Phase I study of triple drug combination shows promise in multiple myeloma patients

In continuation of my updates on Dexamethasone,  Plitidepsin and  Bortezomib 

Dexamethasone    Plitidepsin

 Bortezomib 

PharmaMar (MSE:PHM) announces the positive results from a Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Dr María Victoria Mateos, MD of the Hematological Department of the University Hospital of Salamanca, Spain, the principal investigator of the study, will present the results in an oral session on June 3rd, 2016 during the 52nd Congress of the American Society of the Clinical Oncology (ASCO), taking place in Chicago (USA), June 3 - 7.

The primary objective of this 20-patient study was to identify the recommended dose for the triple combination (dexamethasone / bortezomib / plitidepsin) administered every four weeks. Efficacy and the safety profile were also evaluated. The overall response rate (ORR) was 56%, including very good partial responses (VGPR) in 33% of the patients and a remarkable partial remission in one triple refractory patient. The median progression free survival (PFS) was 8.3 months. Additionally, 90% of the patients showed a DOR of 6 months or more and clinical benefit was observed in 72% of the patients.

Dose limiting toxicities were not seen in any of the evaluated patients; therefore, the full dose of plitidepsin and bortezomib when used alone were established as the recommended dose for the triple combination. The treatment was well tolerated. The hematological toxicity was manageable and the non-hematological toxicity was in general mild, with the exception of one case of creatinine increase.

Out of the 20 patients that participated in the study, 10 are still under the treatment. The median age was 65. All patients had relapsed after previously receiving, on average, 3.5 therapeutic regimens (range 1-10). Forty-five percent of these patients had been subject to a hematopoietic stem cell transplant (8 autologous, 1 allogeneic). Of the 18 patients evaluable for efficacy, 83% (15 patients) had previously received bortezomib and lenalidomide. One was refractory to bortezomib and seven to lenalidomide.

In abstract #8006, Dr María Victoria Mateos and her team explain that despite the recent progress in the treatment of multiple myeloma due to the introduction of proteasome inhibitors (PIs), the new immunomodulatory drugs (IMIDs), and monoclonal antibodies, the illness is still incurable. Therefore, active compounds with novel mechanisms of action and adequate safety profile are needed. Plitidepsin targets the eukaryotic Elongation Factor eEF1A2, an overexpressed protein in multiple myeloma that contributes to its pathogenesis. The positive results from this study will be added to the already extensive data package from Phase II and Phase III trials, where plitidepsin has shown activity and a favorable safety profile in combination with dexamethasone.

DECT trial shows combination of epirubicin and trastuzumab improves outcomes in breast cancer patients

In continuation of my update on epirubicin 

The study entitled "A phase II neoadjuvant sequential regimen of docetaxel followed by high-dose epirubicin in combination with cyclophosphamide administered concurrently with trastuzumab. The DECT trial" has recently appeared in the Journal of Cell Physiology, an international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research of Philadelphia, Temple University Pennsylvania, USA and the Department of Medicine Surgery and Neuroscience at University of Siena.

 epirubicin

"The use of trastuzumab, a monoclonal antibody targeting the HER2 receptor, has dramatically improved the prognosis of the subgroup of breast cancer patients whose tumors overexpress this specific receptor. One of the greatest challenges in these patients has been combining trastuzumab with extremely effective drugs such as anthracyclines at the cost of an acceptable toxicity. Initial evidence seemed to discourage this approach due to the high-rate of cardiotoxicity, i.e., 27%, reported in the pivotal phase III trial of metastatic breast cancer from Slamon and colleagues. Subsequent studies have partly downsized these results. Yet, several doubts have remained concerning the combined use of these drugs. The DECT trial was design to further address this key question. We also used the data from this randomized trial to interpret treatment efficacy in light of hormonal and metabolic determinants, including the expression of estrogen and progesterone receptors and body mass index," says Prof. Antonio Giordano.

