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* Arimoclomol is a drug candidate to treat insulin resistance and diabetic complications such as retinopathy, neuropathy and nephropathy. Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases. Arimoclomol activates the heat shock response. It is believed to act at Hsp70. Arimoclomol has been shown to extend life in an animal model of ALS and was well tolerated in healthy human volunteers in a Phase I study. Arimoclomol also has been shown to be an effective treatment in an animal model of Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy's Disease).

* Benzonatate is a prescription non-opioid alternative for the symptomatic relief of refractory cough. It has been shown to improve cough associated with a variety of respiratory conditions including asthma, bronchitis, pneumonia, tuberculosis, pneumothorax, opiate-resistant cough in lung cancer, and emphysema. Benzonatate also reduces the consistency and volume of sputum production associated with cough in those with chronic obstructive pulmonary disorder (COPD). Compared to codeine, benzonatate has been shown to be more effective in reducing the frequency of induced cough in experiments. Benzonatate does not treat the underlying cause of the cough. Benzonatate has been shown to have use in the suppression of hiccups. Similar to other local anesthetics, benzonatate is a potent voltage-gated sodium channel inhibitor. After absorption and circulation to the respiratory tract, benzonatate acts as a local anesthetic, decreasing the sensitivity of vagal afferent fibers and stretch receptors in the bronchi, alveoli, and pleura in the lower airway and lung. This dampens their activity and reduces the cough reflex. Benzonatate also has central antitussive activity on the cough center in central nervous system at the level of the medulla. However, there is minimal inhibition of the respiratory center at a therapeutic dosage.

* Centhaquin-HS is a hypertonic saline solution of centhaquin citrate dihydrate. Centhaquin enhances the resuscitative effect of hypertonic saline (HS). Large volume resuscitation has been used by emergency medical personnel and surgeons to reverse hemorrhagic shock and to restore end-organ perfusion and tissue oxygenation. Centhaquin is an Alpha 1 adrenergic receptor antagonist and Alpha 2 adrenergic receptor agonist used as analgesic, antihaemorrhagic, antihypertensive, and in cardiovascular therapies such as haemorrhagic shock (Adjuvant therapy) , heart arrest , postoperative pain and as resuscitative agent for hypovolemic shock. Centhaquin is a compound that produces hypotension and bradycardia in higher doses and resuscitation in lower doses. Shock due to severe hemorrhage accounts for a large proportion of posttraumatic deaths, particularly during early stages of injury. A majority of deaths due to hemorrhage occur within the first six hours after trauma, but many of these deaths can be prevented. Shock is accompanied by circulatory failure which is the primary cause of mortality and morbidity. Therefore, a need exists in the art for a resuscitation agent that improves survival time, and can be used with a small volume of resuscitation fluid, for resuscitation in hypovolemic shock. The recording inludes the sound frequencies of centhaquin citrate dihydrate, sodium chloride and water.

* Coblopasvir dihydrochloride is an antiviral drug candidate for the treatment of hepatitis C virus infection. Hepatitis C virus (HCV), or hepatitis C virus infection, is a chronic blood-borne infection. Studies have shown that 40% of chronic liver diseases are associated with HCV infection, and an estimated 8,000-10,000 people die each year. HCV-related end-stage liver disease is the most common indication for liver transplantation in adults. Because the risk of HCV-related chronic liver disease is related to the duration of HCV infection, and the risk of cirrhosis increases in patients who have been infected for more than 20 years, chronic liver disease often progresses to advanced stages with cirrhosis, ascites, jaundice, and rupture of varicose veins. Brain disease, and progressive liver failure, and the risk of liver cancer is also significantly increased.

* CPP-115 is a 4-aminobutyrate transaminase inhibitor,  causing increased levels of GABA, gamma-aminobutyric acid, the chief inhibitory neurotransmitter in humans. It is used for the treatment of Gilles de la Tourette’s syndrome, infantile spasms, partial epilepsies, drug abuse, cocaine dependency and post traumatic stress disorder. Mechanistically, CPP-115 binds to GABA-AT, undergoing product transformation that kills GABA-AT’s function. In rat studies, CPP-115 suppressed spasms at a much lower dose (0.1 mg/kg) than Sabril (>200 mg/kg) and exhibited better tolerance without visual defects. In preclinical studies CPP-115 has been shown to have potentially significant advantages compared to the only approved and marketed current GABA-AT inhibitor (vigabatrin). The hydrochloride salt of CPP-115 has been granted orphan drug designation by the EMA for the treatment of West syndrome, an epileptic disorder of young children which causes developmental problems.

