During the past few weeks the ups and downs of patent publishing have provided us with few good examples of drug repurposing claims, but the three that we are presenting here are quite remarkable. Who would have thought that losartan, one of the popular AT-II receptor antagonists that had been exposed to a cancer scare a brief while ago, could actually assist cancer therapy? That clozapine and olanzapine, two “atypical” antipsychotics with some ocular side effects, could protect the retinal against oxidative damage? Or that a hematopoietic growth factor might help patients suffering from Duchenne muscular dystrophy? – If you want to know more about H.M. Pharma Consultancy’s activities in drug repurposing, please visit our website, contact us at office@hmpharmacon.com, or join our drug repositioning discussion group on LinkedIn.
Also announcing Terrapinn’s inaugural World Drug Repositioning Congress, to be held in London September 11-13, 2012. Register today, and meet us there!
Granulocyte Colony-Stimulating Factor (G-CSF) For Muscular Dystrophy
If we have reviewed only patent applications for new uses of small molecules in our blog contributions so far, it is not because proteins or other biotechnology-generated drugs cannot be repurposed; its just more difficult for several reasons, including (but not limited) to those that complicate the biosimilars business. G-CSF was one of the first recombinant proteins to enter the therapeutic arena, for the treatment of neutropenia. Subsequently it was found to have non-hematopoietic functions as well – just as it happened to be with erythropoietin. Beneficial effects of G-CSF have been recently reported concerning regeneration of damaged myocardial and CNS tissue. Although the revascularization effect in ischemic heart muscle has been called into question (Dan Med J. 2012; 59(3):B4411; PubMed; Heart. 2012; 98(4):282-90 PubMed), there could be potential in other types of muscle degeneration. One of these is Duchenne muscular dystrophy (DMD; see a review on its drug treatment perspectives here), as WO/2012/067262(Individuals [JP]; May 24, 2012) claims. In the mdx/utrnmouse model of DMD, which lack dystrophin and utorofin, a broad range of promising histologic and behavioral improvements were seen. Note in this context that hematopoietic stem cells did not restore dystrophin expression in DMD dogs (Blood 2004; 104(13):4311-8; here). The two inventors are affiliated with the Keio University School of Medicine in Tokyo.
Losartan Improves Delivery and Efficacy of Cancer Therapeutics
Angiotensin II receptor blockers, now generic, remain the mainstay of antihypertensive therapy. However, they briefly came under the suspicion of raising the risk of malignancy until another meta-analysis of 15 clinical trials enrolling 138,769 individuals demonstrated no significant increase in the overall or site-specific cancer risk from telmisartan, irbesartan, valsartan, candesartan, and losartan (J Hypertens. 2011; 29(4):623-3 PubMed). WO/2012/068531(General Hospital Corp. [US]; May 24, 2012) goes a step further: The inventors have discovered that losartan normalizes the interstitial matrix of solid tumors and facilitates the distribution and/or penetration of chemotherapeutics, including nanotherapeutics. For example, losartan reduced collagen I production by carcinoma associated fibroblasts isolated from breast cancer biopsies, and caused a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic and skin tumors in mice. Losartan also improved the distribution, therapeutic efficacy and/or penetration of nanopartices, such as oncolytic herpes simplex viruses (HSV) and pegylated liposomal doxorubicin. – These effects could be related to the abrogation of aberrant TGFβ activation that has just been reported (PLoS One 2012; 7(2):e31384, here). For the peer-review companion paper, see PNAS 2011; 108(7):2909-14 here.
Antipsychotics for Retinal Diseases
Clozapine, olanzapine, and their primary metabolites have several receptor-mediated activities that could make it worthwhile to consider these antipsychotics for retinal neuroprotection, in spite of some established ocular side effects. However, in WO/2012/074788(Allergan [US]; June 7, 2012) their protective effect on the retinal pigment epithelium (the layer of cells that nourish and recycle the photoreceptors) focuses on conditions of oxidative stress, such as hyperoxia-induced neovascularization (important in retinopathy of prematurity) and blue light exposure (important in “dry” macular degeneration and genetically determined retinal dystrophies such as Stargardt disease). Olanzapine-N-oxide and N-demethyl olanzapine mostly share these protective effects, on the mechanistic background of which the patent application does not elaborate. Intravitreal injection and topical treatment by eye drops both work, which is quite astounding in itself.