The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

New research conducted by biologists at Texas A&M University suggests that sertraline (see structure below, ZOLOFT®), one of the most widely prescribed antidepressants in the world, also packs a potential preventative bonus  potent mechanisms capable of inhibiting deadly fungal infections. 

C. neoformans is a potentially dangerous fungal pathogen found in many soils throughout the world that may cause systemic infections, particularly involving the central nervous system. In most cases, the microscopic, airborne fungal cells of C. neoformans cause asymptomatic colonization in the lungs. However, Lin says the fungus is particularly aggressive in people with weakened immune systems and can spread to other parts of the body, such as the brain and spinal cord, resulting in cryptococcal meningitis  a condition that, in absence of treatment, is fatal. 

Rapamycin effective in mouse model of inherited heart disease and muscular dystrophies

In continuation of my update on Rapamycin (Sirolimus)...

Rapamycin, an immunosuppressant drug used in a variety of disease indications and under study in aging research labs around the world, improved function and extended survival in mice suffering from a genetic mutation which leads to dilated cardiomyopathy (DCM) and rare muscular dystrophies in humans. There are currently no effective treatments for the diseases, which include Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy. The familial form of DCM often leads to sudden heart failure and death when those affected reach their 40s and 50s.

Scientists from the Buck Institute and other organizations focused on mutations in the gene LMNA, which produces A-type lamins. Mutations in this gene are associated with at least 13 diseases, with DCM among the most common. DCM accounts for 60 percent of all cardiomyopathy cases. LMNA mutations may account for up to one-third of patients that are diagnosed as having DCM and conduction disease. DCM causes a thinning of the left ventricle and loss of cardiac function. The study showed that deletion of the LMNA gene led to ramped up activity in the molecular pathway mTOR (mammalian target of rapamycin) and that treatment with rapamycin turns down the abnormal signaling. Senior author Brian K. Kennedy, PhD, President and CEO of the Buck Institute for Research on Aging, says treatment with rapamycin extended mouse lifespan by 60 percent in a relatively rapid onset model of disease.

Ref : http://stm.sciencemag.org/content/4/144/144ra103

Rapamycin effective in mouse model of inherited heart disease and muscular dystrophies

Once-daily Gralise significantly reduces pain intensity in PHN patients

Depomed, Inc. announced that a report of Phase 3 data published online this month, ahead of the print edition,  in the Clinical Journal of Pain showed that once-daily Gralise^® (gabapentin) tablets (1,800 mg) formulation significantly reduces intensity of pain in patients with postherpetic neuralgia (PHN). The results showed that patients treated with Gralise experienced a significant reduction (- 2.12) in their average daily pain intensity compared with placebo treated patients (-1.63; P=0.013). This difference from placebo was statistically significant after one week and continued to be superior through the duration of the study. 

About Gralise (below structure-Gabapentin) : Gabapentin (brand names Fanatrex, Gabarone, Gralise, Neurontin, Nupentin) is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain. There are, however, concerns regarding the quality of the trials conducted.

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Depomed - Investor Relations - Press Releases

New agents, Antimicrobial peptides, join the fight against antibiotic-resistant bacteria

Line Hein-Kristensen worked with a new class of antimicrobial agents, the so-called antimicrobial peptides. Antimicrobial peptides are part of the immune system in all life forms, including humans, and constitute the first line of defence against pathogenic organisms entering the body, e.g. via the food that we eat.

Antimicrobial peptides are special in that they act differently to conventional antibiotics and may thus be active against the very bacteria that are resistant to conventional antibiotics. These also include multiresistant bacteria – for example MRSA and ESBL against which we now have only a limited arsenal of treatment options.

Synthetic compound emulating nature.........................

Novel chemical methods have now made it possible to emulate the structure of natural antimicrobial peptides and thus also to develop many novel synthetic variants. Line Hein-Kristensen's PhD project focuses specifically on a series of synthetic compounds that have been designed, synthetised and characterised the Faculty of Health and Medical Sciences, University of Copenhagen.

