Drug Repurposing Patent Applications October

Abstract

AN ALMOST OBVIOUS NEW USE FOR AN ANTICANCER DRUG

WO/2023/184818

Title: Use of mitoxantrone in preparing medicament for preventing or treating acute graft-versus-host disease

Inventor: Qi X

Applicant: Soochow University, Suzhou (China)

Published: October 5, 2023

Mitoxantrone is an anthraquinone topoisomerase II inhibitor with a broad-spectrum anticancer effect, and is mainly used for treating acute leukemias and castration-refractory prostate cancer but continues to be used as a second and third line therapy in late-stage aggressive relapsing and progressive multiple sclerosis: its antiproliferative effect also makes it a powerful suppressant of cellular immunity, although additional mechanisms are likely involved.^1,2 It is quite surprising to see that mitoxantrone does not seem to have been used to treat acute graft-versus-host disease in mismatched hematopoietic stem cell transplants given without prior mitoxantrone treatment for leukemia, but this is what the inventors demonstrate in irradiated Balb/c mice at a dose of 5.2 mg/kg. How practical this is would need to be established; mitoxantrone is less cardiotoxic than doxorubicin, but has many other side effects when given in multiple doses.

FINGOLIMOD FOR ALZHEIMER DISEASE

WO/2023/187091

Title: A sphingosine-1 phosphate receptor (S1PR) modulator for use in treating a patient suffering from Alzheimer's dementia

Inventors: Leßmann V, Gottmann K, Endres T, Kartalou G-I

Applicant: Otto-von-Guericke-Universität Magdeburg, Magdeburg (Germany)

Published: October 5, 2023

Fingolimod is an approved agent for the treatment of relapsing multiple sclerosis (RMS) since 2011. In target tissue, it can be converted to the phosphate, which is a potent modulator of sphingosine-1-phosphate receptors. Reports concerning cognition-restoring effects of S1P receptor modulators (specifically, fingolimod) go back to at least 2017, and a review of the relevant molecular actions was published 4 years ago.³ The inventors themselves have published their findings on reversal of synaptic deficits in the APP/PS1 mouse model of Alzheimer disease by fingolimod, well before the March 2022 priority date of this patent application.⁴

Beyond the fact that other S1P modulators are also claimed, there seems to be little novelty in this document, even the experimental evidence that the inventors present appears to be the same as in their publication: male APP/PS1 mice and littermate controls (wild-type healthy mice) were treated with intraperitoneal injections of fingolimod (dissolved in 3% dimethyl sulfoxide [DMSO], 1.0 or 3.0 mg/kg body weight) every second day for 1–2 months. The data show complete rescue of spine deficits in dendrites distant to plaques in fingolimod-treated APP/PS1 mice, and the significant amelioration of spine deficits in dendrites close to plaques.

At 3.0 mg/kg every second day for 1 month, fingolimod restored the deficit in contextual fear learning in 15-month-old male Alzheimer disease (AD) mice. Ozanimod (1 mg/kg in drinking water for 1 month, starting at 15 months age) had a very similar capacity to restore spine deficits in CAI pyramidal neurons in aged (16-month-old) male AD mice.

GOUT DRUGS FOR ALZHEIMER DISEASE

WO/2023/192453

Title: Chronic stress accelerates the progression of cerebrovascular dysfunction with Alzheimer's disease

Inventors: Chantler P, Kelley EE

Applicant: West Virginia University Boards of Governors on behalf of West Virginia University, Morgantown (USA)

Published: October 5, 2023

Although the title of this document speaks of Alzheimer disease, the invention actually provides methods of treating the interplay between cerebral artery dysfunction (i.e., the vascular component of mixed dementia) and its primary degenerative component with a xanthine oxidase inhibitor, preferably the second-line gout medication febuxostat. An increase in xanthine oxidase levels has been identified in the plasma and postmortem brain tissue of stressed and depressed patients, an apparent defense mechanism against pathological oxidative stress.⁵ The inventors utilized 3xTg AD triple transgenic mice (an advanced model of Alzheimer disease) exposed to their own experimental paradigm of unpredicted chronic mild stress (UCMS), starting at 4 months of age, but the objective was to assess middle cerebral artery function, as measured by its response to acetylcholine.

