Developed by Solvay Pharmaceuticals, cilansetron is a 5-HT3 antagonist indicated for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS). 5-HT(3) receptor antagonists such as cilansetron have been shown to affect gastrointestinal motility. With Phase III registration trials on cilansetron completed, Solvay filed for regulatory approval in Europe and the US in 2004. To ensure that cilansetron is only prescribed to patients with diarrhoea-predominant IBS, Solvay’s regulatory submission included an extensive appropriate use plan. In April 2005, however, Solvay received a “non-approvable” letter from the FDA and a request for additional data to support product registration in the US. Towards the end of 2005, the company announced that it had suspended registration of cilansetron in the US. Meanwhile, discussions continue with the UK’s MHRA about European marketing approval for cilansetron. In 2005, the MHRA also declined to approve cilansetron. Both the agencies requested additional clinical data to further assess the risk-benefit ratio of the compound. Despite the drug being rejected for approval, Solvay believed in the product and felt that the clinical data demonstrated important benefits for men and women suffering from diarrhoea-predominant IBS. However, taking into account the amount of clinical work requested and other business considerations, the company decided to end the development and regulatory activities for cilansetron. The clinical efficacy and safety of cilansetron was established in a series of clinical trials, including a large-scale international Phase III programme involving over 4,000 patients. Overall, results from these trials showed that cilansetron is significantly more effective than placebo in male and female patients with diarrhoea-predominant IBS, an important finding given the traditionally high placebo response rates seen in clinical trials of IBS drugs. Overall responder rates (adequate relief in at least 50% of weekly responses) for patients treated with cilansetron ranged from 52% to 61% compared with 37% to 46% for placebo recipients. The most common side effect of cilansetron is constipation, which is seen in 3-12% of subjects at 6 months. Ischemic colitis, a side effect associated with previous drugs of this class, has been seen in eight subjects (six women and two men) to date. All of these ischemic colitis events have been self-limited and did not require surgery. Because of its high degree of efficacy, the fact that it was well tolerated by the overwhelming majority of patients and that it showed efficacy in both genders, cilansetron represented a major advance in the treatment of irritable bowel syndrome with diarrhea predominance.

Aceclidine is a parasympathomimetic agent used in the treatment of open-angle glaucoma as topical eye drop solution. It is as a muscarinic acetylcholine receptor agonist with weak anticholinesterase activity. Acting directly on the motor end-plate (cholinergic nerve endings) it decreases intraocular pressure and mediates the contraction of iris muscle. Aceclidine increased outflow facility in human eyes in vitro by a direct stimulation of the outflow tissues in the absence of an intact ciliary muscle. This effect was biphasic, occurring at concentrations of 10 uM and lower with no effect at higher concentrations. Passed numerous clinical trials in Russia, France, Italy and other countries and was widely used in Europe but never been in clinical use in USA.

Acecainide (N-acetylprocainamide), the N-acetylated metabolite of procainamide, is a Class III antiarrhythmic agent. Acecainide exerts cardiac anticholinergic effect. It elicits smooth muscle relaxation mainly through the activation of plasma membrane K+ channels. Acecainide markedly reduced premature ventricular beats and prevented induction of ventricular tachycardia. Acecainide appears to offer advantages over procainamide, particularly with respect to the reduced formation of antinuclear antibodies. Acecainide development has been discontinued.

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

trans-Clopenthixol is a typical antipsychotic drug of the thioxanthene class. Clopenthixol is composed of a mixture of cis-clopenthixol and trans-clopenthixol. The two isomers do not differ in several pharmacological properties, for instance, anti-noradrenergic effect. However, cis-clopenthixol possesses anti-dopaminergic effects, while trans-Clopenthixol not. Cis-Clopenthixol indicated for the management of the manifestations of schizophrenia and other mental illnesses with disturbances in thinking, emotional reactions and behavior.

QUININE PHOSPHATE, a salt of quinine, was formerly used for the treatment of malaria.

Phloroglucinol is an organic compound that is used in the synthesis of pharmaceuticals and explosives. Phloroglucinol is a phenol derivative with antispasmodic properties that is used primarily as a laboratory reagent. The mechanism of action is most likely based on the direct inhibition of the voltage-dependent calcium channels of smooth muscle; however, the modulation of prostaglandin or nitric oxide release has also been suggested. Although it has long been used in clinical practice as an antispasmodic for painful urogenital and gastrointestinal conditions, in an early study on anesthetized rats, phloroglucinol was found to be inactive toward the contraction of the duodenum, ileum and colon. Similarly, in anesthetized dogs, phloroglucinol plus trimethyl-phloroglucinol failed to antagonize acetylcholine-induced contraction of the colon. In parallel with animal studies, phloroglucinol plus trimethyl-phloroglucinol had no clear effects in humans on ascending and sigmoid colon hypermotility evoked by neostigmine. However in Irritable bowel syndrome (IBS) patients iv phloroglucinol effectively reduced postprandial rectosigmoid motility increases after a test meal, compared to placebo. In another study of IBS patients, phloroglucinol inhibited phasic contractions provoked by intrarectally injected glycerol, but it did not modify colonic tone. In an open-label study of 100 IBS patients selected according to the Rome II criteria, po 50 mg phloroglucinol was administered three times daily for two months. The 68 patients who completed the study reported significant improvement in abdominal pain, frequency of stools per day, urgency, passage of mucus per the rectum, sense of incomplete defecation and bloating. Nevertheless, straining was unchanged. Further, a multicenter, randomized, double-blind, placebo-controlled trial examined the effects of phloroglucinol/trimethylphloroglucinol (62.2 mg P plus 80 mg TMP three times daily) or placebo for 7 d in 307 IBS patients diagnosed using the Rome II criteria. The relative decrease in pain intensity and the responder rate were significantly higher in the P/TMP-treated group, compared to the placebo-treated group. Further, the treatment effect persisted up to the 7th day in a higher percentage of patients treated with P/TMP than in those treated with placebo.

Oxantel is a narrow-spectrum anthelmintic effective against whipworms in dogs and cats. It is ineffective against other roundworms, flukes, tapeworms or external parasites. Oxantel acts on the nervous system of the worms as inhibitors of acetylcholinesterase. Oxantel, a cholinergic anthelmintic and fumarate reductase inhibitor, significantly inhibited biofilm formation by P. gingivalis and disrupted established biofilms at concentrations below its MIC against planktonic cells. Oxantel was more effective against P. gingivalis in biofilm than metronidazole, a commonly used antibiotic for periodontitis. When oxantel was administrated to human beings for the treatment of trichuriasis, no drug reaction or side effects were reported, and the results of hematologic, biochemical and urinary examinations didn’t reveal any significant drug-related changes.

Garenoxacin is an antibacterial agent active against a range of aerobic Gram-positive and Gram-negative bacteria. It exerts its action by inhibiting bacterial DNA gyrase and topoisomerase IV. The drug was withdrawn from the market in Europe and was never approved in the USA. Garenoxacin is still marketed in Japan under the name Geninax.

Bekanamycin is an aminoglycoside and is a congener of kanamycin. It is given topically as the sulfate for the treatment of eye infections. It is reported to be more toxic than kanamycin A. Antibiotic complex produced by Streptomyces kanamyceticus Okami & Umezawa from Japanese soil. There are no known interactions with other drugs.