being studied at Rice University begins to glow when bound to amyloid protein fibrils of the sort implicated in Alzheimer's disease. When triggered with ultraviolet light, the molecule glows much brighter, which enables real-time monitoring of amyloid fibrils as they aggregate in lab experiments.

Rice chemist Angel Martí said such a powerful probe could be a boon to researchers seeking a way to break up amyloid plaques, which form in the brains of patients with Alzheimer's. Martí's lab reported on the light-switching molecule in the Journal of the American Chemical Society. Rice graduate student Amir Aliyan is lead author of the paper.

Martí and his team study dyes made of metallic complexes that luminesce when attached to amyloid fibrils or DNA. They discovered that when rhenium dipyridophenazine complexes bind with an amyloid fibril in a test tube and are excited with ultraviolet light, the synthetic molecules increase their natural photoluminescence by several orders of magnitude.

"Most dyes decrease their fluorescence upon continuous excitation because they photobleach," Martí said. "This dye does the complete opposite, increasing its emission even more every time you excite it." The effect isn't nearly as strong if the metallic molecule is either floating in a solution or attached to single amyloid strands, he said.

The effect is seen in two stages, he said. The probe incorporates a hydrophobic part that naturally binds to aggregating fibrils and emits light when it does, giving researchers a clear signal that aggregation is happening. Exciting the combined aggregate and probe with ultraviolet light then boosts the light output more than a hundredfold.

The Rice researchers suspect the dramatic increase happens when reactive oxygen species attack the amino acids on the amyloid beta fibril that would normally quench the luminescence of the metal complex.

"Our hypothesis is that upon ultraviolet irradiation, our (rhenium) metal complex produces reactive oxygen species and they're more aggressive than conventional molecular oxygen," Aliyan said. "There are reports that rhenium complexes are capable of activating oxygen from one form to a more aggressive form in solution."

"That's one of our theories," Martí added. "We still don't understand well what is happening. But we know that besides increasing the emission intensity, the complex also chemically modifies the (amyloid) protein."

Martí said experiments that removed as much oxygen as possible eliminated the enhanced fluorescence effect. He said the lab stepped back to test an earlier metallic complex based on ruthenium, which also showed emission when attached to amyloid fibrils. It did not show enhanced emission under ultraviolet light.

"We thought the effect might be happening with ruthenium and we had completely missed it, so we ran a control experiment and nothing happened," he said.

That makes the rhenium complex unique so far. It also gives researchers the opportunity to learn more about amyloid beta proteins and the mechanics of aggregation, Martí said.

"We've always been interested in knowing where these complexes bind," he said. "If they oxidize amyloid beta in the periphery of their binding site, then by tracking the place of oxidation we will know the place of binding. That is called footprinting. It will allow us to specifically explore binding and how chemical modification of the surface of the protein would affect factors like toxicity and aggregation."

Aliyan said the probe allows real-time protein aggregation study as the probe turns on upon aggregation. "To the naked eye, aggregation is not obvious," he said. "You need a probe to follow the process and see if potential drugs can inhibit aggregation or make it faster or slower. Then you can run assays with or without any drug and in a variety of conditions. One would think if there are ways to modify amyloid beta aggregation, maybe there are ways to treat the process." 

Everolimus combined with standard R-CHOP therapy shows promise in treating DLBCL patients

In continuation of my update on everolimus

The targeted therapy everolimus may be safely combined with R-CHOP for new, untreated diffuse large B-cell lymphoma according to the results of a pilot study by Mayo Clinic researchers published in the Lancet Haematology. R-CHOP is a combination of drugs used to treat lymphoma. The combination includes rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

"There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma," says Patrick Johnston, M.D., Ph.D., a hematologist at Mayo Clinic and lead author. "This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial."

The everolimus, R-CHOP combination was well-tolerated by patients with no dose-limiting toxicity reached within the planned dose escalation. The vast majority of patients (96 percent) achieved an overall response, and all responders achieved a complete metabolic response to the treatment. The findings indicate that drugs targeting the P13K-mTOR pathway — a cascade of molecules involved in cell growth and survival — add benefit when combined with standard R-CHOP therapy.

Lymphoma is the sixth most common cancer in the U.S., and diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. The standard accepted treatment for DLBCL is a combination R-CHOP delivered in a 21-day cycle for six cycles. However, this regimen typically cures only approximately 60 percent of patients.