At 6 months of age, UCMS accelerated total and phosphorylated tau protein expression by 83% (p < 0.05) and 350% (p < 0.001), respectively, compared to AD controls. Febuxostat prevented the increased expression of phosphorylated tau and lowered the total tau protein expression in the UCMS group. However, total tau protein expression remained higher compared to AD control levels. Thus, overall, these data suggest that chronic stress accelerates tau pathology in 3xTg mice partly through the xanthine oxidase pathway. This could happen in addition to the induction of an increase in large amyloid oligomers,⁶ a known effect of the xanthine/xanthine oxidase free radical generating system that was not investigated here. For the peer review companion article, see Burrage et al.⁷

POTENTIAL DRUGS TO PREVENT OR TREAT MYOPIA AND CATARACT

WO/2023/196234 and ‘235

Title: Methods, devices, and systems for treating lens protein aggregation diseases

Inventor and Applicant: Glazier AN

Published: October 12, 2023

Protein aggregation in the lens can cause presbyopia by increasing its stiffness, and ultimately cataract. Free radical formation and oxidative stress from endogenous and external sources play a strong role but cannot alone account for changes that result in such aggregation.⁸ Transparency and refractive properties of the lens are maintained by an internal microcirculation system that utilizes spatial differences in ion channels, transporters, and gap junctions to establish standing electrochemical and hydrostatic pressure gradients.⁹ Focusing on these factors in a pair of disclosures, the inventors propose regulating transport of water, sodium, and calcium through lens fiber cell channels using a multitude of agents, mostly in combination, that inhibit calcium ion uptake into the endoplasmic reticulum, block nonselective cation channels, decrease activation of lens tyrosine kinases, and modulate various cellular processes.

Claimed agents include the discontinued antihypertensive antiangina agent mibefradil (a calcium channel blocker), the antimalarial artemisinin, a broad range of tyrosine kinase inhibitors used in oncology (imatinib, dasatinib, and others), inhibitors of the NMDA receptor/Ca²⁺/calmodulin pathway (memantine, dextromethorphan), phenothiazine antipsychotics such as thioridazine, trifluoroperazine, chlorpromazine, and others. No actual data are presented, although the documents provide a long list of possible combinations.

WHAT YOU DROP INTO YOUR TEA MIGHT ALSO TREAT WOUND INFECTION

WO/2023/199057

Title: Compositions for preventing and treating infection comprising an artificial sweetener

Inventor: McCarthy R

Applicant: Brunel University London, Uxbridge (United Kingdom)

Published: October 19, 2023

Before the April 2022 priority dates of this patent application, it had been reported that some artificial sweeteners, including saccharine, sucralose, aspartame, and acesulfame potassium (“ace-K”), can promote the dissemination of antibiotic resistance genes through horizontal transfer either by natural transformation or conjugative gene transfer.¹⁰ Shortly after the priority date, these findings were extended to the demonstration of antibacterial activity; however, these studies were not performed in pathogens.¹¹ To explore the clinical potential of artificial sweeteners, a chronically infected wound was simulated in a porcine ex vivo skin model. Lacerated or superficially burnt skin explants were infected with Pseudomonas aeruginosa or Acetionobacter baumannii and then submerged in a 8.85% (w/v) ace-K solution for 1 h. This wash treatment led to a significant reduction in the number of viable bacteria within the biofilms for both bacterial species, significantly superior to water washes.

Sodium cyclamate, saccharin, and sucralose were also effective, although ace-K was best, with a significant level of inhibition already observed at 0.89%, plateauing at around 5%. Visual analysis of the wells in this assay suggested no growth above this concentration. Biofilm formation was already inhibited at 0.09%, and completely inhibited at 1.77%. The mechanism presumably is membrane disruption.

