Abstract
Unexpected Obesity Drug Candidates
International Patent Application WO/2018/178247,
Obesity is associated with up- or downregulation of certain gene products relative to the levels seen in individuals with a normal body weight, and blood levels for many of these gene products change dramatically during a weight loss intervention. Drosophila is a good genetic model system to study the function of specific genes in adipose biology because fundamental human components and regulating mechanisms of lipid storage and utilization are evolutionarily conserved in the fly. The inventors show that whole body knockdown of ANK1 (the gene coding for ankyrin-R, the prototypical representative of a family of attachment proteins that link the integral membrane proteins to the underlying spectrin–actin cytoskeleton) increases lean body weight and reduces triglycerides in Drosophila. This is not entirely unexpected: A 2005 article had reported that one of the 203 mRNA transcripts downregulated by fasting was the ankyrin repeat and suppressor of cytokine signaling box-containing protein 4 (Asb-4). 1 The inventors proceed to an omnibus claim for the treatment and prevention of obesity covering all agents that have been reported to decrease or otherwise affect the activity of ANK1. Among the explicitly listed agents are acetaminophen, amiodarone, carbamazepine, chlorpromazine, ethinylestradiol, immunosuppressants (cyclosporine, dexamethasone), antibiotics (gentamycins, tetracyclines), and oncology agents (oxaliplatin, tamoxifen, topotecan). All of these agents seem to interact with the transient receptor potential ankyrin 1 (TRPA1) ion channel, which is involved in whole body metabolism, including glucose homeostasis. 2 Supporting data are not presented for any of these.
A Drug for a Rare Liver Disease Addresses Extrahepatic Latent Viruses
International Patent Application WO/2018/178260,
Many viruses, including HIV and hepatitis B virus (HBV), can become latent by establishing their genetic material as episomal structures in the cytoplasm or nucleus. Terminating such latency, even at the price of viral reactivation, is a key element in antiviral therapy. Farnesoid X receptor (FXR) agonists had been suggested for this purpose with respect to liver-residing HBV in WO/2015/036442 by the same applicants. However, the inventors now found that FXR plays a determinant role in the maintenance of active viral episomes in cells from tissues that are not specialized in bile salt synthesis and transport. FXR expression was detected in activated (but not in resting) lymphoid lineage cells. This could allow treatment of infection with viruses such as HIV-1, and polyoma viruses such as BKV, that persist in extrahepatic cells as extrachromosomal DNA. Among the many agents that are claimed is obeticholic acid, a modified bile acid that was approved (as Ocaliva®) for primary biliary cirrhosis in 2016 and is under investigation for nonalcoholic fatty liver disease. The biological data that are presented for HIV-1–infected H9 T-helper cells are for GW4064, a long-discontinued FXR agonist that has been reported to inhibit HCV entry into cells. 3 The effect of FXR agonists is biphasic with an initial transient boost of virus production followed by a sharp and profound decline of viral replication. The inventors had published in 2008 that HCV genotype 1 replication is enhanced by bile acids. 4
Osteoporosis Drugs Stabilize Transplanted Kidneys
International Patent Application WO/2018/190685,
Kidney transplant recipients are often treated with bisphosphonates to prevent decrease of bone mineral density and the drugs generally achieve this, although they do not seem to prevent fractures. 5,6 According to the inventors, they might achieve something else—improve the function of the allografts and increase their long-term survival. According to a retrospective analysis based on hospital data from ∼4,000 patients collected between 1979 and 2016 that is presented, there was little benefit from bisphosphonates for the first 100 months, when differences in graft survival times began to manifest. The inventors do not speculate about the reason and it is not easy to discern one. When kidney allografts suffer from chronic failure without outright rejection, endothelial damage usually is the culprit. 7 Nitrogen-containing bisphosphonates can inhibit the adverse effects of advanced glycation end products in endothelial cells, 8 and ibandronate improves endothelial function in hypertensive rats, 9 in both cases likely by decreasing the production of free radicals. However, it is not obvious why net benefit from bisphosphonates according to this mechanism would become noticeable only 8 years after transplantation.
