The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil.

The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects. In the pH study (n = 17 subjects), there was a lead-in period done under fasting conditions, followed by randomization to a four-way crossover of pentagastrin (6 micrograms/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc). Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given. Peak plasma concentrations (Cmax) and area under plasma concentration-time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p less than 0.0001). Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p less than 0.0001 for both). In the food study (n = 16 subjects), there were two lead-in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four-way crossover of either high or low protein diets, or high or low fat diets. There were six meals in each diet. Dosing with the antibiotic was done at the midpoint of the fourth meal. Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p less than 0.0001), whereas the time to Cmax was unchanged. These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.

Detection of gastroesophageal reflux in the pediatric-age patient by esophageal intraluminal pH probe measurement (Tuttle test).

The esophageal intraluminal pH probe test (Tuttle test) was used in 24 pediatric-age patients who had symptoms of gastroesophageal (GE) reflux to determine its sensitivity in detecting gastric acid reflux and to document its usefulness as a prognostic indicator. Eight children had a positive Tuttle test. Six of these patients failed a trial of medical management and required surgery to control their symptoms. None of these patients had GE reflux on esophagrams. Only one of 16 children with a negative test required surgery. This patient also did not have GE reflux on esophagram. The Tuttle test should be included in the diagnostic evaluation of pediatric patients with the clinical presentation of GE reflux.

Value of esophageal manometric studies in the gastroesophageal reflux of infancy.

Fifteen infants with symptoms of gastroesophageal reflux (GER) were evaluated with esophageal manometric studies. Six infants failed on a medical regimen of frequent thickened feedings and an upright position 24 hours per day for three weeks. These infants had Nissen fundoplications. Their mean lower esophageal sphincter (LES) pressure was 12.7 mm Hg. The nine infants who did well on the medical regimen had a mean LES pressure of 19.6 mm Hg. These means are significantly different (P less than .001). Esophageal manometric studies should be included in the evaluation of all infants with symptoms of chronic GER.

Achalasia: diagnosis, management, and clinical course in 16 children.

Clinical features, radiographic and esophageal manometry findings, and treatment results in 16 patients less than 15 years old with achalasia are described. Esophageal manometry performed in 15 patients showed results similar to those found in adults: (1) increased resting lower esophageal sphincter pressure, (2) incomplete or failure of relaxation of the lower esophageal sphincter on swallowing, and (3) ineffective or absence of peristalsis in all. The most common symptoms in the 16 patients were: dysphagia in 15, postprandial vomiting in 13, and retrosternal pain in five. The average duration from onset of symptoms to diagnosis was 28 months. The esophagram was diagnostic in all patients. Pneumatic dilation was the initial treatment in eight and was successful for more than 1 year in five. Two patients required two dilations and were then symptom-free for more than 1 year, but required a Heller myotomy. The remaining patients underwent Heller myotomy following failure of the second dilation. Three patients underwent myotomy and two patients had myotomy with fundoplication as initial treatment; only one remained symptomatic. Esophageal dilation using a pneumatic dilator should be the initial treatment of choice in school-aged children. However, if more than two dilations are required within 1 year, surgical management is recommended.

Depressed neutrophil chemotaxis in infants with cow's milk and/or soy protein intolerance.

Neutrophil chemotaxis and random migration were studied in 11 infants with active cow's milk and/or soy protein intolerance and in an additional four infants following clinical recovery. Results were compared to 15 age-matched control subjects. Infants with active intolerance exhibited depressed chemotaxis and enhanced random migration. The four recovered infants had values similar to those of control subjects.

Lymphoid polyps (focal lymphoid hyperplasia) of the colon in children.

Lymphoid polyps (focal lymphoid hyperplasia) of the colon are rare in children. These lesions are benign, but must be differentiated from malignant lymphomas. Grasp biopsies of the lesion are inadequate for this purpose and the polyp should be submitted in toto for pathologic examination. No treatment other than local excision is warranted. Two cases are presented and the literature is reviewed.

Recurrent pulmonary disease in children: a complication of gastroesophageal reflux.

To evaluate the role of gastroesophageal reflux (GER) as a possible cause of recurrent pulmonary disease, 30 children, aged 1 to 18 years, were studied prospectively with esophageal function tests. These included esophagram (30 patients), esophageal manometry (29 patients), pH probe (Tuttle) test (29 patients), and esophagoscopy with esophageal biopsy (23 patients). The patients studied had either chronic asthma or two or more documented pneumonias within a one-year period. Nineteen (63%) had GER based on two or more positive tests. Eighteen had positive Tuttle tests; 13 had abnormal manometry studies; nine had esophagitis on biopsy; six had esophagitis on esophagoscopy; and five had reflux on esophagram. Of those with GER, 17 had a history of nocturnal cough and eight vomited during infancy. Children with recurrent pulmonary disease should have esophageal function testing to exclude GER as the cause.

