Inhibition of theophylline clearance by cimetidine but not ranitidine.

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on theophylline pharmacokinetics and to determine whether the previously described cimetidine-theophylline interaction is dose dependent. Twelve healthy adult men were given a 6-mg/kg intravenous aminophylline dose on four occasions. Subjects were randomly assigned four treatments: no treatment (control); cimetidine, 1,200 mg/day; cimetidine, 2,400 mg/day; and ranitidine, 300 mg/day. Cimetidine, 1,200 mg/day, significantly decreased theophylline clearance by 36% (range, 22% to 49%) and increased the mean elimination half-life from 5.7 hours (control) to 9.2 hours. A significant difference was not found between the two cimetidine dosages, indicating dose independence of the interaction over the dosage range studied. Ranitidine did not significantly alter theophylline pharmacokinetics. Theophylline plasma protein binding was not affected by any treatment. The relative effects of cimetidine and ranitidine on the elimination of cytochrome P-450 metabolized drugs such as theophylline indicate a useful property of ranitidine as compared with cimetidine.

Naloxone does not antagonize the antihypertensive effect of clonidine in essential hypertension.

Reports on spontaneously hypertensive rats suggested that naloxone blocked the antihypertensive effects of clonidine. We compared the effects of an 8-hr intravenous naloxone infusion (6 micrograms/kg/hr) or 5% dextrose in water (D5/W) begun 2 hr before single oral doses of clonidine (0.3 mg) in six men with mild to moderate essential hypertension (EHT). Supine and standing (after 5 min) blood pressure (BP) and heart rate (HR) were measured every 20 min. Initial treatment with naloxone or placebo (D5/W) infusion was randomly allocated, with the alternate treatment given 1 wk later. Naloxone did not modify either supine or standing BP or HR. Clonidine induced a gradual, sustained reduction in both supine and standing systolic and diastolic BP and in supine HR, and there was an increase in standing HR. Naloxone did not modify the onset, maximal effect, or recovery of the hypotensive and HR effects of clonidine in both the supine and standing positions. Our data indicate that hypotensive and bradycardiac effects of clonidine in EHT are not mediated by naloxone-sensitive opioid receptors. They also suggest that opioid receptors play no role in the maintenance of hypertension nor in the BP and HR adjustments induced by postural changes in EHT.

Verapamil and propranolol in essential hypertension.

Twenty-four subjects with mild to moderate essential hypertension completed this 9-wk parallel, randomized, double-blind study of the antihypertensive effects of verapamil (V) (240 to 480 mg%) and propranolol (P) (120 to 360 mg%). V lowered systolic and diastolic blood pressures in all postural positions, with an average reduction of 20/16 mm Hg. With the exception of standing systolic blood pressure, P also lowered systolic and diastolic blood pressures in all postural positions, with an average reduction of 9/11 mm Hg. Differences between V and P were significant only for sitting systolic blood pressure. Heart rate was decreased by P but was not affected by V. The PR interval was prolonged by V. Plasma levels of V and P were directly related to dose. Plasma levels of V were linearly related to those of its major metabolite, norverapamil (r = 0.81). There was no correlation between clinical response and the dose or plasma level of V or P, but all subjects who received 480 mg% V had an average blood pressure reduction of 20/16 mm Hg and plasma levels of the parent drug above 200 ng/ml. V is an effective antihypertensive for mild to moderate essential hypertension. Constipation, pedal edema, and a maculopapular rash were reported as side effects of V.

Codeine disposition in smokers and nonsmokers.

The bioavailability of codeine and extent of its transformation to morphine were stated in 12 smoking and 11 nonsmoking subjects after single doses 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12-hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half-life (t1/2), or areas under plasma concentration-time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 +/- 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 +/- 2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 +/- 4.9%) and in nonsmokers (50.2 +/- 2.1%) did not offer. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first-pass O-demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O-demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

A single-dose pharmacokinetic study of the antisickling agent cetiedil.

