Nifedipine gastrointestinal therapeutic system (GITS) for hypertensive patients in a primary care setting: results of the Extended Release Adalat Canadian Trial (EXACT).

Nifedipine gastrointestinal therapeutic system (GITS) is an extended-release dosage formulation that provides sustained blood concentrations of nifedipine over 24 hours. A 20-week, postmarketing surveillance study of the effectiveness and patient tolerability of nifedipine GITS 30 or 60 mg was conducted in the offices of 187 Canadian general practitioners from September 1992 to March 1994. A total of 1700 patients previously or newly diagnosed with mild-to-moderate essential hypertension (sitting diastolic blood pressure, 95 to 114 mm Hg) were included. The 20-week treatment period was completed by 1326 patients. Patients received nifedipine GITS 30 mg initially; the dose could be titrated upward to 60 mg after 3 and 6 weeks. Of all patients entered, 605 (35.6%) reported one or more adverse events. The three most frequently occurring adverse events were headache (12.2%), peripheral edema (8.1%), and dizziness (2.9%). The frequency of adverse events was highest in the first 3 weeks and decreased subsequently. The overall incidence of adverse events was 29.8% in patients receiving 30 mg of nifedipine GITS and 25.3% in those receiving 60 mg; adverse events were the cause of study discontinuation in 12.3% of patients. The overall health status of patients as measured by the SF-36 questionnaire was comparable to that previously reported for healthy individuals. At baseline, mean (+/- SE) systolic/diastolic blood pressure values for all patients were 160.1 +/- 0.4/97.4 +/- 0.2 mm Hg. Final blood pressure readings after 20 weeks of treatment in the 30-mg group (141.5 +/- 0.4/84.8 +/- 0.2 mm Hg) and the 60-mg group (146.6 +/- 0.8/88.8 +/- 0.4 mm Hg) were significantly decreased from baseline. At week 20, the 30-mg dose was sufficient to maintain blood pressure in 74.5% of patients; 25.5% of patients required 60 mg. Subgroup analysis revealed similar responses in patients who had received blood pressure medication before study initiation and those who had not. Response was also independent of age and type of previous antihypertensive therapy. In general medical practice, the 30-mg and 60-mg doses of nifedipine GITS were both effective and well tolerated and had minimal or no negative effects on the overall health status of treated individuals.

Diazepam metabolism by rat and human liver in vitro: inhibition by mephenytoin.

1. Diazepam metabolism and its association with mephenytoin hydroxylase were studied in vitro using human and rat livers. 2. Enzyme kinetic parameters were obtained for the formation of p-hydroxydiazepam (p-hydroxy-DZP), N-desmethyldiazepam (NDZ), and temazepam (TMZ) from diazepam (DZP) in rat liver fractions. The Km values for formation in rat of p-hydroxy-DZP, NDZ and TMZ were 14 +/- 3 (SEM) microM, 44 +/- 4 and 63 +/- 8, respectively; clearance values calculated from Vmax/Km were 5.7, 3.2 and 4.9 ml/g per min, respectively. 3. Mephenytoin (MP) competitively inhibited, in rat liver, the formation of NDZ, but not the formation of p-hydroxy-DZP or TMZ; in human liver neither NDZ nor TMZ formation was inhibited by MP. 4. In seven different human livers the formation of p-hydroxy-DZP represented a minor pathway compared to the formation of NDZ and TMZ.

Metabolism of diazepam in vitro by human liver. Independent variability of N-demethylation and C3-hydroxylation.

The interindividual variability of diazepam metabolism was studied using human livers. The formation of N-desmethyldiazepam (NDZ) and 3-hydroxydiazepam (temazepam, TMZ), was monitored by gas chromatography. In 10 livers, Km values for NDZ and TMZ formation varied independently from each other, each by a factor of 4, from 100 to 400 microM. This variability is consistent with the presence of at least two different cytochrome P-450 species controlling formation of these metabolites. In the same livers, Vmax for NDZ and TMZ production varied 6-fold and 15-fold, respectively.