Ranitidine prevents duodenal ulcers associated with non-steroidal anti-inflammatory drug therapy.

The results of four similarly designed, randomized, double-blind, placebo-controlled studies conducted to evaluate ranitidine as prophylaxis for NSAID-associated damage are reviewed. A total of 673 patients receiving therapeutic dosages of NSAIDs for arthritic or musculoskeletal conditions also received either ranitidine 150 mg twice daily (n = 343) or placebo (n = 330) for four weeks (two studies) or eight weeks (two studies). Endoscopic grading of mucosal lesions was based on a modified Lanza scoring system. All patients had normal baseline endoscopies. After four weeks of treatment a significant protective effect against duodenal mucosal lesions including duodenal ulcers (three studies) and gastric mucosal lesions including gastric ulcers (one study) was observed in patients who received ranitidine compared with those who received placebo. A meta-analysis of the four studies confirmed that significantly fewer patients receiving ranitidine than placebo developed duodenal ulcers (1% vs. 6%, P = 0.01). Endoscopic data at eight weeks from the two longer-term studies showed that duodenal ulcers occurred in ranitidine- and placebo-treated patients at a rate of 1% (2/137) vs. 8% (10/126) (P = 0.02), respectively, in one trial, and 0% (0/57) vs. 8% (4/49) (P = 0.02), respectively, in the other trial. No protective effect in the stomach was evident at eight weeks. We conclude that ranitidine is effective in preventing NSAID-associated duodenal ulcers and may be appropriate prophylaxis for certain high-risk patients.

Gastric acid suppression is greater during intravenous ranitidine infusion versus bolus injections of famotidine.

It has been proposed that famotidine may be effective in maintaining intragastric pH > or = 4 for up to 12 h with a single i.v. 20 mg bolus injection and thereby prevent acute stress-related mucosal haemorrhage. The present study was designed to compare a ranitidine continuous i.v. infusion (6.25 mg/h) vs. famotidine bolus injection (20 mg every 12 h) on 24-h intragastric pH and gastric acid secretion. Twenty-eight healthy volunteers (15 males, 13 females; 20-56 years) participated in two 24-h treatment periods; each test was in random order separated by 7-10 days. After an overnight fast, subjects were intubated and gastric pH and acid secretion measured hourly. Whereas ranitidine maintained gastric pH above 4 for the entire 24-h period, mean pH steadily decreased to a nadir of 2.9 and 3.7, respectively, 12 h after each famotidine injection (P < 0.01 vs. ranitidine). Furthermore, gastric acid secretion increased to 4.4 +/- 1.2 mmol/h 12 h after famotidine injection compared to 1.1 +/- 0.3 mmol/h with ranitidine (P < 0.01). We conclude that ranitidine delivered as a continuous i.v. infusion (6.25 mg/h) is superior to bolus famotidine injections (20 mg) at 12-h intervals in suppressing gastric acid secretion and maintaining an intragastric pH > or = 4. More frequent famotidine dosing, or delivery by continuous i.v. infusion, may be required to provide prolonged acid suppression.

Gastroesophageal reflux in the severely retarded who vomit: criteria for and results of surgical intervention in twenty-two patients.

Forty-two severely retarded patients, ranging in age from 2 to 26 years, were referred for diagnostic evaluation because of chronic vomiting. The diagnosis of gastroesophageal reflux (GER) was made in 28 of the basis of reflux (grade III) on upper gastrointestinal series and the presence of esophagitis either grossly at endoscopy or on esophageal biopsy. Nissen fundoplication was performed in 22 because of the frequent occurrence of complications such as pneumonia, gastrointestinal blood loss, and malnutrition attributable to GER. The incidence of postoperative complications was 59%. However, during a mean follow-up period of 14.1 months, no further vomiting or gastrointestinal blood loss was encountered, and only one patient had a single episode of pneumonia. Weight gain in those who were malnourished was impressive. In addition, the already difficult care of the patients was greatly facilitated. Severely retarded patients with GER who suffer recurrent complications should be considered for Nissen fundoplication.

The safety of ranitidine in elderly versus non-elderly patients.