THE LOOP DIURETIC, FUROSEMIDE RESTORES IMPAIRED COGNITION

WO/2023/203527

Title: Modulators of intracellular chloride concentration for use in the treatment of cognitive decline

Inventors: Cancedda L, Savardi A, De Vivo M, Borgogno M

Applicant: Fondazione Istituto Italiano di Tecnologia, Genova (Italy); Fondazione Telethon ETS, Roma (Italy)

Published: October 26, 2023

GABA_A receptors on central nervous system neurons respond to binding of their endogenous ligand, the main inhibitory neurotransmitter γ-aminobutyric acid, by opening their chlorine ion channel. Depending on its concentration gradient across the cell membrane and the membrane resting potential of the neuron, chloride flow can be bidirectional. The Na⁺-K⁺-2Cl- (Nkcc1) and K⁺-Cl- (Kcc2) cotransporters serve to balance chloride concentrations, and are increasingly recognized as drug targets for neurological and neuropsychiatric therapy.¹² The inventors have shown in animal models that there is a significant increase in the expression of Kcc2 in the hippocampi of elderly mice (24 months and older) and of aged humans (75–80 years), leading to a hyperinhibitory phenotype that results in oversedation following the administration of benzodiazepines and in cognitive decline. The cognitive decline was shown to be reversible by Kcc2 inhibitors, including nonselective chloride cotransporter inhibitors such as the old loop diuretic, furosemide.

In the novel object recognition and localization paradigms, furosemide (25 mg/kg i.p.) restored the poor spatial memory of the elderly mice to the level of young ones. In the FluxOR™ Potassium Ion Channel Assay (Life Technologies), which measures the influx of thallium ions (replacing potassium), which permeate into the cell through Kcc2 expressed in transfected HEK293T cells, was 45.5 μM.

“QUINIMOD” IMMUNE MODULATORS TREAT AORTIC VALVE DISEASE

WO/2023/204511

Title: Composition for preventing or treating valvular calcification

Inventors: Oak MH, Ko JY

Applicant: Mokpo National University Industry-Academia Cooperation Group, Cheonggye-myeon (Korea)

Published: October 26, 2023

The aortic heart valve is under constant mechanical stress from blood flow. Valve interstitial cells produce various biochemical signals, matrix proteins, and matrix remodeling enzymes to maintain valve cell tissue homeostasis.¹³ If this is no longer possible, calcification can occur through a mechanism that starts with an inflammatory response to low-density lipoprotein and lipoprotein(a) accumulation, proceeds to unorganized collagen deposition, and ends with a osteogenesis-like process. The inventors' answer to this challenge is immune modulation with tasquinimod (in Phase III trials for various solid tumors), laquinimod (a Teva agent discontinued from development for multiple sclerosis), and paquinimod (a blocker of S100A8/A9 activation of TLR4 which had obtained European Orphan Drug designation for the treatment of systemic sclerosis in 2011).

An in vitro model was established based on porcine primary heart valve endothelial cells cultured in a calcification-promoting medium. Tasquinimod reduced calcification (as measured by alizarin red staining) by about 20% at 10 μM; paquinimod achieved about 40% at 10 μM, and 50% at 100 μM.

A KINASE INHIBITOR TO BOOST RIFAMPICIN AND ISONIAZID REGIMENS FOR TUBERCULOSIS

WO/2023/207398

Title: Use of anti-idiopathic pulmonary fibrosis drug nintedanib in treatment of tuberculosis

Inventors: Lu Y, Chen X, Qi X, Zheng L Fu L, Zhang W, Wang N

Applicant: Beijing Chest Hospital, Capital Medical University, Beijing (China); Beijing Tuberculosis Chest Cancer Institute, Beijing (China)

