Valproic Acid Shown to Halt Vision Loss in Patients With Retinitis Pigmentosa...

Researchers at the University of Massachusetts Medical School (UMMS) believe, they may have found a new treatment for retinitis pigmentosa (RP), a severe neurodegenerative disease of the retina that ultimately results in blindness. One of the more common retinal degenerative diseases, RP is caused by the death of photoreceptor cells. RP typically manifests in young adulthood as night blindness or a loss of peripheral vision and in many cases progresses to legal blindness by age 40. Dr. Shalesh Kaushal,  chair of ophthalmology and associate professor of ophthalmology and cell biology at UMMS, and his team, describe a potential new therapeutic link between valproic acid and RP, which could have tremendous benefits for patients suffering from the disease. In a retrospective study, valproic acid -  approved by the FDA to reduce seizures, treat migraines and manage bipolar disorder -- appeared to have an effect in halting vision loss in patients with RP and in many cases resulted in an improved field of vision. Results from this study, in conjunction with prior in vitro data, suggest valproic acid may be an effective treatment for photoreceptor loss associated with RP.

UMass Medical School will be the coordinating site for a $2.1 million, three-year clinical trial funded by the Foundation Fighting Blindness/National Neurovision Research Institute quantifying the potential of valproic acid as a treatment for RP. The clinical trials will build upon Kaushal's work in the retrospective study in which patients were treated off-label with doses of valproic acid ranging from 500mg to 750mg per day over the course of two to six months. Treated at a time when patients normally experience rapid vision loss as a result of RP, five of the seven patients in the study experienced improvement in their field of vision.

"Inflammation and cell death are key components of RP," said Kaushal. "It appears the valproic acid protects photoreceptor cells from this. If our observations can be further substantiated by randomized clinical trials then low dose valproic acid could have tremendous potential to help the thousands of people suffering from RP."

Dr. Kaushal and colleagues, having previously demonstrated the use of the small molecule, retinoid, as a pharmacological agent capable of increasing the yield of properly folded RP rhodopsins, began screening other small molecules for similar attributes. Because of its already known qualities as a potent inhibitor of the inflammatory response pathway and cell death, valproic acid was believed to have a unique profile making it a potential candidate as a retinal disease treatment...

Ref : http://www.umassmed.edu/VALPROIC_ACID_SHOWN_TO_HALT_VISION_LOSS_IN_PATIENTS.aspx

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/

Oldest epilepsy drug (Ethosuximide) best for Children with "Petit Mal"....

Ethosuximide ( see structure)  is a succinimide anticonvulsant, used mainly in absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug Valproic acid. There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

Now researchers, lead by Dr. Tracy A. Glauser, Director of Comprehensive Epilepsy Center at Cincinnati Children's Hospital Medical Center, have come up with an interesting finding, i.e., ethosuximide (Zarontin), one of the oldest anti-seizure medications  is most effective at controlling what is called absence or "petit mal" epilepsy, with the fewest side effects. Valproic acid (Valproate, Depakote) came second, and the newest drug, lamotrigine (Lamictal), was third.

The study included children aged 2.5 to 13 years, newly diagnosed with epilepsy and free of other problems, such as autism. They were randomly assigned to one of the three drugs. The study measured primarily whether they were free of seizures without intolerable side effects after 16 weeks, with a few children continuing for as long as 20 weeks. The study also measured how the drugs affected the children's ability to pay attention.

Ethosuximide prevented seizures in 53 percent of the children, slightly less than the 58 percent freedom-from-failure rate of valproic acid but significantly better than the 29 percent for lamotrigine. But only 33 percent of those taking the older drug had significant attention problems, compared to 49 percent of those taking valproic acid, the researchers found. 

Researchers conclude that, it was somewhat unexpected that the oldest of the drugs had as good an effect as the other and better side effects &  the study highlights the importance of looking not only at seizure control but also how the child does otherwise.......

Ref : http://www.cincinnatichildrens.org/about/news/release/2010/epilepsy-trial-3-4-2010.htm

In continuation of my update on Valproic acid...

New research suggests brain tumor patients who take the seizure drug valproic acid on top of standard treatment may live longer than people who take other kinds of epilepsy medications to control seizures. The research is published in the August 31, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.....

Ref : http://www.neurology.org/content/75/24/2229.abstract?sid=49b511a0-d597-4598-865c-297439b6eb39

FDA Approves Recarbrio (imipenem, cilastatin, and relebactam) for the Treatment of Complicated Urinary Tract and Complicated Intra-Abdominal Bacterial Infections

  

Imipenem (Primaxin)                      Cilastatin                                     Relebactam

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved Recarbrio (imipenem, cilastatin, and relebactam) for injection, 1.25 grams, a new combination antibacterial. Recarbrio is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Recarbrio is also indicated in patients 18 years of age or older who have limited or no alternative treatment options, for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis and Pseudomonas aeruginosa.

Approval of these indications is based on limited clinical safety and efficacy data for Recarbrio.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Recarbrio and other antibacterial drugs, Recarbrio should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Relebactam received FDA’s Qualified Infectious Disease Product (QIDP) designation for the treatment of cUTI and cIAI. The New Drug Application (NDA) for Recarbrio received Priority Review designation from the FDA. Merck anticipates making Recarbrio available later this year.

Recarbrio is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of Recarbrio. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. Central nervous system (CNS) adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of Recarbrio, especially when recommended dosages of imipenem were exceeded. These reactions have been reported most commonly in patients with CNS disorders (such as brain lesions or a history of seizures) and/or compromised renal function. Concominant use of Recarbrio, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Additionally, Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including imipenem/cilastatin plus relebactam and may range in severity from mild diarrhea to fatal colitis. See Important Safety Information below.

Recarbrio is a combination of imipenem/cilastatin and relebactam. Imipenem is a penem antibacterial drug, cilastatin sodium is a renal dehydropeptidase inhibitor, and relebactam is a beta lactamase inhibitor. Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity. The bactericidal activity of imipenem results from binding to PBP 2 and PBP 1B in Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent inhibition of penicillin binding proteins (PBPs). Inhibition of PBPs leads to the disruption of bacterial cell wall synthesis. Imipenem is stable in the presence of some beta lactamases. Relebactam has no intrinsic antibacterial activity. Relebactam protects imipenem from degradation by certain serine beta lactamases such as Sulhydryl Variable (SHV), Temoneira (TEM), Cefotaximase-Munich (CTX-M), Enterobacter cloacae P99 (P99), Pseudomonas-derived cephalosporinase (PDC), and Klebsiella-pneumoniae carbapenemase (KPC).

“Recarbrio provides an important addition to our toolkit in the ongoing fight against infections caused by certain Gram-negative pathogens,” said Dr. Keith Kaye, professor of medicine and director of research for the division of infectious diseases, University of Michigan Heath System, and a principal investigator in the clinical program. “Recarbrio offers an additional treatment option for patients with cIAI and cUTI who have limited and, in some cases, no alternative therapeutic options.”

“Today’s announcement is a great example of Merck’s longstanding commitment to infectious diseases research and development, as we continue to search for novel ways to approach difficult-to-treat pathogens,” said Dr. Nick Kartsonis, senior vice president, infectious diseases and vaccines, Merck Research Laboratories.

https://en.wikipedia.org/wiki/Imipenem

https://www.drugbank.ca/drugs/DB01597

https://en.wikipedia.org/wiki/Relebactam