* CORM-2-DMSO. Carbon monoxide (CO)-releasing molecules (CORMs) are used to deliver CO, a biological ‘gasotransmitter’, in biological chemistry and biomedicine. CORMs kill bacteria in culture and in animal models, but are reportedly benign towards mammalian cells. CORM-2 (tricarbonyldichlororuthenium(II) dimer, Ru2Cl4(CO)6), the first widely used and commercially available CORM, displays numerous pharmacological, biochemical and microbiological activities, generally attributed to CO release. Unlike CORM-3, which is water-soluble, CORM-2 requires solubilisation in DMSO where it undergoes extensive ligand exchange with the solvent and isomerises with implications for CO release. Thus far, the amount of CO released from CORM-2 is inadequate to explain its toxicity. Rather, CORM-2 reacts with thiol-containing compounds, of which cysteine (free and in proteins) and reduced glutathione are key players in its physiological effects. These reactions dramatically reduce the toxic effects of CORM-2. While the biological chemistry of Ru complexes is far from completely understood , the toxic effects of Ru CORMs on bacterial and (by extrapolation) mammalian cells can now be largely attributed to the chemical reactivity of Ru, and not CO. CORM-2 has therapeutic effect in heart diseases, hypertrophy, neuralgia, stomach diseases.

* CORM 3 is a ruthenium coordination entity that acts as a water-soluble carbon monoxide-releasing molecule. It has a role as a nephroprotective agent, an antibacterial agent, an anti-inflammatory agent, an anticoagulant, an EC 1.11.2.2 (myeloperoxidase) inhibitor, a neuroprotective agent and a mitochondrial respiratory-chain inhibitor. It is a metal carbonyl and a ruthenium coordination entity.

* Cuspin-1 is small molecule upregulator of the Survival of Motor Neuron protein (SMN), whose decreased levels cause the neurodegenerative disease spinal muscular atrophy (SMA). Mechanistic studies of cuspin-1 revealed that increasing Ras signaling upregulates SMN protein abundance via an increase in translation rate. These findings suggest that controlled modulation of the Ras signaling pathway may benefit patients with spinal muscular atrophy (SMA). ( DOI: 10.1021/cb300374h )

* Diosmin-Rutin. Diosmin is a naturally occurring flavonoid glycoside strengthens vascular walls. Diosmin is a protecting agent and is used for the treatment of chronic venous insufficiency, lymphedema, hemorrhoids and varicose veins. It has been also used for other therapeutic purposes such as cancer, premenstrual syndrome, colitis, and diabetes. An oral phlebotropic drug used in the treatment of venous disease, i.e., chronic venous insufficiency (CVI) including spider and varicose veins, leg swelling (edema), stasis dermatitis and venous ulcers. It is also used as a stand-alone or surgical adjunctive therapy in hemorrhoidal disease (HD). There are extensive clinical trials that show diosmin improves all stages of venous disease including venous ulcers and improves quality of life. There are no prospective studies in arterial disease. Diosmin has been found to be effective in mitigating hyperglycemia in diabetic rats. It is also speculated that diosmin might have potential in the treatment of neurodegenerative diseases, such as Alzheimer’s disease. Diosmin improves lymphatic drainage by increasing the frequency and intensity of lymphatic contractions, and by increasing the total number of functional lymphatic capillaries. Diosmin prolongs the vasoconstrictor effect of norepinephrine on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility, and stasis. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI. Diosmin reduces the expression of endothelial adhesion molecules (ICAM1, VCAM1), and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals and prostaglandins (PGE2, PGF2a). Rutin also called rutoside, is the glycoside flavonoid found in a certain fruits and vegetables. In a clinical trial, rutin was found to aid control of intraocular pressure in patients with primary open angle glaucoma. Traditionally, rutin is used to prevent mucositis due to cancer treatment, to treat blood vessel disease such as varicose veins, bleeding, hemorrhoids.

