Prazosin kinetics in hypertension.

Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two-compartment open model. Terminal half-life (t1/2 beta) was about 3 hr and apparent volume of distribution (Vd beta) about 0.6 l/kg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 l/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first-pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and alpha 1-acid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first-order kinetics with a linear correlation between dose and steady-state plasma concentration (P less than 0.001). There were substantial variations in plasma concentrations between patients and there were also day-to-day variations in concentration within the same patient.

Prazosin dynamics in hypertension: relationship to plasma concentration.

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P less than 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P less than 0.01) during the beta-elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P less than 0.01) with that after the first oral steady-state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.

Concentration-controlled or effect-controlled trials: useful alternatives to conventional dose-controlled trials?

Historically, dose-finding trials have been confirmatory in nature despite the fact that these trials represent an important and essential 'learning' phase in the drug development process. About 10 years ago 2 alternatives to the randomised dose-controlled trial (RDCT) were proposed as being more informative trial types. Controlling systemic drug exposure in order to improve efficiency of a trial forms the basis for the suggestion of a randomised concentration-controlled trial (RCCT). For the common instance where pharmacodynamic variability is larger than pharmacokinetic variability, the randomised effect-controlled trial (RECT), where patients are randomised to the effect of interest was suggested as even more informative. A survey of the literature shows that the RCCT has been sparsely applied and RECT not at all. For RCCT, the practical complications of carrying out the study seldom makes it the study type of choice. For RECT, the limited number of suitable situations for its application and the fact that the same effect is used for randomisation and analysis may explain the lack of applications. As a somewhat more favourable trial type, we suggest the randomised biomarker-controlled trial (RBCT), where patients are randomised to a certain value or range of a biomarker whereas the analysis is performed on another, clinically more relevant, effect. Although the RBCT has some attractive features, for example contributing to validation of a biomarker as a surrogate for clinical outcome, it is unlikely to be extensively used. Instead, the main shift from confirming to learning in dose-finding trials is coming from the incorporation of well-known learning components into the RDCT (e.g. sparse concentration measurements combined with population pharmacokinetic-pharmacodynamic, biomarker measurements and analysis of effect measures throughout the entire trial period).

Intragastric pH after oral administration of single doses of ranitidine effervescent tablets, omeprazole capsules and famotidine fast-dissolving tablets to fasting healthy volunteers.

BACKGROUND: The therapeutic effect of drugs inhibiting acid production on acid-related discomforts is related to both the onset and duration of action of the drug. The effects on gastric pH by single oral doses of some acid-inhibiting drugs were investigated by measuring daytime (morning to lunch) intragastric pH in healthy volunteers. METHODS: This randomized, single-dose, 4-way crossover study included 15 healthy fasting subjects. Effervescent ranitidine tablets 150 and 300 mg, fast-dissolving famotidine tablets 20 mg and capsules of omeprazole 20 mg were administered. Measurements of intragastric pH were performed every 4 s for 10 min prior to drug administration and during the following 4 h. RESULTS: The effervescent ranitidine tablets (150 or 300 mg) produced similar changes in intragastric pH: following an immediate increase to about pH 5, intragastric pH decreased slightly over the next 10-20 min. Thereafter pH increased steadily, reaching pH 4 after 20-40 min and pH 6 after about 70 min. After famotidine, pH 4 was reached after 80 min, significantly slower than ranitidine. After omeprazole, pH 3 was never reached. Ranitidine 150 and 300 mg showed significantly larger integrated pH responses over the 4-h observation period, compared to famotidine (P = 0.0288 and 0.0074) or omeprazole (P < 0.001). CONCLUSIONS: After single-dose administration to healthy fasting volunteers), ranitidine effervescent tablets showed a significantly more rapid onset of action and a significantly larger integrated pH response compared to either famotidine 20 mg fast-dissolving tablets or omeprazole 20 mg capsules.

Pharmacokinetics of intravenous cefuroxime during intermittent and continuous arteriovenous hemofiltration.

The pharmacokinetics of cefuroxime were determined in ten patients during intermittent hemofiltration (IHF) and in three patients during continuous arteriovenous hemofiltration (CAVH). All patients received a bolus dose of 1.5 g of cefuroxime intravenously and the concentrations of cefuroxime in serum and ultrafiltrate were followed during the hemofiltration period and up to 16 hours after injection of cefuroxime. During IHF the mean terminal half-life of cefuroxime was 1.6 +/- 0.3 hours compared with a terminal half-life of 21.7 +/- 5 hours after treatment. The total cefuroxime clearance was 120 +/- 22 ml/min. The hemofiltration clearance represented 86% of the total clearance and the hemofiltration process removed in average 63% of the dose. During CAVH the terminal half-life of cefuroxime was 7.9 +/- 2.2 hours. The total plasma clearance for cefuroxime was 32 +/- 7.5 ml/min where the CAVH-treatment represented only 34% of the total clearance. From these data we suggest that a full loading dose (1.5 g of cefuroxime) should be given after each intermittent hemofiltration treatment when performed every second day. In CAVH, where nonrenal clearance will influence the dosage scheme significantly, we suggest an initial dose of 1.5 g of cefuroxime to be followed by a supplementary dose of 750 mg every 20-24 h.

