Abstract
High Tolcapone Doses Reduce Appetite
International Patent Application WO/2019/129120,
Tolcapone is known as a catechol-O-methyltransferase (COMT) inhibitor, used as an adjunct in the treatment of Parkinson's disease to protect Dopa drugs against excessive degradation by the peripheral enzyme before they can enter the brain. The inventors disclose here that tolcapone also is an inhibitor of fat mass- and obesity-associated (FTO; an AlkB-like α-ketoglutarate and iron [II]-dependent nucleic acid demethylase 1 ) and can reduce appetite. This is not surprising: not only is COMT a methyltransferase but the tolcapone analog, entacapone has been disclosed for the treatment of obesity in WO/2014/082544, by the Beijing National Institute of Biological Sciences. However, the inventors argue that data disclosed in that patent application showed no difference in body-weight-normalized food intakes between the entacapone-treated group and the control group, and that the effect of FTO on food intake remains unclear—a statement that is not supported by dozens of reports published during the past 13 years, 2,3 and has more recently been differentiated on the basis of FTO polymorphisms. 4 Figures show inhibition of FTO by tolcapone in a demethylase assay (IC50 ∼2.5 μM), inhibition of food intake after 2 days (p = 0.039), and decreases of blood glucose (p = 0.024) and body weight after 2 weeks of tolcapone (600 mg/kg). In humans, tolcapone would be administered in doses of several hundred milligrams per day up to 2.5 g/day, far exceeding those currently used in Parkinson's disease.
Lorcaserin for Incontinence
International Patent Application WO/2019/131902,
There are several candidate compounds in development for the treatment of stress urinary incontinence, but fecal incontinence is generally considered to be beyond pharmacological treatment. Takeda claims that both objectives can be achieved with a 5-HT2c receptor agonist that is identifiable as lorcaserin, an antiobesity agent 5 marketed in the United States but not in Europe. 5-HT2c agonists are known to increase urethral reflex closure and flow resistance, and their effect on the pelvic floor might also extend to the anus. The oral human doses claimed here (10 mg and less) are much lower than those used to suppress appetite; plasma levels of only a few nanograms per milliliter (and maybe less) need to be maintained for 24 h. Urethral and anal leak point pressure data in Sprague-Dawley rats are disclosed. For a very similar study from Hokkaido University that might be related to this application, see Ouchi et al. 6 Repurposing of lorcaserin to treat Dravet syndrome, 7 nicotine dependence, and cocaine use 8 has also been investigated.
Tranilast: An Antiallergic not only for Chronic Scars, but Also for Tendon Healing
International Patent Application WO/2019/135363,
Owing to the lack of both cellularity and blood vessels in tendons, their repair is slow and inefficient. Biomaterial-based treatment strategies have shown their potential for tendon healing, 9 but pharmacology does not play a role beyond suppression of inflammation and pain. Seeking suitable repurposing candidates, the present inventors have focused on tranilast, which was initially developed and approved as an antiallergic. Its utility was soon extended to the treatment of hypertrophic scars: it suppresses release of profibrotic transforming growth factor beta (TGF-β) from keloid fibroblasts 10 but has no effect on the healing of deep burn wounds. 11 If it seems paradoxical to use a collagen synthesis inhibitor in a condition that requires such a synthesis, it is because unplanned and uncontrolled collagen deposition during tendon healing would just compound the problem. What the Japanese inventors exploit here (without wishing to be bound by theory) is the ability of tranilast to inhibit the local production and/or secretion of interleukin-6 (and probably other proinflammatory cytokines and matrix metalloproteases) in the affected area. Presence of this effect, reported by researchers from Jilin University in human corneal fibroblasts, 12 is demonstrated in fibroblasts from carpal tunnel syndrome surgery patients.
