Comparison of verapamil and bepridil,two slow channel inhibitors,in protection against calcium-induced arrhythmias

Summary Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl₂-induced arrhythmias has been compared in rats. CaCl₂ was administered i.v. by continuous infusion until death (25 mg·kg^–1·min^–1 or 40 mg·kg^–1·min^–1) or by bolus injection (160 mg·kg^–1). Bepridil (5, 10 mg·kg^–1) or verapamil (2.5,5 mg·kg^–1) were injected 10 min before CaCl₂. Bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1) prolong the survival time during CaCl₂ infusion. After pretreatment, the injection of 160 mg·kg^–1 CaCl₂ is less toxic: 25% of animals are protected by bepridil (5 mg·kg^–1), 41% by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1).At death the myocardial Ca²⁺ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca²⁺/total injected Ca²⁺ is significantly lowered by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.     

Development of a model for integrated pharmacokinetic and pharmacodynamic studies of intravenous anaesthetic agents: Application to minaxolone

Summary This study reports an approach to the investigation of new intravenous anaesthetic agents. Minaxolone (0.5%) was administered to healthy young adult volunteers in three different phases of study: (i) Subanaesthetic constant-rate infusion of 0.01 mg·kg^–1min^–1 for 120 min; (ii) Subanaesthetic and anaesthetic infusion regimens of 0.05 mg·kg^–1 min^–1 for 60 min, followed immediately by 0.020 mg·kg^–1min^–1 for 60 min; approximately four weeks later the same subjects received infusions of 0.01 mg·kg^–1min^–1 and 0.015 mg·kg^–1min^–1 respectively for the same period of time; (iii) Bolus injections of 10 mg and 40 mg over 1 min, at 2 h apart. Similar pharmacokinetic parameters were derived from all three different regimens, most notably characterised by high total body clearance (1.6 to 3.2l·min^–1), correlating with rapid lucid clinical recovery of CNS function. Renal clearance was less than 0.5% of total body clearance, which was consistently 2 to 3 times the clearance of indocyanine green. Terminal half-life was short.The subanaesthetic infusion regimen of minaxolone produced a sleep-like state from which subjects were rousable, obeyed commands readily and maintained verbal contact with investigators, while remaining amnesic throughout. This occurred at blood minaxolone concentration of 0.14 to 0.15 mg·l^–1. In the second stage, general anaesthesia was induced at a mean blood minaxolone concentration of 0.24 mg·l^–1 (SD 0.11). Intravenous bolus injections of 40 mg minaxolone invariably induced anaesthesia with mean blood concentrations of 0.49 mg·l^–1 (SD 0.29) 2 min postinjection. Onset of anaesthesia was very rapid, mean 55 s (SD 10), with a consistent duration of anaesthesia (mean 23 min, SD 3). Recovery was very rapid and lucid, without any tendency to lapse back into sleep again.Generally, the incidence of adverse effects was greatest with anaesthetic bolus doses and least with subanaesthetic infusions. Whilst only mild excitatory movements were observed in 60% of subjects who received the subanaesthetic infusion, these increased in frequency and intensity with the anaesthetic infusions and occurred with the greatest severity in all subjects who received the 40 mg bolus injection. Tachycardia invariably was noted in all phases of study. A remarkably high incidence of respiratory upsets, in the form of tachypnoea, hyperventilation, apnoea, hiccoughs and laryngospasm, was observed with the 40 mg bolus dosage. Minaxolone, therefore, whilst possessing pharmacokinetic properties desirable of an IV anaesthetic agent, had disturbing clinical effects which may limit its clinical use. Using this approach, studies in only 15 volunteer subjects were successful in describing the pharmacokinetics, blood concentration-response relationships as well as the incidence and nature of side effects. On the basis of these data, it was possible to determine that the new drug, minaxolone, did not show sufficient promise to warrant further development. This methodology would seem to provide a useful model in the investigation of new intravenous anaesthetics to optimise patient safety and development costs.     

Pharmacokinetics of vinorelbine in man

Summary The pharmacokinetics of vinorelbine has been investigated by a new HPLC method in 8 cancer patients receiving 8 weekly doses (30 mg·m^–2) administered by brief infusion (15 min).The plasma concentration-time curves showed a tri-exponential decay with a long terminal half-life (44.7 h) and a high volume of distribution (V_z=75.61·kg^–1). The concentrations after the 8th infusion were significantly lower than after the 1st infusion, but without significant modification of CL (1.28 l·h^–1·kg^–1) or AUC (0.80 mg·l^–1·h).The pharmacokinetic parameters exhibited wide inter-individual variations. The results are consistent with those of previous RIA studies, although the HPLC method appears to be more specific and more precise.     

Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg^–1, and the steady-state volume of distribution (V_ss) was 2.16 1·kg^–1. The distribution (t_1/2) and elimination (t_1/2) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min^–1·kg^–1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CV_intra) as it was between patients (CV_inter). The steady-state trough plasma concentration (C_min obs) ranged from 4.8 to 30 mg·1^–1 (mean 16.0 mg·1^–1 and median 14.3 mg·1^–1). Peak concentrations (C_max obs) ranged from 8.35 to 45 mg·1^–1 (25.4 mg·1^–1, and median 23.3 mg·1^–1). The values of V1 and V_ss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg^–1. The mean V_ss was 2.68 1·kg^–1, with a CV_intra of 12.6 to 56% and a CV_inter of 13.2%. A shorter distribution half-life t_1/2 was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t_1/2 and the mean residence time became longer due to a decrease in clearance. For t_1/2 the mean value was 16.3 h. The mean MRT was 21.9 h, CV_intra 9.19 to 48.5%, and the CV_inter 35.3%. The mean clearance was 2.16 ml·min^–1·kg^–1, CV_intra 7.28 to 25.5%, and the CV_inter 20.4%. This value is 50% lower than after a single dose.Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.     

Analysis of the heart rate effects of 5-hydroxytryptamine in the cat; mediation of tachycardia by 5-HT1-like receptors

Summary The effects of 5-hydroxytryptamine (5-HT) on heart rate in anaesthetized cats were analysed both in intact animals and after spinal section plus vagotomy.The intact cat responded to 5-HT (3, 10 and 30 g·kg^–1, i.v.) with a brief, but intense, bradycardia and a longerlasting hypotension. Administration of MDL 72222, a selective antagonist of M-type 5-HT receptors, blocked bradycardia elicited by 5-HT without affecting that caused by stimulation of the vagus nerve.In spinal cats the same doses of 5-HT increased heart rate and blood pressure. These effects remained essentially unchanged after bilateral adrenalectomy, guanethidine, propranolol and burimamide, suggesting that 5-HT acted directly on the myocardium and blood vessels. The tachycardic responses to 5-HT in spinal cats were little affected by 0.5 mg·kg^–1 doses of MDL 72222 or of the 5-HT₂ receptor antagonists, ketanserin, ritanserin or cyproheptadine. In contrast, the non-selective 5-HT receptor antagonist, methysergide, which binds to both 5-HT₁ and 5-HT₂ recognition sites in rat brain membranes, potently antagonized the 5-HT-induced tachycardia in doses of 0.05 to 0.5 mg·kg^–1. However pizotifen and mianserin, two other 5-HT₂ antagonists which show poor affinity for 5-HT₁ recognition sites, were also effective against the tachycardic response to 5-HT in doses of 0.5–4.5 mg·kg^–1. The pressor responses to 5-HT in the spinal cat were markedly inhibited by all six 5-HT₂ antagonists at a dose of 0.5 mg·kg^–1.5-Carboxamido-tryptamine, which has a high and selective affinity for 5-HT₁ recognition sites, elicited marked tachycardia in doses of 0.1–10 g/kg^–1 in spinal cats treated with saline. These responses were not affected in animals treated with 4.5 mg·kg^–1 of ketanserin, which was able to shift the dose-response curve for 5-HT to the right. On the other hand, methysergide (0.5 mg·kg^–1) displaced the dose-response curves for both 5-carboxamidotryptamine and 5-HT to a similar extent.Unlike on the dog saphenous vein, methysergide showed no agonist effects on heart rate in the spinal cat.On the basis of the above results, we conclude that: (i) the reflexogenic bradycardic response elicited by 5-HT overshadows its direct tachycardic response on heart rate in the intact cat; (ii) M-type 5-HT receptors mediate the bradycardic response; (iii) the pressor response to 5-HT in the spinal cat involves 5-HT₂ receptors; (iv) tachycardia by 5-HT in the spinal cat is mediated mainly by 5-HT₁-like receptors, but an additional, though less important, non-5-HT₁ mechanism may also be involved; (v) the cardiac 5-HT₁ receptors are similar, but perhaps not identical, to those delineated in the dog saphenous vein or rat brain membrane preparations; and (vi) the tachycardic responses to 5-HT and, in particular the more selective, 5-carboxamidotryptamine may be conveniently utilized to characterize new chemical compounds designed for potential 5-HT₁ receptor antagonist activity.     