Dr. Johnston and his colleagues scoured the scientific literature in search of ways to improve the cure rate. Two lines of evidence pointed toward targeting the P13K-mTOR pathway. First, numerous studies have demonstrated the importance of this pathway in the pathogenesis of DLBCL cells in the laboratory. Second, clinical studies have documented the single-agent efficacy of everolimus (an mTOR inhibitor) in relapsed DLBCL. Therefore, Mayo Clinic researchers decided to test a regimen that combined the standard R-CHOP with everolimus.

They conducted a phase 1 and feasibility study in 24 patients with new, previously untreated DLBCL in the Alliance for Clinical Trials in Oncology, a National Cancer Institute cooperative group. Patients received everolimus for 14 days in combination with R-CHOP-21. A large proportion of patients achieved an overall response (96 percent) and a complete metabolic response as assessed by positron emission tomography imaging (96 percent). No relapses with DLBCL occurred and all patients achieved the predictive milestone of being event-free at 12 months from enrollment. The treatment was well-tolerated, and the most common adverse events were hematological in nature, such as grade 4 neutropenia (75 percent) and grade 3 febrile neutropenia (21 percent).

"This study is the first to integrate a P13K-mTOR agent with standard RCHOP," says Dr. Johnston. "The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients."

Urolithin A found in pomegranates may improve muscle strength and endurance during aging

In continuation of my update on Urolithin A

Amazentis SA, an innovative life sciences company applying scientific breakthroughs in nutrition to manage health conditions linked to aging, announced today a collaborative publication in Nature Medicine with the École Polytechnique Fédérale de Lausanne (EPFL), demonstrating that the Company's lead product candidate, urolithin A, improves mitochondrial and muscle function, resulting in enhanced muscle strength and endurance during aging. Amazentis is presently evaluating urolithin A in a first human clinical trial with results expected in 2017.

Urolithin A is generated by gut microflora as a natural metabolite of ellagitannins, a class of compounds found in the pomegranate and other fruits and nuts. "We are excited to publish the first data that demonstrate the effects of this gut metabolite on mitochondrial and muscle function," commented Johan Auwerx, Professor at the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland, and lead author. "We believe this research is a milestone in current anti-aging efforts, which have previously focused on traditional pharmaceutical modalities, and illustrates the opportunity of rigorously tested nutritional bioactive agents that we consider to have outstanding potential for human health."

Urolithin A: a potent gut metabolite to rejuvenate mitochondria and reverse muscle aging

Oral administration of urolithin A leads to an improved mitochondrial function by stimulating mitophagy, a process by which damaged mitochondria are recycled to permit a renewal with healthy mitochondria.

"Mitophagy declines in cells as we age, and the reduction in mitochondrial function in the muscles of the elderly is thought to be one of the main causes of age-related muscle impairment. We believe our research, uncovering the health benefits of urolithin A, holds promise in reversing muscle aging," stated Patrick Aebischer, co-author on the article, EPFL President and Chairman and co-founder of Amazentis.

The results are being reported in the current issue of Nature Medicine in an article titled, "Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents".

Age-related muscle decline: a compelling market opportunity for urolithin A

Declining skeletal muscle mass and the resulting loss of strength are hallmarks of aging. These changes can become debilitating and lead to a condition termed sarcopenia, which is thought to affect 30% of those over 60 years old and greater than 50% of individuals over 80 years. Current estimates in the United States project there will be greater than 75 million adults over 60 years by the year 2020.

The resulting reductions in quality of life and independence as a result of muscle decline constitute a growing healthcare issue in the aging population. There are currently no pharmaceutical therapies to treat age-related decline in muscle function and sarcopenia. Nutritional strategies have had limited impact to date, and new scientifically validated solutions are urgently needed.

Upon consumption of pomegranate juice, compounds known as ellagitannins are broken down in the stomach and then transformed by intestinal bacteria into urolithin A. This biotransformation has been shown to vary widely across individuals, with some showing high or low conversion rates, while others have different compositions of microflora and are unable to perform the conversion. Consequently, supplementing individuals with products designed to deliver carefully calibrated doses of urolithin A can overcome this natural diversity in gut microflora found in the general population.

Amazentis has established a technology portfolio and proprietary knowhow around urolithin A, enabling the manufacture and development of advanced nutrition products for oral delivery.

