Prediction of fatty acids composition in the rainbow trout Oncorhynchus mykiss by using Raman micro-spectroscopy.

The importance of poly-unsaturated fatty acids (PUFAs) in food is crucial for the animal and human development and health. As a complementary strategy to nutrition approaches, genetic selection has been suggested to improve fatty acids (FAs) composition in farmed fish. Gas chromatography (GC) is used as a reference method for the quantification of FAs; nevertheless, the high cost prevents large scale phenotyping as needed in breeding programs. Therefore, a calibration by means of Raman scattering spectrometry has been established in order to predict FA composition of visceral adipose tissue in rainbow trout Onchorhynchus mykiss. FA composition was analyzed by both GC and Raman micro-spectrometry techniques on 268 individuals fed with three different feeds, which have different FA compositions. Among the possible regression methods, the ridge regression method, was found to be efficient to establish calibration models from the GC and spectral data. The best cross-validated R2 values were obtained for total PUFAs, omega-6 (Ω-6) and omega-3 (Ω-3) PUFA (0.79, 0.83 and 0.66, respectively). For individual Ω-3 PUFAs, α-linolenic acid (ALA, C18:3), eicosapentaenoic acid (EPA, C20:5) and docosahexenoic acid (DHA, C22:6) were found to have the best R2 values (0.82, 0.76 and 0.81, respectively). This study demonstrates that Raman spectroscopy could be used to predict PUFAs with good correlation coefficients on adipocytes, for future on adipocytes physiology or for large scale and high throughput phenotyping in rainbow trout.

Physiological and behavioral flexibility to an acute CO2 challenge, within and between genotypes in rainbow trout.

Adaptive capacities, governing the ability of animals to cope with an environmental stressor, have been demonstrated to be strongly dependent upon genetic factors. Two isogenic lines of rainbow trout, previously described for their sensitivity and resilience to an acute confinement challenge, were used in the present study to investigate whether adaptive capacities remain consistent when fish are exposed to a different type of challenge. For this purpose, the effects of a 4-hour hypercapnia (CO2 increase) challenge at concentrations relevant in aquaculture conditions are described for the two isogenic lines. Oxygen consumption, cortisol release, group dispersion and group swimming activity were measured before, during and after the challenge. Sensitivity and resilience for each measure were extracted from temporal responses and analyzed using multivariate statistics. The two fish lines displayed significant differences in their cortisol response, translating differences in the stress axis sensitivity to the stressor. On the contrary, both lines showed, for other measures, similar temporal patterns across the study. Notable within line variability in the stress response was observed, despite identical genome between fish. The results are discussed in the context of animal robustness.

The male handicap: male-biased mortality explains skewed sex ratios in brown trout embryos.

Juvenile sex ratios are often assumed to be equal for many species with genetic sex determination, but this has rarely been tested in fish embryos due to their small size and absence of sex-specific markers. We artificially crossed three populations of brown trout and used a recently developed genetic marker for sexing the offspring of both pure and hybrid crosses. Sex ratios (SR = proportion of males) varied widely one month after hatching ranging from 0.15 to 0.90 (mean = 0.39 ± 0.03). Families with high survival tended to produce balanced or male-biased sex ratios, but SR was significantly female-biased when survival was low, suggesting that males sustain higher mortality during development. No difference in SR was found between pure and hybrid families, but the existence of sire × dam interactions suggests that genetic incompatibility may play a role in determining sex ratios. Our findings have implications for animal breeding and conservation because skewed sex ratios will tend to reduce effective population size and bias selection estimates.

Adaptive capacities from survival to stress responses of two isogenic lines of rainbow trout fed a plant-based diet.

The composition of feed for farmed salmonids has strongly evolved during the last decades due to the substitution of fishery-derived fish oil and fishmeal by ingredients of plant origin. Little information is available regarding the effects of this transition on adaptive capacities in fish. Two rainbow trout isogenic lines, known for their divergent ability to grow on a plant-based diet (PBD), were fed for seven months from first feeding either a fully PBD or a control marine-resources diet and were compared for their growing and survival capacities over time and their behavioral and stress responses at similar sizes but different ages. Although fish displayed similar appetitive behaviour, the two lines were highly affected by the PBD translated in decreased growth and apathetic behaviour, but also stronger stress responses displayed by stronger cortisol increases and more stress-related behaviour when isolated. The two lines were found to be similarly sensitive to a PBD for the assessed stress-related parameters, but one line displayed a lower survival during the early rearing period. Overall, these results suggest that a PBD supplied to fish from the alevin stage has strong effects on physiological and behavioural parameters, with possible impairment of fish welfare, but also genome-dependent survival.