"We enrolled 45 HER2-positive breast cancer patients with locally advanced or operable HER2-positive disease to test the efficacy and toxicity of epirubicin combined with trastuzumab. We observed an exceptionally high rate of responses, particularly in the subgroup of patients with inflammatory disease, and no relevant toxicity, including cardiotoxicity. In addition, some specific disease-and patient-related features were associated with better outcomes. More specifically, the highest chances of optimal response were associated with the lack of hormone receptors and higher BMI," says Dr. Maddalena Barba, researcher at the Regina Elena National Cancer Institute of Rome.

"Although current guidelines discourage from the concurrent use of trastuzumab and anthracyclines in HER2-positive breast cancer, we challenged once more the available evidence by administering a less cardiotoxic anthracycline, i.e., epirubicin at a high dose. The results obtained were remarkable in terms of efficacy and absolutely encouraging in terms of toxicity. In addition, our finding on BMI may deserve further investigation in future studies of HER2-positive breast cancer. The goal we pursue is to define the HER2-positive patient profile which better matches with the highest efficacy at the price of an absolutely acceptable toxicity, including cardiotoxicity," clarifies and concludes Prof. Giordano, a renowned expert in breast cancer.

Investigational drug abemaciclib shows durable clinical activity for variety of cancer types

In continuation of my  updates on palbociclib (Ibrance)  and letrozole

Bottom Line: The investigational anticancer therapeutic abemaciclib, which targets CDK4 and CDK6, showed durable clinical activity when given as continuous single-agent therapy to patients with a variety of cancer types, including breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, and melanoma, according to results from a phase I clinical trial.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Senior authors: Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, and Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston.

Background: In February 2015, the U.S. Food and Drug Administration (FDA) approved the CDK4/6 inhibitor palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer.

  letrozole  palbociclib

The oral CDK4/6 inhibitor abemaciclib is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity, according to Shapiro. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays, he said. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors, he added.

 abemaciclib

How the Study Was Conducted and Results: Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was grade 3 fatigue.

In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.

Radiographic responses were observed for some patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor-positive breast cancer, 11 had a partial response, with four of the 11 responders having continued prior endocrine therapy, and an additional 18 patients had stable disease. Among the 68 patients with NSCLC, two had a partial response and 31 had stable disease; one patient who had a partial response and 12 who had stable disease were known to have KRAS-mutant NSCLC. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively.

Author Comment: "These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers," said Shapiro.

"The results of the trial supported the FDA decision to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor-positive advanced or metastatic breast cancer," added Patnaik.

Limitations: Patnaik explained that because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases, she noted.

Maternal pregabalin exposure linked to major birth defect risk

 

In continuation of my update on Pregabalin 

First trimester exposure to pregabalin may be associated with an increased risk of major birth defects (MBDs), an observational study suggests.

The data from eight Teratology Information Services in seven countries on 164 exposed pregnancies showed that the risk of MBDs was increased a significant threefold compared with 656 unexposed pregnancies.

After limiting the findings to just first trimester exposure and excluding chromosomal aberration syndromes, the rate of major congenitalmal formations was 6.0% among 116 infants exposed to pregabalin as neonates versus 2.1% among 580 unexposed infants. These included four chromosomal and eight structural anomalies affecting the central nervous system (CNS), or the skeletal, cardiac, and skin or vascular systems.

"Our results raise a signal for a possible increase in the rate of MBD after pregabalin treatment during the first trimester of pregnancy", say researcher Ursula Winterfield (Centre Hospitalier Universitaire
Vaudois, Lausanne, Switzerland) and colleagues.

The rate of CNS malformations alone was also significantly higher following pregabalin exposure, increased sixfold, at 3.2% compared with  0.5%.

The researchers note that in all four cases of CNS malformations, the mother had been concurrently taking other substances during pregnancy  in addition to pregabalin and genetic causes have not been ruled out,  but they add: "[G]iven that pregabalin is a centrally acting agent, the possibility that these findings may signal a teratogenic effect in humans needs to be considered."

Other secondary outcomes included rates of live births, spontaneous abortions, preterm deliveries and delivery gestational age and birth weight. Of these, only the rate of live births was lower in the pregabalin-exposed group and this was primarily due to a higher rate of elective and medically indicated pregnancy terminations, suggestive of unplanned pregnancies.

Women were mainly taking pregabalin to treat neuropathic pain, but other indications included psychiatric disorders, epilepsy and restless leg syndrome.