Chris Rinsch, Ph.D., a co-author and CEO and co-founder of Amazentis, commented, "Based on the rigorous science being published in Nature Medicine, we have advanced our lead product delivering urolithin A into clinical trials. We believe that this discovery will open the door to a new approach for managing muscle decline by rejuvenating mitochondria. Our vision is to translate breakthrough scientific discoveries in nutrition into clinically validated consumer health products that address today's unmet needs in an aging population."

Leukemia drug increases brain dopamine, lowers toxic proteins linked to Parkinson's or dementia

My updates on  nilotinib

A small phase I study provides molecular evidence that an FDA-approved drug for leukemia significantly increased brain dopamine and reduced toxic proteins linked to disease progression in patients with Parkinson's disease or dementia with Lewy bodies. Dopamine is the brain chemical (neurotransmitter) lost as a result of death of dopamine-producing neurons in these neurodegenerative diseases.

Researchers from Georgetown University Medical Center (GUMC), say the findings, described in the Journal of Parkinson's Disease, support improved clinical outcomes observed and first reported at the Society for Neuroscience annual meeting in October 2015.

The study tested nilotinib taken daily for six months. A much smaller dose of nilotinib (150 or 300 mg once daily) was used compared to the dose for chronic myelogenous leukemia (300-400 mg twice daily). Twelve patients were enrolled in the clinical trial — one patient withdrew due to an adverse event. Researchers say the drug appears to be safe and well tolerated in the remaining 11 participants who completed the study.

In addition to safety, the researchers also examined biological markers in the blood and cerebral spinal fluid as well as cognitive, motor and non-motor improvement. They found significant signs that nilotinib may provide benefit for patients with these neurodegenerative diseases.

"These results need to be viewed with caution and further validated in larger placebo controlled trials, because this study was small, the patients were very different from each other, and there was no placebo," says the study's senior investigator, Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherpeutics Program.

Among the biomarker findings were that:

•The level of the dopamine metabolite homovanillic acid — an indicator that dopamine is being produced — steadily doubled, even with the loss of most dopamine neurons. Most study participants were able to stop using, or reduce their use of, dopamine replacement therapies;

•The level of the Parkinson's related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and

•The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.

In addition, Moussa adds that it appears nilotinib attenuated the loss of CSF alpha-synuclein, a toxic protein that accumulates within neurons, resulting in reduced CSF levels in both Parkinson's disease and dementia with Lewy bodies.

The researchers also said that all 11 patients who tolerated the drug reported meaningful clinical improvements. All patients were at mid-advanced stages of Parkinsonism and they all had mild to severe cognitive impairment.

"Patients progressively improved in motor and cognitive functions as long as they were on the drug — despite the decreased use of dopamine replacement therapies in those participants with Parkinson's and dementia with Lewy bodies," says the study's lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherpeutics Program and director of the Movement Disorders Program at MedStar Georgetown University Hospital.

But three months after withdrawal of the drug, participants returned to the same reduced cognitive and motor state they had before the study began, Pagan adds.

Some serious side effects were reported including one patient who withdrew at week four of treatment due to heart attack and three incidents of urinary tract infection or pneumonia. The researchers say these incidents are not uncommon in this patient population, and additional studies are needed to determine if the adverse events are related to use of nilotinib.

"Long term safety of nilotinib is a priority, so it is important that further studies be conducted to determine the safest and most effective dose in Parkinson's, says Pagan.

The researchers designed the clinical trial to translate several notable observations in the laboratory. The preclinical studies, led by Moussa, showed that nilotinib, a tyrosine kinase inhibitor, effectively penetrates the blood-brain barrier and destroys toxic proteins that build up in Parkinson's disease and dementia by turning on the "garbage disposal machinery" inside neurons.

Their published studies also showed nilotinib increases the levels of the dopamine neurotransmitter — the chemical lost as a result of neuronal destruction due to toxic protein accumulation — and improves motor and cognitive outcomes in Parkinson's and Alzheimer's disease animal models.

"Our hope is to clarify the benefits of nilotinib to patients in a much larger and well controlled study. This was a very promising start," Moussa says. "If these data hold out in further studies, nilotinib would be the most important treatment for Parkinsonism since the discovery of Levodopa almost 50 years ago."

He adds, "Additionally, if we can validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the first treatments for dementia with Lewy bodies, which has no cure, and possibly other dementias."

