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Background: Epidemiologic studies suggest that garlic may have beneficial effects on risk factors associated with cardiovascular disease (CVD). However, these findings are not unambiguously supported by randomized placebo-controlled clinical trials. Objective: We sought to investigate the effects of a chemically well-characterized garlic preparation on biomarkers for inflammation, endothelial function, and lipid metabolism in subjects with risk factors for CVD. Design: This was a double-blind, randomized, placebo-controlled trial in 90 overweight [body mass index (in kg/[m.sup.2]) > 24.5] subjects aged 40-75 y who smoked >10 cigarettes/d. The subjects were randomly assigned to 3 parallel treatment groups: garlic powder (2.1 g/d), atorvastatin (40 mg/d), or placebo. Duplicate measurements were performed at baseline and after 1 and 3 mo of treatment. Treatments were compared with analysis of covariance with baseline as the covariate, and differences between the treatments were reported as mean percentage difference and corresponding 97.5% CI. Results: None of the variables showed significant differences between the garlic-treated and the placebo groups. In contrast, compared with the placebo group, atorvastatin treatment resulted in significantly lower plasma concentrations of C-reactive protein (20.2%; 1.7%, 35.3%), total cholesterol (37.2%; 33.1%, 41.1%), LDL cholesterol (52.7%; 47.9%, 57.1%), triacylglycerols (31.9%; 20.8%, 41.5%), and tumor necrosis factor [alpha] (TNF-[alpha]; 41.9%; 19.0%, 58.3%) and increased the ratio of ex vivo whole blood lipopolysaccharide-stimulated to nonstimulated TNF-[alpha] concentrations (109.7%; 37.9%, 218.9%). Conclusion: We conclude that a chemically well-characterized garlic preparation has no significant effect on inflammatory biomarkers, endothelial function, or lipid profile in normolipidemic subjects with risk factors for CVD. KEY WORDS Garlic, C-reactive protein, CRP, lipids, endothelial function, humans

In a randomized double-blind parallel study in 36 subjects the effect on serum cholesterol of a daily dose of 2 g lipid extracted from green Arabica and Robusta coffee beans was studied. Arabica oil elevated serum total cholesterol by 1.1 mmol/L (95% CI for the difference from placebo: 0.41, 1.73 mmol/L); the effect of robusta oil (+0.5 mmol/L) was not statistically significant (95% CI: -0.01, 0.92 mmol/L). Arabica oil also raised plasma triglycerides by 0.8 mmol/L (95% CI: 0.26, 1.25 mmol/L). The effect of robusta oil on triglycerides was +0.14 mmol/L and not significant (95% CI: -0.26, 0.42 mmol/L). In the 12 subjects taking arabica oil an average serum alanine amino-transferase elevation of 18 U/L (95% CI: 9.4, 28.4 U/L) was observed. Because only arabica oil contains kahweol and arabica coffee contains more cafestol than does robusta oil, this is further evidence for the role of diterpenes in the rise of serum cholesterol and alanine aminotransferase after consumption of boiled coffee.

Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of its unpredictable absorption and narrow therapeutic window. The use of limited sampling models (LSMs) has improved the estimation of the systemic exposure [area under curve (AUC)] compared with C(0h) monitoring, but these equations are rigid and not reliable in patients with an abnormal absorption profile. We developed and validated a limited sampling (t=0, 2 and 3 h) strategy, based on a compartmental population pharmacokinetic (PK) model for CsA after kidney transplantation alone (KTA) and simultaneous pancreas-kidney transplant (SPKT) recipients, a group of patients with unpredictable absorption kinetics.

Background: The optimal dosing strategy for continuous intravenous furosemide infusion is unknown in pediatric patients. Eighteen patients less than 1 year old were studied after cardiac surgery during routine clinical care. The current strategy starts with a continuous infusion of 0.1 mg/kg · h, which may be adapted.Methods: A pharmacokinetic-pharmacodynamic model was developed that linked furosemide dose to furosemide serum concentrations, renal function (creatinine clearance), and urine output. Various regimens were simulated that adapt according to urine production. The modified dosing schedule was prospectively tested in a subsequent population of 18 pediatric patients after cardiac surgery.Results: Data from the follow-up study suggest that urine production is more controlled for the proposed regimen.Conclusions: Both the modeling and simulation results and the follow-up study indicated that a bolus dose of 1 mg/kg followed 6 hours later with a 1- or 2-mg/kg loading dose and a 0.2-mg/kg · h intravenous infusion provides a rational starting point for furosemide therapy after cardiac surgery in pediatric patients less than 1 year old. Adjustment of this regimen every 12 hours in steps of 0.1 mg/kg · h on the basis of clinical assessment should lead to adequate control over urinary output.Clinical Pharmacology & Therapeutics (2002) 72, 383–390; doi: 10.1067/mcp.2002.127608

