Comparative studies of the effects of some antimuscarinic agents on gastric damage and pupillary reflex in the rat.

The effects of some antimuscarinic compounds on oxotremorine-induced gastric damage, the pupil size and the pupillary light reflex have been studied in the rat. Unlike atropine, propantheline and methylscopolamine, pirenzepine is effective in preventing gastric erosions at doses much lower than those that affect pupillary reflex.

Effects of cimetropium bromide on gastrointestinal transit time in patients with irritable bowel syndrome.

Cimetropium bromide is a new antimuscarinic compound with strong antispasmodic activity. The aim of this study was to evaluate the effects of oral cimetropium bromide on total gut transit time in patients with irritable bowel syndrome. Forty patients, divided according to their initial total gastrointestinal transit times and presenting symptoms, were treated with cimetropium bromide 50 mg t.d.s. or placebo for 1 month according to a double-blind, parallel group design. Before and after treatment all subjects ingested 24 radio-opaque markers. The total intestinal transit time was determined by evaluating the rate of disappearance of markers from plain X-ray films of the abdomen taken every 24 h for 4 days. Pain and bowel habits were also monitored. Seven patients did not complete the study. Cimetropium bromide significantly (P less than 0.01) shortened the whole gut transit time in patients with prolonged transit time (80.8 +/- 4.0 h before vs 60.8 +/- 6.7 h after treatment) and improved the global clinical condition significantly compared with placebo (P = 0.029). In patients with a short total intestinal transit time, cimetropium bromide had no effect on whole gut transit time and did not significantly improve symptoms. The results of this study indicate that oral cimetropium bromide is effective both objectively and subjectively in a subgroup of irritable bowel syndrome patients with constipation.

Feprazone: absence of hemolytic effects in glucose-6-phosphate dehydrogenase-deficient subjects.

Some drugs, including nonsteroidal antiinflammatory compounds, can be hemolytic in glucose-6-phosphate dehydrogenase-deficient patients. We have studied the potential hemolytic activity of feprazone, a nonsteroidal antiinflammatory compound in vitro and in vivo. Agents that may be hemolytic for glucose-6-phosphate dehydrogenase-deficient erythrocytes will stimulate the hexose monophosphate shunt in normal erythrocytes. Eleven normal subjects were treated with feprazone and their erythrocytes were incubated in their own sera (containing active feprazone metabolites) and [1-14C]-glucose. Because no statistically significant increase in 14CO2 evolution was observed, 15 pediatric male patients with glucose-6-phosphate dehydrogenase deficiency who required antiinflammatory treatment were treated with feprazone. No hemolytic crises and no statistically significant changes of hematologic tests were observed.

Comparison of the gastric cytoprotective properties of atropine, ranitidine and PGE2 in rats.

In view of the controversy as to whether antisecretory agents such as H2 antagonists and antimuscarinics might be cytoprotective like the PGs, the oral activity of atropine, ranitidine and PGE2 against absolute ethanol-induced lesions was evaluated in rats. The results showed that atropine and PGE2, but not ranitidine, were effective in preventing absolute ethanol-induced gastric damage. The effects were related to the doses of the ulcerogenic agent and of the cytoprotective compound. The anti-ulcer activity of atropine is considered to be an expression of cytoprotection, since the pathogenesis of ethanol-induced gastric damage was independent of gastric pH and atropine, like PGE2, does not affect basal acid secretion at a fully cytoprotective dose. Some studies were undertaken to elucidate the mechanism of gastric cytoprotection by atropine. The possibility that the anti-muscarinic agent might work as a mild irritant was ruled out since, like PGE2, the agent was still effective in PG-deficient rats. The evidence that neostigmine markedly aggravated gastric damage caused by low doses of absolute ethanol and that atropine completely prevented this damage postulates mechanisms involving specific muscarinic receptor interactions.

A new criterion for selection of pharmacokinetic multiexponential equations.

In linear pharmacokinetics, the time course of the plasma concentration of a drug, Ct, is expressed by the sum of exponential terms, (formula; see text) This article proposes a new statistical criterion for discriminating between alternate polyexponential models. According to this new criterion, the model that best interprets a set of experimental data points is that which minimizes the area between the approximate confidence limits of Ct.

Discontinuous oral absorption of cimetropium bromide, a new antispasmodic drug.

The pharmacokinetic profiles of cimetropium bromide, after either intravenous injection of 10 mg or oral ingestion of 200 mg, were determined in eight healthy volunteers. After intravenous administration, the plasma levels and urinary excretion indicated that the drug is distributed and eliminated at a rapid rate (terminal half-life, 50 +/- 8 min) and that urinary excretion is not the exclusive route of elimination (46 +/- 2%) of the administered dose). After oral administration, a low percentage of the drug is absorbed (1-4% of the administered dose), however, the amount is sufficient for therapeutic effect. The absorption is discontinuous, with two distinct phases, and ends abruptly during the second phase.

Luminal bicarbonate outflow in chronic antral erosions is suppressed by pirenzepine.

