NLRP3 inhibition improves maternal hypertension, inflammation, and vascular dysfunction in response to placental ischemia.

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder with end-organ damage that presents after 20 wk of gestation. PE pathophysiology often includes vascular dysfunction and increased inflammation that continues to damage patient health even after PE resolves. Currently, there is no cure for PE beyond delivery of the fetal-placental unit. Previous clinical studies have identified elevated placental NLRP3 expression in patients with PE and suggest NLRP3 as a potential therapeutic target. In this study, we examined the effect of NLRP3 inhibition on PE pathophysiology in the reduced uterine perfusion pressure (RUPP) model rat using MCC950 (20 mg/kg/day) or esomeprazole (3.5 mg/kg/day). We hypothesized that increased NLRP3 in response to placental ischemia impairs anti-inflammatory IL-33 signaling to induce T-helper 17 cell (TH17) and cytolytic NK cell (cNK) activation, which is known to mediate oxidative stress and vascular dysfunction leading to maternal HTN and intrauterine growth restriction. RUPP rats had significantly higher placental NLRP3 expression, maternal blood pressure, fetal reabsorption rate, vascular resistance, oxidative stress, cNKs and TH17s, and decreased IL-33 compared with normal pregnant (NP) rats. NLRP3 inhibition, with either treatment, significantly reduced placental NLRP3 expression, maternal blood pressure, fetal reabsorption rates, vascular resistance, oxidative stress, cNK, and TH17 populations in RUPP rats. Based on our findings, NLRP3 inhibition reduces PE pathophysiology and esomeprazole may be a potential therapeutic for PE treatment.

Genome Sequence of Gordonia rubripertincta Phage Survivors, a Cluster CT Siphovirus.

Bacteriophage Survivors is a siphovirus isolated from Gordonia rubripertincta NRRL B-16540. Survivors has a 45,436-bp genome encoding 69 predicted protein-coding genes, of which 32 have assigned functions. Based on gene content similarity to sequenced actinobacteriophages, Survivors is assigned to phage cluster CT.

Tratamiento de las hepatitis víricas / Treatment of viral hepatitis

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[Prevalence and incidence of hepatitis A in patients with hepatitis B and C]. / Prevalencia e incidencia de la infección por el virus de la hepatitis A en pacientes con hepatitis crónica B y C.

BACKGROUND: Patients with chronic hepatitis are in risk to acquire a fulminant hepatitis associated with hepatitis A virus superinfection. PATIENTS AND METHODS: Antibodies against hepatitis A were study in serum from 353 patients with chronic hepatitis B or C. RESULTS: The prevalence of IgG-HAV antibodies was 81% in chronic hepatitis C patients, and 77% in chronic hepatitis B patients. The presence of anti-HAV antibodies was related to the patients' age. None case of acute hepatitis A in chronic hepatitis patients was detected. CONCLUSIONS: The prevalence of anti-HAV antibodies is high in patients with chronic viral hepatitis but the incidence of the disease is low. Hepatitis A vaccination should do with previously screening.

Quantification of serum hepatitis C virus RNA with daily or standard interferon doses plus ribavirin in nonresponder patients with chronic hepatitis C.

Less than 10% of patients with chronic hepatitis C infected with genotype 1 achieve a sustained response with 12 months of interferon therapy. Viral kinetics studies have shown that HCV may replicate in less than 24 hr, generating over 10(12) copies per day and suggesting the need for more aggressive therapy. The aim of the study was to determine the effect of a higher and daily dosage of IFN-alpha2b plus ribavirin on the viral load and on the response rate in patients infected by genotype 1 and previous nonresponders to interferon. Ten patients with chronic hepatitis C infected with genotype 1 were allocated to receive IFN-alpha2b, 5 MU daily or three times a week for four weeks followed by 5 MU three times a week until week 24 plus ribavirin for the entire period. At week 4 of therapy, a 2 log reduction in HCV RNA levels was achieved in three (60%) patients in the daily group and in one (20%) patient in the three times a week group. At week 24, HCV RNA was negative in four of the five patients in the three times a week group, and three of the four patients in the daily group had a virological response. However, in follow-up, none of these patients experienced a sustained response. The safety of and ability to tolerate the combination therapy was good, anemia being the most common adverse effect. In conclusion, patients previously not responding to interferon achieved a greater virological reduction early in combination therapy compared to a three times a week interferon schedule. However, the virological response at the end of therapy was similar between the two regimens, and no sustained response was observed in any of the treatment groups.

2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide: evaluation of the spin trapping properties.

The 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-l-oxide (EMPO), an easily prepared pyrroline-N-oxide has been tested as a free radical scavenger. Spin adducts of superoxide, hydroxyl radical, and other free radicals were characterized in phosphate buffer at pH 7.0 and 5.6. At pH 7 in phosphate buffer, the EMPO/O(2)(-*) spin adduct was estimated to be about five times more persistent than its DMPO analogue. Furthermore, its decay does not produce the EMPO/HO&z.rad; adduct.

