Three-dimensional molecular modeling and drug design.

A discussion of drug-receptor theory is used to show that the three-dimensional structure, or shape, of molecules is important for biological activity. The computer-assisted molecular modeling system at Merck is described, and it is shown that this system is useful for generating and storing molecular structures, determining preferred conformation, comparing molecular shapes, and computing molecular properties. Applications of the system to the study of anti-inflammatory drugs, somatostatin-like compounds, and dihydrofolate reductase inhibitors are summarized.

A multicenter placebo-controlled clinical trial of oral metoclopramide in diabetic gastroparesis.

Metoclopramide tablets were compared with placebo in the treatment of gastrointestinal symptoms in 40 patients with diabetic gastroparesis. Results of a 3-wk double-blind study indicate that metoclopramide at a dosage of one 10-mg tablet four times daily reduced nausea, vomiting, fullness, and early satiety and improved meal tolerance better than placebo. Statistically significant differences were noted for nausea and postprandial fullness. Mean gastric emptying assessed by radionuclide scintigraphy was significantly improved in the metoclopramide-treated group when compared with their baseline result. Metoclopramide is an effective agent for improving the upper gastrointestinal motor function in diabetic patients with gastroparesis.

A comparison of three defined formula diets in normal volunteers.

Defined formula diets, shown to be clinically effective in separate trials, have never been compared in the same subjects under identical controls. The intent of this study was to determine which one of three diets, (Vivonex, Flexical, or Precision LR) was most effectively absorbed and utilized. Stool weight and frequency, nitrogen balance and fecal fat, ash and moisture were measured. In addition, subjective comments were recorded regarding overall acceptability and ease of preparation. Statistically significant differences were found only in total stool weight. The data imply that the underlying disease state of the patient, the individual's response to the diet, the composition, cost, availability, and storage requirements of the diet must be taken into consideration when selecting a low residue formulation.

Controlled clinical trial of sedative-anticholinergic drugs in patients with the irritable bowel syndrome.

We studied 16 patients with long-standing irritable bowel syndrome of moderate severity using a controlled, double-blind crossover method. Five sedative-anticholinergic drug combinations and a placebo were tested. The subjective response was assessed with four subjective methods to include an increasing number of response variables. The patients preferred 30 mg phenobarbital plus 8 mg belladonna (P & B) to placebo (P = 0.02). Five of ten patients were helped "some" or "a lot" with placebo, while ten of 15 were helped "some" or "a lot" with P & B (P = 0.07). The ten prominent-symptoms method revealed that subjective symptoms such as nervousness, sleep difficulties, and tiredness were experienced as greater problems than diarrhea. The factor analysis method documented a strong placebo response. Simpler evaluation methods such as drug preference and a five-choice method appear more likely to show a positive drug effect, while the inclusion of a larger number of variables appears to emphasize the placebo portion of the response. These observations may help explain some of the apparent discrepancies between the conclusions of some controlled clinical trials and subsequent clinical experience.

The effect of pH and concentration on alpha-methyldopa absorption in man.

An open crossover study of the absorption of alpha-methyldopa has been conducted in normal healthy adult male volunteers in whom a triple lumen perfusion tube had been placed. Three volunteers were perfused on separate occasions with 0.1 mM alpha-methyldopa at pH 4.5, 6.0 and 7.4. Three other volunteers were perfused on separate occasions with 0.1, 1.0 and 10 mM alpha-methyldopa at pH 6.0. Two additional subjects were perfused with 0.1 mM alpha-methyldopa at pH 6.0. Absorption was not a linear function of concentration above 1 mM alpha-methyldopa. There was also a weak trend toward greater absorption near pH 6.0. At higher concentrations of drug in the perfusion solution (10 vs 1 mM), the free fraction of alpha-methyldopa in plasma samples was increased significantly. Thus, although absorption of alpha-methyldopa is more efficient at lower concentrations, bioavailability may not be substantially enhanced due to increased sulphation in the gut wall. Comparison of permeabilities with previous results from our laboratories suggests the rat is a good model for predicting the behaviour of alpha-methyldopa after its oral administration to man.

The role of metoclopramide in peroral jejunal biopsy: a controlled randomized trial.