The average daily dose of pregabalin was 150 mg; 77% of women started treatment before becoming pregnant and discontinued at a median  gestational age of 6 weeks. However, more than half of the patients continued treatment beyond this point and 33% beyond 7 weeks. First trimester pregabalin exposure occurred in 96% of patients.

Winterfield and colleagues acknowledge in Neurology that the small sample size and differences across groups in maternal conditions and exposure to concomitant medication mean definitive conclusions cannot be drawn from their findings.

But despite these limitations, Page Pennell (Harvard Medical School, Boston, Massachusetts, USA) and Kimford Meador (Stanford University School of Medicine, Palo Alto, California, USA) say in a related editorial that "this study reflects the prescribing pattern for pregabalin".

They recommend: "Each woman receiving a prescription for a neuropsychiatric indication should receive counselling about the potential risk-benefit ratio for her individually, effective birth control until pregnancy is desired, and increased monitoring during pregnancy and for her child through early neurodevelopment."

Ref : http://www.neurology.org/content/early/2016/05/18/WNL.0000000000002780

Flavopiridol drug could be effective strategy to impair brain cancer growth

Glioblastoma, the most common form of brain cancer is a deadly disease for which at present there is no cure. Now, researchers have
published research results that show how re   purposing the  old drug
flavopiridol could be an effective strategy to cut short sugar availability and impair cancer growth.

One of the most remarkable feature of glioblastoma cells is their ability to reprogram their metabolism switching towards a glycolytic energetic metabolism, which relies on high glucose uptake and consumption to sustain the cancer cell's malignant activities. However, because flavopiridol, a synthetic flavonoid already used in the past against cancer, inactivates the enzyme glycogen phosphorylase, this metabolic switching could be used as a therapeutic target. The authors set out to test whether flavopiridol could be used to restrain glioblastoma cell growth by decreasing the availability of glucose as substrate for the glycolytic process, cutting off the tumor's energy supply.

The results, published on the Journal of Cellular Physiology, comes from the Sbarro Health Research Organization (SHRO), at the Center for Biotechnology, Temple University and the University of L'Aquila and Siena in Italy.

The ability of Flavopiridol to reduce glycolisys in glioblastoma cells and inhibit their proliferation is a significant step toward deriving new treatments for what is currently an incurable form of cancer. According to Annamaria Cimini of the University of L'Aquila, lead author of the study, "This points toward a possible new use of this compound or flavopiridol-derived formulations in combination with
anti-proliferative agents in glioblastoma patients."

"The design of new flavopiridol-based formulations, aimed at starving cancer cells cutting short the sugar they're addicted to, may open up new therapeutic avenues for patients with glioblastoma," says Antonio Giordano, founder and director of the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology at Temple University in Philadelphia, PA USA in collaboration with the Department of Medicine, Surgery & Neuroscience at the University of Siena, and University of L' Aquila Italy.

 Ref : https://shrodotorg.wordpress.com/2016/05/20/old-drug-could-fight-brain-cancer-by-starving-it-to-death/

Cardioprotective effect proposed for metformin

In continuation of my update on metformin

 

A large retrospective analysis suggests that metformin could be cardioprotective in insulin-dependent patients with Type 2 diabetes.

The findings, based on data from the UK Clinical Practice Research Datalink, found a reduced risk of major adverse cardiac events (MACE) and all-cause mortality among patients taking the drug.

To minimise the effects of confounding by indication, Craig Currie (Cardiff University, UK) and co-workers analysed only patients who had been started on insulin, with metformin started simultaneously or added later.

None of the 12,020 patients analysed had prior MACE or cancer at baseline. During an average 3.5 years of follow-up, the MACE rate among the 5536 patients taking insulin plus metformin was 15.9 per 1000 person-years, compared 26.3 with per 1000 person-years among the 6484 patients taking insulin monotherapy. The all-cause mortality rate was also lower, at 21.2 versus 61.3 deaths per 1000 person-years.