Published: November 2, 2023

Mycobacterium tuberculosis infection typically results in pulmonary lesions that are characterized by granulomatosis, damage of the pulmonary parenchyma, and extensive secondary interstitial fibrosis, which is a common post-tuberculosis lung disease (PTLD) that complicates eradication of the mycobacterium.¹⁴ That alone would have justified investigating nintedanib, a multi-tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, for PTLD. However, the inventors' data show that nintedanib has direct bactericidal activity against M. tuberculosis in macrophages from 25 μg/mL upwards, and it greatly amplifies the action of the standard tuberculosis drugs, rifampicin and isoniazid, in vitro and in a mouse model of tuberculosis. Nintedanib also reduced lung pathohistology in these mice. It is envisaged that once-daily doses of 150 mg of nintedanib ethyl sulfonate and 450–600 mg of rifampicin could shorten the treatment course for tuberculosis patients to 4–5 months.

AN OLD ANTIHISTAMINE FOR ONE OF THE MOST DIFFICULT-TO-TREAT PAIN SYNDROMES

WO/2023/215277

Title: Trimeprazine for use in treating trigeminal neuralgia and for reducing pain related thereto

Inventors: Manders EK, Collins MAD

Applicant: Undaunted Bio, Inc., Pittsburgh (USA)

Published: November 9, 2023

Once chronified, trigeminal neuralgia is among the most difficult to treat neuropathies. Minimal stimulation caused by light touch, talking, chewing, or even a bout of wind can lead to debilitating pain and incapacitation of the patient. Therapy options include anticonvulsants such as valproate, phenytoin, or carbamazepine (sometimes applied locally as a depot injection), clonidine, and surgery.¹⁵ The inventors present a new option: the old histamine receptor blocker, trimeprazine (also known as alimemazine), a phenothiazine derivative used as an antipruritic, sedative, and antiemetic, especially in children.¹⁶ The inventors considered that itch and at least some forms of neuropathy use the same signaling cascade, involving the activation of phospholipase C3 via histamine receptors, which produces the second messenger's diacylglycerol (DAG). DAG activates protein kinase Cɛ, which phosphorylates and thereby opens the Trpv1 channel in the dorsal root ganglion (and likely in the trigeminus as well), resulting in depolarization.

Thereby voltage-dependent sodium channels are activated generating action potentials along the nerve fiber, which leads to the sensation of itch or pain. Since trimeprazine is an histamine H₁ receptor inverse agonist, it would block this signaling cascade. In a case study, trimeprazine 5 mg morning and evening alleviated almost unbearable trigeminal pain to mild facial discomfort, with mild drowsiness as the only side effect. Clinical study protocols for trigeminal and postherpetic neuralgia are also presented. The implication is that any other first-generation antihistamine that is able to cross the blood-brain barrier could be combined with current drugs for neuropathic pain that exert their principal effect locally to provide a therapeutic effect both peripherally (e.g., on neuronal signaling) and centrally (perception of pain).

A OSTEOPOROSIS DRUG COULD PREVENT RETINAL BLINDNESS

WO/2023/220136

Title: Ultralow dosage zoledronic acid for treatment of retinal disease

Inventors: Lakkaraju A, Tan LX, Germer C

Applicant: The Regents of the University of California, Oakland (USA)

Published: November 16, 2023

Zoledronate, available as a generic, is the most potent and most long-acting of several bisphosphonate agents that inhibit the mevalonate pathway enzyme farnesyl diphosphate synthase, and are approved to treat osteoporosis and other degenerative bone diseases.¹⁷ The importance and ubiquity of this pathway have made bisphosphonates a relatively popular for drug repurposing. Zoledronate is no exception, having been claimed for the treatment of lymphangioleiomyomatosis (WO/2017/181934), nonalcoholic fatty liver disease (WO/2017/000902), prevention against radiation damage (WO/2014/162123, WO/2014/162124), and as an analgesic for inflammatory pain (WO/2013/173330), to name just a few. Bisphosphonates have a long list of side effects, including ocular complications, mostly of inflammatory nature and reversible upon discontinuation of the drug.¹⁸