Changes in vertebral structure during growth of reared rainbow trout, Oncorhynchus mykiss (Walbaum): a new approach using modelling of vertebral bone profiles.

Severe bone resorption of the vertebral body in reared rainbow trout was thought to be a dysfunction in mineral balance induced by increased growth rate in unfavourable rearing conditions. To verify this assumption, we sampled market-sized trout (c. 250 g) from 20 fish farms with different rearing conditions. Growth rate was also studied by sampling trout reared in three different water temperatures from fry to market-size. Transverse sections of vertebrae were microradiographed, then digitized. Total bone area (Tt-B.Ar.) and bone profiles were obtained using BONE PROFILER 3.23 software and a mathematical model was developed to statistically compare bone profiles using 12 parameters in four vertebra regions. Tt-B.Ar. and bone profiles were found to vary with rearing conditions and growing temperatures, indicating obvious influences of these factors on bone remodelling. However, vertebral resorption was found to be a general phenomenon. In trout from 190 to 235 mm in length, vertebrae underwent important remodelling resulting in large resorption of the middle area, while the transition and peripheral areas showed an increase in bone deposition. Changes in vertebra architecture seem to be a good compromise between the need to mobilize stored minerals during growth while maintaining vertebral biomechanical properties.

To what extent should we lower HbA1c in diabetic subjects?

Current recommendations regarding glycemic control suggest that HbA(1c) should be lower than 6.5%. This is supported by data regarding microvascular disease, namely retinopathy rather than nephropathy. The question is not completely solved regarding cardiovascular diseases, where a strategy of very low HbA(1c) ("the lower the better") is expected to be effective. Some ongoing studies will help to answer these unsolved questions.

Selection for growth in brown trout increases feed intake capacity without affecting maintenance and growth requirements.

The correlated responses in feed intake and G:F ratio with selection for increased growth rate were evaluated by comparing selected (S) and control (C) brown trout (Salmo trutta) reared under conditions known to affect feed efficiency: feed restriction and periods of compensatory growth. Nitrogen and energy requirements for maintenance and growth were also measured. Trout were allotted at comparable BW (3.7+/-0.06 and 3.8+/-0.04 g, for C and S respectively) to triplicate groups per treatment. The experiment lasted a total of 198 d, during which animals were successively submitted to a 116-d feeding phase and fed 10, 30, 50, 70, 100, and 140% of their usual daily ration (UDR), a 35-d phase of food deprivation, and a 47-d refeeding phase. The G:F of C and S were comparable in all experimental conditions tested. During the feeding phase, S grew better than C only when fed 100 and 140% UDR (P < 0.001). This was explained by a higher feed intake capacity. The requirements for growth and maintenance were similar among the lines, which is in agreement with their comparable loss of weight (mean energy loss of -53 and -55 kJ/(kg x d) for C and S, respectively; P > 0.38) observed during the feed deprivation phase and the lack of differences in carcass composition (fat, P > 0.35; protein, P > 0.54). During the refeeding phase, growth performance and G:F were high in all groups. The daily growth coefficient was higher in S than in C (P < 0.001) because of a higher feed intake (P < 0.001). An increase in absolute individual variability in final BW and length was associated with the level of food restriction in both lines; however, it always remained lower in S than in C. In conclusion, fish selected for growth under ad libitum conditions will only exhibit growth superiority when fed diets close to ad libitum, and there was no evidence that selection was associated with an improvement in efficiency of maintenance nor in retention of body tissues.

Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine.

1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N-hydroxymexiletine. 2. Incubations with genetically engineered microsomes indicated that the formation rate of N-hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N-hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N-hydroxymexiletine was decreased 47 and 51% by furafylline, 40 microm and 120 microm, respectively, and decreased 55 and 67% by alpha-naphthoflavone, 1 microm and 3 microm, respectively (all p < 0.05 versus control). 3. The formation rate of N-hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS-mexiletine, r = 0.7827; R-(-)-enantiomer, r = 0.7034; S-(+)-enantiomer, r = 0.7495), CYP2E1 (S-(+)-enantiomer, r = 0.7057) and CYP1A2 (RS-mexiletine, r = 0.5334; S-(+)-enantiomer, r = 0.6035). 4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N-hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2B6) also appear to play a role in the N-oxidation of this drug.

[Blood pressure monitoring in infants with hemangiomas treated with corticosteroids]. / Surveillance tensionnelle des nourrissons traités par corticothérapie générale pour un hémangiome.