The findings of her research show that the degree of antimicrobial activity against a range of food-borne and nosocomial (hospital-acquired) pathogenic bacteria depends on the chemical structure of custom-designed compounds. The research also shows that the synthetic antimicrobial peptides kill the bacteria by disrupting the bacterial cell membrane.

New agents join the fight against antibiotic-resistant bacteria

Ref :  http://www.dtu.dk/upload/institutter/food/publikationer/2012/phd%20thesis,%20line%20h.%20kristensen.pdf 

Memantine, Drug Shown to Improve Memory in Those With Down Syndrome

In continuation of my update on  memantine

Costa, an associate professor of medicine, and his colleagues studied 38 adolescents and young adults with Down syndrome. Half took the drug memantine, used to treat Alzheimer's disease, and the others took a placebo.

Costa's research team hypothesized that memantine, which improved memory in mice with Down syndrome, could increase test scores of young adults with the disorder in the area of spatial and episodic memory, functions associated with the hippocampus region of the brain.

Participants underwent a 16-week course of either memantine or a placebo while scientists compared the adaptive and cognitive function of the two groups.

While they found no major difference between the groups in adaptive and most measures of cognitive ability, researchers discovered that those taking memantine showed significant improvement in verbal episodic memory. One of the lowest functioning individuals in the study saw a ten-fold increase in memory skills.

"People who took the medicine and memorized long lists of words did significantly better than those who took the placebo," said Costa, a neuroscientist specializing in Down syndrome research. "This is a first step in a longer quest to see how we can improve the quality of life for those with Down syndrome."

Translational Psychiatry - Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial

Eliquis Receives Positive Opinion from CHMP | News | Drug Discovery and Development Magazine

In continuation of my update on Apixaban
Eliquis Receives Positive Opinion from CHMP | News | Drug Discovery and Development Magazine

New drug candidate shows promise against cancer - MIT Media Relations

Drugs containing platinum are among the most powerful and widely used cancer drugs. However, such drugs have toxic side effects, and cancer cells can eventually become resistant to them. Stephen J Lippard, Chemistry Professor, MIT who has spent much of his career studying platinum drugs, has now identified a compound that kills cancer cells better than cisplatin, the most commonly used platinum anticancer drug. The new compound may be able to evade cancer-cell resistance to conventional platinum compounds.

“I’ve long believed that there’s something special about platinum and its ability to treat cancer. Using new variants, we might have a chance of applying platinum to a broader range of cancer types, more successfully,” said Lippard. Lippard is senior author of a paper describing the new drug candidate, known as phenanthriplatin - which is cis-[Pt(NH₃)₂(phenanthridine)Cl]NO_3.

GEN | News Highlights:Green Tea and Gold Nanoparticles Destroy Prostate Tumors

In continuation of my update on green tea

Scientists report on the development of a radioactive gold nanoparticle for prostate cancer therapy that they claim is far less toxic to normal tissues than traditional radiation therapy and results in massive reduction in tumor volume and increased survival in experimental mice after just one dose. The nanoparticles, derived from the Au-198 isotope, incorporate an extract from green tea known as epigallocatechin-gallate (EGCg), which effectively latches the nanoparticles onto the prostate tumor cells and facilitates their internalization.

GEN | News Highlights:Green Tea and Gold Nanoparticles Destroy Prostate Tumors

Scientists develop new strategy to overcome drug-resistant childhood cancer

Researchers at The Institute of Cancer Research in London have found a way to overcome the resistance of cancer cells to a drug called crizotinib, which recently showed positive early results in its first trial in children with cancer.

Crizotinib (see structure) has already been licensed by the US Food and Drug Administration for use in adult cancers, but early experience suggests tumours eventually stop responding to treatment, after developing additional mutations in the ALK gene targeted by the drug.

Cylene's Pol I inhibitor, CX-5461 activates p53 and selectively destroys cancer cells

Cylene Pharmaceuticals  announced that research collaborators at the Peter MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia have established, for the first time, that RNA Polymerase I (Pol I) activity is essential for cancer cell survival and that its inhibition selectively activates p53 to kill tumors. Findings show that Cylene's Pol I inhibitor, CX-5461 (see structure), selectively destroys cancer by activating p53 in malignant but not in normal cells.

