Gender-associated differences in pharmacokinetics and anti-arrhythmic effects of flecainide in Japanese patients with supraventricular tachyarrhythmia

Objective We examined the effect of gender-associated differences in pharmacokinetics on the anti-arrhythmic effects of flecainide in Japanese patients with supraventricular tachyarrhythmia and in healthy subjects. Methods The study population comprised 72 outpatients (52 males and 20 females) treated with oral flecainide for supraventricular tachyarrhythmias. Serum flecainide concentrations were determined by use of high-performance liquid chromatography. The anti-arrhythmic efficacy of flecainide was assessed for at least 2 months through evaluation of symptomatology, electrocardiograms, and Holter monitoring. Pharmacokinetics of flecainide after a single 50-mg dose was examined in 14 healthy subjects (7 males and 7 females). Results The daily dose of flecainide did not differ between males and females (2.87 ± 0.68 versus 2.92 ± 0.90 mg/kg). The serum flecainide concentration was significantly lower in males than in females (315 ± 151 versus 408 ± 184 ng/mL, P < 0.05). Clinically relevant efficacy of flecainide was achieved significantly (P < 0.05) less often in male patients (31 of 52; 60%) than in female patients (19 of 20; 95%). We confirmed that nonrenal clearance of flecainide among healthy subjects was significantly higher in males than in females (0.77 ± 0.16 versus 0.57 ± 0.06 L h⁻¹ kg⁻¹, P < 0.05). Conclusions Our results suggest that the anti-arrhythmic efficacy of flecainide differed between males and females because of gender-associated differences in pharmacokinetics.     

High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfotiamine

Objective: The influence of either orally administered S-benzoylthiamine-O-monophosphate (benfotiamine) or thiamine nitrate on the thiamine status was tested in a randomised, two-group comparison study in 20 end-stage renal disease (ESRD) patients. Main outcome measures were the pharmacokinetics of thiamine diphosphate (TDP) in blood, the in vitro erythrocyte transketolase activity, its activation coefficient (α-ETK) and the TDP concentration in erythrocytes. Methods: After ingestion of a single dose of either 100 mg thiamine nitrate (corresponding to 305 μmol thiamine) or 100 mg benfotiamine (corresponding to 214 μmol thiamine), the blood levels of thiamine phosphate esters were analysed by means of high-performance liquid chromatography for a 24-h period. The TDP concentration in erythrocytes was calculated using the haematocrit and TDP concentration in blood. Erythrocyte transketolase activity and α-ETK were measured before and 10 h after administration. The pharmacokinetics of TDP in blood were compared with healthy subjects of other studies retrieved from database query. Results: Regarding the blood concentrations of TDP, the patients with ESRD had a 4.3 times higher area under the concentration–time curve after benfotiamine administration than after thiamine nitrate. After benfotiamine administration, the peak plasma concentration of TDP exceeded that in healthy subjects by 51%. In the ESRD patients, after 24 h, the mean TDP concentration in erythrocytes increased from 158.7 ± 30.9 ng/ml initially to 325.8 ± 50.9 ng/ml after administration of benfotiamine and from 166.2 ± 51.9 ng/ml to 200.5 ± 50.0 ng/ml after thiamine nitrate administration. The ratio between the maximum erythrocyte TDP concentration and basal concentration was 2.66 ± 0.6 in the benfotiamine group and 1.44 ± 0.2 in the group receiving thiamine nitrate (P < 0.001). After 24 h, it was 2.11 ± 0.4 and 1.23 ± 0.2, respectively. The transketolase activity increased from 3.54 ± 0.7 μkat/l initially to 3.84 ± 0.6 μkat/l after benfotiamine intake (P=0.02) and from 3.71 ± 0.8 μkat/l to 4.02 ± 0.7 μkat/l after thiamine nitrate intake (P=0.08). Likewise, α-ETK decreased from initially 1.10 ± 0.07 to 1.04 ± 0.04 (P=0.04) and from 1.12 ± 0.05 to 1.08 ± 0.06 (P=0.09). After 24 h, the phosphorylation ratio in whole blood decreased from 12.9 ± 6.9 initially to 5.6 ± 3.2 after benfotiamine administration (P=0.02) and from 13.5 ± 7.3 to 9.0 ± 4.8 (P=0.03) after administration of thiamine nitrate. No correlation between erythrocyte TDP concentration and transketolase activity and/or α-ETK was observed in ESRD patients, either before or 10 h after administration. Conclusion: Compared with thiamine nitrate, the oral administration of benfotiamine leads to higher TDP concentrations in erythrocytes accompanied with a significant improvement of the erythrocyte transketolase activity in ESRD patients. Received: 4 October 1999 / Accepted: 15 March 2000     

Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results  For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0-t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0-t . No differences were found for the pharmacodynamic parameter (INR). Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.     

Pharmacokinetics and safety of candesartan cilexetil in subjects with normal and impaired liver function

Objective: The influence of liver disease on the pharmacokinetics of candesartan, a long-acting selective AT₁ subtype angiotensin II receptor antagonist was studied. Methods: Twelve healthy subjects and 12 patients with mild to moderate liver impairment received a single oral dose of 12 mg of candesartan cilexetil on day 1 and once-daily doses of 12 mg on days 3–7. The drug was taken before breakfast. Serial blood samples were collected for 48 h after the first and last administration on days 1 and 7. Serum was analyzed for unchanged candesartan by HPLC with UV detection. Results: The pharmacokinetic parameters on days 1 and 7 revealed no statistically significant influence of liver impairment on the pharmacokinetics of candesartan. Following single dose administration on day 1, the␣mean␣C_max was 95.2 ng · ml⁻¹ in healthy subjects and 109 ng · ml⁻¹ in the patients. The AUC_0−∞ was␣909 ng.h · ml⁻¹ in healthy volunteers and 1107 ng.h · ml⁻¹ in patients and the elimination half-life was 9.3 h in healthy volunteers and 12 h in the patients. At steady state on day 7, mean C_max values were similar in both groups (112 vs 116 ng · ml⁻¹); the AUC_τ was 880 ng.h · ml⁻¹ in healthy subjects and 1080 ng.h · ml⁻¹ in patients while the elimination half-life was 10 h in healthy subjects and 12 h in the patients with liver impairment. The AUC_0−∞ on day 1 was almost identical to the AUC_τ on day 7. A moderate drug accumulation of 20%, which does not require a dose adjustment, was observed following once-daily dosing in both groups. No serious or severe adverse events were reported. Conclusion: Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment is required for such patients. Received: 24 November 1997 / Accepted in revised form: 18 February 1998     

The effects of acute falciparum malaria on the disposition of caffeine and the comparison of saliva and plasma-derived pharmacokinetic parameters in adult Nigerians

Objectives: The pharmacokinetics of caffeine and its dimethylxanthine metabolites were evaluated in Nigerians, for whom it is normal to consume caffeine-containing beverages during ill health and recuperation in the belief that caffeine aids early recovery from illness; however, there are no data defining the kinetics of caffeine in healthy and ill Nigerians. Materials and methods: A single oral dose of 300 mg caffeine was given to ten healthy adult Nigerians and ten adults suffering from acute uncomplicated Plasmodium falciparum malaria infection. Caffeine and its dimethylxanthine metabolites were measured in plasma and saliva of healthy subjects and in plasma of patients suffering from malaria using high-performance liquid chromatography. Results: The plasma pharmacokinetics of caffeine per se in both groups was similar (P > 0.05). The maximum plasma concentration (C_max) of paraxanthine was significantly lower (P < 0.05) in malaria (0.9 ± 0.4 μg/ml) than in healthy controls (1.4 ± 0.5 μg/m1), and the paraxanthine:caffeine area under the plasma concentration–time curve ratio, an index of cytochrome P₄₅₀ (CYP)IA2 activity was significantly lower (P < 0.05) in malaria patients (0.5 ± 0.1) than in healthy controls (0.3 ± 0.2). The elimination half-life of theophylline was longer in malaria, while the area under the plasma concentration–time curve of theobromine was significantly higher (P < 0.05) in malaria (7.1 ± 3.4 μg ml⁻¹ h) than in healthy adults (4.1 ± 2.2 μg ml⁻¹ h). Excellent correlations were found between saliva and plasma concentrations of caffeine (r ²=0.98) with a mean saliva:plasma concentrations ratio of 0.7 ± 0.1. The plasma concentrations (C_max and AUC) were therefore higher than the corresponding salivary levels, so that the apparent oral clearance calculated for saliva exceeded the true oral clearance based on plasma data. Conclusions: Acute Plasmodium falciparum malaria produced significant changes in the disposition of caffeine metabolites. Analysis of concentrations in saliva is a useful non-invasive method for monitoring the kinetics of caffeine and paraxanthine in Nigerians. Received: 14 April 1999 / Accepted in revised form: 30 November 1999     

Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator

Purpose: New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies. Methods: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25–200 mg. Standard pharmacokinetic parameters were assessed. Results: In the single-dose study, time to reach peak concentration (t_max) ranged from 1.3 h to 4.0 h; peak concentration (C_max) ranged from 15 ng/ml to 445 ng/ml; and the estimated terminal elimination half-life (mean ± SD; t_1/2) was 24.8 ± 7.0 h. In the repeated-dose study, t_max ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. C_max ranged from 295 ng/ml to 1043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t_1/2 at all dose levels was 29.7 ± 1.5 h (overall mean ± SD). Strong linear correlations between the dose and C_max and between the dose and the area under the curve were observed in both studies. Conclusion: Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens. Received: 12 July 1999 / Accepted in revised form: 18 May 2000     

Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study

Rationale To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo ¹²³I-ADAM SPECT.Objectives ¹²³I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc.Materials and methods Measures of SERT availability by means of ¹²³I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. ¹²³I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E _max model.Results Mean SERTocc values were 66.4 ± 9.5% in midbrain, 63.0 ± 9.6% in thalamus, and 61.3 ± 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 ± 0.15; thalamus = 0.85 ± 0.13; striatum = 0.70 ± 0.07) and healthy volunteers (midbrain = 1.19 ± 0.22; thalamus = 0.96 ± 0.14; striatum = 0.67 ± 0.15). The E _max model returned a SERTocc_max = 70.5% and a Cp₅₀ = 2.7 ng/ml.Conclusions Using ¹²³I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E _max model is suitable for the study of paroxetine Cp relationship to ¹²³I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic–pharmacodynamic relationships in drug development.     

Safety and pharmacokinetics of a single oral dose of amisulpride in healthy elderly volunteers

Objective: Amisulpride is a substituted benzamide neuroleptic, which binds selectively to dopamine D₂ and D₃ receptors, mainly in the limbic structures. States of delusion and agitation occur frequently in the population aged more than 65 years, especially in demented patients and this sometimes requires the use of neuroleptics. The objectives of this study were to determine the safety and the pharmacokinetic profile of 50 mg of amisulpride administered orally as a single dose to elderly volunteers. Methods: Twenty healthy volunteers (10 men and 10 women) aged 65–79 years were included in this open trial. Frequent measurements of blood pressure and heart rate were made and ECG and blood samples were performed up to 72 h after drug intake. Results: The overall clinical and cardiovascular safety was satisfactory. The mean C_max of the racemate amisulpride in elderly people was 64.1 ± 6.7 ng · ml⁻¹, and was not different from the value of 56 ± 4.1 ng · ml⁻¹ in young subjects. As with the C_max, the mean values of t_1/2 and AUC in elderly people (15.6 ± 1.3 h and 667 ± 51 ng · ml⁻¹· h, respectively) were not different to values observed in young subject (respectively 11.7 ± 0.5 h and 603 ± 25 ng · ml⁻¹· h). Conclusions: A single oral dose of amisulpride was well tolerated and showed a similar pharmacokinetic profile in healthy elderly and young subjects. However, these findings should be confirmed after multiple dosing in a larger population in order to establish the lack of need of dosage adjustment in this elderly population. Received: 13 October 1997 / Accepted in revised form: 11 March 1998     

Site of nicotine absorption from a vapour inhaler – comparison with cigarette smoking

