REDUCAO DA CONCENTRACAO ALVEOLAR MINIMA DO ISOFLURANO E DO SEVOFLURANO PELO SUFENTANIL

Background and Objectives - Inhalational anesthetics have a mild analgesic effect. The reduction of alveolar concentration (MAC) of potent volatile anesthesics by increasing plasma concentrations of opioids is desired in inhalational anesthesia. The purpose of this study was to determine the role of sufentanil in reducing sevoflurane and isoflurane MAC. Methods - Thirty eight adult patients of both genders, physical status ASA I or II, submitted to major abdominal procedures were randomly allocated into two groups. Group I (n = 24) received inahalational anesthesia with sevoflurane and Group II (n = 14) received inhalational anesthesia with isoflurane, both diluted in a mixture of N2O (1 liter) and O2 (0.5 liter). A semi-closed system with CO2 absorber and partial reinhalation was used. Ventilation was mechanically controlled. Sufentanil infusion was administered aiming at obtaining 0.5 ng.ml-1 of plasma concentration. Sufentanil plasma concentration was previously calculated by a computer software. End-tidal concentrations were obtained through a gas analyzer and measured at 15 minutes (M1), 30 minutes (M2), 60 minutes (M3), 90 minutes (M4) and 120 minutes (M5). Systolic and diastolic blood pressure (SBP and DBP) and heart rate (RR) were measured during the same periods with the addition of M0 (pre-anesthetic period). Hourly consumption of the inhalational anesthetic agent (IAC), extubation time (ET = time between admission to the recovery room and extubation) and stay in the post anesthesia recovery room (PA-RR) were also measured. Results - Type and duration of surgeries were similar for both groups. There were no statistically significant differences in MAC, SBP, DBP, RR, IAC, TE and PA-RR between groups. Systolic blood pressure in group I (sevoflurane) showed differences among periods F = 3.82 p < O.05; (M2 = M3)(M4 = M5) and M1 had a intermediate value. MAC in group I showed differences among periods F = 9.0 p < 0.05; M1 < M3. MAC in group II also showed differences among periods F = 13.03 p < O.05; M1 < (M2,M3,M4,M5). Conclusions - Both groups had similar behavior when associated to sufentanil in major abdominal surgeries. Group II showed a higher cardiac and circulatory stability.

Tempo de latencia e duracao do efeito do brometo de rocuronio no paciente submetido ao transplante renal

Background and Objectives - Successful cadaver kidney transplantation relies on a fast procedure. Patients with chronic renal failure may present with a delayed gastric emptying making it critical a fast tracheal intubation and airway maintenance. Rocuronium a recently introduced nondepolarizing neuromuscular blocker with a fast onset. The aim of this study was to evaluate onset time and duration of rocuronium effects in patients undergoing renal transplantation. Methods - Sixty patients were allocated into two groups of 30: Group R (GR) = patients undergoing renal transplantation and Group N (GN) = patients with normal renal function. All patients were premedicated with oral midazolam (15 mg) and anesthesia was induced with 30 μg.kg-1 alfentanil, 0.3 mg.kg-1 etomidate and 0.6 mg.kg-1 rocuronium injected through a central venous catheter. neuromuscular block was monitored by acceleromyography in the ulnar nerve pathway. The following parameters were evaluated: time between administration of rocuronium and first twitch reduction to 5% after supra-maximal stimulation (T1) (onset time = OT); time for first twitch to return to 25% (clinical duration = R25); time elapsed between 25% and 75% recovery of first twitch (relaxation recovery time = R25-75). Heart rate (HR) and mean blood pressure (MBP) were recorded in 6 moments. Results - Median OT was 31 sec. in GR and 47 sec. in GN. Median R25 was 51.5 min in GR and 33.5 min in GN. Median R25-75 was 28 min in GR and 20 min in GN. MBP and HR were higher in GR. Tracheal intubation conditions were excellent for most patients in both groups. Conclusions - These results open the possibility of 0.6 mg.kg-1 rocuronium being injected through a central venous catheter when a faster onset is needed. Due to wide differences in individual responses, monitoring of neuromuscular block is recommended.

