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With recent evolution of cannabis legalization around the world and multiplication of cannabis derived products, identifying and qualifying cannabis consumption has a proven interest. Although blood, plasma, and urine are common matrices widely used in toxicology laboratories, oral fluid presents specific advantages. In the context of doping tests, addiction consultation or roadside checks, where other matrices are impractical to collect or can be adulterated, oral fluid is a promising matrix that allows a non-invasive, rapid, and monitored self-sampling. However, available devices required a consequent volume of oral fluid, more than 250 µL, sometimes difficult to collect. We present here a fully optimized quantitative method for seven cannabinoids, including four metabolites, in oral fluid, Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol; cannabidiol, 7-hydroxy and 7-carboxycannabidiol; and cannabinol. After self-collection of 20 µL using an accurate and precise volumetric absorptive microsampling device (VAMS ® ), cannabinoids were derivatized with 2-fluoro-1-methylpyridinium p-toluenesulfonate to increase sensitivity. The successive steps of the proposed method, including biosampling, 1 h sample preparation with derivatization, and acquisition by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry, were fully optimized. A limit of quantification of 0.5 ng/mL (≈10 pg per sampling) was thus targeted, adapted to the legal threshold required by the authorities and to clinical monitoring. Applied to six cannabis consumers, the proposed method made it possible to quantify in 20 µL oral fluid samples, Δ9-tetrahydrocannabinol ranging from 0.5 to 6236 ng/mL, cannabidiol from 0.6 to 190 ng/mL and cannabinol from 0.5 to 118 ng/mL., Competing Interests: Declarations. Ethics approval: The observational study was conducted in accordance with ethical guidelines established in the Declaration of Helsinki and the French legislation. Our ethics internal review board examined and approved the study design in a meeting on August 4 2023. The decision mentioned that the study did not fell within the scope of Loi Jardé (arrêté du 3 mai 2017 fixant la liste des recherches mentionnées au 2° de l’article L. 1121–1 du code de la santé publique) because it was a secondary analysis of a previous collection. The previously collected urinary and salivary samples were collected in non-treatment seeking healthy volunteers, who gave a written informed consent and were recruited among University of Paris students by word of mouth. Informed consent: Informed consent was obtained from all volunteers. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

