An unusual route of non-intentional intoxication by ecstasy in a toddler.

We report a pediatric case of ecstasy intoxication via an unusual route. A mother called the emergency services after her daughter had inserted an ecstasy pill into her nose. During transportation, the child developed hypertension, tachycardia, and tachypnea. She was admitted to the nearest regional hospital, where a physical examination revealed psychomotor agitation, mydriasis, hypertension, tachycardia, and no hyperthermia. Blood tests showed no abnormalities. She was subsequently transferred to a tertiary-level pediatric hospital. During transportation, she was described as being intensely agitated with persistent mydriasis, tachycardia, and high blood pressure. Urinary toxicological screening confirmed the presence of MDMA. She was discharged after 24 h.

Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19.

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.

A pseudoencephalitis presentation of a pediatric non-intentional intoxication.

UNLABELLED: We report a case of a pseudo encephalitis presentation of pediatric intoxication - Case report - a 7 year-old girl was admitted to our pediatric emergency unit after she developed sudden agitation, visual and tactile hallucinations. She was febrile (38.3 °C). She had not experienced any recent head trauma, infection or toxic ingestion; she did not take any medication for ADD. Her physical exam revealed tachycardia, normal pupils, reflexes and normal plantar responses. Laboratory investigations (complete blood count, basic metabolic panel, plasma lactate level, ammonia level) produced normal results. Lumbar puncture and computed tomography of the brain were normal. A serum and urine drug screening (benzodiazepines, barbiturates, cocaine, cannabis, amphetamines, methadone, ethanol) was negative. An electroencephalogram, performed during an episode of hallucinations, was compatible with benzodiazepine intoxication. A larger toxic detection by liquid chromatography/diode array detector (LC-DAD) detected promethazine and its metabolites. Symptoms lasted 20 h and she finally said she drank syrup from an over-the-counter cough suppressant medication. Comments - Anticholinergic syndrome is not well recognized or evoked in children presenting hallucinations. Promethazine is still present in several over-the-counter medications, alone or in combination with acetaminophen, carbocisteine or opiates. CONCLUSION: Medications containing promethazine should not be prescribed in children. Such intoxication can mimic encephalitis.

Cefepime in intensive care unit patients: validation of a population pharmacokinetic approach and influence of covariables.

AIM: The purpose of our study was to define and validate a population-pharmacokinetic model including the influence of patients' characteristics on the pharmacokinetics of cefepime. PATIENTS AND METHODS: A total of 55 patients were randomized in Group 1 (34 patients, 320 cefepime concentrations) for the model building and Group 2 (21 patients, 196 cefepime concentrations) for the validation group. They received cefepime as 2 g A 2 or as 4 g continuously. The population pharmacokinetic analysis was carried out using NONMEM and a baseline model was constructed for studying the influence of demographic and biological variables. The model was then validated by a comparison of the predicted and observed concentrations in Group 2. A final model was elaborated from the whole population. RESULTS: Total clearance (CL) was significantly correlated with the serum creatinine (CREA) and the central volume of distribution (V1) was correlated with the body weight (WT). The final model was: CL = 7.14 + (-0.0133 A CREA). V1 = (-16.8) + (0.475 A WT). Q (intercompartmental clearance) = 10.5. V2 = 18.1. The mean pharmacokinetic parameters and their individual variability were: CL (8.24 l/h, 45%), V1 (20.89 l, 60%), V2 (17.95 l, 49%), total volume (38.85 l, 42%) and Q (10.56 l/h, 9%). The bias (1.07 mg/l, IC 95% = -40.46 -+42.60), precision (21.19%) and AFE (1.15) demonstrated the performance of the model. CONCLUSION: We have developed and validated a pharmacokinetic model to estimate cefepime concentrations. We showed that serum creatinine and body weight are factors that may influence the standard dose of cefepime. Our model enabled us to predict cefepime concentrations in other patients.

Hepatitis C virus viral load after conversion from tacrolimus to cyclosporine in liver transplant patients: a pilot study.