Dose proportionality of reboxetine enantiomers in healthy male volunteers.

Reboxetine is a racemic mixture of FCE 22071 and FCE 21684 enantiomers. The pharmacokinetics of the enantiomers of reboxetine were observed to be linear in male healthy subjects (n = 6) after the administration of 1.5, 3, 4.5 mg dose of reboxetine as solutions. Kinetic analysis was based on chiral HPLC assay of the enantiomers in plasma collected up to 72 h after each administration. C(max) and AUC were more than double for FCE 22071 (C(max): 38.3+/-13.5, 76. 6+/-26.3, 99.8+/-24.1 ng/mL and AUC(infinity): 605.8+/-233.2, 1288. 3+/-796.4, 1780.7+/-669.3 ng. h/mL for 1.5, 3, 4.5 mg, respectively) than for FCE 21684 (C(max): 15.2+/-5.3, 34.6+/-14.0, 43.1+/-12.3 ng/mL and AUC(infinity): 247.0+/-103.9, 529.1+/-278.4, 773.0+/-355.3 ng. h/mL), whatever the administered dose. The half-lives of the enantiomers were similar (FCE 22071: 13.1, 11.0, 12.6 h and FCE 21684: 12.8, 11.2, 12.2 h after 1.5, 3, 4.5 mg, respectively) and not substantially affected by the dose level.

Pharmacokinetics and tolerance of flunitrazepam in neonates and in infants.

OBJECTIVE: To study the pharmacokinetics of flunitrazepam (used for sedation in neonates and infants), to determine the influence of both gestational and postnatal age on the pharmacokinetic parameters, and to analyze the relationship between the hemodynamic parameters and flunitrazepam plasma concentration. METHODS: Flunitrazepam was infused for 20 minutes as a single dose (0.2 mg x kg(-1)) and as multiple doses (0.1 mg x kg(-1)). Six to eight 1-mL blood samples were collected per patient. Flunitrazepam plasma concentration was measured by gas chromatography-mass spectrometry. RESULTS: Thirty-one patients (25 neonates and six infants) were included in the study. Only three of them received multiple doses. After the single dose (n = 28), half-life was 22.6 +/- 7.3 hours, clearance was 0.15 +/- 0.14 L x kg x h(-1), and volume of distribution was 4.6 +/- 4.1 L x kg(-1) (mean +/- SD). Plasma clearance and volume of distribution significantly increased with postnatal age (P < .05), but no pharmacokinetic parameter varied significantly with gestational age. Diastolic blood pressure significantly decreased with increasing flunitrazepam plasma concentrations (P < .05). CONCLUSION: Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants. Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration.

An approach for dose finding of drugs in infants: sedation by midazolam studied using the continual reassessment method.

AIMS: No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score > or =4 (six-point scale) 30 to 60 min after dosing was rated as a success. METHODS: A double-blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6 mg kg(-1) dose range. RESULTS: Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6 mg kg(-1) dose was 81% (95% CI: 78.5 to 84%). The time to reach a score > or =4 was longer than expected and the median duration-time at score > or =4 was shorter (15 min) than expected. CONCLUSIONS: Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6 mg kg(-1) administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.

[Retrospective survey of fluoroquinolone use in children]. / Enquête rétrospective sur l'utilisation des fluoroquinolones en pédiatrie.

BACKGROUND: Fluoroquinolones (FQ) are contraindicated in children because of the risk of cartilage damage. POPULATION AND METHODS: A retrospective survey concerning the use of FQ in children during the first 6 months of 1993 was organized in 1994. One hundred and sixty-seven Heads of pediatric departments were questioned. RESULTS: One hundred and fifty (90%) of those surveyed responded: 62 (41.3%) were FQ prescribers, 83 (55.3%) were non prescribers and five (3.4%) were not able to answer. Among the 62 prescribers of FQ, 17 departments (27%) were not able to indicate the number of prescriptions and 45 departments (73%) reported one to 75 prescriptions during the study period. Twenty-one departments out of the 45 were not able to identify the children treated with FQ. We obtained a group of 104 children aged 9.0 +/- 5.0 years (mean +/- standard deviation [SD]), treated with 165 courses of FQ during 20 +/- 45 days (1-535 days) with concomitant treatments for 132/165 courses (80%). Fifty children (48%) were suffering from cystic fibrosis, 37 children (36%) were not, and, in 17, the diagnosis was not determined (16%). The FQ treatment administered either orally (73%) or intravenously (26%) was ciprofloxacin in 69% of the courses with a 25.1 +/- 7.0 mg/kg/day oral dose (mean +/- SD dose), and a 23.5 +/- 11.4 mg/kg/day intravenous dose, pefloxacin in 23 courses/165 (14%) with a 17.2 +/- 3.8 mg/kg/day dose, ofloxacin in 15 courses/165 (9%) with a 21.0 +/- 11.9 mg/kg/day dose, norfloxacin in 13 courses/165 (8%) with a 25.6 +/- 7.5 mg/kg/day dose. Twenty-one adverse events were reported in 17 children (16%) (11 of them with cystic fibrosis). These were cutaneous events (photosensitivity, cutaneous eruption) in eight courses, rheumatologic events (arthralgia, arthritis) in seven courses and gastrointestinal events (nausea, vomiting, diarrhea) in three courses. CONCLUSION: This survey shows that FQ are prescribed in children although their use is not approved in this age group and that numerous side effects have been recorded. The absence of exhaustive information (due to the retrospective nature of the survey) and the difficulties in interpreting the side effects for which validity and causal assessment have not been worked out according to a standardized method and in the absence of a control group stress the need for a prospective study.