Subjective gastrointestinal tolerability of acetylsalicylic acid and paracetamol after single dose treatment.

UNLABELLED: A prospective, randomised, double-blind, parallel group, two center, single-dose study was conducted to evaluate and compare the incidence of upper gastrointestinal complaints of acetylsalicylic acid and paracetamol. 600 healthy volunteers received acetylsalicylic acid (2 effervescent tablets of 400 mg), paracetamol (2 effervescent tablets of 500 mg) or placebo (2 effervescent tablets) in three treatment groups. Subjects filled in a questionnaire at 0.5, 1, 2, 3 and 4 h after dosing to evaluate eight upper gastrointestinal symptoms, which were stomach pain, burning sensation, nausea, heartburn, gas, burping, indigestion and upset stomach. The primary study objective was to show equivalence between acetylsalicylic acid and paracetamol. RESULTS: The absolute number of subjects reporting gastrointestinal intolerance were 50 of 200 in the placebo group, 46 of 200 in the paracetamol group and 56 of 201 in the acetylsalicylic acid group. The statistical test showed equivalence between both active substances. CONCLUSION: The rate of gastrointestinal intolerance following a single dose of two effervescent tablets of acetylsalicylic acid is equivalent to that of paracetamol and not different from gastrointestinal intolerance of placebo.

Pharmacokinetics of recombinant human insulin-like growth factor I given subcutaneously to healthy volunteers and to patients with growth hormone receptor deficiency.

The pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) were studied in healthy volunteers and in patients with growth hormone receptor deficiency (GHRD; Laron syndrome). Following single subcutaneous injections of rhIGF-I, 40 and 80 micrograms/kg, to healthy volunteers, the peptide was absorbed slowly, with a maximum concentration reached after about 7 hours. Following daily multiple subcutaneous injections of rhIGF-I, 40 micrograms/kg, trough concentrations of IGF-I were increased by 277 +/- 50 micrograms/l (mean +/- SD) from baseline. IGF-I was thus characterized as a low-clearance peptide, with a clearance and half-life estimated at about 0.20 ml/minute/kg and 20 hours, respectively, in healthy volunteers. The volume of distribution was low, about 0.20-0.36 litres/kg, the bioavailability of subcutaneously administered rhIGF-I was 100%, and the rate of production of IGF-I was estimated to be about 50 micrograms/kg/day (3.5 mg/day). Patients with GHRD had low baseline IGF-I concentrations (30-50 micrograms/l) and a much more rapid turnover of IGF-I compared with that in healthy volunteers. The clearance and half-life of IGF-I were estimated to be about 0.60 ml/minute/kg and 6 hours, respectively. The volume of distribution was about the same as in healthy subjects. Due to the rapid turnover of IGF-I, trough IGF-I concentrations were increased to just above baseline during subcutaneous injections of 40 micrograms/kg once daily for 7 days. The maximum increase in IGF-I levels was 111 +/- 12 micrograms/l and 150 +/- 3 micrograms/l following daily subcutaneous injections of 40 x 1 and 40 x 2 micrograms/kg for 7 days, respectively.

The preparation of ligandin with glutathione-S-transferase activity from porcine liver cytosol affinity chromatography on bromosulphophthalein-Sepharose.

A simple and rapid method for the purification of porcine ligandin with glutathione-S-transferase activity is presented. After ion-exchange chromatography on DEAE-Sephadex, ligandin is isolated from porcine liver cytosol by affinity chromatography on bromosulphophthalein-Sepharose and gel filtration of Sephadex G-100. Evidence is presented that the purified ligandin is homogeneous with respect to polyacrylamide-gel electrophoresis (7.5%) and sodium dodecylsulphate-gel electrophoresis. Physico-chemical investigations show that the purified ligandin has properties similar to those of ligandin isolated from other species with respect to molecular weight, amino-acid composition, secondary structure and catalytic activity. As is the case for human and rat ligandin, porcine ligandin binds bilirubin. Evidence is also presented that porcine liver cytosol contains several bromosulphophthalein-binding proteins with basic isoelectric points lacking catalytic activity.