The effects of pirenzepine and ranitidine on luminal HCO3- outflow occurring in subjects with chronic antral erosions have been investigated in a double-blind study. Thirty outpatients with chronic erosions of the gastric antrum were randomly treated for 4 weeks with either pirenzepine 50 mg b.i.d. or ranitidine 150 mg b.i.d. Endoscopic appearance and intragastric bicarbonate content were assessed before and after treatment. At endoscopic follow-up pirenzepine was found to be significantly more effective than ranitidine in promoting disappearance of antral erosions. In the ranitidine group the abnormally high intraluminal HCO3 content was reduced only in healed subjects, while no changes were observed in patients with persisting erosions. In contrast pirenzepine induced normalization of intragastric bicarbonate both in healed and in unhealed patients. The results suggest that pirenzepine suppresses luminal HCO3 leakage by functionally strengthening mucosal defences even before anatomical repair is obtained.

Comparison of pirenzepine and carbenoxolone in the treatment of chronic gastric ulcer. A double-blind endoscopic trial.

The purpose of the present study was to compare the effectiveness of pirenzepine and carbenoxolone in accelerating the healing of chronic gastric ulcer. Sixty-six out-patients with endoscopically proven gastric ulcer, without major systemic diseases, were admitted to the study. Patients were randomly allocated to either pirenzepine, 50 mg three times a day for 6 weeks, or carbenoxolone, 100 mg three times a day for one week followed by 50 mg three times a day for the remaining five weeks. At 6 weeks, the ulcers had healed in 20 out of 34 patients (59%) treated with pirenzepine, and in 15 out of 29 patients (52%) treated with carbenoxolone. Symptomatic improvement was similar with both drugs. Some major side effects (oedema, hypokalaemia and hypertension) occurred in approximately 30% of patients treated with carbenoxolone; of those receiving pirenzepine 25% complained of minor symptoms (e.g. dry mouth, headache, tachycardia). It is concluded that pirenzepine and carbenoxolone are of similar, but rather limited, efficacy in speeding the healing of chronic gastric ulcer, but show important differences with respect to tolerability.

Possibility of interaction among antibiotics and mucolytics in children.

A controlled clinical trial in children with acute infections of the lower respiratory tract was carried out to see whether or not treatment with ambroxol could bring about faster and better results. One hundred twenty children with acute lower respiratory tract infections were all given antibiotics plus, at random, either ambroxol (1.5-2.0 mg/kg body weight orally) or a placebo. The duration of the trial was ten days. All the patients in both groups were cured clinically. However, remission of the cough, of the chest pathological signs, as well as the improvement of the lung radiographical pictures were significantly more rapid in children treated with ambroxol than in those who received the antibiotic alone. Ambroxol was tolerated perfectly by all the children.

Oral beta 2-selective adrenergic bronchodilators.

Oral beta 2-agonists (carbuterol, pirbuterol, procaterol, bitolterol, clenbuterol) are drugs widely used as bronchodilators. The efficacy and selectivity of bronchodilators drugs depend on their intrinsic pharmacological properties and on the route of administration. The characteristics of the oral route are easy usage, precise dosage and assured effects. Consequently, disadvantages (delayed onset of action, more frequent side-effects) and the indications, (patients with severe chronic airways obstruction, nocturnal asthmatic attacks, and children and elderly subjects) are clearly evident. The most recent beta 2-agonists have an efficient and prolonged bronchodilating action with well-known side-effects. In order to control drug efficiency in a large population and identify type and degree of adverse reactions, a post-marketing surveillance study was programmed for clenbuterol. The results available confirms that long-term treatment with oral clenbuterol is an effective and safe therapeutical approach. During long-term treatment, tachyphylaxis (a diminished responsiveness) develops. This complex biological phenomenon can be studied, in several ways i.e. functional response of target-organ, appropriate biochemical-metabolical indices, and functional evaluation of the cellular beta-receptors in vitro. Also in the light of evaluation of serum levels of cyclic nucleotides (cyclic adenosine and guanosine monophosphates) it appears that the clinical importance of tachyphylaxis is mild and that chronic therapy with beta 2-agonists is safe and effective when used in selected patients.

Pirenzepine in duodenal ulcer. A six week, double-blind study.

Thirty-eight of forty patients satisfactorily concluded a double-blind, placebo-controlled trial to study the effects of pirenzepine (100 mg/day) on duodenal ulcers. After six weeks of treatment 14 of 18 patients (78%) in the pirenzepine-treated group and 7 of 20 patients (35%) in the placebo groups were healed. There was a statistically significant difference (P less than 0.05). The relief of day-time and night-time pain was significantly greater in the pirenzepine-treated group. Pirenzepine-treated patients consumed significantly fewer antacid tablets. The tolerability of pirenzepine was good. Pirenzepine (100 mg/day for six weeks) should be an effective and safe treatment for duodenal ulcers.

Pirenzepine in non-ulcer dyspepsia. A double-blind, placebo controlled trial.

