Drug Repurposing Patent Applications April

Abstract

An Aphthous Ulcer Drug Continues to Find New Uses

International Patent Application WO/2018/059207, New Use of Amlexanox (Inventors: Chen L, Li J, Chen F, Cheng X; applicant: Shanghai Microport Medical Group Co., Ltd., China; published: April 5, 2018).

Amlexanox is a tricyclic amine carboxylic acid with a complex immunomodulatory mechanism that is not well understood. It is the agent in Aphthasol^® mouthwashes and adhesive oral gels and pastes that have been discontinued in the United States, but remain a popular and well-tolerated treatment for recurrent oral ulcers and aphthous stomatitis¹ in other parts of the world. In Japan amlexanox is approved for the treatment of asthma, allergic rhinitis, and conjunctivitis, based on its functions as a mast cell stabilizer. Peer review literature has recent reports showing it to be a potential repurposing candidate for osteoporosis,² obesity,³ epidermiolysis bullosa,⁴ and ischemic brain damage.⁵ The inventors have identified yet another use, prevention and treatment of vascular restenosis based on an inhibitory action of amlexanox toward the proliferation of vascular smooth muscle cells. Amlexanox-coated stents were implanted into the balloon-injured arteries of piglets, and were superior over sirolimus-coated stents as measured by the suppression of intimal hyperplasia after 45 days, without inhibiting endothelial repair. This was probably inspired by an article published in 2000 (not cited by the patent examiner) reporting that amlexanox induces the complete and reversible nonapoptotic inhibition of cell migration and proliferation.⁶ Amlexanox synergized with rapamycin when incorporated into stents.

Also see WO/2018/069769 (Daiichi Sankyo Co., Ltd., published April 19, 2018) for the use of the oral Factor Xa inhibitor anticoagulant, edoxaban, to prevent neointima formation.

PubChem CID: 2161 (amlexanox); 10280735 (edoxaban)

Old Antimalarial Agents Could Treat Deafness in Type Iii Usher Syndrome

International Patent Application WO/2018/068051, Methods of Treating Disorders Associated with Glycosylation-Defective Proteins (Inventors: Alagramam KN, Gopal SR; applicant: Case Western Reserve University, Cleveland, OH, USA; published: April 12, 2018).

The destabilizing N48K missense mutation in CLRN1, the gene encoding the human clarin-1 protein that is involved in maintaining structure and function of cochlear hair bundles⁷ and cone photoreceptors,⁸ is the most common mutation in Usher syndrome type III that combines retinitis pigmentosa and dysacusis. No treatment exists for this rare condition, which is responsible for a large fraction of the inherited deaf–blindness cases in the Ashkenazi Jewish and Finnish populations.⁹ The inventors show that inhibitors of the sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) can be helpful, by enhancing trafficking of the mutant clarin-1 protein (which is retained in the endoplasmic reticulum) to its destination, the inner ear sensory hair cell bundle. This is affected through activation of the GRASP55 cargo-dependent unconventional protein secretory pathway, while the normal protein remains unaffected. Such SERCA inhibitors include the classical antimalarial agents, artemisinin and artesunate, as well as thapsigargin and its tumor-targeted prodrug, mipsagargin.¹⁰ These drugs also improved the microphonic neuronal potential. These experiments, conducted in transgenic Zebrafish larvae expressing human clarin-1,¹¹ could not address the visual impairment component of the mutation. For very closely related research from this group, see Alagramam et al. ¹²

PubChem CID: 68827 (artemisinin); 6917864 (artesunate); 446378 (thapsigargin)

After Multiple Failures, Apilimod Enters a New Field

International Patent Application WO/2018/071548, Apilimod Compositions and Methods for Using Same in the Treatment of Alzheimer's Disease (Inventors: Lichtenstein H, Rothberg JM, Conrad C, Hernandez M; applicant: LAM Therapeutics, Inc., USA; published: April 19, 2018).

