ASSAY and Drug Development TechnologiesVol. 19, No. 7 Patent ReviewFree AccessDrug Repurposing Patent Applications April–June 2021Hermann MuckeHermann MuckeAddress correspondence to: Hermann Mucke, MS, PhD, H. M. Pharma Consultancy, Enenkelstrasse 28/32, Wien A-1160, Austria E-mail Address: h.mucke@hmpharmacon.comH.M. Pharma Consultancy, Wien, Austria.Search for more papers by this authorPublished Online:4 Oct 2021https://doi.org/10.1089/adt.2021.095AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Non-steroidal anti-inflammatory drugs: NOT QUITE EFFECTIVE ENOUGH FOR MUSCULAR DYSTROPHIESWO/2021/059270, Treatment of Genetic Diseases Characterized by Unstable mRNAs (Inventors: Karni M, Amar-Schwartz A; applicant: Yissum Research Development Company of the Hebrew University of Jerusalem; published: April 1, 2021).Nonsense-mediated decay protects the cell against the deleterious effects of aberrant mRNA transcripts that contain premature termination codons or carry a RNA-destabilizing 6-methyladenine methylation mark (m6A). This prevents production of truncated peptides that could have toxic and detrimental effects on the cell and is usually beneficial.1 However, there are genetic disorders in which truncated peptides retain function, such as Becker muscular dystrophy (a milder form of Duchenne muscular dystrophy), in which mRNA degradation acts to worsen the disease phenotype by removing even this limited functional capability.Such patients could benefit from a combination of mRNA stabilizing compounds and nonsense suppression therapy, which enhances read through by allowing near-cognate aminoacyl-tRNAs to outcompete the release factor complex and enter the ribosomal A site to produce a full-length, only slightly aberrant, and possibly functional protein. The first m6A RNA demethylase to be identified was the Fat Mass and Obesity Associated gene product; remarkably, this enzyme is inhibited by the Non-steroidal anti-inflammatory drugs (NSAID), meclofenamic acid. While this fact was published 6 years ago,2 the connection to muscular dystrophy treatment has apparently not been made. Meclofenamic acid and its derivatives mefenamic acid, niflumic acid, flufenamic acid, and clonixin all show at least some increase in dystrophin expression in fibroblasts derived from Duchenne patients, although the effect was not as high as might be desired.c-KIT as A New Target for Addiction Therapy Brings Imatinib into New FocusWO/2021/063387, Use of Composition of Imatinib and Derivative Thereof in Preparation of Drug for Preventing, Treating and Controlling Addiction Relapse (Inventors: Li Y, Zhu S, Ruan J, Zhang X, Chen M; applicant: Wuhan University, Wuhan, China; published: April 8, 2021).WO/2021/063388, Application of c-Kit as Addiction Diagnosis and Monitoring Marker and Addiction Treatment Target (Inventors: Li Y, Hong X, Chen Z, Zhu S, Zhang X, Chen M; applicant: Wuhan University, Wuhan, China; published: April 8, 2021).Using a conditioned place preference paradigm, the inventors have tested the anticancer multikinase inhibitor, imatinib (1–30 mg/kg i.p.), over a 7-day period in Sprague-Dawley rats and mice models of addiction to alcohol, nicotine, cocaine, and morphine. The 15 and 30 mg/kg doses were combined with environmental cues to achieve a realistic setting. For preventing the development of addiction and relapse after drug withdrawal, the dose ratios between imatinib and the respective addictive agent seemed to be at least as important as the imatinib dose. When administered 72 h after drug discontinuation imatinib was also effective against withdrawal symptoms. Immunohistochemistry, immunofluorescence, and molecular imaging revealed that the antiaddictive activity of imatinib is due to its known inhibition of the stem cell factor, c-kit.Except for a 2018 article that had reported that masitinib (another tyrosine kinase inhibitor, approved for veterinary use) reduces self-administration of heroin (but not cocaine) in rats,3 there is very little in the peer review literature suggesting an association between c-kit and addiction. However, Wuhan University had a very similar patent application (CN 105974131) in 2016, and AB Science's WO/2003/07106 claimed c-kit tyrosine kinase inhibitors for