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In experimental pneumonia, nebulization of antibiotics provides high lung tissue concentrations and rapid bacterial killing.To assess the efficacy and safety of nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.Forty patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa were included in a randomized comparative phase II trial. Twenty patients infected with susceptible or intermediate strains received nebulized ceftazidime (15 mg·kg(-1)·3 h(-1)) and amikacin (25 mg·kg(-1)·d(-1)). Seventeen patients infected with susceptible strains received intravenous ceftazidime (90 mg·kg(-1)·d(-1), continuous administration) and amikacin (15 mg·kg(-1)·d(-1)). In three patients infected with intermediate strains, amikacin was replaced by ciprofloxacin (400 mg·12 h(-1)).After 8 days of antibiotic administration, aerosol and intravenous groups were similar in terms of successful treatment (70 vs. 55%), treatment failure (15 vs. 30%), and superinfection with other microorganisms (15 vs. 15%). Antibiotic-induced changes in lung aeration, determined by computed tomography, were not different between groups (increase in gas volume, 159 ± 460 vs. 251 ± 583 ml; decrease in tissue volume, -58 [-77, 25] vs. -89 [-139, 5] ml). Acquisition of per-treatment antibiotic resistance was observed exclusively in the intravenous group. In the aerosol group, four patients infected with intermediate strains were successfully treated. Nebulization induced an obstruction of the expiratory filter in three patients. The obstruction caused cardiac arrest in one patient, who fully recovered after brief cardiopulmonary resuscitation.Nebulization and intravenous infusion of ceftazidime and amikacin provide similar efficiency for treating ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Nebulization is efficient against intermediate strains and may prevent per-treatment acquisition of antibiotic resistance.

Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and IMT outcomes in the postanesthesia care unit (PACU) have not been yet investigated. IMT was administrated as a bolus of 2 or 3 mg every 5 min. Titration was interrupted in case of pain relief (visual analog score ≤30), adverse events, sedation, or failure of morphine titration. Blood samples were collected at the end of morphine titration to determine plasma concentration of morphine and its two metabolites. Data from 214 patients were analyzed; 143 (67%) of the patients achieved complete pain relief, 39 (18%) experienced adverse events, and 32 (15%) failure of morphine titration. At the end of titration, there were no significant differences in morphine, M6G, M3G concentrations between sedated and nonsedated patients (32 vs. 42 ng/mL (P = 0.07), 38 vs. 45 ng/mL (P = 0.51), 300 vs. 342 ng/mL (P = 0.29), respectively), or patients with or without adverse events (40 vs. 41 ng/mL (P = 0.95), 37 vs. 46 ng/mL (P = 0.51), 287 vs. 340 ng/mL (P = 0.72), respectively). Our study demonstrated a lack of relationship between plasma concentrations or ratios of morphine, M3G, and M6G, with IMT outcomes in PACU. This result suggests that the kinetics of morphine and its metabolites have limited value for explaining clinical effects of morphine in this clinical setting.

Objectives Patients with primary systemic (AL) amyloidosis or multiple myeloma are frequently treated with cyclic dexamethasone (DXM) courses and often require oral anticoagulants. We previously reported a strong potentiation of oral anticoagulants with intravenous methylprednisolone and observed a similar potentiation with DXM in 3 patients, which led us to prospectively investigate the interaction between DXM and oral anticoagulants. Methods Nine patients with multiple myeloma (n = 6) or AL amyloidosis (n = 3), including 6 prospective patients, taking fluindione (n = 8) or warfarin (n = 1), were studied for a total of 10 cycles. DXM (40 mg/day for 4 days every 28 days) was administered alone (n = 4) or with melphalan (n = 5). One patient was studied for 2 consecutive cycles after a moderate increase in the international normalized ratio (INR) during the first course of DXM. International normalized ratio (INR) was measured serially during DXM administration. Plasma oral anticoagulant concentrations were measured for 5 cycles. Results The mean INR increased from 2.75 (range: 1.80–3.6) at baseline to 5.22 (3.09–7.07) after DXM. Oral anticoagulants were transiently stopped during 8 cycles and 1 mg oral vitamin K was given during 2. No serious bleeding was observed. Plasma oral anticoagulant concentrations increased after DXM administration. In controls receiving DXM without oral anticoagulants, DXM alone did not increase prothrombin time. Conclusion High dose DXM can potentiate oral anticoagulants and elevate INR substantially. INR should therefore be monitored repeatedly during concomitant administration of these 2 drugs to allow individual adaptation of oral anticoagulant doses.