INTRODUCTION: Alarming hemangiomas can be successfully treated with corticosteroids. The risk of hypertension is poorly documented in this setting. We conducted a prospective study in infants with hemangiomas treated with orally administered prednisone. PATIENTS AND METHODS: Thirty-seven patients with rapidly growing complicated hemangiomas were enrolled between January 1998 and November 1999. Steroid dosages varied from 1 mg/kg/d to 5 mg/kg/d. Blood pressure measurements were performed first twice a month, then monthly at rest with a Critikon Dynamap device. Hypertension was defined as blood pressure superior to 110/60 mmHg, and borderline if superior to 110/60 mmHg on only one or two measurements. RESULTS: Increased blood pressure was found in seven infants (19 p. 100). One infant had hypertension requiring specific treatment and blood pressure was borderline on six patients at one or two occasions. Cardiac ultrasound examination was performed in five patients revealing two cases of myocardic hypertrophy, which regressed after stopping steroids and without relationship to hypertension. CONCLUSION: Even though the definition of hypertension in still arbitrary in infants, the measurement of blood pressure is necessary when steroid therapy is given for the treatment of hemangiomas. Blood pressure measurement can be difficult in very young children and overestimation is frequent if an inadequate device is used. The exact place of cardiac ultrasound remains to be defined in the management of alarming hemangiomas.

Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans.

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.

Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings.

BACKGROUND AND OBJECTIVE: Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. METHODS: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). RESULTS: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(-)-mexiletine (from 41+/-11 L/h to 28+/-7 L/h) and S-(+)-mexiletine (from 43+/-15 L/h to 29+/-11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. CONCLUSION: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates.

Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates.

The effects of gender, time variables, menstrual cycle phases, plasma sex hormone concentrations and physiologic urinary pH on CYP2D6 phenotyping were studied using two widely employed CYP2D6 probe drugs, namely dextromethorphan and metoprolol. Phenotyping on a single occasion of 150 young, healthy, drug-free women and men revealed that the dextromethorphan: dextrorphan metabolic ratio (MR) was significantly lower (P < 0.0001) in 56 female extensive metabolizers (0.008+/-0.021) compared to 86 male extensive metabolizers (0.020 +/-0.040). Urinary pH was a significant predictor of dextromethorphan: dextrorphan MRs in men and women (P < 0.001). Once-a-month phenotyping with dextromethorphan of 12 healthy young men (eight extensive metabolizers and four poor metabolizers) over a 1-year period, as well as every-other-day phenotyping with dextromethorphan of healthy, pre-menopausal women (10 extensive metabolizers and 2 poor metabolizers) during a complete menstrual cycle, did not follow a particular pattern and showed similar intrasubject variability ranging from 24.1% to 74.5% (mean 50.9%) in men and from 20.5% to 96.2% (mean 52.0%) in women, independent of the CYP2D6 phenotype (P = 0.342). Using metoprolol as a probe drug, considerable intrasubject variability (38.6+/- 12.0%) but no correlation between metoprolol: alpha-hydroxymetoprolol MRs and pre-ovulatory, ovulatory and luteal phases (mean +/- SD metoprolol: a-hydroxymetoprolol MRs: 1.086+/- 1.137 pre-ovulatory; 1.159+/-1.158 ovulatory and 1.002+/-1.405 luteal phase; P> 0.9) or 17beta-oestradiol, progesterone or testosterone plasma concentrations was observed. There was a significant inverse relationship between physiologic urinary pH and sequential dextromethorphan: dextrorphan MRs as well as metoprolol: alpha-hydroxymetoprolol MRs in men and women, with metabolic ratios varying up to six-fold with metoprolol and up to 20-fold with dextromethorphan (ANCOVA P < 0.001). We conclude that apparent CYP2D6 activity is highly variable, independent of menstrual cycle phases, sex hormones, time variables or phenotype. Up to 80% of the observed variability can be explained by variations of urinary pH within the physiological range. An apparent phenotype shift as a result of variations in urinary pH may be observed in individuals who have metabolic ratios close to the population antimode.

[POEMS syndrome revealed by a scleroderma-like skin thickening]. / Syndrome POEMS révélé par un aspect de sclérodermie.