Two randomized, placebo-controlled phase II clinical trials are planned for summer/fall in Parkinson's and Alzheimer's diseases. The Translational Neurotherpeutics Program is also planning a small trial in ALS (Lou Gherig's disease).

According to Novartis, the cost (as of Oct. 2015) of nilotinib for the treatment of CML was about $10,360 a month for 800 mg daily. The dose used in this study was lower — 150 and 300 mg daily.

New research shows how cholesterol medicine has beneficial effect on immune defence system

In continuation of my update on simvastatin,  

The cholesterol medicine simvastatin, which is one of the most commonly used pharmaceuticals in the world, also has a beneficial effect on the immune defence system with regard to diseases such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Danish researchers have now explored why this is so, and their findings may result in improved treatment.

New research from Aarhus University has demonstrated how simvastatin, one of the most commonly used medicines in the world - typically prescribed to reduce cholesterol - also has a direct effect on the immune defence system. This discovery opens up new opportunities for treating chronic inflammatory diseases.

Sought-after explanation of unexpected effect

The immune defence system, which normally protects the body against infections and foreign bodies, sometimes attacks the body's own tissue. This error in the immune system - whose cause is unknown - results in a chronic state of inflammation which breaks down the tissue. This, in turn, triggers diseases such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes.

In the case of multiple sclerosis, the immune defence system destroys the central nervous system, while the inflammation affects the kidneys, eyes and sense of touch in both type 1 and type 2 diabetes, leading to a variety of complications. However, simvastatin has been shown to reduce the level of inflammation in these diseases, even though it sometimes has to be administered in high concentrations to have any effect. The reason why it does so has eluded researchers thus far.

"Simvastatin - and statins in general - are not designed to have this effect. We have now identified a new mechanism that forms the basis for the effect, and this opens up new opportunities for developing a better substance to combat these inflammatory diseases. It's an interesting line to pursue because a great many people can take statins without significant side effects," relates Thomas Vorup-Jensen, Professor at the Department of Biomedicine at Aarhus University.

The reason for the positive effect is that the pharmaceutical acts as a 'plug' in the proteins that retain the immune cells in the inflammation zones. With the plug in place, the immune cells can no longer contribute to the inflammation, which is therefore reduced, leaving the patient feeling better. In the case of diabetes, for example, it can help reduce the risk of patients developing complications.

"We initially observed this mechanism in the laboratory. Of course, we now need to establish whether it works in the same way in vivo, but we think it's likely," says Thomas Vorup-Jensen.

FDA approves new topical retinoid gel for OTC treatment of acne

The U.S. Food and Drug Administration today approved Differin Gel 0.1% (adapalene), a once-daily topical gel for the over-the-counter (OTC) treatment of acne. Differin Gel 0.1% is approved for use in people 12 years of age and older.

Differin Gel 0.1% is the first in a class of drugs known as retinoids to be made available OTC for the treatment of acne, and contains the first new active ingredient for acne treatment for OTC use since the 1980s. Differin Gel 0.1% was originally approved in 1996 as a prescription product for the treatment of acne vulgaris in patients 12 years of age and older.

"Millions of consumers, from adolescents to adults, suffer from acne," said Lesley Furlong, M.D., deputy director of the Office of New Drugs IV in the FDA's Center for Drug Evaluation and Research. "Now, consumers have access to a new safe and effective over-the-counter option."

Acne is a common skin disease that affects approximately 50 million people in the United States. Acne pimples form when hair follicles of the skin clog up. Generally, pimples form on the face, neck, back, chest and shoulders. Anyone can get acne, but it is most common in teenagers and young adults. Acne can cause scarring and have adverse psychological effects (for example, poor self-image, depression and anxiety). Several OTC and prescription treatment options are available for people with acne.

Women who are pregnant, planning to become pregnant, or breast-feeding should ask a doctor before use. While topical retinoid products are often prescribed as first-line therapies for acne of all levels of severity, either alone or in combination with other treatments, Differin Gel 0.1% is the first retinoid acne treatment to be made available OTC. While there have been no adequate and well-controlled studies of Differin Gel 0.1% in pregnant women, there is no specific evidence that Differin Gel 0.1%, when used topically as directed, causes birth defects in humans. Some other retinoid drugs have been shown to cause birth defects.

Differin Gel's safety and efficacy were initially established based on five clinical trials in people with mild to moderate acne. To support approval for OTC marketing, the data accrued from 1996-2016 on post-marketing safety, data from consumer studies (a label comprehension study, a self-selection study, and an actual use trial), and data from a maximal use trial were submitted.