An Old Malaria Drug for Triple-Negative Breast Cancer
International Patent Application WO/2019/138203,
The malaria drug hydroxychloroquine is known as a potentiator of chemo- and radiotherapy in various cancers, 13 and it can resensitize estrogen receptor-α positive breast cancers that have developed resistance to targeted therapies, including tamoxifen. 14 Mammacarcinoma subtypes might vary in their sensitivity to hydroxychloroquine autophagy inhibition. 15 That the particularly difficult treatment of triple-negative breast cancers (which express neither estrogen or progesterone receptors nor the receptor tyrosine-protein kinase HER2/neu) can also be achieved with hydroxychloroquine in the neoadjuvant setting, as the inventors have shown using the human MDA-MB-231 cell line in vitro and in mice, has not been reported so far. The in vitro antiproliferative effect is stronger than that of 5-fluorouracil or docetaxel alone. Efficient prevention of metastasis was also seen in mice, with hydroxychloroquine alone and in combination with docetaxel. It can be assumed that the responsible mechanism is the one known for adjuvant hydroxychloroquine, autophagy inhibition. For a more general discussion of the pleiotropic pharmacological actions of chloroquine and hydroxychloroquine, see Shukla and Shukla. 16
Dimethylfumarate and Betamethasone in Friedreich's Ataxia
International Patent Application WO/2019/143560,
Insufficiencies in mitochondrial numbers, mass, or function in neural cells have been identified as common elements in neurodegenerative diseases, and might be causal, or at least substantial contributors, to neuronal death. No specific drugs have been developed to correct these conditions. It is, therefore, of high significance that the autoimmune disorder drug betamethasone, the multiple sclerosis drug dimethylfumarate, the old antipsychotic chlorpromazine, and several of its marketed analogs are supposed to provide a remedy, as the inventors claim. Dimethylfumarate is shown to increase mitochondrial gene expression in retinal cells in the NDUFS4 knockout mouse model of Parkinson's disease and optic neuropathy, to enhance mitochondrial respiration, and to rescue performance in the visual cliff test. Dimethylfumarate and betamethasone increased frataxin expression and mitochondrial DNA copy number in fibroblasts derived from patients with Friedreich's ataxia. The inventors had previously discovered that dimethylfumarate dose-dependently increases frataxin, a mitochondrial protein, the deficiency of which ultimately causes the disease Friedreich's ataxia; and that methylene blue and its analogs (including some of the compounds mentioned earlier) promote Nrf2 and frataxin induction. 17 Enhancement of mitochondrial function and increased frataxin levels by lipophilic methylene blue analogs in models of Friedreich's ataxia have been reported by others. 18 However, frataxin induction can occur in the absence of an increase in mitochondrial biogenesis. There seems to be no clear prior indication for beneficial effects of betamethasone on mitochondrial biogenesis.
When the Classic Alzheimer Drugs do not Work Anymore
International Patent Application WO/2019/145523,
Acetylcholinesterase inhibitors, the standard treatment for mild and moderate Alzheimer's disease, lose their efficacy as the disease progresses. This is not surprising, considering that they can only prevent synaptic catabolism of acetylcholine, whose neuronal synthesis and secretion is increasingly diminished in later-stage disease. Cholinergic terminals appear most vulnerable, whereas the glutamatergic terminals and finally by the GABAergic terminals are affected later. 19 Because the latter two have to balance each other to avoid neuronal excitotoxicity on the one hand and further compromization of cognition on the other, pharmacological intervention might be able to achieve benefits even in the later stages of Alzheimer's disease. The present patent application is an extension of Pharnext's WO2012/117076, which had already disclosed combinations of baclofen (a GABA-B receptor agonist and muscle relaxant) and acamprosate (an NMDA receptor antagonist and positive allosteric modulator of GABA-A receptors used to support alcohol withdrawal and abstinence) for Alzheimer's disease, 20 but did not specify that the combination is effective in patients who have lost responsiveness to cholinesterase inhibitors, and might even restore it. The latter claim would require at least partial regeneration of cholinergic nerves and/or terminals, and is not backed by the extensive animal data, which are otherwise impressive.