Apilimod, an orally active small molecule that inhibits interleukin (IL)-12 and IL-23 production¹³ and has been in (mostly unsuccessful) Phase II clinical trials for Crohn's disease,¹⁴ rheumatoid arthritis,¹⁵ psoriasis,¹⁶ and common variable immunodeficiency, was discovered by Synta Pharmaceuticals Corp. (now Madrigal Pharmaceuticals, Inc.). It is currently investigated by LAM Therapeutics that has filed use patent applications for viral infections (WO/2016/118709), Charcot-Marie-Tooth disease (WO/2016/126707), and various solid tumors (WO/2015/112888, WO/2016/073871, and WO/2017/015262). The anticancer effects of apilimod seem to be based, at least in part, on its more recently discovered additional mechanism, inhibition of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve).¹⁷ In this most recent patent LAM has gone beyond autoimmune diseases and oncology, claiming apilimod as an inhibitor of beta and gamma secretase. The data presented here demonstrate a dose–dependent decrease in Aβ (exponential in the 33–300 nM apilimod range) in an in vitro model system (HeLa cells transiently expressing the APP Swedish/Indiana double mutant, APPSw-I; or the C99 APP truncated mutant fragment that mimics the BACE1 cleaved amyloid precursor protein at the major Asp +1 site of Aβ to generate C99). These investigations followed up on a computational drug repurposing approach that compared the gene expression profiles induced by apilimod in multiple cell lines, at different concentrations and time points, with the gene expression signatures of multiple diseases—a strategy similar to that that had suggested the utility of the anticonvulsant topiramate for inflammatory bowel disease (IBD), and of tricyclic antidepressants for small cell lung cancer. The inventors do not discuss the mechanistic rationale, but it might also be related to apilimod's PIKfyve inhibition: although loss of this signaling kinase function results in neurodegeneration in both mouse models and human patients, the amyloid precursor interacts with a subunit of the PIKfyve complex (Vac14), modulating phosphoinositide dynamics.¹⁸ Apilimod might be able to suppress or modulate PIKfyve/APP binding.

PubChem CID: 10173277 (apilimod)

Nicergoline Rerouted Toward Trypanosomiasis

International Patent Application WO/2018/076019, Ergot Derivative Compounds and Their Use in African Sleeping Sickness and Related Disease (Inventor: Martinov MN; applicant: Far Biotech, Inc., USA; published: April 26, 2018).

Nicergoline (Pfizer's Sermion^® and generics), a semisynthetic ergot-based nootropic with multiple pharmacological mechanisms, was launched in the early 1970s to treat more or less all conditions with cerebrovascular involvement, from dementia to migraine and balance disorders.¹⁹ It might also be directly neuroprotective, with potential applications in glaucoma and neuroretinal diseases (see WO/2004/011003 from Pharmacia Italia). It has also been suggested to be useful in diabetes.²⁰ The inventors are now setting this old compound on a totally unexpected new course—trypanosomiasis—using the same “quantum modeling” computational approach (based on the pharmacologically relevant electron density attributes of molecular structures, followed by more conventional machine-learning algorithms with fuzzy decision-making protocols), that had already served them years ago to suggest 12 known compounds as antimalarial agents.²¹ Nicergoline and its methylergoline metabolites came out on top. Upon verification in vitro, nicergoline displayed a GI₅₀ value of 6 μM against Trypanosoma brucei-infected cells, which would equate 3 μg/mL in blood. This is not very informative: after oral administration, nicergoline is rapidly metabolized to 1-methyl-10α-methoxy-9, 10-dihydrolysergol (MMDL), which is further N-demethylated to 10α-methoxy-9, 10-dihydrolysergol (MDL) as the main metabolite. It is the growth inhibition by MDL that would be of potential therapeutic relevance. There is no discussion of the potential mechanism.

PubChem CID: 34040 (nicergoline)

An Old Nail Fungus Drug for a Genetic Heme Biosynthesis Disorder

International Patent Application WO/2018/078081, Use of Ciclopirox for the Treatment of Congenital Erythropoietic Porphyria (Inventors: Millet Aguilar-Galindo O, Sanz Parra A, Lain Torre A, Urquiza Ortiz PD, Falcón Perez JM; applicant: Asociación Centro De Investigación Cooperativa En Biociencias–Cic Biogune, Spain; published: May 3, 2018).

