Fosinopril improves the electrophysiological characteristics of left ventricular hypertrophic myocardium in spontaneously hypertensive rats

This study investigated the effects of fosinopril on the electrophysiological characteristics of the left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHRs). Twenty-four 10-week-old male SHRs were divided into fosinopril and non-fosinopril groups (n?=?12 each). Twelve 10-week-old Wistar–Kyoto rats were used a control group. Left ventricular mass index and ventricular fibrillation threshold (VFT) were measured after 8 weeks of fosinopril or saline treatment. L-type calcium current (I _CaL), sodium current (I _Na), and transient outward potassium current (I _to) were measured in left ventricular myocytes after 8 weeks of fosinopril or saline treatment using the whole-cell patch-clamp technique. VFT was higher in the fosinopril group than in the non-fosinopril group (17.5?±?1.2 mA vs. 15.6?±?1.1 mA, P?<?0.01). The density of I _CaL was lower in the fosinopril group than in the non-fosinopril group (?7.17?±?0.13 pA/pF vs. ?7.87?±?0.13 pA/pF, P?<?0.05). The density of I _to was higher in the fosinopril group than in the non-fosinopril group (14.46?±?0.28 pA/pF vs. 12.66?±?0.25 pA/pF, P?<?0.05). I _to was positively correlated with VFT (r?=?0.90, P?<?0.001) and was found to be associated independently with VFT (P?<?0.001). Fosinopril improves the electrophysiological characteristics of the left ventricular hypertrophic myocardium in SHRs.     

Diorganotin (IV) derivative of 2-thiophene acetic acid: characterizations and biological activities of {[n-Bu2SnO2C–CH2–C4H3S]2O}2

New organotin (IV) derivatives of thiophene acetic acid have been prepared and characterized by IR, ¹H- and ¹³C-NMR spectroscopic techniques. A single crystal of {[n-Bu₂SnO₂C–CH₂–C₄H₃S]₂O}₂ has been synthesized and its cell parameters were measured. It crystallizes in the monoclinic system (P2₁) [a?=?15.1337(7), b?=?12.2587(5), c?=?18.8766(9), and β?=?105.811(5)°]. The compound showed selective inhibitory effect against β-glucuronidase enzyme (IC₅₀ 3.1?±?0.1?μM), which is more potent than our standard, d-saccharic acid 1,4-lactone (IC₅₀ 48.4?±?1.3?μM). Also, it exhibited immunomodulatory activity, and cytotoxicity against PC-3 cell line (IC₅₀?=?16.9?±?1.3?μM, and 1.2?±?0.1?μM, respectively), which are close to the standards ibuprofen (IC₅₀ 11.8?±?1.8?μM), and doxorubicin (IC₅₀ 0.9?±?0.1?μM), respectively. This compound did not show any significant inhibition for other biological test such as α-chymotrypsin, urease, phosphodiesterase enzymes, and antiglycation activity.     

Evaluating the effects of diclofenac sodium and etodolac on renal hemodynamics with contrast-enhanced ultrasonography: a pilot study

Purpose

Contrast-enhanced ultrasonography (CEUS) is a novel approach used for measuring organ perfusion changes. Studies using CEUS to assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on renal blood flow (RBF) have not yet been conducted. We aimed to evaluate the effects of NSAIDs on the renal hemodynamics of healthy subjects with CEUS.

Methods

We performed CEUS using the bolus injection method in a total of 10 healthy subjects. Measurements were completed over two study days in a randomized, crossover manner. On each study day, CEUS was performed twice, before and after the administration of NSAIDs. Subjects received an injection of contrast medium and images were recorded. A region-of-interest (ROI) was selected within the renal cortex, signal intensity in the ROI of the kidney was measured and a time-intensity curve (TIC) was automatically generated with attached software.

Results

The mean (±SD) peak intensity decreased significantly after an administration of diclofenac sodium (from 26.0?×?10^?4?±?17.4?×?10^?4 AU to 19.2?×?10^?4?±?12.0?×?10^?4 AU; P?=?0.022), but not significantly with etodolac (from 26.5?×?10^?4?±?9.7?×?10^?4 AU to 25.9?×?10^?4?±?20.8?×?10^?4 AU; P?=?0.474). The mean (±SD) percent reduction in intensity following diclofenac sodium administration was significantly reduced compared with etodolac administration (22.2?±?20.5 % vs. 3.4?±?8.9 %, P?=?0.037).