Overall, results from the consumer studies showed that consumers can understand the information on the OTC label, appropriately select whether the product is right for them, and use the product appropriately. The maximal use trial, a study of absorption of the drug through acne-affected skin when applied daily over a large surface area (face, shoulders, upper back and chest), demonstrated that absorption is limited, thus supporting safe use of Differin Gel 0.1% by people using it OTC.

Consumers should follow the Drug Facts label and consult with their health care providers if their symptoms do not improve. The drug should be applied once daily in a thin layer on the affected areas of skin, and it is for external use only. Differin Gel 0.1% should not be used on damaged skin (for example, cuts, abrasions, eczema, or sunburn). People using Differin Gel 0.1% should avoid sunburn and avoid product contact with their eyes, lips and mouth. Differin Gel 0.1% should not be used by people who are allergic to the product. In the first few weeks of use, skin may become irritated (redness, itching, dryness, burning). Consumers should stop use and ask a doctor if irritation becomes severe, if there is no improvement in acne after three months of daily use, if symptoms of allergic reaction appear, or if they become pregnant or are planning to become pregnant while using the drug.

Transplant drug rapamycin may reduce nerve damage, neuropathic pain after spinal cord injury

In continuation of my update on rapamycin

New research in mice indicates that a drug commonly used to suppress the immune system in recipients of organ transplants may also reduce tissue damage and neuropathic pain after spinal cord injury. The findings are published in the Journal of Orthopaedic Research.

   rapamycin

Rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, has a variety of cellular functions and is known to possess both immunosuppressant and anti-tumor properties. In their previous work, investigators at the Tohoku University Graduate School of Medicine in Japan found that rapamycin treatment can reduce nerve damage and locomotor impairment after spinal cord injury. In this latest study, the team examined whether rapamycin also reduces neuropathic pain, a state of chronic pain resulting from injury to the nervous system.

Using a mouse model of thoracic spinal cord contusion injury, the researchers divided the mice into rapamycin-treated and control groups. Rapamycin treatment four hours after spinal cord injury significantly improved locomotor function and reduced mechanical and thermal hypersensitivity in the hindpaws. Close examination of the mechanisms involved revealed that treatment decreased the activity of various pathways involved in pain.

If the findings hold true in humans, rapamycin could provide considerable benefits to spinal cord injury patients, up to 80 percent of whom experience clinically significant pain that is described as burning, stabbing, and electric shock-like. "Further studies to clarify the impact and full effects of mTOR signaling are needed in order to support the clinical use of mTOR inhibitors in patients with spinal cord injury," the authors wrote.

FDA approves new topical retinoid gel for OTC treatment of acne

The U.S. Food and Drug Administration today approved Differin Gel 0.1% (adapalene), a once-daily topical gel for the over-the-counter (OTC) treatment of acne. Differin Gel 0.1% is approved for use in people 12 years of age and older.

Differin Gel 0.1% is the first in a class of drugs known as retinoids to be made available OTC for the treatment of acne, and contains the first new active ingredient for acne treatment for OTC use since the 1980s. Differin Gel 0.1% was originally approved in 1996 as a prescription product for the treatment of acne vulgaris in patients 12 years of age and older.

"Millions of consumers, from adolescents to adults, suffer from acne," said Lesley Furlong, M.D., deputy director of the Office of New Drugs IV in the FDA's Center for Drug Evaluation and Research. "Now, consumers have access to a new safe and effective over-the-counter option."

Acne is a common skin disease that affects approximately 50 million people in the United States. Acne pimples form when hair follicles of the skin clog up. Generally, pimples form on the face, neck, back, chest and shoulders. Anyone can get acne, but it is most common in teenagers and young adults. Acne can cause scarring and have adverse psychological effects (for example, poor self-image, depression and anxiety). Several OTC and prescription treatment options are available for people with acne.

Women who are pregnant, planning to become pregnant, or breast-feeding should ask a doctor before use. While topical retinoid products are often prescribed as first-line therapies for acne of all levels of severity, either alone or in combination with other treatments, Differin Gel 0.1% is the first retinoid acne treatment to be made available OTC. While there have been no adequate and well-controlled studies of Differin Gel 0.1% in pregnant women, there is no specific evidence that Differin Gel 0.1%, when used topically as directed, causes birth defects in humans. Some other retinoid drugs have been shown to cause birth defects.