The researchers repeated these studies with in vivo models of blood cancers and demonstrated that the drug removed malignant cells from the bloodstream, while allowing normal healthy blood cells to grow, thus differentiating CX-5461 from genotoxic treatments. Targeting cancer's dependence upon Pol I to trigger cancer-specific activation of p53 signifies an entirely new approach to cancer therapy.

"The combination of cancer's reliance on Pol I, the impressive preclinical activity of CX-5461, the development of clear predictive and prognostic biomarkers and the novelty of the therapeutic strategy is compelling," continued Dr. Rice. "As such, a First-in-Human clinical trial with CX-5461 is planned in collaboration with our colleagues at Peter Mac later this year."

An unanticipated finding was that malignant cells are considerably more dependent upon maintenance of high levels of Pol I activity than previously believed, and even modest inhibition of Pol I triggers cancer cell death. These results suggest that selective activation of a surveillance pathway to activate p53, using Pol I inhibitors such as CX-5641, is likely to be therapeutically useful in the treatment of a wide range of tumors. In addition, as a cancer-specific inducer of p53, CX-5461 was shown to be 300 times more potent than currently studied non-genotoxic p53 activators with alternate mechanisms.

Cylene's Pol I inhibitor activates p53 and selectively destroys cancer cells

Merck's Phase III trial assessing fracture risk reduction with odanacatib..

Merck announced   an update on the Phase III trial assessing fracture risk reduction with odanacatib, (a cathepsin K/cat-K inhibitor see structure below). The Data Monitoring Committee (DMC) for the study recently completed its first planned interim analysis for efficacy and recommended that the study be closed early due to robust efficacy and a favorable benefit-risk profile. As a result, Merck will begin taking steps to close the trial. The DMC noted that safety issues remain in certain selected areas and made recommendations with respect to following up on them. Merck's previously announced plan to conduct a blinded extension trial will allow further monitoring of the issues. The extension trial will also continue to measure efficacy.    

Merck anticipates submitting regulatory applications for approval of odanacatib in the U.S., European Union (EU) and Japan in the first half of 2013.

"We are encouraged by the Data Monitoring Committee's recommendation to close the trial early," said Peter S. Kim, Ph.D., executive vice president, Merck and president,

Merck Research Laboratories, "and look forward to reviewing the data with the scientific community to bring forward this innovation."

Drug from Mediterranean weed kills tumor cells in mice

The drug G202 is chemically derived from a weed called Thapsia garganica that grows naturally in the Mediterranean region. The plant makes a product, dubbed thapsigargin (see the structure,  that since the time of ancient Greece has been known to be toxic to animals. In Arab caravans, the plant was known as the "death carrot" because it would kill camels if they ate it, the researchers noted.

Thapsigargin is, 

(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-(acetyloxy)-4-(butyryloxy)-3,3a-dihydroxy-3,6,9-trimethyl-8-{[(2Z)-2-methylbut-2-enoyl]oxy}-2-oxo-2,3,3a,4,5,6,6a,7, 8, 9b-decahydro azuleno[4,5-b]furan-7-yl octanoate)

"Our goal was to try to re-engineer this very toxic natural plant product into a drug we might use to treat human cancer," says lead study author Samuel Denmeade, M.D., professor of oncology, urology, pharmacology and molecular sciences. "We achieved this by creating a format that requires modification by cells to release the active drug."

By disassembling thapsigargin and chemically modifying it, the researchers created a form that Denmeade likens to a hand grenade with an intact pin. [Thapsigargin prodrug G-202, is a cytotoxic analog of thapsigargin, 8-O-(12Aminododecanoyl)-8-O debutanoylthapsigargin (12-ADT) linked, via a carboxyl group, to the targeting peptide containing aspartic acid].

The drug can be injected and can travel through the bloodstream until it finds the site of cancer cells and hits a protein called prostate-specific membrane antigen (PSMA). PSMA is released by cells lining tumors of the prostate and other areas, and in effect "pulls the pin" on G202, releasing cell-killing agents into the tumor and the blood vessels that feed it, as well as to other cells in the vicinity. Specifically, G202 blocks the function of a protein called the SERCA pump, a housekeeping protein necessary for cell survival that keeps the level of calcium in the cell at the correct level, the researchers report.

