Faculty Bibliography

We studied the effects of the calcium-channel blocker, nifedipine, on solid and liquid phases of gastric emptying in 10 healthy male volunteers. Each subject underwent a dual-isotope radionuclide gastric emptying determination with and without the preadministration of nifedipine, 30 mg orally, given 20 min prior to ingestion of the test meal over 10 min, following which the subject lay supine under the gamma-counter for 2 hr. Blood samples for measurement of plasma nifedipine concentration were obtained at the time of drug administration and every 30 min throughout the gastric emptying determination. There was a threefold variation in the areas under the plasma nifedipine concentration vs time curve (AUC) obtained in these 10 subjects. Percent gastric retention of either the liquid (water) or the solid (chicken liver) marker was not significantly different after 30 mg oral nifedipine, as compared to the nontreatment day. We concluded that plasma nifedipine concentrations previously reported to be associated with significant esophageal motility effects in humans were not associated with effects on gastric emptying of either liquids or solids

Various oesophageal manometric disorders have been associated with chest pain or dysphagia. The classic motility disorders are achalasia and diffuse oesophageal spasm. In achalasia, a disorder of aperistalsis in the oesophageal body and incomplete relaxation of the lower oesophageal sphincter, either surgical myotomy or pneumatic dilatation is an effective approach, although some investigators have suggested a role for pharmacological therapy. For the treatment of diffuse oesophageal spasm, a disorder of non-peristaltic motor activity in the oesophagus, various pharmacological approaches with nitrates, anticholinergics, and calcium antagonists have been used. In the presence of associated lower oesophageal sphincter dysfunction, bouginage or pneumatic dilatation may be indicated. Long oesophagomyotomy should be considered for those patients who fail to respond to these measures. Recent manometric techniques have led to the identification of patients with chest pain or dysphagia who have abnormalities of increased contractile amplitude ('nutcracker' oesophagus) or duration. An association with gastro-oesophageal reflux or with psychiatric disturbance has been suggested. Treatment directed towards these factors is indicated and may be supplemented by pharmacological intervention, e.g. by calcium antagonists or anticholinergics

Only limited work has been reported about the relationships of cardiovascular effects and plasma concentrations of the calcium-channel blocker nifedipine. In this study, placebo and nifedipine in 10-, 20-, 30-, and 40-mg doses were administered sublingually to ten normal subjects with at least three days between dosing periods. Blood pressure and heart rate were monitored every 30 minutes for two hours, and blood samples were taken after each measurement for determination of plasma nifedipine concentration by a sensitive and specific gas chromatographic method. Systolic blood pressure fell significantly (P less than 0.05) although briefly after 10 mg, but the effect persisted with larger doses. Diastolic blood pressure fell significantly only after 30- or 40-mg dosing. Heart rate increased significantly after all doses of nifedipine with the effect lasting longer with higher doses. Systolic blood pressure measurements were significantly related to the log of the concurrently measured plasma nifedipine concentrations (r = -.82, P less than 0.001). Diastolic blood pressure was also related to log nifedipine concentration (r = -.69, P less than 0.01). Heart rate, too, was linearly related to the log of nifedipine plasma levels (r = .75, P less than 0.001). These data indicate that the hemodynamic effects observed after acute nifedipine administration may be used to estimate whether or not significant quantities of the drug are being absorbed and that the intensity of the hemodynamic effects may, therefore, serve as a bioassay to evaluate the appearance of drug in plasma in therapeutic quantities

We studied the esophageal effects of nifedipine in 20 patients with achalasia (20 mg sublingually) and nine patients with high-amplitude peristaltic esophageal contractions (nutcracker esophagus) (20 mg orally). In patients with achalasia, nifedipine decreased lower esophageal sphincter (LES) pressure by approximately 30%. In ten patients with achalasia, plasma nifedipine concentrations were 45.3 +/- 17.7 and 57.4 +/- 12.8 ng/mL (means +/- SEM) at 30 and 60 minutes, respectively, after drug administration. In patients with nutcracker esophagus, nifedipine decreased LES pressure by approximately 50% and contraction amplitude in the body of the esophagus by approximately 25%. After comparison was made with our previous results in normal subjects, we concluded that (1) nifedipine decreased LES pressure in patients with achalasia to a similar extent to that noted in normal subjects; (2) plasma concentrations measured after 20 mg of nifedipine given sublingually to achalasic patients were similar to those found under similar circumstances in normal subjects; and (3) nifedipine decreased LES pressure and contraction amplitude in patients with nutcracker esophagus to a greater extent than was found in normal subjects. These results suggest that double-blind, placebo-controlled clinical trials of nifedipine in the treatment of achalasia or nutcracker esophagus are indicated

