Abstract
A Prototypical Cholinesterase Inhibitor to Restore Peripheral Nervous System Balance
International Patent Application WO/2019/004808,
Autonomic dysfunction—impairment of the vegetative nervous system that unsettles the balance between the sympathetic and parasympathetic nervous systems—is most apparent by the blood pressure instability and orthostatic intolerance it causes, but it can affect many organs. 1 It is mostly a sequel of neurodegenerative diseases (especially Parkinson disease) or neurotrauma. Only two drugs were approved by the U.S. Food and Drug Administration for the treatment of this condition during the past 20 years: midodrine (Proamatine®, Orvaten®; a prodrug of an α1-receptor agonist) and droxidopa (Northera®), a norepinephrine prodrug. The inventors claim another possibility: 30 mg oral doses of the peripherally acting cholinesterase inhibitor pyridostigmine (available as Mestinon® for myasthenia gravis) every 8 h, which would certainly boost the activity of the sympathetic nervous system. The outline of a proposed clinical study is provided. Getting a patent on this is going to be difficult considering that a review of trials using pyridostigmine in orthostatic intolerance was published 12 years ago, 2 and reports continue to appear in the literature. 3,4
Neuroleptics Treat Some Forms of Meningitis
International Patent Application WO/2019/008141,
Phenothiazines register prominently among the old tricyclic antipsychotic drugs. A recent review states that besides their antipsychotic activity, phenothiazines have a significant antimicrobial effect as well, since they can enhance the bactericidal function of macrophages and inhibit efflux pumps. They are also able to eliminate bacterial resistance plasmids and destroy bacteria by their membrane-destabilizing effect. Their antiviral, antiprotozoal, antifungal, and antiprion activities have also been described. 5 Indeed chlorpromazine, trifluoperazine, methdilazine, and thioridazine are distinctly effective in vitro against M. tuberculosis 6 and staphylococci, 7 even in antibiotic-resistant strains; however, this is not always borne out in animal models of the respective infections. The inventors have instead focused on gram-negative bacteria with type IV pili—primarily meningococci such as N. meningitidis, but also K. pneumoniae, H. influenzae, enteropathic E. coli, and others. Type IV pili not only mediate bacterial attachment to surfaces and motility, but they are also critical for their pathogenic potential. Trifluoperazine induces a drastic loss of the surface expression of meningococcal type IV pili and affects the pilus dynamics by exerting a direct or indirect effect on the pili ATPase, which is responsible for Type IV pilus retraction. Some phenothiazines carrying a piperidine or piperazine substituent (thioridazine, mesoridazine, trifluoroperazine, and others) induce efficient dispersal of meningococcal aggregates at low micromolar concentrations, whereas those with an acyclic substituent (e.g., chlorpromazine or triflupromazine) are mostly ineffective. For the peer review companion article, see Denis et al. 8
From Gout to Epilepsy
International Patent Application WO/2019/012109,
Probenecid, an old uricosuric drug that inhibits organic anion transporters (Urat1, Oat1-Oat4), has an interesting history. Developed in the 1950s to slow the renal elimination of penicillin, it was later used as a diagnostic for depression and other psychiatric disorders 9 before it found its permanent application and is used for the therapy of gout caused by hypoexcretion of uric acid. Today it is mostly limited to patients who have refractory gout or cannot tolerate xanthine oxidase inhibitors. Recently evidence for potential efficacy in traumatic nerve injury has been reported, 10 and a drug target interactome analysis has suggested that probenecid could be used to improve retention of nucleotide analog antiretroviral drugs and the influenza drug oseltamivir. 11 It might even have a direct effect against influenza viruses. 12 The inventors have demonstrated that probenecid blocks ictal discharges in epileptic cortical human tissues ex vivo at 1 mM, and is effective in the kainate mouse model of temporal lobe epilepsy (at 200 mg/kg). The inventors do not discuss the mechanism in this patent application, but their peer review companion article 13 makes it clear that the antiepileptic activity of probenecid is mediated by inhibition of pannexin-1 channels, which promote seizure generation and maintenance through ATP signaling via purinergic receptors. 14 The probenecid doses and concentrations are very high, casting some doubt on clinical applicability.
