Effects of mefloquine alone and with alcohol on psychomotor and driving performance

Objective: To determine whether mefloquine, a quinoline antimalarial drug, affects psychomotor and actual driving performance when given in a prophylactic regimen, alone or in combination with alcohol. Methods: Forty male and female volunteers were randomly assigned in equal numbers to two groups, and were treated double-blind for one month with mefloquine and placebo. The medication was taken in a 250 mg dose on the evenings of Days 1, 2, 3, 8, 15, 22 and 29. Testing was done on Days 4, 23 and 30, the latter after repeated doses of alcohol sufficient to sustain a blood concentration of about 0.35 mg ⋅ml⁻¹. Two real driving tests were used to measure prolonged (1 h) road tracking and car following performance. Critical Flicker/Fusion Frequency (CFF), critical instability tracking and body sway were also measured in the laboratory. Results: Mefloquine caused no significant impairment in any test at any time relative to placebo. It significantly improved road tracking performance on Day 4. A significant interaction between prior treatment and alcohol was found in the body sway test, as the alcohol-induced change was less after mefloquine than placebo. The sensitivity of the driving test and the CFF test were shown by the significant overall effect of alcohol which did not discriminate between the two prior treatments. Conclusion: Mefloquine did not impair driving performance but rather improved it in the longer test, suggesting that the drug may possess psychostimulating properties. Received: 7 December 1995/Accepted in revised form: 27 February 1996     

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. Results: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: C_max = 2.3 ng⋅ml⁻¹, t_max = 2.8 h; slow release: C_max = 1.2 ng⋅ml⁻¹, t_max = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng⋅ml⁻¹). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted. Received: 14 December 1995/Accepted in revised form: 26 March 1996     

The effects of black tea and other beverages on aspects of cognition and psychomotor performance

Nineteen healthy volunteers ingested 400 ml black tea, coffee, caffeinated water, decaffeinated tea or plain water on three occasions through the day (0900, 1400 and 1900 hours). A 2 × 2 factorial design with caffeine (0, 100 mg) and beverage type (water, tea) was employed, with coffee (100 mg caffeine) as a positive internal control, based on a five-way crossover. A psychometric test battery comprising critical flicker fusion (CFF), choice reaction time (CRT), short-term memory (STM) and subjective sedation (LARS) was performed at regular intervals throughout the day, and intensively so immediately following each beverage. Consumption of tea compared to water was associated with transient improvements in performance (CFF) within 10 min of ingestion and was not affected by the time of day. Caffeine ingestion was associated with a rapid (10 min) and persistent reduction in subjective sedation values (LARS), again independent of time of day, but did not acutely alter CFF threshold. Over the whole day, consumption of tea rather than water, and of caffeinated compared to decaffeinated beverages, largely prevented the steady decline in alertness (LARS) and cognitive capacity observed with water ingestion. The effects of tea and coffee were similar on all measures, except that tea consumption was associated with less variation in CFF over the whole day. No significant treatment effects were apparent in the data for the STM. Tea ingestion is associated with rapid increases in alertness and information processing capacity and tea drinking throughout the day largely prevents the diurnal pattern of performance decrements found with the placebo (no caffeine) condition. It appears that the effects of tea and coffee were not entirely due to caffeine per se; other factors either intrinsic to the beverage (e.g. sensory attributes or the presence of other biologically active substances) or of a psychological nature (e.g. expectancy) are likely to play a significant role in mediating the responses observed in this study. Received: 18 September 1997/Final version: 16 February 1998     