Comparative bioavailability study of three sustained release quinidine formulations.

The absorption characteristics of 3 sustained release quinidine formulations were assessed in 12 healthy male volunteers in a randomised 3-way crossover trial. Each formulation ('Quinidex' 300mg, 'Biquin Durules' 250mg and 'Quinaglute Dura-Tabs' 324mg) was administered as a single tablet every 12 hours for 5 days. Peak quinidine serum concentrations of 2.7 +/- 0.8 mg/L occurred 2.5 +/- 1.1 hour after 'Quinaglute' administration, significantly higher (p less than 0.01) than concentrations of 1.6 +/- 0.4 mg/L achieved 4.2 +/- 1.1 hours following 'Biquin' dosing and 1.7 +/- 0.6 mg/L attained 3.9 +/- 2.7 hours after 'Quinidex' ingestion. The extent of absorption based on AUC infinity and normalised for the anhydrous quinidine content was similar for the 3 products. Following multiple dosing, the mean steady-state trough concentration of quinidine was 2.06 +/- 0.56 mg/L for 'Quinidex', significantly greater (p less than 0.05) than that of 'Biquin' (1.18 +/- 0.67 mg/L) or 'Quinaglute' (1.58 +/- 0.58 mg/L). The rate of absorption was found to be much slower for 'Quinidex' than for the other 2 sustained release quinidine formulations. Comparison of the residual sums of squares from simple linear regression of Wagner-Nelson plots did not demonstrate a preference for a zero- or first-order absorption model. Nevertheless, the absorption of 'Quinidex' was twice as prolonged as that of 'Biquin' and 'Quinaglute' regardless of model; first-order absorption half-lives were 2.83 +/- 1.02 hours, 1.25 +/- 0.6 hours and 1.43 +/- 0.88 hours, respectively. The data also suggest that 'Quinidex' absorption may continue beyond 12 hours in some subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of tachyphylaxis in gastric acid secretion during pentagastrin infusion.

Tachyphylaxis to stimulation of gastric juice secretion during intravenous pentagastrin (PG) infusion has been reported in animal studies. We assessed the course of gastric response to PG 2 micrograms/kg/hr over eight hours in eight healthy subjects. Peak H+, pepsin, and volume secretions occurred during the second half hour of stimulation. Peak H+ output was 11.6 +/- 1.3 mmol/0.5 hr or 7.6 +/- 0.8% of the total eight-hour secretion. During subsequent half-hour collection intervals, there was no significant decline in response, and the average output was 10.3 +/- 0.4 mmol/0.5 hr (6.5 +/- 0.1%). Peak pepsin and volume secretions were respectively 10.0 +/- 1.4% (74.8 +/- 11.6 mg/0.5 hr) and 8.8 +/- 1.1% (146.3 +/- 17.4 mL/0.5 hr) of the total eight-hour secretion. Although there was a significant decline in pepsin and volume response subsequent to the peak output, the decline was not continuous, and pepsin and volume secretions were maintained, respectively, at 6.0 +/- 0.2% (46.1 +/- 2.5 mg/0.5 hr) and 6.2 +/- 0.1% (107.5 +/- 3.0 mL/0.5 hr) of the total eight-hour secretion. Our study did not demonstrate any tachyphylaxis in H+ response to continuous PG stimulation. This model appears to be a valid tool for the assessment of histamine-H2 antagonist effects on stimulated gastric juice secretion over 8 hours in humans.

Pharmacokinetics of cimetidine after subchronic administration.

The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26-29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t1/2 beta and V beta were similarly unchanged. However mean renal clearance (CLR) and fe were significantly increased following 2 weeks of drug dosing (CLR 5.41 ml X min-1 X kg-1; fe 0.61) compared to control (CLR 4.00 ml X min-1 X kg-1; fe 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml X min-1 X kg-1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.