Objective: The aim of the study was to assess the site of nicotine absorption during and after use of a nicotine-vapour inhaler compared with that after cigarette smoking. Methods: Using a catheterisation technique, the nicotine plasma concentration–time profiles in arterial and jugular venous blood after using a nicotine inhaler were compared with those achieved after cigarette smoking a in seven healthy habitual smokers. Results: After use of the inhaler, arterial nicotine concentrations rose slowly to a maximum level of 5.9 ± 1.5 ng/ml at a mean time to reach peak concentration (t _max) of 9.0 ± 1.1 min, whereas jugular venous nicotine levels peaked at 25.4 ± 5.4 ng/ml at 6.7 ± 0.3 min. The concentration–time curves indicate that the absorption occurs mainly via the mucosa of the oral cavity and the pharynx, and that there is minimal absorption via the lungs. In contrast, after smoking a cigarette, arterial nicotine plasma concentrations rose quickly to a maximum level of 49.2 ± 9.7 ng/ml after 4.0 ± 0.6 min, while the maximum concentration of nicotine in the jugular vein was 22.4 ± 3.9 ng/ml after 6.4 ± 0.4 min, indicating primarily pulmonary absorption of nicotine. Conclusion: Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine inhaler is probably small. Received: 7 June 1999 / Accepted in revised form: 6 October 1999     

Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers

Objective To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker talinolol. Methods The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant administration of curcumin (300 mg day⁻¹ for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered to be significant at p < 0.05 (two-sided test). Results The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity () of talinolol from 1860.0 ± 377.9 to 1246.0 ± 328.2 ng.h mL⁻¹, the highest observed concentration values (C_max) were significantly decreased from 147.8 ± 63.8 to 106.4 ± 39.9 ng mL⁻¹, and the CL/F was increased from 27.9 ± 5.5 to 43.1 ± 13.4 L.h⁻¹ (p < 0.05). There was no significant difference in sampling time for C_max (t_max) and elimination half-life (t_1/2) values between the two periods (p > 0.05). The interindividual variability in AUC_0–60 and C_max of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC_0–60 and C_max was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively. Conclusion We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration, or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues.     

Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart

Objective: With the aim to obtain a premixed rapid-acting insulin with a serum insulin profile more closely resembling the endogenous meal-stimulated serum insulin profiles, a 30/70 (rapid/intermediate-acting) premixed suspension of the rapid-acting insulin analogue insulin aspart (BIAsp30) was compared with a similar premixed suspension of biphasic human insulin 30/70 (BHI30) after a single subcutaneous injection. Methods: The study had a randomised, double-blind, two-period crossover design. Twenty-four healthy male subjects received a single subcutaneous dose of either 0.2 U · kg⁻¹ bodyweight of BIAsp30 or BHI30 on two study days. Results: BIAsp30 was absorbed faster than BHI30, as reflected in the area under the insulin concentration-time curve from 0 to 90 min after dosing [AUC_{(0–90 min)}]. This was significantly larger for BIAsp30 than for BHI30 (1403 ± 372 versus 752 ± 191 mU · l⁻¹ · min⁻¹ [mean ± SD]; P < 0.0001). Furthermore, the time to maximum serum insulin concentration (t_max) of BIAsp30 was approximately half the t_max of BHI30 (60 [45–70] versus 110 [90–180] min [median, interquartile range]; P=0.0001) and the maximum insulin concentration (C_max) was significantly higher for BIAsp30 than for BHI30 (23.4 ± 5.3 versus 15.5 ± 3.7 mU · l⁻¹ [mean ± SD]; P < 0.0001). The serum glucose profiles showed a significantly earlier onset of the glucose-lowering effect following BIAsp30 than following BHI30. Conclusions: The improved absorption properties of soluble insulin aspart in its premixed formulation provide a basis for a more efficient meal-related glucose control and immediate pre-meal delivery when compared with a similar human premixed insulin in the treatment of diabetes mellitus. Received: 22 November 1999 / Accepted in revised form: 7 April 2000     

Quinolone-induced arthropathy: exposure of magnesium-deficient aged rats or immature rats, mineral concentrations in target tissues and pharmacokinetics

