Today’s discussed patent applications have a clear focus on neurology: Mesna, an extremely small and simple molecule used as a detoxicant, could lessen lumbar pain after failed or partially successful back surgery; dimiracetam, which the Italian arm of SmithKline Beecham had abandoned as an Alzheimer drug candidate, might be useful to prevent the “hand and foot” neuropathy syndrome caused by cancer treatment with Nexavar; and academicians in Chile have rediscovered the potential utility of the edema drug spironolactone for multiple sclerosis. Monoclonal antibodies are rarely repurposed, but we got an example for this too – tumor necrosis factor alpha antagonists could be useful in Dupuytren’s contracture, which affects about 5% of the general population to some degree.
Mesna for Lumbar Pain
Bristol-Myers Squibb’s Uromitexan™ (sodium 2-mercaptoethane sulfonate for injection) is indicated for the reduction and prevention of hemorrhagic cystitis caused by the urinary tract toxicity of oxazaphosphorine anticancer agents such as ifosfamide; it can also act as a detoxifier in acrolein poisoning. But there is more to it: when applied to peridural fibrosis sites during revision lumbar spine surgery it can aid in their dissection (Eur Spine J. 2008;17(12):1752-6; see here). From the same group now comes WO/2012/052888(University of Rome [IT]; April 26, 2012) extending the use of Urometixan to treat pain from Failed Back Surgery Syndrome by peridural infiltrations (50 mg), made above or below the level of the surgical intervention site. A study was conducted in 7 male and 4 female patients (48 – 78 years old) for a 9-month period. Each patient was subjected to 1-4 procedures, and pain in various body positions was evaluated on a numeric rating scale. Moreover, the patients filled the Oswestry Disability Index (ODI) questionnaire, which captures the impact of pain on daily activities. All patients improved to some degree, which is impressive considering how resistant to treatment (even with medullary electrostimulators) this type of pain typically is.
A Failed Nootropic for Sorafenib-Induced Neuropathy
Dimiracetam (2,5-dioxohexahydro-1H-pyrrolo [1, 2-a] imidazole), a chiral bicyclic derivative of the nootropic piracetam, was developed for cognition problems by SmithKline Beecham in the late 1990s (under research code ISF 4185), but it never went beyond Phase I trials at this time. WO/2004/085438(Nikem Research SA), and later a peer review paper (Bioorg Med Chem. 2008; 16(6):3224-32 PubMed) have described dimiracetam derivatives that are active in animal models of neuropathic pain. Dimiracetam itself is now entering another Phase II clinical trial for AIDS-related neuropathic pain (NCT01444690, managed by Neurotune AG as a follow-up to NCT01135251which has been completed). WO/2012/055057(Neurotune [CH]; May 3, 2012), which claims dimiracetam for allodynia in hands and/or feet induced by solid tumor therapy with the kinase inhibitor sorafenib (Nexavar, Bayer and Onyx Pharmaceuticals) is only an incremental intellectual property extension to WO/2008/125674claiming dimiracetam for chronic pain. There seems to be no preference for either of the two enantiomers. The daily human doses are high, as is typical for drugs of the “racetam” family: 800 – 3200 mg for the oral route, 400 – 1000 mg for i.v. or i.m. administration.
Monoclonal Antibodies Repurposed
Dupuytren’s contracture is caused by the accumulation of collagen on the connective tissue of the hand (the palmar fascia) causing it to thicken and shorten, whereupon the fingers (most commonly, the ring finger and little finger) can bend. Treatment is mostly by surgery, although a bacterial collagenase preparation (Xiaflex™, Pfizer and Auxilium) is also available. WO/2012/056044(Imperial Innovations [GB]; May 3, 2012) claims to have found a different approach: downregulation of myofibroblast activity by TNF-α antagonists used for rheumatoid arthritis such as infliximab, adalimumab, golimumab and most preferrably certolizumab pegol (UCB’s Cimzia™), since it causes low injection site reaction and pain. The inventors’ data from over 100 Dupuytren’s cords show that in the majority of patients, myofibroblasts are concentrated in nodules, located at the level of the affected joints. The hypothesis is that such densely packed cellular nodules could exert sufficient force to promote or sustain contracture of the fingers. Their cells then remodel the surrounding matrix to a more shortened configuration. The resulting increased flexion deformity would impair function and the reduced movement at the joint would in turn lead to a reduction in tension sensed by nodular myofibroblasts. The method should also work in related musculoskeletal fibroproliferative disorders such as adhesive capsulitis (the “frozen shoulder” syndrome).
Spironolactone for Multiple Sclerosis
WO/2012/056344(Universidad Católica de Chile [CL]; May 3, 2012) presents an amazing suggestion for the old a potassium-sparing diuretic aldosterone antagonist spironolactone: use it to treat multiple sclerosis. Their experiments show that dendritic cells stimulated with aldosterone induce Th17 CD4+ T helper cells, a phenotype that in recent studies has been associated with the promotion of inflammatory and autoimmune diseases (J Immunology 2010; 184, 191-202; here). This was suppressed by eplerenone and spironolactone. In the murine experimental autoimmune encephalomyelitis model, only spironolactone was effective, even in mice that had not received aldosterone. The inventors suggest that blocking T cell activation by spironolactone is due to a failure in the interaction of autoreactive T lymphocytes and antigen presenting cells, resulting in an inhibition of cellular adaptive response directed towards the myelin sheath. – This sounds fascinating and might be of particular interest to healthcare providers, given the fact that spironolactone costs all but nothing compared to established MS drugs. But how new is it? The inventors do not cite three German key papers that go back three to four decades and would appear to preempt their findings: Z Neurol. 1972; 202(3):217-28 (PubMed) and Klin Wochenschr. 1973; 51(6):286-7 (PubMed) describe a clinical pilot study of spironolactone derivatives in MS patients, and lymphocyte stimulation characteristics of these patients during treatment; Fortschr Med. 1982; 100(41):1922-5 (PubMed) elaborated further on the lymphocyte-suppressant effect. The examiner cited these papers, but only as type A documents, i.e., they were considered background art with no particular relevance to the invention… which does seem a bit strange to us. Note that spironolactone has been repurposed several times already, exploiting its antiandrogenic effect to treat hirsutismin women and to treat female-pattern hair loss (a common off-label use).
P.S.: The May 2012 issue of the Pharmaceutical Patent Analyst went online today, and H.M. Pharma Consultancy is proud to have contributed not only the regular patent commentaries (covering documents from March and April) but also a full review titled “Pharmacological therapies for cataract and refractive errors: landscaping niches of ocular drug patenting.” These pieces are free to download at www.future-science.com/toc/ppa/1/2– please visit and peruse these resources too!