Differin Gel's safety and efficacy were initially established based on five clinical trials in people with mild to moderate acne. To support approval for OTC marketing, the data accrued from 1996-2016 on post-marketing safety, data from consumer studies (a label comprehension study, a self-selection study, and an actual use trial), and data from a maximal use trial were submitted.

Overall, results from the consumer studies showed that consumers can understand the information on the OTC label, appropriately select whether the product is right for them, and use the product appropriately. The maximal use trial, a study of absorption of the drug through acne-affected skin when applied daily over a large surface area (face, shoulders, upper back and chest), demonstrated that absorption is limited, thus supporting safe use of Differin Gel 0.1% by people using it OTC.

Consumers should follow the Drug Facts label and consult with their health care providers if their symptoms do not improve. The drug should be applied once daily in a thin layer on the affected areas of skin, and it is for external use only. Differin Gel 0.1% should not be used on damaged skin (for example, cuts, abrasions, eczema, or sunburn). People using Differin Gel 0.1% should avoid sunburn and avoid product contact with their eyes, lips and mouth. Differin Gel 0.1% should not be used by people who are allergic to the product. In the first few weeks of use, skin may become irritated (redness, itching, dryness, burning). Consumers should stop use and ask a doctor if irritation becomes severe, if there is no improvement in acne after three months of daily use, if symptoms of allergic reaction appear, or if they become pregnant or are planning to become pregnant while using the drug.

Ticagrelor drug shows minor added benefit for patients with history of myocardial infarction

The German Institute for Quality and Efficiency in Health Care (IQWiG) assessed the added benefit of ticagrelor for patients with acute coronary syndrome already in 2011 in its very first dossier assessment, just after the Act on the Reform of the Market for Medicinal Products (AMNOG) had come into force. It was shown then that the drug provided considerable added benefit to patients with mild myocardial infarction without the typical changes in the ECG or with unstable angina pectoris. There was no corresponding proof for severe myocardial infarction.

The approval has now been expanded: Ticagrelor is approved for co-administration with low-dose acetylsalicylic acid (ASA) for prevention of atherothrombotic events after an initial one-year treatment also in specific patients whose myocardial infarction occurred at least one year ago. IQWiG investigated whether the drug has advantages in comparison with the appropriate comparator therapy also for this therapeutic indication. According to the findings, there is an indication of an added benefit with the extent "minor".

Myocardial infarction must have occurred one to three years ago

The expansion of approval applies to adults with a high risk of developing another atherothrombotic event whose myocardial infarction occurred one to three years ago. Risk factors are the following: age of at least 65 years, diabetes mellitus requiring medication, more than one previous myocardial infarction, multivessel coronary heart disease, or chronic renal impairment.

Ticagrelor at a dose of 60 mg is co-administered with ASA for prevention, whereas dosage of the initial treatment (myocardial infarction less than one year ago) is 90 mg. The Federal Joint Committee (G-BA) specified ASA monotherapy under continued basic therapy of the myocardial infarction and measures to achieve an adequate lifestyle as appropriate comparator therapy.

Benefit assessment on the basis of the PEGASUS study

The assessment was conducted based on the three-arm randomized study PEGASUS-TIMI 54. All patients received unblinded ASA as basic therapy and, blinded, ticagrelor in dosages of 60 mg or 90 mg or placebo. Data from the 60 mg arm and the placebo arm were compared for the benefit assessment. About three quarters of these patients complied with the approval, thus constituting the subpopulation relevant for the assessment.

Advantages in mortality and morbidity, but also disadvantages

An indication of an added benefit of the combination in comparison with ASA monotherapy was shown in all-cause mortality. There were also indications of an added benefit in the morbidity outcomes "cardiovascular mortality, nonfatal myocardial infarction and nonfatal stroke" as well as "myocardial infarction".

Data on health-related quality of life were not recorded in the study. In the outcome category of side effects, there was an indication of greater harm from ticagrelor regarding both discontinuation due to adverse events (including bleeding) and severe bleeding, and proof of greater harm from ticagrelor regarding dyspnoea.

These disadvantages did not completely outweigh the advantages, particularly in all-cause mortality. In summary, there is an indication of a minor added benefit of ticagrelor in combination with ASA in comparison with ASA monotherapy for the prevention of atherothrombotic events in patients at risk and a history of myocardial infarction.

