Happy Holidays to all of you! – Yes, this takes us beyond the (nutheads, insert your favorite choice here). And we DO believe that December 21, 2012 WILL see a significant event, the same one as every year around this time: the winter solstice, a.k.a. Return Of The Light as of old Celtic, Germanic, etc. tradition is definitely going to happen. (Not a bad prospect, as I look across the dismal foggy/rainy semi-darkness that engulfs Vienna these days.) Until this is upon us, we hope that these four examples of drug repurposing patent applications will provide some positive distraction. – See you again in 2013!
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A Big Bunch Of Drugs As Autophagy Modulators
Autophagy is a pervasive mechanism of eukaryotic cells that removes toxic macromolecular aggregates, dysfunctional organelles, or microbial pathogens, and is generally involved in the homeostasis of cellular biomass. At the University of New Mexico, many well-known drugs have been investigated for their modulatory actions on autophagy and are sweepingly claimed as “autostatins” on 210 pages in WO/2012/154944 (STC.UNM [US]; Nov. 15, 2012). The inhibitors (tetrachlorisophthalonitrile and phenylmercuric acetate) are preferred in cancer; the agonists (flubendazole, hexachlorophene, propidium iodide, bepridil, clomiphene,, propafenone, metixene, dipivefrin, fluvoxamine, dicyclomine, dimethisoquin, ticlopidine, memantine, bromhexine, norcyclobenzaprine, diperodon, nortriptyline) are preferred in most other disease states (neurodegeneration, chronic inflammation, diabetes and metabolic syndrome, muscle degeneration and atrophy, frailty in aging, stroke and spinal cord injury, arteriosclerosis, infectious diseases, and other conditions). The disclosure is actually much broader, with large parts relating to immunomodulatory cytokines. It also provides a clinically usable assay based upon the discovery that the LC3 polypeptide (a commonly used autophagosome marker previously found only on intracellular membranes) is expressed on the surface of primary lymphocytes. We lack the time to investigate all implications raised here, and present this only as a pointer.
Selumetinib For Spinal Muscular Atrophy
In September 2011 Array BioPharma Inc. announced negative results from a Phase II clinical study conducted by AstraZeneca comparing the MAP kinase kinase (MEK) inhibitor, selumetinib(AZD6244/ARRY-886) in combination with docetaxel with docetaxel alone in the second-line treatment of 87 patients with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer. This was the first completed randomized combination trial with a MEK inhibitor. (For all trials involving selumetinib see here.) A few months earlier French researchers had filed the priority document for WO/2012/160130 (Université Paris Descartes [FR]; Nov. 29, 2012) which claims the candidate compound (and others such as U0126, PD98059, PD0325901, AZD8330 [ARRY-42704], CI-1040 [PD 184352], and PD318088) for spinal muscular atrophy, one of the recessive “polyglutamine diseases.” While AKT signaling is downregulated in these patients, the MEK/ERK pathway is upregulated. Mouse studies have shown that ERK hyperphosphorylation is functionally linked to Fibroblast Growth Factor receptor-1 (PLoS One 2012; 7(2): e31202, here). Extensive Western blot protein phosphorylation data from the spinal cords of knockout transgenic SMA-like (Smn-/-/SMN2+/+) mice, as well as survival data, are presented.
Clenbuterol For Autism
The β2-adrenergic receptor agonist, clenbuterolis marketed as a bronchodilator for asthma in severalcountries, and has gained some notoriety as a doping agent (because it increases metabolism and protein synthesis in striated muscles). WO/2012/165984 (Stowarzyszenie Św. Celestyna [PL]; Dec. 6, 2012)makes a different claim, for pediatric autism. Three cases are presented indicating that daily oral doses of 20-30 µg (preferably, 0.2-0.5 μg/kg) given for 3-12 months resulted in increased interest in the environment, as well as improvement with respect to understanding, concentration, attention, and speech. The inventors appreciate that patent application US20100130566 claimed the use of adrenergic agonists for autism; however, the “Experimental Section” of this document from individual inventors does not present any data. – Note that prenatal exposure to the β2 agonist terbutaline(but not other compounds with this action) has been reported to massively increase the risk of autism spectrum disorders (J Neurodev Disord.2011; 3(4): 307-15; here).
Bisacodyl: Not Only Constipation –Glioblastoma As Well
WO/2012/168885 (Université de Strasbourg [FR]; Dec. 13, 2012)claims the colonicsecretagoguelaxative, bisacodyland its metabolite, 4,4′-(dihydroxy-diphenyl)-(2-pyridyl) methane (DDPM) for cancer, in particular for eradication of cancer stem cells in glioblastoma. Bisacodyl is said to act by stimulating apoptotic pathways in a pH-dependent fashion: itaffectscancer cell survival at the low pH values that are found in intratumor microenvironments whereas no cytotoxic activity is observed at physiological pH levels. Bisacodyl and DDPM exhibit much lower EC50values than proton pump inhibitors or urocanic acid. Preferred daily doses are 10 to 40 mg (0.1 – 6 mg/kg/day). Extensive cellular in vitro data are presented. – Recently the laxative effect of bisacodyl has been linked to decreased aquaporin-3 expression in the colon (Am J Physiol Gastrointest Liver Physiol. 2011; 301(5): G887-95; here).