Nebentan (YM598) is an orally active synthetic substituted phenylethenesulfonamide. As a selective endothelin A receptor antagonist, YM598 inhibits endothelin-mediated mechanisms involved in tumor cell growth and progression, angiogenesis, and metastasis. The inhibitory dissociation constant value of YM598 was 0.772 nM for native human ETA receptors, and 143 nM for native human ETB subtypes. The calculated selectivity ratio of YM598 for ETA versus ETB receptors was 222. In pithed rats, YM598 inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner, after both intravenous and oral administration. YM598 showed not only superior antagonistic activity and higher-selectivity for endothelin ET(A) receptor in vitro, but at least a 30-fold higher potency in vivo than bosentan.

Pilsicainide is marketed in Japan as (Sunrythm). Pilsicainide controls the cardiac conduction abnormalities and improves the symptoms of arrhythmia with the blocking action on Na channel. It is usually used to treat tachycardiac arrhythmia. Pilsicainide did not affect the resting membrane potential. Under the voltage-clamp condition, pilsicainide inhibited the transient outward current (Ito) that is more prominent in the atrium than in the ventricle in a concentration-dependent manner. However, in contrast to other class Ic agents, the inhibition to Ito by pilsicainide was observed only at much higher concentrations (IC50-300 uM) and did not affect the inactivation time-course of Ito. Moreover, the drug (10 uM) did not significantly affect the Ca2+, delayed rectifier K+, inward rectifying K+, acetylcholine-induced K+ or ATP-sensitive K+ currents. From these results pilsicainide could be differentiated as a pure Na+ channel blocker from other class Ic agents with diverse effects on membrane currents and should be recognized accordingly in clinical situations. A single oral dose of pilsicainide effectively restores normal sinus rhythm in patients with recent-onset atrial fibrillation and a healthy left ventricle. Long-term therapy with pilsicainide is successful in treating chronic atrial fibrillation

Otilonium is a musculotropic spasmolytic agent belonging to the family of quaternary ammonium derivatives and successfully used in the treatment of patients affected by Irritable bowel syndrome (IBS) due to its specific pharmacokinetic and pharmacodynamic properties. The positive polarity of the head of the Otilonium molecule determines the main pharmacokinetic property of this drug: a minimal systemic absorption and the consequently high safety profile. Studies on animal models revealed a specific Otilonium accumulation in colonic circular muscle at therapeutic µm concentrations, while its plasma levels were 1000 times lower, together with a poor penetration of the drug in the central nervous system. Consistently, after oral administration to healthy volunteers, the Otilonium plasmatic concentration was very low, less than 1% of the drug was eliminated by urine, and 97% was eliminated by feces. Recent clinical studies showed comparable safety and tolerability for Otilonium and placebo. Otilonium was shown to inhibit the main patterns of human sigmoid motility in vitro, including: the tone of smooth muscle cells (SMCs); the rhythmic phasic contractions induced by the interstitial cells of Cajal; and the strong contractions induced by stimulation of enteric motor neurons mainly by blocking the calcium influx through L-type calcium channels on SMCs. Recent in vitro studies using cultured human colonic SMCs to further assess the musculotropic spasmolytic properties of Otilonium confirmed that this drug causes smooth muscle relaxation through the inhibition of voltage-gated calcium channels (L-type > T-type) and the inhibition of muscarinic and tachykinergic effects.