After accounting for multiple confounders, including cumulative insulin exposure, patients given metformin had a significant 25% reduced risk of MACE and a 40% reduced risk of mortality, the team reports in  PLoS ONE

Among patients matched for the propensity to be prescribed metformin, outcome rates were 14.9 versus 22.2 per 1000 person-years for MACE and 23.1 versus 44.4 per 1000 person-years for mortality. The mortality difference persisted after accounting for confounders, at a 30% reduction, although the difference in MACE became nonsignificant.

The team found no association between cancer risk and metformin treatment, despite previous suggestions that it may have a protective effect.

Currie et al note that the various contraindications and cautions for metformin treatment, such as tissue hypoxia and renal impairment, mean that "the population of people receiving insulin in combination with metformin may be healthier than the monotherapy group."

Given this, and other drawbacks of a retrospective study, they conclude that more research is needed "to determine the risks and benefits of insulin in type 2 diabetes and the possible benefits associated with the administration of concomitant metformin."

 Ref : http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0153594

New drug that combines methicillin with polymer BPEI can combat MRSA

A University of Oklahoma team of chemists has developed a new antibiotic formulation to fight the sometimes deadly staph infection  caused by methicillin-resistant  S. aureus or MRSA and other antibiotic-resistant infectious bacteria. The new drug to treat MRSA combines traditional Food and Drug Administration-approved antibiotics, such as methicillin, with the polymer BPEI.

Charles Rice, principal investigator and professor in the Department of Chemistry and Biochemistry, OU College of Arts and Sciences, with team members Robert Cichewicz and Daniel Glatzhofer, both OU chemistry professors, has been able to invigorate older drugs from the penicillin family by combining them with BPEI. While this new formulation requires FDA approval, the approach restores efficacy to obsolete antibiotics.

"The use of first-line antibiotics to kill MRSA or other infectious bacteria will improve patient outcomes and lower the economic burden,"  Rice said. "The discovery in our laboratory has made it possible to create an effective antibiotic that can reduce expensive hospitalization costs."

Leading up to the discovery, Rice was working in his laboratory when he discovered a way to neutralize the MRSA bacteria so that it is no longer resistant to methicillin. This method can be used to neutralize other infectious bacteria. The takeaway from these experiments is that any number of penicillin-type drugs combined with BPEI or related polymers could create a new first-line drug for treating infectious diseases and change how MRSA and other infectious bacteria are treated.

The Centers for Disease Control considers MRSA a serious threat to human health. MRSA infected 80,500 people in 2011 and nearly one in seven cases resulted in death. When MRSA colonies invade host tissue, they release toxins that cause tissue injury leading to patient morbidity. Until now, more costly and highly toxic antibiotics of last resort were used to treat MRSA. The new first-line combo drug developed at OU by Rice and his team has the potential to change how patients with MRSA are treated.

Ref : https://ou.edu/content/publicaffairs/archives/OUTeamDevelopsNewAntibioticFormulationtoFightMRSAandOtherAntibioticResistantBacteria.html

Understanding potential of illicit drug ketamine in treating depression

In continuation of my update on Ketamine 

Advancing the understanding and treatment of psychiatric disorders is
a principal goal of neuroscientists. As mental disorders are the
leading cause of disabilities worldwide, it is concerning that there are
few effective therapeutics on the market due to the lack of knowledge
regarding pathophysiology. In particular, the main treatment for major
depressive disorders are antidepressants, which target the monoaminergic
system and include selective serotonin reuptake inhibitors (SSRIs).
However, these drugs take six weeks on average before symptom relief and
many individuals are unaffected by them.

Ketamine, a synthetic analogue of PCP, has recently taken the
spotlight as a novel, fast-acting antidepressant. The benefits of
ketamine include a one-time, low-dose IV infusion, where symptoms are
alleviated within hours and which lasts for up to two weeks in patients
with depression. Even more compelling is that this regimen affects
patients with treatment-resistant depression, meaning those who do not
respond to current antidepressants. These effects are especially
important in helping individuals with depression who may be experiencing
suicidal ideation because of ketamine's fast-acting nature and it is
the only treatment effective for treatment resistant patients.