Effect of diprafenone on the pharmacokinetics of digoxin

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 × 1 mg) or digoxin and diprafenone (3 × 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone). Blood and urine samples were collected for pharmacokinetic analyses. Diprafenone caused a statistically significant increase in digoxin trough concentrations [1.4 (SD 0.2) vs 1.6 (0.3) ng ⋅ml⁻¹], AUC_0–24 values [41 (7) vs 48 (9) ng⋅h⋅ml⁻¹ and C_ss-max [3.9 (0.6) vs 5.5 (0.9) ng⋅ml⁻¹]. In all volunteers the parameters tended to return to the original values after administration of diprafenone was discontinued [1.4 (0.3) ng⋅ml⁻¹, 39 (11) ng⋅h⋅ml⁻¹, and 3.9 (1.1) ng⋅ml⁻¹ for trough concentration, AUC_0–24 and C_max respectively]. The mean relative magnitude of the increase in AUC_0–24 and trough concentration values corresponded to the mean relative decrease in the renal clearance of digoxin (in both cases approximately 20%). This suggests that the increase in AUC and C_ss was caused by reduced renal clearance of digoxin. Received: 10 July 1995 /Accepted in revised form: 5 October 1995     

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers

Objective: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. Results: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC_0–∞12.6 μg ⋅ h ⋅ ml⁻¹) in comparison with healthy volunteers (AUC_0–∞39.3 μg ⋅ h ⋅ ml⁻¹). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free C_max (5.0 vs. 2.6 ng/ml) but similar free AUC_0–∞(0.13 vs. 0.11 μg ⋅ h ⋅ ml⁻¹) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemo- dialysis. Conclusion: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound non-steroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free C_max value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable. Received: 22 January 1996/Accepted in revised form: 19 June 1996     

Single oral doses of amisulpride do not enhance the effects of alcohol on the performance and memory of healthy subjects

Objectives: Amisulpride is a benzamide antipsychotic that binds selectively to dopamine D₂- and D₃-receptors, preferentially in limbic and hippocampal structures. Since other substituted benzamides have a limited or negligible interaction with alcohol on human performance, amisulpride was studied for this potential. Methods: In a randomised double-blind crossover study, 18 young, non-smoking men took single oral doses of placebo and amisulpride 50 mg and 200 mg, without and with ethanol (0.8 g ⋅kg⁻¹) taken 30 min later. Objective performance tests and self-ratings were done at baseline and 1.5, 3.5 and 6.5 h after drug intake. Memory (immediate and delayed recall) was tested 2 h after dosing. Breath ethanol and the plasma concentrations of amisulpride and prolactin were measured. Three-way ANOVA + Newman-Keul tests were used for statistical analyses; interactions were confirmed by factorial contrast ANOVA. Results: Mean blood ethanol was 0.94, 0.62 and 0.26 g ⋅l⁻¹ at the three test times. It produced significant impairment in all performance tests (symbol digit substitution, simulated driving, body sway, flicker fusion, tapping, nystagmus), reduced both immediate and delayed recall in memory tests, and caused subjective clumsiness, muzziness and mental slowness, mainly between 1.5 to 4.5 h after dosing. Amisulpride, 50 and 200 mg elevated plasma prolactin but had minimal or no effect on performance, attention and memory. The decreases in immediate free recall after the 50 mg dose and in delayed free recall after the 200 mg dose were slight. Amisulpride neither modified blood ethanol concentrations nor enhanced the detrimental effect of ethanol on skilled and cognitive performance; it slightly antagonised ethanol in the digit copying test. Ethanol did not modify the effect of amisulpride on plasma prolactin, and the plasma concentrations of amisulpride were little changed by ethanol. Conclusions: Amisulpride in single oral doses of 50 and 200 mg did not interact significantly with the effects of high, moderate or low concentrations of ethanol on human skilled and cognitive performance. The drugs did interact pharmacokinetically. Received: 22 December 1995/Accepted in revised form: 1 April 1996     

Influence of repeated oral doses of ethinyloestradiol on the metabolic disposition of [13C2]-ethinyloestradiol in young women