Organophosphate induced delayed neuropathy in genetically dissimilar chickens: Studies with tri-ortho-cresyl phosphate (TOCP) and trichlorfon

Measurements of plasma cholinesterase (pl.ChE), brain cholinesterase (Br.ChE) and brain Neuropathy Target Esterase (Br.NTE) were made in three different lineages of chickens. All birds received toxicants through gavage in a single oral dose between 08:00 and 09:00 h, after overnight fast. Babcock chickens were treated with 800 mg/kg tri-ortho-cresyl phosphate (TOCP) or 80 mg/kg trichlorfon. The TOCP group had 82% Br.NTE inhibition, when compared to the control group, and no birds displayed symptoms of clinical organophosphate-induced delayed neuropathy (OPIDN). Hy-line w36 lineage chickens were given 1600 mg/kg TOCP and despite this higher dose, Br.NTE inhibition was similar that presented by Babcock chickens. Isabrown chickens were given 1600 mg/kg TOCP or 80 mg/kg trichlorfon. At 36 h all trichlorfon treated birds had from 80 to 90% inhibition of Pl.ChE and Br.ChE, when compared to controls. However, Br.NTE was inhibited less than 20%, and there were no clinical signs of OPIDN. All TOCP treated isabrown chickens had more than 80% Br.NTE inhibition while one of them exhibited just light signs of OPIDN, two chickens became totally paralyzed. This finding suggested that chicken strain was important in the appearance of OPIDN. In addition, 70-80% of NTE inhibition was necessary but was not sufficient to produce OPIDN in chickens, since babcock and hy-line w36 chickens exhibited NTE inhibition in the range of 70-80% without clinical signs of OPIDN. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Intravenous versus nebulized ceftazidime in ventilated piglets with and without experimental bronchopneumonia: Comparative effects of helium and nitrogen

Background: Lung deposition of intravenous cephalosporins is low. The lung deposition of equivalent doses of ceftazidime administered either intravenously or by ultrasonic nebulization using either nitrogen-oxygen or helium-oxygen as the carrying gas of the aerosol was compared in ventilated piglets with and without experimental bronchopneumonia. Methods: Five piglets with noninfected lungs and 5 piglets with Pseudomonas aeruginosa experimental bronchopneumonia received 33 mg/kg ceftazidime intravenously. Ten piglets with noninfected lungs and 10 others with experimental P. aeruginosa bronchopneumonia received 50 mg/kg ceftazidime by ultrasonic nebulization. In each group, the ventilator was operated in half of the animals with a 65%/35% helium-oxygen or nitrogen-oxygen mixture. Animals were killed, and multiple lung specimens were sampled for measuring ceftazidime lung tissue concentrations by high-performance liquid chromatography. Results: As compared with intravenous administration, nebulization of ceftazidime significantly increased lung tissue concentrations (17 ± 13 vs. 383 ± 84 μg/g in noninfected piglets and 10 ± 3 vs. 129 ± 108 μg/g in piglets with experimental bronchopneumonia; P < 0.001). The use of a 65%/35% helium-oxygen mixture induced a 33% additional increase in lung tissue concentrations in noninfected piglets (576 ± 141 μg/g; P < 0.001) and no significant change in infected piglets (111 ± 104 μg/g). Conclusion: Nebulization of ceftazidime induced a 5- to 30-fold increase in lung tissue concentrations as compared with intravenous administration. Using a helium-oxygen mixture as the carrying gas of the aerosol induced a substantial additional increase in lung deposition in noninfected piglets but not in piglets with experimental bronchopneumonia. © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Effects of acetylsalicylic acid and acetic acid solutions in VX2 carcinoma cells. In vitro analysis

Purpose: To analyze, in vitro, the effects of acetylsalicylic acid (aspirin) and acetic acid solutions on VX2 carcinoma cells in suspension and to examine the correlation between these effects and neoplastic cell death. Methods: The VX2 tumor cells (107 cells/ml) were incubated in solutions containing differing concentrations (2.5% and 5%) of either acetylsalicylic acid or acetic acid, or in saline solution (controls). Every five minutes, cell viability was tested (using the trypan blue test) and analyzed under light microscopy. Results: Tumor cell viability (in %) decreased progressively and, by 30 minutes, neoplastic cell death had occurred in all solutions. Conclusion: Based on this experimental model and the methodology employed, we conclude that these solutions cause neoplastic cell death in vitro.