It is therefore of particular interest to see extremely low zoledronate doses being claimed to treat retinal diseases that result from lipofuscin deposition, especially the nonexudative form of age-related macular degeneration. The disclosure provides topical ophthalmic preparation comprising 0.001–0.05 mg doses of zoledronic acid, intravitreal implants loaded with 0.001–0.3 mg, and systemically administered formulations containing 100 ng to 10 μg/kg body mass. The rationale is that zoledronate also inhibits acid sphingomyelinase, an enzyme that is activated under conditions of abnormal cholesterol homeostasis and disrupts autophagy in the retinal pigment epithelium through lipofuscin bisretinoids.¹⁹ Extensive in vitro data and in vivo data with Abca4 knockout mice (a model for visual cycle deficit conditions) are presented.

ANGIOTENSIN RECEPTOR BLOCKERS IN EPILEPSY

WO/2023/225640

Title: Methods and compositions for the treatment of epilepsy

Inventors: Hammer MF, Bahramnejad E

Applicant: Arizona Board of Regents on behalf of the University of Arizona, Tucson (USA)

Published: November 23, 2023

The inventors write that “one of the unique and inventive technical features of the present invention is using an angiotensin receptor blocker (e.g., candesartan) to prevent or slow the progression of epileptogenesis,” stating that protection of the blood-brain barrier is supposed to be the most significant mechanism. Mice with a knock-in gain-of-function mutation (Scn8a-N1768D) in the voltage-gated sodium channel, Nav1.6 that were treated with candesartan at different stages of epileptogenesis demonstrated statistically significant delay of seizure onset age; increased adult survival and a reduction in seizure frequency; and increased juvenile survival. Functional alterations of the blood-brain barrier indeed occur during epileptogenesis and seizures, but the cause and effect relationship is not clear.²⁰ While it might not yet have been reported for candesartan, and while not all sartans have the same secondary pharmacological profile, data demonstrating prevention of seizure kindling and attenuation of blood-brain barrier permeability by losartan were reported years ago.^21,22

ATROPINE FOR CRYPTOSPORIDIOSIS

WO/2023/228257

Title: Anti-cryptosporidium drug and method for preventing or treating cryptosporidiosis

Inventors: Kato K, Bin Kabir H

Applicant: Tohoku University, Sendai (Japan)

Published: November 30, 2023

Cryptosporidiosis is a parasitic disease that causes severe diarrhea and sometimes respiratory infections, and is particularly severe in immunocompromised patients. During a screen of traditional Chinese medicine agents, the inventors found that atropine, the prototypical antimuscarinic agent still in use in ophthalmology and cardiology, is highly effective against Cryptosporidium parvum. Dose-response curves in cultures showed an EC₅₀ value of 253.5 ± 30.3 nM for atropine sulfate. However, these promising in vitro efficacy data did not translate well: in a mouse model of cryptosporidiosis, it took 100 and 200 mg/kg to reduce oocyst shedding by 59% and 58%, respectively. There is not much in the literature to explain this discrepancy, or the strong in vitro effect, cholinesterases are produced by some parasites but nothing seems to be known concerning muscarinic receptor involvement. For the peer review companion article, see Kabir et al.²³

COMMON ANTIHYPERTONICS FERVENT CORNEAL FIBROSIS AND OPACITY

WO/2023/229667

Title: Topical angiotensin II receptor blockers (ARBs) for treating eye conditions

Inventor: Wilson SE

Applicant: The Cleveland Clinic Foundation, Cleveland (USA)

Published: November 30, 2023

Fibrotic corneal scarring due to keratitis after microbial infections or traumatic injury (including surgery) to the front of the eye is an important cause of vision loss. That angiotensin II receptor blockers (the sartan drug class) are a promising strategy for antifibrotic therapy has been known for many years, it has first been shown in the liver,²⁴ and later in the kidneys, heart, pancreas, and lungs; however, it does not immediately follow that the strategy of suppressing profibrotic factors such as TGF-β would also work in the avascular cornea. Rabits were subjected to descemetorhexis (i.e., excision of the central Descemet's membrane, which lies between the corneal stroma and the endothelial layer).

