Happy New Year 2014! – Here are comments on seven international drug repurposing patent applications, all published in December 2013. – CuresWithinReach, a U.S. medical research non-profit organization and a major driver in the repurposing field, has listed us right on top of their list of the Blogs we Like section of their blog, re:Rx. Thank you CWR, H.M. Pharma Consultancy is honored!
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Transporter Modulators and H4 Receptor Blockers for Inner Ear Disorders
The sensory epithelial cells in the vestibular organ, which monitors positional and acceleration data of the head, can be affected by cancer drugs such as platinum compounds. WO/2013/178763(Sensorion [FR]; Dec. 5, 2013) claims to have found antidotes for this specific type of vestibulotoxicity: inhibitors of organic cation uptake such as cimetidine, amantadine, memantine, and linagliptin(many more are mentioned); or activators of multidrug resistance-associated outflux transporters (e.g., probenecid, benzylpenicillin, dexamethasone, triamcinolone acetonide, mifeprostone). Rats were scored for vestibular deficits after transtympanic injection of cisplatin and evaluated for 336 hours. Pretreatment of adult rats with systemic injection of cimetidine reduced vestibular toxicity and behavioral deficits induced by cisplatin.
Tinnitusis generated in the cochlea, the inner ear organ that is concerned with hearing, and is distinct from the vestibular organ (although vestibular dysfunction and tinnitus often are comorbid conditions). WO/2013/182711(Sensorion [FR]; Dec. 12, 2013) claims histamine H4 receptor blockers – including Alcaftadine, PF-3893787, JNJ 10191584, JNJ 10191584, A-943931, and A-987306– for treating this condition. Note that the histamine analog, betahistine has been used to treat both vestibular disorders and tinnitus for decades; it was first registered in Europe in 1970 for the treatment of Ménière’s disease.
An Anti-Arrythmic Drug for Leishmaniasis
Dronedarone, an anti-arrythmic drug (Sanofi’s Multaq®), is an amiodarone derivative in which the 2,5-diiodophenyl moiety of the parental drug has been replaced with an unsubstituted phenyl group. Recently its utility in Chagas disease was reported (Antimicrob Agents Chemother. 2012; 56(7):3720-5, here; review in Nat Rev Cardiol. 2012; 9(10):605-9, here). But according to WO/2013/182423(Sanofi [FR]); Dec.12, 2013) Trypanosoma cruzi is not the only protozoal parasite targeted by dronedarone – it also acts against Leishmania ssp., and is supposed to be particularly suitable for topical treatment of cutaneous leishmaniasiscaused by L. amazonensis strains. When mice were infected with promastigotes in the right ear pinna and treated with 20 mg of the appropriate topical dronedarone formulation once a day for 30 days, an aqueous gel was almost as effective as the reference treatment, intralesional meglumine antimoniate (Glucantime®). The document states that “the animals looked happy throughout the treatment” – so lets hope that leishmanisis patients will also have reason to smile…
Lamotrigine for Cognitive Impairment
Cognitive impairment resulting from anticonvulsant treatment is extremely well documented, and so it is interesting to see WO/2013/183985(Univ. Rotterdam [NL]; Dec. 12, 2013) claim hyperpolarization-activated cyclic nucleotide-gated (HCN) channel agonists, such as lamotrigine(GlaxoSmithKline’s Lamictal®), for restoring cognitive deficits in neurofibromatosis type I. In NFl-exon 9a mutant mice which have reduced HCN channel function, lamotrigine improved spatial memory in the water maze, and motor learning in the rotarod paradigm. – This is not without precedence: clinical trials have found that lamotrigine has potential to reduce cognitive symptoms of schizophrenia, and it counteracts ketamine-induced learning and memory impairment in healthy human subjects (Arch Gen Psychiatry 2000; 57(3):270-6, here). It would be interesting to see if ivabradine(Servier’s Procoralan®), the first explicit HCN channel modulator drug to win regulatory approval (for angina pectoris) could also be repurposed along these lines.
Laquinimod for Ocular Inflammation
Teva and its Swedish partner Active Biotech are developing laquinimod, a quinoline-3-carboxamide immunomodulator, for multiple sclerosis in Phase III. Trials to investigate it for Huntington’s disease are being designed, and a Phase II study for lupus nephritis (NCT01085097) has produced promising results. Autoimmune inflammation is a key element in nephritis as well as in MS, so it makes sense to look for additional related conditions. In the case of WO/2013/184650(Teva Pharmaceuticals [IL]; Dec. 12, 2013) this is uveitisand allergic conjunctivitis. Rodent models demonstrated efficacy of a 1-5% laquinimod sodium aqueous solution in both conditions. Limited surprise here, but still an interesting perspective.
Eltoprazine Can Do It All (or at least, a lot)
The phenylpiperazine 5-HT1A/B receptor partial agonist, eltoprazinewas created by Duphar in the 1980s (as DU-28853) and was subsequently developed by Solvay to treat pathological aggression (Drug Metabol Drug Interact. 1990; 8(1-2):85-114, here). PsychoGenics re-developed it for adult attention-deficit hyperactivity disorder; successful conclusion of an exploratory Phase II study was announcedin 2008. In 2011 the company commenced a Phase II trial (NCT01266174) for cognitive dysfunction in schizophrenia which in January 2014 is still listed as recruiting patients. The utility of eltoprazine to treat drug addiction (WO/2011/000564) and obesity (WO/2011/000563) was claimed by Merz+Co; a third patent application, WO/2011/000562,was for movement disorders: Huntington’s disease, restless leg syndrome, and graft-induced dyskinesia (a side effect that may develop after intrastriatal embryonic mesencephalic tissue grafting in Parkinson’s disease). Now WO/2013/188210(PsychoGenics [US]; Dec. 19, 2013) makes more general claims for dyskinesia caused by dopaminergic drugs in Parkinson’s disease. The disclosure describes a pilot study during which eltoprazine was administered to 18 PD patients with levodopa-induced dyskinesia; symptoms were significantly reduced at the 5 mg dose (p = 0.0007) and the 7.5 mg dose (p = 0.0467), as compared to placebo, without affecting L-DOPA efficacy. The career of this 30 year-old drug candidate might not be over yet.
A Century-Old Diuretic, Now for Dental Hypersensitivity
As a final for the past year we report WO/2013/191763(Theocorp [US]; Dec. 27, 2013) which claims that the addition of theobromine(a structurally simple but quantitatively prominent cacao alkaloid, used to treat edema and angina from 1916 onward) to commercially available dental products achieves accelerated occlusion of so-called dentinal canaliculi. These result when the enamel that completely covers healthy teeth is damaged (or when recession of gingival tissue exposes parts of the tooth that are normally covered), exposing the microchannels leading to the pulp and the nerve which then becomes irritated. The abstract of the companion peer review paper (Oral Health Prev Dent. 2012;10(3):275-82) can be accessed here; it was followed up by Caries Res. 2013; 47(5):399-405 (here). Note that theobromine has been reported as a potential cariostatic agent decades ago (Friuli Med. 1969; 24(5):525-9, here). Eating lots of dark chocolate might also produce this effect to a degree, but that has considerable medium-term side effects beyond acute theobromine poisoning…