Objectives: This study was designed to assess the concentration-effect relationships for the antihypertensive effects of rilmenidine in patients to aid in the design of an optimized concentration profile of a sustained-release formulation.Methods: A placebo-controlled, randomized, double-blind, 2-way partial crossover study was performed in subjects with hypertension. Patients were randomized to receive 2 of 3 possible 12-hour infusion regimens, each consisting of a loading phase (2 hours) and a maintenance phase (10 hours): low-profile infusion (total dose of rilmenidine, 1.45 mg), high-profile infusion (total dose, 3.3 mg), or placebo. Drug plasma concentrations, adverse events, blood pressure, heart rate, and visual analog scales were measured frequently, up to 24 hours after dosing. Salivary flow was determined for up to 15 hours.Results: The high concentration profile was well tolerated and continued to produce a significant blood pressure reduction of 10.4 mm Hg (systolic)/5.8 mm Hg (diastolic) after 24 hours. The low concentration profile showed no significant effects on blood pressure compared with placebo after 24 hours. Decreases in salivary flow were −36% for the high-profile infusion and −20% for the low-profile infusion compared with placebo. Pharmacokinetic-pharmacodynamic analyses showed infusion rate-independent, linear concentration-dependent reductions in diastolic blood pressure and salivary flow up to the maximum observed rilmenidine concentration for both types of infusion.Conclusions: The high concentration profile was well tolerated and still produced a significant blood pressure reduction after 24 hours. Pharmacokinetic-pharmacodynamic relationships were linear and unaffected by the rate of infusion. These results should aid in the design of an optimal slow-release profile.Clinical Pharmacology & Therapeutics (2002) 72, 419–428; doi: 10.1067/mcp.2002.127638

Nonlinear mixed effects modeling (NONMEM) and nonparametric expectation maximization (NPEM2) have both been used in population modeling of tobramycin. We compared both methods for differences in population pharmacokinetic parameters in relation to error models used. Predictive performance was compared between models. A group of 470 neonates who had received tobramycin according to a gestational age (GA)–dependent dosing interval was analyzed according to a one-compartment model with NONMEM and NPEM2. Additional models were constructed where the assay error pattern in NPEM2 mimicked NONMEM residual error and vice versa. Individual pharmacokinetic parameter estimates were compared. Predictive performance was evaluated in a separate group of 61 patients. Population estimates and variation coefficients (CV) for optimal models were NONMEM Kel0.071 h−1(27), Vd0.59 L/kg (9); NPEM2 Kel0.079 h−1(42), Vd0.65 L/kg (48). Forcing NONMEM to use the NPEM2 error pattern as residual error or vice versa resulted in smaller differences in CVs of the estimates. NONMEM gave less bias (P< 0.05) than NPEM2 and comparable precision with this approach. In conclusion NONMEM and NPEM2 are dissimilar in population estimates. Differences in ranges of pharmacokinetic parameter estimates between NONMEM and NPEM2 are largely determined by the method of incorporating error patterns in both programs.

Our objective was to individualize tobramycin dosing regimens in neonates of various gestational ages with use of early therapeutic drug monitoring. This study was performed in neonatal patients with suspected septicemia in the first week of life. All patients received tobramycin, 4 mg/kg per dose, as a 30‐minute intravenous infusion, with a gestational age–related initial interval of 48 hours (<32 weeks), 36 hours (32‐36 weeks), and 24 hours (≥37 weeks). The target serum peak and trough serum concentrations were 5 to 10 mg/L and 0.5 mg/L, respectively. Serum trough samples and 1‐ and 6‐hour samples were taken after the first dose. Tobramycin concentrations were used to obtain gestational age–dependent population models with nonparametric expectation maximization software. To investigate the effect of timing of sampling in a second group of patients, serum trough samples and 3‐ and 8‐hour samples were taken after the first dose of tobramycin was administered. Serum trough concentrations were predicted by use of linear pharmacokinetics in both groups and by use of the population models with bayesian feedback of 1 or 2 serum concentrations in the second group. These predicted concentrations were compared with actual serum trough concentrations. The predictive performance of the 1‐ to 6‐hour and 3‐ to 8–hour models and the population models were compared with a gestational age–related model without therapeutic drug monitoring. A total of 247 patients were analyzed: 206 with 1‐ to 6‐hour serum samples and 41 with 3‐ to 8‐hour serum samples. Peak serum concentrations were above 5 mg/L in 90.8% of cases, and trough serum concentrations were above 1 mg/L in 25.5% of cases. The 3‐ to 8‐hour linear model had a bias of −0.31 mg/L and a precision of 0.48 mg/L, and it performed significantly better than the 1‐ to 6‐hour model. The best nonparametric expectation maximization model had a bias of −0.11 mg/L and a precision of 0.45 mg/L. None of the models yielded a significant improvement of predictive performance over the model without therapeutic drug monitoring. Routine early therapeutic drug monitoring does not improve the model‐based prediction of initial tobramycin dosing intervals in neonates in the first week of life. Clinical Pharmacology & Therapeutics(2002) 71, 349–358; doi: 10.1067/mcp.2002.123595