With recent evolution of cannabis legalization around the world, cannabis edibles are booming, and determining their concentration in Δ9-tetrahydrocannabinol (Δ9-THC), the regulated psychoactive substance, remains a challenge for toxicology laboratories, which must prove whether the product has legal status or not. Cannabinoids are a large family of structurally similar and lipophilic molecules, requiring dedicated pre-analytical methods, as well as efficient chromatographic separation to differentiate cannabinoid isomers which are distinguished by their psychoactive properties and their legal status. Here, we present two independent cases of cannabis edibles, for which we performed analysis of homemade cannabis chocolate cakes and of the resins and herbs used for cooking. Quantitation was carried out with a new developed standard addition method, to avoid matrix effects and matrix-dependent calibration. Extraction by QuEChERs method, followed by targeted and non-targeted analysis by ultra-high performance liquid chromatography hyphenated to high resolution mass spectrometry (UHPLC-HRMS) allowed the identification of several phytocannabinoids, mainly Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and their acid precursors Δ9-THC acid (THCA) and CBD acid (CBDA). Δ9-THC was identified in significant concentrations (mg/g) in both edibles, even though one was prepared with CBD herb. This work highlights the need to analyze cannabis edibles, as well as the resins and herbs used in their preparation if it is homemade, and it proposes a reliable analytical method for toxicology laboratories., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective: Imipenem is recommended in patients with chemotherapy-induced febrile neutropenia. Although alterations of antibiotic pharmacokinetic parameters have been reported in such patients, little data is available on imipenem., Methods: Prospective, single-center, non-interventional pharmacokinetic cohort study in adults with chemotherapy-induced febrile neutropenia. Critically ill patients were excluded. Imipenem was administered as a 30-min infusion of 1000 mg/8h. Total imipenem plasma concentrations were assayed by high-performance liquid chromatography during neutropenia and just after neutrophil recovery. We estimated population pharmacokinetic parameters of imipenem by non-linear mixed-effect modelling using the SAEM algorithm., Results: Sixteen patients were included in the study, including nine women (56.3%), median age 37 years (range, 18.3; 78.3). Eight patients had an hematological malignancy (50.0%) and seven had a solid tumor (43.8%). Imipenem pharmacokinetics were best described by a one-compartment model with first-order elimination. Mean values for imipenem were: clearance 14.3L/h and 10.9L/h and volume of distribution 20.7L and 14.5 L during neutropenia and after recovery, respectively. Imipenem plasma area under the curve at steady state was reduced by 23% during neutropenia. However, all patients achieved a pharmacodynamic target of %fT >MIC  ≥ 40% with a regimen of 1000 mg/8 h or 500 mg/6 h, for MICs up to 2 mg/L. The pharmacodynamics profile for a target of %fT > MIC = 100% was however less favorable with 500 mg/6 h or 1000 mg/8 h either during or after neutropenia., Conclusion: Pharmacokinetic/pharmacodynamic goals for imipenem were similar in patients during and after neutropenia, despite reduced plasma exposure., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background: Hydrocortisone premedication reduces the risk of antibodies to infliximab [ATIs] formation in patients receiving infliximab [IFX] therapy for inflammatory bowel disease [IBD]., Aim: We aimed to determine the safety of hydrocortisone premedication withdrawal in IBD patients with sustained clinical response on maintenance therapy with IFX., Methods: We performed an observational prospective pharmacoclinical study in a tertiary referral centre, including all consecutive IBD outpatients with no previous IFX infusion reaction and in clinical remission on maintenance IFX [alone or in combination therapy] for at least 6 months. This cohort was followed for 1 year after discontinuation of hydrocortisone premedication., Results: Among the 268 IBD outpatients, 95 patients met the inclusion criteria [mean age 38 years; 64% male; 80% Crohn's disease; 45% combination therapy]. The median IFX duration was 5 years [0.54-14] with a mean infused dose of 533 mg [200-1000] and a mean interval duration of 7.9 weeks [4-10]. None of the patients developed permanent ATIs or infusion-related reaction at 1 year. Four patients developed transient ATIs without loss of clinical response. There was no significant variation of infliximab serum trough levels [5.5 µg/mL vs 5.9 µg/mL] measured at the time of the three IFX infusions before and after hydrocortisone withdrawal. Loss of response rate to IFX was 18% at 1 year., Conclusions: Hydrocortisone discontinuation is safe in IBD patients with sustained clinical remission on maintenance therapy with IFX. Our data suggest that routine premedication with hydrocortisone is unnecessary in patients in prolonged remission under IFX maintenance therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRN I- A/FG K GS/T pfdhfr / pfdhps haplotypes, including the pfdhps A581G and A613S/T mutations, was high at delivery among post-SP treatment isolates (18.2%) compared to those of first antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine [IPTp-SP]; 6.1%; P =  0.03). Regarding the pfk13 marker gene, two nonsynonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance of additional mutations associated with increased SP resistance as well as emergence of resistance against artemisinin derivatives., (Copyright © 2020 American Society for Microbiology.)

The metabolic consequences in vivo of various balanced solutions are poorly known in critically ill patients. The main objective of this study was to describe the metabolic consequences of Plasmalyte versus Ringer lactate (RL) in critically ill burn patients, with a special focus on the plasma clearance of buffer anions (i.e., gluconate, acetate, and lactate). We conducted a randomized trial between August 2017 and October 2018 in a tertiary teaching hospital in Paris, France. Patients with burn total body surface area >30% were randomized to receive Plasmalyte or RL. The primary end point was the base excess 24 h after inclusion. The secondary end points were acetate, gluconate, and lactate plasma concentration, the strong ion difference (SID). Twenty-eight patients were randomized. Twenty-four hours after inclusion, plasma BE was not significantly different in the Plasmalyte and RL groups {-0.9 [95% confidence interval (95% CI): -1.8-0.9] vs. -2.1 [95% CI: -4.6-0.6] mmol/L, respectively, P = 0.26}. Plasma gluconate concentration was higher in the Plasmalyte group ( P < 0.001), with a maximum level of 1.86 (95% CI: 0.98-4.0) mmol/L versus 0 (95% CI: 0-0.15) mmol/L. Plasma acetate and lactate were not significantly different. Ionized calcium level was lower in the Plasmalyte group ( P = 0.002). Hemodynamics did not differ between groups. To conclude, the alkalinizing effect of Plasmalyte was less important than expected with no difference in base excess compared with RL, in part due to gluconate accumulation. Acetate and lactate did not significantly accumulate. Plasmalyte led to significantly lower ionized calcium levels. NEW & NOTEWORTHY During fluid resuscitation in burns the alkalinizing effect of Plasmalyte was less important than expected, with no difference in base excess compared with Ringer lactate (RL), in part due to gluconate accumulation. Acetate and lactate did not significantly accumulate. Plasmalyte led to significantly lower ionized calcium levels.

