Biomedical subjects

R C Schoemaker

Publications and source records attributed to R C Schoemaker.

At least 73 records · Page 4Linked to original sources

PubMed1997

Effect of changes in liver blood flow on the pharmacokinetics of saruplase in patients with acute myocardial infarction.

BACKGROUND: The recombinant unglycosylated single chain urokinase-type plasminogen activator saruplase is cleared for a large part by the liver. A large interindividual variation in saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of saruplase. METHODS AND RESULTS: Thirteen AMI patients were enrolled in this open label study. Patients received a bolus injection of 20 mg saruplase followed by a one-hour infusion of 60 mg saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, alpha2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and alpha2-antiplasmin (r = -0.84; p <0.01 and r = -0.65; p <0.05). CONCLUSIONS: Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow.

Aged↗

PubMed1996

Pharmacokinetics of the conventional and microemulsion formulations of cyclosporine in pancreas-kidney transplant recipients with gastroparesis.

Cyclosporine (CsA) is an immunosuppressive drug requiring dose individualization and regular control due to its highly variable pharmacokinetics. Since gastroparesis may influence the absorption of CsA, a randomized cross-over study was performed to assess the pharmacokinetics and tolerability of a novel microemulsion CsA formulation in comparison with the standard CsA dosage form in six stable pancreas-kidney transplant recipients with scintigraphically proven gastroparesis. The absorption of CsA was investigated during three 2-hr study days during each treatment period, and a full pharmacokinetic profile was done for each formulation. No adverse events or differences in tolerability/safety parameters between the treatments were found. The average AUC (0-->2 hr) was 150% higher after the novel formulation. The coefficient of variation in AUC (0-->2 hr) for both formulations was comparable (37% after the microemulsion and 40% after the standard formulation). The median time at which blood CsA levels exceeded the preceding trough level by 20% was 30 min (range: 30 -> 718 min) after the standard formulation. With approximately the same average dose, the AUCss tau after the microemulsion was 81% higher than the standard formulation, while predose and 12-hr trough levels were similar. The average maximal CsA plasma level after the microemulsion was 396 ng/ml (95% CI: 71-722 ng/ml) higher than after the standard formulation. The median time at which the highest blood levels were observed was 90 min (range: 150 -> 718 min) after the standard formulation. The time profiles of the CsA metabolites followed those of the parent compound. The microemulsion resulted in a higher systemic exposure to CsA than the standard formulation in pancreas-kidney transplant patients with diabetic gastroparesis, but substantial variability in blood concentrations remained.

Adult↗

PubMed1996

Effects of increased liver blood flow on the kinetics and dynamics of recombinant tissue-type plasminogen activator.

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 alpha 2-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 alpha 2-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.

Adult↗

PubMed1996

Pharmacokinetic and pharmacodynamic profiles of sumatriptan in migraine patients with headache recurrence or no response.

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.

Adolescent↗

PubMed1996

Estimating impossible curves using NONMEM.

1. On fitting model equations to experimental data, the situation may arise that individual subjects provide insufficient information to obtain adequate parameter estimates due to the fact that not all aspects are exhibited by all subjects or that the models are simply too complex. This may be solved by applying nonlinear mixed effect modelling to the data, which integrates the information provided by different subjects. 2. We aim to provide insight into the methodology and its use in these situations, illustrated by three examples: determination of pharmacokinetics in a rising dose design, where the lower doses provide insufficient information (due to assay limitations) to estimate terminal half-life; determination of the kinetics of the low molecular weight heparin enoxaparine (Clexane) using anti-Xa activity, effectively dealing with lingering low/basal activity; simultaneous estimation of the pharmacokinetics and pharmacodynamics of the low molecular weight heparin dalteparin (Fragmin) after subcutaneous and intravenous administration.

Antihypertensive Agents↗

PubMed1996

Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol.

1. Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double-blind, placebo controlled six-way cross over experiment in 12 healthy volunteers, aged 19-26 years. 2. Bretazenil (0.5 mg), diazepam (10 mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target-blood concentration of 0.5 g l-1 or a control infusion of 5% w/v glucose at 1 week intervals. 3. CNS effects were evaluated between 0 and 3.5 h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales. 4. Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol > diazepam+alcohol > or = bretazenil > diazepam > alcohol > placebo. 5. There were no consistent indications for synergistic, supra-additive pharmacodynamic interactions between alcohol and bretazenil or diazepam. 6. Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests. 7. No significant pharmacokinetic interactions were found. 8. Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.

