Single-dose pharmacokinetics and pharmacodynamics assessment of oestriol and trimegestone containing vaginal rings in healthy women with childbearing potential.

PURPOSE: To evaluate the pharmacokinetics and pharmacodynamics of oestriol (E3) and trimegestone (TMG) in healthy women after application of three different vaginal rings over 21 days. The vaginal rings had a nominal delivery rate of 0.413/0.050 mg/day (Test 1), 0.311/0.090 mg/day (Test 2) and 0.209/0.137 mg/day (Test 3) E3/TMG. METHODS: Thirty-five healthy women were randomised to receive a single application of Test 1, 2 or 3 (Clinical Trial NCT03343912). The E3 and TMG plasma concentration was determined by LC-MS/MS. Oestradiol (E2) and progesterone (PG) serum concentrations, and bleeding patern were determined as pharmacodynamic parameters. Safety was assessed by evaluation of adverse events and local tolerability. RESULTS: The total and maximum exposure of E3 and TMG increased in a proportional ratio to dose. However, not in a magnitude which was expected from the dose differences for E3. During Test 2 and 3 treatment all E2 and PG values remained on a well suppressed level until end of treatment. E2 and PG serum levels increased distinctly earlier after ring removal with Test 1 compared to Test 2 and 3. Test 3 achieved 95.24% of "no bleeding" days under treatment followed by Test 1 (91.67%), and Test 2 (86.15%). CONCLUSIONS: The Test 3 formulation presented the best dose combination of E3/TMG for contraception. Moreover, all vaginal rings were well tolerated.

Pharmacodynamic evaluation of L-carnitine and piracetam in muscle injury induced by the chronic use of simvastatin.

OBJECTIVES: To evaluate the effect of L-carnitine and piracetam on the muscle injury induced by simvastatin in healthy male subjects during the therapy with oral doses of 10 mL of a solution containing L-carnitine 100 mg/mL + piracetam 80 mg/mL (test group) or placebo (control group) and 40 mg simvastatin once a day during 35 consecutive days. The effect of L-carnitine and piracetam in the reduction of myopathic symptomatology caused by exercise, as well as safety and tolerability were also evaluated. MATERIALS AND METHODS: This study was performed on two different occasions, of which 42 subjects were investigated on occasion 1 and 19 on occasion 2. Discomfort or pain was evaluated according to modified Borg scale. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (γ-GT), creatine kinase (CK), and lactic dehydrogenase (LDH) were evaluated on the 4th, 11th, 18th, 25th, and 32nd day after therapy, and before and until 4 hours after an exercise test performed on a treadmill on day 36. RESULTS: A higher incidence of pain or discomfort was observed in the control group than in the test group, mainly in occasion 1 (29% vs. 62% experienced pain or discomfort in any period, p = 0.0295). The serum levels of AST, ALT, and LDH were statistically different, with lower values in the test group compared to the control group. CONCLUSION: Concomitant use of L-carnitine and piracetam might have a muscle-protective effect and protection against simvastatin-induced myalgia. Furthermore, the formulation was safe and well tolerated by the subjects investigated in this trial.

Bioavailability study of two 81-mg coated tablet formulations of acetylsalicylic acid in fed healthy subjects
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OBJECTIVE: To perform a comparative bioavailability study between a test (re-formulation) and a reference acetylsalicylic acid formulation (Ecasil-81, 81 mg coated tablet) in healthy subjects under fed condition. MATERIALS AND METHODS: Healthy subjects (n = 48) were included in this monocentric, open-label, randomized, two-way crossover pharmacokinetic study. They received a single 81-mg oral dose of a test or a reference formulation of acetylsalicylic acid under fed condition, with a 7-day washout period between the treatments. Blood samples were collected over a period of 36 hours. The salicylic acid plasma concentration was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Pharmacokinetic analysis was performed using WinNonlin software. RESULTS: The geometric mean and 90% confidence interval of test/reference formulation ratios were 109.32% (102.54 - 116.54%) and 106.94% (102.97 - 111.07%) for salicylic acid Cmax and AUC0-last, respectively. Food decreased the AUC and Cmax (p < 0.001) and delayed the tmax (p = 0.0077). The investigated women presented higher AUC0-∞ and Cmax values (p < 0.001) than men. The clinical and laboratory exams did not show significant alterations. CONCLUSION: The re-formulation is bioequivalent to the reference formulation regarding the absorption extent and rate in fed healthy subjects. The administration of acetylsalicylic acid with food decreased its bioavailability. Moreover, differences in salicylic acid disposition related to sex were observed. The treatments were well tolerated by the investigated subjects.

