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.

RATIONALE:In experimental pneumonia, nebulization of antibiotics provides high lung tissue concentrations and rapid bacterial killing.OBJECTIVES:To assess the efficacy and safety of nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.METHODS: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)).MEASUREMENTS AND MAIN RESULTS: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.CONCLUSIONS: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.

To compare the efficiency of an Aeroneb Pro vibrating plate and an Atomisor MegaHertz ultrasonic nebulizer for providing ceftazidime distal lung deposition.

A novel technique for collection of capillary blood, termed volumetric absorptive microsampling (VAMS), has been recently cleared by the FDA for collection of human blood. VAMS absorbs a fixed volume of blood (10 μl) and overcomes area bias and homogeneity issues associated with dried blood spot (DBS). This study is the application of VAMS for therapeutic drug monitoring (TDM) in human capillary blood. A liquid chromatography–tandem mass spectrometry (LC–MS/MS) workflow for analysis of VAMS samples was developed and validated. Concentrations of hydroxychloroquine (HCQ) and its metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), in capillary blood on VAMS samplers were compared to those in venous blood in rheumatoid arthritis patients. Feasibility of capillary blood collected on both VAMS and DBS cards were evaluated on patients. Stability of dried capillary blood on VAMS was also examined. Our results established that VAMS is a simple and accurate sampling technique that delivers the benefits of DBS sampling while overcoming the issues associated with hematocrit and homogeneity. It requires a small blood volume, simplifies sample logistics management, and may allow sample collection in the patient’s home setting.

BACKGROUND:Poor adherence to treatment is difficult to diagnose accurately. Hydroxychloroquine (HCQ) has a long elimination half-life and its concentration in whole blood can be measured easily. OBJECTIVE:To evaluate the utility of a very low blood HCQ concentration as a marker of poor compliance in patients with systemic lupus erythematosus (SLE). METHODS:HCQ concentrations were determined on a blinded basis in 203 unselected patients with SLE. At the end of the study, the patients were informed of the results and retrospectively interviewed about their adherence to treatment. RESULTS:14 (7%) patients said that they had stopped taking HCQ (n = 8) or had taken it no more than once or twice a week (n = 6). Their mean (SD) HCQ concentration was 26 (46) ng/ml. range (0-129 ng/ml) By contrast, the other patients had a mean HCQ concentration of 1079 ng/ml range (205-2629 ng/ml). 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 patients with SLE. Regular drug assays might help doctors in detect non-compliance and serve as a basis for counselling and supporting these patients.

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 (17 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. (c) 2007 Published by Elsevier Masson SAS.

Les cures de dexaméthasone sont souvent utilisées pour traiter l'amylose AL et le myélome multiple, deux maladies qui obligent souvent à un traitement antivitamine K en raison de thromboses (parfois liées au thalidomide) ou d'une amylose cardiaque ou rénale. Nous avons observé une potentialisation nette des antivitamines K par la méthylprednisolone puis, chez trois malades, par la dexaméthasone. Nous avons donc réalisé une étude prospective des interactions entre dexaméthasone et antivitamines K. Nous avons étudié neuf malades, dont six de façon prospective, pendant dix cycles de dexaméthasone au total. Parmi eux, six avaient un myélome et trois une amylose AL ; huit prenaient de la fluindione et un de la warfarine. Les cures de dexaméthasone (40 mg/j pendant quatre jours tous les 28 jours) ont été données seules (quatre malades) ou en association avec du melphalan (cinq malades). Chez un malade, deux cures consécutives ont été étudiées en raison d'une augmentation modérée du International normalized ratio (INR) pendant la première cure. L'INR a été mesurée de façon répétée pendant les cures. Les concentrations plasmatiques d'antivitamine K ont pu être obtenues pendant cinq cures. L'INR moyen a augmenté de 2,75 (extrêmes, 1,80 et 3,6) initialement à 5,22 (3,09 et 7,07) après la cure. Le traitement antivitamine K a été interrompu pendant huit cycles et une prise orale de 1 mg de vitamine K a été administrée pendant deux cycles. Aucune complication hémorragique grave n'a été constatée. Les concentrations plasmatiques d'antivitamine K ont augmenté après l'administration de dexaméthasone. Chez des malades témoins traités par dexaméthasone sans antivitamines K, le temps de prothrombine ne s'est pas allongé pendant les cures. La dexaméthasone à posologie élevée peut potentialiser les antivitamines K, conduisant à une augmentation marquée de l'INR. Une surveillance étroite de l'INR est donc indispensable en cas d'administration concomitante de ces deux médicaments, de façon à permettre l'adaptation de la posologie d'antivitamine K.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Cigarette smoking has been suspected to increase the risk and the activity of systemic lupus erythematosus (SLE)1 2 and cutaneous lupus.3 4 Some data indicate that cigarette smoking might interfere with the effectiveness of hydroxychloroquine and chloroquine in cutaneous lupus.3 4 As these antimalarial agents are partly metabolised via the cytochrome P450 enzyme system and as the constituents of cigarette smoke are known potent inducers of cytochrome P450, it has been hypothesised that the resistance of cutaneous lupus might be explained by a modification of the metabolism of these …