Administration, Oral↗

PubMed1996

Self-medication of a single headache episode with ketoprofen, ibuprofen or placebo, home-monitored with an electronic patient diary.

1. The objective of this study was to investigate the efficacy of home-medicated non-steroidal anti-inflammatory (NSAID) analgesics, using an electronic patient diary. Single doses of ketoprofen 25 mg and ketoprofen 50 mg were compared with ibuprofen 200 mg and placebo in the treatment of a single occasion of episodic tension-type headache, using a double-blind, randomized, parallel group design. 2. A total of 166 patients with headache compatible with episodic tension-type headache and no refractory headaches or contraindications to NSAIDs were contacted by advertisements and selected by questionnaires. Patients performed the study at home, using an electronic diary for headache assessment, with a form to allow comments and corrections. Visual analogue scales (VAS 10 cm) of headache severity, five-item headache relief rating (HRR) scales, and time of intake of 'escape' analgesics were scored regularly, for 4 h following intake of trial medication. 3. VAS-scores (n = 1407) and HRRs (n = 452) were returned by 159 patients. Of these scores, 1.5% were inadvertently omitted from the electronic diary or modified on the comment forms. 4. Headache (VAS and HRR) improved more with all three NSAIDs than with placebo, although the effect of ibuprofen was significant for HRR only. After 2 and 4 h respectively, the reduction in VAS-ratios was 17 and 19% with placebo, 18 and 53% with ibuprofen 200 mg, 41 and 61% with ketoprofen 25 mg, and 47 and 59% with ketoprofen 50 mg. After 4 h, headache improved strongly (highest HRR) in 18% of patients on placebo, 39% on ibuprofen 200 mg, 62% on ketoprofen 25 mg, and 55% on ketoprofen 50 mg. Headache disappeared completely (VAS-score = 0) in one patient (3%) with placebo (after 180 min), 10% with ibuprofen 200 mg (average 211 min), 18% with ketoprofen 25 mg (159 min), and 28% with ketoprofen 50 mg (146 min). 5. The effects of ketoprofen 50 mg were more pronounced than those of ibuprofen 200 mg, which seemed to start later. Ketoprofen 25 mg and 50 mg were very similar, suggesting a maximal effect of the lower dose. Mild to moderate adverse events were reported by 9% of the patients, half of which occurred with ketoprofen 50 mg. Treatment of headache with ketoprofen can start with 25 mg, and possibly less. 6. Although a direct comparative study would be necessary to determine the relative benefits of the novel electronic patient diaries over traditional paper-and-pencil methods, this study has shown the usefulness of this newer technique to detect differences in efficacy between low doses of analgesics under ambulant conditions, with very limited loss of data. Electronic patient diaries appear to be an important new attribute for the efficacy assessment of self-medicated drugs.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1995

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril.

The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

Biological Availability↗

PubMed1995

Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age.

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, 1/2, 1, 2, 4, 8, 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.

Ceftazidime↗

PubMed1995

The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients.

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.

Adult↗

PubMed1995

Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase.

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, alpha 2-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.

Adult↗

PubMed1995

A placebo-controlled parallel study of the effect of two types of coffee oil on serum lipids and transaminases: identification of chemical substances involved in the cholesterol-raising effect of coffee.

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.

Administration, Oral↗

PubMed1995

Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks.

The multiple-dose pharmacokinetics of amoxicillin (AM [administered twice daily in a 25-mg/kg of body weight intravenous dose]) in 17 preterm infants (11 males; gestational age, 29 +/- 1.9 weeks; birth weight, 1,175 +/- 278 g) were evaluated on day 3 of life. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after the intravenous dose. A high-performance liquid chromatography method was used to determine AM concentrations in serum. AM pharmacokinetics followed a one-compartment open model. The glomerular filtration rates of all patients were simultaneously studied by means of the 24-h continuous inulin infusion technique. The elimination half-life, apparent volume of distribution, and total body clearance of AM (mean +/- standard deviation) were 6.7 +/- 1.7 h, 584 +/- 173 ml, and 62.4 +/- 23.3 ml/h, respectively. The mean (+/- standard deviation) AM peak and trough levels were 53.6 +/- 9.1 and 16.0 +/- 4.9 mg/liter, respectively. All infants had a serum trough level above 5 mg/liter. The total body clearance and apparent volume of distribution of AM and the clearance of inulin increased significantly with increasing gestational age. The total body clearance of AM (1.0 +/- 0.4 ml/min) and the clearance of inulin (1.0 +/- 0.3 ml/min) were similar. The total body clearance of AM increased significantly with increasing clearance of inulin. We conclude that an AM dose of 25 mg/kg every 12 h given to preterm infants in the first week of life with gestational ages of less than 32 weeks results in serum levels well above the MIC for major microorganisms involved in neonatal infections.