Melatonin Agonist + Tetracycline = Less Delirium in the icu
International Patent Application WO/2018/193652,
The pathogenic mechanism of delirium—an acute confusional state with hallucinations and impairment of cognition, precipitated by organic causes or anesthesia and usually fully reversible—is still not entirely clear. Postoperative cases, in which its occurrence indicates increased morbidity and mortality, can be prevented or treated with atypical antipsychotics. In critically ill patients, disturbances of the sleep–wake cycle are more obviously involved, suggesting that melatonin or its receptor agonists could be helpful. A recently published study 10 seems to confirm this, although improved outcomes are not consistently seen. 11 With current guidelines making no pharmacological recommendations for either the prevention or treatment of delirium in intensive care units, this has been tried—and reported—almost since the millennium. The inventors add tetracycline antibiotics (e.g., minocycline) to the melatonin receptor agonists (melatonin, or ramelteon, or tasimelteon [marketed as Rozerem® and Hetlioz®, respectively, for insomnia]) to combat “brain nerve inflammation.” Clinical case reports are presented in support. Japanese and Australian researchers had suggested in 2014 and 2012, respectively, that minocycline could be useful in delirium by inhibiting the activation of microglia. 12,13 A melatonin–minocyclin combination therapy did not improve functional deficits after traumatic brain injury in rats, 14 but melatonin had been used as an antioxidant in this setting, which involves acute neuroprotection. Combinations of a circadian rhythm regulator and an agent that prevents “sterile” inflammatory responses in the brain could be a useful addition to intensive care unit practices.
A Cancer Drug Prevents Postsurgery Complications
International Patent Application WO/2018/195392,
Although advances in abdominal surgery techniques have led to a decrease in the incidence of peritoneal adhesions, they still pose a very significant problem during recovery. 15 Their formation has three stages: first comes failure of timely resolution of a blood clot, followed by the influx of inflammatory cells consisting of multiple cell types, and production of a variety of cytokines and factors that allows a connective tissue scar to be formed. The critical cells in this final step are myofibroblasts that are generated through transdifferentiation of mesothelial cells in the abdominal cavity. 16 The inventors had previously reported 17 that U0126, a selective MEK1/2 inhibitor research tool, blocked the rat peritoneal mesothelial–mesenchymal transition induced by TGF-β, which is critical for the fibrotic response. It was only a minor inventive leap to investigate and claim the MEK1/2 inhibitor trametinib (approved for metastatic melanoma as Mekinist®) for the same purpose. In a C57BL/6 mouse model of peritoneal adhesions caused by cecal abrasion surgery, trametinib (administered through an osmotic pump at 0.1–3.0 mg/kg per day) either completely prevented or greatly diminished the initial formation of adhesions during the first 8 days postsurgery, without adverse effects on wound healing. In cell cultures, trametinib blocked the effect of TGF-β on rat mesothelial cells that retained their epithelioid morphologic characteristics.
