The pathophysiology and treatment of gastroesophageal reflux disease: new concepts.

In summary, the recent understanding of the pathogenesis of gastroesophageal reflux disease as owing to LES incompetence has led to improvement in both the diagnosis and the treatment of this disorder. Diagnosis now dependent on demonstrating the presence of reflux, an incompetent sphincter mechanism, or some complication of reflux. Treatment is focused on reducing the endogenous factors that contribute to reflux, or actually restoring the sphincteral barrier to reflux by pharmacologic or surgical means.

Bethanechol or cimetidine in the treatment of symptomatic reflux esophagitis: a double-blind control study.

We conducted a double-blind study to compare the effectiveness of oral bethanechol chloride or cimetidine in treating reflux esophagitis to evaluate the drugs' effects on the symptoms of esophagitis and its verification by endoscopy. Forty-three patients were treated with either 300 mg of cimetidine or 25 mg of bethanechol chloride, each administered four times a day for six weeks. In addition to this drug treatment, the patients all received conventional medical therapy. Patients who were treated with either of the two drugs experienced a decrease in symptoms and less severe endoscopic lesions. While cimetidine treatment resulted in complete endoscopic healing in 15 of 22 patients, bethanechol treatment resulted in the same healing in 11 of 21 patients. During therapy, neither endoscopic lesions or symptoms worsened. Our study indicated that either cimetidine or bethanechol is an effective drug in treating reflux esophagitis. The effects of the two drugs can be favorably compared.

The necessity of human trials of putative therapies for Alzheimer's disease.

The absence of a suitable animal model for Alzheimer's disease leaves therapeutic trials in human subjects as a necessity. Reasonable criteria can be formulated for deciding which therapies should be tested. Scientific rationale and likelihood of success should be major considerations. Novel approaches of delivering drugs to the central nervous system should not be discouraged so long as complication rates can be shown to be low.

Methodological considerations in cognitive disorders or: "the baby needs enough bath water".

Establishing treatment efficacy for neuropsychiatric disorders is an often protracted process due to vagaries of symptoms, course, and probably the inherent variability of the central nervous system. No single study design is likely to be definitive. Thorough evaluation of intracranial drug infusion for illnesses such as Alzheimer's Disease will require extended, multidisciplinary work before true evaluation can confidently be made.

Novel CNS-directed drug delivery systems in Alzheimer's disease and other neurological disorders.

Increasing knowledge of the neurochemical aspects of central nervous system function raises the possibility of treating Alzheimer's disease (AD) and other neurological diseases by the appropriate manipulation of neurotransmitters, neuromodulators, neurohormones or neurotrophic factors. Clinical application of this knowledge may, however, be inhibited by long standing problems with drug delivery to the central nervous system (CNS). Novel, CNS-directed, drug delivery systems might be used to overcome many of these problems. The problems encountered in drug delivery to the brain, present experience with the clinical use of some novel drug delivery systems and the advantages and disadvantages of these systems will be discussed.

Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants.

The anticholinergic properties of currently available antidepressants sometimes cause sexual dysfunction. Bethanechol, a cholinergic drug, was found to give total relief of impotence in two men and of anorgasmy in one woman; none of the subjects suffered side effects.

Treatment of nortriptyline's side effects in elderly patients: a double-blind study of bethanechol.

A double-blind, placebo-controlled study of bethanechol was conducted in 26 elderly depressed patients being treated with nortriptyline. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed a trend toward improvement on an objective measure of salivary flow. The potential use of bethanechol in older patients to reduce morbidity and improve compliance with medication regimens is discussed.

Intracerebroventricular bethanechol for Alzheimer's disease. Variable dose-related responses.

Five male patients participated in a pilot open-label study of dose-related aspects of response to intracerebroventricular bethanechol in Alzheimer's disease. No patient had remission of symptoms, but three patients improved symptomatically and on tests of memory. Improvement was evident over a restricted range of doses for each subject, and symptoms were worse at doses below and above the optimal range. There was little overlap in the range of doses producing improvement among these three. Two patients had no consistent improvement in memory, and agitation, depression, paranoia, and seizures developed during treatment. Qualitative differences and variability in dosages producing responses complicate the identification of true drug response in the treatment of Alzheimer's disease.