* Esketamine is a medication used as a general anesthetic and for treatment-resistant depression. Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors. The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly. Esketamine is a general anesthetic and is used for similar indications as ketamine. Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks. Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant. Most common side effects when used in those with treatment resistant depression include dissociation, dizziness, nausea, sleepiness, anxiety, and increased blood pressure.

* Esreboxetine-TRK 700. Esreboxetine succinate is a selective norepinephrine reuptake inhibitor for the treatment of neuropathic pain, fibromyalgia and a variety of other indications.. It is the (S,S)-(+)-enantiomer of reboxetine and is even more selective in comparison. TRK 700 is an analgesic drug for the treatment of neuropathic pain, postherpetic neuralgia and  fibromyalgia. Fibromyalgia is a disease in which systemic pain is the main symptom and neuropsychiatric symptoms and autonomic nervous system symptoms are secondary symptoms.

* Ginkgo Biloba Tonic. Ginkgo biloba has been used for centuries as part of the ancient Chinese pharmacopoeia in the treatment of respiratory ailments, cognitive impairment, and circulatory disorders. In recent years, Ginkgo has gained great worldwide acceptance for treatment of a number of medical conditions including tinnitus, cognitive decline in dementia, intermittent claudication, asthma, macular degeneration and, most recently, antidepressant induced sexual dysfunction. Case reports have confirmed GBE’s beneficial effect on ASD. An open clinical trial of Ginkgo biloba extract with 63 patients was found to be effective in 84% of patients with ASD. All phases of the sexual response cycle were improved (desire, excitement, orgasm and resolution). Minimal side effects were reported which included gastrointestinal upset, headache, CNS stimulation and easy bruisability. There were no serious adverse events. Possible mechanisms of action may include improved circulation and prostaglandin agonist effects, as well as neurotransmitter and nitric oxide second messenger modulation. Although Ginkgo biloba is relatively safe, it also works as a potent inhibitor of platelet activating factor. Therefore, patients taking aspirin, nonsteroidal anti-inflammatory agents, and anti-coagulants, or patients with a coagulopathy should consult a physician and exercise caution when considering adding GBE to their existing regimen. The bilobalides, ginkgolides, flavonoids, and other substances unique to the tree restore better blood flow to all parts of the body but particularly to the brain, allowing improved use of oxygen. Ginkgo’s antioxidant actions also stabilize the structure of brain and nerve cells and protect them from oxidative attacks from free radicals. Research indicates ginkgo action of supporting healthier circulation in the eyes, make it an herb of choice for natural treatment eye health and macular degeneration. Ginkgo’s hallmark effect is increased circulation, which is important in maintaining our energy level and one of the factors in stopping early hair loss. Increasing genital blood flow heightens responsiveness, making for higher libido in both men and women. Good circulation means getting the full benefit from the foods we eat and the vitamins and herbal supplements we take. Medicinal uses: Allergies, Alopecia, Asthma, Bronchitis, Circulation, Eyes/Vision, Libido, Longevity Tonics,  Memory/Focus, Varicose Veins. Properties: Anti-inflammatory, AntiCancer, Antioxidant, Antitussive, Astringent, Cardiac tonic Cordial,  Tonic, Vasodilator, Vermifuge. The extract contains flavone glycosides (quercetin, kaempferol, and isorhamnetin) and terpene lactones (GB, ginkgolides A, B, and C, and bilobalide).

* Licofelone is a dual COX/LOX inhibitor that was studied in clinical trials as a treatment for osteoarthritis. Licofelone is both an analgesic and an anti-inflammatory. Inhibition of 5-lipoxygenase (5-LOX) may reduce the gastrointestinal toxicity associated with other nonsteroidal anti-inflammatory drugs (NSAID), which only inhibit cyclooxygenase (COX). Licofelone is the first drug to inhibit both.