Randomized, double-blind, phase III clinical study of a novel nanotechnological topical anesthetic formulation containing lidocaine 25 mg/g and prilocaine 25 mg/g (nanorap) in skin phototypes I-III patients with ablative fractional CO2 laser treatment indication in the forehead.

BACKGROUND AND OBJECTIVES: Nanotechnology may increase the speed of penetration into the skin. This study evaluated the efficacy, safety, and pharmacokinetics of a novel topical anesthetic nanocapsule formulation (2 g) containing 2.5% lidocaine and 2.5% prilocaine (nanorap-test formulation) compared to placebo (control formulation) in skin types I-III patients of both sexes submitted to the ablative fractional CO2 laser treatment. METHODS: The patients (n = 120) included in this double-blind, single-center, randomized trial, received topical application of 2 g of the test formulation (50 mg lidocaine + 50 mg prilocaine) and placebo on the forehead region. Efficacy was assessed as pain sensation in four quadrants of each side of the forehead using a visual analogue scale immediately (0 min) and at 30, 60, and 90 minutes after laser application compared to placebo. The safety and tolerability of the test product were evaluated based on the occurrence of systemic adverse events as well as the occurrence of immediate and late skin reactions. Pharmacokinetic evaluation was performed in plasma of eight patients using a validated LC-MS/MS method for drugs quantification. RESULTS: Nanorap induced a clinically significant reduction in the pain assessment at all evaluated times (57.2%, 41.6%, 38.6%, and 37.3% at 0, 30, 60, and 90 minutes after drug application, respectively. Mean values of Cmax were 14.20 and 5.36 ng/ml and tmax were 3.5 and 1.8 hour for lidocaine and prilocaine, respectively. No systemic adverse events were observed. CONCLUSION: The nanorap formulation demonstrated a clinically and statistically significant efficacy providing analgesia after the ablative fractional CO2 laser therapy in the investigated patients, when compared to placebo. The product also presented good safety and tolerability. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Capecitabine bioequivalence in healthy volunteers.

Capecitabine is a prodrug and is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors. Clinical and pharmacokinetic studies of capecitabine have been performed in patients with cancer. This study aims to evaluate the bioequivalence of two capecitabine formulations (150-mg tablet) using healthy male subjects under nonfasting conditions. The study was conducted as an open, randomized, three-period, semi-replicated design with three sequences (RRT, RTR, TRR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). A single capecitabine tablet (150 mg) was given in each occasion. Plasma capecitabine concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of capecitabine/Xeloda® (T/R) percent ratio were 104.34% (98.74 - 110.25%) for AUClast, 103.06% (97.48 - 108.96%) for AUCinf, and 104.07% (88.13 - 122.90%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the capecitabine formulation elaborated by Eurofarma Laboratórios Ltda. is bioequivalent to Xeloda® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform capecitabine bioequivalence studies in healthy male subjects.
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Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial.

BACKGROUND: Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. METHODS: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. RESULTS: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95%CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 ± 129 pg/mL before treatment and 241 ± 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 ± 109 pg/mL before treatment, and 168 ± 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95%CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. CONCLUSION: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02632812 . Registered 14 December 2015.

Tolerability of 2.5% Lidocaine/Prilocaine Hydrogel in Children Undergoing Cryotherapy for Molluscum Contagiosum.

The tolerability of a 2.5% lidocaine/prilocaine hydrogel (Nanorap, Biolab Indústria Farmacêutica Ltd., Sao Paulo, Brazil) was evaluated in 20 children ages 2 to 11 years undergoing cryotherapy for molluscum contagiosum (MC). The product was well tolerated, with only two children presenting with eczema at the application site. These adverse reactions were considered unlikely to be related to the test product, because a patch test was negative in one of the individuals and the other event occurred in only one of the two treated areas. Nanorap is an efficacious and well-tolerated option for topical anesthesia in children undergoing cryotherapy for MC.