Despite the clinically proven advantages of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), utilisation has been low in many African countries. To increase uptake and achieve the desired effect, the World Health Organization revised the policy to a monthly administration. Assessing the coverage and impact of the revised policy on pregnancy and neonatal outcomes is, therefore, a necessity. A 2-parallel cross-sectional hospital-based study was carried out among pregnant women attending first antenatal care (ANC) and delivery. Maternal and cord blood samples were assayed for malaria parasites by quantitative PCR targeting both the 18S rDNA and the acidic terminal segment of Plasmodium falciparum var genes, and plasma SP levels were measured by liquid chromatography coupled to tandem mass spectrometry. Parasite prevalence was similar between the two study sites but decreased significantly between the first ANC (9% or 43%) and delivery (4% or 11%) based on the qPCR target. At delivery, 64.5% of women received ≥3 IPTp-SP dose, 15.5% received 2 doses and 6% had 1 dose. Taking ≥3 IPTp-SP doses was associated with an average birth weight increase of more than 0.165 kg. IPTp-SP uptake was associated with plasma SP level at delivery (OR = 32.3, p ≤ 0.005, 95% CI (13.3;78.4) for those that reported ≥3 IPTp-SP doses) while the same trend of improved birth weight was observed with high plasma SP levels. The new IPTp policy is well implemented and well utilised by women in the sites considered in this study and translates to the improved birth weight observed. This study confirms the interest and the clinical benefit expected from this policy change.

In South America, Plasmodium vivax resistance to chloroquine was recently reported in Brazil and Bolivia. The objective of this study was to collect data on chloroquine resistance in French Guiana by associating a retrospective evaluation of therapeutic efficacy with an analysis of recurrent parasitemia from any patients. Patients with P. vivax infection, confirmed by microscopy and a body temperature of ≥37.5°C, were retrospectively identified at Cayenne Hospital between 2009 and 2015. Follow-up and treatment responses were performed according to the World Health Organization protocol. Parasite resistance was confirmed after dosage of a plasma concentration of chloroquine and microsatellite characterization. The pvmdr1 and pvcrt-o genes were analyzed for sequence and gene copy number variation. Among the 172 patients followed for 28 days, 164 presented adequate clinical and parasitological responses. Eight cases of treatment failures were identified (4.7%; n  = 8/172), all after 14 days. The therapeutic efficacy of chloroquine was estimated at 95.3% (95% confidence interval [CI], 92.5 to 98.1%; n  = 164/172). Among the eight failures, five were characterized: two cases were true P. vivax chloroquine resistance (1.2%; 95% CI, 0 to 2.6%; n  = 2/172), and three cases were found with subtherapeutic concentrations of chloroquine. No particular polymorphism in the Plasmodium vivax pvmdr1 and pvcrt-o genes was identified in the resistant parasites. This identified level of resistance of P. vivax to chloroquine in French Guiana does not require a change in therapeutic recommendations. However, primaquine should be administered more frequently to limit the spread of resistance, and there is still a need for a reliable molecular marker to facilitate the monitoring of P. vivax resistance to chloroquine., (Copyright © 2019 Musset et al.)