Resume Objectifs Les cures de dexamethasone sont souvent utilisees pour traiter l'amylose AL et le myelome multiple, deux maladies qui obligent souvent a un traitement antivitamine K en raison de thromboses (parfois liees au thalidomide) ou d'une amylose cardiaque ou renale. Nous avons observe une potentialisation nette des antivitamines K par la methylprednisolone puis, chez trois malades, par la dexamethasone. Nous avons donc realise une etude prospective des interactions entre dexamethasone et antivitamines K. Methodes Nous avons etudie neuf malades, dont six de facon prospective, pendant dix cycles de dexamethasone au total. Parmi eux, six avaient un myelome et trois une amylose AL ; huit prenaient de la fluindione et un de la warfarine. Les cures de dexamethasone (40 mg/j pendant quatre jours tous les 28 jours) ont ete donnees seules (quatre malades) ou en association avec du melphalan (cinq malades). Chez un malade, deux cures consecutives ont ete etudiees en raison d'une augmentation moderee du International normalized ratio (INR) pendant la premiere cure. L'INR a ete mesuree de facon repetee pendant les cures. Les concentrations plasmatiques d'antivitamine K ont pu etre obtenues pendant cinq cures. Resultats L'INR moyen a augmente de 2,75 (extremes, 1,80 et 3,6) initialement a 5,22 (3,09 et 7,07) apres la cure. Le traitement antivitamine K a ete interrompu pendant huit cycles et une prise orale de 1 mg de vitamine K a ete administree pendant deux cycles. Aucune complication hemorragique grave n'a ete constatee. Les concentrations plasmatiques d'antivitamine K ont augmente apres l'administration de dexamethasone. Chez des malades temoins traites par dexamethasone sans antivitamines K, le temps de prothrombine ne s'est pas allonge pendant les cures. Conclusion La dexamethasone a posologie elevee peut potentialiser les antivitamines K, conduisant a une augmentation marquee de l'INR. Une surveillance etroite de l'INR est donc indispensable en cas d'administration concomitante de ces deux medicaments, de facon a permettre l'adaptation de la posologie d'antivitamine K.

Objective: Poor adherence to treatment is very difficult to diagnose accurately. Hydroxychloroquine (HCQ) has a long elimination half-life and its concentration in whole blood can be measured easily. We evaluated the utility of a very low blood HCQ concentration as a marker of poor compliance in patients with systemic lupus erythematosus (SLE). Methods: We determined HCQ concentrations on a blinded basis in 203 unselected SLE patients. At the end of the study, patients were informed of the results and retrospectively interviewed about their adherence to treatment. Results: 14 patients (7%) said they had stopped taking HCQ (n=8) or had taken it no more than once or twice a week (n=6). Their mean HCQ concentration was 26 ± 46 ng/mL [0-129]. In contrast, the other patients had a mean HCQ concentration of 1079 ng/mL [205-2629]. The principal barriers to adherence were related to HCQ treatment characteristics. Adherence subsequently improved in 10 of the 12 patients whose blood HCQ concentrations were remeasured. Conclusions: Very low whole-blood HCQ concentrations are an objective marker of prolonged poor compliance in SLE patients. Regular drug assays might help physicians to detect noncompliance and serve as a basis for counseling and supporting these patients.

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

beta-adrenoceptor antagonists, especially atenolol, reduce perioperative cardiac morbidity. Because there are no data on the bioavailability of atenolol given by nasogastric tube in the postoperative period, we assessed the efficacy of this route of administration in 18 patients scheduled for abdominal surgery. We found a 36% reduction in the area under the atenolol concentration curve and a 46% reduction in the peak concentration of atenolol in the postoperative period compared with preoperative values. In addition, patients had more rapid mean heart rates on the second postoperative day compared with the day before surgery. We conclude that the administration of atenolol via nasogastric tube in the postoperative period does not result in adequate plasma concentrations.