Objective: To examine the influence of daily oral administration of ethinyloestradiol on the total clearance of ¹³C-labeled ethinyloestradiol in women. Methods: 19, healthy, young women received a single IV dose of 0.06 mg ¹³C-ethinyloestradiol. Subsequently, they were treated with daily oral doses of 0.06 mg ethinyloestradiol for 8 days. On the last day of oral treatment, they received a further IV dose of 0.06 mg ¹³C-ethinyloestradiol. The pharmacokinetic parameters clearance, area under the serum level-time curve, terminal half-life, steady-state volume of distribution and mean residence time of ¹³C-ethinyloestradiol in each volunteer were evaluated after both IV doses, and the corresponding pairs of parameters were examined statistically for the significance of intraindividual differences. Results: Following the first (second) intravenous administration, the mean area under the curve was 2.54 (2.67) ng⋅h⋅ml⁻¹. The terminal half-life and mean residence time were 9.7 (9.6) h and 10.5 (10.1) h, respectively. The steady-state volume of distribution was 4.3 (3.9) l⋅kg⁻¹ and the clearance was 7.0 (6.6) ml⋅ min⁻¹⋅kg⁻¹. No significant difference was observed in any of these parameters between the first and the second IV doses of ¹³C-EE₂. Conclusions: Since the clearance in particular remained unchanged after repeated oral administration of ethinyloetradiol, the hypothesis that ethinyloestradiol can inhibit its own metabolism in vivo can be rejected. Received: 25 July 1995/Accepted in revised form: 27 November 1995     

Comparison of the pharmacokinetics of tirilazad mesylate in healthy volunteers and stable subjects with mild liver cirrhosis

Objective: The pharmacokinetics of tirilazad mesylate and an active reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg ⋅kg⁻¹ tirilazad mesylate over 10 min. Results: Mean tirilazad AUC_0–∞ was 8.83 μmol h⋅l⁻¹ and 18.6 μmol h⋅l⁻¹ in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l⋅h⁻¹) was approximately 2.1 fold lower than in healthy volunteers (27.8 l⋅h⁻¹). The differences were statistically significant. Mean U-89678 AUC_0–∞ in cirrhotic subjects (3.88 μmol h⋅l⁻¹) was 2.5 fold higher than in healthy controls (1.53 μmol h⋅l⁻¹), but the difference was marginally significant. Conclusion: These results indicate that clearance of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decreases in liver blood flow and/or intrinsic clearance. The results of this study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment. Received: 10 August 1995/Accepted in revised form: 10 July 1995     

Effect of stiripentol on carbamazepine plasma concentration and metabolism in epileptic children

Objective: To study the relationship between the plasma concentration of stiripentol (STP), a new antiepileptic drug, and its inhibitory effect on the formation of carbamazepine epoxide (CBZE) in epileptic children treated with carbamazepine (CBZ) either alone or in combination with another antiepileptic drug. Methods: Minimum plasma concentration of antiepileptic drugs was measured before initiation of STP therapy (day 0) and on days 28 (STP 60 mg⋅kg⁻¹⋅day⁻¹) and 84 (STP 90 mg⋅kg⁻¹⋅day⁻¹) by HPLC. Results: The CBZE/CBZ plasma concentration ratio decreased exponentially with increasing minimum plasma STP concentration (r = 0.80). The asymptote of the curve allowed the calculation of the minimum plasma STP concentration required to obtain the maximum inhibitory effect, i.e. 6.7 mg⋅l⁻¹. Conclusion: The inhibitory effect of STP on CBZ metabolism expressed as the CBZE/CBZ plasma concentration ratio is dependent on STP plasma concentration, with a maximum effect at an average of 7 mg⋅l⁻¹. The present data suggest that in order to evaluate the anticonvulsant efficacy of STP as add-on therapy, the minimum plasma STP concentration should be maintained above 7 mg⋅l⁻¹ and the dosage of CBZ should simultaneously be decreased in steps by more than 50% to minimize the change in CBZ plasma concentration. Received: 27 September 1995 / Accepted in revised form: 5 January 1996     

Discriminative stimulus effects of S(−)–methcathinone (CAT): a potent stimulant drug of abuse