The authors conducted a retrospective review of 21 United States trials of ranitidine in acid peptic diseases and compared the adverse events in elderly (> or = 65 years) and nonelderly (< 65 years) patients. Ranitidine dosages ranged from 150 mg/day to 300 mg twice daily for treatment periods of 4 to 52 weeks. Of the 4041 patients included in this review, 402 elderly and 2188 nonelderly patients received ranitidine and 245 elderly and 1206 nonelderly patients received placebo; 29%, 29%, 32%, and 26% of these patients, respectively, reported some type of adverse event. When only drug-related adverse events (as judged by the investigators under blinded conditions) were evaluated, these percentages dropped to 2%, 2%, and 1% and 2%, respectively. Gastrointestinal adverse events (e.g., nausea and diarrhea) and central nervous system adverse events (e.g., headache and dizziness) were the most common (0.7% and 0.8%, respectively), with comparable incidence rates in the elderly and nonelderly patients. The authors conclude that ranitidine is as safe in elderly patients as it is in nonelderly patients. No difference in the incidence of adverse events was found between older and younger patients who received ranitidine or placebo.

The effect of itazigrel and aspirin on the mucosa of the esophagus, stomach, and duodenum of normal subjects.

The effects of aspirin, itazigrel (U-53,059; a new antiplatelet drug), and placebo on the mucosa of the esophagus, stomach, and duodenum were evaluated in this double-blind, randomized, placebo-controlled study. Six normal male subjects were included in each of five treatment groups: aspirin (325 mg each morning for five doses), aspirin (325 mg tid for 12 doses), itazigrel (25 mg each morning for five doses), itazigrel (50 mg tid for 12 doses), and placebo. Aspirin and itazigrel, at all doses investigated, significantly inhibited ex vivo, ionophore (A23187)-stimulated thromboxane B2 synthesis. Collagen-induced platelet aggregation was significantly inhibited on day 3 (P = .021) and day 5 (P = .002) in both aspirin and itazigrel groups as compared with placebo. Upper gastrointestinal endoscopy was performed before the first dose of drug (day 1) and two hours after the last dose (day 5) for each subject. A rating scale was used to score the amount of mucosal damage. The baseline (day 1) endoscopic scores revealed no significant differences between groups. On day 5, neither placebo nor itazigrel treatment groups showed any significant change compared with baseline. On day 5, both aspirin groups had significantly (P less than .001) more mucosal damage than the placebo group and either itazigrel group. It is concluded that in this relatively acute study, at doses that produce comparable inhibition of platelet aggregation and platelet cyclo-oxygenase, itazigrel was superior to aspirin in terms of toxicity to the upper gastrointestinal tract.

Arbaprostil's [15(R)-15-methyl PGE2] effects on intrauterine pressure in the nonpregnant and pregnant human female--a report of four clinical trials.

Four clinical trials evaluating arbaprostil's effects on the human uterus are reported. The initial two trials measured intrauterine pressures in nonpregnant and pregnant human females following arbaprostil doses of 10, 25, and/or 50 mcg. No statistical differences were found at any dosage level in either study for average uterine resting pressures, average peak pressures, the number of contractions or Montevideo units. Subsequently, two trials determined the abortifacient potential of arbaprostil in pregnant women during the first trimester. The first utilized total daily doses of 400 and 800 mcgs. while the second used total daily doses of 1200 and 1600 mcgs. Vaginal spotting was noted in one woman receiving 400 mcgs, three receiving 1200 mcgs. and in two receiving 1600 mcgs. One episode of moderate bleeding was seen in the latter study. Based on these studies, arbaprostil exhibits little potential for inducing abortifacient activity at these dosages in these patient populations.

Randomized multicenter trial documenting the efficacy and safety of a lactose-free and a lactose-containing formula for term infants.

OBJECTIVE: To evaluate the efficacy and safety of a new lactose-free infant formula. DESIGN: Randomized, prospective, double-blind, controlled, outpatient, multicenter, parallel 12-week trial. SETTING: Ambulatory-care facilities of the participating centers. SUBJECTS: 137 healthy term infants (approximately 7 days old at the time of study enrollment). INTERVENTION: Healthy term infants, whose mothers had decided not to breast-feed, were randomly assigned 1 of the 2 study formulas. MAIN OUTCOME MEASURES: Weight, length, and occipitofrontal circumference measurements were obtained at baseline and when the infant was 2, 4, 8, and 12 weeks old. Formula acceptance and tolerance were also assessed at weeks 2, 4, 8, and 12. Serum albumin concentration, creatirune level, and blood urea nitrogen were determined at baseline and week 12. Adverse events were assessed throughout the study. STATISTICAL ANALYSES PERFORMED: Each baseline anthropometric and laboratory variable was analyzed for comparability between groups using the Student t test and was also analyzed using a repeated-measures analysis of variance method. Covariance analysis was applied to the final laboratory data using the respective baseline data as covariates. Decisions about equality of mean responses to formula effects were based on the .05 level of significance in all cases. RESULTS: One hundred four infants completed the study. No significant differences between the 2 formula groups were noted for any of the growth and blood parameters. APPLICATIONS: This new formula is an effective and safe lactose-free nutrition alternative for infants who require such a diet.