Traumatic abdominal aortic pseudoaneurysm treated with balloon-expandable bifurcated endoprosthesis.

A 22-year-old man came to our institution with upper gastrointestinal bleeding and massive intra-abdominal hemorrhage. His history included an abdominal gunshot, with aortic and multiple intestinal perforations, 9 months before. At the time of the original injury, he was treated elsewhere by primary closure of the aortic laceration and multiple intestinal resections. An aortic pseudoaneurysm was revealed by means of an angiogram of the descending aorta. Conventional surgical procedures were deemed not feasible because of previous abdominal operations, so a balloon-expandable bifurcated endoprosthesis was constructed and inserted into the terminal aorta through the femoral approach, with resolution of the abdominal aortic pseudoaneurysm.

Vigabatrin: placental transfer in vivo and excretion into breast milk of the enantiomers.

AIMS: Vigabatrin is a new antiepileptic medication consisting of a racemic mixture of 50% active S enantiomer and 50% inactive R enantiomer. Since patients suffering from epilepsy may become pregnant, it is important to understand the extent of placental transfer of such medication. METHODS: During steady-state, vigabatrin enantiomer concentrations were measured in maternal and umbilical blood and in breast milk of two patients. RESULTS: The concentration ratios from the umbilical vein to maternal plasma were R:0.068, S:0.16; 4h25 min after drug administration (case 1) and R: 1.39, S: 0.91; 9h after drug administration (case 2). The milk: plasma concentration ratio was lower than 1 at pre dose sampling in both cases, as well as 3 and 6 h post dose in one case. An estimate of the maximum amount of R and S enantiomers of vigabatrin that a suckling infant would ingest in a day is 3.6% and 1% of the weight-adjusted daily dose respectively. CONCLUSIONS: These results would suggest a slow placental transfer of the vigabatrin enantiomers and that the quantity ingested through milk is small.

Isoniazid dose adjustment in a pediatric population.

This retrospective analysis was designed to evaluate the inactivation index (I3) method used to adjust the isoniazid dose during long-term administration in a pediatric population. Before starting on antituberculosis therapy, sixty-one children received one 10 mg.kg-1 isoniazid test-dose (D). The isoniazid and acetyl isoniazid concentrations were measured by high-performance liquid chromatography on a plasma sample collected 3 hours (C3h) after administration. The patients were separated into slow and fast acetylator groups according to the metabolic ratio. The dose adjustment method using the I3 is based on the assumption that there is a linear correlation between C3h and D [C3h = (I3 x D) - 0.6] in which the slope is I3 and the Y intercept is equal to -0.6 mg.l-1. I3 was determined from a single plasma concentration determination and used to calculate the dose recommended to obtain a desired C3h equal to 1.5 micrograms.ml-1: recommended dose (mg.kg-1) = (1.5 + 0.6)/I3.I3 was significantly higher in the slow acetylator group (0.55 +/- 0.16) than in the fast one (0.26 +/- 0.13), which leads us to recommend a significantly lower dose in the slow acetylator group (4.2 +/- 1.5 mg.kg-1) than in the fast one (10.3 +/- 4.6 mg.kg-1). The data obtained in a subgroup of 21 patients who had at least three consecutive determinations of C3h after different dosages allowed us to verify that there was a linear correlation between C3h and the dose. The mean slope of the correlation lines in that subgroup was 0.61 +/- 0.25 and the 95% confidence interval of the estimated Y-intercept include the theoretical value of -0.60, which shows that our data are consistent with those previously reported in adults. The percentage of patients with a C3h plasma concentration within the expected range (1.5 +/- 0.5 micrograms.ml-1) was significantly higher (69%) in those whose dose was derived from the calculation than in the others (25%). Within each acetylator group, the range of the recommended dose varied widely, and these results emphasize the usefulness of individual dose adjustment based on the inactivation index method.