Single-dose administration of 5-hydroxytryptophan (5-HTP) is regularly used as a challenge test of the serotonergic system. The use of 5-HTP has been limited by an apparent small window between the occurrence of neuroendocrine endpoints and the occurrence of side effects. Therefore, many dosing strategies have been tried with and without concurrent administration of carbidopa, a peripheral inhibitor of the decarboxylation from 5-HTP to serotonin.

The receptor involved in the serotonin (5-hydroxytryptamine 5-HT)-induced vasodilatation in the human forearm has not yet been identified. Experimental data point to the 5-HT2Breceptor located on the endothelium. RS-127445 (2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropyl-pyrimidine) is a novel potent and selective 5-HT2Breceptor antagonist. The effect of oral RS-127445 (500 mg) on 5-HT-induced vasodilatation was studied in a double-blind, randomized, placebo-controlled, crossover study in six healthy volunteers. On each study day 5-HT (0.5 ng/kg/min) was infused into the brachial artery for 8 min, before drug administration and at intervals of 20, 65, 110, 230, and 470 min after oral ingestion. At each infusion, plasma samples for study drug assay were taken and forearm blood flow was assessed using venous occlusion plethysmography. Although (log) drug concentrations exceeded pKi, there was no correlation between RS-127445 concentrations and 5-HT-induced vasodilatation. 5-HT-induced vasodilatation did not differ between treatments and time points. It appears that there is no functional involvement of 5-HT2Breceptors in 5-HT-mediated vasodilatation in the human forearm.

Background: A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to study sedative drug effects.Methods: Hypnograms from 21 patients with primary insomnia were collected during a randomized, placebo-controlled crossover study of 20 mg temazepam. A separate daytime session was performed to determine the pharmacokinetics of 20 mg temazepam and its effect on saccadic eye movement and electroencephalogram. A first-order Markov model was developed to describe the probability of sleep stage changes as a function of time after drug intake and time after last sleep stage change. The influence of temazepam concentration on the probability to change sleep stage was incorporated into the model.Results: Transitions between sleep stages were profoundly influenced by the time of the night and by the time since the last change of sleep stage. Temazepam reduced the time spent awake. This effect could be attributed to four mechanisms: (1) transition to “deeper” sleep was facilitated, (2) transition to “lighter” sleep was inhibited, (3) regardless of sleep stage, the transition to wake state was inhibited, and (4) return to sleep was facilitated. Daytime sensitivities to temazepam, measured with the surrogate markers saccadic peak velocity and electroencephalogram beta activity, each correlated with one of the transition probabilities influenced by temazepam.Conclusions: By the development of a Markov model for these non-ordered six categorical data, the effect of temazepam on the sleep-wake status could be interpreted in terms of known mechanisms for sleep generation and benzodiazepine pharmacology.

Objectives: Recombinant tissue factor pathway inhibitor (rTFPI) has been shown to be an effective treatment in animal models of sepsis and is under investigation for human use. Reduced liver blood flow during septic shock may substantially alter the pharmacokinetics of rTFPI because clearance of rTFPI approaches liver blood flow. The aim of this study was to examine the effect of exercise-induced reduction in liver blood flow on the pharmacokinetics and pharmacodynamics of rTFPI.Methods: This was a two-way, open-label, randomized crossover study in eight healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with intravenous sorbitol (50 mg/min) for 4 hours. Sorbitol was used as a biomarker for liver blood flow. The subjects were randomized to remain supine or to exercise on a bicycle ergometer for 30 minutes starting at the beginning of the third hour of the infusion.Results: Exercise reduced liver blood flow (mean ± SEM) from 1.44 ± 0.06 L/min to 0.40 ± 0.03 L/min. The average clearance of rTFPI decreased from 0.73 ± 0.04 L/min in the supine position to 0.25 ± 0.02 L/min during exercise. This decrease in rTFPI clearance resulted in an 80% (95% confidence interval [CI], 60% to 102%) increase in plasma rTFPI levels during exercise. The average maximal prothrombin time and activated partial thromboplastin time values during exercise were 1.4 (95% CI, 0.4 to 2.5) and 4.4 (95% CI, 2.7 to 6.1) seconds higher compared with the supine steady-state level.Conclusions: Reduction in liver blood flow by exercise markedly increased rTFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied.