Methcathinone (“CAT”) is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the present study, S(−)-methcathinone [S(−)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established, the S(−)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60–90 min. In tests of stimulus generalization (substitution), the S(−)-CAT (ED₅₀ = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED₅₀ = 0.17 mg/kg), S(−)-cathinone (ED₅₀ =  0.19 mg/kg), S(+)-amphetamine (ED₅₀ = 0.23 mg/kg), aminorex (ED₅₀ = 0.27 mg/kg), (±)-CAT (ED₅₀ = 0.25 mg/kg), (±)-cathinone (ED₅₀ = 0.41 mg/kg), R(+)-CAT (ED₅₀ = 0.43 mg/kg), cis-4-methylaminorex (ED₅₀ = 0.49 mg/kg), methylphenidate (ED₅₀ = 0.83 mg/kg), and cocaine (ED₅₀ = 1.47 mg/kg). S(−)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol (AD₅₀ = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(−)-CAT stimulus. It is concluded that S(−)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic mechanism. Received: 4 August 1997/Final version: 27 March 1998     

Difference in rates of the reaction of various mammalian oxyhemoglobins with phenylhydrazine

 Second order rate constants for the initial reaction of 12 mammalian oxyhemoglobins (Hb) with equimolar phenylhydrazine (PHZ), a compound inducing Heinz body hemolytic anemia, were determined by recording continuous changes in absorbance with time at 577 nm. The rate constants were varied in a range from 43 m^-1 ⋅ s^-1 with pig Hb to 255 m^-1 ⋅ s^-1 with dog Hb. On the other hand, isosbestic points at 526 and 587 nm were common to all the reaction processes. The aerobic reaction of Hb with PHZ resulted in denaturation of hemoprotein, and final reaction products were determined to be β-meso-phenylbiliverdin IXα and N-phenylprotoporphyrin IX. These results suggest that the reactivity of PHZ to Hb is influenced by the globin molecule, and the oxidative cleavage of the porphyrin ring causes the denaturation of hemoprotein. Received: 25 May 1994/Accepted: 10 August 1994     

Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy

Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy. Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal. Plasma concentrations of idebenone and its main metabolites were determined and the pharmacokinetic parameters of idebenone after single and repeated doses were estimated. During the single dose study, the mean plasma concentrations of idebenone and its main metabolites and mean pharmacokinetic parameters were comparable to published results (C_max = 452.2 ng ⋅ ml⁻¹, t_max = 2.3 h, AUC = 26 μg ⋅ ml⁻¹⋅ h, t_1/2β = 16.5 h). During the repeated doses study, no significant difference was found between mean residual plasma concentrations of idebenone on Day 2 (47 ng ⋅ ml⁻¹) and Day 5 (70.6 ng ⋅ ml⁻¹), and mean t_1/2β of idebenone after the single and after repeated dose studies, i.e., there was no evidence of accumulation. Although idebenone did not appear to accumulate during this study, the coadministration of anticonvulsants, often prescribed during mitochondrial encephalomyopathy, can affect its pharmacokinetics. Received: 2 January 1995/Accepted in revised form: 1 April 1996     

Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes

Objective: Interindividual variations in immunoreactivity and function of three major human drug metabolising P450 monooxygenases has been investigated in liver microsomes from 42 Caucasians (kidney donors or liver biopsies). Methods: Diclofenac 4′-hydroxylation, dextromethorphan O-demethylation and midazolam 1′-hydroxylation, measured by HPLC in incubates, were used as probes to determine CYP2C9, CYP2D6 and CYP3A4 function kinetics, respectively. Immunoquantification of the three isoforms was achieved by Western blotting, using rabbit polyclonal antibodies raised against human CYP2C9 and human CYP3A4, and mouse monoclonal antibody raised against human CYP2D6. Results: Diclofenac 4′-hydroxylation exhibited Michaelis-Menten kinetics with k_M= 3.4 μmol ⋅l⁻¹ and V_max = 45 nmole ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP2C9 was correlated with V_max and CL_int. Dextromethorphan O-demethylation in EM (extensive metabolisers) liver microsomes also showed Michaelis-Menten kinetics, with k_M = 4.4 μmol ⋅l⁻¹ and V_max = 5.0 nmol ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP2D6 was correlated with V_max and CL_int. Midazolam 1′-hydroxylation also exhibited Michaelis-Menten kinetics with k_M = 3.3 μmol ⋅l⁻¹ and V_max = 35 nmol ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP3A4 was correlated with V_max and CL_int. Immunoreactivity and function were correlated for each isozyme, but there was no cross correlation between isozymes. Conclusion: The velocity of metabolite formation (V_max) by the three major human drug metabolising P450 monooxygenases is correlated with their immunoreactivity in liver microsomes. Interindividual variation was much larger for V_max than k_M. Interindividual variability was more pronounced for CYP2D6, probably due to the presence of several different functional alleles in the population of extensive metabolisers. Received: 27 December 1995/Accepted in revised form: 29 March 1996     