Control of gastric pH with cimetidine: boluses versus primed infusions.

Previous studies suggest that antacids are more effective than intravenous cimetidine in maintaining the gastric pH above 4.0 in acutely ill patients. We hypothesized that this was because blood levels of cimetidine are not sustained at therapeutic levels with the bolus doses. The purpose of this study was to compare gastric pH and serum cimetidine levels when cimetidine was administered as bolus versus infusion. We studied 23 acutely ill patients who received intravenous cimetidine given as boluses and primed infusions. The gastric pH could be maintained above 4.0 with infusions of up to 50 mg/h (1200 mg/day) in 20 patients, compared with only 5 patients with bolus administrations of up to 300 mg every 6 h (1200 mg/day). The differences in ability to maintain the gastric pH above 4.0 were entirely due to the reduced ability of bolus infusion to maintain an adequate serum level. Neither technique could maintain the pH above 4.0 in 3 patients, all of whom had received cimetidine recently. A gastric pH greater than 4.0 correlated directly with a therapeutic serum cimetidine level. We conclude that infusions of cimetidine are better able to sustain therapeutic blood levels and, therefore, are superior to bolus cimetidine in maintaining gastric pH above 4.0. Some patients, however, may not respond to cimetidine even if therapeutic levels are achieved and may require supplemental antacids.

In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase.

Human liver preparations were used to screen various drugs for their capability of binding to mephenytoin p-hydroxylase and sparteine monooxygenase, two cytochrome P-450-catalyzed activities that are independently heritable. For this screening, any indication of competitive inhibition by the drug was interpreted as an indication of binding. Among 64 drugs and alkaloids tested, 24 compounds caused inhibition of mephenytoin p-hydroxylation but the inhibition was weak in most cases; by contrast, 40 of the 64 compounds inhibited sparteine oxidation, the inhibition being potent in many cases. The only fairly strong inhibitors of mephenytoin p-hydroxylation were the alkaloid papaverine and the monoamine oxidase inhibitors tranylcypromine and nialamide. The results of these inhibition studies confirm the independence of the two monogenic defects observed in different populations. Metabolism is possibly altered in poor metabolizers of mephenytoin with fewer drugs than in poor metabolizers of sparteine.

Benzydamine: a critical review of clinical data.

Over 40 published and unpublished articles on double-blind controlled clinical trials with the local application of benzydamine as an antiinflammatory drug were reviewed with special reference to the randomization of patients, the description of the disease entity, the clinical trial and its statistical analysis. It was concluded that benzydamine applied locally consistently produced relief of pain with a demonstratable antiinflammatory effect and caused infrequent side-effects. Hence it was considered a safe and effective method of producing pain relief by local application.

A human cytochrome P-450 characterized by inhibition studies as the sparteine-debrisoquine monooxygenase.

The present study compares the debrisoquine monooxygenase and the sparteine monooxygenase activities of human liver microsomes. In the presence of 14 competitive inhibitors, apparent inhibition constants (Ki) as determined by these two activities ranged over four orders of magnitude with a correlation coefficient 0.99. These in vitro results represent the strongest evidence to date that the debrisoquine monooxygenase and the sparteine monooxygenase are identical and involve a single isozyme of cytochrome P-450.

A controlled trial of the effect of parenteral nutritional support on patients with respiratory failure and sepsis.