BACKGROUND: POEMS syndrome is a rare form of plasma-cell dyscrasia characterized by the various association of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal component and Skin changes. The most frequent skin changes such as hyperpigmentation, hypertrichosis, scleroderma-like skin thickening and angiomas are not pathognomonic but nearly constant. However, they are rarely isolated. CASE REPORT: A 57-year-old Caucasian woman presented with a 6 month history of skin thickening on both hands and feet, Raynaud's phenomenon and facial telangiectasias. Physical examination on presentation revealed hepatomegaly, signs of a sensorimotor peripheral neuropathy which was demyelinating in type on electrophysiological assessment, and ankle edemas. Initial laboratory investigations revealed a platelet count of 900 000/mm(3), a monoclonal IgG lambda gammapathy. Plasma-cells were slightly increased (10 p. 100 of marrow elements) and full skeletal radiographs showed no focal osteosclerotic or lytic lesion. A diagnosis of POEMS syndrome was made. The patient was treated with tamoxifen, methylprednisolone and plasmapheresis without improvement in polyneuropathy or in skin changes. DISCUSSION: Our patient satisfied the criteria for POEMS syndrome. The most typical feature here was the scleroderma-like skin change, which has been recognized by other authors. But, in the present case, Raynaud's phenomenon, skin thickening and facial telangiectasias were present 6 months before the diagnosis, and initially suggestive of systemic scleroderma, confirmed histologically. The pathogenesis of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network, but an increase in serum Vascular Endothelial Growth Factor (VEGF) levels could well account for other manifestations such as skin thickening.

Clinical pharmacokinetics of mexiletine.

Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely absorbed following oral administration with a bioavailability of about 90%. Peak plasma concentrations following oral administration occur within 1 to 4 hours and a linear relationship between dose and plasma concentration is observed in the dose range of 100 to 600 mg. Mexiletine is weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 hours). It undergoes stereoselective disposition caused by extensive metabolism. Eleven metabolites of mexiletine are presently known, but none of these metabolites possesses any pharmacological activity. The major metabolites are hydroxymethyl-mexiletine, p-hydroxy-mexiletine, m-hydroxy-mexiletine and N-hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy-mexiletine and m-hydroxy-mexiletine is genetically determined and cosegregates with polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6] activity. On the other hand, CYP1A2 seems to be implicated in the N-oxidation of mexiletine. Various physiological, pathological, pharmacological and environmental factors influence the disposition of mexiletine. Myocardial infarction, opioid analgesics, atropine and antacids slow the rate of absorption, whereas metoclopramide enhances it. Rifampicin (rifampin), phenytoin and cigarette smoking significantly enhance the rate of elimination of mexiletine, whereas ciprofloxacin, propafenone and liver cirrhosis decrease it. Cimetidine, ranitidine, fluconazole and omeprazole do not modify the disposition of mexiletine. Conversely, mexiletine is known to alter the disposition of other drugs, such as caffeine and theophylline. Factors affecting the elimination of mexiletine may be clinically important and dosage adjustments are often necessary.

[Significance of exercise induced ST elevation in patient without a history of previous myocardial infarct]. / Signification d'une élévation du segment ST liée à l'effort chez des patients sans antécédent d'infarctus.

UNLABELLED: Between 1980 and 1995, we observed twenty-five patients (22 males, 3 females) at the mean age of 50.6 +/- 13 years, without previous myocardial infarction who presented exercise induced ST elevation on a bicycle stress test. METHODS: Significant ST elevation was defined as a > or = 1 mm change present in > or = 1 lead measured 0.08 sec after the J point and in 3 consecutive beats. All patients have undergone coronary angiography in the days following the exercise test. RESULTS: Most of patients (56%) presented a history of typical angina that was either purely exertional (8 pts) or also occurred at rest (6 pts). Others (36%) had non typical angina or no angina (8%); 78% of pts were smokers. Sixteen patients (group I) had ST elevation during exercise (exercise duration: 7.6 +/- 4 min; peak heart rate: 135.5 +/- 29 batt/min; ST = 3.5 +/- 1.5 mm) and nine (group II) during the recovery phase (exercise duration 16.3 +/- 1.6 min; p < 0.05; peak heart rate 168 +/- 22 batt/min; p < 0.05; ST: 5.8 +/- 3 mm; p < 0.05). In group I, 1 patient had no vessel disease, 12 had one vessel disease, 3 had multivessel disease with 6 cases of hypersevere coronary stenose (> 90%). In group II, 4 patients had normal coronary arteries, there was one vessel coronary artery disease in 4 patients and multivessel in one subject, without hypersevere coronary stenosis. Correlation between anatomic location of stenosis and electrocardiographic ST elevation was excellent, particularly in case of single vessel disease (100%). All patients underwent one or more new exercise tests after therapeutic intervention (surgery n = 3; angioplasty n = 7; medical treatment n = 15), only 2 patients had persistent exercise induced ST elevation. During follow-up (5 +/- 3 years), 3 patients died (2 cardiac deaths) and 3 had recurrent angina controlled by new treatment. CONCLUSION: Exercise-induced ST elevation is a rare phenomenon in patients without prior myocardial infarction. When occurring purely during exercise, coronary lesions are frequent and often servere, in the other hand ST elevation of the recovery phase is frequently associate with normal arteries or less severe lesions. In most cases, revascularisation or medical therapy can abolish clinical and electrocardiographic abnormalities.