Haemodynamic effects and pharmacokinetics of oral d-and l-nebivolol in hypertensive patients

Objective: Nebivolol is a selective β₁-adrenergic receptor blocker possessing an ancillary vasodilating effect. The objective of the present study was to study the haemodynamic and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind, placebo-controlled cross-over study. Methods: Fifteen patients, 12 men and 3 women, with essential hypertension were investigated. Blood pressure and peripheral circulation were determined after acute oral nebivolol administration, 5 mg daily, and after 4 weeks treatment. Results: The acute effect on blood pressure upon single-dosing was weak and non-significant. After 4 weeks both systolic blood pressure (152 vs 163 mmHg) and diastolic blood pressure (89 vs 97 mmHg) were significantly reduced after nebivolol treatment as compared to placebo. Following the first dose the venous volume was higher on placebo (5.88 ml ⋅ 100 ml⁻¹ tissue) as compared to active nebivolol treatment (5.17 ml ⋅ 100 ml⁻¹ tissue), while there were no statistically significant differences with regard to venous plethysmographic findings after 1 month on placebo (5.53 ml ⋅ 100 ml⁻¹ tissue) or on active treatment (5.97 ml ⋅ 100 ml⁻¹ tissue). Calculated peripheral resistance did not differ between active treatment (617 units) or placebo (548 units) after the first dose, whereas it was significantly lowered after 4 weeks of nebivolol treatment (483 units) as compared to placebo (593 units). Conclusions: Oral nebivolol 5 mg once daily lowered blood pressure and heart rate during steady state compared to placebo. Moreover, venous volume was reduced during acute but not steady-state dosing, while peripheral resistance was unaffected in the acute phase but reduced during steady state. Plasma concentrations of the separate enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive patients were similar to those in healthy subjects. Received: 1 March 1996/Accepted in revised form: 2 July 1996     

Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide

Objective: To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. Methods: 12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril, hydrochlorothiazide and the two drugs together were administered. Blood and urine were collected up to 48 hours for measurement of the concentrations of moexipril and its metabolite moexiprilat. In addition, the urine samples were analysed for hydrochlorothiazide. Results: For the area under the plasma concentration-time curve calculated from time 0 to a concentration greater than zero, AUC(0–t), the study showed a mean value of moexipril 437 ng ⋅ ml⁻¹⋅ h⁻¹ following administration of moexipril alone and 416 ng ⋅ ml⁻¹⋅ h⁻¹ following moexipril concomitantly with hydrochloro- thiazide. The corresponding values for the metabolite moexiprilat were 203 and 215 ng ⋅ ml⁻¹⋅ h⁻¹, respectively. The c_max of moexipril and the metabolite (data of the metabolite in parenthesis) were 245.4 (70.8) ng ⋅ ml⁻¹ after administration of moexipril alone and 241.0 (69.2) ng ⋅ ml⁻¹ after coadministration of hydrochlorothiazide. The mean total renal excretion (TUE) of hydrochlorothiazide was 15.2 mg when administered alone and 15.1 mg when given together with moexipril. The corresponding mean TUE-values for moexiprilat were 334 (1200) and 453 (1460) μg. Conclusion: The coadministration of moexipril with hydrochlorothiazide had no demonstrable effect on the measured pharmacokinetic parameters of moexipril, its active metabolite moexiprilat or hydrochlorothiazide. Received: 10 July 1995/Accepted in revised form: 3 March 1996     