Cetiedil citrate is an antisickling agent shown to be effective in reducing the severity and duration of acute sickle cell crisis. With the use of a sensitive GC/MS assay, the pharmacokinetic profile of cetiedil was studied in normal men and in men with sickle cell anemia who were not in crisis at the time of study. A peak cetiedil concentration of 70 to 200 ng/ml was found immediately after a 30-minute drug infusion. The plasma level then gradually declined to approximately 10 ng/ml during a 3-hour distributive phase. Computer analysis of the data was most consistent with a three-compartment model. No pharmacokinetic differences were found between the normal men and the subjects with sickle cell. Because the cetiedil plasma levels achieved during this in vivo study are well below concentrations that exhibit antisickling activity in vitro, additional clinical studies will be necessary before an optimal dosing regimen can be established.

Intestinal dilatation associated with phenothiazine therapy: a case report and literature review.

The authors describe a fatal episode of intestinal dilatation associated with chlorpromazine therapy. A total of 26 similar cases associated with phenothiazine or tricyclic antidepressant therapy, including 9 fatalities, has been reported in the literature. The authors cite experimental evidence supporting this association. They emphasize the difficulty of recognizing this syndrome in the psychotic patient; careful evaluation is indicated in the constipated patient who exhibits vomiting, abdominal pain, distension, or tenderness.

Lidocaine prophylaxis in acute myocardial infarction.

Primary ventricular fibrillation (PVF) occurs in approximately 3--10% of uncomplicated acute myocardial infarction (AMI) patients. The major reason for this variability in incidence appears to be population diferences in the time from symptom onset to admission. Other risk factors have not been consistently shown to influence the risk of PVF. Warning arrhythmias do not warn of impending PVF in from 20--80% of AMI patients; thus, antiarrhythmic therapy reserved for those with warning arrhythmias may fail to prevent PVF in a significant number of patients. Although a review of 13 controlled trials of lidocaine prophylaxis shows only two suggesting a protective effect from this drug, only one study was free of major defects in trial design. This trial showed a striking decrease in PVF incidence when lidocaine was employed. Lidocaine should probably be administered to all uncomplicated AMI patients during the first 48 hours after infarction. Its utility in preventing ventricular fibrillation in complicated AMI patients and in the very early AMI period is unclear.

Identical multiple congenital anomalies/mental retardation (MCA/MR) syndrome due to del(2)(q32) in two sisters with intrachromosomal insertional translocation in their father.

We report two sisters with a deficiency of band 2q32 that resulted from meiotic crossover events in their father, who is a balanced, intrachromosomal insertional translocation heterozygote. This three-break rearrangement involving a single chromosome is among the rarest class of human structural chromosome abnormalities. A review confirms the theoretically predicted high risk of unbalanced progeny for such translocation heterozygotes. Fertility of carriers seems to be unimpaired in either sex. Available information is insufficient to define the effect of insertional translocation on homologue pairing, crossover frequency, and other meiotic phenomena.

Prediction of operative cholangiography in patients undergoing elective cholecystectomy with routine liver function chemistries.

A retrospective reviews of 195 consecutive patients who underwent elective cholecystectomy and operative cystic duct cholangiography (OCDC) were reviewed to establish criteria to correlate the preoperative laboratory data of liver chemistry tests and the actual biliary tract disease found in each patients. Patients who had a history of jaundice or other clinical indication for common bile duct exploration were excluded from this study. The patients were divided into four groups based on the results of the OCDC: I negative, II false positive, III false negative, and IV positive for choledocholithiasis. The results of the preoperative liver chemistry studies of the patients in each of the four groups were analyzed by the chi 2 method. The four liver chemistry tests were lactate dehydrogenase, SGOT, bilirubin, and alkaline phosphatase. When results of all preoperative liver chemistry tests were normal, there was no incidence of choledocholithiasis. As the number of chemistry test result elevations increased from one to four, the incidence of choledocholithiasis increased from 17% to 50% (p less than 0.001). Preoperative liver chemistry tests in selected patients undergoing elective cholecystectomy may provide a valuable indicator to the surgeon as to whether an OCDC should be performed at the time of surgery.

Inhibition of tolbutamide elimination by cimetidine but not ranitidine.

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on tolbutamide pharmacokinetics. Twelve healthy men were given a 1-g oral dose of tolbutamide on three occasions. Subjects were randomly assigned to three treatments in a crossover fashion: cimetidine 1,200 mg/d, ranitidine 300 mg/d, and placebo. Cimetidine significantly increased the tolbutamide area under the plasma concentration-time curve by 20% (range, -5% to 42%), increased the elimination half-life by 17%, and decreased the carboxytolbutamide:tolbutamide plasma ratio from 0.042 to 0.036. Ranitidine did not significantly alter tolbutamide pharmacokinetics.

