Attracting more and more customers who entrust us with ever more work and responsibility is excellent for our business but it cuts down on the time we can spend on writing blog posts such as this one. Sorry for that — the upside is of course that it means that we can sustain a profitable business & go on doing other things, so please stay tuned — we will continue to share information (and some opinions) on recent drug repurposing patent applications. Here are five examplesfrom the first half of November 2012. – Please attribute to H.M. Pharma Consultancy when citing from this post.
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From Pain to Depression: Use Extension or Repurposing?
While the analgesic efficacy of tapentadol(a μ-opioid receptor agonist and norepinephrine reuptake inhibitor) is generally known, WO/2012/146383(Grünenthal [DE]; Nov. 1, 2012) shows that its originator wants to tap into the even larger market of depression. The company went back to the records of a clinical trial investigating the tapentadol for low back pain, where the Hospital Anxiety and Depression Scale score had been used to correct for what was observed as undesired comorbidity, especially in the patient sub-population with a neuropathic component. Tapentadol was also effective in the treatment or prevention of depression and/or of anxiety in these patients. – The three-way interaction between pain, anxiety, and depression has been extensively investigated (see e.g., here), and that a WHO Step II analgesic would also improve the psychiatric sequelae is no great surprise. It would of course take investigations in depression patients without pain to prove the point for actual repurposing towards mood disorders.
A Pesticide for Cancer
4-Cyclopropyl-6-methyl-N-phenylpyrimidin-2-amine, a methionine biosynthesis inhibitor better known as cyprodinil, is a foliar fungicide (introduced in 1993 by Ciba) for which the Codex Alimentarius sets fairly strict maximum residue limits (see here). It is intriguing to learn from WO/2012/146933(CXR Biosciences [GB]; Nov. 1, 2012) that it is also an inhibitor of PIM kinases, and a potential anticancer. In an inhibition assay at 10μΜ and 100μΜ against a panel of 30 protein kinases, the most potent activity was against PIM1, at an IC50 of about 300μΜ (although the text confusingly states PIM3, which had an IC50 of 1.7 mM, to be the the prime target). In any case the cytostatic activity against OVCAR3 and HepG2 cancer cell lines was much lower, at EC50 values of 5 µM and 49 µM, respectively. In animal experiments, the acute safety window (ratio LD50/NOEL) was 200 and the plasma half-life was about 24 hrs. In athymic nude mice with PC3 or HT-29 tumor cell xenografts, cyprodinil (10 mg/kg p.o. for 28 days) reduced the fraction of animals developing tumors to 83% vs. 100% in controls, and tumors that developed were 50% smaller.
Tacrolimus for Pulmonary Arterial Hypertension
In PAHthe right – not the left – heart ventricle is affected by hypertension overload because the pulmonary artery suffers endothelial dysfunction and smooth muscle hypertrophy, causing pressure to rise in the lung circulation and hemodynamics to deteriorate — all without a pressure rise in the general (left-heart) circulation. Tacrolimus(marketed as Prograf®), an immunosuppressant and multi-kinase inhibitor, is useful in systemic sclerosis (in the course of which PAH frequently develops) and the subendothelial proliferation in the pulmonary artery is also kinase-driven — which is why e.g. imatinib is useful in this condition. WO/2012/151153(Stanford Univ. [US]; Nov. 8, 2012) claims tacrolimus for those cases of PAH for which defective signaling by BMPR2 (receptor for bone morphogenetic protein type II), ALK1 (the activin A receptor) or endoglin has been established. This makes sense in the above context but pretty much restricts the utility to familial cases. At 15 ng/ml (the therapeutic serum level used to induce immunosuppression), but also at the immunologically sub-effective 0.2ng/ml, effects comparable to those of bone morphogenic protein-4 (10 ng/ml) were seen in vitro. A 3-week treatment with tacrolimus (0.05 mg/kg/d; serum levels, 0.2ng/ml) in mice with a conditional deletion in BMPR2 in endothelial cells and exposed to hypoxia prevented the development of PAH and right ventricular hypertrophy.
Quetiapine for Insomnia
Atypical antipsychotics are approved for treating several psychiatric conditions, most of which involve extreme agitation, such as acute psychosis and mania. One widely used “atypical” is quetiapine (AstraZeneca`s Seroquel®), which acts primarily as an antagonist of histamine receptors and adrenergic receptors at very low doses but activates the adrenergic system and binds strongly to serotonin receptors and autoreceptors as the dose increases. At high doses, quetiapine starts blocking dopamine receptors at a significant degree. It has been used to treat insomnia in patients with comorbid psychiatric disorders; would it make sense to take it if you just can’t sleep? Yes, states WO/2012/154174(Individual [US]; Nov. 15, 2012) — provided you keep the dose quite low, at about 12.5 mg/day (the marketed tablets come at strengths from 25 to 400 mg). Presentations with biphasic dissolution profiles are presented, with each of the two phases preferably releasing 3-6 mg quetiapine. No biological data are presented.
Bethanechol for Dry Mouth
The muscarinic acetylcholine receptor agonist bethanecholis primarily used for urinary retention (as Urecholine® tablets); but – as is predictable with such compounds – it is also a sialogogue, i.e., it stimulates salivary flow. This has been known for years (see eg., Spec Care Dentist. 2006; 26(4):164-70; PubMed), so one has to wonder why WO/2012/153110(Acacia Pharma [GB]; Nov. 15, 2012) would claim it for xerostomia now. The application mentions none of these prior art pieces, although it cites Acacia’s own WO/2011/058366(published after the current application’s priority date) which discloses preclinical and clinical studies showing the utility of bethanechol in the treatment of dry mouth. The added value of the current application seems to be the enhanced results that were obtained by using dimethyl isosorbide as a mucosal penetration enhancer — understandable since bethanechol is a quaternary ammonium compound with a calculated log P value of around -4, one of the lowest values for an approved drug. The international search report cites PCT documents from 1998 and 2007 but no peer-review literature.