However, there are many downsides to the use of ketamine as an
antidepressant, especially with long-term or repeated use. For example,
ketamine is an illicit drug with high abuse potential, commonly known as
the party drug "Special K." Therefore, close clinical monitoring of the
use of this drug is necessary. In regards to neuroscience research in
the past decade, it has been demonstrated that chronic, low-dose
ketamine has been used to study learning and memory deficits in a rodent
model of schizophrenia. The biochemical data from these animals reveal a
change in a specific type of neuron in the brain that is important for
network activity underlying normal cognitive functioning. This begs the
question: Can ketamine work as an antidepressant without producing
cognitive deficits associated long-term use?

In order to address this question, we need to understand the molecular
mechanisms that ketamine is utilizing to produce these beneficial
antidepressant effects. Although researchers do not know exactly how
ketamine works, we know that it is in a different way than current
antidepressants on the market. There is no clear answer yet, but researchers have produced some promising results. Using ketamine to
deepen our understanding of depression will advance the field of neuroscience and ultimately lead to a more effective treatment for the  disorder.

Early aspirin benefits after minor stroke 'underestimated'

In continuation of my updates on aspirin

A meta-analysis of individual patient data has thrown light on the benefits of aspirin for secondary prevention in patients with ischaemic stroke.

The findings, published in The Lancet,  show  that the effectiveness of aspirin is limited to patients with mild or moderate stroke, but that the benefits for these patients are large, most particularly within the first 2 weeks after stroke.

Across 15,778 patients in 12 randomised trials, those who took aspirin versus placebo after a stroke had a 53% reduction in the risk of recurrent stroke within 12 weeks, with a larger effect during the first
6 weeks than the second 6 weeks, at 58% and 40%, respectively. Besides being less likely to have a recurrent stroke, patients taking aspirin also had less severe strokes when they did occur, report Peter
Rothwell (University of Oxford, UK) and co-authors.

Aspirin conferred risk reductions of 71% for disabling or fatal ischaemic stroke and 64% for fatal stroke during the first 6 weeks. It also conferred a 79% reduced risk of myocardial infarction. These
benefits remained evident up to 12 weeks of follow-up, with the largest benefits observed within the first 2 weeks. 

During the first 2 weeks, the largest risk reductions were seen for disabling or fatal stroke among patients with an initial transient ischaemic attack or minor stroke, with a 93% risk reduction compared
with a 64% reduction for all patients during the same time period. Just three trials randomised their 40,531 participants within 48 hours of the initial stroke. Among these patients, there was a clear effect of initial stroke severity; aspirin roughly halved recurrent stroke risk among patients with mild or moderate stroke, but had no effect for those with severe stroke.

Patients' risk of having a recurrent stroke fell over time, regardless of treatment, but the benefits of aspirin also declined, with no effect seen after 12 weeks. However, patients also given dipyridamole (11,937 in eight trials) saw a benefit after this point, with dipyridamole providing risk reductions of 24% for any stroke and 56% for disabling or fatal stroke, despite having no effect over the first 12 weeks.

In an accompanying commentary, Graeme Hankey             (The University of Western Australia, Perth) says the study results imply that the benefits of early aspirin may have been underestimated and its longer-term effects overestimated.Not only that, but he suggests clinicians have "been unaware of the
benefits of aspirin in reducing the severity of early recurrent ischaemic stroke, and underestimated the effect of dipyridamole in preventing long-term recurrent stroke". He says the findings "have implications for clinical practice", in that they underline the importance of rapid assessment of patients with minor symptoms and prompt administration of aspirin. And from a public health perspective, he suggests that patients with transient symptoms may be encouraged to take aspirin while waiting for medical attention.

 Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2816%2930468-8/abstract

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Early aspirin benefits after minor stroke 'underestimated'

Natural product darwinolide may help combat fatal MRSA infection

A serious and sometimes fatal bacterial infection, known as methicillin-resistantStaphylococcus aureus (MRSA), may soon be beatable thanks to the efforts of University of South Florida scientists who have isolated and tested an extract from a sponge found in Antarctica. The sponge extract, known as Dendrilla membranosa, yields a new, natural product chemical which has shown in laboratory tests that it can eliminate more than 98 percent of MRSA cells. The research team has named the new chemical "darwinolide."

The study describing their methods and results was published this week in the American Chemical Society's journal Organic Letters.