Parp Inhibitors Close Chronic Wounds
International Patent Application WO/2018/197463,
Poly(adenosine diphosphate-ribose)polymerase (PARP) is a nuclear enzyme that has an essential role in recognizing and repairing DNA damage, controlling RNA transcription, mediating cell death, and regulating immune response. Hopes for inhibitors of this mechanism in oncology took longer than expected to materialize, but meanwhile there have been several papers concerning their utility in the healing of chronic wounds in animal models. Many of these published reports are cited in this patent application, including one identifying promotion of angiogenesis as the putative mechanism, 18 one investigating 3-aminobenzamide for accelerating wound healing in irradiated mice, 19 and one demonstrating efficacy of olaparib (approved for breast and ovarian cancer as Lynparza®) in a murine model of third-degree burn injury. 20 The inventors investigated such effects in patient tissues and made interesting discoveries. Talazoparib and rucaparib (also approved for breast and/or ovarian cancer, as Talzenna® and Rubraca®, respectively), olaparib, veliparib (in clinical trials), and AZD 2461 strongly enhanced healing in the fibroblast-derived matrix but had at most a marginal effect on fibroblast proliferation in the absence of wound exudate; veliparib was most effective for diabetic wounds. Dexamethasone and ascorbic acid potentiated the positive enhancing effect of veliparib and talazoparib. Surprisingly, niraparib (which inhibits both PARP-1 and PARP-2 with an IC50 in the low nanomolar range) did not show any activity in the assays. AG-14351, which has comparable inhibitory effect on PARP-1, exhibited only a very weak effect, 10 μM. Other experimental PARP inhibitors (BGP-15, 3-AB,1,5-IQD, and PJ-34) were also found to be either inactive or only weakly active in both the 2D fibroblast proliferation assay and the 3D fibroblast-derived matrix formation assay. Also notable in this context is WO/2018/203762, claiming the NSAID sulindac for diabetic wounds.
A Breast Cancer Kinase Inhibitor For Atherosclerosis And Hepatic Steatosis
International Patent Application WO/2018/202866,
Cdkn2b (p15) and Cdkn2a (p16) are inhibitors of cyclin-dependent kinases Cdk4 and Cdk6. The genes coding for p15 and p16 are frequently deleted or inactivated in tumors and can be functionally replaced by Cdk4/6 inhibitors such as palbociclib, which is marketed (as Ibrance®) for use in combination with aromatase inhibitors to treat metastatic breast cancer in postmenopausal women (and most recently, men). The current invention claims it for use in the treatment and/or prevention of cardiometabolic diseases in which there is an inhibition or other alteration of regulatory T cells—atherosclerosis, acute coronary syndrome and myocardial infarction, type 2 diabetes and obesity-linked insulin resistance, dyslipidemia, and hepatic steatosis. Palbociclib increased Treg cells in human lymphocytes in vitro. Additional data show increased Treg/Thl7 cellular ratios, decreased proinflammatory Ly6Chi monocytes, and decreased insulin release in a mouse model of dyslipidemia and accelerated atherosclerosis. It also decreased hepatic steatosis in a mouse model deficient in hepatic lipase. Altered expression of cell cycle kinases, including Cdk6, has been reported in regulatory T cells. 21 Although published data suggest that one or more CDKN2A transcripts modulate platelet production and activity in the setting of hypercholesterolemia, 22 this cannot be immediately assumed for palbociclib, which is only a mimetic of CdkN2a. For the peer review companion article, see Vinué et al. 23
From Sickle Cell Disease to Male Fertility
International Patent Application WO/2018/208826,
The peer review literature does not suggest beneficial effects of hydroxyurea, the original drug for sickle cell disease, on male fertility—quite the contrary is true: adverse effects on sperm and semen, which are already compromised by the disease, have been reported on multiple occasions. 24 –26 It is indeed surprising if the inventors now report that “hydroxyurea has positive effects on sperm motility, longevity, and other factors related to sperm health, including in sperm of humans.” Concentrations of 18 μg/mL seem to be preferred; concentrations that inhibit HIV replication are tolerated, and could reach 250 μg/mL. A washing step with a mixture of HTF-HEPES medium comprising 0.5% bovine serum albumin is optionally included to remove seminal plasma. The positive effects on spermatozoa on motility and viability remain after cryopreservation, making the method attractive in artificial insemination settings. There is no indication concerning the potential mechanism. Also note WO/2018/232352 from the University of California claiming hydroxyurea for prevention of congenital heart disease; in this case, the compound's ability to inhibit nucleotide biosynthesis enzymes is exploited.