Preventing Side Effects of Vesicular Monoamine Transporter Drugs
International Patent Application WO/2019/016357,
Selective 5-HT1a receptor agonists acting at presynaptic terminals were once hoped to assist with neurotransmitter release—primarily serotonin for depression and anxiety, 15 but also dopamine 16 and acetylcholine. There are also clear implications regarding neuroprotection. None of these hopes was ever quite fulfilled. Tandospirone was launched as an anxiolytic in Japan and China (as Sediel®) in 2004, but at the same time repinotan, in phase II trials for stroke, 17 was discontinued—5 years after the development of flesinoxan for anxiety disorders was terminated. Flibanserine, originally developed for depression, was diverted to the controversial indication female hypoactive sexual desire disorder for which it ultimately received FDA approval in 2015 (as Addyi®), but its success on the market is limited. The inventors have tried a somewhat different angle by claiming these 5-HT1a agonists (as well as sarizotan and befiradol) to counteract the depressogenic and parkinsonism side effects of tetrabenazine and its derivative, valbenazine (Ingrezza®), which inhibit the vesicular monoamine transporter. 18 Rat data (obtained in the Porsolt forced swimming paradigm and for tetrabenazine-induced catalepsy behavior) are presented in support. The applicant, Neurolexis had inlicensed befiradol for the treatment of levodopa-induced dyskinesia in Parkinson's disease in September 2013; the phase II clinical trial that had been announced as a first development goal at this time has not commenced at the time of this writing (May 2019). Also note that WO/2016/005527 (from befiradol's original developer, Pierre Fabre Medicament) claims formulations of befiradol to ameliorate and/or prevent extrapyramidal side effects associated with neuroleptics treatment, dyskinesia arising from long-term levodopa therapy in Parkinson's disease, and for involuntary movement in Huntington's disease.
Clenbuterol for Lupus
International Patent Application WO/2019/020634,
Clenbuterol is a long-acting β2 adrenergic receptor agonist, and as such it also inhibits the production of proinflammatory cytokines (TNF-α, IL-6, IL-1β) by intersecting with the NF-κB signaling cascade at different levels. 19 This anti-inflammatory action is what it makes clenbuterol useful as an asthma drug. It also is what mediates its beneficial effects in sepsis 20 and neuroinflammation. 21 The inventors noticed that this repression profile matches the overshooting inflammatory cytokine profile in the autoimmune disease, systemic lupus erythematosus (SLE). 22 Besides lupus nephritis, cachexia is claimed to be best suited for treatment with long-acting β2 adrenergic receptor agonists—which is not surprising given the well-known anabolic effects of these drugs. According to the invention, clenbuterol is administered (preferably through the oral route) in a dosage from 10 to 250 μg/day, preferably from 40 to 80 μg/day. In the NZBWF1/J mouse model of spontaneous SLE, 10 μg/mL clenbuterol in drinking water (given for 7 weeks between 7.5 and 9 months of age) was effective in preserving renal function: proteinuria was delayed by at least 2 months and was significantly less intense than in the untreated group (p < 0.05), kidney histology was better preserved, and CXCL13 (a chemoattractant for B cells and inductor of ectopic lymphoid structures in the kidney as a result of chronic inflammation processes) was significantly downregulated. In retrospect, it is quite surprising that this opportunity does not seem to have occurred to anybody before, especially since reports of beta blockers triggering clinical or subclinical SLE have been in the literature since the early 1970s 23 and continue to be published to this day. 24
One More Option for Gaboxadol
International Patent Application WO/2019/028234,