Background: Sevoflurane has anti-inflammatory proprieties and short lasting effects making it of interest for procedural sedation in critically ill patients. We evaluated the pharmacokinetics of sevoflurane and metabolites in severely ill burn patients and controls. The secondary objective was to assess potential kidney injury., Methods: Prospective interventional study in a burn and a surgical intensive care unit; 24 mechanically ventilated critically ill patients (12 burns, 12 controls) were included. The sevoflurane was administered with an expired fraction target of 2% during short-term procedural sedation. Plasma concentrations of sevoflurane, hexafluoroisopropanolol (HFIP) and free fluoride ions were recorded at different times. Kinetic Pro (Wgroupe, France) was used for pharmacokinetic analysis. Kidney injury was assessed with neutrophil gelatinase-associated lipocalin (NGAL)., Results: The mean total burn surface area was 36±11%. The average plasma concentration of sevoflurane was 70.4±37.5mg·L -1 in burns and 57.2±28.1mg·L -1 in controls at the end of the procedure (P=0.58). The volume of distribution was higher (46.8±7.2 vs 22.2±2.50L, P<0.001), and the drug half-life longer in burns (1.19±0.28h vs 0.65±0.04h, P<0.0001). Free metabolite HFIP was higher in burns. Plasma fluoride was not different between burns and controls. NGAL did not rise after procedures., Conclusion: We observed an increased volume of distribution, slower elimination rate, and altered metabolism of sevoflurane in burn patients compared to controls. Repeated use for procedural sedation in burn patients needs further evaluation. No renal toxicity was detected., Trial Registry Number: ClinicalTrials.gov Identifier NCT02048683., (Copyright © 2018 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: We sought to determine the frequency of and risk factors for early (30-day) postoperative complications after ileocecal resection in a well-characterized, prospective cohort of Crohn's disease patients., Methods: The REMIND group performed a nationwide study in 9 French university medical centers. Clinical-, biological-, surgical-, and treatment-related data on the 3 months before surgery were collected prospectively. Patients operated on between 1 September 2010 and 30 August 2014 were included., Results: A total of 209 patients were included. The indication for ileocecal resection was stricturing disease in 109 (52%) cases, penetrating complications in 88 (42%), and medication-refractory inflammatory disease in 12 (6%). A two-stage procedure was performed in 33 (16%) patients. There were no postoperative deaths. Forty-three (21%) patients (23% of the patients with a one-stage procedure vs. 9% of those with a two-stage procedure, P=0.28) experienced a total of 54 early postoperative complications after a median time interval of 5 days (interquartile range, 4-12): intra-abdominal septic complications (n=38), extra-intestinal infections (n=10), and hemorrhage (n=6). Eighteen complications (33%) were severe (Dindo-Clavien III-IV). Reoperation was necessary in 14 (7%) patients, and secondary stomy was performed in 8 (4.5%). In a multivariate analysis, corticosteroid treatment in the 4 weeks before surgery was significantly associated with an elevated postoperative complication rate (odds ratio (95% confidence interval)=2.69 (1.15-6.29); P=0.022). Neither preoperative exposure to anti-tumor necrosis factor (TNF) agents (n=93, 44%) nor trough serum anti-TNF levels were significant risk factors for postoperative complications., Conclusions: In this large, nationwide, prospective cohort, postoperative complications were observed after 21% of the ileocecal resections. Corticosteroid treatment in the 4 weeks before surgery was significantly associated with an elevated postoperative complication rate. In contrast, preoperative anti-TNF therapy (regardless of the serum level or the time interval between last administration and surgery) was not associated with an elevated risk of postoperative complications.

Aims: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients., Methods: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes., Results: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose., Conclusions: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients., (© 2015 The British Pharmacological Society.)

Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine. At the neuromuscular junction, AChE is mainly anchored in the extracellular matrix by the collagen Q, whereas in the brain, AChE is tethered by the proline-rich membrane anchor (PRiMA). The AChE-deficient mice, in which AChE has been deleted from all tissues, have severe handicaps. Surprisingly, PRiMA KO mice in which AChE is mostly eliminated from the brain show very few deficits. We now report that most of the changes observed in the brain of AChE-deficient mice, and in particular the high levels of ambient extracellular acetylcholine and the massive decrease of muscarinic receptors, are also observed in the brain of PRiMA KO. However, the two groups of mutants differ in their responses to AChE inhibitors. Since PRiMA-KO mice and AChE-deficient mice have similar low AChE concentrations in the brain but differ in the AChE content of the peripheral nervous system, these results suggest that peripheral nervous system AChE is a major target of AChE inhibitors, and that its absence in AChE- deficient mice is the main cause of the slow development and vulnerability of these mice. At the level of the brain, the adaptation to the absence of AChE is nearly complete., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

A nationally-representative sample of 2,696 preschool children living in Congo was examined during Au gust-September 2003 to determine the rates of vitamin A deficiency. Ninety clusters of 30 children, aged six months to six years, were selected, using a randomized two-level cluster-sampling method. Vitamin A deficiency was determined by assessing the prevalence of active xerophthalmia (nightblindness and/or Bitot spots) in the cross-over sample of 2,696 individuals. A semi-quantitative seven-day dietary questionnaire was concurrently applied to the mothers of children enrolled to estimate the latter's consumption of vitamin A-rich food. Vitamin A status was assessed by performing the modified relative dose-response test (MRDR) on dried blood spots (DBS) from a subsample of 207 children aged less than six years and the impression cytology with transfer (ICT) test on a subsample of 1,162 children. Of the children enrolled, 5.2% suffered from nightblindness, 8.0% had Bitot spots, and 2.5% had other vitamin A deficiency sequellae. Fifty-three percent of the ICT tests showed the presence of vitamin A deficiency. The biochemical MRDR test showed that the vitamin A status of 30% of the study children was critical. Twenty-seven of them had retinol levels of < 10 microg/dL [mean +/- standard deviation (SD) 7.02 +/- 2.0 microg/dL], and 50% had retinol levels of 10-20 microg/dL (mean +/- SD 14.2 +/- 2.83 microg/dL). The poor health status and low rates of consumption of vitamin A-rich food are the main factors determining critical status. Vitamin A deficiency, reflecting poor nutrition and health, is a serious public-health issue among children aged less than six years in Congo.