that purpose, with the rationale of destroying mast cells: the inventors had observed that mastocytosis patients are more inclined to develop substance use disorders.Aldose Reductase Inhibitors Boost Activity of Loss-Of-Function Phosphomannomutase 2WO/2021/071965, Aldose Reductase Inhibitors for Treatment of Phosphomannomutase 2 Deficiency (Inventors: Perfetti R, Shendelman S; applicant: Applied Therapeutics, Inc., New York, USA; published: April 15, 2021).Phosphomannomutase 2 (PMM2) isomerizes mannose 6-phosphate to mannose 1-phosphate, a precursor to guanosine diphosphate (GDP)-mannose, which is necessary for the production of dolichol-linked oligosaccharides; these serve as glycan donor substrates in protein N-glycosylation. PMM2 deficiency is the most common congenital disorder of N-glycosylation, all of which are very rare. The disease is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.4 Dietary mannose supplementation improves glycosylation in the majority of patients, but this requires doses of 1–2 g/kg/day.5 The old carbonic anhydrase inhibitor, acetazolamide, is well tolerated and effective for the motor cerebellar syndrome6 but does not treat the visceral symptoms.The inventors propose aldose reductase inhibitors (once hoped to offer therapeutic options for complications of uncontrolled diabetes such as neuropathy and cataract but never broadly marketed) as reactivators of mutated PMM2. Fibroblast cell lines derived from four individual PMM2-congenital disorder of glycosylation (CDG) patients with different heterozygous amino acid substitutions were incubated with 50 nM zopolrestat for 24 h, seeded in a 96-well plate, lysed by two cycles of freeze–thawing, the lysate was subjected to a kinetic PMM2 enzymatic assay with or without 200 mM mannose-1-phosphate as substrate, and results were compared to those without zopolrestat pretreatment. The results varied greatly among patients: 3%, 13%, 20%, and 72% increase in PMM2 enzymatic activity—which suggests that zopolrestat has quite strict binding requirements.A different group, composed of scientists from the Mayo Clinic and the rare disease drug repurposing company, Perlara public benefit corporation (PBC), has reported similar findings for epalrestat (the only aldose reductase inhibitor approved for use in some countries) which had been identified using a worm-based phenotypic screen7; enzyme activity gains had ranged from 30% to 400% over baseline, depending on genotype.THE Most Popular Antihistamine, an Immunological Response Modifier in CancerWO/2021/076033, Desloratadine for the Treatment and/or Prophylaxis of Cancers (Inventors: Olsson H; applicant: Hakmed AB, Lund, Sweden; published: April 22, 2021).That histamine H1 (and to a degree, also H2) receptor blockers have antiproliferative properties is hardly new; the respective literature reports date back to at least 1990.8 In 2013 it was reported that desloratadine inhibits Stat3 and c-Myc and induces apoptosis in cutaneous T cell lymphoma cell lines.9 In WO 2016/116438, Belina Pharma AB had claimed desloratadine and ebastine for the treatment of breast cancer.The inventors mined the Swedish Drug Prescription Registry, which contains data on almost 100 million units of prescription pharmaceuticals dispensed per year from 2005 onward, to investigate the effects of the six major H1-blocking antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine, and loratadine) on cancer-specific and overall mortality. Both peri- and postdiagnostic antihistamine use was analyzed, using Cox regression models, as well as different subgroups of patients with regard to age, gender, and tumor status. They found a strong 5-year survival benefit (15%–35%) for desloratadine users in a diverse set of tumor types: lung cancer, prostate cancer, pancreatic cancer, gastric cancer, kidney cancer, ovarian cancer, colorectal cancer, and Hodgkin's disease, whereas no effect was observed with other tumor types, for example, brain cancer, uterine cancer, and lymphohematopoietic malignancies. The other antihistamines showed no such pronounced effects.Many of the responsive tumor types are known to respond to immune checkpoint blockade, which suggests that desloratadine modulates the CTLA-4/PD-1 pathway. For