A potent and specific agonist for a delta subunit-containing GABAA receptor subtype that is expressed exclusively outside of the synapse, gaboxadol reached phase III trial for insomnia before Merck & Co. and Lundbeck discontinued it in March 2007: it failed to show significant effects in sleep onset and sleep maintenance while patients with a history of drug abuse experienced a steep increase in psychiatric adverse events with gaboxadol. The agent was picked up by Ovid Therapeutics (New York), which commenced redevelopment for Angelman Syndrome and Fragile X Syndrome and filed WO/2019/055369 for narcolepsy but had already moved outside the rare disease field with WO/2018144827 for tinnitus. A Brazilian study had already studied the effect of gaboxadol on fasting and overload blood glucose in streptozotocin-induced diabetic rats but had found only a minor hypoglycemic effect that was limited to moderately hyperglycemic animals. 25 However, sensitivity of δ-subunit containing GABAA receptors is increased after several days of hyperglycemia with or without hypoinsulinemia, which could contribute to diabetic autonomic dysregulation. 26 Treating this serious consequence of diabetic neurodegeneration does not seem to be the intent of the studies that Ovid is planning in treatment-naive patients with type 2 diabetes. The clinical endpoints for the three clinical trials of once-daily gaboxadol monotherapy administered orally at 5, 10, and 20-mg doses versus placebo over a 6-month period (with or without metformin or a dipeptidyl peptidase-4 inhibitor) are those routinely employed in diabetes trials. Deuterium-enriched gaboxadol is also contemplated. Note that lesogaberan (AZD-3355), a peripherally restricted high-affinity GABAB receptor-specific agonist originally developed for the treatment of gastroesophageal reflux disease, promotes human β cell replication and islet cell survival in immune deficient mice. 27
Perspectives for Beta Blockers in Rare Cancers Expand Further
International Patent Application WO/2019/030151,
In tumor cells from patients with the rare but devastating von Hippel–Lindau disease (VHL), a protein inhibiting the expression of hypoxia inducible factor (HIF) is dysfunctional, leading to a constitutive expression of HIF (and ultimately activating transcription of >200 other target genes involved in tumor development and angiogenesis) even in normoxic conditions. Carriers of the autosomal recessive mutation develop multiple tumors throughout life. 28,29 In 2009 it had been reported that the HIF-regulating von Hippel–Lindau tumor suppressor protein-E3 ligase complex ubiquitylates the β2 adrenoceptor, decreasing receptor abundance. 30 This suggests that beta blockers could be as effective in this tumor-causing disease as they have proven to be in hemangioma. 31 The VHL Spanish Alliance had conducted a clinical trial with seven VHL patients with retinal hemangioblastomas who received propranolol (120 mg/day) for 12 months. Growth of the ocular tumors was halted or reversed throughout and in some cases visual acuity increased, but low blood pressure was a side effect. 32 The inventors believe that a more specific β2 blocker might avoid this, and took a second look at ICI 118,551, a decades-old discontinued compound that is now used as a research tool for β2 blockade. 33 It decreases viability of hemangioblastoma cells from VHL patients and inhibits hemangiosphere formation from VHL patients, inhibits cell migration and angiogenesis of endothelial cells, and decreases HIF activity induced by hypoxia. Two other β2 selective antagonists with an alkanolamine scaffold, butoxamine and prenalterol, are also named as suitable for the purpose of the invention.
Device Technology Enables an Alternative Use for a Multiple Sclerosis Drug
International Patent Application WO/2019/036363,
Glatiramer acetate, the first noninterferon immunomodulatory drug product (Copaxone® and generics) for multiple sclerosis, is a mixture of peptides produced by random copolymerization of alanine, lysine, tyrosine, and glutamic acid in a molar ratio of 6:1.9:4.7:1. In keeping with its properties, it was launched as an injectable drug, and attempts to develop effective oral formulations have failed in the clinic. 34 That glatiramer could be a treatment for colitis and other inflammatory bowel diseases based on its ability to shift T cell populations from inflammatory Th1 to regulatory Th2/3 subtypes had been shown in mouse models years ago. 35,36 At least in the rat, the colonic wall is less proteolytically active toward glatiramer compared with the wall of the more proximal regions of the small intestine, and glatiramer can penetrate from the lumen into the colonic wall. 37 The problem is how to get it there without being digested, and without invasive methods. The inventors propose to do this with an ingestible polycarbonate-coated device with self-localization capacity that signals from the intestine when it has detected transition from one intestinal segment to the next, and releases glatiramer locally at the treatment site. This is a good example how a drug–device combination can make drug repurposing possible where formulation technologies have failed.