Oral losartan (5 mg/kg three times per day for 1 month) or additionally losartan eye drops (30 μL of 0.1 mg/mL six times per day) resulted in a significant decrease of postsurgical corneal opacity. Collagen type IV staining intensity in immunohistochemistry images of posterior stroma was quantitated; smooth muscle actin-positive posterior corneal fibrosis was significantly reduced in the eyedrop-only group, with additional oral treatment not producing further improvement. For the peer review companion articles, see Pereira-Souza et al.²⁵ and Sampaio et al.²⁶ For clinical trial suggestions with losartan, see Wilson.²⁷

ANOTHER TETRACYCLINE ANTIBIOTIC WITH ONCOLOGY POTENTIAL

WO/2023/233397

Title: Eravacycline for treating cancer

Inventors: Ben-Shabat S, Shapira B, Rokach L, Shtar G, Mazuz E, Jabrin A

Applicant: B. G. Negev Technologies and Applications Ltd at Ben-Gurion University, Beer Sheva (Israel)

Published: December 7, 2023

Eravacycline is a fluorinated broad-spectrum tetracycline antibiotic that is closely related to tigecycline. In the United States and Europe, it is indicated for the treatment of complicated intra-abdominal infections in adults.²⁸ Tetracycline antibiotics such as minocycline and doxycycline have significant repurposing potential,²⁹ and tigecycline is considered a promising oncology drug candidate that interferes with multiple cancer-related pathways.³⁰ This would already have suggested similar potential for eravacycline. However, the inventors detected its effect against pancreatic adenocarcinoma using a deep neural network (Chemprop) model that was trained on a set of 451 molecules with known anticancer activity that were collected from DrugBank, ClinicalTrials.gov, and cancer.com, along with the drugs' associated Medical Subject Headings (MeSH) terms. Eight hundred drugs without anticancer activity were randomly sampled from the list of FDA-approved drugs after filtering out those that were already examined in cancer-related clinical trials.

A separate second message passing neural network was trained for in silico yeast screening using the ExCAPE-DB20 database, which includes over 1.5 million molecules, 1,300 target yeast proteins, and 70 million drug-target interactions. Eravacycline was evaluated in multiple cell culture paradigms using human breast, lung, colon, and pancreatic adenocarcinoma cell lines, and finally because of its particularly strong and selective viability reduction in the p53-Y220C cancer cell line BXPC-3, it was tested in an athymic nude mice xenograft tumor model based on this cell line. Taken together, the results suggest that eravacycline restores p53 function, possibly by thermodynamically stabilizing its structure to affect its DNA binding. This reactivates apoptotic signaling pathways in tumor cells either by transactivation-dependent or independent pathways. Or, alternatively, by blocking the MDM2-p53 interaction, wild-type p53 function is retained and its tumor suppressor function is reactivated.

ANTABUSE SCORES AGAIN

WO/2023/236229

Title: Use of disulfiram drug in treatment of osteoarthritis

Inventors: Yu Y, Liu Y, Chen F, Wang G

Applicant: Shenzen Institutes of Advanced Technology, Shenzen (China)

Published: December 14, 2023

Disulfiram, originally used as an alcohol-aversive agent (ANTABUSE) due to its inhibition of aldehyde dehydrogenase, is close to the top of the list of approved agents with repurposing claims. Although a 1953 article had indicated synergy between disulfiram and cortisone in the treatment of arthritis,³¹ this has apparently not been followed up. The inventors did so, and loaded disulfiram into a PLGA and PLGA-block-PEG gel delivery system (preferably with a 10% w/w load of the drug) for intraarticular injection. Experiments in chondrocyte cultures had shown that 100 ng/mL disulfiram or less promoted cell survival while 200 ng/mL or higher reduced it. In a rat iodoacetic acid osteoarthritis model, the gel formulation improved the number, average thickness, and separation of bone trabecula, as well as bone mineral density, as demonstrated by micro-computed tomography imaging.