* Musculoskeletal Injury Mix is based upon the idea that Hypericin and Chlorogenic acid can help cure musculoskeletal trauma, Bromelain is a natural remedy to help reduce inflammation,  Hydroxytyrosol and Vitamin E can help reduce pain. St. John’s wort' Hypericin appears to inhibit the neuronal uptake of serotonin, norepinephrine, dopamine, gamma-amino butyric acid (GABA) and L-glutamate, which may contribute to its antidepressant effect. Hypericin may also prevent the replication of encapsulated viruses probably due to inhibition of the assembly and shedding of virus particles in infected cells.  St. John’s wort' Chlorogenic acid is antioxidant, antibacterial, hepatoprotective, cardioprotective, anti-inflammatory, antipyretic, neuroprotective, anti-obesity, antiviral, anti-microbial, anti-hypertension, free radicals scavenger and a central nervous system stimulator. Bromelain is an anti-inflammatory and is used in treating tendinitis, arthritis and swelling and pain related to muscle injuries. Hydroxytyrosol affects the expression of various components of the inflammatory response, possibly through the modulation of the nuclear factor-kappa B (NF-kB) pathway. The effects include the modulation of pro-inflammatory cytokines, such as the inhibition of interleukin-1alpha (IL-1a), IL-1beta, IL-6, IL-12, and tumor necrosis factor-alpha (TNF-a); increased secretion of the anti-inflammatory cytokine IL-10; inhibition of the production of certain chemokines, such as C-X-C motif chemokine ligand 10 (CXCL10/IP-10), C-C motif chemokine ligand 2 (CCL2/MCP-1), and macrophage inflammatory protein-1beta (CCL4/MIP-1b); and inhibition of the expression of the enzymes inducible nitric oxide synthase (iNOS/NOS2) and prostaglandin E2 synthase (PGES), which prevent the production of nitric oxide (NO) and prostaglandin E (PGE2), respectively. In addition, hydroxytyrosol is able to regulate the expression of other genes involved in the regulation of tumor cell proliferation, such as extracellular signal-regulated and cyclin-dependent kinases. Also, hydroxytyrosol scavenges free radicals and prevents oxidative DNA damage. This induces apoptosis and inhibits proliferation in susceptible cancer cells. Hydroxytyrosol doubles the amount of vitamin C in plasma. Vitamin E or  alpha-tocopherol inhibits the activity of protein kinase C (PKC) and PKC-mediated pathways. Alpha-tocopherol also modulates the expression of various genes, plays a key role in neurological function, inhibits platelet aggregation and enhances vasodilation.

* Nicotine is a chiral alkaloid. The primary therapeutic use of nicotine is treating nicotine dependence to eliminate smoking and the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, inhalers, or nasal sprays to wean them off their dependence. A 2018 Cochrane Collaboration review found high quality evidence that all current forms of nicotine replacement therapy (gum, patch, lozenges, inhaler, and nasal spray) therapies increase the chances of successfully quitting smoking by 50–60%, regardless of setting. Nicotine is highly addictive, addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence. Nicotine dependence involves tolerance, sensitization, physical dependence, and psychological dependence. Nicotine dependence causes distress. Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits (nAChRalpha9 and nAChRalpha10) where it acts as a receptor antagonist. A 2015 review noted that stimulation of the alpha4beta2 nicotinic receptor is responsible for certain improvements in attentional performance . Alpha4beta2 is also the biological target that mediates nicotine's addictive properties. Nicotine has potential beneficial effects, but it also has paradoxical effects, which may be due to the inverted U-shape of the dose-response curve or pharmacokinetic features. Randomized trials and observational studies of nicotine replacement therapy in cardiovascular patients show no increase in adverse cardiovascular events compared to those treated with placebo. Using nicotine products during cancer treatment is counterrecommended, as nicotine promotes tumour growth, but temporary use of NRTs to quit smoking may be advised for harm reduction. Nicotine potential interacts with sympathomimetic drugs (adrenergic agonists) and sympatholytic drugs (alpha-blockers and beta-blockers). Nicotine and cigarette smoke both induce the expression of liver enzymes (e.g., certain cytochrome P450 proteins) which metabolize drugs, leading to the potential for alterations in drug metabolism. Smoking cessation may decrease the metabolism of acetaminophen, beta-blockers, caffeine, oxazepam, pentazocine, propoxyphene, theophylline, and tricyclic antidepressants, leading to higher plasma concentrations of these drugs.

