Synthesis produces new fungus-derived antibiotic

A fortuitous collaboration has led to the total synthesis of a recently discovered natural antibiotic. The laboratory recreation of a fungus-derived antibiotic, viridicatumtoxin B, may someday help bolster the fight against bacteria that evolve resistance to treatments in hospitals and clinics around the world.

As part of the process, Rice organic chemist K.C. Nicolaou and structural biologist Yousif Shamoo and their colleagues created and tested a number of variants of viridicatumtoxin B that could lead to the simplified synthesis of a new generation of more effective antibiotics.

The work reported this month in the Journal of the American Chemical Society (JACS) focused on a tetracycline discovered in 2008 by scientists who isolated small amounts from penicillium fungi. The yield wasn't nearly enough for extensive testing, but it provided a basis for the discoverers to analyze its structure through magnetic resonance imaging, Nicolaou said.

"We're inspired by molecules that are biologically active and have the potential to become medicines one day," he said.

The new discovery belongs to a class of antibiotics known as tetracyclines for their distinctive molecular structure. They proved potent  in  initial tests on
Gram-positive bacteria, so named for a staining technique to mark bacteria that are more susceptible to antibiotics than their Gram-negative counterparts.

The first tetracyclines, discovered in the late 1940s, ushered in a new class of
powerful antibacterial agents to treat high-mortality diseases,    among  them
anthrax and plague as well as such bacterial infections as chlamydia, syphilis
and Lyme disease.

To find new weapons, especially  against  "superbugs" that resist nearly all antibiotics, synthetic chemists pursue the complex  process  of  mimicking the
structures of effective natural molecules as they build drug candidates atom by atom.

"Tetracyclines are widespread antibiotics today, but bacteria are building resistance to a lot of them," Nicolaou said. "This new tetracycline is not plentiful in nature, so the only way we can make it available to study by biologists for its potential in medicine is to synthesize it in the laboratory."

Ref : http://pubs.acs.org/doi/abs/10.1021/ja506472u

Synthesis produces new fungus-derived antibiotic 

Experimental Drug Would Help Fight Ebola if Supply Increases, Study Finds - NYTimes.com

A new study provides strong evidence that the experimental drug given to two American aid workers stricken with Ebola in Africa really works and could make a difference in the current outbreak — if more of it could be produced.

In the study, all 18 monkeys exposed to a lethal dose of Ebola virus survived when given the drug, known as ZMapp, even when the treatment was started five days after infection, when the animals were already sick.

Moreover, the monkeys’ symptoms, such as excessive bleeding, rashes and signs of liver toxicity, eventually disappeared. By contrast, all three monkeys in the control group died.

Experts said these were the best monkey results reported to date for any Ebola drug, raising hopes that the drug will work in people.

Experimental Drug Would Help Fight Ebola if Supply Increases, Study Finds - NYTimes.com

Chili peppers for a healthy gut: Spicy chemical may inhibit gut tumors

In continuation of my update on capsaicin

Researchers report that dietary capsaicin – the active ingredient in chili peppers – produces chronic activation of a receptor on cells lining the intestines of mice, triggering a reaction that ultimately reduces the risk of colorectal tumors....

Chili peppers for a healthy gut: Spicy chemical may inhibit gut tumors  

Pesticide DDT linked to slow metabolism, obesity and diabetes, mouse study finds -- ScienceDaily

A new study in mice is the first to show that developmental exposure to DDT increases the risk of females later developing metabolic syndrome -- a cluster of conditions that include increased body fat, blood glucose, and cholesterol.

Pesticide DDT linked to slow metabolism, obesity and diabetes, mouse study finds  

Researchers uncover how malaria parasite becomes resistant to fosmidomycin drug

Researchers have uncovered a way the malaria parasite becomes resistant to an investigational drug. The discovery, at Washington University School of Medicine in St. Louis, also is relevant for other infectious diseases including bacterial infections and tuberculosis.

The study appears July 24 in Nature Communications.

Many organisms, including the parasite that causes malaria, make a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy, whether plants, animals or bacteria. In malaria, the investigational drug fosmidomycin blocks isoprenoid synthesis, killing the parasite. But over time the drug often becomes less effective.

"In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study," said senior author Audrey R. Odom, MD, PhD, assistant professor of pediatrics. "We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?"

Fosmidomycin, an antibiotic, is being evaluated against malaria in phase 3 clinical trials in combination with other antimalarial drugs.

Using next-generation sequencing technology, the research team compared the genetics of malaria parasites that responded to the drug to the genetics of malaria parasites that were resistant to it. With this approach, Odom and her colleagues found mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

"The PfHAD1 protein is completely unstudied," Odom said. "It's a member of a larger family of proteins, and there are almost no biological functions assigned to them."

In malaria parasites, Odom's team showed that the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing. Since isoprenoids are necessary for life, it's not clear why the organism would purposefully slow down isoprenoid production.