Inhalable ibuprofen holds potential to treat cystic fibrosis

In continuation of my update on Ibuprofen 

Ibuprofen: You can buy it at any drug store, and it will help with that stabbing headache or sprained ankle. One of the ways it does so is by reducing inflammation, and it is this property that may also help patients with cystic fibrosis.

Research has found that ibuprofen, when taken at high doses, helps slow the progression of lung function decline in people with cystic fibrosis, a disease caused by having two 'bad' copies of a gene that codes for a protein important in fluid secretion. Improved lung function is important, given that most people diagnosed die by their early 50s, usually due to chronic lung infections caused by their inability to move particles, including bacteria, up and out of the lungs. The downside is that ibuprofen doses that high, when taken routinely, can result in gastrointestinal (GI) bleeding and—when combined with the antibiotics that these patients often have to take for their recurring lung infections—acute kidney injury.

But what if you could get the drug just to the area that needs it: the lungs? You could harness ibuprofen's benefits without the negative side effects.

Carolyn Cannon, MD, PhD, an associate professor at the Texas A&M Health Science Center College of Medicine, is working on a way to do just that.

"We feel that nanoparticle ibuprofen delivered by aerosol to the lungs would be a fantastic therapeutic," Cannon said. And because it is essentially a repurposed drug—only the delivery method is different—the development and regulatory approval process should be relatively easy, in comparison to the requirements for a novel therapeutic.

"The researchers who performed the original ibuprofen study thought it was working solely by inhibiting the migration of a type of white blood cell, called the neutrophil, to the lung. It goes hand-in-hand with acute inflammation," Cannon said. "However, although this may be one mechanism of action, at the high doses that were being given to the cystic fibrosis patients, the drug also has antimicrobial properties."

The inhaled ibuprofen would work in conjunction with the antibiotics the patient is already being given for the underlying infection. "We determined that not only does ibuprofen act as an antimicrobial itself, it is also synergistic with the antibiotics we already give to these patients," Cannon said.

"Together, they kill the pathogens much better than either one does alone and we could get the same great effects of the high concentrations of ibuprofen without the side effects."

Cannon and her team are pursuing international patent protection on this technology and, in the next year or so, hope to begin discussions with the Food and Drug Administration (FDA) about working towards receiving Investigational New Drug (IND) status to allow for future clinical trials.

"We have several nanoparticle formulations, one of which, developed by our collaborator, Dr. Hugh Smyth at the University of Texas in Austin, is almost pure ibuprofen," Cannon said. "We are excited about this formulation, but we still have to prove that it achieves our goal of high lung concentrations of the drug and low systemic concentrations."

To test this, this summer Cannon and Smyth and their teams plan to deliver the ibuprofen nanoparticles to the lungs of animal models and measure the drug concentrations in the lungs and serum at different time points. "This type of experiment addresses the pharmacokinetics of the drug and aims to investigate our hypothesis that we can achieve high local concentrations in the lung while maintaining low systemic concentrations," Cannon said. She and her collaborators will also investigate the capacity of the ibuprofen nanoparticles to improve pneumonia survival rates in animal models.

"The staff in the Office of Technology Translation at the Health Science Center have been wonderful through the whole process," Cannon said. "They have served as advocates for our projects with the Texas A&M Technology Commercialization (TTC) team, which has helped actualize our vision to move our inventions from the lab into use by patients."

Diabetes drug metformin could help reduce toxic acid levels linked to MSUD

In continuation of my update on metformin 

Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the dysfunction of an enzyme which breaks down three essential amino acids: leucine, isoleucine and valine. Left untreated, infants die from a toxic buildup of resulting keto-acids within weeks of birth. Those who are diagnosed early can live a normal life, but are forced to eat a very controlled, formula-based diet. The only proven treatment for the disease, which is characterized by sweet-smelling urine, is a liver transplant. Publishing in Scientific Reports, researchers at the Buck Institute show that the widely-used diabetes drug metformin reduces the toxic acid levels associated with MSUD in both skin cells derived from MSUD patients and in mice. The discovery offers the possibility of a new treatment for a disorder identified 1 in 180,000 births.

