Once again, we have selected a few goodies for those who are interested in the patenting aspects of drug repurposing, or who simply appreciate a bit of early warningfrom this arena. This issue’s highlight probably is Sanofi going after Vertex/J&J’s and Merck’s HCV protease inhibitors, telepravir and boceprevir, claiming them for cardiorenal disorders. We also like Bayers idea of suggesting theirfungicide, fluopyram, for parasitic infections — by now they might have some undisclosed preclinical tox data in their lab journals.Nometics’ idea of a transdermal patch releasing the generically available beta-blocker propanolol – not for hypertonia or arrythmia but for locally killing off residual melanoma cells after surgical excision – is also quite ingenious.
Do you have an idea for an early-stage drug repurposing project? H.M. Pharma Consultancy is the right address for backing it up with the proper IP, or for testing the patent waters with you.
Melatonin For Mucositis
Most classical chemo- and radiotherapies for cancer (i.e., those that do not target cancer-specific biomarkers or metabolic pathways) exploit the fact that tumor cells divide more rapidly than most non-transformed cells. Unfortunately this is not true for mucosal tissue, which is constantly abraded and needs permanent replenishment. Oral and intestinal mucositis is a common dose-limiting factor in cancer therapy. Inflammation of the oral cavity as a side effect of radiation therapy of head and neck tumors is a severe blow to quality of life as well as to nutrition. WO/2013/057354(Granada University [ES]; April 25, 2013) claims hydrogels containing melatonin, the “sleep neurohormone” which is widely available OTC for jet lag and sleep disorders, as a cell protectant. Extensive data are presented for tongue homogenates from irradiated rats. Almost as an afterthought the inventors claim that they have demonstrated for the first time a direct relationship between mitochondrial damage, activation of the inflammasome, and radiation-induced mucositis. – That might be true, but the utility of melatonin as an antioxidant for therapy-induced mucositis has been stated for many years (e.g., Int J Antimicrob Agents2000;16(2):161-3 [here] and Integr Cancer Ther. 2007; 6(3):281-92 [here]). The international search report does not cite any of these papers.
Incivek / Incivo And Victrelis – For More Than Just Hepatitis C
Telaprevir, which was co-developed by Vertex Pharmaceuticals and Johnson & Johnson, is an inhibitor of hepatitis C virus NS3/4a serine protease that augments interferon/ribavirin therapy of HCV infection. Serine protease inhibitors tend to act across several enzymes of this mechanistic type, and indeed the application states that J. Biol. Chem. 2010; 285: 34337-47 (here) discloses inhibitory activity of telaprevir against cathepsin A. This lysosomal protease displays carboxypeptidase activity at acidic pH, and deamidase and esterase activities at neutral pH, against various naturally occurring bioactive endogenous peptides that are involved in atherosclerosis, heart failure, renal diseases, and inflammation. So why would WO/2013/072328(Sanofi [FR]; May 23, 2013) claim teleprevir for the treatment of these diseases on the basis of this activity – with a November 2011 priority date? Most likely the explanation is simply that the connection between teleprevir and the specific diseases had not been explicitly made before. In vitro data for cathepsin A inhibition are provided and show an IC50 value of about 100 nM. Testing in unilaterally nephrectomized rats that are made salt-sensitive by treatment with desoxycorticosterone acetate, and which develop high blood pressure, endothelial dysfunction, myocardial hypertrophy and fibrosis as well as renal dysfunction when given 1% NaCl in drinking water, is only “prophetic,” i.e., contemplated. WO/2013/072327(Sanofi [FR]; May 23, 2013) is the analogous application claiming boceprevir(Merck & Co.’s Victrelis).
A Propranolol Patch for Melanoma
Almost three decades ago a paper in a Russian journal (Eksp Onkol.1984; 6(6):50-3; here) reported that lung metastases from melanoma B16 cells in mice were promoted by the beta-adrenoreceptors; not surprisingly at this time, it was all but ignored in the West. But a few years later it was shown that the melanoma cell line A-375 expresses beta 2-adrenoceptors (Br J Dermatol. 1990;123(2):163-70; here). Today we know that these receptors are upregulated in human melanoma, and that their activation (e.g., by physical and/or mental stress) releases pro-tumorigenic cytokines and metalloproteases (Lab Invest. 2013; 93(3):279-90; here). Clinical studies seem to offer preliminary support for beta blockers as adjunct in cancer therapy. In WO/2013/072762(Nometics [CA]; May 23, 2013) we see a practical application of these insights: A transdermal system containing propranolol, to be applied to the surgery site immediately following excision.Propanolol is quite lipophilic, so it should be possible to attain appreciable local concentrations in the subdermis.
From Crop Protection To Nematodes
Fluopyram, a pyridinyl-ethylbenzamide succinate dehydrogenase inhibitor, is a new broad-spectrum fungicide developed by Bayer CropScience, mostly promoted for use against mildew on grape and fruit cultures but also useful for wheat leaf blotch (EFSA J 2013;11(4):3052, here). In WO/2013/076231(Bayer [DE]; May 30, 2013) the company claims an additional pharmaceutical use, for treating and preventing endoparasitic infections (especially by helminthic nematodes) of mammals. In humans Ancylostoma spp, Necator spp., Trichuris spp., Strongyloides spp. und Enterobius spp. are named as preferred targets. Provided that other aspects of human toxicology do not intervene this could make very good sense: succinate dehydrogenase (and fumarate reductase, which catalyzes the opposite reaction) is present as a parasite-specific complex in mitochondria. No human data are presented, but doses from 10-50 mg/kg were effective against Haemonchus contortus in sheep.
A Phytocannabinoid For Type 1 Diabetes
Delta9-tetrahydrocannabivarin(THCV; propyl-tetrahydrocannabinol) is a neutral CB1 receptor antagonist that induces hypophagia in lean mice. It is pharmacology different from the CB1 inverse agonists/antagonists that had been investigated for type 2 diabetes and dyslipidemia but were discontinued due to adverse psychiatric effects (Nutr Diabetes2013; 3:e68, here), and is a potential drug candidate. As is the case with other phytocannabinoids, THCV can be expected to influence the endocannabinoid signalling system which modulates reactive oxygen species production. Indeed, WO/2013/076471(GW Pharma [GB]; May 30, 2013) claims just that, for protecting pancreatic islet beta cells particularly in the context of type 1 diabetes. In db/db mice THCV (10 mg/kg) caused a greater retention of insulin in pancreatic islets than cannabidiol, with less weight gain, and pancreatic beta cell mass was higher. See WO/2009/007697describing a formulation which comprises a ratioed mix of THCV and cannabidiol based on the pharmacology of the respective compounds.