Too much! Or more precisely, too many. February 2014 has been so studded with international drug repurposing patent applications that we have to split the discussion. For starters, we present: rebamipide for dyslipidemia; cyclodextrins as drugs in their own right, for lysosomal storage diseases; new facettes of the old anti-helminthic, niclosamide in cancer; and an adenosine A3 receptor agonist that might ring in the post-Viagra era. Stay with us, we will post a discussion of applications from the second half of the month soon.
https://www.hmpharmacon.com| office@hmpharmacon.com | Bitmessage: BM-2DB4Z3ee6C9mbtKx92q56Xt1uT1YNBeiq9
——————–
A Gastroprotectant For Dry Eye — Now for Atherosclerosis
Rebamipideis a multifunctional mucin secretagogue with additional properties that synergize to protect mucosal tissue, especially in the stomach and oral cavity; it is approved as an anti-ulcerant (Mucosta®) in several Asian countries. Attempts by Otsuka Pharmaceuticals and Acucela, Inc. to extend its use to the treatment of severe dry eyehad their first success in Japan where the eyedrops were launched in January 2012 — a classical case of on-target repurposing by the originator (see study NCT00201981and Am J Ophthalmol. 2014; 157(3):576-583; here). But now comes a third-party patent application from Korea, WO/2014/021637 (Catholic University-Industry Coop. Foundation [KR]; Feb. 6, 2014) with claims for use in hyperlipidemia and atherosclerosis. The primary idea is that rebamipide’s anti-inflammatory actions (suppression of TNF-α, IL-6 and IL-1 β secretion by macrophages) would inhibit foam cell induction; this plays on the concept of atherosclerosis as an inflammatory disease with free radical involvement. It is less clear how rebamipide would “lower the levels of total cholesterol, LDL-cholesterol and neutral fat to improve blood lipid and fatty liver” — but then, the compound is known to modulate gene expression, at least in the intestinal mucosa (J Gastroenterol Hepatol. 2012; 27(12):1816-24; here) and the corneal epithelium (Curr Eye Res. 2014; 39(2):133-41, here) – why not elsewhere, too?.
Cyclodextrin – Now an Active Ingredient
In the earlier days of drug delivery, cyclodextrins were among the hottest tools for solubilizing active ingredients. Today 2-hydroxypropyl-beta cyclodextrin (HP-β-CD) is an approved standard excipient. But a drug? Yes, according to WO/2014/022841 (U.S. DHHS [US], Feb. 6, 2014), for Niemann-Pick disease Type C1, an autosomal recessive lysosomal storage disease characterized by a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. This was one of the first projects taken on by the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS) – which is heavily engaged in drug repurposing. A progress report has just been published (Curr Top Med Chem. 2014; 14(3):330-9, here). A phase I trial (NCT01747135) is currently recruiting patients, with an estimated completion in December 2014. The patent application extends to methyl-β-cyclodextrin, vitamin E and its analogs such as δ-tocopherol which has also raised hopes as a treatment for NPC1 (J Biol Chem. 2012; 287(47):39349-60, here), and to related lysosomal storage disorders including Wolman, Niemann Pick Type A, Farber, Tay-Sachs, and Batten diseases. Alpha-, beta-, and gamma-cyclodextrins can reduce cholesterol accumulation in NPC cells, increase intracellular Ca2+ concentrations, and enhance exocytosis.
Tapeworms and Cancers Disappear
Niclosamideis an old antihelminthic, said to act by disrupting the pH homeostasis of the parasite and uncoupling of the mitochondrial respiratory chain (Arzneimittelforschung1970; 20(2):203-5, here) — although this does not quite explain its selective action against tapeworms. The first indications that niclosamide might have potential in cancer therapy came from its actions against Notch signalling in a human leukemia cell line (J Cell Biochem. 2009; 106(4):682-92, here). Since then corroboration – especially in difficult-to-treat solid tumors – has come from many sides: niclosamide reverses acquired radioresistance of human lung cancer cells (Mol Cancer Ther. 2014; 13(3):606-16, here), and resistance to erlotinib in non-small-cell lung cancer (Mol Cancer Ther. 2013; 12(10):2200-12, here), by disrupting the JAK/STAT pathway, and this is at least one explanation of its efficacy against breast cancer (PLoS One 2014; 9(1):e85887, here). In glioblastoma, it simultaneously inhibits intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-κB signaling (Clin Cancer Res. 2013; 19(15):4124-36, here). Disclosures WO/2014/023329 and WO/2014/023732 (Life & Brain GmbH [DE]; Feb. 13, 2014)are relatively minor elements in this exciting repurposing story; these documents claim combinations with alkylating agents, in the most preferred embodiment with temozolomide, for the treatment of tumors characterized by underexpression of NFKBIA, the gene which encodes IκBα (the major negative regulator of NF-κB).
The A3 Receptor Does it All
CF-101(IB-MECA) is an adenosine A3 receptor agonist which has been investigated for several conditions where activation of this anti-inflammatory receptor might be useful: rheumatoid arthritis (Arthritis Rheum. 2009; 60(10):3061-71, here), psoriasis (J Eur Acad Dermatol Venereol. 2012; 26(3):361-7, here), and ocular conditions such as dry eye (Ophthalmology 2011; 118(5):1011-2, here) and uveitis (Int J Mol Med. 2011; 28(5):727-31, here), but there also is the less obvious utility in colon carcinoma (Neoplasia 2005; 7(1):85-90, here). WO/2014/024195 (Ca-Fite Biopharma [IL]; Feb. 13, 2014)offers yet another application: sexual dysfunction in its broadest sense, based on spontaneous patient reports made during the compound’s Phase III study for dry eye (NCT01235234), and also during the Phase II trials for arthritis and psoriasis. (Hah! Shades of the Viagra story!) In addition, mice treated with an A3AR allosteric enhancer, LUF6000/CF602, exhibited erections. This is not unexpected though: adenosine is a key regulatory of erectile status, of at least the same importance as nitric oxide. There even is an “priapism phenotype” of adenosine deaminase-deficient mice (J Clin Invest. 2008; 118(4):1491-501, here). It is only the A3 receptor that has not been described in this context. And this subtype is important because it might be cardioprotective in diabetes (Recent Pat Cardiovasc Drug Discov. 2012; 7(1):59-70, here), a condition that has erectile dysfunction as a frequent side effect.