Fifty patients (with non-ulcer dyspepsia) were admitted to a double-blind, placebo-controlled trial to study the effects of pirenzepine (100 mg/daily) on non-ulcer dyspepsia. Ten patients did not complete the trial. After 4 weeks of treatment, statistically significant improvement (P less than 0.001) was observed endoscopically in the pirenzepine group. The relief of dyspepsia was significantly greater in the pirenzepine-treated group. The tolerability of pirenzepine was good.

Cytoprotection by PGE2, atropine, pirenzepine and vagotomy in rats.

Gastric cytoprotective effects of vagotomy, PGE2 and antimuscarinic compounds (pirenzepine, atropine) were studied in the rat. Both pharmacological and surgical treatment prevented the gastric damage induced by intragastric administration of acetylsalicylic acid plus hydrochloric acid. The mechanisms of action are discussed.

Long-term treatment of duodenal ulcer with pirenzepine. A double-blind, placebo-controlled trial.

Sixty out-patients with duodenal ulcers that were healed at the end of a 4-week treatment with pirenzepine, cimetidine or placebo were admitted to a double-blind placebo-controlled trial to study the effectiveness of pirenzepine (100 mg/daily) in preventing recurrence of ulcers. Six patients did not complete the trial. After 12 months of treatment 15 of the 26 patients had recurrences in the pirenzepine-treated group and 27 of the 28 in the placebo group. The difference is highly significant (X2 = 9.570, P less than 0.01). The tolerability of pirenzepine was good.

Indomethacin-induced intestinal ulcers in rats: effects of salicylazosulfapyridine and dexamethasone.

Characteristics of inflammatory bowel diseases have been hypothesized to resemble those of the syndrome of intestinal ulceration induced in the rat by non-steroidal anti-inflammatory compounds. However, no systematic studies have been undertaken to examine this possibility. Therefore, we have studied the influence of some pharmacological agents, such as steroids and salicylazosulfapyridine (SAS), which are clinically useful in the treatment of inflammatory bowel diseases, and to review published data on other pharmacological approaches commonly used for the therapy of inflammatory bowel diseases that have been shown to counteract indomethacin-induced intestinal toxicity. Orally administered SAS 100 to 800 mg/kg or dexamethasone 0.05 to 0.1 mg/kg exerted dose-related, anti-ulcer activity, with ED50 values and 95% confidence limits of 145 (95-222) mg/kg SAS and 0.184 (0.152-0.224) mg/kg dexamethasone. Other treatments, including cholestyramine, low-residue diets and antibiotics have also been reported to ameliorate clinical and experimental intestinal diseases. The clinical significance of present findings has been discussed.

Cimetropium bromide, a new antispasmodic agent, has no hemolytic effects in humans.

Many agents have been reported to cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. We investigated whether cimetropium bromide, a new antispasmodic drug, can be safely given to these patients. In the first study, ten healthy volunteers were given 50 mg, p.o. 3 times per day, before meals for 1 week. Blood samples were drawn before and after treatment and stimulation of the hexose monophosphate shunt (HMS) was evaluated. No significant stimulation of HMS was observed. In a second study, 12 G6PD-deficient patients with spastic colon were given cimetropium bromide and placebo according to a double blind, cross-over design. None of the patients showed any significant abnormalities in any of the several hematologic parameters tested.

Transverse and sigmoid colon motility in healthy humans: effects of eating and of cimetropium bromide.

There have been few studies of the motility of the colon proximal to the rectosigmoid area. For this purpose we evaluated (1) fasting and postprandial transverse and sigmoid colon motor activity and (2) the effects of a new nonselective anticholinergic drug, cimetropium bromide, on transverse and sigmoid motor responses to eating. Two paired studies were carried out in 11 healthy volunteers by means of a colonscopically positioned manometric probe. After placebo, eating significantly increased transverse and sigmoid motility indices throughout the recording period. Cimetropium significantly reduced the motor responses to eating in both the transverse and the sigmoid colon.

Action of mifentidine on the secretory response to sham feeding and pentagastrin and on serum gastrin in duodenal ulcer patients.

A study has been done in 10 duodenal ulcer patients of the effect of a single oral dose of 10 mg mifentidine on the acid and pepsin responses to sham feeding after 1 h 30 min and to pentagastrin after 4 h 15 min. The study followed a double-blind, randomized, placebo-controlled, cross-over design. Gastric juice was collected for 5 h 15 min after treatment. Blood was sampled for up to 3 h 30 min to determine the effects of mifentidine on serum gastrin. Mifentidine suppressed basal acid output by 77% and sham feeding-stimulated acid output by 71% vs the placebo values. Pentagastrin-stimulated acid output was inhibited by 30% throughout the pentagastrin infusion. The suppressant effect of the drug on pepsin output was not as marked as on acid secretion. Mifentidine did not affect the serum gastrin level during the basal and sham feeding phases. No untoward effects were reported by the patients. The results show that 10 mg mifentidine p.o. produced a large reduction in the acid output in response to sham feeding and pentagastrin without affecting the serum gastrin responses.