Background: Recently the value of vancomycin therapeutic drug monitoring, as well as the required therapeutic range, has been subject of debate, resulting in new recommendations. This study was performed to incorporate these new insights in an up-to-date dosing scheme for neonates of various gestational ages.Methods: In this retrospective study with prospective validation, 108 newborns with suspected central line–related septicemia during the first month of life received 30 mg/kg/day vancomycin divided into two doses regardless of gestational or postconceptional age. Trough and peak vancomycin serum concentrations were determined before and after the third dose. Vancomycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Model parameters were evaluated and then used to simulate vancomycin dosing for different dose and dose interval combinations. Targets were a trough concentration between 5 and 15 mg/L and a peak below 40 mg/L. In the prospective study, the optimal scheme was tested in 22 patients.Results: Of the 108 patients, 34.3% of measured trough concentrations and 17.6% of peak concentrations were outside the desired therapeutic range. The model that best fitted the data included clearance and volume per kilogram and was independent of gestational age. Simulation of various dosing schemes showed that a dosing schedule of 30 mg/kg/day, irrespective of gestational age, in three doses was optimal, and this scheme was prospectively tested. Mean trough concentrations before the second dose were 8.2 ± 2.2 mg/L versus a predicted trough of 8.9 ± 2.5 mg/L. No peak levels higher than 40 mg/L were found.Conclusions: The use of the proposed schedule leads to adequate vancomycin trough serum concentrations, and there is no need for routine monitoring of peak serum concentrations. (Clin Pharmacol Ther 2000;67:360-7.)Clinical Pharmacology & Therapeutics (2000) 67, 360–367; doi: 10.1067/mcp.2000.105353

Objective: Recently a few cases of long QT syndrome were reported during treatment with cisapride. In most of these cases, risk factors for cardiac arrhythmias or pharmacologic interactions might have been involved, and the role of cisapride remained unclear. Macrolides such as clarithromycin potentially interact with the metabolic elimination of cisapride and have overlapping indication areas. We therefore studied whether combined treatment with clarithromycin and cisapride leads to pharmacokinetic changes and increased QT intervals.Methods: The study was an open, randomized, 2-way crossover study with washout periods of 1 week. Twelve healthy volunteers were recruited. Treatments were cisapride (10 mg 4 times a day) for 10 days with concomitant clarithromycin (500 mg twice a day) from days 6 through 10, or clarithromycin (500 mg twice a day) for 10 days combined with cisapride (10 mg 4 times a day) from days 6 through 10. Frequent ECG recordings were performed for 24 hours before drug treatment (baseline). After 5 days of monotherapy and combination therapy, frequent ECG recordings and assessments of plasma drug levels were performed for 24 hours.Results: Clarithromycin alone was associated with a minimal increase in QTc intervals. Monotherapy with 10 mg cisapride 4 times a day led to a concentration-dependent QTc elevation, amounting to 6 ms during steady state. Combination of cisapride and clarithromycin caused an average QTc increase of 25 ms above pretreatment values and 3-fold increases in cisapride concentrations.Conclusions: QTc elevations after cisapride or clarithromycin alone remained within the normal range of diurnal variation. Coadministration of cisapride and clarithromycin produced a substantial QT prolongation. The data support the recently purported interaction between cisapride and clarithromycin and thus the filed contraindication to combine these drugs.

A randomized, single-centre, cross-over study was designed to compare the bioavailability of two pharmaceutical formulations of recombinant human follicle stimulating hormone (recFSH; Puregon®): (i) a dissolved cake injected by a normal syringe; and (ii) a ready-for-use solution injected using a device referred to as Puregon®Pen. Twenty-two healthy female volunteers underwent one of two administration sequences: Puregon®Pen/syringe or syringe/Puregon®Pen, by which they received a single subcutaneous dose of recFSH (150 IU). Endogenous gonadotrophin production had been previously suppressed using an oral contraceptive (Lyndiol®). Pharmacokinetic parameters characterizing rate [peak concentration (Cmax) and time of peak concentration (tmax)] and extent [area under the curve (AUC) and clearance (CL)] of absorption were obtained from 20 subjects. After injection with both formulations, serum FSH concentrations reached a peak of 3.4 IU/l at 13 h after injection. The elimination half-life was approximately 34 h, irrespective of formulation. A difference of approximately 18% was found between serum FSH concentrations obtained using the two formulations, which was caused by differences between the anticipated and the actual volume injected with the normal syringe. After correction for injection losses by weighing the amount injected with a normal syringe, the two formulations were found to be bioequivalent with respect to Cmax, AUC and CL. For tmax, bioequivalence could not be proven due to high intra-subject variability and broad absorption peaks of FSH. Both methods were well tolerated, local reactions being generally mild and short-lived.