pancreatic cancer, the routinely prescribed dose of desloratadine (5 mg/day) increased 5-year survival by more than one third, the best drug response ever reported for this deadly carcinoma. In clinical studies desloratadine has shown minimal side effects at doses up to 45 mg/day, which offers exciting treatment possibilities. Also see Hakmed's WO/2021/040600 which specifically addresses melanoma and the peer review companion article by Fritz et al.10Topical Antihypertonics for FibromyalgiaWO/2021/076218, Methods for Prevention and Treatment of Fibromyalgia by Contact Vasodilators (Inventor and applicant: Weinberg A; published: April 22, 2021).Fibromyalgia is a complex syndrome of chronic musculoskeletal pain with discrete tender points, fatigue, disordered and nonrefreshing sleep, and a degree of cognitive impairment centered on memory (“brain fog”).11 Although involvement of the immune system is strongly suspected12 its etiology remains unclear, the absence of reliable biomarkers and the overlap with the broader chronic widespread pain syndrome create a diagnostic conundrum,13 and no specific treatment exists. The inventor advances the theory that fibromyalgia is a chronic vascular insufficiency syndrome created by reduced capillary density leading to reduced fiber/capillary ratio in skeletal muscle and in the central nervous system. Treatment with topical antihypertonics of any type—calcium channel blockers, ACE inhibitors, AT-II receptor blockers, beta blockers—is claimed as a means to dilate the remaining capillaries and so improve blood supply; systemic administration is stated to be useless.The document presents no supporting data (the anecdotical cases are hypothetical), but the literature lends some support to the theory. Functional disturbances of microcirculation, in part, traceable to morphological abnormalities are present in fibromyalgia patients, and their peripheral blood flow is as much reduced as in systemic sclerosis patients.14 The literature of capillary insufficiency in fibromyalgia can be traced for at least 25 years.15 The fact that fibromyalgia incidence and prevalence are strongly associated with aging could also point to a role of capillary tube regression, a little-researched phenomenon. (See, e.g., WO/2021/076961 claiming thrombin generation inhibitors as a therapy.)AN Advanced Cancer Drug Prevents Chemotherapy-Induced AlopeciaWO/2021/084541, Treatment of Hair Loss Disorders with a Topical EGFR Inhibitor (Inventors: Arkind M, Zighelboim M, Nov O, Nemann K; applicant: Sol-Gel Technologies Ltd., Neiss Ziona, Israel; published: May 6, 2021).Epithelial expression of the epidermal growth factor receptor (EGFR) is important in follicular development and hair growth, controls hair shaft differentiation in a p53-independent manner,16 and protects the hair follicle from immunological reactions that cause alopecia: genetic EGFR deficiency causes epithelial inflammation.17 In contrast, EGFR inhibitors used in cancer therapy can induce terminal differentiation of the hair follicle, which in certain cases may be associated with trichomegaly.18 It is only logical that EGFR inhibitors have been investigated as a possible countermeasure for chemotherapy-induced alopecia, and indeed erlotinib or gefitinib can suppress alopecia and catagen progression by cyclophosphamide19 and other directly DNA-damaging cancer drugs.The considerable systemic side effects of EGFR inhibitors and the easy accessibility of hair follicles in the scalp suggest topical formulations at low concentrations, which are what the inventors have developed. Microdissected full length hair follicles were obtained from a male donor, and the protective effect of 0.5 or 2 μM erlotinib against paclitaxel was evaluated. While erlotinib did not protect premature onset of the catagen phase under these conditions, it prevented apoptosis of keratinocyte stem cells, which are then able to regenerate new hair follicles and maintain all cell lineages of the follicle.Bexarotene and Glitazones Restimulate an Axis Maintaining the Myelin SheathWO/2021/092279, Methods for the Treatment of Dysmyelinating/Demyelinating Disorders (Inventors: Hu J, Zhou X; applicant: Board of Regents, The University of Texas System; published: May 14, 2021).Multiple sclerosis is the most widespread demyelinating disease, but some rare diseases such as X-linked adrenoleukodystrophy and adrenomyelopathy also belong in this group; and demyelination is also involved in chemotherapy-induced cognitive impairment.20 This invention attempts to address this by restoring Qki-PPARβ-RXRα-dependent lipid metabolism in myelin, which has very recently been shown to be indispensable for the maintenance of the mature myelin sheath.21The inventors show that activating this nuclear receptor axis, which is a major regulator of the adrenoleukodystrophy-related ABCD2 gene, reduces diffuse white matter changes. The inventors confirmed that Qki-depleted mice, as well as those treated with doxorubicin and methotrexate, exhibited delayed-onset demyelination and myelin lipid reduction in the corpus callosum 6 months (but not 4 months) after chemotherapy cessation, with minimal changes in myelin protein levels and oligodendrocyte numbers, when their Qki-PPARβ-RXRα was activated. There are no Qki agonists yet, but PPARβ agonists such as sodelglitazar, lobeglitazone, netoglitazone, or isaglitazone are supposed to be hopeful candidates, and the well-established anticancer retinoid X receptor (RXR) agonist bexarotene together with a high fat diet is effective as well. It would be interesting to see if these compound classes synergize at low doses. Note the November 2020 article from the University of Texas, coauthored by one of the inventors, showing that bexarotene alone for only 5 days is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance in mice.22Antiallergics For the Most Difficult Form of Heart FailureWO/2021/094296, Use of Mast Cell Stabilizer for the Treatment of Heart Failure with Preserved Ejection Fraction (Inventors: Renault, M-A, Couffinhal T, Chapouly C, Guimbal S; applicant: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris (France); Université de Bordeaux, Bordeaux, France; published: May 20, 2021).To investigate whether microvessel disease may promote development of heart failure with preserved ejection fraction, the inventors performed a transcriptomic analysis of the cardiac vascular RNA fraction of leptin receptor deficient female mice; this diabetic-obese model develops diastolic dysfunction with cardiomyocyte hypertrophy, vascular leakage, endothelial cell activation, and leukocyte infiltration (but not cardiac fibrosis) at an age of 3 months. Besides confirming endothelial dysfunction, this also revealed a strong increase in several mast cell markers, associated with increased levels of circulating IgE. Histology confirmed an accumulation of mast cells in the heart, confirming a long-known fact observed in mice susceptible to developing chronic dilated cardiomyopathy,23 and most recently observed in patients with hypertensive heart disease.24After treatment with the antiallergic mast cell stabilizer, cromolyn (50 mg/kg/day) for one month, the percentage of degranulating mast cells in the murine hearts and end diastolic pressure were significantly reduced. Cardiac microvessel density was not modified, but capillary diameter and albumin extravasation were reduced, and CD45+ leukocyte recruitment also decreased significantly. To verify that cardiac capillary permeability and vasodilation were indeed due to histamine release, 2-month-old Leprdb/db mice were treated with the H1 receptor blocker, cetirizine (4 mg/kg/day). As expected, both the diameter of cardiac capillaries and their permeability were significantly reduced versus vehicle-treated mutant mice. Beyond cromolyn and cetirizine, claims extend to other antiallergics such as lodoxamide, nedocromil, and ketotifen but also to dihydropyridine calcium channel blockers such as nicardipine and nifedipine—because mast cells express L-type calcium channels which can also activate them.25Antidiabetics for a Hepatic Autoimmune DiseaseWO/2021/102251, Use of Sglt2 Inhibitors to Treat Primary Biliary Cholangitis (Inventors: Wilkinson WO, Green JT; applicant: Avolynt, Inc., Research Triangle Park, USA; published: May 27, 2021).Sglt2 is a low affinity, high capacity sodium-glucose cotransporter located mainly in the S1 segment of the proximal tubule of the kidney. Sglt2 inhibition by