Congenital erythropoietic porphyria (CEP; Günther disease), the rarest of the heme group biosynthesis deficiencies,²² is a consequence of a malfunction in the uroporphyrinogen III synthase that catalyzes the cyclization of the highly instable linear tetrapyrrole hydroxymethylbilane (preuroporphyrinogen) to form isomer III porphyrinogen, a precursor of heme. In the absence of sufficient enzyme functionality, the substrate spontaneously degrades to uroporphyrinogen I, which accumulates in the body. Bone marrow transplantation remains the only available treatment. Although inhibitors of porphobilinogen deaminase (the enzyme catalyzing the preceding step) have been suggested by the applicant in WO/2012/017088, this would also impair any remaining capacity for heme synthesis. The inventors took a much more challenging path by looking for compounds that would boost the efficacy of mutant uroporphyrinogen III synthase. And behold!—they identified ciclopirox, an antifungal that was disclosed by Hoechst AG in 1972 (U.S. patent 3,883,545), and first appeared in the peer reviewed literature in 1976.²³ It is still in broad use for the treatment of athlete's foot, ringworm, and onychomycosis.²⁴ Ciclopirox regulates the porphyrin concentration in a validated cellular model of CEP as well as in a mouse model (homozygous for the P248Q mutation of uroporphyrinogen III synthase), at extracellular concentrations that are reached by the currently approved dosing regimens. The potential mechanism is not discussed. Recently ciclopirox has shown remarkable activity in pancreatic cancer models,²⁵ and in Ewing sarcoma it acts on EWS-FLI1 (a common fusion transcript structure in these patients), affecting vasculature development and DNA replication.²⁶ Reports on its anticancer activity go back to 2010. Ciclopirox acts on otherwise drug-resistant pathogenic bacteria by interfering with their galactose metabolism,²⁷ and it is active in a mouse model of ocular herpesvirus infection.²⁸

PubChem CID: 2749 (ciclopirox)

Luminol Shines in Multiple Sclerosis

International Patent Application WO/2018/082814, Use of 5-Amino-2,3-Dihydro-1,4-Phthalazinedione in the Treatment of Chronic Progressive Multiple Sclerosis (Inventors: Brysch W, Kaiser A, van Laak C, Ludescher B, Shah M, von Wegener J; applicant: Metriopharm AG, Switzerland; published: May 11, 2018).

From the title of this patent document, one would probably not immediately identify it as a case of drug repurposing. However, this compound, also known as 3-aminophthalhydrazide, is Luminol—a chemical that emits strong blue chemiluminescence in the presence of oxidizing agents. It is frequently used as a highly sensitive indicator for redox reactions in cell assays, on Western blots, and in preclinical imaging²⁹; and also by forensic investigators to visualize trace amounts of blood at crime scenes or on textiles, even after machine washing.³⁰ It is no newcomer to the drug patenting theater either, having been claimed for a broad range of acute and chronic inflammatory disorders (WO/2004/041169 and WO/2007/018546 from Bach Pharma, Inc.; WO/2012/127441 from Semorex Technologies, Ltd.) and for neurodegeneration.³¹ Listed conditions include the classical relapsing-remitting multiple sclerosis (MS) (for which the most recent mention was probably made in Metriopharm's WO/2016/096143) but without experimental evidence, or at concentrations that promote apoptosis. The inventors have undertaken to demonstrate efficacy in the classical experimental autoimmune encephalomyelitis mouse model of primary progressive MS. Five groups of 10 animals each were treated with Luminol sodium salt (0.5, 1.5, and 4.5 mg/kg or dexamethasone 0.3 mg/kg also as a positive control) for 40 days consecutively under a late prophylactic regimen with daily i.p. injections starting on day 7 after the initializing immunization with the myelin oligodendrocyte glycoprotein. All doses were effective in reducing the clinical score, the highest one being equivalent to dexamethasone. This 4.5 mg/kg·per day dose also equaled dexamethasone 0.3 mg/kg in a therapeutic setting.

PubChem CID: 10638 (Luminol)

An Unexpected Use for Insulin

International Patent Application WO/2018/087298, Rectal Insulin for Treatment of Inflammatory Bowel Diseases (Inventors: Olsen J, Yassin MT, Pedersen EA; applicant: University of Copenhagen, Denmark; published: May 17, 2018).