Inflammatory cytokine expression levels were all reduced after treatment with 50 ng/mL disulfiram. For the peer review companion article, see Liu et al.³² Also note WO/2021/135654 (Guangzhou Medical University) claiming disulfiram for prevention of Nrlp3 inflammasome activation.

THIAZOLINEDIONE ANTIDIABETICS REDUCES SKIN DAMAGE FROM THERAPEUTIC RADIATION

WO/2023/240139

Title: Topical rosiglitazone for radiation-induced skin injury

Inventor: Agarwal S

Applicant: The Brigham Women's Hospital, Inc., Boston (USA)

Published: December 14, 2023

Patients with cancer of the breast or head and neck often receive radiation therapy, which invariably results in some degree of lymphedema and soft tissue injury. Oral complications include inflammation followed by fibrosis in the mucous membranes, and the skin in the irradiated area may become so thin and atrophic that autologous transplants are required. There is no sufficient evidence for establishing a standard treatment to prevent or mitigate radiation-induced cutaneous injury.³³ The inventors took advantage of the fact that peroxisome proliferator-activated receptors (PPARs) are expressed in human skin and have important roles in skin cell differentiation and lipogenesis.³⁴

PPAR agonists are available: agents of the thiazolinedione class that had been developed as insulin sensitizers but largely failed their expectations as stand-alone antidiabetics.³⁵ This is especially true for the PPAR-γ agonist rosiglitazone, once a drug with $2.5 billion annual sales but suspended in 2006 for its presumed cardiovascular risk; although the FDA (but not the EMA) lifted its ban in 2013 the drug never recovered. It might make a small comeback as a topical drug according to this invention, which is built on the premise that dermal adipocytes play a protective role against radiation-induced tissue injury. A mouse model of secondary lymphedema which recapitulates fibrosis and adipose tissue deposition showed increased thickness of the skin and of the subdermal layer alone at both 1 and 3 weeks after lymphadenectomy. Rosiglitazone produced modest initial reductions in limb circumference and edema after 1 week.

Upon detailed histologic evaluation, however, an unexpected reduction in subdermal adipose tissue and overall skin thickness (but not dermal thickness) was noted. The inventor believes that these and the other experimental data that are disclosed here pave the way for inquiries into the use of rosiglitazone as an adjunct therapy to be initiated simultaneously with nonsurgical compression therapy.

THIAZOLINEDIONE ANTIDIABETICS FOR DUCHENNE MUSCULAR DYSTROPHY

WO/2023/244738

Title: Thiazolinediones for the treatment of muscular dystrophies

Inventors: Nagy L, Sweeney L, Hammers D, Patsalos A

Applicant: The Johns Hopkins University, Baltimore (USA); University of Florida Research Foundation, Inc., Gainesville (USA)

Published: December 21, 2023

Peroxisome proliferator-activated receptors (PPARs) have important functions in tissue energy homeostasis,³⁶ including muscle metabolism and function. The PPAR-δ subtype might play the most significant role,³⁷ but there are no selective agonists on the market and the alpha subtype is also important in skeletal muscle.³⁸ But even PPAR-γ agonists, such as rosiglitazone, can treat muscle degeneration in cancer cachexia models.³⁹ One of the genes this receptor regulates is the one coding for Growth Differentiation Factor 3 (GDF3), which is exclusively expressed in the context of regenerating muscle and molecularly contributes to myoblast fusion.⁴⁰ It was only a minor inventive step to investigate thiazolidinediones for the treatment of Duchenne muscular dystrophy and related degenerative or inflammatory muscle wasting diseases.

Preliminary data obtained on gastrocnemius muscle of pioglitazone-treated 2-month-old D2.mx mice revealed three bioinformatically predicted k-means clusters of gene expression that overlap with the three areas of distinct histological features annotated manually by a pathologist. Short-term (4 weeks) treatment of 8-month-old animals with 10 mg/kg pioglitazone resulted in significant decreases in diaphragm fibrosis and an increase in embryonic myosin heavy chain staining, an indicator of activated muscle regeneration. Many more experiments are described but were prophetic at the time of filing.