The role of soluble fiber intake in patients under highly effective lipid-lowering therapy.

BACKGROUND: It has been demonstrated that statins can increase intestinal sterol absorption. Augments in phytosterolemia seems related to cardiovascular disease. OBJECTIVE: We examined the role of soluble fiber intake in endogenous cholesterol synthesis and in sterol absorption among subjects under highly effective lipid-lowering therapy. DESIGN: In an open label, randomized, parallel-design study with blinded endpoints, subjects with primary hypercholesterolemia (n = 116) were assigned to receive during 12 weeks, a daily dose of 25 g of fiber (corresponding to 6 g of soluble fibers) plus rosuvastatin 40 mg (n = 28), rosuvastatin 40 mg alone (n = 30), sinvastatin 40 mg plus ezetimibe 10 mg plus 25 g of fiber (n = 28), or sinvastatin 40 mg plus ezetimibe 10 mg (n = 30) alone. RESULTS: The four assigned therapies produced similar changes in total cholesterol, LDL-cholesterol, and triglycerides (p < 0.001 vs. baseline) and did not change HDL-cholesterol. Fiber intake decreased plasma campesterol (p < 0.001 vs. baseline), particularly among those patients receiving ezetimibe (p < 0.05 vs. other groups), and ß-sitosterol (p = 0.03 vs. baseline), with a trend for lower levels in the group receiving fiber plus ezetimibe (p = 0.07). Treatment with rosuvastatin alone or combined with soluble fiber was associated with decreased levels of desmosterol (p = 0.003 vs. other groups). Compared to non-fiber supplemented individuals, those treated with fibers had weight loss (p = 0.04), reduced body mass index (p = 0.002) and blood glucose (p = 0.047). CONCLUSION: Among subjects treated with highly effective lipid-lowering therapy, the intake of 25 g of fibers added favorable effects, mainly by reducing phytosterolemia. Additional benefits include improvement in blood glucose and anthropometric parameters.

Development and validation of a rapid and sensitive LC-ESI-MS/MS method for ondansetron quantification in human plasma and its application in comparative bioavailability study.

The validation of a high throughput and specific method using a high-performance liquid chromatography coupled to electrospray (ES+) ionization tandem triple quadrupole mass spectrometric (LC-ESI-MS/MS) method for ondansetron quantification in human plasma is described. Human plasma samples were extracted by liquid-liquid extraction (LLE) using methyl tert-butyl ether and analyzed by LC-ESI-MS/MS. The limit of quantification was 0.2 ng/mL and the method was linear in the range 0.2-60 ng/mL. The intra-assay precisions ranged from 1.6 to 7.7%, while inter-assay precisions ranged from 2.1 to 5.1%. The intra-assay accuracies ranged from 97.5 to 108.2%, and the inter-assay accuracies ranged from 97.3 to 107.0%. The analytical method was applied to evaluate the relative bioavailability of two pharmaceutical formulations containing 8 mg of ondansetron each in 25 healthy volunteers using a randomized, two-period crossover design. The geometric mean and respective 90% confidence interval (CI) of ondansetron test/reference percent ratios were 90.15% (81.74-99.44%) for C(max) and 93.11% (83.01-104.43%) for AUC(0-t). Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) and AUC(0-inf), it was concluded that the test formulation is bioequivalent to the reference one with respect to the rate and extent of absorption of ondansetron.

Pharmacokinetics, Pharmacodynamic Efficacy Prediction Indexes and Monte Carlo Simulations of Enrofloxacin Hydrochloride Against Bacterial Strains That Induce Common Clinical Diseases in Broiler Chickens.

