Coliopan a hyoscyarnine derivative originally developed by Eisai Research Laboratories is a parasympatbolytic agent. Coliopan possesses antispasmodic action on smooth muscle, acts to inhibit gastric secretion and has anti-ulcer effects. Coliopan is also reported lo act to normalize gastric emptying and to increase blood flow in gastric mucosa. Double blind controlled clinical trials have proven its effectiveness in relieving spasmodic pain associated with gastrointestinal disorders and peptic ulcers.
Pharmacology: Pharmacodynamics: Inhibition of gastrointestinal motility:
Butropium bromide reduces the tone and motility of parasympathetically innervated smooth muscle of the gastrointestinal tract by acting on the acethylcholine receptors as the nerve endings. Experiments on the isolated jejunum of rabbits, the isolated proximal colon of mice, and the isolated gallbladder of guinea pigs indicate that butropium bromide is more effective than atropine in inhibiting the motility of smooth muscle. In experiments with the isolated ileum of mice, Butropium bromide exhibited a papaverine like action. In clinical studies, Butropium administered into the duodenum decreased the intestinal motility within 15 minutes after administration.
Butropium bromide administered orally to rats decreased incidence of pyloric ligation-induces ulceration. Specific experimental observations from these experiments include an increase in intragastric pH, a reduction in the volume of gastric juice, a lower total acidity and suppression of pepsin secretion. In rats pretreated orally with Butropium bromide is considered to be as potent as that of atropine.
Inhibition of Gastric Secretion:
The oral administration of Coliopan was found to significantly inhibit gastric secretion in healthy men.
Normalization of Gastric Secretion:
Clinical studies have shown that Butropium bromide normalizes delayed or accelerated gastric emptying in patients with digestive ulcers. In general, high doses of Butropium bromide normalize gastric emptying by accelerating that which is delayed and delaying that which is accelerated.
Clinical Effects: Double-blind controlled studies have shown Coliopan to be effective and symptomatic relief of spasmodic pain. Relief of abdominal pain began in an average of 39 minutes after oral administration of 10mg Coliopan, and this effect was sustained for 24 minutes.
Adverse Reactions: In a survey 2,057 patients treated orally with Coliopan, adverse effects were reported for 189 patients (9.19%). The most common untoward effects were dryness of the mouth (121 patients: 5.88%), constipation (19 patients: 0.92%), impaired ocular accomodation (10 patients: 0.49%), tachycardia (10 patients: 0.49%) and urinary retention (10 patients: 0.49%).
Animal Studies: Absorption, Distribution and Excretion:
Oral doses of 3mg/kg of 3
H-labelled butoxybenzyl hyoscyamine bromide were administered to rats and guinea pigs. Peak plasma concentration of 0.012g/mL and 0.013g/mL, respectively, occured 1 hour after administration and gradually declined there after. Tissue distributor in animal models showed that radioactivity was high in the gut and stomach, and secondly in the liver and kidneys. No radioactivity was detected in the brain. Compared with guinea pigs, radioactivity in the pancreas and adrenal glands was markedly higher in rats.
The radioactivity in the tissues of rats and guinea pigs disappeared within 3 to 11 days after administration. Approximately 1% of the administered radioactivity was excreted in the urine and 98 to 99% was excreted during the first 5 days after oral administration.
Acute Toxicity (LD 30mg/kg)
: (See table).
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Butropium bromide was administered orally in doses of 63, 125, 250 and 500mg/kg/day to male and female rats for 5 consecutive weeks. Butropium bromide was well tolerated and no abnormal findings were noted in body weight, organ weights, blood and urinary tests and pathological examination. Mydriasis and sluggish movements, however, were observed at the doses greater than 125mg/kg/day.
Male and female rats given 6, 125, 100 and 400 mg/kg/day of Butropium bromide orally for 25 consecutive weeks showed no sign of toxicity, with the exception that mydriasis and sluggish movements were observed in some animals receiving a daily dose of 100mg/kg.
Butropium bromide, administered orally in doses of 60, 240 and 500mg/kg/day to pregnant mice and rats during organogenesis, caused a decrease in weight gain or death in some mice receiving the higher doses of 240 or 500mg/kg/day dose, and death in some rats at highest dose level. Neither an increase in fetal resorption nor dysmorphologic effects were induced, although a decrease in the mean fetal weight and retarded ossification were noted in the live fetuses form the late stage of gestation. Postnatal growth was not effected.