While years ago the highly-resistant MRSA infection was particularly problematic in places such as hospitals and nursing homes, it has developed into an infection that can be found in commonly-used places such as gyms, locker rooms and schools.

"In recent years, MRSA has become resistant to vancomycin and threatens to take away our most valuable treatment option against staph infections," said study co-author and USF microbiologist Dr. Lindsey N. Shaw.

MRSA is unique in that it can cause infections in almost every niche of the human host, from skin infections, to pneumonia, to endocarditis, a serious infection of tissues lining the heart. Unfortunately, the pace of the pharmaceutical industry's efforts to find new antibiotics to replace those no longer effective has slowed in recent years, said Shaw.

Like many other bacterium, the MRSA bacteria forms a biofilm.

"Biofilms, formed by many pathogenic bacteria during infection, are a collection of cells coated in a variety of carbohydrates, proteins and DNA," said Shaw. "Up to 80 percent of all infections are caused by biofilms and are resistant to therapy. We desperately need new anti-biofilm agents to treat drug resistant bacterial infections like MRSA."

USF chemistry professor Dr. Bill Baker and colleagues have literally gone to the 'ends of the Earth' to help in the fight against MRSA. Baker, who also serves as director of the USF Center for Drug Discovery and Innovation (CDDI), studies the chemical ecology of Antarctica and dives in the frigid waters near Palmer Station to retrieve marine invertebrates, such as sponges, to carry out "natural product isolation," which means drawing out, modifying and testing natural substances that may have pharmaceutical potential.

His group led the effort to extract and characterize chemical structures to create darwinolide from the freeze-dried Antarctic sponges and then test in Shaw's lab to determine its effectiveness against the MRSA bacteria.

"When we screened darwinolide against MRSA we found that only 1.6 percent of the bacterium survived and grew. This suggests that darwinolide may be a good foundation for an urgently needed antibiotic effective against biofilms," said Baker, whose research team "rearranged" the chemical composition of the extracted sponge.

In the last 70 years, despite the discovery and use of antibiotics to treat infections, bacterial disease remains the second-leading cause of death globally, especially among children and the elderly, noted the researchers. In the U.S. alone there are two million hospital acquired infections annually with at least 100,000 deaths, many resulting from bacteria resistant to current antibiotics.

"We suggest that darwinolide may present a highly suitable scaffold for the development of urgently needed, novel, anti-biofilm-specific antibiotics," concluded the researchers.

Ref : http://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b00979?journalCode=orlef7

Natural product darwinolide may help combat fatal MRSA infection: A serious and sometimes fatal bacterial infection, known as methicillin-resistant Staphylococcus aureus (MRSA), may soon be beatable thanks to the efforts of University of South Florida scientists who have isolated and tested an extract from a sponge found in Antarctica.

Ramizol drug shows promise in treatment of Clostridium difficile infections

 

A scientific paper released today in the Journal of Antibiotics presents the pre-clinical development of Ramizol, a first generation drug belonging to a new class of styrylbenzene antibiotics with a novel mechanism of action.

The research was undertaken by Australian company Boulos & Cooper Pharmaceuticals in partnership with the University of South Australia, Flinders University, Eurofins Panlabs and Micromyx LLC. The study found that over 99.9% of the drug, administered orally, stays in the gastrointestinal tract where it can reach the bacteria in the colon at high enough concentrations to yield a therapeutic effect.

Chief Executive Officer of Boulos & Cooper Pharmaceuticals, Dr Ramiz Boulos, said "this new class of antibiotics has antioxidant properties and can be manufactured for a low cost; benefits that will be felt by the end-user".

The new antibiotic has low frequency of resistance and shows promise as a monotherapy for the treatment of Clostridium difficile associated disease. Dr Boulos stated "we are very excited about these results given the unforgiving nature of Clostridium difficile infections". He added "In a world where there are few treatment options, we are desperate for new antibiotics to fight intractable infections".