Flumethrin is a type II synthetic pyrethroid insecticide used externally in veterinary medicine against parasitic insects and ticks on cattle, sheep, goats, horses, and dogs, and the treatment of parasitic mites in honeybee colonies. In veterinary medicine, it is applied topically to sheep, cattle, and goats, as a 1% w/v pour-on or as a plunge dip for the control of ticks, lice, and mites. The pour-on is applied at a rate of 2 mg/kg BW. The plunge dip is diluted at a rate of 1-litre product in 900 liters water. For control of scab, the sheep must be dipped for one minute. Plastic strips impregnated with 3.6 mg Flumethrin are hung in beehives for the diagnosis and treatment of varroatosis in honeybees. Four strips per hive are used for mature colonies and 2 per hive for immature colonies. Flumethrin causes a long-lasting prolongation of the normally transient increase in sodium permeability of the nerve membrane during excitation, resulting in long-lasting trains of repetitive firing. The cyano group on the phenoxy-fluorobenzyl alcohol moiety is considered to be responsible for the long-lasting prolongation of sodium permeability. The type II pyrethroids produce a distinct poisoning syndrome which is characterized by choreoathetosis (sinuous writhing of the whole body) and salvation. Flumethrin on the membrane of nerve cells blocking the closure of the ion gates of the sodium channel during re-polarization. This strongly disrupts the transmission of nervous impulses, causing spontaneous depolarization of the membranes or repetitive discharges. At low concentrations insects and other arthropods suffer from hyperactivity. At high concentrations, they are paralyzed and die. Sensory and nervous cells are particularly sensitive. Flumethrin is a complex mixture of stereoisomers. The molecule contains three asymmetric carbon atoms, there is cis-trans isomerism at the cyclopropane ring and cis-trans isomerism at the carbon-carbon double bond of the alkene. So there are 16 different isomers. Commercial Flumethrin typically contains 92% of the trans isomers on the cyclopropane ring and the cis-configuration at the olefinic carbon-carbon double bond and 8% of the isomer with cis geometry on the cyclopropane ring and the cis-configuration at the olefinic carbon-carbon double bond.

Methylephedrine is one of the ephedra alkaloids that is found in varying amounts in different species of the plant genus Ephedra. Methylephedrine is a popular antitussive, bronchodilator, analgesic, antipyretic, and widely used mixed with other drugs in preparations for treatment of the common cold. N-Methylephedrine, its salts, optical isomers, and salts of optical isomers are in FDA list of Exempt chemical mixtures.

Lappaconitine is an alkaloid isolated from the root of Aconltitum sinomantanum Nakai. It has a strong analgesic activity that does not involve the opioid receptor. It was shown to have class-I antiarrhythmic action and irreversibly blocks cloned human heart (hH1) channels by binding to the site 2 receptor.

Ginsenoside Rg3 (Rg3) is one of the most effective steroidal saponins extracted from Ginseng, a common Traditional Chinese medicine (TCM) herb which tonifies Qi in TCM theory and inhibits tumors. Rg3 suppresses tumor growth and tumor angiogenesis. For its significant antitumor effects, Rg3 has been used in clinical trials in combination with chemotherapy regimens. 20(S) and 20(R) forms of ginsenosides are stereoisomers of each other that depend on the orientation of the C-20 hydroxyl in ginsenosides. In general, the 20(S) compounds have been shown to possess better anti-proliferative effects than their 20(R) counterparts whereas 20(R) compounds such as 20(R)-Rg3 have been shown to inhibit cancer cell invasion and metastasis. Ginsenoside Rg3 regulates voltage-gated ion channels such as Ca(2+), K(+), and Na(+) channels, and ligand-gated ion channels such as GABAA, 5-HT3, nicotinic acetylcholine, and N-methyl-D-aspartate (NMDA) receptors through interactions with various sites including channel blocker binding sites, toxin-binding sites, channel gating regions, and allosteric channel regulator binding sites when the respective ion channels or receptors are stimulated with depolarization or ligand treatment. Shenyi capsule which contains ginsenoside Rg3 as the main ingredient has been approved by China Food and Drug Administration (CFDA) to be used clinically for cancer treatment.

Benidipine is an orally triple L-, T-, and N-type calcium channel blocker for the treatment of hypertension and angina pectoris synthesized and developed by Kyowa Hakko Kogyo Co., Ltd. Benidipine, approved in Japan in November 1991, has become one of the three best selling CCBs and is highly useful as a potent, long-lasting antihypertensive and antianginal agent.

Bucindolol is a third-generation, non-selective β-adrenergic receptor blocker, that acts on both β-1 and β-2 receptors. Bucindolol’s additional α-1 antagonistic activity contributes to its mild vasodilator effect. It was rejected by the FDA for the heart failure, because of the unreviewed submissions deal with comparative effectiveness, clinical pharmacology, some aspects of pharmacogenetic data, and toxicology/metabolism. In addition, bucindolol is in the phase II of clinical trial for the treatment of atrial fibrillation.

Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, is an anti-anginal drug. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. Perhexiline is used for reducing the frequency of moderate to severe attacks of angina pectoris due to coronary artery disease in patients who have not responded to other conventional therapy or in whom such therapy may be contraindicated. Heart Metabolics Limited is developing perhexiline for the treatment of hypertrophic cardiomyopathy