Quinolone treatment or magnesium deficiency induce identical cartilage lesions in juvenile rats and show additive arthropathogenic effects. It has been shown previously that neither condition is arthropathogenic in 8-week-old rats. Joint cartilage from aged individuals is rather prone to pathological alterations but information on prolonged quinolone treatment and/or dietarily induced magnesium deficiency in aged animals is not available. We treated magnesium-deficient (n = 9) aged Wistar rats (age 15 months) and age-matched controls with daily doses of 600 mg ofloxacin/kg body wt. by gastric intubation for 28 days. Further groups of magnesium-deficient and control rats (n = 9 and n = 10, respectively) received the vehicle only. Peak plasma concentrations of ofloxacin in adult rats were 20.5 ± 5.6 mg/l (mean ± SD) following treatment with a single dose of 600 mg/kg body wt. At the end of the experiment the degree of magnesium deficiency was most pronounced in plasma (Mg²⁺-def., 0.33 ± 0.12 mmol/l; control, 0.97 ± 0.08 mmol/l) and less pronounced in sternal cartilage (Mg²⁺-def., 10.8 ± 3.6 mmol/kg dry wt; control, 13.3 ± 2.8 mmol/kg dry wt), whereas the magnesium concentration in femoral bone remained unchanged (Mg²⁺-def., 201 ± 13 mmol/kg dry wt; control, 204 ± 11 mmol/kg dry wt). Histological investigation of the knee joints revealed no cartilage lesions following ofloxacin treatment, magnesium deficiency or a combination of both conditions. By contrast, cartilage lesions such as scars and erosions of the joint surface, chondrocyte clusters within acellular areas of the cartilage matrix and persisting clefts were detectable in knee joints from 7 of 10 adult rats (age 9 months) which had been treated with 4 × 600 mg fleroxacin/kg body wt. at 5 weeks of age. Mean plasma concentration of fleroxacin in juvenile rats was approx. 50 mg/l between 1.5 and 6 h after dosing and the drug was still detectable in plasma 48 h after dosing (0.4 ± 0.1 mg/l). Our data indicate that joint cartilage in aged rats is not altered by a 4-week quinolone treatment, even during magnesium deficiency. Cartilage lesions in adult rats were only detectable if the animals had been treated during the sensitive phase at 5 weeks postnatally. Received: 3 March 1997 / Accepted: 15 May 1997     

Clinical pharmacokinetics of ciprofloxacin in patients with major burns

Objective: To better master the use of ciprofloxacin (CPF) in burn patients, a clinical study, including pharmacokinetics in serum and urine, was undertaken in a pathophysiologically homogeneous population of major-burn subjects. Methods: Twelve major-burn patients who were infected with Pseudomonas aeruginosa, enterobacteria and gram-positive cocci, received CPF (600 mg t.i.d.). The mean body surface area affected by third-degree burns was 31.8 ± 14.5%. Two series of blood samples were drawn after the first and seventh doses; urine was collected during the first infusion. Levels of CPF in serum and urine were measured by means of high-performance liquid chromatography. A non-compartmental method was used for kinetic and graphic analysis of concentration–time pairs. Results: No adverse effects were noted. Trough concentrations measured on day 3 (mean ± SD) were above the minimum inhibitory concentration (MIC) for the organism responsible for infection; i.e., 2.0 ± 1.2 μg · ml⁻¹, and maximum concentrations were high 9.9 ± 3.4 μg · ml⁻¹. An area under the concentration–time curve (AUC)/MIC ratio above 125 SIT⁻¹ (where SIT is the serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in 11 patients with a MIC of 0.5 μg · ml⁻¹. There was a statistically significant difference between C_min and AUC determined on day 1 and day 3. In contrast to healthy volunteers, CPF clearance rates were notably decreased. Conclusion: The pharmacokinetics of CPF was altered in major-burn patients. The recommended dosage regimen for administration of CPF, i.e. 600 mg t.i.d. shows no adverse effects and a good microbiological efficacy. Received: 13 October 1998 / Accepted in revised form: 8 June 1999     