Objective: To establish a tobramycin dosing schedule for neonates of various gestational ages.Methods: This was a retrospective study with prospective validation. A retrospective study in 470 neonates, with suspected speticemia in the first week of life, was performed. All patients received tobramycin according to the following scheme: neonates with a gestational age of less than 28 weeks received 3.5 mg/kg every 24 hours, neonates from 28 to 36 weeks received 2.5 mg/kg every 18 hours, neonates older than 36 weeks received 2.5 mg/kg every 12 hours. Trough and peak tobramycin serum levels were determined before drug administration and 30 minutes after the fourth dose. Tobramycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Individual empirical Bayes estimates were generated on the basis of the population estimates and used to calculate predicted peak and trough levels for different doses and dosing intervals. To establish an optimal dosing regimen, target trough levels were set at below 2 mg/L and target peak levels were set above 5 to 10 mg/L. The dosing regimen was prospectively evaluated in 23 patients.Results: Of the 470 patients, 19.1% of measured peak and 32.8% of measured trough tobramycin serum levels were outside the desired therapeutic range, and 48.8% of neonates with a gestational age of less than 28 weeks had an aberrant trough level. With use of population estimates, the following dosing regimen was recommended: gestational age below 32 weeks, 4 mg/kg every 48 hours; gestational age between 32 and 37 weeks, 4 mg/kg every 36 hours, gestational age above 37 weeks, 4 mg/kg every 24 hours. With this dosing schedule, predicted peak levels were higher than 5 mg/L in 95.1% of the neonates. Predicted trough levels were higher than 2 mg/L in 1.9% of the neonates and higher than 1 mg/L in 7.6%. Prospectively measured peak levels were higher than 5 mg/L in all but one infant. Measured trough levels were higher than 2 mg/L in three patients and marginally higher than 1 mg/L in four patients.Conclusions: With the use of this proposed schedule, taking into account differences in gestational ages, predicted peak levels will be therapeutic, whereas predicted trough levels will minimize toxicity.

Background: The removal of recombinant tissue-type plasminogen activator (rt-PA; alteplase) by the liver is so rapid that liver blood flow becomes rate determining for its clearance. In patients with myocardial infarction changes in liver blood flow may result from impaired cardiac performance or drug treatment.Objective: To estimate the effect of variations in liver blood flow on t-PA plasma concentrations during thrombolytic therapy.Methods: Fifteen patients with acute myocardial infarction were investigated in an open single-center study at the coronary care unit of University Hospital Leiden. Patients received thrombolytic treatment with 100 mg rt-PA over 3 hours. Liver blood flow was estimated by indocyanine green clearance and by Doppler echocardiography. Concentrations of t-PA antigen, t-PA activity, indocyanine green, α2-antiplasmin, fibrinogen, and fibrin and fibrinogen degradation products were measured.Results: Indocyanine green clearance and clearance of both t-PA antigen (r = 0.78; p < 0:01) and t-PA activity (r = 0.54; p < 0.05) were significantly related. Significant associations between t-PA antigen and fibrin and fibrinogen degradation products and between t-PA antigen and α2-antiplasmin were also found.Conclusions: The liver blood flow of patients with myocardial infarction is inversely correlated with plasma concentrations of t-PA. In patients with severely impaired liver blood flow and heart failure, high t-PA plasma concentrations may occur if standard doses are given. This finding could contribute to optimization of the dosage of t-PA in certain patient groups.

Background and objective: quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect.Methods: The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated.Results: The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters.Conclusion: In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.

The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 ± 1.13 h versus3.85 ± 0.40 h) and serum trough concentrations (46 ± 14 mg/L versus23 ± 7 mg/L) of CAZ were significantly (p< 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 ± 25.1 mL/h versus205.7 ± 55.4 mL/h), CAZ clearance per kg (40.9 ± 6.1 mL/h/kg versus60.8 ± 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 ± 0.43 versus4.73 ± 0.89) were significantly (p< 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.

AimsThe central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long‐term users of temazepam and lorazepam in a clinical population.