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36+/-0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl-nefopam was 0.62+/-0.23. The half-life of nefopam was similar whether administered orally (5.1+/-1.3 hr) or intravenously (5.1+/-0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6+/-3.0 versus 5.1+/-1.3 hr, P 24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90+/-142 versus 35+/-84 (P=0.27) and 66+/-74 versus 46+/-54 mm x hr (P=0.36), respectively. The AUC0-->24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68+/-65 versus 27+/-30 (P=0.005) and 54+/-63 versus 28+/-48 mm x hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.

Objective: To determine the cardiovascular, subjective effects and potential of abuse liability of single dose (–) ephedrine (E) administered orally (50 mg) or intranasally (10 mg and 5 mg). Methods: Sixteen healthy Caucasian men with no history of drug/alcohol/nicotine abuse or dependence received intranasal single doses of E 5 mg, 10 mg and oral doses of 50 mg and placebo in a double-blind, double-dummy, crossover study. Dependent measures included assessment of subjective feelings by Addiction Research Centre Inventory (ARCI), Profile of Mood States (POMS), visual analogue scales (VAS); "drug liking", "any drug effect", subjective quality of sleep and blood pressure and heart rate. Plasma E concentrations were also determined. Results: (–) E increased supine systolic, diastolic blood pressure (P

Aims Despite a lack of data, the antiviral agent ganciclovir is not indicated in AIDS patients with diarrhoea because of its presumed poor oral bioavailability. To assess the effect of diarrhoea on ganciclovir intestinal absorption, we conducted a pharmacokinetic study in 42 HIV-infected patients categorized into three groups: A, HIV stage A and B (n = 15); B, AIDS stage C (n = 13); C, AIDS with chronic diarrhoea and wasting syndrome (n = 14).

We investigated human immunodeficiency virus (HIV) type 1 RNA, proviral DNA, and antiretroviral drug-resistant variants in cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy. The prevalence of detectable HIV-1 RNA in genital secretions was inversely related to the number of antiretroviral drugs taken by the patients. Proviral DNA was detected in approximately half of all samples of cervicovaginal secretions from HIV-1-infected women, regardless of the presence or absence of HIV-1 RNA in cervicovaginal secretions and of the antiretroviral regimen. In cervicovaginal secretions of most women with persisting genital viral replication, HIV variants exhibiting mutations associated with drug resistance against protease and reverse-transcriptase pol genes were found. Our observations indicate that antiretroviral therapy is not effective in purging the female genital tract of cell-associated provirus and that antiretroviral drugs that penetrate the female genital tract at suboptimal concentrations exert a potent selective pressure on genital HIV variants when local replication of free HIV-1 RNA persists.

A high-performance liquid chromatography procedure for the determination of ephedrine and norephedrine using fluorimetric detection in plasma samples is described. A double liquid–liquid extraction was performed, followed by derivatization with 9-fluorenylmethyl chloroformate. The extracts were chromatographed with a 5-μm C 18 (150×4.6 mm I.D.) column using a mobile phase composed of acetonitrile and water (52:48; v/v). The excitation and emission wavelengths were respectively 264 nm and 313 nm. Calibration curves were linear over the range 0 to 300 ng/ml for each analyte. The specificity of the method was demonstrated with several FMOC-reacting drugs. The limits of quantification are similar to those obtained with the reference method: 2 ng/ml for ephedrine and 5 ng/ml for norephedrine. This method has been successfully applied to the determination of ephedrine and norephedrine plasma levels after administration of low doses of ephedrine to healthy subjects.

A new high-performance liquid chromatography (HPLC) assay was developed for the simultaneous determination of tacrine (THA), nimodipine, and their three metabolites (MI, MII, and MIII) using a 1-ml plasma sample volume. A liquid-liquid extraction procedure was coupled with a reverse-phase HPLC separation. Quantification was performed by fluorometric detection for THA and metabolites and by ultraviolet detection for nimodipine and metabolites. Peak-height ratios were linear across the ranges 0.5 to 100 micro/l for THA and its three metabolites; 2 to 500 microg/l for nimodipine, MII, and MIII; and 4 to 500 microg/l for MI. Correlation coefficients were better than 0.998 for all compounds. Accuracy and precision were less than 12% for the entire concentration range for each substance. This method is sensitive and selective. Analysis of plasma samples collected from patients with Alzheimer disease demonstrated that the assay is suitable for clinical and pharmacokinetic trials including drug-drug interactions studies.

