Efforts towards finding new uses for known, discontinued or candidate drugs never abate. And while patent examiners might take the occasional summer break the PCT publishing outlet discharges a steady stream of documents. In the second half of July (the first two weeks were “dry” as far as repurposing is concerned) we noted Novartis claiming its α7 nicotinic receptor agonistcandidatedrug, AQW051 for disorders of sleep and recovery from anesthesia; the University of Manitoba claimed the generic acetylcholinesterase inhibitor, galantamine for bowel inflammation; Alienor Farma of France found that BMS’ Sustiva is a cancer drug at high but tolerable doses; and Korean Boryung Pharma claimed its antihypertensive, Kanarb for cancer.
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An alpha7 Nicotinic Agonist for Narcolepsy and Emergence from Anesthesia
WO/2014/111751(Novartis [CH]; July 24, 2014) claims several families of α7 nicotinic acetylcholine receptor agonists, most of which seem to have originated from the company’s own programs, for narcolepsy and cataplexy. Supporting biological data were obtained with mice with a knockout of the orexin peptide gene; these express a phenotype with cataplexy events and a disrupted sleep pattern including fragmented sleep and sleepiness in their active period. The preferred compound appears to be (3R)-3-[6-(4-methylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane, a quinuclidine ether which is identifiable as AQW051and was first disclosed in Novartis’ WO/2004/022556. This compound has been clinically investigated for Alzheimer’s disease and L-dopa dyskinesia in Parkinson’s disease, and has completed Phase II studies for cognitive impairment in schizophrenia (NCT01163227, NCT01730768) with undisclosed results. There appear to be no peer review papers on AQW051, but some background can be found here. For more on the role of the cholinergic and orexinergic systems in regulation of sleep and arousal see Ann N Y Acad Sci. 2008; 1129: 26-34 (here). – WO/2014/111838(Novartis [CH]; July 24, 2014) makes corresponding claims for supporting awakening from general anesthesia.
An Alzheimer Drug for Inflammatory Bowel Diseases
WO/2014/113893(Univ. Manitoba [CA]; July 31, 2014) presents a much more established cholinergic drug, galantamine(Janssen’s Razadyne®; a reversible cholinesterase inhibitor and nicotinic acetylcholine receptor modulator) for a new use in ulcerative colitis and Crohn’s disease. Decreased efferent vagus nerve activity is observed in inflammatory bowel disease; galantamine’s known extra-CNS effects include activation of efferent vagus nerve activity and of the cholinergic anti-inflammatory pathway (mediated by central [!] muscarinic acetylcholine receptors which respond to increased cholinergic tone). So the well-supported findings in this application are not really a fundamental surprise — but on the other hand, loose bowels and other intestinal disturbances are a significant initial side effect of galantamine (and other cholinesterase inhibitors) taken by Alzheimer patients (Consult Pharm. 2004;19(8): 713-20; here). The inventors found no evidence for a significant role of peripheral muscarinic receptors in mediating protective cholinergic effects, but identified a vagus nerve – spleen axis as an important mediator of the central cholinergic regulation of colitis severity.
An AIDS Drug in Overdose Treats Cancer
Efavirenz(Bristol Myers Squibb’s Sustiva®), a non-nucleoside reverse transcriptase inhibitor, is claimed for the treatment of malignancies in WO/2014/114971(Alienor Farma [FR]; July 31, 2014). The daily doses are high, between 1800 and 2200 mg, and achieve plasma concentration in excess of 3 µg/ml. (For the treatment of HIV infection, doses of 600 mg/day and plasma concentrations of 1.5 µg/ml are typical.) In a clinical trial with patients suffering from hormone-refractory prostate cancer, the “AIDS treatment dose” was effective, halting progression in 28 % of patients at 3 months while the “cancer dose” pushed success rates (as defined by PSA levels) to 71%. It is this high-dose regimen that constitutes the invention. Decreasing the elevated endogenous reverse transcriptase activity in cancer cells (in normal cells, its expression is strongly repressed by methylation of its promoter) has long been known to reduce proliferation and promote differentiation and to antagonize tumor growth in animal models (Genes Chromosomes Cancer 2006; 45(1): 1-10, here, and WO/2003/055493).
Fimasartan for Cancer
Years ago, a partial and non-predefined meta-analysis raised the possibility that angiotensin receptor antagonists in particular may increase the incidence of cancer. Today we know that the opposite is true; many of these drugs have been shown to have antiproliferative effects. According to WO/2014/115977(Boryung Pharma [KR]; July 31, 2014) this is also true for fimasartan(Boryung’s Kanarb®), the most recent addition to this indispensable class of (now mostly generic) antihypertensive drugs (Am J Cardiovasc Drugs 2011; 11(4): 249-52; here). The exact details are difficult to make out in the garbled machine translations, but according to Xenobiotica 2014 Jul 18:1-9 (here) fimasartan glucuronide is a ligand for breast cancer response protein (BCRP).