This continues the discussion of documents published in February 2014, an incredible month in terms of patenting in this field. This time we present: a dopamine agonist delivered transdermally for headaches; endothelin receptor blockers, marketed for pulmonary hypertension, might be repurposed for cognitive impairment and Alport syndrome; the hypertension drug telmisartan act against demyelinating diseases; an old drug used for gout might be useful in heart failure, while an old dementia drug is suggested for sexual dysfunction; and the immunomodulator laquinimod, not yet approved for multiple sclerosis and other autoimmune conditions, is anti-excitatory and might have potential in schizophrenia, epilepsy, and attention deficit disorder.
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Parkinson’s, Restless Legs, and Headache
The selective dopamine agonist, pramipexole(Boehringer Ingelheim’s Mirapex) did not have it easy. Initially approved in 1997 for Parkinson’s disease, with a 2006 second approval for moderate to severe Restless Leg syndrome, it was off to a good start on the movement disorder market when it was hit by side effects and safety issues – first compulsive behavior (including gambling), then a link to heart failure. WO/2014/025638 (Mylan [US]; Feb. 13, 2014) claims it in transdermal patches to treat cluster headaches and migraines, in line with observations recently published by a Japanese group after the document’s priority date (Tremor Other Hyperkinet Mov (N Y) 2013 Sep 3;3, here). The cluster headache indication should be unpatentable over Cephalalgia 2006; 26(6):761-2 (here), a paper that both the inventors and the examiner failed to cite. Cephalalgia2013; 33(15):1272-6 (here) reports a patient whose cluster headache was successfully treated with rotigotine, a dopamine agonist that is exclusively available as a transdermal patch.
Endothelin Receptor Antagonists for Tauopathies…
Pulmonary arterial hypertension and cancer come to mind when you read “endothelin receptor antagonist,” but there has also been a trickle of papers showing benefits of these drugs in amyloid-overexpressing animal models of Alzheimer’s disease. The effect has been linked to improvement of endothelial function and cerebral bloodflow in amyloid angiopathy through blockade of the vascoconstrictive effects of endogenous endothelin. (Neurobiol Aging 2006; 27(3):446-50, here; Pharmacol Res. 2011; 63(6):525-31, here). WO/2014/025837 (Univ. Texas [US]; Feb. 13, 2014) carefully circumnavigates this prior art by focusing on misfolded and/or hyperphosphorylated tau protein and claiming utility for the associated neurological diseases. The rationale here is that blockade of astrocyte endothelin receptors prevents their phosphorylation triggered by endothelin produced by endothelial cells and hence, prevents tau production. An interesting application is chemotherapy-related cognitive impairment resulting from treatment with paclitaxel or temozolomide; traumatic brain injury is another. ETA antagonists (BQ123), ETB antagonists (PD143296, BQ788), and dual antagonists (PD145065, TAK-044, tezosentan, or bosentan) are claimed, preferably formulated with CNS-targeted liposomes as a delivery system.
…And for Alport Syndrome
Alport syndrome(hereditary nephritis) is a primary basement membrane disorder caused by mutations in the collagen type IV genes that prevent the proper production or assembly of the type IV collagen network, causing defects in the kidney, inner ear, and eye. WO/2014/028059 (Boys Town Natl. Research Hospital [US]; Feb. 20, 2014)claims a method of inhibiting deposition of laminin 211 in the glomerular basement membrane by administering an inhibitor of Rac1 and/or of Cdc42 (GTPase of the Rho-subfamily) — and because endothelin suppresses cell migration to the basement membrane via the JNK signaling pathway in a manner dependent upon Rac1 and Cdc42, this can be done with endothelin receptor antagonists such as bosentan(Actelion’s Tracleer™) or ambrisentan(Letairis™ / Volibris™, by GlaxoSmithKline and Gilead). An experimental design for testing in C57 Bl/6 X-linked Alport mice is described, but no data are presented.
