Effects of direct and indirect acetylcholine receptor agonists on growth hormone secretion in humans.

Cholinergic pathways in the central nervous system positively influence growth hormone (GH) secretion. In fact pyridostigmine, a cholinesterase inhibitor, enhances both basal and GH-releasing hormone (GHRH)-induced GH secretion while, conversely, pirenzepine, an antagonist of muscarinic M1 receptors, inhibits the GH response to GHRH and to other physiological and pharmacological stimuli. The effect of the cholinergic system on GH secretion probably takes place via inhibition of the release of endogenous somatostatin. In this study in 36 normal adults (26 males and 10 females, age 22-35 years) we compared the effects of three cholinesterase inhibitors (pyridostigmine, 120 mg p.o., n = 19; neostigmine, 10 micrograms/kg i.v., n = 6; physostigmine, 12.5 micrograms/kg i.v., n = 6) and bethanechol, a direct muscarinic receptor agonist that is mainly active on muscarinic M3 receptors (25 micrograms/kg i.v., n = 5), on both basal and GHRH (1 microgram/kg i.v.)-stimulated GH secretion. Pyridostigmine, neostigmine and physostigmine induced a significant GH increase (peak vs. basal levels, mean +/- S.E.: 10.4 +/- 1.6 vs. 0.6 +/- 0.2 micrograms/l, P = 0.0001; 13.3 +/- 1.2 vs. 0.5 +/- 1.1 micrograms/l, P = 0.004; and 14.9 +/- 3.1 vs. 2.7 +/- 1.1 micrograms/l, P = 0.025;, respectively). These drugs also induced a similar potentiation of the GH response to GHRH (peak: 48.3 +/- 5.6 vs. 16.2 +/- 2.2 micrograms/l, P = 0.0001; 49.2 +/- 2.2 vs. 19.9 +/- 5.1 micrograms/l, P = 0.006; and 76.9 +/- 12.4 vs. 18.1 +/- 5.3 micrograms/l, P = 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Nortriptyline in the hospitalized elderly: tolerance and side effect reduction.

This article describes two separate but related studies regarding the use of nortriptyline (NT) in the treatment of depressed elderly inpatients. The first study assesses medication tolerance to NT during the acute treatment of late-life depression. The second describes a placebo-controlled study of the effect of bethanechol in reducing antimuscarinic side effects of NT. Antidepressant pharmacotherapy was considered for 72 patients with late-life depression; 17 (24%) did not receive NT; 5 (7%) because of absolute or relative medical contraindications. Of the 55 patients who started on NT, 9 percent had side effects that necessitated medication discontinuation. A separate sample of 26 elderly depressed patients being treated with NT participated in a double-blind, placebo-controlled trial of bethanechol. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed improvement on an objective measure of salivary flow.

Intraesophageal balloon distention versus drug provocation in the evaluation of noncardiac chest pain.

Intraesophageal balloon distention (IEBD) has been advocated as an effective provocative test for the evaluation of chest pain and dysphagia. The normal esophageal response to intraesophageal balloon distention is to generate a sustained contraction proximal to the balloon while showing a distinctive absence of activity distal to the balloon. We evaluated intraesophageal balloon distention in 62 patients with noncardiac chest pain and compared the diagnostic results to those obtained by using a combination of acid infusion, edrophonium (80 micrograms/kg iv) and bethanechol (80 micrograms/kg sq). These 62 patients were also compared with 10 normal volunteers who underwent intraesophageal balloon distention. Abnormal distal manometric activity consistent with spasm and was seen in 38/62 (61%) patients. Distal manometric activity was not seen in any normal volunteer. Diagnostic results (symptom reproduction with manometric changes but without EKG changes) were seen in 26/62 (42%) patients, but in nine of the 62 (14%) patients with combined drug provocation (p less than 0.05). Intraesophageal balloon distention is superior to a combination of provocative drugs in evaluating noncardiac chest pain symptoms. The presence of abnormal manometric activity distal to the balloon may represent regulation of esophageal motility.