Crohn's disease and ulcerative colitis are complex relapsing-remitting autoimmune disorders of the intestinal mucosal barrier, caused by an interplay of genetic susceptibility, aberrations of the intestinal microbiome, and psychological stress. Aminosalicylates and corticosteroids still constitute to the first-line therapies, whereas previously intractable cases usually respond well to antitumor necrosis factor (TNF) monoclonal antibodies. These are expensive and can have serious side effects. It is, therefore, of particular interest to see that rectal administration of another much cheaper biological—insulin—is supposed to treat IBDs. When mice with intestinal-specific inactivation of the insulin receptor were subjected to the azoxymethane/dextran sulfate sodium (AOM/DSS) protocol (wherein colitis is induced by DSS that promotes AOM-induced tumors), animals lost more weight during the DSS treatment (a measure of inflammation severity in this colitis model), their recovery progressed more slowly, and they developed twice as many tumors compared with wild-type controls. In wild-type mice subjected to the AOM/DSS regimen, animals treated with rectal insulin presented with a statistically significant difference in weight loss from DSS start (day 1) to beginning of remission, and had a significantly better inflammation score upon colonoscopy, and less rectal bleeding. Based on gene expression data, the inventors speculate that improved epithelial ion transport might be responsible for the insulin effects. Could there be other explanations? The insulin receptor's endogenous ligands also include the insulin-like growth factors (IGFs), IGF-I and IGF-II. It is well known that the IGF system (which includes specific binding proteins) is disturbed in inflammatory bowel syndromes.³² In children with IBD, low IGF-I levels correlate with fatigue.³³ In rats with acute endotoxemia, activation of IGF-1/IGFBP3 signaling improves intestinal mucosal barrier function.³⁴ And in adult nondiabetic and nonobese patients with IBD, protracted anti-TNF therapy improves insulin sensitivity, whereas it has no effect on lipid levels.³⁵

Palovarotene: From Chronic Obstructive Pulmonary Disease to a Rare Skeletal Disorder

International Patent Application WO/2018/090137, Methods for Treating Multiple Osteochondroma (Inventors: Lemire I, Harvey M, Grogan DR, Desjardins C; applicant: Clementia Pharmaceuticals, Inc., Canada; published: May 24, 2018).

Hereditary multiple exostoses (HME) is a rare (1 in 50,000) musculoskeletal pediatric disorder characterized by a plurality of osteochondromas that form next to the growth plates of long bones, ribs, and vertebrae. Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate synthesis. The specific molecular mechanism leading to the disruption of the cartilage structure and the subsequent formation of exostoses is still not resolved.^36,37 The inventors' answer is palovarotene, a retinoic acid receptor-related orphan nuclear receptor gamma (ROR-γ) agonist in-licensed from Roche Pharmaceuticals, where it was previously evaluated (under research codes R-667 and RO-3300074) in >800 individuals including healthy volunteers and patients with emphysema and COPD.³⁸ In a Fsp1-Ext1 conditional knock-out mouse model of multiple osteochondroma, treatment was initiated on day 14 postpartum and continued daily for 4 weeks. No lesions were observed at some of the rib bones in palovarotene-treated mice, whereas vehicle-treated animals showed at least one lesion in every rib. The retinoid-related orphan nuclear receptor subfamily is involved in many biological processes, with ROR-γ taking part in immune cell differentiation and interactions.³⁹ It is expressed in cartilage.⁴⁰ Clementia has just begun recruiting patients for a Phase II clinical trial (NCT03442985) that tests paloverotene 2.5 or 5.0 mg versus placebo in multiple osteochondroma patients, and is scheduled for completion in February 2021. For the peer review companion article, see Inubushi et al. ⁴¹ Also see Clementia's WO/2017/210792 claiming palovarotene for an even rarer ossifying genetic disorder, fibrodysplasia ossificans progressiva, for which a Phase III clinical trial (using 5 mg/day for maintenance and 20 mg/day for flareups) has commenced in November 2017.

PubChem CID: 10295295 (palovarotene)

Another Hard Look At An Old Angina Drug

International Patent Application WO/2018/093839, Therapy for Fatty Acid β- Oxidation and Transport Disorders (Inventors: Mohsen A-WA, Vockley G; applicant: University of Pittsburgh, USA; published: May 24, 2018).

Screening for small chaperone molecules that bind and stabilize structurally compromised enzymes at sites away from their catalytic sites has been a major drug discovery strategy for quite some time. Provided herein are methods of detecting ligand-stabilizing enzymes of the β-oxidation pathway and/or fatty acid mitochondrial transport having missense mutations. Enzymatic reactions downstream from the defective enzyme are targeted by inhibitors, with the intention of accumulating their substrate(s) or product(s) that may, in turn, bind to the pathway's upstream unstable variant enzyme, or subunit thereof. The inventors claim that very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency⁴² and related mutations of enzymes in the mitochondrial β-oxidation pathway can be treated by blocking long-chain 3-ketoacyl-CoA thiolase (LCKAT), which catalyzes the last step in the β-oxidation cycle. LCKAT inhibition is the mechanism of trimetazidine (Vastarel^® and generics). This 40+ year old drug is sold under many brand names to treat stable angina pectoris by enhancing glucose oxidation, which requires less oxygen than β-oxidation and, therefore, is directly beneficial in cardiac ischemia.^43,44 By changing the AMP/ATP ratio trimetazidine also triggers the AMPK cascade, preventing apoptosis.⁴⁵ In cell lines from patients with β-oxidation pathway disorders, the inventors observed dose-dependent increases in VLCAD activity at trimetazidine concentrations up to 20 μM, caused by reduced enzyme turnover rather than by increased expression. Levels of most acylcarnitines were reduced up to 30%–40%, which is clinically significant. Synergism was observed between trimetazidine and the PPARδ agonists GW501516 and GW610742. This is not surprising because oxidation of very long fatty acids takes place not in mitochondria but in peroxisomes, using the same enzyme complexes but without coupling to ATP synthesis.