Glitazones for Influenza and Bacterial Infections
International Patent Application WO/2019/154958,
NEET proteins are a family of recently discovered highly conserved 2Fe-2S proteins 21 characterized by a unique “NEET fold”, as well as two distinct domains: a beta-cap and a 2Fe-2S cluster-binding domain. 22 Their role appears to be in iron homeostasis and reactive oxygen generation; the three human NEET proteins that have been identified so far (mitoNEET, NAF-1, and MiNT, expressed by the three CISD genes) have attracted attention primarily for their possible role in cancer. 23 The peer review literature does not seem to hold any suggestions that NEET proteins could have a direct role in infection, but binding affinities to mitoNEET have been published 24 for several known compounds: the diuretic, furosemide; the antidiabetic potassium channel blocker, glibenclamide; various thiazolinedione PPAR agonists; the ryanodine receptor antagonist and muscle relaxant, dantrolene; and the anticancer drug, doxorubicin. The thiazolidinediones pioglitazone, rosiglitazone, troglitazone, and rivoglitazone are most preferred. Infection-related literature data for this compound class are ambiguous, although pioglitazone is beneficial in sepsis models and has been in a Phase I clinical trial in critically ill patients. 25 The inventors prepared a CRISPR/Cas9 CISD2 knockout clone of the A549 human cell line, and found expression of the viral nucleoprotein protein to be inhibited upon infection with an H1N1 influenza virus. Pioglitazone was one of three compounds tested in an influenza virus replication assay in wild-type A549 cells and found an IC50 value of 38 μM, which is probably not low enough for an antiviral drug, but an interesting lead.
Trimetazidine: An Old Angina Pectoris Drug for Some Cases of Liver Failure
International Patent Application WO/2019/161308,
Acute-on-chronic liver failure (ACLF) is a specific syndrome where patients with underlying cirrhosis not only develop acute decompensation, but also experience organ failure and have high short-term mortality. In contrast with other cases of fulminant liver failure, surviving patients do not recover beyond their chronic condition, and remain at risk for another acute failure episode. There is no approved specific therapy, but the inventors have found a possibility: trimetazidine, a decades-old multimechanism agent that is used as a drug for angina pectoris and related forms of ischemic heart disease in many European countries.
26,27
It protects against cardiotoxic chemotherapies
28
and promotes healing in the rat sciatic nerve injury model.
29
The inventors enrolled 133 subjects presenting with acute decompensation of cirrhosis and suspected ACLF in a three-arm randomized controlled study. Patients were randomized to receive either
Topical Esomeprazole for Radiodermatitis
International Patent Application WO/2019/169175,
Several approaches have been evaluated for the prevention and treatment of radiation dermatitis, which has up to 95% incidence in patients who receive chemoradiation for breast cancer, sarcoma, or head-and-neck cancer. In most of these cases, the inflammation subsides with mild erythema. However, 20%–25% of the patients develop moist desquamation and ulceration that can lead to fibrosis and long-lasting or permanent scarring. 30 The inventors have found that H+/K+ATPase pump inhibitors (the “prazole” drug class used to inhibit gastric acid secretion) activate heme oxygenase by inducing nuclear translocation of Nrf2 either through phosphorylation of Erk1, Nrf2 itself, or by attacking the sulfhydryl group in Keap1 and disassociating the Keap1-Nrf2 complex. Figures show the effects of “dermaprazole” (a 1%–5% cream formulation of esomeprazole) in cell extracts from a human 3D skin model at baseline and after 14 Gray radiation, in comparison with 1% topical hydrocortisone (the current standard treatment for radiodermatitis). This is less surprising when a 2015 article reporting a preclinical study of esomeprazole in a rat model of bleomycin-induced lung injury is considered, 31 along with the role of the Nrf2 signaling pathway in clinical radiotherapy tolerance. 32 For the peer review companion article, see Pham et al. 33
Sitaxentan, A Better Endothelin Receptor Blocker for Digital Ulcers
International Patent Application WO/2019/173215,