Effects of avitriptan, a new 5-HT1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential

Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-N-methyl-1H-indole-5-methanesulfonamide monofumarate), a new 5-HT_1B/1D receptor agonist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 μg·kg^–1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean ± SEM i.v. dose of avitriptan eliciting a 50% decrease (ED₅₀) in the porcine carotid arteriovenous anastomotic blood flow was calculated to be 76 ± 23 μg·kg^–1 (132 ± 40 nmol·kg^–1) and the highest dose (300 μg·kg^–1) produced a 72 ± 4% reduction. In recent comparative experiments (DeVries et al. 1996), the mean ± SEM ED₅₀ (i.v.) of sumatriptan in decreasing carotid arteriovenous anastomotic blood flow was 63 ± 17 μg·kg^–1 (158 ± 43 nmol·kg^–1), with a reduction of 76 ± 4% by 300 μg·kg^–1, i.v. Both avitriptan (pD₂: 7.39 ± 0.09; E_max: 13.0 ± 4.5% of the contraction to 100 mM K⁺) and sumatriptan (pD₂: 6.33 ± 0.09; E_max: 15.5 ± 2.3% of the contraction to 100 mM K⁺) contracted the human isolated coronary artery. The above results suggest that avitriptan should be able to abort migraine headaches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demonstrated the therapeutic action of the drug in acute migraine. Received: 23 August 1996 / Accepted: 19 October 1996     

Determination of the relative bioavailability of nedocromil sodium to the lung following inhalation using urinary excretion

Objective: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses were compared. Results: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin with cimetidine. Mean values for C_max (the maximum concentration) were 5.11 ng · eq · ml⁻¹ and 4.54 ng eq · ml⁻¹, for t_max (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC_0–24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq · h · ml⁻¹ and 58.5 ng eq · h · ml⁻¹, and for t_1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change from baseline for total cholesterol were −29.5% and −29.9%, for low-density lipoprotein (LDL) cholesterol −41.0% and −42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides −33.8% and −25.8%, respectively. Conclusions: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced by coadministration of cimetidine. Received: 17 February 1997 / Accepted in revised form: 3 November 1997     

Occupancy of dopamine D<Subscript>1</Subscript>, D<Subscript>2</Subscript> and serotonin<Subscript>2A</Subscript> receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol

Rationale Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D₂, D₁ and 5-HT_2A receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol’s interaction with 5-HT_2A and/or D₁ receptors. Objectives To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 ± 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 ± 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 ± 5.5 mg/day). Materials and methods Each patient underwent two PET scans with 3-N-[¹¹C]methylspiperone (target: frontal 5-HT_2A), [¹¹C]SCH23390 (striatal D₁) or [¹¹C]raclopride (striatal D₂). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls. Results D₂-RO under FLX was between 50% and 70%, indicating an ED₅₀ of about 0.7 ng/ml serum. 5-HT_2A and D₁-RO was 20 ± 10% and 20 ± 5% (mean, SEM). Under HAL, D₁-RO was 14 ± 6% and under RIS not significantly different from zero. Conclusions We were able to demonstrate a moderate 5-HT_2A and D₁ occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol’s efficacy on negative symptoms is based on its interaction with 5-HT_2A and/or D₁ receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D₁ or 5-HT_2A antagonism may contribute to flupentixol’s efficacy on negative symptoms.     

Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients

Objective: To investigate the effects of rifampicin on the pharmacokinetics of itraconazole in humans. Methods: Our study was conducted with six healthy normal volunteers and three AIDS patients. All subjects received a 200 mg single dose of oral itraconazole on day 1 and day 15 and 600 mg of oral rifampicin once daily from day 2 to day 15. Itraconazole pharmacokinetics studies were carried out on day 1 (phase 1) and day 15 (phase 2). The limit of detection for itraconazole concentration was 16 ng · ml^–1. Results: Concentrations itraconazole were higher when it was administered alone than when it was administered with rifampicin. Coadministration of rifampicin resulted in undetectable levels of itraconazole in all subjects except one normal volunteer. The mean AUC_0–24 was 3.28 vs 0.39 μg · h · ml⁻¹ in phase 1 and 2, respectively, in healthy normal volunteers. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 88% compared with phase 1. The mean AUC_0–24 was 1.07 vs 0.38 μg · h · ml^–1 in phase 1 and 2, respectively, in AIDS patients. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 64% compared with phase 1. Conclusion: Rifampicin has a very strong inducing effect on the metabolism of itraconazole, so that these two drugs should not be administered concomitantly. Received: 2 September 1997/Accepted in revised form: 16 December 1997     