UNLABELLED: We assessed whether conversion from tacrolimus (TAC) to cyclosporine (CsA) was associated with a reduction in hepatitis C virus (HCV) viral load among HCV-positive liver transplant (OLT) patients. PATIENTS AND METHODS: Nine OLT patients with recurrent HCV have TAC and prednisone immunosuppression. None received any HCV antiviral therapy. After the last intake of TAC, the patients underwent a 12-hour area under the curve (AUC(12)) measurement of both TAC and HCV viral loads. The next morning (D(0)) patients were given CsA (4 mg/kg bid). At the first intake of CsA and at 1 month (M(1)) later, the patients underwent AUC(12) for CsA and HCV viral loads. Biological data, including aspartate (AST) and alanine (ALT) aminotransferase, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), and bilirubin levels, were collected during AUC(12), and at M(1) and M(3). RESULTS: With respect to liver enzymes (AST, ALT, GGT), there was no significant difference between D(0), M(1), and M(3). Conversely, there was a significant decrease in AP between D(0) and M(3) (P = .02), and a significant increase in total bilirubin between D(0) and M(1) (P = .04), and between D(0) and M(3) (P = .01). HCV viral load significantly increased by M(3) (P = .01). At no time (D(0), M(1)) was there any correlation between the AUC(12) of TAC or CsA, and between AUC(12) HCV viral load. CONCLUSION: This pilot study found no acute or chronic anti-HCV effects from CsA that were evident within 12 hours after CsA administrations or beyond 1 month of CsA therapy, respectively.

Pharmacokinetics of ceftazidime and cefepime in burn patients: the importance of age and creatinine clearance.

AIM: The standard dosage recommendations for beta-lactam antibiotics can result in very low drug levels in intensive care (IC) patients and burn patients in the absence of renal dysfunction. We studied the pharmacokinetic parameters and serum concentrations of ceftazidime (CF) and cefepime (CE) in burn patients and analyzed the modifications according to clinical and biological parameters and in particular age and creatinine clearance. MATERIAL AND METHODS: Two pharmacokinetic studies were carried out with daily doses of 1 g x 6 for CF (n = 17) and 2 g x 3 for CE (n = 13). Creatinine clearance (CL(CR)) was both estimated and measured. Blood was sampled at steady state after an initial and a subsequent antibiotic dose. C(max) (maximal) and C(min) (minimal) concentrations were measured by HPLC. The influence of clinical and biological data was analyzed using ANOVA, ANCOVA and stepwise multiple linear regression. RESULTS: The ratio of C(min) to the low MIC break point (4 mg/l) was lower than 4 in 52% of subjects receiving CF and in 80% of subjects receiving CE. The C(min) of CF was correlated with measured CL(CR) and was higher in mechanically ventilated patients than in non-ventilated patients. The clearance of CF was correlated with age. The C(min) of CE was correlated with age and drug clearance with measured CL(CR). Therefore dosage adjustment of these drugs in burn patients needs to take into account age, measured creatinine clearance and the danger of low concentrations occurring when the creatinine clearance is greater than 120 ml x min(-1). CONCLUSION: In burn patients, the pharmacokinetic disposition of CF and CE was much more variable than in healthy subjects. Age and CL(CR) were predictors of the disposition of these antibiotics. Shortening the dosage interval or using continuous infusions will prevent low serum levels and keep trough levels above the MIC for longer periods of time. In view of the lack of a bedside measurement technique for ceftazidime and cefepime levels, we suggest a more frequent use of measured CL(CR) in order to attain efficacious clinical concentrations.