A VERY EXPENSIVE REPURPOSING ALTERNATIVE FOR A RARE DISEASE

WO/2023/247736

Title: Alpha1-antitrypsin for use in the treatment of diseases or disorders of the nervous system such as chronic inflammatory demyelinating polyneuropathy

Inventor: Zhukovsky N

Applicant: Ageronix SA, Carouge (Switzerland)

Published: December 28, 2023

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that targets myelin sheaths specifically in the peripheral nerves, causes progressive weakness, and sensory loss similar to Guillain–Barré syndrome but with a much more protracted and painful course. It is a rare disease, with an incidence and prevalence of 0.2–1.6 and 0.8–8.9 per 100,000, respectively, depending on geography and diagnostic criteria.⁴¹ Besides plasma exchange, the main treatment is intravenous immunoglobulin and, in refractory cases, rituximab—all quite expensive. Alpha1 antitrypsin, the alternative that the inventors propose here, would certainly not be cheaper: the commercial preparations that are approved for treating patients with genetic deficiency of this major circulating protease inhibitor have annual treatment costs up to $100,000 in the United States.⁴² Alpha1 antitrypsin is supposed to inhibit TACE (ADAM17) which is known for its inhibitory effect on Schwann cell-mediated myelination.⁴³

An unusually large amount of data are presented, including experimental evidence for reduction of inflammatory gene expression by α1-antitrypsin and in vivo nerve conduction data obtained with a mouse model of Charcot-Marie-Tooth disease type 1A, which is also characterized by progressive Schwann cell demyelination.⁴⁴

Footnotes

DISCLAIMER

As the sole author of this article, all contributions according to the CRediT taxonomy as stipulated in are exclusively mine. No other persons were involved in preparing this article.

DISCLOSURE STATEMENT

No competing financial interests exist.

FUNDING INFORMATION

No funding was received for this article.

Abbreviations Used

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Drug Repurposing Patent Applications October–December 2023

Abstract

AN ALMOST OBVIOUS NEW USE FOR AN ANTICANCER DRUG

FINGOLIMOD FOR ALZHEIMER DISEASE

GOUT DRUGS FOR ALZHEIMER DISEASE

POTENTIAL DRUGS TO PREVENT OR TREAT MYOPIA AND CATARACT

WHAT YOU DROP INTO YOUR TEA MIGHT ALSO TREAT WOUND INFECTION

THE LOOP DIURETIC, FUROSEMIDE RESTORES IMPAIRED COGNITION

“QUINIMOD” IMMUNE MODULATORS TREAT AORTIC VALVE DISEASE

A KINASE INHIBITOR TO BOOST RIFAMPICIN AND ISONIAZID REGIMENS FOR TUBERCULOSIS

AN OLD ANTIHISTAMINE FOR ONE OF THE MOST DIFFICULT-TO-TREAT PAIN SYNDROMES

A OSTEOPOROSIS DRUG COULD PREVENT RETINAL BLINDNESS

ANGIOTENSIN RECEPTOR BLOCKERS IN EPILEPSY

ATROPINE FOR CRYPTOSPORIDIOSIS

COMMON ANTIHYPERTONICS FERVENT CORNEAL FIBROSIS AND OPACITY

ANOTHER TETRACYCLINE ANTIBIOTIC WITH ONCOLOGY POTENTIAL

ANTABUSE SCORES AGAIN

THIAZOLINEDIONE ANTIDIABETICS REDUCES SKIN DAMAGE FROM THERAPEUTIC RADIATION

THIAZOLINEDIONE ANTIDIABETICS FOR DUCHENNE MUSCULAR DYSTROPHY

A VERY EXPENSIVE REPURPOSING ALTERNATIVE FOR A RARE DISEASE

Footnotes

DISCLAIMER

DISCLOSURE STATEMENT

FUNDING INFORMATION

Abbreviations Used

References