There have been few randomized and controlled therapeutic studies for cutaneous symptoms of scleroderma, which are particularly pronounced and function-limiting on hands and fingers but have no broadly approved specific drug treatment. 34 Initially there had been considerable enthusiasm for targeting the endothelin axis; ET-A/B receptor dual antagonists such as bosentan and macitentan, which are approved for the treatment of idiopathic pulmonary hypertension, have been investigated (and are being used off-label) for digital ulcers. However, clinical trials did not produce strong and robust evidence with respect to healing of established ulcers or prevention of new ones 35 ; these drugs are not among the broadly expert-supported treatment modalities. 36 There has never been anything to suggest that selective ET-A receptor antagonists would perform better; there is considerable functional cross talk between the subtypes. It is, therefore, quite surprising that the inventors found that topically administered sitaxentan, a pulmonary hypertension drug that was withdrawn from the market soon after its European approval, is superior to bosentan in several important mechanisms of cutaneous fibrosis. This includes the production of collagen, which was originally believed to require inhibition of both receptors to be efficiently reduced. 37 The presented data were obtained with cultured fibroblasts from human male and female skin that were stimulated into the profibrotic phenotype with TGF-β and investigated in a confluent monolayer scratch assay that provides a rough in vitro approximation to wound closure. Sitaxentan significantly outperformed bosentan at 30 and 100 μM, but not at 10 μM.
A Multiple Sclerosis Drug Helps Infarcted Hearts to Regenerate
International Patent Application WO/2019/175869,
Cardiac regenerative medicine focuses on stem-cell therapy to replace the massive loss of functional cardiomyocytes that occurs in myocardial infarction and chronic heart disease, an approach that is almost certain to succeed—but not quite yet. Immunological aspects of heart failure, although incompletely understood, 38 could provide solutions: regulatory T cells can be beneficial in healing after myocardial infarction 39 and in postischemic heart disease. 40 The inventors concluded that established drugs for autoimmune diseases might be useful in this setting, and found that this is the case with glatiramer acetate, a standardized copolymer of amino acids and the first noninterferon drug for multiple sclerosis. Immediately after initiation of myocardial infarction, mice were treated with 2 mg/animal per day i.p. for 7 or 14 days, or i.m. for 14 days. The effect versus the control groups (sham-opened chest with or without injection of phosphate-buffered saline) was strongest in the long-treated i.p. group and did not diminish significantly if glatiramer acetate was administered 24 or 48 h postinfarction. Treatment decreased the scar area and effected an antiparallel change in decreasing neutrophil and increasing macrophage populations 24 hours postinfarction, a feature that was recently shown to promote cardiac regeneration. 41 It should be noted that glatiramer acetate treatment is associated with elevated risk for coronary artery disease. 42
Silodosin: The Male Contraceptive, Finally?
International Patent Application WO/2019/180217,
The search for a reliable contraceptive for males has taken many paths and many turns, including sophisticated attempts to interfere with sperm motility or their capability of penetrating into the oocyte. Among the oldest attempts are the α1 adrenoceptor antagonists that have been used to treat benign prostate hyperplasia for decades—and are known to cause ejaculatory disorders as an extremely frequent side effect. The first attempt to exploit this for use as a “pill for men” was with prazosin, which proved inadequate. 43 The retrograde ejaculation that alpha antagonists, including the most recent ones such as silodosin, 44 cause in a significant fraction of patients, explains only a part of the azoospermia that seems to be mostly attributable to a loss of seminal emission. 45 A prospective double-blind randomized placebo-controlled crossover study conducted in India by another group tested 8 mg silodosin as an on-demand male contraceptive, reporting reversible azoospermia, no unintended pregnancies, and no dropouts due to drug-related adverse events. 46 In the present application the French inventors claim that continuous daily administration is also a safe and effective option if an extended release formulation with a 12 mg dose is used that causes no substantial orthostatic hypotension.