Valacyclovir is an effective oral agent for the treatment of herpes virus infection, however, the pharmacokinetics of the drug are altered in renal failure. It is increasingly recognized that dose adjustment of oral valacyclovir in renal failure is necessary to avoid neurotoxicity. We studied this drug in a continuous ambulatory peritoneal dialysis (CAPD) and immunocompromised patient. She developed neurotoxicity with an adjustment dosage of valacyclovir for a cutaneous zoster infection. The elimination half-time (15 h) was similar to that reported for end-stage renal disease patients, while the steady-state volume of distribution (85 l) and the area under the curve concentration (127 mg/l·h) were greater. The mean CAPD dialysance was only 5.27 ml/min with less than 1% of an administered dose being recovered in the 24-hour dialysate. 48 h after interrupting treatment, she recovered normal neurological status and 500 mg of valacyclovir every 2 days was effective and well tolerated.

Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and IMT outcomes in the postanesthesia care unit (PACU) have not been yet investigated. IMT was administrated as a bolus of 2 or 3 mg every 5 min. Titration was interrupted in case of pain relief (visual analog score ≤30), adverse events, sedation, or failure of morphine titration. Blood samples were collected at the end of morphine titration to determine plasma concentration of morphine and its two metabolites. Data from 214 patients were analyzed; 143 (67%) of the patients achieved complete pain relief, 39 (18%) experienced adverse events, and 32 (15%) failure of morphine titration. At the end of titration, there were no significant differences in morphine, M6G, M3G concentrations between sedated and nonsedated patients (32 vs. 42 ng/mL (P = 0.07), 38 vs. 45 ng/mL (P = 0.51), 300 vs. 342 ng/mL (P = 0.29), respectively), or patients with or without adverse events (40 vs. 41 ng/mL (P = 0.95), 37 vs. 46 ng/mL (P = 0.51), 287 vs. 340 ng/mL (P = 0.72), respectively). Our study demonstrated a lack of relationship between plasma concentrations or ratios of morphine, M3G, and M6G, with IMT outcomes in PACU. This result suggests that the kinetics of morphine and its metabolites have limited value for explaining clinical effects of morphine in this clinical setting.

To compare the efficiency of an Aeroneb Pro vibrating plate and an Atomisor MegaHertz ultrasonic nebulizer for providing ceftazidime distal lung deposition.In vitro experiments. One gram of cetazidime was nebulized in respiratory circuits and mass median aerodynamic diameter of particles generated by ultrasonic and vibrating plate nebulizers was compared using a laser velocimeter. In vivo experiments. Lung tissue concentrations and extrapulmonary depositions were measured in ten anesthetized ventilated piglets with healthy lungs that received 1 g of ceftazidime by nebulization with either an ultrasonic (n = 5), or a vibrating plate (n = 5) nebulizer.A two-bed Experimental Intensive Care Unit of a University School of Medicine.Following sacrifice, 5 subpleural specimens were sampled in dependent and nondependent lung regions for measuring ceftazidime lung tissue concentrations by high-performance liquid chromatography.Mass median aerodynamic diameters generated by both nebulizers were similar with more than 95% of the particles between 0.5 and 5 microm. Lung tissue concentrations were 553 +/- 123 [95% confidence interval: 514-638] microg g(-1) using ultrasonic nebulizer, and 452 +/- 172 [95% confidence interval: 376-528] microg g(-1) using vibrating plate nebulizers (NS). Extrapulmonary depositions were, respectively, of 38 +/- 5% (ultrasonic) and 34 +/- 4% (vibrating plate) (NS).Vibrating plate nebulizer is comparable to ultrasonic nebulizers for ceftazidime nebulization. It may represent a new attractive technology for inhaled antibiotic therapy.