The role of sigmoidoscopy, radiographs, and colonoscopy in the diagnostic evaluation of pediatric age patients with suspected juvenile polyps.

Juvenile polyps are the most common cause of painless hematochezia in pediatric Age patients after the first year of life. This study evaluated the role of rigid proctosigmoidoscopy, air contrast barium enema examinations, and colonoscopy in the diagnostic approach to 43 such patients. During sigmoidoscopy, polyps were removed from 31 children. On subsequent barium enema examination, more proximal lesions were found in only 4 of these 31 patients, but were seen in 7 of the 12 children who had negative sigmoidoscopic evaluations. Fourteen children had colonoscopy performed. This group included the latter 12 patients plus 2 of the former 4 who again developed hematochezia. Polypectomies were done during 11 of these procedures. Eight of these 11 children had proximal lesions seen during radiographic studies. The diagnostic approach to pediatric age patients with painless hematochezia should include an initial rigid sigmoidoscopic examination. Barium enema evaluation should be reserved for those patients requiring colonoscopy. The latter examination should be performed in all children who have had negative sigmoidoscopic examinations plus those who have had polyps removed from the rectum and then again develop hematochezia.

Pharyngoesophageal pulsion diverticulum (Zenker) in a ten-year-old boy.

Posterior pharyngoesophageal pulsion diverticula are rare during the pediatric years. We present the third case (a 10-yr-old). Proper diagnosis was made during fiberoptic esophagoscopy.

Gastric emptying and the pharmacokinetics of the cephalosporin antibiotic, cefpodoxime proxetil.

The effects of gastric motility on the pharmacokinetics of cefpodoxime proxetil, an oral, broad spectrum, third-generation cephalosporin antibiotic were evaluated in 12 healthy subjects. In this open-label, crossover trial, each subject took a 200 mg dose (two 100 mg film-coated tablets) in each study period. There was an initial fasting period followed by a control period and then either a propantheline or metoclopramide period. Gastric motility was measured using [99mTc]-labeled sulfur colloid in oatmeal in the control, propantheline and metoclopramide periods. Treatment with propantheline or metoclopramide was given 30 min before dosing with the antibiotic and the radioisotope. Serial images with a gamma counter were made every 15 min for 2 h. Gastric emptying time was faster than control with metoclopramide, but generally slower with propantheline than control. The mean peak plasma concentration, mean area under plasma concentration time curve and mean half-life of cefpodoxime proxetil were similar in all groups as compared to control. The mean time to peak plasma concentration was delayed in the propantheline period and peak plasma concentrations were greater at all sampling times at six hours after dosing. This study utilized the gastric nuclear scan with modification of gastric motility by metoclopramide and propantheline and with simultaneous determination of the disposition of cefpodoxime proxetil to understand the absorption of the drug.

Gastrointestinal symptoms in Rocky Mountain Spotted Fever. Histopathologic finding of ulcerative enteritis with vascular.

Gastrointestinal symptoms are often in patients with Rocky Mountain Spotted Fever (RMSF), particularly early in the course of the illness. However, changes in the gastrointestinal tract have not been reported in a child who has survived. We document vasculitis in the terminal ileum of a child with RMSF who also had radiographic findings consistent with involvement of the entire small bowel. An appreciation for the gastrointestinal manifestations should facilitate a rational approach to their management and prevent a delay in diagnosis.

Gastroesophageal reflux in children: clinical manifestations, diagnosis, pathophysiology, and therapy.

Gastroesophageal reflux in infants and children is a challenging diagnostic problem. A careful history and physical examination are of foremost importance. In infants, the esophageal manometry study and the Tuttle test are helpful in confirming gastroesophageal reflux. In older children, these two studies as well as the Bernstein test should be done to document reflux. The presence of esophagitis or esophageal strictures is best determined by esophagoscopy with concomitant grasp or suction biopsies. A medical regimen should be tried for three to six weeks in all children except those with esophageal strictures or severe malnutrition. Medical failures should be treated surgically with Nissen fundoplications, performed by a competent pediatric surgeon. The prognosis for children undergoing surgical correction is excellent.