Shy-Drager syndrome: diagnosis and treatment of cholinergic dysfunction.

Two patients with Shy-Drager syndrome demonstrated unusually widespread and unequivocal cholinergic dysfunction as well as the usual evidence of adrenergic insufficiency. Progressive constipation preceded impotence, nocturia, hesitancy in micturition, anhidrosis, orthostatic hypotension, and xerostomia. Nonautonomic neurologic signs appeared several years later. Cholinergic dysfunction involved eyes, lacrimal glands, salivary glands, heart, gastrointestinal tract, urinary bladder, and sweat glands. Subcutaneous administration of bethanechol chloride--a muscarinic receptor agonist--improved tearing, salivation, sweating, and gastrointestinal and bladder functions. Daily administration of this drug resulted in symptomatic improvement of the autonomic functions, and relapse followed discontinuation of treatment.

Management of bladder dysfunction in multiple sclerosis.

Sixty-seven consecutive patients participated in a prospective urodynamic study of the diagnosis and treatment of urinary bladder symptoms in multiple sclerosis. The etiology of symptoms was classified as either failure to store urine (30%), failure to empty the bladder (18%), or a combination of the two (50%). Treatment was individualized on the basis of the underlying pathophysiology and consisted of intermittent self-catheterization (21%), none (20%), surgical (12%), drugs (9%), voiding maneuvers (6%), and external condom drainage (6%). In 18 patients (27%), lesser forms of treatment were unsuccessful, and indwelling vesical catheters were required. Symptoms correlated poorly with urodynamic findings, and treatment based on symptoms alone would have been ineffective in over half the patients.

Stable bimodal response to cholinomimetic drugs in Alzheimer's disease. Brain mapping correlates.

We investigated quantitative EEG brain mapping as a physiologic marker of drug response while studying the stability of intersubject variability in patients with Alzheimer's disease (AD) who were receiving bethanechol through intracerebroventricular (ICV) shunts. Two of the patients had previously demonstrated cognitive and behavioral improvements on medication; the third had cognitive deterioration complicated by agitated depression. All three patients were reexamined in a dose-response paradigm. Serial brain mapping examinations were performed along with brief cognitive testing. All patients showed drug responses that were comparable with responses during their initial dose-response phase. There were strong linear correlations between global decreases in 2 to 6 Hz slow-wave activity and cognitive improvement. Brain mapping demonstrated that slowing decreased in magnitude and field with increasing dose until optimal dose was reached; with supra-optimal doses, the magnitude and field of the slowing increased dramatically. These results suggest that the quality of cholinomimetic drug responses are stable over time in individual patients, and that magnitude and pattern of slow-wave activity as measured by brain mapping may be useful in monitoring treatment with cholinomimetic agents.

Management of reflux esophageal disease.

Although frequent or prolonged exposure of the esophageal mucosa to gastric contents results in epithelial damage, it is also becoming clear that the pathophysiology of reflux esophageal disease may be multifactorial. The severity of this disease may relate to the frequency of reflux episodes, certainly to the duration of mucosal exposure to refluxed material, and probably to as yet unquantified factors of mucosal resistance and the specific noxiousness of refluxed gastroduodenal and pancreatic secretions. The phenomenon of esophageal clearance is a critical determinant in preservation of mucosal integrity, and a disturbance in this function may lead to severe signs and symptoms of reflux esophageal disease. A detailed analysis of the specific pathophysiologic abnormalities in individual patients may permit more "tailored" therapeutic approaches and more favorable results.

Acquired postganglionic cholinergic dysautonomia: case report and review of the literature.

An 8-year-old girl with acute abdominal pain had cholinergic autonomic dysfunction. There have been only four patients with acquired postganglionic cholinergic dysautonomia described in the literature. The characteristic clinical features are atony of the bowel and bladder, lack of tears, saliva, and sweat, internal ophthalmoplegia, and normal adrenergic functions. Special studies for autonomic nervous function help in confirming this diagnosis. The exact pathogenesis of the disorder is still not clear. This case demonstrates successful treatment with bethanechol chloride.

The evaluation of gastroesophageal reflux before and after medical therapies.