Metoclopramide is known to enhance gastric emptying and stimulate duodenal and small-intestinal peristaltic activity. The effect of the drug on peroral jejunal biopsy was examined in a controlled, double-blind, randomized trial. Forty-nine patients (24 females and 25 males) who required jejunal biopsy for diagnostic purposes were admitted to the study. All the biopsies were performed by the same operator using the Quinton multipurpose suction biopsy tube and applying the same technique. Twenty-four patients ranging in age from 18 to 67 years (mean 44.5) received placebo intravenously (sodium metabisulfite), and 25 patients from 16 to 73 years old (mean 39.9) received 10 mg of metoclopramide intravenously prior to the jejunal intubation. Objective parameters of the study were (1) time in minutes required for the intubation at the biopsy site, ie, the area at the ligament of Treitz, and (2) fluoroscopy time. Intubation time in the placebo group was 22.3 +/- 1.9 min (mean +/- SEM) vs 11.3 +/- 1.4 min in the metoclopramide group (P less than 0.001). Fluoroscopy exposure time was 2.47 +/- 0.25 in the placebo group vs 1.40 +/- 0.12 min in the metoclopramide group (P less than 0.001). Subjective clinical evaluation of the operator's assessment of the procedure was based on a 0-4 scale (much easier = 0, easier = 1, average = 2, harder = 3, and much harder = 4). Metoclopramide administration resulted in a significantly easier performance of the procedure (P less than 0.001) but did not influence patient tolerance. Three patients who received metoclopramide and one receiving placebo developed mild to moderate drowsiness of short duration. The results of this controlled trial indicate that metoclopramide significantly shortens the time required for jejunal biopsy and reduces fluoroscopy exposure. Its regulatory action on gastrointestinal motility contributes to the easier performance of a valuable diagnostic procedure.

Sudden onset of slow gastric emptying of food.

Three healthy, young adults suddenly experienced the onset of slow gastric emptying. Their symptoms began in February, 1975 in association with a brief illness consistent with a viral gastroenteritis. They complained of early satiety, nausea, and vomiting when they ate solid food and they had lost 11-25 kg in body weight in 8-12 mo. On admission, their physical examinations and laboratory studies were within normal limits. Their stomachs emptied a barium mixture normally, and fiberoptic endoscopy did not detect any abnormalities. The slowed gastric emptying of food was documented with radioisotopic gastric emptying studies. The prolonged emptying rates of 2 patients were reduced 90% with metoclopramide. In association with metoclopramide therapy, the patients were able to eat more food, and they regained 8-10 kg of body weight in 4-6 mo. Their histories raise the possibility that their initial illness may have damaged the mechanisms which control the gastric emptying of food.

Isolation of non-O1 Vibrio cholerae associated with enteric disease of herbivores in western Colorado.

Non-O1 Vibrio cholerae was isolated from a horse (Equus caballus), a lamb (genus Ovis), and two American buffalo (Bison bison) suffering from enteric disease in the western part of Colorado. In 1981, a foal died of apparent respiratory failure. Necropsy findings included heart failure and gastroenteritis. V. cholerae serovar 347 (Smith) was isolated from the colon of this animal. V. cholerae serovar 27 (Smith) was isolated in 1983 from the intestine of a feedlot lamb suffering from pneumonia and severe watery diarrhea. In 1984, an enteric disease occurred in a herd of American bison. The sick animals were depressed and separated from the herd, dying in about 3 days. Of approximately 100 adult bison, 7 died. Necropsy of one animal revealed that gross lesions were limited to the gastrointestinal tract. V. cholerae serovar 27 (Smith) was isolated from the abomasum, duodenum, and colon of this animal. A swab specimen from the intestine of another dead bison also yielded V. cholerae serovar 27 (Smith).

Isolation of non-O1 Vibrio cholerae serovars from surface waters in western Colorado.

Non-O1 Vibrio cholerae was isolated from rivers, creeks, washes, irrigation canals, and ditches in western Colorado during the summer of 1985. The organism occurred in fresh water (less than or equal to 5 mmol of Na+ per liter) as well as in water of higher salinity (approximately equal to 17 mmol per liter). Sixteen serovars of non-O1 V. cholerae were Sixteen serovars of non-O1 V. cholerae were identified among the environmental isolates. All of the isolates were cytotoxic to Y-1 mouse adrenal cells.

The cholesteryl octanoate breath test: a new procedure for detection of pancreatic insufficiency in the rat.