Senior author and Buck faculty Arvind Ramanathan, PhD, says metformin reduced the levels of toxic ketoisocaproic acid (KIC) in patient-derived fibroblasts by 20 to 50 percent and significantly reduced KIC levels in the skeletal muscle of mice bred to have the disease by 69 percent. "We think there is a clear path to a clinical trial and we are hoping that physicians who treat MSUD patients will start pushing in that direction," he said. "There is a definite need for novel interventions."

Ramanathan, who specializes in metabolomics, came to the MUSD discovery as he was studying various compounds and the enzymes they impact in the context of aging. The work could provide a mechanistic explanation for metformin's success in controlling diabetes and possibly extending healthspan in both animals and humans. The research also highlights similarities between a rare pediatric disease and normal aging - and shows how studying one can inform the other.

Researchers studied the enzyme BCKDH, which is defective in MSUD and also decreases in activity with normal aging. Ramanathan says decreased BCKDH is implicated in obesity and diabetes; he believes it may be involved in a number of other age-related conditions as well. Ramanathan also studied an enzyme upstream of BCKDH - called BCAT. He says in MSUD, BCAT converts leucine, isoleucine and valine to toxic ketones in the mitochondria of skeletal muscle -resulting in the muscle weakness and atrophy associated with MUSD. "We think the same process may be afoot with age-related sarcopenia and frailty," he said. "Interestingly, metformin interacts with BCAT and in our MSUD mice treatment with metformin significantly reduced toxic acid buildup in the skeletal muscle."

"This is a prime example how aging research can have a significant impact on people at any age and the work also highlights the value of studying drugs already approved by the FDA," said Brian Kennedy, PhD, senior co-author and Buck Institute CEO. "In this case, we hope our discovery will help those living with MUSD. We plan on building on these insights to further our research aimed at extending the healthy years of life for all of us."

Deutetrabenazine may help improve chorea symptoms in patients with HD

People with Huntington disease (HD) experienced improvements in chorea while taking deutetrabenazine (SD-809) compared to placebo, according to a paper published today in the Journal of the American Medical Association (JAMA). Although the topline results of the trial have been released previously, the complete peer-reviewed publication about the First-HD clinical trial is now published in a premier medical journal.

Deutetrabenazine was investigated in the First-HD study, a Phase 3 clinical trial which was led by the Huntington Study Group (HSG) on behalf of Teva Pharmaceuticals. In the double-blind, placebo-controlled trial, deutetrabenazine significantly decreased chorea, the involuntary movements that many individuals with HD experience.

"Patients' chorea and motor scores improved compared to placebo over the course of 12 weeks," said Samuel Frank, MD, HSG's principal investigator of First-HD and director of the Huntington Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center in Boston. "In addition, both the participants and their study physicians reported overall improvement."

First-HD enrolled 90 patients at 34 HSG research sites between August 2013 and August 2014. The trial followed patients for 12 weeks on the medication and measured their chorea, as well as patients' and clinicians' impression of improvement.

"As a physician who cares for people with HD, it's gratifying to see positive results from a well-designed, fully enrolled trial. Until we find a cure, we aim to bring our patients more treatment options to relieve symptoms," Frank said. "We are grateful to the people who participated in this trial and their families and support systems that made their participation possible. Research in the HD community depends on volunteers enrolling in trials."

At the end of May, Teva Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) asked for more data on deutetrabenazine, which had been under review to treat chorea associated with HD. The request for more data is common when the FDA is asked to approve new medications, and this is the first deuterated compound to be reviewed by the FDA. Michael Hayden, M.D., Ph.D., Teva's president of Global R&D and chief scientific officer said Teva plans to respond to the request in the third quarter of 2016.

There is only one drug currently approved to treat chorea associated with Huntington disease: tetrabenazine. Deutetrabenazine is structurally related to tetrabenazine with deuterium atoms placed at key positions in the molecule, prolonging plasma half-life and reducing metabolic variability, without changing target pharmacology. This can translate into effective symptom control with fewer medication doses a day, lower total daily doses, and improved tolerance. In First-HD, both patient and clinician overall assessments were significantly better in the deutetrabenazine treated group compared to placebo after 3 months. The deutetrabenazine group improved in a quality of life measure while the placebo group worsened.

"Overall status and quality of life measures are especially relevant in chorea, where no single number captures what is clinically meaningful to patients themselves," said Claudia Testa, MD, PhD, HSG's co-principal investigator for First-HD and director of the HDSA Center of Excellence at Virginia Commonwealth University. "It's exciting to see how treating an HD symptom can make a real-life positive impact."