PubChem CID: 21109 (trimetazidine)

Dopaminergic Agonists for Ms

International Patent Application WO/2018/101261, Prophylactic Agent, Onset-Suppressing Agent, or Therapeutic Agent for Progressive Immune Demyelinating Diseases (Inventors: Oki S, Yamamura T; applicant: National Center of Neurology and Psychiatry, Tokyo, Japan; published: June 7, 2018).

Bromocriptine is a potent dopamine D2 receptor agonist, with some weaker effects on serotonin and adrenergic receptors. It is routinely used to treat hyperprolactinemia. In 1991, scientists working at the Massachusetts General Hospital published observations concerning the preventive effect of continuous administration of bromocriptine in acute experimental allergic encephalomyelitis (EAE), the standard rodent model of MS. This pretreatment reduced prolactin levels, which rise threefold over basal levels in this model, to those of sham-immunized rats.⁴⁶ Three years later, a team from Amsterdam extended this to therapeutic effects: in acute EAE, both severity and duration of the clinical signs were reduced by daily bromocriptine injections. In chronic relapsing EAE, there was no effect during the first attack, but both severity and duration were reduced during the subsequent second attack.⁴⁷ Prolactin secretion is also increased in patients with MS.⁴⁸ In an open clinical pilot study, 2.5 mg bromocriptine twice daily did not suppress disease progression.⁴⁹ Given all this, what could prompt a patent application claiming bromocriptine and virtually all other dopaminergic agonists, and also dopamine reuptake inhibitors such as vanoxerine (clinically investigated for cocaine dependence and cardiac arrhythmia) for MS? The explanation is likely found in a narrowing of the condition (secondary progressive MS), and in a new mechanistic finding: the compounds also seem to repress Zbtb20, a zinc finger transcription factor that is required for anterior pituitary development and promotes prolactin expression,⁵⁰ and also of the T-box transcription factor eomesodermin (eomes) in CD4⁺ T cells, which is important for the late stages of disease progression.⁵¹ Data obtained with the inventors' NR4A2-deficient EAE mouse model of late-stage MS are presented.

PubChem CID: 31101 (bromocriptine); 3455 (vanoxerine)

A Thromboxane A2 Antagonist, New for Migraine?

International Patent Application WO/2018/104235, Picotamide for Use in Migraine (Inventor: Pause A; applicant: Curatis AG, Switzerland; published: June 14, 2018).

Picotamide, a derivative of methoxy-isophtalic acid, is an antiplatelet drug that inhibits thromboxane A2 (TxA2) receptors and TxA2 synthase to an almost equivalent degree at physiological concentrations. It also antagonizes the proaggregatory and vasoconstrictive effects of serotonin and adrenalin, suggesting that it might have additional mechanisms unrelated to TxA2 inhibition.⁵² Although it has a quite presentable peer review record going back at least 40 years,⁵³ it has never seen broad use, being actively marketed (as an anticoagulant) only in Italy. An open pilot trial in patients with migraine aura, published in 2004 and cited in the application, has shown promising results.⁵⁴ Neither the inventor nor the patent examiner (who cites Dybly AG's WO/2008/142106, claiming picotamide salts, and WO/2008/142106 claiming combinations with nafronyl for the treatment of intermittent claudication) has considered this report as novelty damaging for the present patent application, wherein Curatis reports a multicenter randomized double-blind placebo-controlled crossover study comparing 300 mg picotamide twice daily with placebo. Beyond a strong placebo effect (which is almost always present in migraine studies), a reduction in the number of headache events lasting at least 3 weeks was observed in both trial sequences. This might be the trial listed in the EudraCT database as 2011-006207-36, started in March 2012.

PubChem CID: 4814 (picotamide)

An Antimuscarinic Parkinson Drug Prevents Nightmares in Post-Traumatic Stress Disorder

International Patent Application WO/2008/142106, Drug for Nightmare Prevention, Amelioration, or Treatment for PTSD Patients (Inventor: Sogo K; applicant: Sogo PTSD Institute, Japan; published: June 21, 2018).