Arthritis: a New Perspective for an Old Antipsychotic
International Patent Application WO/2018/213027,
Pimozide, a diphenylbutylpiperidine-class “typical” antipsychotic discovered at Janssen Pharmaceutica in 1963, acts as an antagonist at the dopamine transporter and at several postsynaptic receptors, including Dl, D2, D3, D4, α1/2-adrenergic, and 5-HT2A receptors. Only relatively recently it was found that pimozide decreased tyrosine phosphorylation of STAT5 (one of the JAK-STAT transcriptional regulators) and the expression of STAT5 target genes, and can induce cell cycle arrest and apoptosis in leukemia cell lines. 27 The expression of the STATs is elevated in peripheral blood leukocytes and synovial fluid cells from arthritis patients 28 ; methotrexate, the first-line therapy for rheumatoid arthritis, is also a JAK/STAT pathway inhibitor 29 ; and it is known that dopaminergic drugs (including pimozide) have potent effects on T cells. 30 Connecting all these dots, it is not difficult to presume that STAT5 inhibitors, including pimozide, could be useful in rheumatoid arthritis—which is what the inventor has confirmed in the adjuvant arthritis rat model. Similar benefit from the atypical antipsychotic, quetiapine, has been reported years ago, 31 and was later ascribed to inhibition of Akt/Erk pathway signaling. 32 This could be particularly useful in anti-TNF nonresponders.
A First-Generation Antidiabetic Protects DNA Against UV Damage
International Patent Application WO/2018/215628,
In human skin cells, DNA damage caused by ultraviolet radiation is believed to be repaired solely through the nucleotide excision repair (NER) pathway; its defects (as in Xeroderma pigmentosum, Cockayne syndrome, UV-sensitive syndrome, and photosensitive subtypes of trichothiodystrophy) cause increased or extreme sensitivity to sunlight. Who would have thought of old sulfonylurea antidiabetics (acetohexamide and glimepiride) as potential remedies, as the inventors did? Some sulfonylureas, such as glibenclamide, have antioxidative effects but these did not matter in the inventors' assay that was based on clearance of cyclobutane–pyrimidine dimers in DNA of NER-deficient ΔXPA cells: the potent antioxidant N-acetylcysteine had a very minor effect. Instead, cell cycle profile analysis revealed that acetohexamide and glimepiride exert their protective effects by inhibiting expression of MUTYH, a DNA repair glycosylase 33 that had not previously been implicated in the removal of UV-induced lesions. Knockdown of MUTYH conferred resistance to UV irradiation that was comparable with wildtype cells, similar to the effect of treatment using the compounds of the invention. For the peer review companion article, see Mazouzi et al. 34
Antibiotics Treat Pulmonary Hypertension
International Patent Application WO/2018/219187,
Pulmonary administration of low doses of cephalosporin (1, 10, or 100 μg/kg) in the rat model of monocrotaline- induced pulmonary hypertension reduces pulmonary artery pressure, mitigates right ventricular hypertrophy, alleviates pulmonary vascular remodeling, and reduces pulmonary vascular thickness by inhibiting vascular smooth muscle cell proliferation. Two companion documents, WO/2018/219188 and ‘189, continue from this patent application with a focus on cefminox and cefmetazole, respectively. The inventors do not speculate on the mechanism, but a peer review article from a different (and probably unrelated) Chinese source reports that cefminox is a dual agonist of PPARγ and the prostacyclin receptor (both well-established molecular targets in the therapy of pulmonary hypertension), and is effective in a hypoxia-driven rat model. 35
A Mucolytic Drug for Neuropathy
International Patent Application WO/2018/229119,
Bromhexine is a secretolytic drug that was first introduced in 1963 and is still in use as an over-the-counter expectorant 36 in many European countries. It has very few side effects and is known to pass the blood–brain barrier. No potential for treating pain has been reported so far. However, another closely related mucolytic, ambroxol, has been shown (by a team including the inventor) to alleviate trigeminal neuralgia and complex regional pain syndrome in humans. 37,38 Nine case reports for pure pain and two for fibromyalgia are presented, all for topical administration. It seems possible that bromhexine, like ambroxol, 39 blocks sodium currents in sensory neurons, with a preference for tetrodotoxin-resistant currents mediated by Nav1.8.