A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients

Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml^–1, C_max was 832 vs 871 ng⋅ml^–1 and t_max was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely. Received: 19 October 1995/Accepted in revised form: 8 January 1996     

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone

Objective: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. Methods: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. Results: Itraconazole significantly increased the C_max of zopiclone from 49 to 63 ng ⋅ ml⁻¹. The t_1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0–∞) of zopiclone was increased from 415 to 719 ng ⋅ ml⁻¹ h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. Conclusion: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults. Received: 15 April 1996 /Accepted in revised form: 4 June 1996     

Influence of renal failure on cytochrome P450 activity in hypertensive patients using a “cocktail” of antipyrine and nifedipine

Objective. Two substrates were coadministered in a “cocktail” approach to evaluate the contribution of renal failure to drug oxidation. Patients. Nineteen hypertensive patients, nine of them with chronic renal failure (CL_CR 38.9 vs 102.3 ml⋅min⁻¹⋅1.73 m⁻²), were investigated after peroral administration of a combination of antipyrine (500 mg, in capsules) and nifedipine (10 mg, in Oxcord capsules) in the morning after an overnight fast. Results. This “cocktail” approach made it possible to characterize in vivo the activities of different forms of cytochrome P₄₅₀ in a single-study protocol using the total clearance of nifedipine and clearance for production of 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine (OHA) and norantipyrine (NORA). With this “cocktail” approach (antipyrine plus nifedipine), we can suggest a selective effect on the activities of cytochrome P₄₅₀ forms associated with the formation of dehydronifedipine (P₄₅₀ III A₄) and of NORA in patients with mild renal failure under long-term antihypertensive therapy. Received: 12 July 1994 /Accepted in revised form: 7 October 1995     

Reproducibility of airway response to inhaled bradykinin and effect of the neurokinin receptor antagonist FK-24 in asthmatic subjects

Objective: Inhaled neurokinins have been shown to induce bronchoconstriction in asthmatic subjects. We have investigated the effect of a neurokinin receptor antagonist, FK-224, on bradykinin (BK)-induced bronchoconstriction, and have compared its effect with the spontaneous variability of BK responsiveness. Methods: Thirteen subjects with mild extrinsic bronchial asthma participated in the study. Four BK inhalation challenge tests (Study Days 2 to 5) were performed over a period of several weeks. On Study Days 4 and 5 subjects inhaled either 2 mg FK-224 or placebo 30 min before the BK challenge. Results: The geometric mean PC₂₀FEV₁ of BK was 0.04, 0.06, and 0.10 mg⋅ml⁻¹ on the first and second BK challenge and after placebo. Mean PC₂₀FEV₁ after FK-224 was 0.20 mg⋅ml⁻¹ and was not different from placebo, whereas there was a significant effect in PC₁₅FEV₁. The mean shift in PC₂₀FEV₁ after FK-224 vs placebo was 1.0 doubling concentrations. The mean changes in BK responsiveness on the second BK challenge and placebo days compared to the first BK challenge were 0.6 and 1.3 doubling concentrations. We observed a significant fall in FEV₁ after inhalation of saline plus ethanol, which was the diluent for BK (mean decrease 4.2%). Conclusion: The data demonstrate that inhalation of 2 mg FK-224 is only marginally effective against BK-induced bronchoconstriction in mild asthmatic subjects and that its effect is similar to the variability in BK responsiveness assessed over several weeks. Received: 18 August 1995/Accepted in revised form: 3 January 1996     

Pharmacokinetics of flosequinan in patients with heart failure

Objective: The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure. Results: After a single dose of 100 mg, C_max of the parent compound (2.52 mg ⋅ l⁻¹) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (C_max 8.4 vs 3.21 mg ⋅ l⁻¹). No adverse effects were observed. Conclusion: It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity. Received: 16 January 1995/Accepted in revised form: 30 October 1995