Conclusions

These finding suggests that diclofenac sodium (P?=?0.022), but not etodolac (P?=?0.474), affects renal hemodynamics even in healthy subjects.     

Biological activities of the red algae Galaxaura rugosa and Liagora hawaiiana butters

The biological activities; antimicrobial, antioxidant and anticancer, of the red algae Galaxaura rugosa and Liagora hawaiiana were determined. The total ethanol, lipoidal matters, chloroform, n-butanol, aqueous extracts and powder of both algae showed and bacterial and antifungal activities. However, the chloroform extract of Galaxaura rugosa showed antibacterial activity against Klebsiella pneumoniae (24?mm, 0.15?mg/ml) higher than gentamycin (23?mm, 0.49?mg/ml). Moreover, the total ethanol, lipoidal matter and chloroform extracts showed antifungal activity (21, 22 and 25?mm, 1.25, 0.312 and 0.156?mg/ml) similar to the antibiotic Ketoconazole activity (23, 24 and 27?mm, 1.25, 0.312 and 0.156?mg/ml) against Aspergillus fumigatus, A. niger and Candida trobicalis, respectively. A good antioxidant activity (80.96%, IC₅₀?=?27.8?µg/ml) was provided by Galaxaura rugosa. The anticancer activity results revealed that the lipoidal matters of Galaxaura rugosa and Liagora hawaiiana possessed antitumor activity (IC₅₀?=?15?±?1.7 and 21.2?±?1.6, respectively) against lung carcinoma (A-549) better than vinblastine sulfate (IC₅₀?=?24.6?±?0.7). Although, the lipoidal matters of Galaxaura rugosa and Liagora hawaiiana antitumor activity against cervical carcinoma (HeLa) and intestinal carcinoma (CACO-2) (IC₅₀?=?10.2?±?0.6 and 12.2?±?0.6, respectively) preferable than vinblastine sulfate (IC₅₀?=?59.7?±?2.1 and 30.3?±?1.4, respectively).     

EFFECT OF DIETARY FAT REDUCTION AND INCREASED AEROBIC EXERCISE ON CARDIOVASCULAR RISK FACTORS

1. The combined effect of dietary fat reduction and increased aerobic exercise on coronary heart disease (CHD) risk factors was investigated in healthy, normolipidaemic, normotensive, sedentary individuals. 2. After a baseline period of 2 weeks, 21 subjects were randomly allocated to one of two intervention groups (low fat exercise (LFEX) or low fat control (LFQ) for 8 weeks. Both groups were counselled to reduce their dietary fat intake to 20–25% energy from fat. The LFEX group was also required to commence an aerobic exercise programme (4X45 min per week). 3. In both groups, the falls in total cholesterol seen at week 4 were not maintained at the end of the study; however, the LFEX group maintained a fall in low-density lipoprotein (LDL) o. 0.21±0.11 mmol/L. At the end of the study, the LFC group experienced a fall in high-density lipoprotein (HDL)-cholesterol of 0.16±0.05 mmol/L, due to a 0.19±0.07 mmol/L fall in the HDL2 subfraction. The LFEX group experienced no change in HDL (?0.09 ±0.06 mmol/L) or HDL₂ (?0.09 ±0.05 mmol/L). 4. At the end of the study the LFEX and LFC groups experienced a 7±3 and 5±lmmHg fall in systolic blood pressure, respectively, while the LFEX group also observed a 4±2 mmHg fall in diastolic bloo. pressure. 5. The benefits of a low-fat diet combined with aerobic exercise include a reduction in LDL and blood pressure, while maintaining HDL through th. HDL₂ subfraction.     

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat.

2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t_1/2 of 4–5?h) in comparison to ciprofibrate (t_1/2 of 76?h).

3. The area under the plasma drug concentration versus time curve (AUC) _0–24 (μg±?h/ml± SD) for bezafibrate (dose 125mg/kg per day) was 1553±334, which was less than half the value of 3748±358 achieved by ciprofibrate (10?mg/kg per day) after 7 days.

4. Oral administration of ciprofibrate at 10?mg/kg every 48?h produced similar sustained plasma concentrations to those achieved by bezafibrate 125?mg/kg dosed every 12?h. The AUC0–48 values (μg±h/ml±SD) achieved were 5124±450 for bezafibrate compared to 4207±240 for ciprofibrate.

5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.     