the gliflozin class of drugs enhances glycemic control by increasing urinary glucose excretion; they are used as second-line antidiabetics. Given the central role of the liver in glucose production, it is not surprising that gliflozins have massive indirect effects of hepatic metabolism. They slow the progression of liver fibrosis associated with Type 2 diabetes26 and restrict hepatocarcinogenesis (often developed against a fibrosis background) and liver tumor growth by inhibiting its glucose uptake.27,28The inventors state that Sglt2 is also expressed in the central vein and biliary tract of the liver (although they do not demonstrate it in the document). They used a murine model of the autoimmune disease, primary biliary cholangitis (the TIA mouse, deficient for the expression of tumor necrosis factor-α, interleukin-10, and activation-induced cytidine deaminase), to assess the effectiveness of remogliflozin etabonate (an ester prodrug) administered in the chow (0.03% w/w) for 7 weeks. Histology showed significant reductions in inflammatory cell infiltration, bile ductular proliferation, and interface hepatitis compared to controls. Only clinical studies can show if remogliflozin, or any other Sglt2 inhibitor, could synergize with the currently approved drug treatments, ursodeoxycholic and obeticholic acid.Non-Nucleoside Reverse Transcriptase Inhibitor HIV Drugs Could Boost Conventional Chemotherapy in NeuroblastomaWO/2021/104487, Composition Including Rilpivirine and Use Thereof for Treating Tumors or Cancer (Inventors: Lee WYT, Poon CSD, Lai KL, Huang J, Li HY; applicant: Aptorum Therapeutics Ltd., Hong Kong, China; published: June 6, 2021).Rilpivirine, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), is used as a component in the drug cocktails for the treatment of HIV infection. In addition to inhibiting or inducing several relevant drug-metabolizing enzymes and drug transporters, it activates the pregnane X nuclear receptor.29 In a 2015 article reporting the in vitro efficacy of NNRTIs against BxPC-3 pancreatic cancer cells, its EC50 was found to be 8.9 μg/mL, a level not reached in HIV therapy where patients rarely exceed plasma concentrations of 0.5 μg/mL.30The inventors tested rilpivirine in combination with many common anticancer agents against many human neuroblastoma cell lines (SK-N-SH, SK-N-BE(2), SH-SY5Y, IMR-32) and against other cancer cell lines, determined levels and kinetics of cleaved poly(ADP-ribose)polymerase and phospho-histone H2A.X, and calculated a combination index. The most promising combinations with cisplatin (7 mg/kg), carboplatin (80 mg/kg), or vincristine (1 mg/kg) were tested in neuroblastoma xenograft mouse models, with the conventional chemotherapeutics administered only on day 1, while rilpivirine (400 mg/kg/day) was given for 21 consecutive days. Potentiation by rilpivirine was seen in all three cases, suggesting that it might reduce the dosing frequency of the cytotoxic chemotherapy drugs during the treatment of neuroblastoma.THE Therapeutic Range for Anakinra Expands FurtherWO/2021/113334, Treatment of Lower Airways Disorders (Inventors: Baranowski LA, Lortie BA, Bishop JP, et al.; applicant: Altavant Sciences GmbH, Basel, Switzerland; published: June 10, 2021).Anakinra is a slightly modified recombinant version of the IL-1 receptor antagonist protein, an endogenous factor that negatively modulates the inflammatory response. Originally approved for the treatment of rheumatoid arthritis, it was immediately apparent as a biotechnology on-target repurposing candidate for conditions involving chronic overshooting IL-1 mediated inflammation, from dry eye syndrome to various rare diseases.31Altavant, a subsidiary of Sumitomo Dainippon Pharma Co., Ltd. specialized in rare respiratory diseases, is now attempting to extend that range to bronchiolitis obliterans (for which a clinical study is delineated with formulation ALTA-2530), toxic inhalation syndromes (including vaping-associated lung injury), pulmonary Langerhans cell histiocytosis, diffuse panbronchiolitis, and reactive airway dysfunction syndrome. The buffered liquids for nebulization are designed to deliver 0.125 to 5.0 mg anakinra per day to the lower airways. The aerosols have been extensively