* PR1P peptide (DRVQRQTTTVVA) is derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. The Prominin-1-Derived peptide improves cardiac function following ischemia making PR1P a potential non-invasive candidate therapeutic for Myocardial Infarction. PR1P is able to increase the activity of vascular endothelial growth factor (VEGF) in cells lining the inside of blood vessels, can reduce lung cell death and tissue damage in a mouse model of emphysema. To investigate its therapeutic potential in emphysema, the researchers treated human lung cells cultured in a lab dish and mouse models of the disease with the PR1P peptide. In both cases, PR1P increased VEGF signaling and prevented the protein from being destroyed. The team also discovered that in mice, inhalation of the peptide was sufficient to increase the levels of VEGF found in the lungs within 30 minutes. Moreover, 24 hours later, the levels of VEGF in these animals remained two-times higher compared to those seen in vehicle-treated (control) mice. Additionally, PR1P also lowered lung cell death — one of the hallmarks of emphysema — both in lab-cultured cells and in cells in the animals’ lungs. Finally, the researchers showed that PR1P was able to reduce lung injury in mice with emphysema that were followed for up to 21 days without triggering any undesirable side effects. “Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation,” they wrote. These other diseases include, for instance, acute respiratory distress syndrome (ARDS), a common and severe lung disease in which the team is already testing PR1P. PR1P also ameliorates neurodegeneration through activation of VEGF signaling pathway and remodeling of the extracellular environment in optic neuropathies. Optic neuropathies are the most commonly occurring neurodegenerative diseases, characterized by progressive retinal ganglion cell (RGC) degeneration. PR1P prevented RGC apoptosis resulting in improvement of retinal function in the rat ONC (optic nerve crush) model. PR1P treatment significantly increased phosphorylation of ERK and AKT and expression its downstream proteins c-fos and Egr-1 in the retina. Additionally, PR1P beneficially increased the MMP-9/TIMP-1 ratio and promoted glial activation in the retina of ONC rats.

* Pracinostat is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties. Pracinostat selectively inhibits HDAC class I, II, IV without class III and HDAC6 in class IIb, but has no effect on other Zn-binding enzymes, receptors, and ion channels. It accumulates in tumor cells and exerts a continuous inhibition to histone deacetylase, resulting in acetylated histones accumulation, chromatin remodeling, tumor suppressor genes transcription, and ultimately, apoptosis of tumor cells. In March 2014, pracinostat was granted the status of Orphan Drug for acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration. Claims exist about its use in hematological tumors, breast cancer, colon cancer, prostate cancer, pancreas cancer, leukemia, lymphoma, ovary cancer, melanoma and neuroblastoma.

* Pralnacasan is a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE, aka Caspase-1). Pralnacasan has also been investigated for the treatment of Partial Epilepsy; advancing to Phase II clinical trials. Pralnacasan is an oral, anti-cytokine drug candidate. Pralnacasan inhibits interleukin-1beta converting enzyme (ICE), an enzyme that regulates the production of IL-1 and IFN gamma – intercellular mediators that initiate and sustain the process of inflammation. Inhibiting ICE may be an effective strategy for curtailing damaging inflammatory processes common to a number of acute and chronic conditions, such as rheumatoid arthritis (RA) and osteoarthritis.

* PYY peptide-long. Peptide YY (97 aa) also known as peptide tyrosine tyrosine is a peptide that in humans is encoded by the PYY gene. PYY is found in L cells in the mucosa of gastrointestinal tract, especially in ileum and colon. Also, a small amount of PYY, about 1-10%, is found in the esophagus, stomach, duodenum and jejunum. PYY concentration in the circulation increases postprandially (after food ingestion) and decreases by fasting. In addition, PYY is produced by a discrete population of neurons in the brainstem, specifically localized to the gigantocellular reticular nucleus of the medulla oblongata. PYY exerts its action through NPY receptors; it inhibits gastric motility and increases water and electrolyte absorption in the colon. PYY may also suppress pancreatic secretion. It is secreted by the neuroendocrine cells in the ileum and colon in response to a meal, and has been shown to reduce appetite. PYY works by slowing the gastric emptying; hence, it increases efficiency of digestion and nutrient absorption after a meal. Research has also indicated.