Naphthalene Biomarkers and Relationship with Hemoglobin and Hematocrit in White, Black, and Hispanic Adults: Results from the 2003–2004 National Health and Nutrition Examination Survey

Naphthalene is an important contaminant in indoor and outdoor air. Acute overexposure can have toxic effects, resulting in hemolysis. There have been no studies evaluating the impact of environmental exposure on red blood cell indices. We examined 1- and 2-hydroxynaphthalene urinary metabolites (NAP1 and NAP2) in non-Hispanic White, non-Hispanic Black, and Mexican-American adults in the USA and their relationship with hemoglobin (Hb) and hematocrit (HCT). Using the 2003–2004 National Health and Nutrition Examination Survey data, weighted generalized linear regression analyses were used to examine the association between Hb (in grams per deciliter) and HCT (in percent) with NAP1 and NAP2 (per 100,000 ng/L). Beta coefficients ± SE are reported. NAP1 and NAP2 were highest in non-Hispanic Blacks, followed by non-Hispanic Whites, and lowest in Mexican-American adults. There was a positive association between NAP1 and Hb (0.39?±?0.11, p?=?0.0034) and HCT (1.14?±?0.28, p?=?0.0009) after adjusting for age, gender, race, education, and smoking. Stratified analysis by smoking showed similar results with the association being stronger for smokers (Hb 0.63?±?0.23, p?=?0.02; HCT 1.43?±?0.79, p?=?0.09) than nonsmokers (Hb 0.34?±?0.14, p?=?0.03; HCT 1.08?±?0.42, p?=?0.02). The association was also stronger for non-Hispanic blacks (Hb 0.54?±?0.20, p?=?0.02; HCT 1.43?±?0.55, p?=?0.02) than for non-Hispanic whites (Hb 0.37?±?0.18, p?=?0.06; HCT 1.20?±?0.51, p?=?0.03) and was not significant for Mexican-Americans (Hb 0.30?±?1.7, p?=?0.10; HCT 0.99?±?0.52, p?=?0.08). NAP2 was not significantly associated with Hb or HCT. The observed disparity in NAP1 and NAP2 levels by race/ethnicity is consistent with published literature. The origin of these differences in exposure is unclear but may reflect differences in environmental exposure as well as genetic susceptibility. The positive association between NAP1 with HCT and Hb is an unexpected finding. Further research is needed to understand the possible biological mechanisms or other explanations for this association.     

Studies on a new potential dopaminergic agent: in vitro BBB permeability,in vivo behavioural effects and molecular docking evaluation

2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (P_e), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (P_e?=?0.32?±?0.01?×?10^?6?cm/s). Using the Caco-2 cell system, the P_{app AP-BL} in absorptive direction (3.36?±?0.02?×?10^?5?cm/s) was significantly higher than the P_{app BL-AP} in secretive direction (1.75?±?0.07?×?10^?5?cm/s), suggesting a polarized transport. The efflux ratio (P_{app AP-BL}/P_{app BL-AP}?=?0.52?±?0.02) indicated a low affinity of DA-PHEN to efflux carriers. The forced swim test highlighted a reduction of immobility time in both pre-test and test sessions (p?<?0.0001), with an exacerbation in the number of headshakes and divings in the pretest (p?<?0.0001). Morris water maze strengthened the hypothesis that DA-PHEN induces adaptive responses to environmental challenges which are involved on cognitive functions (DA-PHEN versus CTR: escape latency; p?<?0.001; distance swum p?<?0.001, time spent on target quadrant p?<?0.001), without any change in locomotor activity for the administered dose. The molecular docking revealed the interaction of DA-PHEN with the identified D1 site mapping human brain receptor.     

Antimicrobial,antioxidant and anticancer activities of Laurencia catarinensis,Laurencia majuscula and Padina pavonica extracts