Objective To study the possible relationship between whole-blood hydroxychloroquine (HCQ) concentrations and clinical efficacy of HCQ in patients with systemic lupus erythematosus (SLE). Methods Whole-blood HCQ concentrations were measured, under blinded conditions, in 143 unselected patients with SLE who had been receiving HCQ 400 mg daily for at least 6 months. The relationship of these concentrations to current disease activity and to subsequent exacerbations during 6 months of followup was investigated. Results At baseline, 23 patients had active disease (mean ± SD SLE Disease Activity Index 12.4 ± 7.5). The mean whole-blood HCQ concentration in this group was significantly lower than that in the 120 patients with inactive disease (694 ± 448 ng/ml versus 1,079 ± 526 ng/ml; P = 0.001). Among the 120 patients who had inactive disease at baseline, the mean HCQ concentration at baseline in the 14 (12%) who had disease exacerbations during followup was significantly lower than that in the patients whose disease remained inactive. Multivariate logistic regression showed that the HCQ concentration was the only predictor of exacerbation (odds ratio 0.4 [95% confidence interval 0.18–0.85], P = 0.01). Receiver operating characteristic curve analysis showed that a whole-blood HCQ concentration cutoff of 1,000 ng/ml had a negative predictive value of 96% for exacerbation during followup. Conclusion Low whole-blood HCQ concentrations are associated with SLE disease activity and are a strong predictor of disease exacerbation. Regular drug assaying and individual tailoring of treatment might help to improve the efficacy of HCQ treatment in patients with SLE.

Aims To evaluate the effects of combined antiretroviral drugs (HAART) on liver CYP3A4 activity using the [14C-N-methyl]-erythromycin breath test (ERMBT). Methods HIV-infected patients (31 women, 30 men) with mean (± SD) age of 38 ± 9 years were enrolled and underwent complete clinical and laboratory evaluation. Patients were divided into five groups and were treated with two nucleoside analogues (NAs) and one of the following: nelfinavir alone (n = 13), any ritonavir-boosted protease inhibitor with (n = 8) or without (n = 13) nevirapine, nevirapine alone (n = 15), or a third NA (n = 12). Three or four ERMBTs were performed 7 days prior to (D−7) and at the beginning of treatment (D0), D14 (only for patients taking nevirapine) and on D28. Results Mean baseline liver CYP3A4 activity displayed high interindividual variability (47%) but low intraindividual variability (15%). Women had 30% higher ERMBT values than men [2.7 ± 1.3 vs. 1.9 ± 0.7; 95% confidence interval (CI) 20.5, 49.5; P = 0.003]. The ERMBT data correlated with body weight, α- and β-globulins and alanin aminotransferases (0.10

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR-) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03+/-0.02l/h) than in normal control (0.09+/-0.05l/h), in normal probenecid (0.10+/-0.07l/h) and in TR- control rats (0.13+/-0.07l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

Beraprost sodium (BPS), an orally active PGI2 (prostaglandine 12) analogue possesses vasodilatating and platelet aggregation inhibiting properties. It is being developed in peripheral arterial occlusive disease. As in future clinical practice BPS might be co-prescribed with oral anticoagulants, we investigated its interaction with fluindione, a vitamin K antagonist in healthy subjects in a randomised, double-blind, placebo-controlled, crossover study. Twelve healthy Caucasian male subjects randomly received BPS 40 microg t.i.d. or placebo for 3 days. There was a 7 day wash out between the two treatment periods. On day 3 of each treatment, the subjects ingested concomitantly a single oral dose of 20 mg of fluindione. The main assessment criterion was fluindione's pharmacokinetics. Secondarily, pharmacodynamic measurements of coagulation (prothrombin time, and International Normalised Ratio, INR) and platelet function (in vitro closure time assessed by PFA-100) were performed. Fluindione was assayed by HPLC with UV detection up to 96 h post-drug. No statistical difference could be evidenced on any fluindione pharmacokinetic parameters between BPS and placebo phases: t 1/2 (h): 35.9 (8.2) vs. 34.0 (4.2) [90% CI 105.8 (95.5-116.2)]; T(max) (h): 2.0 (0.5-6.0) vs. 4.0 (0.5-6.0) [90% CI 136.4 (70.7-208.9)]; Cmax (mg/L): 3.1 (0.6) vs. 2.9 (0.5) [90% CI 94.1 (85.8-103.2)]; AUC 0-inf (mg/h/L): 117.0 (31.5) vs. 113.9 (33.8) [90% CI 97.6 (87.5-108.8)]. The studied doses of BPS did not affect platelet function, at least as assessed by the in vitro platelet function testing. Twenty milligrams of fluindione marginally modified the PT ratio and INR, however, no statistically significant difference was found between BPS and placebo phases. In conclusion, a 3 day regimen of BPS 40 microg t.i.d. by oral route does not seem to affect pharmacokinetic parameters of a fluindione 20 mg single dose.

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.