"The exciting thing is that the cancer itself is activating its own demise," says senior study author John Isaacs, Ph.D., professor of oncology, urology, chemical and biomedical engineering at Johns Hopkins.

Because the drug is targeted to the SERCA pump, which all cells need to stay alive, researchers say it will be difficult for tumor cells to become resistant to the drug, because they cannot stop making the protein.

More : http://stm.sciencemag.org/content/4/140/140ra86

Drug from Mediterranean weed kills tumor cells in mice

Cranberry products associated with prevention of urinary tract infections

Use of cranberry-containing products appears to be associated with prevention of urinary tract infections in some individuals. 

Chih-Hung Wang, M.D., of National Taiwan University Hospital and National Taiwan University College of Medicine, and colleagues reviewed the available medical literature to reevaluate cranberry-containing products for the prevention of UTI.

"Cranberry-containing products tend to be more effective in women with recurrent UTIs, female populations, children, cranberry juice drinkers, and people using cranberry-containing products more than twice daily," the authors note.

The authors identified 13 trials, including 1,616 individuals, for qualitative analysis and 10 of these trials, including 1,494 individuals, were included in quantitative analysis. The random-effects pooled risk ratio for cranberry users vs. nonusers was 0.62, according to the study results.

"In conclusion, the results of the present meta-analysis support that consumption of cranberry-containing products may protect against UTIs in certain populations. However, because of the substantial heterogeneity across trials, this conclusion should be interpreted with great caution," the authors conclude.

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Cranberry products associated with prevention of urinary tract infections

Tolfenamic acid appears to reduce esophageal tumors

A new study by researchers at MD Anderson Cancer Center Orlando finds that Tolfenamic acid (TA, see structure), a non-steroidal anti-inflammatory drug (NSAID), commonly used to relieve pain, inflammation and migraines has now been found to reduce esophageal tumors.

The study, led by Pius Maliakal, PhD and Riyaz Basha, PhD, researchers at MD Anderson Orlando's Cancer Research Institute, found that Tolfenamic acid prevented tumor growth and lessened the size of esophageal tumors in a rat model. Tolfenamic acid has been found to decrease certain proteins that are critical for cancer cell growth and the progression of esophageal tumors.

MD Anderson Orlando researchers are at the forefront of Tolfenamic acid research. It was this same research team that found that Tolfenamic acid inhibits tumor growth in pancreatic cancer. MD Anderson Orlando is poised to begin a new Phase I Clinical Trial for pancreatic cancer patients using Tolfenamic acid in a few months.

Further research will be required before Tolfenamic acid can be used as a safe and effective drug for esophageal cancer prevention. At present, this drug is an approved anti-inflammatory agent in Europe, South America and Asia, but is not yet approved for use in the United States.

Tolfenamic acid appears to reduce esophageal tumors

Eltrombopag can raise blood cell levels in some people with severe aplastic anemia

Eltrombopag, a drug that was designed to stimulate production of platelets from the bone marrow and thereby improve blood clotting, can raise blood cell levels in some people with severe aplastic anemia who have failed all standard therapies.

About one-third of aplastic anemia cases do not respond to standard therapy, a combination of immune-suppressing drugs. Although bone marrow stem celltransplantation is an option for some, patients without a matched donor have few treatment options. The findings of this new clinical study, carried out by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, suggest eltrombopag (see structure) could be a second-line therapeutic option for them.

Aplastic anemia is a rare blood disorder, with about 600 new cases in the U.S. each year. Aplastic anemia results from the destruction of bone marrow stem cells, which mature into red blood cells that carry oxygen, white blood cells that fight infection, and platelets that prevent excess bleeding. Symptoms of the disorder include fatigue, frequent infections, and hemorrhaging. In severe cases unresponsive to treatment, death can occur.

The research team in the NHLBI Hematology Branch tested eltrombopag because this drug had previously been shown to boost platelet levels in both healthy people and people with reduced platelets due to hepatitis C infection or immune thrombocytopenia, blood disorders that like aplastic anemia result in low platelet counts and increased risk of bleeding.

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa073275