In a double-blind controlled trial in nine patients with tinnitus we measured the lidocaine plasma concentrations during and after intravenous administration of lidocaine or placebo and scored the level of tinnitus on a visual analog scale. No patient showed any effect during the placebo infusion. Administration of lidocaine resulted in total suppression or suppression to a non-annoying level of tinnitus in five patients, slight suppression but still annoying tinnitus in two patients, and worsening tinnitus in one patient. No effect of lidocaine was observed in one patient. Most relief was obtained at plasma concentrations between 1.5 and 2.5 µg/ml. In this concentration range a significant (p < 0.05) effect of lidocaine on tinnitus was observed. However, notable side effects were observed at plasma concentrations greater than 2.0 μg/ml. The effect persisted until plasma levels of about 0.5 μg/ml were reached. A large variability in the effects existed because of variations in lidocaine kinetics and because of the presumed psychologic components of tinnitus.Clinical Pharmacology and Therapeutics (1993) 54, 415–420; doi:10.1038/clpt.1993.168

ABSTRACT: The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 ± 1.13 h versus 3.85 ± 0.40 h) and serum trough concentrations (46 ± 14 mg/L versus 23 ± 7 mg/L) of CAZ were significantly (p < 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 ± 25.1 mL/h versus 205.7 ± 55.4 mL/h), CAZ clearance per kg (40.9 ± 6.1 mL/h/kg versus 60.8 ± 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 ± 0.43 versus 4.73 ± 0.89) were significantly (p < 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.

In this phase I study a novel potassium channel opener (YM934) was administered to young healthy male volunteers to identify a dose with minimal cardiovascular effects. The study was carried out using a double‐blind, placebo‐controlled rising dose design with oral YM934 in single doses of 20 μg, 60 μg, and 180 μg. During each study day frequent blood samples were obtained for drug assay, measurements of cardiovascular parameters, and parasympathetic activity. The drug was well tolerated, with headache being the only significant adverse event. No relationship could be detected between dose or plasma concentration of YM934 and headache. No significant changes in routine laboratory and pharmacodynamic parameters occurred between placebo and active drug treatment. The pharmacokinetics of YM934 were characterized by a rapid oral absorption, an elimination half‐life of 30 hours, and an oral clearance of 1.7 L/h. The obtained data allow estimation of a YM934 dose regimen with minimal cardiovascular (side) effects to be used for future efficacy studies.

Objective: The objectives of this study were (1) to determine the effects of gestational age on ceftazidime pharmacokinetics in the preterm infant, (2) to relate these effects to changes in glomerular filtration rate (GFR), and (3) to establish appropriate dosage recommendations for preterm infants on day 3 of life.Methods: Multiple-dose pharmacokinetics of ceftazidime (administered twice daily in a 25 or 50 mg/kg body weight intravenous dose) were evaluated in 136 preterm infants on day 3 of life. Blood samples were collected from an arterial catheter 0, ½, 1, 2, 4, 8, and and 12 hours after the intravenous dose. An HPLC method was used to determine ceftazidime concentrations in serum. The GFR was studied simultaneously by means of the 24-hour continuous inulin infusion technique.Results: The total body clearance, volume of distribution, and elimination serum half-life of ceftazidime (mean ± SD) were 55.7 ± 34.4 ml/hr (37.3 ± 11.9 ml/hr/kg), 496 ± 228 ml (350 ± 96 ml/kg), and 6.95 ± 2.32 hours, respectively. The mean ± SD peak and trough levels were 114.9 ± 39.4 and 33.9 ± 17.8 mg/L. All infants had a serum trough level above 5 mg/L. Clearance and volume of distribution of ceftazidime and GFR increased significantly with increasing gestational age, whereas serum trough levels and serum half-life of ceftazidime decreased significantly with increasing gestational age. Ceftazidime clearance increased significantly with increasing GFR. Prenatal exposure to indomethacin resulted in significantly lower GFR values and ceftazidime clearances.Conclusions: Dosage recommendations for ceftazidime administration in preterm infants during the first week of life should be based on gestational age and GFR. Additional adjustments in dosage are indicated in preterm infants who are exposed prenatally to indomethacin.

Objective: To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator.Methods: This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, α2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography.Results: The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: −35%, −19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics.Conclusions: u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.

Objective: To estimate the effect of grapefruit juice on cyclosporine and prednisone metabolism.Methods: This was an open, placebo-controlled, two-way crossover study performed in the academic departments of clinical pharmacology and nephrology. On two study occasions, 12 kidney transplant patients with stable cyclosporine trough levels received either grapefruit juice or water every 3 hours for a period of 30 hours. The main outcome measures were peak concentration and time to peak, area under the concentration-time curve, the ratio of the area under the curve of the metabolites/area under the curve of the parent drug, terminal half-life, and 24-hour trough levels of cyclosporine.Results: Grapefruit juice increased the peak concentration of cyclosporine by 185 ng/ml (95% confidence interval, 60 to 310; p = 0.008). The ratio of the area under the curve of the metabolites of cyclosporine to the area under the curve of cyclosporine was reduced by 0.137 on the grapefruit day (95% confidence interval, −0.221 to −0.054; p = 0.004). After grapefruit juice, no significant changes were observed in the area under the curve and the time to peak of cyclosporine, prednisone, and prednisolone. Cyclosporine trough levels were unchanged by grapefruit juice.Conclusions: Grapefruit juice inhibits the metabolism of cyclosporine for a brief period after administration, which may be explained by the inhibition of cytochrome P450 enzymes in the gut wall and to a lesser extent by inhibition of these enzymes in the liver. Grapefruit juice can be one of the factors leading to intraindividual variability in the pharmacokinetics of cyclosporine. Grapefruit juice had no significant effect on the metabolism of prednisone or prednisolone.