Ref : http://www.nature.com/ncomms/2014/140724/ncomms5467/full/ncomms5467.html

Researchers uncover how malaria parasite becomes resistant to fosmidomycin drug

Antifungal drug resistance evoked through RNAi-dependent epimutations

Microorganisms like bacteria and fungi can evade treatment by acquiring mutations in the genes targeted by antibiotics or antifungal drugs. These permanent mutations were once thought to be the only way for drug-resistant strains to evolve. Now a new study has shown that microorganisms can use a temporary silencing of drug targets -- known as epimutations -- to gain the benefits of drug resistance without the commitment.

Though the new mechanism was discovered in a fungus called Mucor circinelloides, it is likely to be employed by other fungi as well as bacteria, viruses and other organisms to withstand treatment with various drugs. The finding appears July 27, 2014, in Nature.

"This mechanism gives the organism more flexibility," said Joseph Heitman, M.D., Ph.D., senior study author and professor and chair of molecular genetics and microbiology at Duke University School of Medicine. "A classic, Mendelian mutation is a more permanent binding decision, like a traditional marriage. These epimutations are reversible, more akin to moving in together. If conditions change, it is easier to revert to the way things were."

The epimutations are so transient, in fact, that the researchers almost disregarded them. Cecelia Wall, a graduate student in Drs. Heitman and Maria Cardenas' labs, had been looking for mutations that would make the human fungal pathogen M. circinelloides resistant to the antifungal drug FK506 (also known as tacrolimus). This pathogen causes the rare but lethal fungal infection mucormycosis, an emerging infectious disease that predominantly affects individuals with weakened immune systems.

Ref:http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13575.html

Antifungal drug resistance evoked through RNAi-dependent epimutations

Flamel Technologies Announces FDA Approval of Vazculep

 Flamel Technologies (NASDAQ: FLML) today announced that the U.S. Food and Drug Administration (FDA) has approved the company's New Drug Application (NDA) for Vazculep (phenylephrine hydrochloride). Vazculep Injection is an alpha-1 adrenergic receptor agonist indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. Flamel expects to launch Vazculep in the next few months in 1 mL single use vials, and 5 mL and 10 mL pharmacy bulk package vials. The drug strength is the same in all vials at 10 mg/mL. Phenylephrine hydrochloride is used in operating rooms and is injected intravenously either as a bolus or in a dilute solution as a continuous infusion.

Flamel Technologies Announces FDA Approval of Vazculep

FDA Approves Beleodaq (belinostat) for Peripheral T-Cell Lymphoma

The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The action was taken under the agency’s accelerated approval program...

FDA Approves Beleodaq (belinostat) for Peripheral T-Cell Lymphoma

Protein once seen as promising anti-cancer compound helps to stabilize neural circuits

Researchers at UC San Francisco (UCSF) have discovered that endostatin, a protein that once aroused intense interest as a possible cancer treatment, plays a key role in the stable functioning of the nervous system.

A substance that occurs naturally in the body, endostatin potently blocks the formation of new blood vessels. In studies in mice in the late 1990s, endostatin treatment virtually eliminated cancer by shutting down the blood supply to tumors, but subsequent human clinical trials proved disappointing.

"It was a very big surprise" to find that endostatin, through some other mechanism, helps to maintain the proper workings of synapses, the sites where communication between nerve cells takes place, said Graeme W. Davis, PhD, Hertzstein Distinguished Professor of Medicine in the Department of Biochemistry and Biophysics at UCSF and senior author of the new study. "Endostatin was not on our radar."

Protein once seen as promising anti-cancer compound helps to stabilize neural circuits

FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia

Eagle Pharmaceuticals, Inc. (“Eagle” or “the Company”) (Nasdaq:EGRX) today announced that the U. S. Food and Drug Administration (FDA) has approved Ryanodex (dantrolene sodium) for injectable suspension indicated for the treatment of malignant hyperthermia (MH), along with the appropriate supportive measures. MH is an inherited and potentially fatal disorder triggered by certain anesthesia agents in genetically susceptible individuals. FDA had designated Ryanodex as an Orphan Drug in August 2013. Eagle has been informed by the FDA that it will learn over the next four to six weeks if it has been granted the seven year Orphan Drug market exclusivity.

FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia

High-dose fluticasone effective against eosinophilic esophagitis, study shows...

I continuation of y update on Fluticasone..

Results from a clinical trial show that high doses of the corticosteroid fluticasone propionate safely and effectively induce remission in many people with eosinophilic esophagitis (EoE), a chronic inflammatory disease of the esophagus characterized by high levels of white blood cells called eosinophils. However, some trial participants did not respond to fluticasone even after six months of high-dose treatments, providing evidence that certain people with EoE are steroid-resistant. By analyzing gene expression -- the degree to which certain genes are turned on or off -- in esophageal tissues, the scientists identified a cluster of genes that may help predict steroid responsiveness.

Ref :Read more

High-dose fluticasone effective against eosinophilic esophagitis, study shows

Bowel cancer breakthrough may benefit thousands of patients

Researchers at Queen's University have made a significant breakthrough that may benefit
patients with bowel cancer. 