Ref : http://bouloscooper.com/wp-content/uploads/2014/10/Ramizol-A-new-treatment-for-Clostridium-difficile-asociated-disease.pdf

Magic mushroom compound psilocybin could provide new avenue for antidepressant research

In continuation of my update on psilocybin

The small feasibility trial, which involved 12 people with treatment-resistant depression, found that psilocybin was safe and well-tolerated and that, when given alongside supportive therapy, helped reduce symptoms of depression in about half of the participants at 3 months post-treatment. The authors warn that strong conclusions cannot be made about the therapeutic benefits of psilocybin but the findings show that more research in this field is now needed.

"This is the first time that psilocybin has been investigated as a potential treatment for major depression," says lead author Dr Robin Carhart-Harris, Imperial College London, London, UK. "Treatment-resistant depression is common, disabling and extremely difficult to treat. New treatments are urgently needed, and our study shows that psilocybin is a promising area of future research. The results are encouraging and we now need larger trials to understand whether the effects we saw in this study translate into long-term benefits, and to study how psilocybin compares to other current treatments."

Depression is a major public health burden, affecting millions of people worldwide and costing the US alone over $200 billion per year. The most common treatments for depression are cognitive behaviour therapy (CBT) and antidepressants. However, 1 in 5 patients with depression do not respond to any intervention, and many relapse.

"Previous animal and human brain imaging studies have suggested that psilocybin may have effects similar to other antidepressant treatments," says Professor David Nutt, senior author from Imperial College London "Psilocybin targets the serotonin receptors in the brain, just as most antidepressants do, but it has a very different chemical structure to currently available antidepressants and acts faster than traditional antidepressants."

The trial involved 12 patients (6 women, 6 men) with moderate to severe depression (average length of illness was 17.8 years). The patients were classified as having treatment-resistant depression, having previously had two unsuccessful courses of antidepressants (lasting at least 6 weeks). Most (11) had also received some form of psychotherapy. Patients were not included if they had a current or previous psychotic disorder, an immediate family member with a psychotic disorder, history of suicide or mania or current drug or alcohol dependence.

Patients attended two treatment days -- a low (test) dose of psilocybin 10mg oral capsules, and a higher (therapeutic) dose of 25mg a week later. Patients took the capsules while lying down on a ward bed, in a special room with low lighting and music, and two psychiatrists sat either side of the bed. The psychiatrists were present to provide support and check in on patients throughout the process by asking how they were feeling. Patients had an MRI scan the day after the therapeutic dose. They were followed up one day after the first dose, and then at 1, 2, 3, and 5 weeks and 3 months after the second dose.

The psychedelic effects of psilocybin were detectable 30 to 60 minutes after taking the capsules. The psychedelic effect peaked at 2-3 hours, and patients were discharged 6 hours later. No serious side effects were reported, and expected side effects included transient anxiety before or as the psilocybin effects began (all patients), some experienced confusion (9), transient nausea (4) and transient headache (4). Two patients reported mild and transient paranoia.

At 1 week post-treatment, all patients showed some improvement in their symptoms of depression. 8 of the 12 patients (67%) achieved temporary remission. By 3 months, 7 patients (58%) continued to show an improvement in symptoms and 5 of these were still in remission. Five patients showed some degree of relapse.

The patients knew they were receiving psilocybin (an 'open-label' trial) and the effect of psilocybin was not compared with a placebo. The authors also stress that most of the study participants were self-referred meaning they actively sought treatment, and may have expected some effect (5 had previously tried psilocybin before). All patients had agreement from their GP to take part in the trial. They add that patients were carefully screened and given psychological support before, during and after the intervention, and that the study took place in a positive environment. Further research is now needed to tease out the relative influence of these factors on symptoms of depression, and look at how psilocybin compares to placebo and other current treatments.

Writing in a linked Comment, Professor Philip Cowen, MRC Clinical Scientist, University of Oxford, Oxford, UK, says: "The key observation that might eventually justify the use of a drug like psilocybin in treatment-resistant depression is demonstration of sustained benefit in patients who previously have experienced years of symptoms despite conventional treatments, which makes longer-term outcomes particularly important. The data at 3 month follow-up (a comparatively short time in patients with extensive illness duration) are promising but not completely compelling, with about half the group showing significant depressive symptoms. Further follow-ups using detailed qualitative interviews with patients and family could be very helpful in enriching the assessment."
Ref :http://dx.doi.org/10.1016/S2215-0366(15)00576-3