Both intracellular calcium ions and neural input are important in esophageal smooth muscle contraction. The aim of this study was to compare the effects of well-tolerated doses of the calcium-channel blocker, nifedipine (20 mg sublingually/buccally) with the anticholinergic, propantheline bromide (15 mg orally) and the combination of these two agents on esophageal motor function. Seven healthy volunteers underwent manometric evaluation after nifedipine, propantheline bromide, the combination, and placebo on different days. Lower esophageal sphincter pressure decreased significantly (P less than 0.05 vs basal and placebo) by 32% after nifedipine, but fell only 21% after propantheline bromide. After the combination lower esophageal sphincter pressure fell by 45% (P less than 0.05 vs basal and placebo and nifedipine alone). Contraction amplitude in the body of the esophagus decreased significantly (P less than 0.05 vs basal and placebo) by 26% after propantheline bromide, but fell only 11% after nifedipine. The combination led to a decrease of 37% in contraction amplitude, but this was not significantly different from that obtained with propantheline bromide alone. No drug or combination had any effect on other manometric parameters. These data show that in the normal subjects studied with the above doses: (1) nifedipine has a greater effect than propantheline bromide on the lower esophageal sphincter; (2) propantheline bromide has a greater effect than nifedipine on esophageal contraction amplitude; and (3) the combination of nifedipine and propantheline bromide has an enhanced effect on both lower esophageal sphincter pressure and esophageal contraction amplitude

We describe a patient with dysphagia and chest pain, whose sole esophageal manometric abnormality was an elevated lower esophageal sphincter pressure. A radionuclide esophageal emptying test showed prolongation of emptying. After bougienage and medications failed to give relief, pneumatic dilatation gave excellent subjective and objective results

We studied the effects of the calcium-channel blocker nifedipine on esophageal smooth muscle function in 10 normal volunteers. Lower esophageal sphincter pressure and relaxation and esophageal contraction amplitude, peristalsis, velocity, and duration after wet swallows were determined before and for 120 min after the sublingual/buccal administration of placebo and of nifedipine in doses of 10, 20, 30, and 40 mg. Blood samples for measurement of plasma nifedipine concentration were obtained at baseline and every 30 min during this 120-min period. Nifedipine led to decreases in sphincter pressure of 13.3%, 29.9%, 34.3%, and 35.1% as the dose was increased from 10 mg to 40 mg. These changes were significantly (p less than 0.05) different from baseline and placebo for the 20-, 30-, and 40-mg doses and were more sustained with the higher doses, lasting as long as 90 min. Contraction amplitude fell 5.3%, 5.9%, 13.5%, and 19.6% at the corresponding doses. These changes were significantly (p less than 0.05) different from baseline and placebo only for the 30- and 40-mg doses, with the effect lasting up to 60 min. Peak plasma nifedipine concentration ranged from 28.7 +/- 3.7 ng/ml (mean +/- SEM) after 10 mg to 138.7 +/- 43.7 ng/ml after 40 mg of the drug, and occurred at either the 30- or 60-min measurement. The mean percent of decrease in sphincter pressure and contraction amplitude in the esophageal body correlated (p less than 0.001) with plasma nifedipine levels. There were no changes in sphincter relaxation or in peristalsis, velocity, or duration of contraction with any dose of nifedipine. It is concluded that (a) nifedipine significantly decreases lower esophageal sphincter pressure and contraction amplitude in the body of the esophagus, (b) the effect on sphincter pressure requires a lower dose of nifedipine and is more marked than that on contraction amplitude, and (c) the effects on both sphincter pressure and contraction amplitude correlate with plasma nifedipine levels. Calcium-channel blockers such as nifedipine may have a role in the treatment of motility disorders of the lower esophageal sphincter or esophageal body, and further controlled clinical studies are indicated

Review of esophageal motility tracings performed during a three-year period yielded 112 patients who underwent the test because of chest pain of unclear etiology. Thirteen patients had high-amplitude peristaltic contractions. All 13 patients had pressurelike pain, ten had dysphagia, and six had symptoms of gastroesophageal reflux. The presence of an elevated lower esophageal sphincter pressure in five patients suggested a spectrum of hypertensive disorders of the esophagus variously affecting the body, the sphincter, or both. This latter subgroup responded to esophageal bougienage. Six patients had objective evidence for gastroesophageal reflux. These patients had at least partial relief from antireflux measures. High-amplitude peristaltic contractions should be considered in the differential diagnosis of noncardiac chest pain, since recognition of this entity can lead to appropriate management and symptom relief

A 40-year-old man with jejunoileal bypass developed a syndrome of bizarre behavior, slurred speech, ataxic gait, and inappropriate affect, associated with a metabolic acidosis characterized by an increase in the anion gap. Serum L-lactate level was normal, but high-resolution proton nuclear magnetic resonance spectrums of the patient's serum showed a high concentration of lactate. A diagnosis of D-lactic acidosis was confirmed by a specific enzymatic assay for D-lactate. The D-lactic acidosis was cleared using antibiotic therapy, suggesting that D-lactate is produced from fermentation of ingested carbohydrate by colonic bacteria. Nuclear magnetic resonance spectroscopy is a rapid screening test for identifying organic acids in patients with unexplained acidosis. Neuropsychiatric symptoms in patients with short bowel syndrome may be associated with D-lactic acidosis