The preparations for launching the journal, Drug Repurposing, Rescue, and Repositioning slowly heat up, while the examiners at the patent offices as well as the publication division of the WIPO simply carry on; making sure that our clever wetware search algorithms never run out of new repurposing patent applications. For March 2014 we present: old drugs that could be cognition boosters under certain circumstances although they are commonly known to cause sedation and amnesia; gamma secretase inhibitors are dug up from the graveyard of failed Alzheimer drugs to treat deafness; NSAIDs are claimed for their (novel?) action against dry cough; the old antidiabetic. metformin might treat systemic lupus; and if your clothes don’t fit anymore you might want to consider the antibiotic, rifaximin.
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Some Old Drugs as (Paradoxical) Nootropics
As WO/2014/037412 (Pharnext [FR]; March 13, 2014)correctly states, the GABA-B receptor agonist baclofencan induce anterograde amnesia in rodents (Behav Neural Biol. 1994; 61(2):181-5; here) and humans (Anesth Analg. 2008; 106(4):1284-7; here). The NMDA receptor antagonist, acamprosateimpairs free recall in healthy young human subjects (J Stud Alcohol.1999; 60(2):172-5; here). The inventors claim to have found combinations of baclofen with acamprosate, or with the loop diuretic torasemide, that stimulate cognition, particularly in healthy subjects. The same is supposed to hold for combinations of the sulfonamide antibacterial, sulfisoxazolewith torasemide, and for combinations of the old anti-arrhythmic cardiovascular agent mexiletinewith Amgen’s new calcimimetic, cinacalcet(Sensipar® / Mimpara®). Data show significantly improved learning and working memory of mice in the T-maze alternation task in mice, at drug concentrations that are an order of magnitude lower than those used for their conventional applications. A 10-day placebo-controlled clinical study in two cohorts of healthy young and elderly subjects started with 6 mg baclofen plus 0.4 mg acamprosate and escalated to 15 mg/1 mg; Cogstate® scores and electrophysiological measurement of cognitive event-related potentials (a measure of attention) produced significant results. We cannot conceive of immediate explanations for these findings, which are worth of detailed follow-up.
Failed Alzheimer Drug Candidates For Deafness
The auditory hair cells of the cochlear sensory epithelium are among the most sensitive ones in the human body. Their development depends of active Notch signaling, which ends shortly after birth; although there is limited potential for partial regeneration, deafness due to hair cell loss is irreversible. That pharmacological inhibition of Notch signaling by gamma-secretase inhibitors – all of which are failed candidate drugs for Alzheimer’s disease – generates supernumerary hair cells in embryonic or neonatal cochleae has been reported years ago, by a team from Kyoto University (Neuroreport 2007; 18(18):1911-4; here), but WO/2014/039781 (Massachusetts Eye & Ear Infirmary [US/US]; March 13, 2014) – the patent companion to the peer review paper in Neuron 2013; 77(1):58-69 (here) – is the first work to demonstrate this in adult animals, with restoration of auditory capacity. Bristol-Myers Squibb’s avagacestat(development ended in December 2012) and Eli Lilly’s semagacestat(terminated August 2010) are just two examples of the secretase inhibitors that are explicitly claimed.
NSAIDs for Dry Cough
The classical non-steroidal anti-inflammatory drugs, ibuprofenand flurbiprofen, have been claimed for many other applications already, but WO/2014/039939 (Reckitt Benckiser [US]; March 13, 2014) attempts to give the matter yet another spin: Although the inventors cite the paper “Chronic cough responsive to Ibuprofen” in Pharmacotherapy1992; 12(4):331-3 (here), as well as “The effects of sulindacon the abnormal cough reflex associated with dry cough” in J Pharmacol Exp Ther. 1990; 255(1):161-4 (here) and several Japanese and Korean patent documents, they maintain that none of these documents interfere with their novelty claim. They chose to “examine coughing in an indirect manner, as an almost surreptitious, secondary part of a study that focused on the relief of sore throat,” to avoid suppression of coughing in the observational setting. Flurbiprofen 8.75 mg lozenges eliminated coughing in 50% of patients (placebo: 4%); but it is difficult to tell how much effect the reduction of sore throat symptoms might have had.
Yet Another Perspective For an Old Antidiabetic
The simple biguanide, metformin– the oldest but also the most successful oral antidibetic drug worldwide, on the basis of filled prescriptions – has recently been reported as a promising treatment for solid tumors of the pancreas (Anticancer Res. 2014; 34(4):1765-9; here), the prostate (Int J Mol Med. 2014 Mar 20; here), and the breast (Clin Cancer Res. 2014 Mar 28; here). Its utility in polycystic ovary syndrome has been known for longer. The most recent work has provided indications that metformin is an immunomodulator that downregulates Th17 cell differentiation and attenuates murine autoimmune arthritis (Int Immunopharmacol. 2013; 16(1):85-92; here). WO/2014/042392 (Catholic University Industry Academic Cooperation Foundation [KR]; March 20, 2014) is an extended intellectual property companion for this paper, claiming metformin primarily for systemic lupus and psoriasis where a very similar type of imbalance and suppression of regulatory B-cells by STAT3 is seen.
An Antidiarrhetic as a Slimming Drug
Rifaximin, a semisynthetic non-absorbed pyrido-imidazo rifamycin, is used in the treatment of traveler’s diarrhea and received orphan drug status from the U.S. Food and Drug Administration for hepatic encephalopathy in 1998 (because it reduces the production of ammonia by gut bacteria; see Patient Prefer Adherence2014; 8:331-8, here). WO/2014/043432 (Salix Pharmaceuticals [US]; March 20, 2014) also hinges on effects on the gut microbiota but claims utility for weight reduction in severely obese people. Sixty-six patients with a body mass index >30 were randomized (2: 1) to receive rifaximin 550 mg or placebo twice daily for 20 days, and were followed for up to six months. Patients lost a mean of 4.5 lbs in the rifaximin group over a mean follow-up of 4.9 months (placebo: -0.7 lbs over a mean of 4.1 months), which was statistically significant (P < 0.03) when compared to baseline weight. Diabetics tended to lose more weight (-6.1 lbs), and patients with underlying lipid disorders lost the least (-0.7 lbs). Triglycerides were the only significant laboratory difference between groups (p<0 .04="" span="">