The antimicrobial, antioxidant, and anticancer activities of ethanolic extract of Laurencia catarinensis, L. majuscula and Padina pavonica were determined. The highest antibacterial activity; 23.40?±?0.58?mm (00.98?µg/ml) and 22.60?±?2.10?mm (03.90?µg/ml) were obtained against Klebsiella pneumonia by Laurencia catarinensis and Padina pavonica, respectively. However, Padina pavonica showed excellent antibacterial activity against Bacillus subtilis (21.7?±?1.5?mm; 1.95?µg/ml), Staphylococcus aureus (21.7?±?0.58?mm; 1.95?µg/ml), Streptococcus pyogenes (20.7?±?1.2?mm; 1.95?µg/ml) and Acinetobacter baumannii (20.1?±?1.2?mm; 3.9?µg/ml). Moreover, the highest antifungal activity; 24.7?±?2.0?mm (0.98?µg/ml), 23.7?±?1.5?mm (0.98?µg/ml), 23.6?±?1.5?mm (0.98?µg/ml) was obtained by Padina pavonica against Candida tropicalis, C. albicans and Aspergillus fumigatus, respectively. The algal extracts showed DPPH radical scavenging activity in a concentration–dependent manner with maximum scavenging activity (77.6%, IC₅₀?=?5.59?µg/ml and 77.07%, IC₅₀?=?14.3?µg/ml) was provided by Padina pavonica and Laurenica majuscula, respectively. The in vitro antitumor activity revealed that the IC₅₀ values of Padina pavonica were 58.9, 115.0, 54.5, 59.0, 101.0, 101.0, and 97.6?µg/ml; Laurencia catarinensis were 55.2, 96.8, 104.0, 78.7, 117.0, 217.0, 169.0?µg/ml; and Laurencia. majuscula were 115.0, 221.0, 225.0, 200.0, 338.0, 242.0, and 189.0?µg/ml; respectively against A-549 (Lung carcinoma), Caco-2 (Intestinal carcinoma), HCT-116 (Colon carcinoma), Hela (Cervical carcinoma), HEp-2 (Larynx carcinoma), HepG-2 (Hepatocellular carcinoma), and MCF-7 (Breast carcinoma) cell lines.     

Effect of pramlintide as an adjunct to basal insulin on markers of cardiovascular risk in patients with type 2 diabetes

ABSTRACT

Objective: Intensification of insulin therapy in patients with type 2 diabetes, while improving glycemic control, often leads to an increase in body weight and other markers of cardiovascular risk. The effects of pramlintide as an adjunct to basal insulin titration (without mealtime insulin) on glycemia and cardiovascular risk markers were examined.

Research design and methods: This was a post hoc analysis of a 16-week, double-blind, placebo-controlled study in patients with type 2 diabetes (N?=?211) using insulin glargine (without mealtime insulin)?±?oral agents. Patients were randomized to treatment with placebo or pramlintide (60 or 120?µg with major meals), and insulin glargine was titrated to target a fasting plasma glucose concentration of ≥70 to <100?mg/dL.

Main outcome measures: Endpoints included the change from baseline to Week 16 in body weight, high sensitivity C-reactive protein (hsCRP), triglycerides, HDL, LDL, and blood pressure.

Results: Pramlintide-treated patients lost weight and placebo-treated patients gained weight during 16 weeks of treatment (?1.6?±?0.3?kg vs. +0.7?±?0.3?kg, p?<?0.001; mean?±?SE). hsCRP was reduced in pramlintide-treated versus placebo-treated patients (?0.8?±?0.2?mg/L vs. 0.1?±?0.2?mg/L, p?<?0.01; mean?±?SE). Patients with baseline hsCRP?>?3?mg/L (high cardiovascular risk) demonstrated greater hsCRP reductions with pramlintide versus placebo treatment at Week 16 (p?<?0.05). Patients with baseline triglycerides ≥150?mg/dL or ≥200?mg/dL (high cardiovascular risk) showed significant reductions from baseline in triglyceride concentrations with pramlintide (?43?±?14?mg/dL or ?59?±?19?mg/dL; p?<?0.05; mean?±?SE) but not with placebo (1?±?29?mg/dLor ?3?±?54?mg/dL; mean?±?SE). No significant differences between pramlintide and placebo were observed for changes in HDL, LDL, or blood pressure. Pramlintide treatment was generally well tolerated. The most frequent adverse event related to pramlintide was mild-to-moderate nausea (31% pramlintide vs. 10% placebo). Pramlintide added to basal insulin did not increase the incidence of hypoglycemia. A limitation of the study was its relatively short duration.

Conclusions: Pramlintide, as an adjunct to basal insulin, was associated with improvements in several cardiovascular risk markers, warranting long-term clinical studies to determine its potential effects on cardiovascular risk.     

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers

Purpose

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers.

Methods

In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600?mg of icotinib. Plasma was sampled for up to 72?h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS).

Results

Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC_0-∞ and C_max (14.56 ±5.31?h?mg/L and 2.32?±?0.49?μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7?±?6.11 and 3.28?±?0.48, P?=?0.046 and 0.047). The mean CL/F (44.18?±?12.17?L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42?±?9.23?L/h, P?=?0.013).

Conclusions

The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.     

Involvement of serotonin 5-HT3 receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain

Rationale

Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression.