Estimation of CYP2C19 activity by the omeprazole hydroxylation index at a single point in time after intravenous and oral administration

Objective The purpose of this study was to identify the common time point to achieve hydroxylation index (HI: omeprazole plasma concentration/5-hydroxyomeprazole plasma concentration) reflecting AUC_OPZ/AUC_5OH-OPZ after intravenous (IV) and oral (PO) administration. Methods Twenty young and 28 elderly healthy subjects, including different CYP2C19 genotypes, were enrolled in the study. The young subjects received either 40 mg PO or 20 mg IV omeprazole, whereas the elderly subjects received 10 mg IV. The relation between AUC_OPZ/AUC_5OH-OPZ and HI was determined by Spearman’s rank correlation. Multiple stepwise linear regression analysis was performed to identify the common time point to calculate HI that reflects AUC_OPZ/AUC_5OH-OPZ after IV. Results In the correlation between HI and AUC_OPZ/AUC_5OH-OPZ IV at observed time points, HI_3h showed the highest correlation coefficients (r = 0.894, p < 0.001) in all 48 subjects. The correlation of HI between IV and PO at observed time points showed that HI_3h was highest (r = 0.916, p < 0.001) in 20 young subjects. Additionally, there was no significant difference between HI_3h of IV and that of PO (12.9 ± 15.9 and 12.9 ± 15.1, p = 0.997). The regression equation of HI_3h was the best to estimate AUC_OPZ/AUC_5OH-OPZ (AUC_OPZ/AUC_5OH-OPZ = 1.37 • HI_3h + 0.18 • Age – 7.83, r ² = 0.883, p < 0.001). Conclusions This study demonstrated that HI_3h after omeprazole IV was able to estimate AUC_OPZ/AUC_5OH-OPZ, as well as HI_3h after PO. Additionally, CYP2C19 activity can be estimated more definitely by using HI after omeprazole IV without intestinal absorption.     

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure

Objective: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL_CR) 64 ml · min⁻¹; range 42–77 ml · min⁻¹], eight patients with severe chronic renal failure (mean CL_CR, 18 ml · min⁻¹; range 11–29 ml · min⁻¹) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days. Results: No statistical differences of either maximum concentration (C_max) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, C_max and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat. Conclusion: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency. Received : 11 July 1997 / Accepted in revised form : 6 October 1997     

Multiple-dose pharmacokinetics of cefepime in long-term hemodialysis with high-flux membranes

Objective: Among uremic patients on hemodialysis, infectious complications leading to a high incidence of morbidity and mortality are a well-documented problem. In this multi-dose study, the safety, tolerance, and pharmacokinetics of cefepime during high-flux hemodialysis were investigated and an improved dosing schedule is presented. Methods: Six long-term hemodialysis patients received 2 g cefepime i.v. at the end of hemodialysis three times per week. Results: Trough levels of cefepime were 23.3 ± 7.3 mg/l and peak serum concentrations 165.6 ± 48.7 mg/l. After 3.5 h of high-flux hemodialysis, 72.2 ± 6.4% of cefepime was eliminated. The intradialytic half-life was 1.6 ± 0.29 h and the interdialytic half-life 22.0 ± 2.14 h. Conclusion: A dosage of 2 g cefepime after each hemodialysis session achieved drug levels well above the minimal inhibitory concentration (MIC)₉₀ for most of the target pathogens. Thus, the described dosing schedule is an efficient and cost saving antmicrobial therapy for severe infections in long-term hemodialysis patients with no residual renal function. Received: 12 October 1999 / Accepted in revised from: 12 January 2000