Implications of intraindividual variability in bioavailability studies of furosemide.

Intrasubject variation in bioavailability (rate and extent) and disposition of furosemide 40 mg was investigated using a repeated, randomized, double-blind cross-over study in 8 healthy subjects. Two generic tablet formulations (Lasix and Furix) and intravenous furosemide were compared on 6 separate days. Extensive intrasubject variability after oral administration was observed in AUC, mean absorption time (MAT) and urinary excretion. The variability (error variance) within the dosage forms was as large as that between the two generics. These variations most probably depended on the absorption process, since the repeated i.v. doses showed only marginal intrasubject variability. Absolute bioavailability was 56% for Lasix and 55% for Furix (AUC). The range was 20 to 84% between individuals and the maximal range within one individual was 20 to 61%. Confidence interval and Bayesian analysis showed a high probability of non-equivalence not only between but also within the generics when the separate cross-over experiments were analyzed (8 observations). When extending the analysis to 16 observations, bioequivalence was demonstrated for the two generic tablets. Rate of absorption, quantified as MAT, was 128 min for Lasix and 98 min for Furix (16 observations). Since MAT was significantly longer (p less than 0.001) than the mean residence time after the i.v. dose (57 min), absorption was evidently the rate-limiting step in the overall kinetics of oral furosemide. Intraindividual variation in absorption is a confounding factor in bioavailability studies of furosemide using limited numbers of subjects. This is important to consider when designing and evaluating bioavailability studies for drugs showing these variations.

Steady-state kinetics of sustained-release phenylpropanolamine.

The plasma concentrations and the urinary excretion of phenylpropanolamine were studied in eight healthy volunteers during a dose interval in steady state after intake of a sustained-release preparation of the drug (Rinexin, AB Leo). The plasma and urine levels were determined by a gas chromatographic method using electron capture detection, with a detection limit of about 10 ng/ml. The sustained-release action of the dosage form was consistent in all subjects, with a flat plasma concentration-time profile between 2 and 8 h after dose intake. Cmax was 167 +/- 28 ng/ml (mean +/- SD) and Cmin 59 +/- 19 ng/ml. The terminal plasma half-life was 5.6 +/- 1.0 h, total body clearance 0.57 +/- 0.14 l/kg/h, Vdarea 4.4 +/- 1.2 l/kg, and the fraction excreted unchanged in the urine 86 +/- 13%. In conclusion, phenylpropanolamine was found to be a high clearance drug characterized by extensive renal elimination of unchanged drug. The plasma levels showed only small interindividual variations in our healthy volunteers. Caution should be taken in treating patients with impaired renal function.

Pharmacokinetics of intravenous recombinant human erythropoietin in patients with chronic renal failure.

In order to improve our understanding of the dose-concentration and concentration-effect relationships, the pharmacokinetics of recombinant erythropoietin were studied after the initial dose (n = 6) and after repeated doses (n = 9) administered intravenously in patients with chronic renal failure. Several venous blood samples were collected before (to obtain the baseline concentration) and after an intravenous dose of erythropoietin. A radioimmunoassay was used to determine the erythropoietin concentration in the samples. The apparent volume of distribution at steady state was 4.2 +/- 0.91 (initial dose) and 3.7 +/- 0.61 (repeated dosing), which is close to the assumed plasma volume in these patients. The half-life was 5.3 +/- 1.3 h and 5.8 +/- 1.2 h in the two groups, respectively, and is therefore too short for any accumulation to be expected when dosing three times per week. Consequently, no difference in baseline values could be detected between the groups. The clearance of erythropoietin in the groups was estimated to be 11.4 +/- 7.0 ml min-1 and 7.8 +/- 3.8 ml min-1, respectively. Erythropoietin kinetics did not differ after repeated dosing compared to the single initial dose. Intravenous administration of erythropoietin will result in high peak concentrations followed by a rapid decline to basal values.

Doxycycline carrageenate--an improved formulation providing more reliable absorption and plasma concentrations at high gastric pH than doxycycline monohydrate.

The effect of increased gastric pH (obtained by pre-treatment with omeprazole) on the bioavailability of doxycycline monohydrate and doxycycline carrageenate has been investigated in 24 healthy volunteers, using an open, randomised, four-treatment, four-period, cross-over, 2 x 2 factorial design. Each subject received a single dose of 100 mg of each of the doxycycline formulations with and without pre-treatment with omeprazole (40 mg daily for 7 days). The two formulations were bioequivalent (rate and extent) during fasting without omeprazole pre-treatment, whereas after omeprazole, the monohydrate showed a highly significant decrease in bioavailability (38% for AUC and 45% for Cmax) compared to the carrageenate formulation, which was not affected by prior administration of omeprazole. Many of the subjects did not reach a therapeutic plasma level of doxycycline during the combination of omeprazole and doxycycline monohydrate, and most adverse events (mainly gastrointestinal) were reported after this combination. As large populations of patients have a high gastric pH due to frequent use of H2-blockers, proton pump inhibitors and antacids, as well as to physiological achlorhydria, the decreased absorption of doxycycline monohydrate may well have a clinical impact, for example when the patients are treated with tetracyclines for an infection.