Assessment of renal function in clinical practice at the bedside of burn patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In burn patients it has been shown ([2]), that there is a correlation between the creatinine clearance (CL(CR)) and the clearance of inulin. * The CL(CR) has never been studied in burn patients who have normal serum creatinine. * The Robert, Kirkpatrick and sMDRD formulae have never been evaluated in burn patients. WHAT THIS STUDY ADDS: * Despite burn patients having normal serum creatinine concentrations, the study showed that there are large variations in CL(CR) which cannot be detected by single serum creatinine measurements, and which have important implications for drug therapy. * It showed that the formulae currently used to calculate creatinine clearance on the basis of serum creatinine are inadequate for use in burn patients, and they should be abandoned in favour of direct measurement from a 24 h urine collection. AIMS: The aim of this study was to evaluate whether the renal function of burn patients could be correctly assessed using a single serum creatinine measurement, within normal limits, and three prediction equations of glomerular filtration taking into account, serum creatinine, age, weight and sex. METHODS: This was a prospective study comprising 36 adult burn patients with a serum creatinine <120 micromol l(-1), within the second or third week following the burn injury. Renal function was assessed using serum creatinine, 24 h urinary CL(CR), and the Cockcroft-Gault, Robert, Kirkpatrick and simplified MDRD equations. RESULTS: Despite normal serum creatinine concentrations in all patients, a significant number had a decreased CL(CR). The urinary CL(CR) was <80 ml(-1) min(-1) 1.73 m(-2) in nine patients (25%), and <60 ml(-1) min(-1) 1.73 m(-2) in five patients (14%). Between the groups having a CL(CR) lower or greater than 80 ml(-1) min(-1) 1.73 m(-2) there were no differences in gender, burn indices, percentage of mechanically ventilated patients or length of hospital stay, but a difference in age. The highest CL(CR) (>140 ml(-1) min(-1) 1.73 m(-2)) was found in 13 patients younger than 40 years. Regression analysis, residual and Bland-Altman plots revealed that neither the Cockcroft-Gault, Robert, Kirkpatrick nor sMDRD equations were specific enough for the assessment of renal function. CONCLUSIONS: In burn patients with normal serum creatinine during the hypermetabolic phase, serum creatinine and creatine based predictive equations are imprecise in assessing renal function.

Increased amikacin dosage requirements in burn patients receiving a once-daily regimen.

Altered pharmacokinetics in burn patients may affect antibiotic plasma concentrations. Typical once-daily dosing (ODD) of 15 mg/kg amikacin (AMK) in burn patients does not always produce peak concentrations (C(max)) reaching the therapeutic objective of six to eight times the minimal inhibitory concentration (MIC). We recorded plasma concentrations following administration of 20 mg/kg AMK in burn patients and studied factors affecting pharmacokinetics. Mean C(max) was 48.3+/-10.8 mg/L and the C(max)/MIC ratio was 6+/-1.35. Statistical analysis demonstrated a relationship between C(max) and the area of the burn and Unit Burn Standard, and between AMK clearance and creatinine clearance (Cl(CR)). We conclude that ODD regimens of AMK in patients with burns >15% body surface area and/or with Cl(CR) >120 mL/min could require doses >20 mg/kg to reach adequate C(max). In all cases, patient therapeutic drug monitoring is essential to ensure the safe usage of these dosing recommendations.

Pharmacokinetics and bioequivalence of two trimebutine formulations in healthy volunteers using desmethyl-trimebutine levels.

Trimebutine tablets (dimethylamino-2-phenyl-2-n-butyl-3,4,5- trimethoxybenzoate maleate, CAS 34140-59-5, reference) and a new tablet formulation (Eurogalena, test) were administered in 24 healthy volunteers of both sexes according to a cross-over design, in a single dose of one 100 mg tablet of each formulation. Blood samples were drawn off over a 24-h period, before (time 0) and after each administration at specific intervals. Trimebutine and its main active metabolite, desmethyl-trimebutine, were measured in plasma using a validated HPLC method with UV detection. For both compounds, the sensitivity was 20 ng.ml-1 and the analytical method was proved to be linear for concentrations between 20 ng.ml-1 and 5000 ng.ml-1, with a variability less than 11%. The non-compartmental method was used for pharmacokinetic analysis. The confidence interval approach was used for comparison of the formulations according to the EU guidance note on bioavailability and bioequivalence on Cmax, AUC0-t and AUC0-infinity, log transformed. Tmax values were statistically compared using the Friedman non-parametric test. No trimebutine concentration was measured in the plasma samples. The obtained data with desmethyl-trimebutine proved the bioequivalence of the two tested formulations.

Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC.

A simple and sensitive HPLC method has been developed to measure trimebutine (CAS 39133-31-8, maleate: CAS 34140-59-5) and its main metabolite desmethyl-trimebutine in human plasma. The method was validated according to the Washington Consensus Conference on the Validation of Analytical Methods. It involved extraction of the plasma with n-hexane containing 2-pentanol, followed by reversed-phase HPLC using a Partisil ODS2 10 microns column and UV detection at 265 nm. The retention times of the internal standard (procaine), desmethyl-trimebutine and trimebutine were 2.4, 4.3 and 6.5 min, respectively. The standard curves were linear from 20 ng.ml-1 (limit of quantitation) to 5000 ng.ml-1 for both compounds. The coefficient of variation for all the criteria of validation were less than 15%. The extraction recoveries obtained for trimebutine and desmethyl-trimebutine were about 90%. Both compounds were very stable upon storage in plasma. The method was tested by measuring the plasma concentrations following oral administration to humans during a bioequivalence study and was shown suitable for pharmacokinetic studies.

Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis.

The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.

Population pharmacokinetics of carboplatin in children.

OBJECTIVES: In pediatric patients, administration of carboplatin according to body surface area results in a large variation in the area under the plasma ultrafilterable carboplatin concentration versus time curve. A population pharmacokinetic study using the NONMEM program was undertaken to determine the effects of a variety of covariates on the clearance of ultrafilterable carboplatin. PATIENTS: Plasma carboplatin pharmacokinetics were determined in 57 children (2 months to 18 years old, with serum creatinine levels ranging from 27 to 268 mumol/L) treated for various tumor types. RESULTS: The best fit corresponded to the formula: clearance (ml/min) = 2.85.weight.(1-0.00357.serum creatinine).(1-0.372.Np) + 8.7 (with serum creatinine in micromoles per liter, weight in kilograms, and Np = 1 or 0 for unilateral nephrectomy or not, respectively). The interindividual variability in clearance, as expressed by the coefficient of variation, decreased from 74% (no covariates) to 49% by taking account of weight, and to 29% under the final regression formula. CONCLUSION: The ability of this formula to predict carboplatin clearance in children should be evaluated prospectively and compared to a method based on the determination of the glomerular filtration rate.

[Prediction of carboplatin clearance from morphological and biological patient characteristics]. / Prédiction de la clairance du carboplatine à partir des caractéristiques morphologiques et biologiques du patient.

Hematologic toxicity of carboplatin is largely dependent on its pharmacokinetics. Its seems likely that therapeutic efficacy is also related to plasma drug exposure. Dosage adjustments based on isotopic determination of glomerular filtration rate have been proposed but their ambulatory use is not conceivable. A population pharmacokinetic study was undertaken to determine a relationship between patient characteristics and carboplatin clearance. Plasma carboplatin pharmacokinetics were determined as ultrafilterable platinum in 70 patients (23 to 84 years old) treated with different combination regimens including carboplatin at doses ranging from 184 to 950 mg (1-hr i.v. infusion) for various tumor types. Data were analysed using Nonlinear Mixed Effects Model (NONMEM). The data from 34 patients (46 cycles) were used to obtain the most predictive formula for the carboplatin clearance (ml/min): [formula: see text] The obtained formula was prospectively evaluated with the data from 36 other patients (43 cycles) and compared to other methods available to predict carboplatin clearance. Prospectively this formula predicted the clearance with a good precision (median absolute percent error of 10% range 0-30%) and minimal bias (median percent error: 2% range--25-30%). This method of prediction was as accurate as the one which requires the glomerular filtration rate to be measured by 51Cr-EDTA injection. This formula should allow to individualize very easily the carboplatin dosage in adults by multiplying the calculated carboplatin clearance by the area under the curve desired for administration.

[Relations between hematological toxicity and total and free plasma levels of etoposide in daily oral administration]. / Relation entre la toxicité hématologique et les concentrations plasmatiques totales et libres d'étoposide administré quotidiennement par voie orale.

This study was undertaken in order to evaluate the inter- and intra-individual pharmacokinetic variabilities and their impact on the toxicity of oral Vépéside Sandoz administered daily for 21 days. The pharmacokinetic results confirmed the low bioavailability of this formulation (14% +/- 10%) and its large interindividual variability. Moreover, a great intraindividual variability was shown between day 1 and day 21. This fact can explain that the relationship between the relative decrease in neutrophil count and the pharmacokinetic parameters was observed only with either the mean area under the curve of concentrations versus time (AUC) or the mean residual concentrations (Cr). The determination of the fraction of plasma etoposide unbound, which ranged from 4.6 to 24.8%, improved the pharmacokinetic-pharmacodynamy relationship for AUC but not for Cr. This study showed the potential interest of etoposide drug monitoring. However, no dosage adjustment could be performed with this oral etoposide formulation because of its large intraindividual bioavailability. Since this study was performed, the Sandoz company withdrew this formulation, and replaced it by one identical with that available in other countries.