Determinação de cetamina em plasma por HPLC: Aplicação em um estudo de farmacocinética de associação medicamentosa em cães

A S(+) cetamina é um fármaco amplamente utilizado na medicina para induzir anestesia e a associação com midazolam é empregada para minimizar seus efeitos adversos. Associações medicamentosas podem resultar em interações farmacocinéticas e a disponibilidade de métodos bioanalíticos para a determinação da cetamina em plasma constitui ferramenta útil para a avaliação do perfil cinético do fármaco administrado isoladamente ou em associação. O presente estudo teve como objetivo o desenvolvimento e validação de um método analítico para determinação da cetamina em plasma por cromatografia líquida de alta eficiência (HPLC) e a investigação do perfil farmacocinético da cetamina em quatro cães hígidos da raça Beagle. A S(+) cetamina (10mg/kg) foi administrada pela veia cefálica em dose única isoladamente (protocolo I) ou associada ao midazolam (0.2mg/kg) (protocolo II) em estudo cruzado com intervalo de uma semana para washout. Amostras seriadas de sangue foram coletadas no intervalo de oito horas e analisadas por HPLC para a avaliação do perfil farmacocinético utilizando modelo bicompartimental. O método bioanalítico apresentou limites de confiança aceitáveis para sua aplicação em estudos de farmacocinética e os parâmetros área sob a curva (ASC0-8), volume de distribuição (Vd), clearance total (Clt), meia vida de eliminação (t/12 ß), constante de eliminação (ß), meia vida de distribuição (t1/2α) e constante de distribuição (α) não mostraram diferenças estatísticas significativas entre os grupos (p < 0.05, Wilcoxon). Os resultados obtidos sugerem que a redução dos efeitos colaterais da cetamina decorrente do uso da associação cetamina-midazolam não está relacionada a alterações no perfil farmacocinético da cetamina.

Mutagenic and genotoxic effect of hydroxyurea

The hydroxyurea, a cytotoxic drug, is the mainly available therapeutical strategy for the treatment of sickle cell disease. This study aimed to evaluate the mutagenic and genotoxic potential of the hydroxyurea through the Salmonella/Microsome assay and micronucleus test in peripheral blood of mice. The doses were evaluated at 29.25-468 μmol/plate in Salmonella/Microsome assay in presence and absence of metabolic activation the drug. In the micronucleus test the doses were evaluated at 12.5; 25; 50; 75 and 100 mg/kg. The results show that hydroxyurea present mutagenic activity in TA98 and TA100 in doses above 117 μmol/plate and 234 μmol/plate respectively. The drug induced a significant increase in the frequency of micronuclei in reticulocytes of mice at concentrations of 50, 75 and 100 mg/kg, compared to negative control (water). These results demonstrated the mutagenic and genotoxic potential of hydroxyurea. © 2011 Santos et al.

Pharmacokinetics of dexmedetomidine administered intravenously in isofluraneanesthetized cats

Objective-To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats. Animals-6 healthy adult domestic female cats. Procedures-Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 X g for 10 minutes at 4°C. The plasma was harvested and stored at -20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography-mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models. Results-A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min·ng/mL and 17.6 ± 1.8 ng/mL, respectively. Conclusions and Clinical Relevance-Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.

Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats

This study reports the effects of dexmedetomidine on the minimum alveolar concentration of isoflurane (MAC iso) in cats. Six healthy adult female cats were used. MAC iso and dexmedetomidine pharmacokinetics had previously been determined in each individual. Cats were anesthetized with isoflurane in oxygen. Dexmedetomidine was administered intravenously using target-controlled infusions to maintain plasma concentrations of 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20ng/mL. MAC iso was determined in triplicate at each target plasma dexmedetomidine concentration. Blood samples were collected and analyzed for dexmedetomidine concentration. The following model was fitted to the concentration-effect data: where MAC iso.c is MAC iso at plasma dexmedetomidine concentration C, MAC iso.0 is MAC iso in the absence of dexmedetomidine, I max is the maximum possible reduction in MAC iso, and IC 50 is the plasma dexmedetomidine concentration producing 50% of I max. Mean±SE MAC iso.0, determined in a previous study conducted under conditions identical to those in this study, was 2.07±0.04. Weighted mean±SE I max, and IC 50 estimated by the model were 1.76±0.07%, and 1.05±0.08ng/mL, respectively. Dexmedetomidine decreased MAC iso in a concentration-dependent manner. The lowest MAC iso predicted by the model was 0.38±0.08%, illustrating that dexmedetomidine alone is not expected to result in immobility in response to noxious stimulation in cats at any plasma concentration. © 2011 Blackwell Publishing Ltd.