Chloroquine excretion following malaria prophylaxis.

Urinary excretion of chloroquine and its desethyl-metabolite was monitored for up to 395 days after the last dose of oral chloroquine (300 mg base) taken once weekly for 10 weeks as malaria prophylaxis. Concentrations in plasma could be followed for up to 70 days after the last dose. A three exponential decay was applied to the urinary excretion data. The half-life of the terminal phase varied from 45 to 55 days for chloroquine and from 59 to 67 days for the metabolite. Mean residence time was approximately 20 days for the parent compound and 35 days for the metabolite, indicating that the terminal phases are of less importance for the effective half-lives.

Discrepancy between bioavailability as estimated from urinary recovery of frusemide and total diuretic effect.

1. Frusemide was given at a dose of 60 mg as two oral controlled release (CR) formulations and as plain tablets in a randomised, balanced, three way cross over design to 26 healthy volunteers. Urinary volume, and contents of frusemide, sodium, chloride and potassium were measured in samples taken over 24 h. 2. There was a marked difference between the CR formulations on one hand and the plain tablets on the other, in excretion of frusemide and diuresis vs time. The total diuretic/saluretic effect was only marginally lower (19 and 28% respectively, P less than 0.05) after CR compared with plain tablets although the fraction absorbed was markedly decreased (39 and 51% lower, respectively, P less than 0.05), estimated as urinary recovery of frusemide. The total diuresis of the two CR formulations did not differ although the urinary recovery was significantly different (P less than 0.05). 3. The diuretic effect vs frusemide excretion rate showed minimal counter-clockwise hysteresis after plain tablets while the CR formulations produced clockwise hysteresis indicating tolerance. 4. In agreement with the concept of efficiency, the higher diuretic/saluretic effect per amount of excreted frusemide may be a consequence of the slower output of frusemide in urine with the CR formulations compared with plain tablets. The major part of the pharmacological effect was produced with a higher efficiency after CR compared with plain tablets. It should be noted that the pharmacokinetics of a drug and its pharmacodynamic potency independently determine the total response.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of loracarbef on the normal oropharyngeal and intestinal microflora.

20 healthy volunteers received loracarbef capsules 200 mg b.i.d. for 7 days. Saliva and stool specimens were taken before loracarbef administration and on the 2nd, 5th, and 7th day during the administration period, and again 2, 5 and 9 days after withdrawal of the antibiotic to study the effect of loracarbef on the normal microflora. The concentrations of loracarbef in serum, saliva and faeces were determined by an agar diffusion method. The mean serum peak concentration attained after 1 h was 6.8 mg/l and the saliva concentrations were in the range 0-0.9 mg/l. The loracarbef concentrations in faeces ranged from 0 to 0.9 mg/kg. The changes in the the oropharyngeal microflora were minor and only bacteroides rods were affected. In the intestinal aerobic microflora, the number of enterococci and streptococci slightly increased while staphylococci, micrococci, corynebacteria, bacillus and enterobacteria were not affected. The number of bifidobacteria and eubacteria in the anaerobic microflora decreased while no other bacterial groups were affected. One week after withdrawal of loracarbef, both the oropharyngeal and intestinal microflora had returned to normal. No new colonizing loracarbef resistant microorganisms were observed during the investigation period.

Impact of dirithromycin on the normal oral and intestinal microflora.

Twenty healthy volunteers received 500 mg of dirithromycin orally once daily for seven days. The concentrations of dirithromycin in serum and saliva were low (less than or equal to 1.5 mg/l), while the faecal concentrations were high (greater than or equal to 12 mg/kg). The numbers of streptococci, Haemophilus and Neisseria increased in the aerobic oral microflora during dirithromycin treatment. In the aerobic intestinal microflora, the numbers of enterobacteria decreased significantly, while streptococci and staphylococci increased. New colonizing dirithromycin resistant enterobacteria were isolated during and after treatment. The anaerobic intestinal microflora was also affected; thus the numbers of gram-positive cocci, bifidobacteria, eubacteria and bacteroides decreased, while the numbers of clostridia and lactobacilli increased. Dirithromycin has an ecological impact on the oral and intestinal microflora.