Gastroesophageal scintigraphy is a quantitative technique that can be employed to detect and quantitate gastroesophageal reflux before and after the application of therapeutic modalities, including change in body position, bethanechol, atropine, antacids, and antacid-alginate compounds. Five groups of 10-15 patients each were studied before and after using each therapeutic modality and before and after atropine. The results were compared to the patient's symptomatology and to the acid reflux test. Gastroesophageal scintigraphy was performed following oral administration of 300 microCi 99mTc-sulfur colloid in 300 ml acidified orange juice. Thirty-second gamma camera images were obtained as the gastroesophageal gradient was increased from approximately 10 to 35 mm Hg at 5 mm Hg increments using an inflatable abdominal binder. Data were processed using a digital computer. Reflux was reduced by change in position from recumbent to upright, and by the use of subcutaneous bethanechol, oral antacid, or oral antacidalginate compound. Atropine increased reflux. Gastroesophageal scintigraphy is more sensitive than fluoroscopy, correlates well with clinical symptomatology, and is a reliable and convenient technique for the quantitative estimation of reflux before and after therapy.

Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report.

A 43-year-old man who experienced profound dose-related erectile and ejaculatory dysfunction without loss of libido on three separate antidepressants and on the anorectic agent mazindol is described. Bethanechol chloride 20 mg p.o., taken 1 to 2 hours prior to sexual activity, permitted satisfactory erection and ejaculation during sexual intercourse, while the patient continued to take protriptyline or mazindol. Bethanechol chloride may prove to be of use in treating sexual dysfunction associated with drugs or conditions which increase sympathetic tone.

Gastroesophageal reflux causing stridor.

We describe an infant with stridor associated with gastroesophageal reflux (GER). This is the first report in which there is clear documentation by pH probe of a temporal association between individual episodes of GER and stridor. We review the literature and speculate on the relationship between these two phenomena. GER should be considered in patients with stridor.

Intracellular Escherichia coli in urinary malakoplakia: a reservoir of infection and its therapeutic implications.

Urinary malakoplakia may pursue an aggressive clinical course with persistent infection, despite seemingly appropriate antibiotic therapy. The authors studied seven adult females with urinary malakoplakia. Specific immunocytochemical staining demonstrated intracellular Escherichia coli in malakoplakia tissue in four patients. In two of the four patients, the bacteria were present despite antibiotic-induced sterile urines at time of biopsy. Cessation of therapy consistently lead to recurrent bacteriuria in these patients. In one such patient, the intracellular bacilli were confirmed as E. coli by culture of crushed malakoplakia tissue and electron microscopic study; the organisms were a routine E. coli strain susceptible to multiple previously administered antibiotics. Only sequential treatment with bethanechol chloride and trimethoprim-sulfamethoxazole, however, eliminated the infection; all three drugs are thought to be capable of enhancing intracellular killing of bacteria. Conventional antibiotic therapy failed to halt progression of disease in other malakoplakia patients. The data indicate that intracellular bacteria may serve as a reservoir of persistent/recurrent infection in urinary malakoplakia. Optimal therapy should include therapeutic agents that may control intracellular organisms.

Management of vesical dysfunction in multiple sclerosis.

Using urodynamic testing, vesical dysfunction in patients with multiple sclerosis can be classified and basic therapeutic principles outlined. Satisfactory voiding patterns can be achieved in most patients with multiple sclerosis without surgical procedures. Flexibility and willingness to change programs as the disease process changes make possible reasonably satisfactory results.

Treatment of delayed onset of spontaneous voiding after surgery for incontinence.

A preliminary study on 40 female patients who had undergone colposuspension surgery was carried out using four drugs in an attempt to reduce the time taken to void spontaneously following surgery and to define the cause of delay. Oral diazepam given as night sedation, was found to be the most effective drug.

Action of oral and parenteral bethanechol on decompensated bladder.

A double blind balanced Latin-square study was conducted on 20 adult patients with decompensated bladders to determine the relative effectiveness of oral and parenteral bethanechol chloride (Urecholine) on the stretch response of bladder muscle. Detrusor reaction was measured by modified cystometry. Five mg. of subcutaneous bethanechol chloride produced a significant increase in intravesical pressure which was more rapid in onset, of larger magnitude, and of shorter duration than oral doses of 100 and 200 mg.