Lack of effect of histamine H2-receptor antagonists on indocyanine green disposition measured by two methods.

Eleven healthy male volunteers were treated according to a randomized, crossover design with ranitidine (300 mg/day), cimetidine (1200 mg/day), or nothing for 48 hours. Ninety minutes after the 48-hour dose, each volunteer was given 0.5 mg/kg indocyanine green by iv bolus. Indocyanine green plasma concentrations were measured by the traditional spectrophotometric method at 800 nm and by HPLC simultaneously monitored at 214 and 656 nm. Neither histamine H2-receptor antagonist altered the disposition of indocyanine green. The mean (+/- S.D.) plasma clearance by the spectrophotometric method was 7.48 +/- 2.07 (control), 7.15 +/- 3.07 (ranitidine), and 6.88 +/- 1.35 ml/min/kg (cimetidine). The power to detect a 20 per cent change is 0.87. The spectrophotometric method generally produced a biexponential plasma concentration decay, whereas the HPLC method resulted in a monoexponential decay. Analysis of the 5- to 15-minute data by the conventional technique showed that although indocyanine green total plasma clearance was not significantly different for the two methods (P greater than 0.10), the volume of distribution was significantly greater (P less than 0.001) and the elimination rate constant was significantly smaller (P less than 0.001) for the spectrophotometric than the HPLC method. Although neither ranitidine nor cimetidine chronic administration alters indocyanine green disposition by either method, the absolute values of the pharmacokinetic parameters are dependent upon the analytical technique employed.

The influence of H2-receptor antagonists on steady-state concentrations of propranolol and 4-hydroxypropranolol.

Twelve healthy male volunteers were treated with 1200 mg/day cimetidine, 300 mg/day ranitidine, or no H2-receptor antagonist (control) for seven days in a sequence determined by Latin-square design. Each treatment period was separated by a seven-day washout. On the third day of each treatment period, 80 mg propranolol every 12 hours for nine doses was initiated. Whole blood concentrations of propranolol and 4-hydroxypropranolol were measured at 12 time points during the 12-hour period following administration of the last propranolol dose. Heart rate was measured before each blood sample was withdrawn. Cimetidine treatment was associated with a 47 per cent increase in the area under the propranolol concentration-time curve and a 17 per cent increase in elimination half-life of propranolol. Ranitidine had no significant effect on the concentration-time profile of propranolol. There were no significant differences in the 4-hydroxypropranolol pharmacokinetic parameters during any of the treatments. There was, however, a significant decrease in the average 4-hydroxypropranolol-to-propranolol steady-state concentration ratio during the cimetidine treatment. There was no significant difference in heart rate between any of the treatments. The elevation of propranolol concentrations during cimetidine treatment is likely due to metabolic inhibition by cimetidine.

Factors associated with nephrotoxicity and clinical outcome in patients receiving amikacin.

Data from 60 patients treated with amikacin were analyzed for factors associated with nephrotoxicity. In 42 of these patients, data were examined for factors associated with clinical outcome. Variables evaluated included patient weight, age, sex, serum creatinine level, creatinine clearance, duration of therapy, total dose, mean daily dose, organism minimum inhibitory concentration (MIC), mean peak levels, mean trough levels, mean area under the serum concentration-time curve (AUC), total AUC, mean AUC greater than MIC, total AUC greater than MIC, mean Schumacher's intensity factor (IF), total IF, In (mean maximum concentration [Cmax]/MIC). Model-dependent pharmacokinetic parameters were calculated by computer based on a one-compartment model. When the parameters were examined individually, duration of therapy and total AUC correlated significantly (P less than .05) with nephrotoxicity. In contrast, a stepwise discriminant function analysis identified only duration of therapy (P less than .001) as an important factor. Based on this model and on Bayes' theorem, the predictive accuracy of identifying "nephrotoxic" patients increased from 0.17 to 0.39. When examined individually, mean IF, MIC, total dose, mean daily dose, and ln (mean Cmax/MIC) correlated significantly (P less than .05) with cure. In contrast, a simultaneous multivariable analysis identified IF, MIC, and total dose according to one model and ln (mean Cmax/MIC) according to a second statistical model of parameters selected to have the greatest prospective value. Based on Bayes' theorem and the first model, the predictive accuracy of identifying patients not cured increased from 0.19 to 0.83. For the second model, the predictive accuracy increased from 0.19 to 0.50.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of concomitant ipsilateral fractures of the humerus and forearm.