Janus Kinase Inhibitors for a Disfiguring Skin Disorder
International Patent Application WO/2019/040706,
Vitiligo—the depigmentation of otherwise normal skin—occurs most often on the face and extremities. It is an autoimmune cutaneous disease in which melanocytes are selectively destroyed by CD8+ T cells. 38 The initiating event for this autoimmune attack is unknown but recently has become clear that JAK1 overexpression may be involved in the pathogenesis. 39 The inventors claim virtually all JAK/STAT inhibitors that have been disclosed in the literature as treatments, in topical and/or oral formulations, and describe the predicted results from experiments in many different animal models of vitiligo. They also present results obtained with an unnamed JAK inhibitor (SCHEMBL ID: 15393262) in a model developed at the University of Massachusetts Medical School that involves the adoptive transfer of T cells from a T cell receptor transgenic mouse into a host mouse, followed by activation of those transgenic T cells in vivo subsequent to infection with a virus expressing its cognate antigen. This results in elevated levels of melanocytes in the epidermis and a mouse that has black hair and black skin, making the destruction of melanocytes easier to score. Five weeks after initiation of dosing, vitiligo scores were reduced to 30%–40% of baseline. The problem with this patent application is that there is substantial prior art for JAK inhibitors in vitiligo that predates the August 2017 priority date, based on ruxilitinib (Jakafi®, approved for myelofibrosis) 40 and tofacitinib (Xelianz®, approved for ulcerative colitis). 41 Also see a recently published literature review on JAK inhibitors in vitiligo. 42
From Osteoporosis to Copd
International Patent Application WO/2019/041404,
A bisphosphonate, approved for the treatment of osteoporosis and other bone metabolic disorders (as Zometa® and Aclasta®) but in inhalable form, for treating chronic obstructive pulmonary disease (COPD) and/or asthma—this is what the inventors claim in this patent document, without presenting biological data. This is not the first time that a nebulized presentation of a bisphosphonate has appeared in the peer review literature: nanoparticles of alendronate sodium have been investigated as potential inhalable chelators for heavy metal dust and radioactive particles deposited in the lungs, 43 and a dry powder inhaler loaded with alendronate solid lipid nanoparticles has been proposed for systemic delivery. 44 More serious with respect to the obviousness and inventiveness aspects is a 2015 article reporting that inhaled alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signaling 45 —which is most relevant in allergic asthma, but also in COPD. Zoledronic acid seems to be a particular interesting compound when it comes to repurposing of bisphosphonates with their numerous pharmacological activities—see, for example, WO/2017/000902 and WO/2017/181934 from Nanjing University for fatty liver disease and pulmonary lymphangioleiomyomatosis, respectively, and WO/2014/162123 (University of Sheffield) as a cytoprotectant against damage from chemical or radiation insult.
An Antidepressant that Acts on Kupffer Cells
International Patent Application WO/2019/046959,
Primary biliary cholangitis is a prototypical autoimmune disease, characterized by antimitochondrial antibodies targeting lipoic acid containing immunodominant epitopes, particularly the pyruvate dehydrogenase complex, on the inner mitochondrial membrane. 46 How could mirtazapine, a noradrenergic and specific serotonergic antidepressant marketed as Remeron® and under other names, interfere here? It has a definite anti-inflammatory effect, a feature shared with other antidepressants 47 that the inventors show extends to the murine hepatic immune system. Although treatment with 10 mg/kg does not alter total number of hepatic immune cells (measured as CD45+ leukocyte counts), it shifts immune cell subset populations: there is a very pronounced reduction of classical inflammatory monocytes (p < 0.0003; n = 5 mice/group), but “repair” monocytes are also significantly reduced. At 20 mg/kg, mirtazapine profoundly attenuates concanavalin A-induced immune-mediated hepatitis, and modulates hepatic cytokine/chemokine and adhesion molecule expression in this mouse model: CXCL-10 levels are increased while CXCL9, CXCL2, CXCL1, CCL11, CCL2, and ICAM-1 are reduced. Mirtazapine treatment resulted in enhanced VCAM-1 staining intensity in the hepatic sinusoidal endothelium and a marked increase in VCAM-1 expression intensity in sinusoidal immune cells (likely Kupffer cells). For the peer review companion article, see Almishri et al. 48
A Cephalosporin Antibiotic Helps With Getting off Tobacco
International Patent Application WO/2019/060171,
Cefdinir (Cefzon®, Omnicef®) is a third-generation semisynthetic cephalosporin antibiotic. There is nothing in the scientific literature to suggest that 125–600 mg/day (which is in the range of the approved antibacterial doses), given in one or two daily increments, should help smokers to quit, and the very short patent document (the specification part has only six pages) does not offer an explanation either, nor does it provide any data beyond C max, T max, and exposure for oral 300 and 600 mg doses in adults—which is obviously not new. However, there is a related cephalosporin, ceftriaxone, which has a remarkable amount of literature in the context of animal models of addiction—to nicotine, 49 alcohol, 50 and even cocaine. 51 In all these cases, the antiaddictive effect of ceftriaxone is rooted in antiexcitatory effects, with the GLT-1 glutamate transporter being the most interesting target; this extends the potential effect to chronic neurodegenerative disorders. 52 Cefdinir is highly likely to act through similar mechanisms.