Objective: To investigate the influence of increased liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue-type plasminogen activator (rt-PA) and to study the changes in endogenous urokinase-type plasminogen activator (u-PA).Methods: This open, randomized, crossover trial was carried out in a clinical research unit. Eight healthy, nonsmoking volunteers received linear infusions of 24 mg rt-PA and 92 mg indocyanine green over 160 minutes. Sixty minutes after the infusions were started, the subjects consumed a standardized meal to increase liver blood flow on one occasion and abstained from taking food on the other occasion. Plasma concentrations of indocyanine green, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, total u-PA antigen, plasmin-activatable single-chain u-PA (scu-PA), active two-chain u-PA (tcu-PA), fibrinogen, total fibrin, and fibrinogen/fibrin degradation products (TDP), and α2-antiplasmin were measured.Results: After the consumption of the meal, the area under the curve (AUC) was 35% (95% confidence interval [CI]: 25%, 43%) lower for indocyanine green, 15% (CI: 6%, 24%) lower for t-PA antigen, and 11% (CI: 2%, 19%) lower for t-PA activity compared to the AUC after subjects abstained from food. No changes were observed in fibrinogen, TDP, or α2-antiplasmin concentrations that were attributable to the intake of food. The infusion of rt-PA caused a fivefold increase in the concentration of active tcu-PA and a concomitant decrease in scu-PA concentrations by more than 50%.Conclusions: Increased liver blood flow results in an increase in t-PA clearance. The conversion of the inactive zymogen scu-PA to the active tcu-PA is increased by an infusion of rt-PA, but total u-PA antigen concentrations remain unchanged.

Objectives: Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with migraine do not experience headache relief after sumatriptan, and up to 40% may experience recurrence of headache within 24 hours. We studied whether pharmacokinetic or pharmacodynamic differences may explain these different clinical effects.Methods: We compared the pharmacokinetic profiles of subcutaneous sumatriptan in 14 patients who consistently had headache relief without headache recurrence, in 12 patients who had headache recurrence in every attack, and in six patients who did not have headache relief after sumatriptan. Because the antimigraine action of sumatriptan may be mediated through vasoconstriction of cranial blood vessels, we also compared in these patients changes in blood vessel diameter and blood velocity in the common, internal, and external carotid arteries.Results: Despite sufficient power of the study, no important differences in pharmacokinetic and pharmacodynamic profiles between the three patient groups were detected.Conclusion: Headache recurrence and lack of headache relief after sumatriptan do not appear to be explained by pharmacokinetic or pharmacodynamic differences between patients, which may be an important finding for the development of novel antimigraine drugs.

The hemodynamic effects of the calcium entry blocker felodipine were studied during and after different infusion rates. Eight healthy normotensive volunteers had their individual pharmacokinetics of felodipine determined, and they subsequently entered a double-blind, randomized, crossover study. Individualized infusions of felodipine were given by a computerized infusion pump to reach plasma concentrations of 6 ng/ml (15.6 nmol/L) after 20 minutes, to be sustained for 8 hours (fast infusion) or the same plasma concentration after 8 hours (slow infusion). Control infusions with saline and vehicle were given. Blood pressure, heart rate, ECG conduction times, and baroreceptor sensitivity by the Valsalva test were measured, as well as the plasma concentrations of felodipine. The infusion system used produced the expected plasma concentration–time profiles with higher plasma concentrations after the fast infusion until 8 hours. Both slow and fast infusion increased heart rate (p < 0.05) and produced a similar decrease in diastolic blood pressure (p < 0.05). Slow infusion therefore reduced blood pressure more effectively. The tachycardia after the fast infusion was more pronounced during the first hour of the infusion but was indistinguishable from the slow infusion later, when plasma concentrations were still significantly different. Baroreceptor responsiveness was diminished by both felodipine treatments. There was no obvious difference in side effects caused by the two infusion regimes. The initial tachycardia after felodipine can be diminished by a slow rate of administration of the drug with a similar effect on blood pressure.