Sleep disturbances, especially the frequent and highly intrusive nightmares, are a core feature of post-traumatic stress disorder (PTSD) that worsens the symptoms during day of the condition, and impacts recovery.^55,56 Hypnotics are hardly a causative treatment, but the atypical antipsychotic olanzapine can help,⁵⁷ and so does prazosin, an α₁ adrenoceptor inverse agonist that is approved for hypertension but also is frequently used off label in PTSD; the nightmares seem to be associated with stimulation of α₁ receptors in the prefrontal cortex.⁵⁸ The inventor has investigated an anticholinergic agent, the old muscarinic receptor blocker and anti-parkinsonian agent trihexyphenidyl (triphenidyl, benzhexol), and found a 2 mg dose at bedtime to be highly effective with respect to PTSD nightmares, with a complete remission rate of 92% and a partial remission rate of 8%. This is not totally surprising: although the ascending fibers releasing norepinephrine and acetylcholine are highly active during wakefulness, the neocortical tone is sustained mainly by acetylcholine during rapid-eye-movement sleep, when dreams occur.⁵⁹ Intense dreaming is a known side effect of cholinergic medications used for Alzheimer's disease.

PubChem CID: 5572 (trihexyphenidyl)

Ibudilast Enters the Cancer Arena

International Patent Application WO/2018/119262, Methods of Treating Glioblastoma Multiforme Using Ibudilast (Inventors: Matsuda K, McDonal K; applicant: MediciNova, Inc., USA; published: June 28, 2018).

The anti-inflammatory brain-penetrating agent, ibudilast, discovered by Kyorin Pharmaceutical Co. Ltd., has been widely used in Japan for relieving symptoms associated with ischemic stroke and asthma. Originally understood to be only a nonselective inhibitor of cyclic nucleotide phosphodiesterases, its primary activity at clinically relevant plasma or central nervous system (CNS) concentrations is the selective inhibition of macrophage migration inhibitory factor (MIF)⁶⁰ and, secondarily, phosphodiesterases 3A, 4, 10A1, and 11A1.⁶¹ Additional activities include leukotriene D₄ and platelet activating factor antagonism, Toll-like receptor-4 blockade, and anti-inflammatory modulation of the cytokine spectrum.⁶² Ibudilast is thought to exert a neuroprotective role in the CNS of mammals, presumably through a combination of neurotrophic factor induction and suppression of the activation of glial cells⁶³; which is why MediciNova has it in Phase II clinical trials (as MN-166) for MS (U.S. Patent No. 6,395,747) and amyotrophic lateral sclerosis (U.S. Patent No. 9,314,452), based on a 2004 licensing agreement with Kyorin. With the present patent application, the company has added the difficult primary brain cancer, glioblastoma, to the long list of potential new indications for ibudilast. In Balb/c nude mice intracranially injected with the human glioblastoma cell line RN1, 5 and 20 mg/kg ibudilast slightly increased median survival (to 114 and 111.5 days, respectively compared with 100.5 days for controls), and seemed to partially reverse temozolomide resistance in this cell line. A design for a single-center open-label clinical study in patients with grade 4 glioblastoma, who would receive ibudilast up to 100 mg/day for 1 year in an adjunctive setting, is laid out in detail. As of October 2018, clinicaltrials.gov does not list any study with ibudilast in malignancies.

PubChem CID: 3671 (ibudilast)

Footnotes

Abbreviations Used

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Drug Repurposing Patent Applications April–June 2018

Abstract

An Aphthous Ulcer Drug Continues to Find New Uses

Old Antimalarial Agents Could Treat Deafness in Type Iii Usher Syndrome

After Multiple Failures, Apilimod Enters a New Field

Nicergoline Rerouted Toward Trypanosomiasis

An Old Nail Fungus Drug for a Genetic Heme Biosynthesis Disorder

Luminol Shines in Multiple Sclerosis

An Unexpected Use for Insulin

Palovarotene: From Chronic Obstructive Pulmonary Disease to a Rare Skeletal Disorder

Another Hard Look At An Old Angina Drug

Dopaminergic Agonists for Ms

A Thromboxane A2 Antagonist, New for Migraine?

An Antimuscarinic Parkinson Drug Prevents Nightmares in Post-Traumatic Stress Disorder

Ibudilast Enters the Cancer Arena

Footnotes

Abbreviations Used

References