We treated nineteen patients with concomitant ipsilateral fractures of the humerus and forearm resulting in a so-called floating elbow. The injuries that were treated without open reduction and internal fixation had a high incidence of non-union of the humerus. This has led us to prefer open reduction and internal fixation of both the humerus and the forearm fracture.

Estimating environmental exposures to sulfur dioxide from multiple industrial sources for a case-control study.

This paper first discusses how population exposures to environmental pollutants are estimated from environmental monitoring data and the problems that are encountered in estimating risk from pollutants on the basis of ecologic studies. We then present a technique of estimating individualized exposures to an atmospheric pollutant, sulfur dioxide (SO2), through atmospheric transport modeling for a case-control study. The transport model uses the quantities of SO2 released from 30 geographically identified industrial facilities and meteorological data (wind speed and direction) to predict the downwind ground-level concentrations of SO2 at geographically identified residences, receptors, of 797 study subjects. A distribution of facility SO2 emissions, uncertainties in effective stack height, and model uncertainty are incorporated to examine the uncertainty in the predicted versus ambient monitoring SO2 levels, and to generate an exposure uncertainty distribution for both the cases and controls. The transport model's accuracy is evaluated by comparing recorded ambient measurements of SO2 with the model's predicted SO2 estimates at geographically identified ambient monitoring stations.

Wolman's disease: report of a case, with multiple studies.

We studied a case of Wolman's disease that is apparently the first to be reported in a black infant. Culture of the skin fibroblasts showed massive accumulation of neutral lipids, accompanied by decreased esterolytic activity as measured by fluorometric assay. Electrophoresis showed decreased activity of an esterase allotype, with low electrophoretic mobility.

Severe hypophosphatemia in postoperative patients.

Severe hypophosphatemia may develop in postoperative patients for several reasons including alcohol withdrawal, diabetic ketoacidosis, nutritional recovery (refeeding) syndrome, and severe respiratory alkalosis. Severe hypophosphatemia may result in central nervous system abnormalities, muscle weakness, and renal, hepatic, cardiac, and respiratory dysfunction. Hypophosphatemia may be prevented by close monitoring of phosphorus concentrations in serum, especially in patients predisposed to developing this problem. Proper techniques for the maintenance and repletion of phosphate for both enteral and parenteral use are described.

Historical dose reconstruction project: estimating the population at risk.

This paper discusses methods used to estimate the size and location of the populations that lived around the Feed Materials Production Center near Ross, Ohio, from 1950 through 1990. This information will support an historical dose reconstruction for environmental exposures to radionuclides from this facility that is currently being done by the Centers for Disease Control and Prevention through a contract with Radiological Assessments Corporation. Available sources of data include (1) the U.S. Census, Ohio Township data; (2) the U.S. Census, Ohio Township block data; and (3) U.S. Geological Survey topographical maps that show structures. A distribution of age and sex is estimated that, together with population estimates, will provide information needed to estimate collective dose rates over time and to examine the feasibility of studying the relationship between exposure to radionuclides released from the Feed Materials Production Center and adverse health outcomes.

Hospital food service: is a chilled meal system best?

Royal Prince Alfred Hospital, Sydney, introduced the first chilled meal system into a major Australian hospital twenty years ago. Recently the food service has been converted back to a centralised system with conventional food production. The change has resulted in reduced operating costs and better quality food. This suggests that a chilled food system is not always the most economical form of hospital food service.

Recurrent substitutions of arginine 789 by cysteine in pro-alpha 1 (II) collagen chains produce spondyloepiphyseal dysplasia congenita.

A child with typical spondyloepiphyseal dysplasia congenita had a recurrent, heterozygous substitution of arginine 789 by cysteine in the triple helical domain of alpha 1 (II) chains of type II collagen. The amino substitution was due to the transition of cytosine 2913 to thymine in exon 41 of the COL2A1 gene. The amino acid substitution involved the Y position of a Gly-X-Y triplet.