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 [(14)C-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, alpha- and beta-globulins and alanin aminotransferases (0.10 < r(s) < 0.20; P < 0.01). Whereas nevirapine had no effect on liver CYP3A4 activity, nelfinavir-based and ritonavir-boosted drug regimens inhibited it by 69% (95% CI 64.7, 72.9; P = 0.005) and by 95% (95% CI 93.3, 96.7; P = 0.001), respectively.CONCLUSION:Evaluation of the effect of HAART on liver CYP3A4 activity may aid in preventing inappropriate treatment regimens in HIV-infected patients.

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.

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.

Adefovir is transported by the organic anion transporter (OAT I) 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 +/- 0.021/h) than in normal control (0.09 +/- 0.051/h), in normal probenecid (0.10 +/- 0.071/b) and in TR- control rats (0.13 +/- 0.071/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. (c) 2006 Elsevier B.V. All rights reserved.

L'adéfovir est sécrété dans les urines par le transporteur organique anionique tubulaire (OAT1) et par les protéines de résistance multiple aux produits (MRP2, 4 et 5). Nous avons étudié la clairance de l'adéfovir chez le rat normal après inhibition des transporteurs par le probénécide ainsi que chez le rat TR- déficient en MRP2. Après traitement par probénécide ou placebo, la pharmacocinétique de l'adéfovir (10 mg/kg) a été étudiée par une approche de type pharmacocinétique de population (NONMEM). La fraction de substance excrétée dans les urines est basse dans nos expériences. La clairance rénale de l'adéfovir est significativement plus basse (p<0,05) chez les rats TR- traités par probénécide (0,03±0,02 l/heure) que chez les rats témoins normaux (0,09±0,05 l/heure), chez les rats normaux traités par probénécide (0,10±0,07 l/heure) et chez les rats TR- témoins (0,13±0,07 l/heure). In vivo chez le rat, la mutation de MRP2 seule n'affecte pas la clairance de l'adéfovir suggérant que MRP2 ne joue pas un rôle clé dans la sécrétion de l'adéfovir. Une inhibition pharmacologique supplémentaire des transporteurs diminue sa clairance rénale, ce qui peut refléter une inhibition de mécanismes de compensation mis en œuvre en l'absence de MRP2.

Purpose: The objective of this study was to investigate the pharmacokinetic/pharmacodynamic properties of an antiretroviral therapy in HIV-infected patients. Method: Eight HIV-infected patients received zidovudine, lamivudine, and indinavir as their first antiretroviral treatment. Pharmacokinetic data were analyzed separately using a one-compartmental model with first-order absorption, and the individual estimates were used to simulate drug concentrations. To determine the relationship between drug concentrations and the antiviral effect, an in vitro E-max model was tested. Alternatively, a dynamic model was built describing the viral and cellular pathophysiology, including the turnover of viral replication in infected cells and the production of virus under treatment. Result: The E-max model fit poorly the experimental data. The complex model was not identifiable with the data available in this study, however a simplified model allowed us to estimate the pharmacodynamic parameters reflecting the decrease of both infected cells and viral load under antiretroviral treatment. Conclusion: Using potent highly active antiretroviral therapy, the treatment was so effective that it was not possible to estimate the parameters of the relationship between drug concentrations and the reduction of viral load. Even if the relationship does exist, the direct response model of antiretroviral agents cannot be demonstrated, however the simplified model provides an understanding of the synergy of such a combination and offers suggestions as how to prevent the emergence of viral resistant strains.

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D-2 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 mug/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 E-max 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 AUC(0-->infinity) and C-max (normalised to the dose 1 mug/kg), t(1/2)alpha and t(1/2)beta. 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). E-max 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 mug/kg (P < 10(-4)). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid E-max PD model, respectively.