characterized: ALTA-2530 nebulization produced rhIL-1Ra particles with mass median aerodynamic diameters of −2.5 to 4 μm, consistent with delivery to small bronchioles. Concentrations in the lungs of Sprague Dawley rats were determined, together with pharmacokinetics. Subcutaneous administration of anakinra as a protectant against inhaled endotoxin (a model of asthma with neutrophil predominance, which is difficult to treat with corticosteroids) has been clinically tested before,32 but Altavant seems to have presented the first inhalable formulations.AN Anticonvulsant to Improve Glaucoma Surgery SuccessWO/2021/118469, Use of Valproic Acid for Reducing Post-Operative Scarring Following a Glaucoma Surgery (Inventors: Seet LF, Wong TTL; applicant: Santen Pharmaceutical Co., Ltd., Osaka, Japan; Singapore Health Services Pte Ltd., Singapore; published: June 17, 2021).Glaucoma surgery attempts to lower intraocular pressure by creating an artificial channel to drain aqueous humor. Like every surgical wound the cut will heal with a degree of inflammation followed by scarring. In the case of the scarred conjunctiva this can cause severe local irritation, and the surgery will fail altogether if the newly created ocular drainage channel is obstructed by scar tissue. Antimetabolites (mitomycin-C or 5-fluorouracil, sometimes also anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab) are routinely applied during glaucoma surgery to prevent proliferation of fibroblasts.The first-generation anticonvulsant sodium channel blocker and GABAergic agent, valproic acid, has been reported to influence migration of limbal epithelial stem/progenitor cells in a complex manner,33 and most recently its chymase inhibition and the subsequent prevention of mast cell activation have been identified as a novel mechanism that could explain the capability of valproate to prevent the formation of postsurgery peritoneal adhesions.34 Although retinal thinning has been reported during long-term use of valproate,35 it also improves contrast threshold sensitivities in epileptic patients receiving it on long term.36 The inventors had already reported in 2016 that valproic acid suppresses type I collagen production in conjunctival fibrosis and had made the connection with glaucoma filtration surgery37—which can be expected to create preemption problems with their patent application.A New Therapeutic Angle on Polycystic DiseasesWO/2021/122239, Inhibition of Tmem16A by Benzbromarone or Niclosamide for Treating Polycystic Kidney Disease and/or Polycystic Liver Disease (Inventors: Kunzelmann K, Schreiber R, Buchholz B; Applicant: Universität Regensburg, Regensburg, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; published: June 24, 2021).Tmem16A (anoctamin 1) is an important calcium-activated chloride channel in airway smooth muscle, and antagonists such as the first-generation uricosuric, benzbromarone,38 as well as the antihelminthics, niclosamide and nitazoxanide,39 have attracted interest mostly as potential novel therapies for asthma.However, the inventors had reported that Tmem16A drives proliferation of renal cyst-forming epithelial cells,40,41 making it a potential therapeutic target in polycystic kidney disease (PKD) and, by extension, also in polycystic liver disease. Combining these facts for drug repurposing might have been a small imaginative step, but one that the inventors support with a great deal of substantial molecular data (in part collected using renal organoid models) showing that disturbed Ca2+ signaling in PKD relies on Tmem16A. Polycystin-1 deficient collecting duct cells were then cultured in a collagen-I matrix to form cysts in vitro. Treatment with either 0.1 or 1 μM niclosamide or with an exemplary niclosamide derivative, nitazoxanide, significantly decreased the mean cyst volumes. Benzbromarone significantly inhibited cyst growth in PKD1 knockout mice, a model of autosomal dominant PKD.REFERENCES1. Lindeboom RGH, Vermeulen M, Lehner B, Supek F: The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet 2019;51:1645–1651. Crossref, Medline, Google Scholar2. Huang Y, Yan J, Li Q, et al.: Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. 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