New England and Old England are battered by storm, rain and snow; Vienna is calm and actually too warm for that time of the year, but we are battered by work…. which is good of course… but can play havoc with our schedules. – Well, but here are repurposing patent applications, all from for January 2014 with one interesting exception from December 2013. – Dear Readers, we would appreciate your feedback concerning the future development of these drug repurposing patent reviews. Should these be fed to a separate blog? Should we do PDFs, even ebooks perhaps? – In any case we will continue to post links on the relevant LinkedIn discussion groups.
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Cilostazol for Mild Cognitive Impairment
Ooops, we almost missed that one — the abstract of WO/2013/187075 [Foundation for Biomedical Research and Innovation [JP]; Dec. 19, 2013) claims 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]3,4-dihydrocarbostyril for mild cognitive impairment. This is cilostazol(Otsuka Pharmaceutical’s Pletal), a vasodilative phosphodiesterase-3 inhibitor with antiplatelet action that is used for intermittent claudication as a symptom of peripheral vascular disease. Cilostazol inhibits platelet aggregation and is a direct arterial vasodilator. This is interesting because PDE-3 is more involved in cardiovascular function, lipolysis and fertility than in cognition. Different Japanese researchers have published rat data (long after the 2012 priority dates of this application) showing that oral cilostazol significantly improved hippocampus-dependent long-term memory (Psychopharmacology (Berl). 2014 Jan 25, here). Of higher relevance even though cognitive decline was not improved but only stabilized (while the control group declined) is an earlier clinical study in mixed Alzheimer’s and vascular dementia (Geriatr Gerontol Int. 2013;13(1):90-7, here). Earlier, cilostazole had been shown effect in a mouse model of beta-amyloid induced memory impairment (Br J Pharmacol. 2010; 161(8):1899-912, here).
ACE Inhibitors for Optic Neuropathy
Loss of optic nerve fibers can be caused by tumors, infections or inflammatory processes in the eye but can also have toxic or hereditary origin (Leber’s optic neuropathy, Kjer’s syndrome, and others). There is no approved treatment, but WO/2014/001889 (Individual [TN]; Jan. 3, 2014) claims most marketed angiotensin-converting enzyme inhibitors for that exact purpose. – ACE produces the vasoconstrictor angiotensin, and the presence of AT-II receptors in the arterioles feeding the optic nerve head has been demonstrated more than two decades ago (Invest Ophthalmol Vis Sci. 1991; 32(1):21-6, here). Eye drops containing 2% (w/v) ramiprilate, instilled twice daily for 3 months, are stated to have improved vision in patients with congenital optic atrophy or central artery occlusion of the retina. – The ACE inhibitor ramipril is known to protect rats against optic neuropathy triggered by brain irradiation (Radiat Res. 2004; 161(2):137-42, here; J Neurooncol. 2007 Apr;82(2):119-24, here). – Olmesartan(Daiichi Sankyo’s Benicar/Olmetec, an angiotensin type 1 receptor antagonist, has a beneficial effect on blood flow in the ischemic optic nerve head (Ophthalmic Res. 2003; 35(6):351-4, here). Note that an anti-glaucoma effect has been reported for diminazene, an activator of ACE2 and antiinfective veterinary drug (Invest Ophthalmol Vis Sci. 2013; 54(6):4296-306, here).
A Russian Psycho-Nootropic for Parkinson’s Disease
Although 4-phenylpiracetam is obviously a close relative of piracetam, it has a stronger psychotropic component in addition to its nootropic background activity. In the Soviet Union, where it was developed 30 years ago, the racemate (Phenotropil, Carphedon) was typically prescribed as a general stimulant or to increase tolerance to extreme cold and stress. Apparently it has also been used by cosmonauts. Animal experiments suggest that the memory-improving activity is due to the R-form while R and S stereoisomers both mediate the antidepressant and locomotor activity (Basic Clin Pharmacol Toxicol. 2011; 109(5):407-12, here). WO/2014/005721 (Merz Pharma [DE]; Jan. 9, 2014) is now claiming the R-form for fatigue (particularly mental fatigue) in Parkinson’s disease. The document cites several studies published in papers that are not represented in PubMed; doses of 100 or 200 mg/day are said to have resulted in a decrease in neurological deficiencies, hypokinesia, depression, sleep disturbances, and reactive anxiety; while it didn’t affect mental abilities. There is no interaction with L-dopa. The inventors attribute the utility in Parkinson’s disease to dopamine re-uptake inhibitor activity of (R)-phenylpiracetam.