Amoxicillin↗

PubMed1995

Once-daily versus twice-daily administration of ceftazidime in the preterm infant.

Ceftazidime pharmacokinetics in 28 preterm infants (gestational ages, 25.6 to 31.9 weeks) were studied on day 3 of life. Patients with suspected septicemia were randomized on day 1 of life in two groups. One group (n = 13) was administered 25 mg of ceftazidime per kg of body weight once daily, and the other (n = 15) was given 25 mg of ceftazidime per kg twice daily. Both groups also received 25 mg of amoxicillin per kg twice daily. Blood samples were collected on day 3 of life with an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an intravenous bolus injection. An additional blood sample was taken at 24 h from the group dosed once a day. High-performance liquid chromatography was used to determine serum ceftazidime concentrations. The pharmacokinetics of ceftazidime were best described by using a one-compartment model. The half-life for the elimination of the drug from serum, apparent volume of distribution, total body clearance of ceftazidime, and inulin clearance were not significantly different for both groups. The ceftazidime/inulin clearance ratio was 0.72 for both groups. However, trough concentrations in serum for the twice-daily group were significantly (P < 0.001) higher (42.0 +/- 13.4 mg/liter) than those for the once-daily group (13.1 +/- 4.7 mg/liter). The latter concentrations were all still substantially higher than the MIC of ceftazidime for major neonatal pathogens. We conclude that the currently recommended dosage of 25 mg of ceftazidime per kg twice daily for preterm infants with gestational ages below 32 weeks may be adjusted during the first days of life to one daily dose at 25 mg/kg, provided that for the empirical treatment of septicemia, amoxicillin at 25 mg/kg is also given twice daily.

Ceftazidime↗

PubMed1995

The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn.

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.

Asphyxia Neonatorum↗

PubMed1995

Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin.

1. The effects of postnatal age and postnatal exposure to indomethacin on the pharmacokinetic parameters of ceftazidime (CAZ) were investigated in 23 preterm infants (gestational age 28.7 +/- 1.7 weeks; weight 1086 +/- 311 g) on day 3 and day 10 after birth. 2. CAZ (25 mg kg-1) was administered by intravenous bolus injection. Blood samples were drawn from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after the dose and CAZ concentrations in serum were determined by h.p.l.c. CAZ pharmacokinetics followed a one-compartment open model. 3. The glomerular filtration rate (GFR) of all infants was studied by means of the 24 h continuous inulin infusion technique. 4. The total body clearance of CAZ (34.7 +/- 9.2 vs 50.6 +/- 19.6 ml h-1, P < 0.05; 30.7 +/- 5.9 vs 41.6 +/- 9.0 ml h-1 kg-1, P < 0.05) and GFR (0.72 +/- 0.11 vs 0.91 +/- 0.15 ml min-1, P < 0.05) increased, whereas the apparent volume of distribution (425 +/- 147 vs 352 +/- 108 ml, P < 0.05; 363 +/- 59 vs 292 +/- 44 ml kg-1, P < 0.005) and the elimination half-life (8.7 +/- 2.8 vs 5.0 +/- 0.9 h, P < 0.005) decreased significantly between day 3 and day 10 after birth. Clearance of CAZ increased with increasing GFR (r = 0.81, P < 0.001). 5. In infants with postnatal exposure to indomethacin the changes in CAZ pharmacokinetics were markedly reduced. 6. These results indicate that the dosage regimen of CAZ should be adjusted after the first week of life except in infants who were postnatally exposed to indomethacin.

Age Factors↗

PubMed1994

Repeated measures for two within-subject factors: analysis and missing data solutions.

The statistical analysis of the repeated measures design with two factors within and no factors between subjects, which is popular in clinical pharmacology, is discussed. Use of restricted maximum likelihood (REML) methodology is compared to an imputation procedure in small sample situations with missing data and is illustrated by simulations. While imputation leads to undesirable results that are not easily corrected, REML estimation in which test statistics are compared to an F-distribution provides an elegant tool for the analysis of these designs.

Algorithms↗

PubMed1993

Tinnitus suppression by intravenous lidocaine in relation to its plasma concentration.

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 micrograms/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 micrograms/ml. The effect persisted until plasma levels of about 0.5 microgram/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.

Adult↗