[Pharmacologic effects and safety profile of bethanechol in the differential diagnosis of pseudo-anginal thoracic pain]. / Effetti farmacologici e profilo di sicurezza del betanecolo cloruro nella diagnosi differenziale del dolore toracico pseudo-anginoso.

The use of bethanecol has recently been proposed to improve the diagnostic accuracy of esophageal manometry in identifying the origin of symptoms in patients with non cardiac chest pain. In this study we report our experience in 30 patients who underwent esophageal functional studies. Despite its low diagnostic value, bethanecol test (two subsequential doses of 50 micrograms/kg) demonstrated an excellent safety profile, there were few side effects, and patients tolerance was good. The Holter electrocardiographic study showed an isolated case of transient atrioventricular block.

Prospective evaluation of high-dose bethanechol in investigation of esophageal chest pain.

We compared the value of bethanechol 80 micrograms/kg subcutaneously, acid infusion with a 0.1 normal hydrochloric acid, and edrophonium 80 micrograms/kg intravenously as provocative agents to reproduce chest pain and manometric alterations in 72 patients with noncardiac chest pain. No patient developed typical chest pain and manometric alteration with acid infusion, while five (6.9%) patients developed these changes with edrophonium and four (5.6%) with bethanechol. Only one patient developed diagnostic changes exclusively with bethanechol. All patients tested with bethanechol developed some degree of local pain or significant cholinergic symptoms, with two patients requiring atropine for relief. Side effects from edrophonium were infrequent (28% of patients tested) and did not require atropine administration. We conclude that, using the parameters of typical chest pain and the development of manometric alterations as proof of the esophageal origin of chest pain, bethanechol at 80 micrograms/kg adds little information beyond that obtainable with edrophonium. Further, the high incidence of bethanechol-related side effects at 80 micrograms/kg suggests that this dose should not be generally recommended.

The use of anxiolytic and parasympathomimetic agents in the treatment of postoperative urinary retention following anorectal surgery. A prospective, randomized, double-blind study.

Approximately 30 percent of patients undergoing anorectal surgery will develop acute urinary retention. The cause of this complication is poorly understood. Anxiety, anal distention, bladder distention as a result of vigorous hydration during surgery, and reflex inhibition of the urinary bladder detrusor muscle secondary to pain have been postulated as contributing factors. A four-armed prospective, double-blind, randomized trial was carried out to determine whether an anxiolytic agent (midazolam, 5 mg intramuscularly) and/or a parasympathomimetic agent (bethanechol, 10 mg subcutaneously) reduce the incidence of postoperative urinary retention following anorectal surgery. One hundred thirty-two patients (ages, 18 to 50 years), in acute urinary retention 6 to 12 hours following anorectal surgery, were enrolled. Sixty-nine percent of patients responded to bethanechol. Side effects were minimal. Midazolam alone had no effect on retention. Bethanechol and midazolam in combination resulted in less retention than midazolam and a placebo (P less than 0.05). Bethanechol alone was better than a placebo (P less than 0.002). Mean intraoperative intravenous fluid volume for the entire study group was 900 cc. Initial postoperative urinary volumes of patients who failed the treatment protocol were significantly higher than in those responding to bethanechol (mean of 527 cc vs. 241 cc, P less than 0.001). The use of an anxiolytic agent was not effective in the treatment of postoperative urinary retention. Bladder distention may increase the incidence of urinary retention. Bethanechol, in a dose of 10 mg subcutaneously, significantly lowered the incidence of postoperative urinary catheterization and should be considered as initial treatment of postoperative urinary retention following anorectal surgery.

Intracerebroventricular bethanechol chloride infusion in Alzheimer's disease. Results of a collaborative double-blind study.

The use of intracerebroventricular bethanechol chloride infusion in patients with Alzheimer's disease was first reported in 1984. An initial trial in four patients demonstrated the feasibility of this approach for cholinergic drug delivery to the brain, but objective improvement in cognitive function was not documented. A collaborative placebo-controlled double-blind crossover study has now been carried out in 49 patients with biopsy-documented Alzheimer's disease. The results demonstrate a statistical improvement in Mini-Mental State scores and significantly slower performance on Trails A testing during drug infusion. Other neuropsychological test scores were not similarly affected. The degree of improvement was not sufficient to justify further treatment of Alzheimer's disease patients by intracerebroventricular infusion of bethanechol chloride. The drug delivery system used in the study was well tolerated, with two irreversible complications in more than 50,000 patient days.