Dr Sandra van Schaeybroeck and her team have discovered how two genes cause bowel cancer cells to become resistant to treatments used against the disease. The research, which was funded by Cancer Research UK, was published this month in the international journal CellReports.

The activity of the two genes, called MEK and MET, was uncovered when the researchers looked at all the different pathways and interactions taking place in bowel cancer cells.

Dr van Schaeybroeck and her group found that these bowel cancers switch on a survival mechanism when they are treated with drugs that target faulty MEK genes. But when the researchers added drugs that also block the MET gene, the bowel cancer cells died.

The team are now testing a new approach to target these two genes in the most aggressive forms of bowel cancer in a European Commission funded clinical trial that is being led by Dr van Schaeybroeck.

Bowel cancer breakthrough may benefit thousands of patients

Zydelig Approved for Three Types of Blood Cancer

 Zydelig (idelalisib) has been approved by the U.S. Food and Drug Administration to treat relapsed forms of blood cancer, including chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL), the FDA said Wednesday in a news release.

The approval for the three forms of blood cancer covers instances when the cancer returns despite treatment with at least one other therapy, the agency said.

The drug's label will include a boxed warning that the medication could cause liver toxicity, diarrhea, high blood sugar, elevated liver enzymes, high blood triglycerides [a blood fat] and inflammation of the colon (colitis). Other side effects noted during clinical testing included fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash.

Zydelig is marketed by Gilead Sciences, based in Foster City, Calif.

Zydelig Approved for Three Types of Blood Cancer 

New combination drug controls tumor growth, metastasis in mice...

Researchers at UC Davis, University of      Massachusetts  and Harvard  Medical  School  have
created a combination drug that controls both tumor growth and metastasis. By combining a COX-2 inhibitor, similar to Celebrex, and an epoxide hydrolase (sEH) inhibitor, the drug controls angiogenesis (blood vessel formation), limiting a tumor's ability to grow and spread. The study appears today in the journal Proceedings of the National Academy of Sciences.

"We've   been   studying  the  effects of  COX  and  sEH  inhibitors, both    by themselves  and in combination, for several years," said senior author and UC Davis Distinguished Professor Bruce Hammock. "We were surprised to find that the dual inhibitor was more active than higher doses of each compound, either individually or together. By combining the two molecules into one we got much greater potency against several diseases and completely unique effects in terms of blocking tumor growth and metastasis."

Both COX and sEH enzymes control lipid signaling, which has long been associated with inflammation, cell migration, proliferation, hypertension and other processes. COX inhibitors block production of inflammatory and pain-inducing lipids, while sEH inhibitors preserve anti-hypertensive, anti-inflammatory and analgesic compounds. Separate COX and sEH inhibitors were previously found to work together in reducing inflammation and neuropathic pain.

After testing individual COX-2 and sEH inhibitors, the team synthesized the drug (PTUTB), the first combined COX-2/sEH inhibitor. They then tested the dual inhibitor against human lung and breast tumors, both in vitro and in mice. They found that PTUTB blocked angiogenesis, inhibiting the proliferation of endothelial cells, which are critical to blood vessel formation. This in turn limited tumor growth and metastasis, reducing lung and breast tumor growth by 70 to 83 percent. 

In breast and lung cancers, the dual inhibitor blocked angiogenesis, which blocked the growth of solid tumors," said Hammock. "This represents a new mechanism to control blood vessel and tumor growth."

Robert Weiss, a co-author and professor of nephrology at UC Davis, added that the combination drug achieved the results with minimal side effects and no cardiovascular or gastrointestinal effects.

"This is particularly important when administering COX-2 inhibitors, which have well-known cardiovascular risks," he said. "However, the added sEH  inhibitor appears to block COX-2's side effects."

The research was initiated by first author Guodong Zhang when he was a postdoctoral fellow in the Hammock laboratory. Zhang previously demonstrated that sEH inhibitors improve the power of omega-3 fatty acid (fish oil) diets to reduce tumor growth and metastasis, and implicated epoxides of the dietary supplement DHA as the causative agent.

New combination drug controls tumor growth, metastasis in mice  

Liver Cancer Drug Fails to Live Up to Early Promise...

In continuation of my update on everolimus

Although it looked promising in early studies, the drug everolimus didn't improve survival for people with advanced liver cancer in its latest trial, a new study found.

The findings from the phase 3 clinical trial are disappointing because earlier research suggested that everolimus (Afinitor) prevented tumor progression and improved survival for in advanced liver cancer. Normally, these patients can expect a median overall survival of less than one year.

The only drug currently shown to significantly improve survival of advanced liver cancer patients is sorafenib (Nexavar). But that drug's benefits are temporary and the cancer eventually progresses, according to background information in the new study.

The current study included 546 adults with advanced liver cancer whose disease progressed during or after treatment with sorafenib, or who could not take sorafenib. The patients were divided into two groups, with 362 given everolimus and 184 given a placebo.

Liver Cancer Drug Fails to Live Up to Early Promise