Pharmacokinetic parameters and efficacy prediction indexes (Cmax/MIC90 and AUC0-24/MIC90) of an enrofloxacin hydrochloride (ENR-HCl) veterinary product soluble in water were determined in healthy broiler chickens of both sexes after a single oral dose of ENR-HCl (equivalent to 10 mg ENR base/kg bw). Monte Carlo simulations targeting Cmax/MIC90 = 10 and AUC0-24/MIC90 =125 were also performed based on a set of MIC (minimum inhibitory concentration) values of bacterial strains that induce common clinical diseases in broiler chickens and that showed to be susceptible to ENR-HCl. Plasma concentrations of ENR and its main metabolite ciprofloxacin (CIP) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma concentration-time curves were found to fit a non-compartmental open model. The ratio of the area under the plasma concentration-time curve (AUC) of CIP/ENR was 4.91%. Maximum plasma concentrations of 1.35 ± 0.15 µg/mL for ENR-HCl and 0.09 ± 0.01 µg/mL for CIP were reached at 4.00 ± 0.00 h and 3.44 ± 1.01 h, respectively. Areas under the plasma vs. time concentration curve in 24 h (AUC0-24) were 18.91 ± 1.91 h × µg/mL and 1.19 ± 0.12 h × µg/mL for ENR-HCl and CIP, respectively. Using a microbroth dilution method, the minimum inhibitory concentration (MIC90) values were determined for ENR-HCl for 10 bacterial strains (Mycoplasma gallisepticum, Mycoplasma synoviae, Avibacterium paragallinarum, Clostridium perfringens, Escherichia coli, Pseudomonas aeruginosa, Salmonella ser. Enteritidis, Salmonella ser. Gallinarum, Salmonella ser. Pullorum, and Salmonella ser. Typhimurium), which are the most common causes of infectious clinical diseases in broiler chickens. In summary, the PK/PD ratios and Monte Carlo simulation were carried out for ENR-HCl in poultry, which due to its solubility was administered in drinking water. The PK/PD efficacy prediction indexes and Monte Carlo simulations indicated that the ENR-HCl oral dose used in this study is useful for bacterial infections in treating C. perfringens (Gram-positive), E. coli and S. ser. Enteritidis (Gram-negative) and M. gallisepticum bacteria responsible for systemic infections in poultry, predicting a success rate of 100% when MIC ≤ 0.06 µg/mL for E. coli and S. ser. Enteritidis and MIC ≤ 0.1 µg/mL for M. gallisepticum. For C. perfringens, the success rate was 98.26% for MIC ≤ 0.12. However, clinical trials are needed to confirm this recommendation.

Simultaneous determination of losartan and hydrochlorothiazide in human plasma by LC/MS/MS with electrospray ionization and its application to pharmacokinetics.

A method based on a simple liquid-liquid extraction (LLE) followed by high-performance liquid chromatography with negative ion electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) detection was developed for the simultaneous determination of losartan (LOS) and hydrochlorothiazide (HCTZ) in human plasma, using valsartan (VAL) and chlorthalidone (CHTD) as an internal standard, respectively. The acquisition was performed in multiple reactions monitoring (MRM) and the limit of quantification was 4 ng/mL for both LOS and HCTZ. The method was linear in the studied range (4-800 ng/mL for LOS and 4-500 ng/mL for HCTZ). The intra-assay precisions ranged from 2.6-11.9% for LOS and 1.4-8.2% for HCTZ, while the inter-assay precisions ranged from 1.0-8.0% for LOS and 2.5-7.7% for HCTZ. The intra-assay accuracies ranged from 91.3 to 107.6% for LOS and 91.5 to 105.8% for HCTZ, while the inter-assay accuracies ranged from 99.9 to 106.4% for LOS and 97.4 to 101.4% for HCTZ. The analytical method was applied to a bioequivalence study, in which 28 healthy adult volunteers (14 men) received single oral doses (100 mg LOS + 25 mg HCTZ) of reference and test formulations, in an open, two-period, balanced randomized, crossover protocol. Based on the 90% confidence interval of the individual ratios for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference Hyzaar formulation with respect to the rate and extent of absorption of both LOS and HCTZ.

Quantification of estradiol cypionate in plasma by liquid chromatography coupled with tandem mass spectrometry: Application in a pharmacokinetic study in healthy female volunteers.

