The response we keep getting from our drug repurposing information services is just amazing! We truly seem to have hit a nerve here. With new chemical entities constantly dropping out of clinical development and hardly any new mechanisms with superior potential, revisiting old drugs or discontinued candidate compounds, repurposing is more attractive than ever. – An although the news might not have spread beyond our LinkedIn discussion group, 2014 is going to see the launch of the world’s first scientific journal dedicated exclusively to drug repurposing and repositioning. – Stay tuned! And if you have a project idea please contact us as per below.
https://www.hmpharmacon.com| office@hmpharmacon.com| Bitmessage: BM-2DB4Z3ee6C9mbtKx92q56Xt1uT1YNBeiq9
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Triptans and Buspirone for Movement Disorders
WO/2013/156035(Concit Pharma [DK]; Oct. 24, 2013) builds on the company’s earlier application WO/2012/048710which had shown that the migraine drug zolmitriptangenerally failed to inhibit levodopa-induced dyskinesia (LID) in Parkinson’s disease patients when administered alone, but potentiated LID inhibition by the 5-HT1A agonist buspironeThis was observed even at doses of buspirone which alone failed to produce a significant effect on LID, and were much lower than those used to treat depression and anxiety. Now the company claims an actual fixed dose combination matrix tablet coprising zolmitriptan 1 mg extended release in the core, with a buspirone 10 mg immediate release coating. This formulation provides the correct kinetics for both drugs, in the correct sequence (the 5-HT1A agonist comes first), as was demonstrated in four cynomolgus monkeys.
Angiotensin II Receptor Agonists for Cerebral Malaria
A paper published a few months ago (PLoS One 2013; 8(4):e62999, here) provided the first experimental evidence for the older hypothesis that angiotensin II protects against cerebral malaria. (The suggested sequence is that rupture of P. falciparum – infected red blood cells interferes with endothelial junctions, which are under the control of angiotensin II.) Well before that paper, WO/2013/158628(New York University [US]; Oct. 24, 2013) was filed that claims an angiotensin type-2 receptor agonist and an antimalaria drug (at a weight ratio in the range of about 1:7 to about 1:1500) for treating cerebral malaria. Among the agonists are CGP-42112A(a peptidomimetic created at Ciba-Geigy and claimed in WO/1999/43339); tricyclic compounds disclosed in WO/2003/064414, WO/2006/109048, WO/2004/046137, and WO/2004/046141; or bicyclics disclosed in WO/2004/085420, WO/2004/046128, and WO/2006/109058. (All applications by Vicore Pharma, Sweden) The cerebral malaria therapeutics include nicotinic α7 acetylcholine receptor agonists, iloprost, and S1P receptor agonists. – Interestingly, losartan (the prototypical AT-II receptor antagonist) acted in a similar way as the agonists.
An Old Antihistamine for Cystic Fibrosis
Tritoqualine(inhibostamine, hypostamine), a synthetic oral antihistamine that inhibits histidine decarboxylase but is an histamine H4 receptor agonist, has once been reported to show efficacy in liver cirrhosis models (Nihon Yakurigaku Zasshi 1986; 87(3):291-300, here). The mechanism was not evident at this time, and apparently this lead was not pursued. In WO/2013/164204(Orphan Synergy Europe [FR]; Nov. 7, 2013) the inventors show that the compound also inhibits release of interleukin-8, a potent proinflammatory activator for neutrophils that is an important in the pathogenesis of cystic fibrosis. Surprisingly, modulation of IL- 8 release is independent of the initial stimulus. This is important because CF frequently starts with a perinatal lung infection. – Three weeks later, another French patent application – WO/2013/175116(Individual [FR]; Nov. 28, 2013) claiming tritoqualine as an H4 agonist for CF was published; it focuses on the treatment of the respiratory damage caused by the thickened sputum and the reduction and prevention of bronchial superinfections. – Some antihistamines come with safety warnings for possible drying or thickening of lower airway secretions.
Tramadol for Depression
Gruenenthal’s opiate receptor agonist, tramadol (a synthetic analog of codeine), is a potent analgesic and a controlled substance. Obviously chronic pain can cause depression, will worsen existing depression in the majority of cases, and can make it more difficult to treat. But what WO/2013/164561(E-Therapeutics [GB]; Nov. 7, 2013) claims is that sub-analgesic doses of tramadol (60-80 mg;100 mg is considered the minimal analgesic dose for an adult) can treat depression even with no coexistent pain, and can treat cases that do not respond to conventional antidepressants. Plans for a single centre, double blind, non-inferiority Phase II clinical study to evaluate Viotra™ (extended release tramadol HCl) vs. amitriptyline for major depressive disorder with unsatisfactory response to SSRIs are outlined; subjects will take 20 mg or 70 mg tramadol, or 75 mg amitriptyline, once daily in the evening over 8 weeks. – A quick literature search shows a case report of tramadol precipitating serotonin syndrome in a patient on antidepressants (J Neuropsychiatry Clin Neurosci. 2012; 24(4):E52, here) – evidence for increase in 5-HT tone -, and a study from a group of Polish researchers investing synergies between tramadol and venlafaxine (Pfizer’s Effexor®) in rats (Pharmacol Rep. 2012;64(6):1350-8, here).
Methazolamide for Liver Disease
Methazolamideis an old carboanhydrase inhibitor that is used as an oral glaucoma drug, with a label that carries a blood glucose level safety warning for diabetes patients. Those who follow diabetes research or monitor the peer review literature for drug repurposing might have already seen the August 2012 report from Australia’s Deakin University in Diabetes (here) that revealed methazolamide as an hepatic insulin sensitizer. WO/2013/173859 (Verva Pharmaceuticals [AU]; Nov. 18, 2013) also comes with diabetes claims but goes significantly further by showing that administration of methazolamide to diabetics, whether treated with another antidiabetic agent or not, results in a reduction in serum alanine aminotransferase (ALT; an unspecific marker of liver damage) and reduces hepatic lipid levels. This effect, which points towards potential in non-alcoholic steatohepatitis, does not seem to have appeared in the peer review literature so far.