Carvedilol for Diabetes
Older studies have suggested that beta blockers (especially first-generation ones, can raise the risk for type 2 diabetes by as much as 25%, but the recent NAVIGATOR study did not show more this (BMJ2013; 347:f6745, here). In an earlier study from Tulane University the risk of new-onset diabetes among hypertensive patients initiating carvedilol(Coreg, Dilatrend, generics) was similar to that seen with older beta-blockers (Curr Med Res Opin. 2011; 27(4):799-807, here). Now WO/2014/012084 (Individual [US]; Jan. 16, 2014) claims that carvedilol, at 25 or 50 mg given twice daily, increases insulin receptor sensitivity to a point where it could even replace insulin. An study was performed on two groups of 5 outpatients each, with diabetes and a history of uncontrolled blood sugar. Group I was already taking insulin; these patients received carvedilol in addition. Group 2 was unable to control their blood sugar with diet or oral medication and patients were given additional carvedilol instead of being started on insulin. – A recent study (Cardiovasc Diabetol. 2012; 11:14, here) has shown that carvedilol significantly improved glycemic control in type 2 diabetics with systolic heart failure; this improvement was non significantly better than that obtained with the more beta-1 receptor – selective bisoprolol.
Baclofen and Acamprosate for Macular Degeneration
With VEGF receptor blocker antibodies and VEGF-binding proteins, “wet” age-related macular degeneration (so called because the microvessels supporting the neuroretina become leaky) became a pharmacologically treatable disease of the eye. The dry form, where this vascular disorder is absent but protein and lipid aggregates (drusen) slowly destroy the retina, gets much less attention because it is not as fast and thorough in causing blindness – and because there is no single easy target. WO/2014/013025 (Pharnext [FR]; Jan. 23, 2014) claims that a combination of two well-seasoned drugs – the muscle-relaxing GABA-B receptor agonist baclofenand the NMDA receptor blocker acamprosate(Merck-Serono’s Campral™, an anti-craving agent in alcohol withdrawal therapy) are effective in reducing angiogenic damage, oxidative stress, and mitochondrial dysfunction in both types of AMD. Notably, there is also an effect on damage from retinal beta amyloid deposits in Alzheimer patients. While there are recent literature reports indicating that retinal arteriolar responses to baclofen resemble those observed with GABA (Invest Ophthalmol Vis Sci. 2013 ; 54(10):6798-805, here) nothing can be easily found for acamprosate.
S-Pindolol for Muscle Wasting
Finally we report the publication of WO/2014/016585 (PsiOxus [GB]; Jan. 30, 2014) claiming the S-form of the beta receptor modulator pindolol for cachexia and sarcopenia. Referred to by the company as Anabolic Catabolic Transforming Agent (ACTA) under research code MT-102, it has completed two clinical studies, one of which (NCT01238107) was ACT-ONE, a Phase II trial conducted in Germany, India, and Malaysia during which MT-102 was administered to subjects with cancer cachexia over a 16-week period (J Cachexia Sarcopenia Muscle 2011; 2(4):201-207, here). This builds on WO/2008/068477 (with David Cavalla, now CEO of the drug repurposing specialist Numedicus Ltd., as the sole inventor) which had made more general claims extending to (S)-propranolol, tertatolol or bopindolol. MT-102 can oppose excess catabolism by blocking beta-1 adrenergic receptors, it increases tissue anabolism via partial beta-1 adrenergic agonism, and its 5-HT1A receptor modulator activity could antagonise fatigue. – Note that beta2 agonists such as clenbuterol are frequently abused by athletes for their muscle anabolic effect.