The combination of medroxyprogesterone acetate 25 mg + estradiol cypionate 5 mg is a highly effective, monthly injectable contraceptive. For the first time, this study presents the development and validation of a sensitive method for estradiol cypionate analysis in human plasma by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Aliquots (500 µL) of plasma were extracted with ethyl ether (100%) and derivatized with dansyl chloride. Its separation was performed on a Jones Chromatography Genesis C8 column and the quantification was performed with a mass spectrometer equipped with an electrospray interface operating in negative ion mode. The run time was 6 min and the calibration curve was linear over the range of 0.005-0.15 ng/mL. The method was applied to evaluate the pharmacokinetics of estradiol cypionate in plasma collected up to 1008 h (42 days) after a single intramuscular administration of 25 mg/mL medroxyprogesterone acetate +5 mg/mL estradiol cypionate to healthy female volunteers (n = 12). The estradiol cypionate maximum plasma concentration (Cmax) was 0.14 ± 0.08 ng/mL reached at 16.83 ± 21.07 h and the area under the plasma concentration versus time curve (AUC0-last) was 14.07 ± 6.32 ng.h/mL. Elimination half-life (t½), apparent volume of distribution (Vd/F), apparent clearance (CL/F) and mean residence time (MRT) were 89.65 ± 76.04 h, 28038 ± 9636 L, 49.02 ± 10.62 L/h and 576.05 ± 238.32 h, respectively, showing that the estradiol cypionate release from the administration site was prolonged and there was no drug accumulation.

Pharmacokinetics of Riluzole in Beagle Dogs.

BACKGROUND: Riluzole is a benzothiazole anticonvulsant used in the treatment of patients with amyotrophic lateral sclerosis and it is being investigated for clinical use in patients with spinal cord injury. The present study evaluated the pharmacokinetics of riluzole in beagle dogs after oral dose administration. METHODS: The oral doses (1.5, 5, 15 and 50 mg/kg) of riluzole were administered to beagle dogs and blood samples were collected from 0 h to 24 h post drug administration. Riluzole was quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). RESULTS: The method was sensitive, precise, accurate and selective to riluzole quantification in plasma of beagle dogs. The pharmacokinetics following oral administration was linear from 1.5 to 15 mg/kg and the t1/2 was 2.16, 1.5, 1.8 and 3.0 h after oral administration of 1.5, 5.0, 15 and 50 mg/kg riluzole. CONCLUSION: The riluzole pharmacokinetics was linear up to 15 mg/kg and had a significantlyshorter t1/2 in beagle dogs than in humans.

Additive effects of plant sterols supplementation in addition to different lipid-lowering regimens.

OBJECTIVE: Plant sterol (PS) supplementation has been widely used alone or combined with lipid-lowering therapies (LLTs) to reduce low-density lipoprotein (LDL) cholesterol. The effects of PS added to high-intensity LLT are less reported, especially regarding the effects on cholesterol synthesis and absorption. METHODS: A prospective, randomized, open-label study, with parallel arms and blinded end points was designed to evaluate the effects of addition of PS to LLT on LDL cholesterol, markers of cholesterol synthesis, and absorption. Eighty-six patients of both genders were submitted to a 4-wk run-in period with atorvastatin 10 mg (baseline). Following, subjects received atorvastatin 40 mg, ezetimibe 10 mg, or combination of both drugs for another 4-wk period (phase I). In phase II, capsules containing 2.0 g of PSs were added to previous assigned treatments for 4 wk. Lipids, apolipoproteins, plasma campesterol, ß-sitosterol, and desmosterol levels were assayed at all time points. Within and between-group analyses were performed. RESULTS: Compared with baseline, atorvastatin 40 mg reduced total and LDL cholesterol (3% and 22%, respectively, P < .05), increased ß-sitosterol, campesterol/cholesterol, and ß-sitosterol/cholesterol ratios (39%, 47%, and 32%, respectively, P < .05); ezetimibe 10 mg reduced campesterol and campesterol/cholesterol ratio (67% and 70%, respectively, P < .05), and the combined therapy decreased total and LDL cholesterol (22% and 38%, respectively, P < .05), campesterol, ß-sitosterol, and campesterol/cholesterol ratio (54%, 40%, and 27%, P < .05). Addition of PS further reduced total and LDL cholesterol by ∼ 7.7 and 6.5%, respectively, in the atorvastatin therapy group and 5.0 and 4.0% in the combined therapy group (P < .05, for all), with no further effects in absorption or synthesis markers. CONCLUSIONS: PS added to LLT can further improve lipid profile, without additional effects on intestinal sterol absorption or synthesis.

