[Preventive role of pirenzepine in gastric damage during cytostatic therapy. A controlled randomized double-blind study with placebo]. / Ruolo preventivo della pirenzepina nel danno gastrico in corso di terapia citostatica. Studio in doppio cieco randomizzato controllato con placebo.

Steroids and cytostatic drugs have an undoubtedly damaging action on the gastroduodenal mucosa. The action of pirenzepine was compared with that of the placebo in preventing the gastroduodenal lesions brought on by antiblastic therapy. Sixty patients were separated into two random group under double blind conditions and received 100 mg/die/os of pirenzepine or equivalent placebo for a continuous period of 12 weeks. Antiblastic drugs were administered at the same time. Final endoscopic control and symptomatological findings showed a statistically significant different in favour of the pirenzepine-treated group as early as the 6th week of treatment. No side-effects attributable to pirenzepine were reported.

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.

Manometric evaluation of cimetropium bromide activity in patients with the nutcracker oesophagus.

There are at present few therapeutic alternatives to calcium channel blockers for the medical treatment of patients with nutcracker oesophagus. For this reason, we evaluated by means of a low-compliance manometric system the effect of a new anticholinergic compound, cimetropium bromide (10 mg intravenously), on oesophageal variables of eight patients with nutcracker oesophagus, in a single-blind study. Eight age-matched healthy volunteers served as controls. In both patients and controls, cimetropium bromide significantly decreased lower oesophageal sphincter pressure and the distal and proximal mean contraction amplitude of the oesophageal body. Apart from an increase in pulse rate, no noteworthy side effects were observed. It is concluded that cimetropium bromide may be an effective therapeutic option in patients with nutcracker oesophagus.

Oral cimetropium bromide, a new antimuscarinic drug, for long-term treatment of irritable bowel syndrome.

Most drugs are ineffective for the long-term treatment of irritable bowel syndrome (IBS). The beneficial effects of medical treatment of IBS are poor and last for only a relative short time. Over a period of 6 months, we investigated the effectiveness of cimetropium bromide, a new antimuscarinic compound, in patients with IBS. Forty-eight patients were treated at random and in double-blind fashion with cimetropium bromide (50 mg, tid) or placebo for 6 months. Personal diary cards and monthly check-ups guaranteed the monitoring of symptoms (mainly pain). In addition, personality patterns (MHQ-CBA tests) were obtained for the patients before and after therapy, both to detect possible psychoneurotic traits and to observe the changes in these traits in relation to the changes in pain symptoms. Three patients on placebo and one on cimetropium dropped out. At the end of therapy, pain scores had decreased an average of 16% in the placebo group and 87% in the cimetropium group (p less than 0.01). Twenty patients (87%) on cimetropium versus five patients (24%) on placebo considered themselves to be globally improved (p less than 0.01). The MHQ test showed significant improvement in the anxiety score in the cimetropium group only. The CBA test confirmed a significant decrease in anxiety state (STAI-X-1) after cimetropium treatment. Eleven patients (48%) on cimetropium reported side effects (mainly dry mouth and sleepiness), but none withdrew from the study. The results of this trial indicate that long-term treatment of IBS with cimetropium bromide significantly improves symptoms and associated psychological disorders.

Pharmacokinetics of mifentidine after single and multiple oral administration to healthy volunteers.

1. The pharmacokinetics of mifentidine, a new long acting histamine H2-receptor antagonist, were studied using two protocols. 2. In one study, on 5 different days six normal male subjects were given 2.5, 5, 10, or 20 mg mifentidine or placebo orally 60 min before starting a 3 h continuous gastric aspiration during which time blood samples were taken for measurement of mifentidine concentration. 3. The area under the curves of mifentidine plasma levels (AUC) vs time for the four doses was linearly related to the dose for each individual subject (r = 0.972, P less than 0.001). After doses of 2.5, 5, 10 and 20 mg, mifentidine reduced hydrogen ion output by respectively 36, 37, 60 and 75% and secretory volume by 1, 17, 40, and 47%. The effects at the two highest doses were statistically significant. AUC was correlated positively with the percentage reduction in hydrogen ion output (r = 0.802, P less than 0.001) and volume (r = 0.834, P less than 0.001) over a 3 h period. 4. In the second study, the pharmacokinetics were evaluated after once-daily treatment for 14 days in seven subjects given 10 mg and in seven others subjects given 20 mg. 5. After multiple dosing, renal clearance was similar for the two doses (11.6 +/- 2.11 l h-1 for the low dose and 17.0 +/- 2.0 l h-1 for the high dose). Plasma half-life (t1/2 lambda 2) was 16.0 +/- 3.0 h after the 10 mg dose and 11.9 +/- 1.2 h after 20 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects.

Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H2-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study. No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r = 0.983). The apparent plasma clearance was 38.1 l.h-1, 31.0 l.h-1, and 47.4 l.h-1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41 l/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion. The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H2-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.

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.

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.

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.

Ambroxol for the prevention of chronic bronchitis exacerbations: long-term multicenter trial. Protective effect of ambroxol against winter semester exacerbations: a double-blind study versus placebo.

In a 6-month, double-blind multicenter trial conducted over the winter, the effects of daily administration of ambroxol retard (75 mg) were compared with those of placebo in preventing exacerbations and improving symptoms and clinical signs in chronic bronchitis patients. The trial was completed by 110 patients in the ambroxol group and by 104 in the placebo group. Initially, there were no significant differences between the groups. By the end of the 2nd month of treatment, 67.2% of the ambroxol group had had no exacerbations compared to 50.4% in the placebo group. At the end of the 6-month trial, 45.5% of the treatment group had had no exacerbations, compared to only 14.4% of the control group. These differences were statistically significant. Patients in the treatment group lost significantly fewer days through illness (442) and had fewer days when they needed antibiotic therapy (371) compared to the placebo group patients (837 and 781). Ambroxol also produced statistically significant symptomatic improvement, measured as difficulty in expectoration, coughing, presence of dyspnea and the auscultatory signs as compared to controls. Since ambroxol was well tolerated and compliance was good, it appears like a drug of choice for pharmacological prophylaxis of chronic bronchitis.

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.

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.

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.

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.

Pirenzepine in erosive duodenitis. A controlled clinical trial versus ranitidine.

Fifty-five outpatients with chronic duodenal erosions and no previous ulcer history were treated, in a double-blind fashion, with either pirenzepine (50 mg twice daily) or ranitidine (150 mg twice daily) for 6 weeks. The drugs were equally effective in inducing symptomatic relief. At endoscopic control, 70.4% of subjects in the pirenzepine group and 39.3% of ranitidine-treated patients showed complete healing (p less than 0.05). The results suggest that acid secretion is not an important factor in the pathogenesis of erosive duodenitis and that other mechanisms (such as impaired mucosal blood flow) must be considered.

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.

Identification of muscarinic receptor subtype mediating colonic response to eating.

The colonic motor response to eating requires cholinergic transmission. Recent studies have identified two subclasses of muscarinic receptor, the M1 and the M2 subtype. The aim of this study was to evaluate the muscarinic receptor subtype responsible for mediating the gastrocolonic response. Spike potential (SP) activity and intraluminal pressure were recorded, during fasting and after eating a 1000-kcal mixed meal, from the distal colon of 10 healthy volunteers. In each subject three paired studies were carried out: either atropine (a nonselective antimuscarinic, 1 mg), pirenzepine (a selective M1 antimuscarinic, 10 mg), or saline were infused intravenously before eating, using a double-blind crossover design. The meal significantly increased colonic spike potential activity (17.6 +/- 3.9, SP/30 min) above fasting values (2.7 +/- 0.6, P less than 0.01) in the control study. There was no postprandial increase in spike potential activity (3.3 +/- 0.9, SP/30 min) after atropine. The meal also significantly increased spike potential activity (15.4 +/- 3.3 SP/30 min, P less than 0.01) above fasting levels and equal to that of the controls, in the pirenzepine study. These data suggest that the colonic motor response to eating is mediated through the M2 but not the M1 subtype of muscarinic receptors.