* Runcaciguat (BAY 1101042) is an orally active stimulator of soluble guanylate cyclase, and is used in the research of cardiovascular and renal diseases combined with selective partial adenosine A1 receptor agonists. Given the broad impact of oxidative stress in cardiovascular and cardiorenal diseases, runcaciguat might become a new treatment modality for a broad variety of diseases in these indication space but also beyond. After a successful completion of phase 1 clinical studies, runcaciguat is currently investigated in a clinical phase 2 study for the treatment of patients with chronic kidney disease (CKD) and nonproliferative diabetic retinopathy (NPDR.)

* SW-033291 is a small-molecule inhibitor targeting 15-hydroxyprostaglandin dehydrogenase (15-PDGH) and subsequently elevating the production of prostaglandin E2 (PGE2), has been proved to accelerate the recovery and potentiate the regeneration of multiple tissues including the bone, liver, and colon. SW033291 stimulates tissue regeneration, catalyzing faster regrowth and healing of damaged tissues. SW033291 acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. SW033291 heals damage in multiple tissues, which suggests that it may have applications in treating many diseases.

* Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin (TTR) protein by binding in one of the two thyroxine-binding sites of the tetramer. It  is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis (ATTR). It can be used to treat both hereditary forms (hATTR), familial amyloid cardiomyopathy (FAC) and familial amyloid polyneuropathy (FAP), as well as wild-type transthyretin amyloidosis (wtATTR, formerly called senile systemic amyloidosis). It works by stabilizing the protein transthyretin. In people with ATTR these strands separate and form clumps that harm tissues including nerves and the heart. In people with FAP, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves.   

* Tenapanor-A250. Tenapanor, used in form of tenapanor hydrochloride, is a treatment for adults with a disease of the gut called irritable bowel syndrome with constipation commonly referred to as IBS-C. Tenapanor acts as an inhibitor of the sodium-proton exchanger NHE3. This antiporter protein is found in the kidney and intestines, and normally acts to regulate the levels of sodium absorbed and secreted by the body. When administered orally, tenapanor selectively inhibits sodium uptake in the intestines, limiting the amount absorbed from food, and thereby reduces levels of sodium in the body. This may make it useful in the treatment of chronic kidney disease and hypertension, both of which are exacerbated by excess sodium in the diet. Studies in mice demonstrated DRA inhibitor A250 a 4,8-dimethylcoumarin compound’ efficacy in a loperamide model of constipation, and provided novel data that clarified the mechanisms of intestinal fluid absorption.  A250 greatly reduces urine sediment in oxalate nephropathy model and prevents renal damage in the same model. Inhibition of SLC26A3 by DRA inhibitor A250 provides a novel anti- absorptive therapy for constipation. It is believed that inhibition of SLC26A3, alone or together with drugs acting on alternative anti-absorptive or pro-secretory mechanisms, could be highly effective in treating refractory constipation. Inhibition of SLC26A3 reduced manifestations of constipation with comparable efficiency to a blocker of intestinal Na+ absorption, the NHE3 inhibitor tenapanor, and when co-administered SLC26A3 and NHE3 inhibitors fully reversed constipation. Theoretically, SLC26A3 inhibition could be more effective than NHE3 inhibition for constipation therapy as it blocks absorption in the distal colon where stool is dehydrated to its final form. It is surprisingly found that additive or synergistic actions of NHE3 and SLC26A3 inhibitors in preventing loperamide-induced constipation. The ability of small molecule inhibitors of NHE3 (tenapanor) and SLC26A3 (the 4,8-dimethylcoumarin drug “DRAinh-A250”) to reduce intestinal fluid absorption makes them valuable therapies for irritable bowel syndrome with constipation and for relief of constipation in cystic fibrosis.