Paraoxon induces respiratory toxicity. Atropine completely reversed parathion- and paraoxon-induced respiratory toxicity. The aim of this study was to assess the peripheral or central origin of ventilatory effects of low-dose paraoxon. Male Sprague-Dawley rats were given paraoxon 0.215 mg/kg subcutaneously and treated with either atropine (10 mg/kg sc) or ascending doses of methylatropine of 5.42 (equimolar to that of atropine), 54.2, and 542 mg/kg administered subcutaneously 30 min after paraoxon. Ventilation at rest was assessed using whole-body plethysmography and rat temperature using infra-red telemetry. Results are expressed as mean+/-SE. Statistical analysis used two-way ANOVA for repeated measurements. Paraoxon induced a significant decrease in temperature 30 min after injection lasting the 90 min of the study period. This effect was partially corrected by atropine, but not by methylatropine whatever the dose. Paraoxon induced a decrease in respiratory rate resulting from an increase in expiratory time associated with an increase in tidal volume. Atropine completely reversed the ventilatory effects of low-dose paraoxon while the equimolar dose of methylatropine had no significant effects. The 54.2 and 542 mg/kg doses of methylatropine had no significant effects. Atropine crosses the blood-brain barrier and reverses peripheral and central muscarinic effects. In contrast, methylatropine does not cross the blood-brain barrier. Atropine completely reversed the ventilatory effects of low-dose paraoxon, while methylatropine had no significant effects at doses up to 100-fold the equimolar dose of atropine. We conclude that the ventilatory effects of low-dose paraoxon are mediated by disrupted muscarinic signaling in the central nervous system.

Respiratory failure, through a combination of muscarinic, nicotinic, and central effects, is the primary cause of death in acute organophosphate poisoning. However, the mechanisms inducing respiratory failure remain unclear. In rats poisoned subcutaneously with paraoxon at doses near the LD(50), we studied the pattern of respiration using whole body plethysmography and the occurrence of respiratory failure using arterial blood gases. Subsequently, we studied the effects of atropine on paraoxon-induced modification of ventilation and arterial blood gases. Fifty and 75%, but not 10% of the subcutaneous LD(50) of paraoxon induced marked and sustained signs and symptoms. At 30min post-injection and throughout the study, there was a significant decrease in the respiratory frequency (34% (50% versus solvent), and 29% (75% versus solvent)) and a significant increase in the expiratory time (72% (50% versus solvent) and 60% (75% versus solvent)) with no modifications of the inspiratory time. The tidal volume was significantly increased for the 75% but not for the 50% dose. Apnea was never detected. Even at the 75% dose, paraoxon had no effects on PaO(2), PaCO(2) or HCO(3)(-); however, a significant decrease in arterial pH was observed at 30min (7.34+/-0.07 versus 7.51+/-0.01, p=0.03). Atropine completely reversed the paraoxon-induced respiratory alterations. We conclude that paraoxon, at doses equal to 50 and 75% of the LD(50), alters ventilation at rest without inducing respiratory failure during the study period.

Objectives: A representative sample of 5722 pre-school children living in rural and urban areas of the Congo was examined between July and September 1999 for assessing Vitamin A deficiency., Methods: Using a randomized two-level cluster sampling method, 190 clusters of 30 children aged from 6 months to 6 years were selected in order to assess the prevalence of active xerophthalmia (night blindness and/or Bitot spots). Concurrently, the children's height and weight were determined. A semi-quantitative seven-day dietary questionnaire was applied to the mothers of 5722 children to estimate the latter's consumption of Vitamin A rich foodstuffs. The prevalence of biochemical deficiency was assessed based on the serum retinol concentrations analyzed in dried blood spots from a sub-sample of 300 children living in the Pointe-Noire area., Results: Among the 5722 children studied, 0.7% were found to suffer from night blindness and 7.7% had Bitot spots. The weekly intake of Vitamin A rich foods was estimated in 5722 children. Our data suggest that Vitamin A rich food consumption was lower in rural zones than in urban area according to the food frequency method threshold values. The serum retinol levels were lower than 10 microg/dl in 18% (95% confidence interval [C.I.]: 13.7, 22.3) [8.04+/-2.87 microg/dl] and less than 20 microg/dl in 49% (95% C.I.: 43.4, 54.6) [15.05+/-2.76 microg/dl] of the 300 studied children. We have established a significant relation between mean serum retinol levels and high rate of Vitamin A food intake (chi-square=59.64, 2 d.d.l., p<0.05) in the sample studied. The mean serum retinol concentrations did not differ significantly between the various Z-scores of weight for age (W/A) and height for age (H/A) patterns. But children with a weight for height (W/H) ratio below -2 standard deviation (S.D.) had significantly lower serum retinol values [9.33+/-1.3 microg/dl] than those with a W/H ratio greater than or equal to -2S.D. [10.82+/-4.84 microg/dl]., Conclusion: These data suggest that Vitamin A deficiency is still a serious public health problem in rural areas of the Congo in which this study was carried out.