The Renin-Angiotensin System: More than Hypertension
WO/2014/026164 (Univ. of California [US]; Feb. 13, 2014)claims angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (in particular telmisartan; Boehringer Ingelheim’s Micardis™) “for preventing or slowing myelin deterioration or loss from any cause,” including multiple sclerosis, and “the age-related breakdown of myelin that leads to Alzheimer’s disease.” Beta blockers, which can also mitigate activation of the renin-angiotensin system by lowering renin, are also claimed. – Data suggesting a significant beneficial effect of the ACE inhibitor captoprilin the rat experimental autoimmune encephalitis model which still is the standard model for multiple sclerosis, were published two decades ago (Immunopharmacol Immunotoxicol. 1995; 17(3):471-91, here); serum levels of ACE are elevated in human MS corresponding to disease activity (Arch Neurol. 1997; 54(8):1012-5, here). In some embodiments the angiotensin blocker is combined with a retinoid X receptor agonist, in particular the anticancer drug bexarotene(Eisai/Valeant’s Targretin™ and generics). Reports that link telmisartan to neuroprotection and improvement of cognitive impairment are numerous (e.g., J Renin Angiotensin Aldosterone Syst. 2014 Mar 12, here), others speak about cancer (Molecules 2014; 19(3):2862-76, here) and fracture healing (PLoS One 2014 Mar 18;9(3):e92085, here).
A Gout Drug for Heart Failure
Probenicidis a competitive inhibitor of the kidney organic anion transporter, and used to be the predominant drug (Benemid, Probalan) to treat gout by decreasing uric acid reabsorption in the renal proximal tube. It can also decrease renal excretion of other drugs, such as beta-lactam antibiotics and oseltamivir. It might enter a second life for treating cardiomyopathy, as WO/2014/028042 (Univ. of Cincinnati [US]; Feb. 20, 2014)claims. This is not because of the uricosuric (high uric acid levels in plasma are cardiotoxic) or diuretic effects but because probenicid also is a selective agonist of transient receptor potential vanilloid 2 (TRPV 2), a weakly calcium-selective cation channel that is activated by swelling of cells and heat; it acts as a positive inotrope in a murine model of heart failure. The companion paper is J Cardiovasc Pharmacol Ther. 2013;18(3):280-9 (here).
A Complex Immunomodulator as an Anti-Excitatory Drug
Teva and its partner, Active Biotech are developing the immunomodulator, laquinimod (intended trade name: Nerventra®) primarily for multiple sclerosis where it upregulates brain-derived neurotrophic factor (Am J Pathol. 2012;180(1):267-74, here), but the road has been bumpy. Branching out to Huntington’s and Crohn’s disease and lupus is attempted but has not progressed as far. But the company has been looking elsewhere as well: WO/2014/028397 (Teva Pharm. Ind. [IL]; Feb. 20, 2014) presents work derived from observations in the experimental autoimmune encephalitis mouse model. Surprisingly, at higher concentrations (10-30 μΜ in corticostriatal slices from wildtype mice), laquinimod showed direct effects on neuronal synaptic activity, by enhancing GABAergic inhibitory transmission and reducing excitatory transmission. This suggests utility in schizophrenia, epilepsy, spasticity and attention deficit disorder; mentioned in the descriptive part of the application although the formal claims are for “the manufacture of a medicament for increasing the duration or frequency of GABA-A mediated inhibitory postsynaptic currents” and “for decreasing the duration or frequency of spontaneous glutamate-mediated excitatory postsynaptic currents in a human subject.” WO/2014/028399 (Teva Pharm. Ind. [IL]; Feb. 20, 2014) is a variant of the above document that focuses on cannabinoid receptor type 1 function and attention deficit disorder.
An Old Cholinergic Drug for Sexual Dysfunction
The role of the brain cholinergic system in sexual behavior is slowly emerging (Pharmacol Biochem Behav. 2014; 120C:50-6, here). From Russia, where many acetylcholinesterase inhibitors have originated, comes WO/2014/031034 (Konsortsium-Pik [RU]; Feb. 27, 2014)claiming ipidacrine(a close cousin of tacrin, marketed as Aksamon, Amiridin, and Neuromedin for cognitive deficiencies and paralytic symptoms) for sexual dysfunction. This is a cholinesterase inhibitor, mixed muscarinic antagonist / inverse agonist, and K/Na channel blocker (CNS Drug Rev 1998; 4(3):247-59, here). Rat data are presented. Practicability might depend on the required doses; much like apomorphin, which has similar sexual effects, cholinesterase inhibitors tend to induce emesis and diarrhea.