Pharmacokinetics of ornidazole in neonates and infants after a single intravenous infusion

Summary The single dose pharmacokinetics of ornidazole has been evaluated in 12 neonates or infants (aged 1 to 42 weeks) after the infusion of 20 mg/kg over 20 min. Plasma disposition was described by a two-compartment open model. The distribution phase was short (T_1/2 (1)=0.31 h) and was followed by an elimination phase (t_1/2 (2)=14.67 h). The mean apparent volume of distribution was 0.96 l/kg^–1. These results did not differ from data previous by reported in adults. Total plasma clearance was between 0.4 and 1.4 ml·min^–1·kg^–1. The plasma concentration 24 h after the infusion was 7.32 mg·l^–1, which was above the minimum inhibitory concentration for clinically significant anaerobic bacteria. Based on the pharmacokinetic results and residual concentrations at 24 h, a single daily infusion of ornidazole 20 mg·kg^–1 appears adequate for therapy in neonates and infants.     

Pharmacokinetics of midazolam during continuous infusion in critically ill neonates

Summary Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus (0.2 mg·kg^–1) immediately followed by continuous infusion of 0.06 mg·kg^–1·h^–1 was administered to 15 critically ill neonates at a gestational age of 32.8 weeks, who required sedation for mechanical ventilation. Heart rate and blood pressure were closely monitored.Hypotension occurred in 4 patients after the bolus dose or during the continuous infusion. Three of them had also been given fentanyl. Individual pharmacokinetic parameters were calculated: plasma clearance was 3.9 ml·min^–1, elimination half-life was 12.0 h. Because of its short half-life compared to diazepam, midazolam may be used during the neonatal period to achieve rapid, brief sedation. However, it should be administered cautiously to neonates, particularly in premature infants, or if fentanyl is also given.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

Cardiac and microcirculatory effects of different doses of prostaglandin E1 in man

Summary A cumulative dose response to intravenous PGE₁ was established in 12 healthy volunteers. Systolic time intervals, including pre-ejection period (PEP), the ventricular ejection time (VET) and the RR-interval, were continuously determined, and transcutaneous oxygen pressure (tcpO₂) was recorded.RR-intervals fell in a dose dependent manner, reaching a significantly lower level at 128 ng·kg^–1·min^–1 of PGE₁ (basal value 842 ms falling to 756 ms). PEP decreased from 89 ms to 74 ms and the ratio PEP/VET decreased from 35% to 30%, indicating increased myocardial contractility. The maximal increase in tcpO₂ was 125% on the calf and 60% on the foot. The peak tcpO₂ was observed at an infusion rate of 16 ng·kg^–1·min^–1 PGE₁. A decline in tcpO₂ was seen at infusion rates >64 ng·kg^–1·min^–1 PGE₁, indicating a decrease in skin perfusion.The results indicate that the effects of intravenous PGE₁ on skin perfusion occur at a lower threshold than the increase in myocardial contractility. A maximal increase in skin perfusion can be achieved with doses of PGE₁ devoid of systemic haemodynamic effects.     

The disposition of intravenous doxapram in man

Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg^–1) and by intravenous infusion (6.5 mg · kg^–1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min^–1 · kg^–1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml^–1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml^–1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.     

Intravenous infusion of iloprost in arterial occlusive disease: dose-dependent effects on skin microcirculation

Summary Transcutaneous oxygen pressure (tcPo₂), laser Doppler flux and capillary microscopy have been used to examine the forefoot skin in 5 healthy men and 8 patients with severe peripheral arterial occlusive disease in order to evaluate the dose dependent effects of iloprost on skin microcirculation. Iloprost was infused IV starting at 0.0625 ng·kg^–1·min^–1 and doubling the dose every 15 min up to 2 ng·kg^–1·min^–1.While tcPo₂ at an electrode core temperature of 44°C decreased in both patients and controls, there was a significant dose dependent increase in tcPo₂ (37°C) in the controls from 0.25 ng·kg^–1·min^–1. In the patients the reaction was variable: it was decreased in two and increased in 6, with a maximum either at 0.25–0.5 ng·kg^–1·min^–1 (n=3) or at the highest dose (1.0 or 2.0 ng·kg^–1·min^–1; n=3). Mean laser Doppler flux in both groups was increased, although the reaction was not consistent in the patients. Density of forefoot skin capillaries was reduced in 3 patients, and in the others the flow velocity was very low. During infusion of iloprost, both an increase in capillary density and blood cell velocity were observed. The effects were of variable intensity and occurred at varying doses, some appeared early and diminished as the dose was increased, and others were found only at 2 ng·kg^–1·min^–1.Adverse effects were numerous, extending from harmless skin flushing to mental changes and a quickly reversible attack of angina pectoris. It may be possible to divide patients into those with early effects on the microcirculation, at doses of 0.25–0.5 ng·kg^–1·min^–1, and those in whom the microcirculatory response is preceded and counteracted by the adverse effects.     