Background: We evaluated a new, automated multicapillary zone electrophoresis (CE) instrument (Capillarys), 4.51 software version; Sebia) for human serum protein analysis., Methods: With the Capillarys beta1-beta2+ reagent set, proteins were separated at 7 kV for 4 min in 15.5 cm x 25 micro m fused-silica capillaries (n = 8) at 35.5 degrees C in a pH 10 buffer with online detection at 200 nm. Serum samples with different electrophoretic patterns (n = 265) or potential interference (n = 69) were analyzed and compared with agarose gel electrophoresis (AGE; Hydrasys)-Hyrys, Hydragel protein(e) 15/30 reagent set; Sebia)., Results: CVs were <3.5% for albumin, <11% for alpha(1)-globulin, <4.1% for alpha(2)-globulin, <7.4% for beta-globulin, and <5.8% for gamma-globulin (3 control levels); measured throughput was 60 samples/h. In patients without paraprotein (n = 116), the median differences between CE and AGE were -5.4 g/L for albumin, 4.0 g/L for alpha(1)-globulin, 0.7 g/L for alpha(2)-globulin, 0.6 g/L for beta-globulin (P <0.001 for all fractions), and -0.1 g/L for gamma-globulin (not significant). More samples had at least one gamma-migrating peak detected by CE (n = 135 vs 130; paraprotein detection limit, approximately 0.5-0.7 g/L), but fewer were quantified (n = 84 vs 91) because of gamma- to beta-migration shifts. There was a 1.2 g/L median difference between CE and AGE for gamma-migrating paraprotein quantification (n = 69; P <0.001). Several ultraviolet-absorbing substances (lipid emulsion, hemoglobin) or molecules (contrast agent, gelatin-based plasma substitute) induced CE artifacts., Conclusions: The Capillarys instrument is a reliable CE system for serum protein analysis, combining advantages of full automation (ease of use, bar-code identification, computer-assisted correction of alpha(1)-globulins) with high analytical performances and throughput.

A capillary zone electrophoresis (CZE) technique was developed for the determination of poorly separated monoclonal serum proteins by agarose gel electrophoresis (AGE). A P/ACE 5500 capillary instrument (Beckman) was used under the following conditions: 57 cm x 50 microm I.D. fused-silica capillary, pH 9.6 borate buffer, and 214 nm on-line detection. Sixty patients (61 +/- 13 years) with a well isolated (n=24, group A) or poorly separated monoclonal band(s) by AGE (n=36, group B) were included in this study. Within- and between-run precision for CZE was below 4% for albumin and 7% for gamma-globulin. A 100% (group A) or 61% agreement (group B, more bands detected by CZE in 10 cases) was obtained between CZE and AGE for the number of monoclonal bands. In group B, quantification was possible in 92% of samples by CZE vs. 64% by AGE (P<0.05, chi-square). The proposed CZE method appears as an additional helpful technique for the determination of poorly separated monoclonal serum proteins by AGE., (Copyright 2002 Elsevier Science BV.)

We here describe an ion-exchange high-performance liquid chromatography technique with electrochemical detection for rapid quantification of glutathione, homocysteine, cysteinylglycine, and methionine. The analytical validation of the technique showed within-assay and between-assay coefficients of variation between 3.1 and 4.3%, and 3.7 and 8.6%, respectively. Percentages of recovery for overload and dilution tests were between 87 and 120%. Detection limits were 1 micromol/L for methionine and 0.5 micromol/L for other compounds. There was no interference with any physiological and pharmacological substances possessing a thiol function. Aminothiol concentrations determined in 100 control subjects (50 women and 50 men) showed no age- or sex-rated differences for except for homocysteine which was increased (+ 28%) in oldest subjects of both sexes. In 60 patients at risk (30 with chronic renal failure, 30 with diabetes), homocysteine concentration was significantly increased. No variation in other aminothiols was observed in diabetic subjects. Methionine was decreased and cysteinylglycine was increased in patients with chronic renal failure. The present technique-rapid, easy to use, and reliable-appears suitable for routine application in the exploration of aminothiol metabolic pathways including mechanisms of hyperhomocysteinemia.

