Its a weekend again — a time to relax a bit from the deadline-driven consulting work (interesting as it is), and a time to share data and opinions on a few drug repurposing patents which crossed our desks during the past weeks. We have: an oxycodone/naloxone combination for multiple symptoms of Parkinson’s disease; an abandoned antihyperlipidemic for pancreatitis; a nootropic for benign tremor; and decades-old approved drugs that could help with filariasis.
Opiate Receptor Agonists plus Antagonists for Parkinson’s
That the opioid system is involved in Parkinson’s disease, and might be useful to treat L-Dopa induced dyskinesia (LID) is not a new insight; for example, the kappa opioid receptor agonist nalfurafin(Toray Industries’ TRK-820; launched in Japan in March 2009 as a treatment for hemodialysis-related uremic pruritus under the brand name REMITCH®) is effective in a rat model of LID even when co-administered with L-dopa (Eur J Pharmacol. 2009; 620(1-3): 42-8 PubMed). WO/2012/089738(Euro-Celtique [LU]; July 5, 2012) goes a step beyond, claiming to treat not only LID but also non-motor symptoms of Parkinson’s disease — pain, constipation, and drooling. This is said to be accomplished by combining an opioid agonist (such as oxycodone, hydromorphone or buprenorphine) and an antagonist with minimal oral bioavailability (preferably naltrexone) in a single dose form. One clinical study demonstrated that subjects with moderate to severe non malignant pain taking an oxycodone + naloxone prolonged release dosage form had improvement in constipation compared to subjects taking oxycodone SR alone. Another study investigating the same medications was actually for low back pain adequately controlled by an opioid analgesic which includeded two Parkinsonian patients. – Euro-Celtique SA acts as a patent holding agent for Napp / Purdue / Mundipharma Independent Associated Companies, a corporate constellation with heavy involvement in opiate analgesics.
Gemcabene for Pancreatitis
Alcohol abuse and gallstones are the two main causes of pancreatitis, accounting for 80%-90% of all cases. High levels of triglycerides are associated with the acute form, which can chronify. This is the rationale in WO/2012/092103(Michigan Life Therapeutics [US]; July 5, 2012) which proposes gemcabene(CI-1027, PD-72953), a carboxyalkylether developed by Pfizer for low-density lipoprotein (LDL) cholesterol lowering but now presumed discontinued. The clinical data provided in this patent application are from the Phase II LDL reduction study (AAPS J 2005; 7(3): E513–E522; PDF) and do not directly support the utility of gemcabene in pancreatitis. The preferred dose is 150 – 300 mg.
ST-101: Essential Tremor as an Added Utility
Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ST101; ZSET1446) is in a Phase II study (NCT00842816) for Alzheimer’s disease by Sonexa Therapeutics. It is an acetylcholine release enhancer (JPET2006; 317(3): 1079-8; PubMed), an activator of hippocampal calmodulin kinase II and protein kinase C (JPET2008; 326(1): 127-34; PubMed) and promoter of hippocampal neurogenesis (JPET2010; 333(1): 43-50; PubMed)and an inducer of an alternate form of amyloid precursor protein cleavage that prevents beta-amyloid formation (Ann Neurol.2011; 69(5): 831-44; PubMed) — in other words, it is a classical multifunctional nootropic, and one of the more interesting ones. The original developer has found another use: WO/2012/094612(Zenyaku Kogyo [JP]; July 12, 2012) claims essential (“benign”) tremor as a therapeutic target. At 1 and 10 mg/kg, ST101 reduced tremor in harmaline-treated ICR mice. A Phase II trial (NCT01332695), again sponsored by Sonexa, has been completed in December 2011 (no results reported yet); clearly there is no time being wasted here.
Death to Nematode Endosymbionts
Wolbachiaare endosymbiontic intracellular bacteria that infect arthropods as well as nematodes that cause tropical diseases such as elephantiasis and onchocerciasis; these archaic bacteria are causally involved in disease manifestation (Endocr Metab Immune Disord Drug Targets2012; 12(1): 53-6 PubMed). Antibiotics can assist with the treatment of Wolbachia-related filariasisbut are relatively expensive and require a minimum 4-6 week duration of treatment — a difficult proposal in Third World countries. In WO/2012/097258(Univ. California [US]; July 19, 2012)inventors have used Drosophilatissue culture cells that are constitutively infected with Wolbachiaand carry a GFP-Jupiter transgene for fluorescent labelling of microtubules (to delineate cellular boundaries) as a basic paradigm for high-throughput screening of anti-Wolbachiacompounds. A screen of 2,000 FDA-approved drugs from the Spectrum chemical library collection at the UCSC Chemical Screening Center was conducted, and revealed pararosanilinepamoate, pyrviniumpamoate, clofoctol, and isoreserpineas most effective.