* Terevalefim is a small molecule which mimics the activity of hepatocyte growth factor (HGF). Through its actions, it activates the c-Met cascade, exhibits c-Met dependence and c-Met receptor activation. As it is able to activate repair pathways, it has been tested in clinical trials for acute kidney injury and in delayed graft function. Recent studies suggest that hepatocyte growth factor (HGF), a pleiotropic cytokine, has multiple activities including promoting elastin synthesis, anti-apoptosis, suppressing inflammation, inducing angiogenesis and proliferation of lung epithelial and endothelial cells, and ultimately, lung regeneration. HGF production in pulmonary fibroblasts of emphysema patients is impaired. Terevalefim has the potential to stimulate regenerative processes in the lung and thus reverse established emphysema. In hepatic fibrosis Terevalefim opposes the hepatic fibrogenic gene program. In preclinical models of liver fibrosis, Terevalefim is therapeutic, attenuating profibrotic gene and protein expression, accelerating collagen catabolism, and improving hepatic function. Terevalefim has oral bioavailability and oral efficacy, and data from pharmacokinetic/acute safety studies indicate that it is safe and has properties consistent with a drug-like compound.Terevalefim has the orphan drug status for renal failure. It is an anti-ischaemic, antifibrotic, used in heart failure, urologic and vascular disorders. Highest development phases, Phase III for Delayed graft function. Phase II for Acute kidney injury, Acute lung injury, Renal failure. Preclinical for Brain injuries. No development reported for Heart failure. Discontinued for Hepatic fibrosis, Myocardial infarction, Stroke.

* Tetrachlorodecaoxide (TCDO) is a chlorite-containing, immunomodulatory, macrophage-activating drug. Tetrachlorodecaoxide is used in the management of radiation cystitis, is effective in the treatment of diabetic foot ulcers, and is used in wound healing, where the mechanism of action is activation of the macrophage system, and increasing the partial pressure of oxygen in the wound. There is anecdotal  evidence  that  tetrachloro  decaoxide (TCDO) was  of  benefit  in the  treatment  of  varicella zoster. Direct application of TCDO has been used in the management of conditions such as impetigo contagiosa, decubital ulcer, chronic  leg ulcer, ulcers in wounds, burns, super infected skin  disease and  semi-malignant  skin tumour.  

* Tezacaftor, also known as VX-661, is CFTR modulator. VX-661 is potentially useful for treatment of cystic fibrosis disease. Cystic fibrosis (CF) is a genetic disease caused by defects in the CF transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel. The most common mutation, delta508CFTR, produces a protein that is misfolded and does not reach the cell membrane. VX-661 can correct trafficking of delta508CFTR and partially restore chloride channel activity. VX-661 is currently under Phase III clinical trial. VX-661 is a cystic fibrosis transmembrane conductance regulator modulator. VX-661 is currently under investigation for the treatment of cystic fibrosis. VX-661 has also shown promise in treating sarcoglycanopathies, Brody’s disease, cathecolaminergic polymorphic ventricular tachycardia, limb girdle muscular dystrophy, asthma, smoke induced chronic obstructive pulmonary disorder, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick’s disease, polyglutamine neurological disorders such as Huntington’s, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatombral pallidoluysian, and myotonic dystrophy, as well as spongifiorm encephalopathies, such as hereditary Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, Gerstrnarm-Straussler-Scheinker syndrome, chronic obstructive pulmonary disorder, dry-eye disease, or Sjogren’s disease, osteoporosis, osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham’s Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter’s Syndrome type III, Dent’s disease, hyperekplexia, epilepsy, lysosomal storage disease, Angelman syndrome, and primary ciliary dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus, and ciliary aplasia.

* Tolimidone (CP-26154; MLR-1023) is a compound which was found to stimulate secretion of gastric mucosa. Tolimidone is also a novel, clinical stage drug candidate for the treatment of Type 2 Diabetes and Nonalcoholic Steatohepatis (NASH). Tolimidone improves glycemic control by selectively activating the enzyme lyn kinase, which has been shown to modulate the insulin-signaling pathway. Tolimidone is the first described specific and direct activator of Lyn kinase that elicits glycemic control activity through potentiation of insulin activity. Lyn kinase is an enzyme that modulates insulin sensitivity and dyslipidemia. Lyn kinase may also play a role in promoting liver regeneration and hepatocyte preservation. Tolimidone does not activate the PPAR pathway. Tolimidone has demonstrated improvement in multiple components of NASH in a comprehensive pre-clinical model of NASH: Reduction in NAS score, Decrease in liver weight, Reduction in adiposity, Decrease in insulin resistance. Adhera is developing MLR-1023 (tolimidone) as a new drug for Type I diabetes with a focus on C-peptide positive patients.