4-methylpyrazole (4-MP) was administered IV during haemodialysis of two ethylene glycol-intoxicated patients with anuric renal failure. The plasma 4-MP concentration decreased after each pass through the dialyser, indicating its dialysability in humans. In these two cases, the extraction coefficient was 0.78 and 0.71, and the mean dialysance was calculated to be 137 and 117 ml.min-1, corresponding to a 4-MP removal rate of 83 and 50 mg.h-1, respectively. The results imply that a higher rate of 4-MP infusion would be needed to replace 4-MP lost due to metabolism and to haemodialysis. The treatment of two ethylene glycol poisoned patients who were haemodialysed raised the problem of the dialysance of 4-MP. A recent study in pigs indicated that the amount of 4-MP removed by haemodialysis was significant [8]. No data were available for man. The aim of the study was to evaluate the dialysability of 4-MP in the two intoxicated patients, and to estimate how to compensate for 4-MP elimination during haemodialysis.

The uptake of iron by the liver and cerebellum was measured in rats using [59Fe]transferrin. An acute ethanol load (50 mmol/kg body wt., i.p.) elicited a significant increase in the hepatic and cerebellar non-heme iron concentration. The uptake of 59Fe by the liver and the cerebellum was significantly greater in the ethanol-treated rats than in control animals. The administration of allopurinol prior to the ethanol load prevented the changes in liver and cerebellar non-heme iron content. Moreover pretreatment with allopurinol reduced the ethanol-induced enhancement of 59Fe uptake by the liver and completely prevented the changes in 59Fe uptake by the cerebellum. These effects of allopurinol lead us to suggest that oxygen-derived free radicals are involved in the ethanol-induced disturbances of iron uptake both at the hepatic and cerebellar level.

This study has given evaluation of a new pneumallergen diagnostic test CIS Allergen Screen I in comparison with Pharmacia Cap System and intradermal skin test. Five allergens (Mite (DPT) D1, Mite (DF) D2, Cat E1, Dog E2, Orchard grass G3) have been studied with in vitro tests (CIS Allergen Screen I Cap System) and the results obtained gave on patient to patient comparison a sensitivity of 91%, a specificity of 100% and on allergen comparison a sensitivity of 84%, a specificity of 99% and an accuracy of 93%. Compared with intradermal skin test for two allergens (Mite (DT) D1 and Orchard grass G3), CIS Allergen Screen I have good results to G3 but less specificity and sensitivity to D1. These results could be to depend on different standardisation between allergen extracts especially for Mite.

Potentially fatal ethylene glycol intoxication in an adult with normal renal function was treated with 4-methylpyrazole administered three hours after the incident occurred. The plasma ethylene glycol concentration was 3.5 g l-1 on admission. The metabolic acidosis present on admission resolved within four hours, and the subsequent clinical course was uneventful. The apparent plasma half-life of ethylene glycol was 16 h and the mean renal and plasma clearances of ethylene glycol were 24 and 25 ml min-1, respectively. These results support the hypothesis that complete blockade of hepatic metabolism of ethylene glycol is achieved by 4-methylpyrazole. The only side-effect observed as a result of treatment was a transient slight increase in serum transaminase activity.

An acute ethanol load (50 mmol/kg, i.p.) induces an increase in the total non-heme iron and in the low-molecular-weight non-heme iron complexes (LMW-Fe) content both in liver and cerebellum. This increase in LMW-Fe is associated with a decrease in some essential trace elements (selenium, zinc, copper) playing a role in the anti-oxidant system. These changes could contribute to the enhancement in lipid peroxidation which occurs at the hepatic and cerebellar level following the ethanol administration. The administration of allopurinol prior to the ethanol load prevents the changes in non-heme iron and trace elements. This prevention may contribute to the protective effects of allopurinol on the ethanol-induced oxidative stress.

The steady-state population pharmacokinetics of theophylline were studied in 52 asthmatic adult patients who received sustained-release theophylline as armophylline or euphylline. A total of 92 steady-state plasma theophylline concentration-dosage pairs were analyzed using a nonlinear mixed effects model. The pharmacokinetic model used was a one-compartment open model with single path Michaelis-Menten elimination. Dosage was adjusted to body weight. The effects of age, gender, alcohol consumption, cigarette smoking, dosage form, concurrent treatment with beta-agonists or steroids, outpatient dosing, and plasma caffeine concentration on maximum elimination rate (Vm) and Michaelis constant for theophylline metabolism (Km) were investigated. Hypothesis testing produced a final model in which Km = 0.42 (mg/l), and Vm (mg/kg per day) was based on cigarette smoking and dosage form, with Vm = 7.54 + 2.01 (smoking) + 1.08 (euphylline). Estimated coefficients of variation for interindividual variability in Km and Vm were 162.6% and 48.1%, respectively. Residual variability in dosage rates was estimated as 0.90 mg/kg per day. The identification of factors influencing theophylline disposition should prove useful for the a priori design of theophylline dosage regimens and monitoring of drug levels during therapy.