Effects of bethanechol and adreno-blockers on thermoregulation in spinal cord injury.

The authors report two cases of hypothermia due to a treatment associating Bethanechol and Adreno-Blockers. They emphasize the mechanisms of thermoregulation and discuss the pathophysiology of such hypothermia incidents. The most evident explanation is heat loss, principally mediated through Bethanechol, whereas mechanisms of heat preservation are prevented by Adreno-Blockers. Patients susceptible to this risk must be carefully monitored.

Acute dystonic reaction to bethanechol--a direct acetylcholine receptor agonist.

Bethanechol is a direct agonist of the acetylcholine receptor that was recently introduced in the therapy of gastro-oesophageal reflux. Acute dystonic reactions to bethanechol were observed in a 10-month-old infant who also demonstrated similar dystonic reactions to dopamine receptor blocking agents of two different classes. This first report of acute dystonic reaction to cholinergic agonists in human is in accord with the current theories of the rôle of acetylcholine and dopamine in the pathogenesis of acute dystonic reactions.

Preliminary report: intracranial cholinergic drug infusion in patients with Alzheimer's disease.

After toxicity studies in dogs, a preliminary feasibility trial of the continuous intracranial infusion of a muscarinic agonist was begun in four patients with biopsy-documented Alzheimer's disease. During the last 8 months, a totally implantable infusion system has been used to deliver bethanechol chloride into the cerebrospinal fluid of these patients at doses of 0.05 to 0.7 mg/day. Complications have been few and resolved spontaneously or were easily reversible. The subjective response to this treatment has been encouraging, with reports of improved cognitive and social function during drug infusion and a return to base line function with single-blind saline placebo infusions. Obviously, further evaluation will be necessary to demonstrate the efficacy of this treatment, and a double-blind placebo-controlled crossover trial is now being done. However, we think the preliminary results are encouraging and warrant the consideration of this approach as a potential treatment in patients with Alzheimer's disease.

[Sucralfate (Ulcogant). The mechanism of action of a cytoprotective agent]. / Sucralfat (Ulcogant) Der Wirkmechanismus eines Zytoprotektivums.

The new antiulcer drug sucralfate is characterized by a multiple mode of action. Its predominant feature is a protection of the mucosa from endogenous and exogenous noxious agents. These cytoprotective properties result from a locally formed layer covering ulcers and erosions which inhibits the diffusion of H-ions and pepsin to the damaged mucosa. This layer is also stable against exogenous substances with deleterious effects on the mucosa like alcohol and salicylates. Furthermore, sucralfate binds pepsin and bile acids. Recently, a stimulating effect of sucralfate on the release of prostaglandins and the regeneration of epithelial cells in the gastric mucosa was demonstrated. There is no influence of sucralfate on the production of gastric juice and pH. Since sucralfate is minimally absorbed it is a safe and well tolerated drug.

Double-blind controlled trial of bethanechol and antacid versus placebo and antacid in the treatment of erosive esophagitis.

To determine the value of bethanechol in the treatment of erosive esophagitis, a double-blind study was undertaken in which 28 patients were randomized to either bethanechol and antacid, or placebo and antacid. Patients were evaluated clinically, endoscopically, and by esophageal manometry before and after 8 wk of therapy. After treatment both groups showed significant improvement in heartburn and in healing of esophageal lesions. Patients who received bethanechol plus antacids did not show a greater improvement than patients who received placebo plus antacids in any category, nor did patients in the bethanechol-treated group have a greater incidence of complete healing. In addition, pretreatment mean lower esophageal sphincter pressure was normal in approximately 30% of patients with erosive esophagitis and this finding was associated with a greater chance for complete healing of esophageal lesions. These results fail to show that the addition of bethanechol to an intensive antacid regimen is more effective than the antacid regimen alone in the treatment of erosive esophagitis and that patients with esophagitis and normal lower esophageal sphincter pressures respond more favorably to medical treatment.