A breath test for the detection of pancreatic insufficiency was developed and tested in rats. The test features the hydrophobic molecule cholesteryl-1-14C-octanoate, which liberates 14C-octanoic acid when hydrolyzed by carboxyl ester lipase (cholesterol esterase). The 14C-octanoate is absorbed passively and rapidly metabolized to 14CO2, which is excreted in expired air. The compound was administered as an emulsion of cholesteryl octanoate, triglyceride, and lecithin to rats with mild pancreatic insufficiency induced by injecting the pancreatic duct with zein. The animals had exocrine pancreatic hypofunction based on the enzyme content of pancreas at autopsy. Amylase was reduced by 97.1 +/- 1.4%, whereas chymotrypsin was reduced by 73 +/- 14%. The p-aminobenzoic acid test was abnormal at 1 wk (21.68 +/- 8.4%), but become normal at 3 months (72.08 +/- 5.8%) after zein injection. Despite this, the animals gained weight and absorbed fat normally. The 14CO2 excretion rate in the 110-min interval after feeding was significantly reduced to 60% of sham-operated animals. Peak 14CO2 collections 20 min after feeding were reduced by 75 +/- 11%. 14CO2 output was completely normalized by administration of pancreatin prior to the test meal. The results suggest that a sensitive, noninvasive method for detecting deficiency of pancreatic carboxyl ester lipase (cholesterol esterase) secretion in the rat has been developed.

Changing distribution of primary cancers in the large bowel.

Analysis of the changing distribution of origin site of 1,990 colorectal cancers observed at a large midwestern hospital shows a statistically significant trend of a decreasing percentage of distal (rectum, P=.0192) and an increasing percentage of proximal (cecum, P=.0015) large-bowel lesions during a period of at least 30 years. Mortality data for 11,635 colorectal cancers in the state of Kansas for this period confirm this trend (P less than .0001). The respective decrease and increase may well be the result of more than one factor. Results of digital examination of the rectum and sigmoidoscopy are less likely to diagnose large-bowel cancer as they did 30 years ago. Stool screening for occult blood, barium enema roentgenographic examination, and colonoscopy become more important diagnostic tools in light of this trend.

Digestion of tripeptides and disaccharides: relationship with brush border hydrolases.

Intestinal digestion of two tripeptides (leucyl-glycyl-glycine, prolyl-glycyl-glycine) and two disacchrarides (sucrose, maltose) was examined in the hamster by intestinal perfusion in vivo and hydrolysis of the substrates by microvillus membranes. Perfusion studies showed that luminal disappearance rates of leucyl-glycl-glycine were significantly higher than prolyl-glycyl-glycine (P less than o.001), sucrose (P less than 0.001), and maltose (P less than 0.005). Hydrolytic products of leucyl-glycyl-glycine, sucrose, and maltose were detected in the gut lumen in appreciable concentrations, whereas negligible concentrations of prolyl-glycyl-glycine products were present. Leucyl-glycyl-glycine hydrolysis in microvillus membranes was markedly higher than prolyl-glycyl-glycine (P less than 0.001), which was predominant in the cytoplasmic fraction. These results indicate that leucyl-glycyl-glycine, like sucrose and maltose, is hydrolyzed at the membrane. With some tripeptides, i.e., leucyl-glycyl-glycine, digestion occurs at the microvillus membrane with subsequent transport of hydrolytic products into the intestinal epithelial cell. Other tripeptides, i.e., prolyl-glycyl-glycine, may cross the membrane and undergo intracellular hydrolysis by cytoplasmic peptidases.

Right colon loop: a potential pitfall for total colonoscopy.

A right colon loop can occur during total colonoscopy. A light on the anterior abdominal wall in the right lower quadrant and a fluoroscopic view may imply that the tip of the colonoscope is in the cecum. The right colon loop can be documented by roentgenograms and the injection of a radioopaque solution. An arrest in embryological development with overdistension with air accounts for the right colon loop. An unrecognized right colon loop could account for a failure to see a cecal carcinoma.

Cimetidine, antacid, and hospitalization in the treatment of benign gastric ulcer: a multicenter double blind study.

Two hundred forty patients with benign gastric ulcer were treated in a controlled clinical trial to assess the effect on healing of cimetidine, antacids, and hospitalization. Inpatients and and outpatients were randomly assigned to one of three treatments: cimetidine plus antacid, cimetidine plus dummy antacid, or placebo tablet plus antacid. In 206 patients who met criteria for analysis, ulcer healing as shown by endoscopy occurred by 12 days in 11 to 26 percent and by 42 days in 58 to 76 percent. There were no significant differences in healing between hospitalized and nonhospitalized patients or between treatment subgroups. Symptomatic response was equivalent in all groups. The median antacid consumption was 328 mEq of in vitro buffering capacity per day. Patients taking antacids experienced significant diarrhea compared with those taking no antacid. This investigation suggests that the effect of cimetidine is equivalent to that of large amounts of antacid, but because a true placebo group was not studied it is not possible to conclude from this study alone whether either agent influenced healing. In contrast to widespread belief, initiation of treatment in the hospital did not enhance healing, but because patients were not randomly assigned to inpatient and outpatient status no final conclusion about the effect of hospitalization on healing can be drawn.