Introduction and aim of study. Cyclosporin A (CsA) is commonly used as prophylaxis against Graft versus Host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (SCT). Therapeutic drug monitoring is necessary because of its unpredictable absorption and narrow therapeutic window. Usually dose adjustments are based on trough levels, although these correlate poorly with CsA systemic exposure in adults. The aim of this study was to investigate intravenous and oral CsA pharmacokinetics in children after SCT and to develop a limited sampling strategy in order to determine CsA systemic exposure. Methods. Pharmacokinetics was investigated in children, aged 1.8 to 16.1 yrs, 2 to 43 days after stem cell infusion (median: 25 days), after intravenous or oral administration of CsA in, respectively, 9 and 8 children. Parameter estimation was performed using nonlinear mixed effect modeling as implemented in the NONMEM program. Results and conclusions. Pharmacokinetics were described adequately with a two-compartment model with lag time (population estimates: Cl=10.5 l/h; Vc=15.5 L; Vp=60.6L; t ½ absorption=1.01 h, Tlag=0.6 h). Combination of Cthrough and a Bayesian fitting procedure with the pharmacokinetic model can adequately estimate the systemic exposure to CsA (r2=0.90, Figure 1). The estimation of actual AUC improves when more concentration time-points are used. No relation between body weight and clearance was found (Figure 2). Based on these data, CsA should not be dosed per kilogram body weight. A regimen with a fixed dose for all, adjusted on through levels in combination with the described pharmacokinetic model, may be more appropriate. (open circles: oral administration; closed circles: intravenous administration) Figure Figure Figure Figure

Amoxicillin (AM) is one of the most frequently used antibiotics in the treatment of bacterial infections in the preterm infants. Despite the widespread use of AM in neonatal intensive care units, pharmacokinetic studies in preterm infants are not available. The recommended dosage of AM is 50-100mg/kg/24h. We studied the multiple-dose pharmacokinetics of AM (25 mg/kg q12h) in 17 preterm infants (gest. age 29 ± 1.9 wks) on day 3 of life. Blood samples were taken before (t = 0) and 1/2, 1, 2, 4, 8, and 12 hrs after the AM dose and analyzed by HPLC-assay.The glomerular filtration rate (GFR) of all infants was simultaneously studied by means of the 24h continuous inulin infusion technique to investigate the effect of GFR on the clearance of AM. The results were:Conclusions. 1. Amoxicillin 25 mg/kg q12h results in adequate serum levels of AM in preterm infants with a gestational age below 32 weeks on day 3 of life. 2. The total body clearance of AM (1.0 ± 0.4 ml/min) and the GFR (1.0 ± 0.3 ml/min) are equal, indicating that AM is primarily excreted by glomerular filtration in the preterm infant.

meta-Chlorophenylpiperazine (mCPP) is a compound that is frequently used in challenge tests of the serotonergic system. Its human pharmacology is largely unexplored. The objective of this study was to investigate the pharmacokinetic and pharmacodynamic profile of mCPP. Eight female and six male healthy volunteers were included in a randomized, double-blind, double-dummy, three-way crossover design of single-dose intravenous (0.1 mg/kg), oral (0.5 mg/kg), and placebo treatment, with 24-hour follow-up. mCPP showed a large variability in clearance (11-92 mL/hr) and bioavailability (14-108%). Two female subjects dropped out because of headache and dysphoria. During the 27 occasions in which mCPP was administered, autonomic physical symptoms were observed in 23 subjects and disturbances of mood in 6 subjects. Oral and intravenous mCPP caused sudden increases in cortisol levels, prolactin levels, and total scores of the Body Sensation Questionnaire. Administration of mCPP also led to concentration-dependent increases of saccadic peak velocity and adaptive tracking performance and to a decrease of electroencephalographic occipital theta activity. No clinically relevant effects on electrocardiogram, temperature, and blood pressure were found. In conclusion, it is doubtful whether mCPP is a useful compound for challenge tests in view of the large pharmacokinetic variability after intravenous and oral administration. The effects of mCPP are consistent with disinhibition of the central nervous system. (J Clin Psychopharmacol 1998;18:289-295)

Ceftazidime (CAZ) pharmacokinetics were studied on day 3 of life in 28 preterm infants who were randomized at birth to receive once or twice daily 25 mg/kg CAZ. Thirteen infants were treated once daily, 15 infants twice daily. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, 12h after the CAZ dose in both groups and an additional sample at 24h in the once daily group and analyzed by HPLC-assay. The results were (mean±SD):Conclusions. 1. Twice daily dosing of 25 mg/kg CAZ results in high serum trough levels of CAZ. 2. Dosage reduction from twice to once daily results in a significant decrease of serum trough levels of CAZ to more desired levels. 3. The frequency of CAZ administration may be adjusted after the efficacy of once daily 25 mg/kg CAZ has been studied.