Asymmetric periflexural exanthem of childhood: a clinical, pathologic, and epidemiologic prospective study.

OBJECTIVE: To assess the clinical, pathologic, and epidemiologic features of asymmetric periflexural exanthem of childhood (APEC), a clinically distinctive eruption, especially its link with pityriasis rosea and pattern of transmission. DESIGN: A prospective case series, including an analysis of epidemiologic triggering factors and mode of transmission. Pathologic study, including immunohistochemistry of the inflammatory infiltrate. SETTING: A mixed, community-based referral center. PATIENTS: A total of 37 girls and 30 boys with typical APEC referred from April 1994 to December 1996 were included in the study; 82% came from the greater Bordeaux area in France. INTERVENTION: None. MAIN OUTCOME MEASURE: Possible interhuman transmission of APEC. RESULTS: [corrected] No triggering factor was identified; no interhuman transmission occurred; and no demonstrable link with pityriasis rosea was apparent. Several new clinical variants were recognized or confirmed (high fever, facial and peripheral involvement, prolonged course). Distinctive perisudoral interface CD8+ infiltrate was suggestive of diagnosis. CONCLUSIONS: Interhuman transmission was doubtful, but inoculation disorder was still possible. Histopathologic findings seem more specific than previously thought.

Stereoselective disposition of the antiarrhythmic agent mexiletine during the concomitant administration of caffeine.

Caffeine consumption is extensive in industrialized countries and its role in drug-drug interactions is often overlooked. CYP1A2, the major cytochrome P450 isoform involved in the metabolism of caffeine, has also been implicated in the formation of N-hydroxymexiletine, the major metabolite of mexiletine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition of mexiletine. Fourteen healthy volunteers--10 extensive metabolizers (EMs) and 4 poor metabolizers (PMs) of CYP2D6--received a single 200 mg oral dose of racemic mexiletine hydrochloride on two occasions (1 week apart): once by itself and once during administration of caffeine (100 mg four times daily). Serial blood and urine samples were collected and pharmacokinetic parameters were estimated. Although the total clearance of mexiletine was not significantly altered by the coadministration of caffeine in EMs and PMs, a stereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the partial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucuronide was reduced from 126 +/- 48 mL/min to 106 +/- 32 mL/min and 152.6 (73.4-196.2) mL/min to 109 (77-127) mL/min by the coadministration of caffeine in EMs and PMs, respectively. Consequently, the R/S ratio for urinary recovery and the partial metabolic clearance of mexiletine to N-hydroxymexiletine were 28% lower during the coadministration of caffeine. In conclusion, data obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrations. However, results obtained suggest that CYP1A2 is involved in the formation of N-hydroxymexiletine.

[Classification and management of mastocytosis in the child]. / Classification et prise en charge des mastocytoses de l'enfant.

OBJECTIVE: Mastocytosis is a frequently observed condition in children. We analyzed the initial manifestations and clinical course. PATIENTS AND METHODS: We restrospectively studied 49 cases of mastocytosis in children (29 boys and 20 girls) managed in our unit between 1985 and 1995. All of the children had typical manifestations. Photographic documents were available in all cases. RESULTS: There was pigmentary urticaria in 32 cases and a mastocytoma in 17. Axanthelasmoid aspect and bullae were observed in some cases in both of these clinical forms. Complementary explorations demonstrated one case of duodenal mast cell infiltration. Excepting the case with skin and duodenal manifestation, all of our patients improved and clinical cure was obtained during growth. DISCUSSION: The association of dermal atopia and mastocytosis does not influence the clinical course of these two conditions. The development of bullae does not appear to be a factor of poor prognosis. The xanthelasmoid aspect of the lesions and the similar course in childhood mastocytosis and juvenile xanthogranulma would suggest that a common process with a histological spectrum including mastocytoma and xanthoma is involved. In our experience, counselling against the use of anti-cough medicines containing codeine is an essential part of management. Antihistamine agents may be prescribed for pruritus.