Energy and protein metabolism was studied in 11 septic patients receiving ventilatory support while on three different intravenous regimens. They received 5% dextrose in water (D5W), and one of two different regimens of parenteral nutritional support (PNS); either amino acid and dextrose (PNA) or amino acid and dextrose and lipid (PNB). All patients were given D5W and PNS in random order. The energy intake was targetted to exceed by 50% the measured metabolic rate. On D5W the mean measured energy expenditure was only 15.2% above the expected energy expenditure (p<0.02). A respiratory quotient of 0.75 while on D5W showed that in the absence of PNS the major part of energy requirements came from fat oxidation. In addition, on D5W these patients were in negative nitrogen and protein (synthesis-catabolism) balance. With PNS the metabolic rate rose significantly (p<0.02). While on PNA, the CO2 production was significantly higher than with PNB, and despite receiving all non-protein energy as glucose, the patients continued to oxidise fat to meet about 30% of their energy requirements. Continued fat oxidation was found to be associated with insulin resistance and high catecholamine levels, suggesting a cause and effect relationship. PNS caused an increase in protein (synthesis - catabolism) and nitrogen balances, and reduced leucine oxidation. The fall in leucine oxidation was greater on PNB than on PNA. Protein and nitrogen balances, expressed per gram of amino acid infused, were significantly better with PNB than PNA. It was concluded that insulin resistance may make fat an efficient source of energy.

In vitro metabolism of sparteine by human liver: competitive inhibition by debrisoquine.

Population data indicate that the genetic control is the same for the oxidation of sparteine and debrisoquine, although whether the level of control is regulatory or enzymatic is not clear. Therefore, the influence of debrisoquine on the rates of in vitro formation of the two dehydrogenated metabolites of sparteine in the 9000 x g supernatant fractions of human liver was examined. The interaction of these two drugs was competitive, indicating that the same form of cytochrome P450 is responsible for their biotransformation. Antipyrine at concentrations as high as 4 mM had no effect on sparteine oxidation.

Ranitidine kinetics and dynamics. I. Oral dose studies.

Ranitidine, an H2-receptor antagonist, has been shown to reduce pentagastrin-stimulated gastric secretion. We examined the relationship between inhibition of gastric secretion and ranitidine serum concentration. Twelve normal male subjects received 20, 40, or 80 mg of ranitidine orally 90 min before starting a 3-hr continuous infusion of pentagastrin, 2 micrograms/kg/hr. Ranitidine, 20, 40, and 80 mg, reduced hydrogen ion output by 29%, 50%, and 70% and secretion volume by 21%, 37%, and 47%. Pepsin activity was reduced by 8%, 50%, and 49% by the same doses. Peak serum concentration was correlated positively with percent reduction in hydrogen ion output (r = 0.81, P less than 0.001) and volume (r = 0.71, P less than 0.01) over a 2-hr period. A 50% inhibition of hydrogen ion output was associated with a peak ranitidine serum concentration of 165 micrograms/l and subjects reached peak serum concentration 60 to 120 min after oral dosing. An appropriate therapeutic effect should be achieved with 8 hourly doses of 80 mg ranitidine. No clinically significant subjective or toxic biochemical effect of ranitidine was seen after single doses. White blood cell count was reduced in 11 of 12 subjects 7 days after ranitidine, an observation which calls for further investigation.

Ranitidine kinetics and dynamics. II. Intravenous dose studies and comparison with cimetidine.

Intravenous ranitidine has been shown to reduce pentagastrin-stimulated gastric secretion. Eight normal men received, in randomized order, 60 mg ranitidine or 300 mg cimetidine intravenously over 2 min. Both ranitidine and cimetidine induced decreases in volume hydrogen ion content and pepsin activity of stimulated gastric juice. Ranitidine half-life (t1/2) was 2.1 +/- 0.1 hr and cimetidine (t1/2) was 1.5 +/- 0.1 hr. Ranitidine volume of distribution was 1.6 +/- 0.1 l/kg and that of cimetidine was 1.12 +/- 0.12 l/kg. The clearance of ranitidine was 0.54 +/- 0.04 l/kg hr-1 and that of cimetidine was 0.5 +/- 0.05 l/kg hr-1. It is suggested that the intravenous loading dose of ranitidine necessary to attain a serum concentration of 200 micrograms/l (which would achieve a 50% inhibition of gastric acid) is 0.3 mg/kg, followed by an infusion rate of 0.11 mg/kg hr-1.