Role of kinins and sensory neurons in the rat pleural leukocyte migration induced by Phoneutria nigriventer spider venom.

The leukocyte migration induced by Phoneutria nigriventer spider venom (PNV) has been investigated in rats using the pleurisy model. Intrapleural injection of PNV (10-100 microg/cavity) caused a dose- and time-dependent leukocyte accumulation. The bradykinin B(2) receptor antagonist Hoe 140 (0.5 mg/kg) substantially inhibited PNV-induced cell accumulation, whereas the angiotensin-converting enzyme inhibitor captopril (2 mg/kg) potentiated by 80% this effect. The non-specific kallikrein inhibitor aprotinin and the plasma kallikrein inhibitor soybean trypsin inhibitor greatly reduced PNV-induced leukocyte migration, whereas the selective tissue kallikrein inhibitor P(ac)-F-S-R-EDDnp failed to affect PNV-induced responses. Treatment of rats with capsaicin (50 mg/kg) at the neonatal stage resulted in 67% inhibition of the PNV-induced cell migration. The neurokinin NK(1) receptor antagonist SR140333, but not the NK(2) receptor antagonist SR48968, reduced by 55% venom-induced cell accumulation. We conclude that bradykinin generation is involved in the PNV-induced pleural leukocyte migration in rats, where it can directly activate sensory nerves contributing to a neurogenic inflammatory mechanism.

Comparative bioavailability of two oral formulations of clozapine in steady state administered in schizophrenic volunteers under individualized dose regime.

In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from 4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to 101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h, respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients regarding both the rate and extent of absorption.

Euterpe oleracea (açai) modifies sterol metabolism and attenuates experimentally-induced atherosclerosis.

AIM: Euterpe Oleracea (açai) is a fruit from the Amazon region whose chemical composition may be beneficial for individuals with atherosclerosis. We hypothesized that consumption of Euterpe Oleracea would reduce atherosclerosis development by decreasing cholesterol absorption and synthesis. METHODS: Male New Zealand rabbits were fed a cholesterol-enriched diet (0.5%) for 12 weeks, when they were randomized to receive Euterpe Oleracea extract (n = 15) or water (n = 12) plus a 0.05% cholesterol-enriched diet for an additional 12 weeks. Plasma phytosterols and desmosterol were determined by ultra-performance liquid chromatography and mass spectrometry. Atherosclerotic lesions were estimated by computerized planimetry and histomorphometry. RESULTS: At sacrifice, animals treated with Euterpe Oleracea had lower levels of total cholesterol (p =0.03), non-HDL-cholesterol (p = 0.03) and triglycerides (p = 0.02) than controls. These animals had smaller atherosclerotic plaque area in their aortas (p = 0.001) and a smaller intima/media ratio (p = 0.002) than controls, without differences in plaque composition. At the end of the study, campesterol, ß-sitosterol, and desmosterol plasma levels did not differ between groups; however, animals treated with Euterpe Oleracea showed lower desmosterol/campesterol (p = 0.026) and desmosterol/ ß-sitosterol (p =0.006) ratios than controls. CONCLUSIONS: Consumption of Euterpe Oleracea extract markedly improved the lipid profile and attenuated atherosclerosis. These effects were related in part to a better balance in the synthesis and absorption of sterols.

Riscos e benefícios no uso de ciclosporina / Risks and benefits in cyclosperine use

A ciclosporina (CsA) tem sido utilizada desde a sua descoberta como o principal agente inibidor das reaçöes decorrentes de rejeiçäo a orgäos transplantados em humanos. O processo de rejeiçäo é complexo, e os efeitos colaterais do uso da CsA, hepato e nefrotoxicidade, hiperplasia gengival e alteraçöes na dentinogênese, säo comuns durante a terapia pós-transplante. Embora sejam conhecidos os mecanismos farmacocinético e farmacodinâmico no que diz respeito ao processo de rejeiçäo, há poucas informaçöes conclusivas sobre o quadro odontológico