An acute ethanol load (50 mmol/kg, i.p.) produced altogether a decrease in the non-heme iron content of the serum and an increase in the iron content in liver and cerebellum. Subcellular fractionation studies indicated that the non-heme iron accumulated by the liver, 4 hr after the ethanol load, was recovered in light mitochondria, microsomes and cytosol, and that iron accumulated by the cerebellum was localized in heavy mitochondria, light mitochondria, microsomes and cytosol. The low molecular weight chelatable (LMWC) iron content as well as the percentage of total non-heme iron represented by LMWC-iron were increased in the cytosol of liver and cerebellum after the ethanol load. These results suggest that an acute ethanol load induces (i) a shift in the distribution between circulating and tissular non-heme iron; (ii) an increase in the cytosolic LMWC-iron which, by favouring the biosynthesis of reactive free radicals, may contribute to lipid peroxidation in liver and cerebellum.

A non-exponential mathematical equation was used to extrapolate the 'predictive line' for plasma paraquat concentrations beyond 24 h. Plasma paraquat concentrations were measured in 30 patients who were admitted more than 24 h after overdose. The extrapolated line accurately predicted the outcome in 27 of these 30 patients. Urine paraquat concentrations were measured in 53 patients. All patients with urine paraquat concentrations of less than 1 mg/l (colourless or light blue test result using the colorimetric test) within 24 h of overdose survived. In contrast, patients with urine paraquat concentrations of more than 1 mg/l had a high probability of death. Even if plasma paraquat concentrations have a higher predictive value, urine data may contribute to a more rapid evaluation of prognosis.

14 patients with heavy metal poisoning received 2,3-dimercaptosuccinic acid (DMSA). 12 subjects were given 30 mg/kg/day for 5 days; 1 subject was started on a lower dose because of a history of atopy; another subject was treated for 15 days because of very high initial blood lead concentrations. In the 9 subjects who had lead poisoning, DMSA decreased blood lead concentrations by 35 to 81%, and induced a 4.5- to 16.9-fold increase in mean daily urinary excretion of the metal. In the acutely arsenic-poisoned case, the plasma arsenic concentration on day 7 was half the pretreatment value, while no clear decrease was observed in a chronically exposed subject. In 3 mercury cases, DMSA increased daily mercury urinary excretion 1.5-, 2.8- and 8.4-fold, respectively, while blood mercury concentrations remained below detection limits. No serious side effects were observed and 3 weeks after administration of the drug the clinical condition of all subjects was either stable or improved. These results indicate the efficacy of DMSA for lead poisoning in humans and provide a rationale for further investigating its usefulness in mercury and arsenic poisoning cases.

The authors describe a new micromethod for iron quantification in serum by ICPAES. Because the high temperature of quantification, the results are not affected by the iron chelating drugs used for the treatment of major thalassaemia (desferrioxamine).

Desferrioxamine (DFO) plus ferrioxamine (FO) variations and alterations in plasma and urinary iron (Fe) levels were investigated in eight children with thalassaemia major during a 12-h s.c. DFO infusion at a dose of 40 mg/kg body weight. During the infusion, blood samples were regularly taken and total urine was also regularly collected in all patients. In the plasma, a mean DFO plus FO plateau level of 9 mg/l was reached after 4 h and remained steady in the subsequent 8 h. At 30 h the mean DFO plus FO concentration in plasma was still 4.5 mg/l. At 30 h, the urinary excretion ranged from 15% to 70% of the infused dose (mean: 42%). In plasma, the Fe concentration increased on average by 20% (range 10%-30%), remained steady during the DFO infusion, then returned to the basal level after 16-24 h. Urinary Fe excretion started early and still persisted 18 h after the infusion. The amount excreted at 30 h ranged from 5 to 27 mg (mean: 13.6 mg). This study emphasizes the delay in obtaining a DFO plus FO plateau in plasma, the important interindividual variations and the slow decrease of the drug after the end of the infusion. It points out the delay and the values of the urinary Fe excretion compared to the plasmatic and urinary drug variations.

A technique is described in which the toxicokinetics of paraquat on passage through the heart and lung were studied by means of blood samples drawn simultaneously from the pulmonary and radial arteries in six cases of acute human life-threatening paraquat intoxications. There was a trend for the radial plasma concentrations of paraquat to be greater than or equal to the pulmonary concentrations. This data suggests that from a clinical point of view the distribution of paraquat into the lungs is not a slow process. There may also exist some efflux of the paraquat into the circulation. This efflux of paraquat may result from direct lung and/or heart injury induced by massive paraquat poisoning.