Dose-dependent absorption and elimination of cefadroxil in man

Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg^–1.As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg^–1, the peak plasma concentrations, normalized to 5 mg · kg^–1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l^–1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l^–1.When the same subjects were given 5 mg·kg^–1 of cefadroxil together with 45 mg·kg^–1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil.Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil.The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg^–1 was significantly increased by the simultaneous administration of high-dose cephalexin.The renal clearance of cefadroxil ranged from 98 ml·min·l^–1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l^–1 to 156 mg·l^–1 at concentrations greater than 40 mg·l^–1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.     

Pharmacokinetics of ethanol in plasma and whole blood: estimation of total body water by the dilution principle

Summary The pharmacokinetics of ethanol in plasma and whole blood have been investigated and the results used to estimate the volume of total body water (TBW) by means of the dilution principle. Fifteen men (mean age 62 y) were given 0.6 g ethanol/kg body weight as an intravenous infusion over 1 h.The peak concentration of ethanol in plasma was 120 mg·dl^–1 compared to 108 mg·dl^–1 for whole blood. The disappearance rate of ethanol from plasma was 18.6 mg·dl^–1·h^–1 compared to 17.0 mg·dl^–1·h^–1 for the whole blood concentration-time data. The apparent volume of distribution of ethanol (V_z) was 0.54 l·kg^–1 according to plasma kinetics compared to 0.59 l·kg^–1 for the kinetics derived from whole blood. The mean area under the curve (AUC) was 294 mg·dl^–1×h for plasma kinetics compared to 266 mg·dl^–1×h for whole blood. The TBW was 40.9 l or 50.9% of body weight for the plasma concentration-time data. This agreed well with the 40.3 l or 50.1% of body weight obtained using whole blood.     

Oxolinic acid and diazepam: Their reciprocal antagonism in rodents

The stimulant effects of oxolinic acid were investigated in rats and mice. This drug, given orally, consistantly induced, in doses ranging from 16 to 256 mg·kg^-1, locomotor stimulation and stereotyped behavior.These effects were antagonized by pimozide (1 mg·kg^-1), -methyltyrosine (64 mg·kg^-1) or reserpine (4 mg·kg^-1, 24 h before testing) pretreatment, suggesting a facilitatory role of oxolinic acid on catecholaminergic processes.Diazepam (4–16 mg·kg^-1) reduced the stimulant effects induced by oxolinic acid but not those induced by amphetamine; oxolinic acid (8 mg·kg^-1) markedly reduced the antipunishment effect elicited in rats by diazepam (2 mg·kg^-1). Since benzodiazepines have been reported to enhance GABA functioning, these data suggest that oxolinic acid may impair GABA transmission. However, neither muscimol (0.5–1 mg·kg^-1) or -acetylenic-GABA (16–64 mg·kg^-1) selectively reduced the stimulant effects elicited by oxolinic acid. Therefore, the possible facilitation exerted by this drug on catecholaminergic systems may not derive from the release of an inhibitory GABAergic control.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

Penetration of cefoperazone into ascites

Summary The pharmacokinetics of cefoperazone was studied in eleven cirrhotic patients with ascites after i.v. administration of a single dose of 15 mg·kg^–1 (n=7) or after three doses of 15 mg·kg^–1 given at 12 h intervals (n=4). The concentrations of cefoperazone in serum and ascitic fluid were determined by HPLC. The peak serum cefoperazone concentration after a single i.v. injection of 15 mg·kg^–1 was 96.0 mg·l^–1. The serum elimination half-life was longer (5.0 h) than in normal subjects. The penetration of cefoperazone into ascites was satisfactory (32.3% and 58.3% after single and repeated injections, respectively).Ascitic fluid concentrations of cefoperazone exceeded 5.4 mg·ml^–1 from 0.5 to 6 h after the single i.v. injection, levels which are well above the MIC of most pathogens found in spontaneous bacterial peritonitis. Adjustment of the dose of cefoperazone in cases of severe hepatic insufficiency does not appear to be necessary provided that renal function is normal.     

Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans

Summary Plasma concentration-time data for benzoic and hippuric acids and urinary excretion-time data for hippuric acid were analyzed simultaneously after oral doses of 40, 80 or 160 mg/kg sodium benzoate administered at least one week apart to 6 healthy subjects.The mean AUCs of benzoic acid after the doses of 80 and 160 mg/kg of sodium benzoate were 3.7- and 12.0-times greater, respectively, than after 40 mg/kg. However, the mean AUC of hippuric acid was roughly proportional to the benzoate doses. The observed data were explained by a one-compartment model with first-order rate absorption and Michaelis-Menten elimination of benzoic acid, together with a one-compartment model with first-order elimination for hippuric acid.Although the maximum rate of biotransformation of benzoic acid to hippuric acid varied between 17.2 and 28.8 mg·kg^–1·h^–1 among the six individuals, the mean value (23.0 mg·kg^–1·h^–1) was fairly close to that provided by daily maximum dose (0.5 g·kg^–1·day^–1) recommended in the treatment of hyperammonaemia in patients with inborn errors of ureagenesis.The individual maximum rate of metabolism can be estimated from the urinary excretion rate of hippuric acid 1.5 to 3 h after the single oral dose of 80 to 160 mg·kg^–1 sodium benzoate. The justification of this concept requires further studies in patients with inborn errors of urea synthesis.This study was supported in part by a grant-in-aid from the Ministry of Human Health and Welfare, Tokyo, Japan     

Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393)

Recombinant hirudins are currently under investigation for use in myocardial infarction and unstable angina. In this study the influence of piroxicam on the pharmacodynamics and pharmacokinetics of a recombinant hirudin preparation (CGP 39393) administered intravenously was determined. Twelve healthy, male volunteers received piroxicam 10 mg and matching placebo once daily for 12 days according to a double-blind, randomised cross-over design. On the 12th day, the dose of piroxicam was followed by a 6-hour infusion of hirudin 0.1 mg·kg^–1·h^–1. Plasma concentrations and urinary excretion of hirudin and repeated measurements of the activated partial thromboplastin time (APTT), bleeding time and platelet adhesion index were assessed up to 24 h after the start of the infusion. The maximum APTT was 83 s (placebo) and 84 s (piroxicam), 3 to 4 h after the start of the infusion, and was comparable on both study days. The AUD_0–24 (APTT) came to 913 s·h·kg^–1 under placebo and it was slightly increased to 1,017 s·h·kg^–1 after piroxicam; the 95%-confidence interval according to MOSES ranged from 0.97 to 1.24, and the point estimator was 1.10. Bleeding time was significantly prolonged from 290 s under placebo to 345 s under piroxicam before the start of the infusion of hirudin. No further prolongation was found during or after the infusion. No change was observed in the platelet adhesion index. Responsiveness parameters according to a sigmoidal E_max-model were obtained from the hirudin-plasma concentration/effect (i.e. APTT-prolongation)-curves after placebo and piroxicam. Maximal APTT-prolongation (E_max; i.e. peak APTT minus the baseline value) was 53 s after placebo and 52 s after piroxicam. The EC₅₀ was 34 nmol·l^–1 after placebo and 40 nmol·h·l^–1 after piroxicam. The AUC₀ of hirudin was to 539 nmol·h·l^–1·kg^–1 under placebo and 557 nmol·h·l^–1·kg^–1 after piroxicam coadministration; the 95%- confidence interval according to MOSES ranged from 0.95 to 1.14, and the point estimator was 1.03. No period effect was detected. There were no significant differences between the other pharmacokinetic parameters except V_ss, which was increased slightly from 0.23 l to 0.27 l under piroxicam. The results do not show a clinically relevant pharmacodynamic and/or pharmacokinetic interaction between hirudin and piroxicam.     

The effect of selective and non-selective cholinergic blockade on bombesin- and peptone-stimulated gastrin release

Summary We have studied the effects of the selective muscarinic M₁-receptor antagonist pirenzepine and the non-selective muscarinic antagonist atropine on bombesin- and peptone-stimulated gastrin release in healthy subjects.Pirenzepine (i. v. bolus 0.6 mg/kg) and atropine (i. v. bolus 15 µg/kg, followed by an infusion of 5 µg·kg^–1·h^–1) were given in doses equipotent in terms of reduction of gastric acid secretion. Neither affected bombesin- or peptone-stimulated gastrin release.These findings do not support the involvement of M₁-receptors in the cholinergic regulation of gastrin release and suggest that the reduction in acid secretion caused by pirenzepine is not mediated by inhibition of gastrin release.     

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment

Summary Twenty patients (aged 26–70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg·kg^–1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets.On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg·l^–1 respectively, after the infusion, and 8.0 and 10.4 mg·l^–1, respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg·l^–1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg·l^–1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes).The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.