* Tropisetron hydrochloride is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug has also been approved for the prophylaxis and treatment of post-operative nausea and vomiting. 5-HT3 receptors are excitatory ligand-gated cation channel receptors that can be found in the presynaptic vagal afferents, the area postrema and the gastrointestinal tract. Stimulation of these receptors seems to be important in the emetic response and the gag reflex. It has also been shown that tropisetron shows agonistic effects on the 7 nicotinic acetylcholine receptor. This receptor is associated with auditory sensory gating, a neural mechanism believed to have important roles in information processing and cognition, both diminished in people with schizophrenia. Tropisetron acts as both a selective 5-HT3 receptor antagonist and alpha7-nicotinic receptor agonist. Tropisetron is a well-tolerated drug with few side effects. Headache, constipation, and dizziness are the most commonly reported side effects associated with its use. Hypotension, transient liver enzyme elevation, immune hypersensitivity syndromes and extrapyramidal side effects have also been associated with its use on at least one occasion.There have been no significant drug interactions reported with this drug’s use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system. Tropisetron improved the treatment of tendinopathies considerably, with the effect being comparable to the topical application of local anaesthetics combined with depot corticosteroids. Tropisetron as a treatment for trigger points in myofascial pain syndrome also brought about rapid and prolonged relief in the majority of cases. The analgesic effect was far superior to the action of local anaesthetics. 5-HT3 receptor antagonists from various sources have been published for a wide variety of uses, for example for the treatment of visceral pain, migraine, vascular and cluster headache, trigeminal neuralgia, arrhythmia, serotonin-induced gastro-intestinal disorders, including emesis induced by anti-cancer agents, anxiety, stress-related psychiatric disorders, depression, cognitive disorders, social withdrawal, panic attacks, agoraphobia, lung embolism, rhinitis or serotonin-induced nasal disorders, fibromyalgia and local treatment of pain caused by various non-inflammatory or inflammatory conditions. Furthermore, 5-HT3 receptor antagonists are useful for the treatment of diseases caused or influenced by activation of thrombocytes. Thrombocytes play a central role in blood coagulation (clotting) and are therefore of high importance in the pathogenesis of cardiac infarction and stroke,  also in thrombosis of the veins and inflammatory conditions in the development of atherosclerosis.

* VPS35  Factor or vacuolar protein sorting ortholog 35 is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's Disease (PD) and Alzheimer's Disease (AD). There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. VPS35 levels peak at postnatal days 10-15 and then decline to a low, stable level throughout adulthood. Various mechanisms in PD are thought to contribute to the generation of reactive oxygen species ROS, including the metabolism of dopamine, calcium homeostasis imbalances, dysfunction in PD-causing gene products (e.g. DJ-1, PINK1, parkin or alpha-synuclein), aging as well as mitochondrial dysfunctions. VPS35 represents an important regulator of crucial pathways involved in PD pathogenesis controlling the accumulation and clearance of alpha-syn, mitochondrial dynamics and synaptic functions. VPS35 can clear tau proteins, a hallmark of Alzheimer’s disease, in the brain. In progressive supra-nuclear palsy PSP and Picks’ disease, tau is the only protein to form deposits in the brain, unlike Alzheimer’s disease, where both tau and beta-amyloid accumulate.

* WAY-315193 is a norepinephrine reuptake inhibitor, used for multiple indications including major depressive disorder, attention deficit hyperactivity disorder, chronic fatigue syndrome, nervous system disorders, sexual dysfunction, gastrointestinal and genitourinary disorders, stress urinary incontinence, gynecological disorders, vasomotor symptoms, and pain disorders such as diabetic neuropathy and fibromyalgia.