Istradefylline is a first-in-class adenosine A2A receptor antagonist antiparkinsonian agent and has been marketed as the brand name NOURIAST® in Japan since May 30, 2013. NOURIAST is indicated for the improvement of wearing-off phenomena in patients with Parkinson’s disease on concomitant treatment with levodopa-containing products.

Alpelisib (BYL719) is a PI3Kα-selective inhibitor. PI3K-AKT-mTOR pathway is frequently activated in cancer, therefore investigational PI3K inhibitor alpelisib is considered to be effective as an anticancer agent and has been in clinical development by Novartis. Alpelisib have demonstrated activity in preclinical models of solid tumors and had favorable tolerability profiles, with the most common adverse events consistent with “on-target” inhibition of PI3K in early clinical studies. There are ongoing clinical trials of alpelisib in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme. Combination therapy with other chemo therapeutics may be preferable.

Uridine triacetate (formally PN401) is an acetylated prodrug of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation. Uridine triacetate under VISTOGARD trade name is a uridine replacement agent approved for the emergency treatment of fluorouracil or capecitabine overdose (regardless of the presence of symptoms) or early-onset severe or life-threatening cardiac or central nervous system (CNS) toxicity and/or early-onset unusually severe adverse reactions (eg, gastrointestinal [GI] toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration in adult and pediatric patients. Uridine competitively inhibits cell damage and cell death caused by fluorouracil. Fluorouracil is a cytotoxic antimetabolite that interferes with nucleic acid metabolism in normal and cancer cells. Cells anabolize fluorouracil to the cytotoxic intermediates 5-fluoro-2’-deoxyuridine-5’- monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP inhibits thymidylate synthase, blocking thymidine synthesis. Thymidine is required for DNA replication and repair. Uridine is not found in DNA. The second source of fluorouracil cytotoxicity is the incorporation of its metabolite, FUTP, into RNA. This incorporation of FUTP into RNA is proportional to systemic fluorouracil exposure. Excess circulating uridine derived from VISTOGARD is converted into uridine triphosphate (UTP), which competes with FUTP for incorporation into RNA. Uridine triacetate is also approved for the treatment of hereditary orotic aciduria under XURIDEN trade name. Uridine triacetate provides uridine in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis.

Regadenoson (Lexiscan), a low affinity agonist of the A2A adenosine receptor, increases coronary blood flow (CBF) and mimics the increase in CBF caused by exercise. Myocardial uptake of the radiopharmaceutical is proportional to CBF creating the contrast required to identify stenotic coronary arteries. It is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress. The most common adverse reactions to Lexiscan are dyspnea, headache, flushing, chest discomfort, dizziness, angina pectoris, chest pain, and nausea. Methylxanthines, e.g., caffeine and theophylline, may interfere with the activity of Lexiscan. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to Lexiscan.

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. Pemetrexed, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and and to a lesser extent aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Glyburide, a second-generation sulfonylurea antidiabetic agent, lowers blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonyl-urea hypoglycemic drugs. The combination of glibenclamide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Glyburide is twice as potent as the related second-generation agent glipizide. Sulfonylureas such as glyburide bind to ATP-sensitive potassium channels on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. Glyburide is indicated as an adjunct to diet to lower the blood glucose in patients with NIDDM whose hyperglycemia cannot be satisfactorily controlled by diet alone. Glyburide is available as a generic, is manufactured by many pharmaceutical companies and is sold in doses of 1.25, 2.5 and 5 mg under many brand names including Gliben-J, Daonil, Diabeta, Euglucon, Gilemal, Glidanil, Glybovin, Glynase, Maninil, Micronase and Semi-Daonil. It is also available in a fixed-dose combination drug with metformin that is sold under various trade names, e.g. Bagomet Plus, Benimet, Glibomet, Gluconorm, Glucored, Glucovance, Metglib and many others.

Since its discovery as component of the tea leaf by Albert Kossel in 1888, the history of theophylline (CAS 58-55-9) has been a long and successful one. At the turn of the century, theophylline became less expensive due to chemical synthesis and was primarily used as diuretic in subsequent years. It was Samuel Hirsch who discovered the bronchospasmolytic effect of theophylline in 1992, however, despite this pioneering discovery theophylline continued to be used primarily as diuretic and cardiac remedy. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase(PDE)3 and PDE4, but the anti-inflammatory effect may be due to histone deacetylase (HDAC) activation, resulting in switching off of activated inflammatory genes. Theophylline is indicated for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Caffeine is a methylxanthine alkaloid found in the seeds, nuts, or leaves of a number of plants native to South America and East Asia that is structurally related to adenosine and acts primarily as an adenosine receptor antagonist with psychotropic and anti-inflammatory activities. Upon ingestion, caffeine binds to adenosine receptors in the central nervous system (CNS), which inhibits adenosine binding. This inhibits the adenosine-mediated downregulation of CNS activity; thus, stimulating the activity of the medullary, vagal, vasomotor, and respiratory centers in the brain. The anti-inflammatory effects of caffeine are due the nonselective competitive inhibition of phosphodiesterases. Caffeine is used by mouth or rectally in combination with painkillers (such as aspirin and acetaminophen) and a chemical called ergotamine for treating migraineheadaches. It is also used with painkillers for simple headaches and preventing and treating headaches after epidural anesthesia. Caffeine creams are applied to the skin to reduce redness and itching in dermatitis. Healthcare providers sometimes give caffeine intravenously (by IV) for headache after epidural anesthesia, breathing problems in newborns, and to increase urine flow. In foods, caffeine is used as an ingredient in soft drinks, energy drinks, and other beverages.

There is no available information related any biological and pharmaceutical application of ammonium tetrachlorozincate.

Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of heart failure. Neladenoson bialanate maintains the cardioprotective effects of adenosine without the undesired side effects of a full agonist. Of particular importance in this clinical development is the potential influence of concomitant use of β-blockers as they have the potential to increase the risk of AV conduction abnormalities with A1R agonist treatment. Two small phase 2a pilot studies evaluating the short-term safety of neladenoson bialanate in patients with HFrEF pretreated with β-blockers have recently completed, and the results are pending (ClinicalTrials.gov identifiers: NCT02040233 and NCT01945606). In a small phase 1 trial in healthy volunteers pretreated with the β-blocker metoprolol succinate, a single 50 mg oral dose of neladenoson bialanate administered together with metaprolol succinate was found to be well tolerated. Notably, no higher degree AV block, prolongation of the PR interval, or relevant decreases in heart rate or systemic blood pressure were observed.