Biocompatible microemulsion modifies the pharmacokinetic profile and cardiotoxicity of doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic with a broad antitumor spectrum. However, the clinical use of DOX is limited because of its cardiotoxicity, a dose-dependent effect. Colloidal drug delivery systems, such as microemulsions (MEs), allow the incorporation of drugs, modifying the pharmacokinetic (PK) profile and toxic effects. In this study, we evaluated the PK profile and cardiotoxicity of a new DOX ME (DOX-ME). The PK profile of DOX-ME was determined and compared with that of the conventional DOX after single-dose administration (6mg/kg, intravenous) in male Wistar rats (n = 12 per group). The cardiotoxicity of DOX formulations was evaluated by serum creatine kinase MB (CKMB) activity in both animal groups before and after drug administration. The plasma DOX measurements were performed by high-performance liquid chromatography with fluorescence detection, and the CKMB levels were assayed using the CKMB Labtest® kit. The ME system showed a significant increase in plasma DOX concentrations and lower distribution volume when compared with conventional DOX. Serum CKMB activity increased after conventional DOX administration but was unchanged in the DOX-ME group. These results demonstrate modifications in drug access to susceptible sites using DOX-ME. DOX-ME displayed features that make it a promising system for future therapeutic application. © 2012 Wiley Periodicals, Inc.

High dosage folic acid supplementation, oral cleft recurrence and fetal growth

Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats

Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.68). In animals exposed to gasoline, we observed an increase in AUC0-∞ for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Chirality 25:206-210, 2013. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy

The purpose of this study was to develop a mucoadhesive stimuli-sensitive drug delivery system for nasal administration of zidovudine (AZT). The system was prepared by formulating a low viscosity precursor of a liquid crystal phase, taking advantage of its lyotropic phase behavior. Flow rheology measurements showed that the formulation composed of PPG-5-CETETH-20, oleic acid and water (55, 30, 15% w/w), denominated P, has Newtonian flow behavior. Polarized light microscopy (PLM) revealed that formulation P is isotropic, whereas its 1:1 (w/w) dilution with artificial nasal mucus (ANM) changed the system to an anisotropic lamellar phase (PD). Oscillatory frequency sweep analysis showed that PD has a high storage modulus (G′) at nasal temperatures. Measurement of the mucoadhesive force against excised porcine nasal mucosa or a mucin disk proved that the transition to the lamellar phase tripled the work of mucoadhesion. Ex vivo permeation studies across porcine nasal mucosa exhibited an 18-fold rise in the permeability of AZT from the formulation. The Weibull mathematical model suggested that the AZT is released by Fickian diffusion mechanisms. Hence, the physicochemical characterization, combined with ex vivo studies, revealed that the PPG-5-CETETH-20, oleic acid, and water formulation could form a mucoadhesive matrix in contact with nasal mucus that promoted nasal absorption of the AZT. For an in vivo assessment, the plasma concentrations of AZT in rats were determined by HPLC method following intravenous and intranasal administration of AZT-loaded P formulation (PA) and AZT solution, respectively, at a dose of 8 mg/kg. The intranasal administration of PA resulted in a fast absorption process (Tmax = 6.7 min). Therefore, a liquid crystal precursor formulation administered by the nasal route might represent a promising novel tool for the systemic delivery of AZT and other antiretroviral drugs. In the present study, the uptake of AZT absorption in the nasal mucosa was demonstrated, providing new foundations for clinical trials in patients with AIDS. © 2012 Elsevier B.V. All rights reserved.