Objectives

This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect.

Methods

Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats.

Results

Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E _max?=?141?±?13 %) and simultaneously decreased NA in the PFC (E_max?=??46?±?7 %). In the local presence into the LC of the α₂-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (E_max?=?157?±?25 %) and PFC (E_max?=?175?±?24 %). Local citalopram (0.1–100 μM) into the LC induced NA increase in the LC (E_max?=?210?±?25 %) and decrease in the PFC (E_max?=??38?±?9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT₃ receptor antagonist MDL72222 (1 μM) but not the 5-HT_1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (E_max?=?158?±?26 %). Local citalopram into the PFC enhanced NA (E_max?=?376?±?18 %) in the area, which was prevented by MDL72222.

Conclusions

The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT₃ receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT₃ receptors and somatodendritic α₂-adrenoceptors in the LC play an important role in the global effect of SSRIs.     

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory

Rationale

The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.

Objectives

To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D₂ receptor occupancy and changes in working memory.

Methods

Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [¹¹C]raclopride and [¹⁸?F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [¹⁸?F]FDG scan.

Results

The mean (±SD) D₂ receptor occupancies were 22.2?±?16.0 % in the 2 mg group, 35.5?±?3.6 % in the 5 mg group, 63.2?±?9.9 % in the 10 mg group and 72.8?±?2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t?=?2.705, df?=?14, p?=?0.017). Greater striatal D₂ receptor occupancy was related to greater decrease in frontal metabolism (r?=??0.659, p?=?0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r?=??0.597, p?=?0.019) under the greatest task load.

Conclusions

Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D₂ receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.     

Comparative extrapyramidal effects of Rauwolfia vomitoria, chlorpromazine and reserpine in mice

Most antipsychotics interfere with the dopaminergic system, resulting in extrapyramidal effects. This study compared the extrapyramidal effects of chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res), used as antipsychotics, in mice. Ninety age-matched male CD-1 strain of mice (25?C33?g body weight) were divided into 3 groups, each consisting of 5 subgroups (n?=?6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0?mg/kg, i.p.) was administered 30?min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0?mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6?mg/kg, i.p.) were administered 24?h before testing. Locomotor behaviour (open field test) and motor coordination (acceleratory rotarod) were assessed. Mice were also observed for 10?min for tremor and vacuous chewing movement (VCM). CPZ and Res dose-dependently decreased locomotor behaviour and impaired motor coordination (p?<?0.01). RV also decreased locomotor behaviour (4.0?mg/kg; p?<?0.05) but had minimal effect on motor coordination. VCM was lower in the RV group (0.17?±?0.16/10?min) than the Res (6.8?±?1.36/10?min) and Cpz groups (7.83?±?1.95/10?min): F _(4,25)?=?10.703; p?<?0.01. The frequency of bouts of tremor was also lower in the RV group (1.17?±?0.72/10?min) than the Res (21.2?±?5.63/10?min) and Cpz (7.83?±?1.59/10?min) groups: F _(4,25)?=?11.012; p?<?0.001. The root bark extract of R. vomitoria, therefore, has great potential in the management of psychotic disorders.     

Fenofibrate and colestipol: Effects on serum and lipoprotein lipids and apolipoproteins in familial hypercholesterolaemia

Summary Effects on serum lipoproteins were studied in ten patients with familial hypercholesterolaemia (FH) during consecutive eight-week treatment periods with fenofibrate 0.3 g/day, fenofibrate plus colestipol, 15 g/day, and fenofibrate 0.25 g/day plus colestipol. VLDL, LDL, HDL, HDL₂, and HDL₃ were isolated by ultracentrifugation and precipitation. Lipids and apolipoproteins A–I and B were determined by enzymatic and immunonephelometric techniques, respectively. Administration of fenofibrate alone resulted in decreases in VLDL and LDL cholesterol (–48% and –18%) and in serum apolipoprotein B (–10%), but in increases in HDL, HDL₂, and HDL₃ (+25%, +26%, and +24%), and in serum apolipoprotein A–I (+6%). Addition of colestipol produced a further reduction in LDL cholesterol (–31%) and in serum apolipoprotein B (–19%). The effects were maintained with less fenofibrate. In FH, an acceptable therapy combines the favourable effects of sufficient lowering of LDL and of a rise in HDL.     

Impaired social behavior in chicks exposed to sodium valproate during the last week of embryogenesis

Rationale and objectives

To evaluate direct exposure to sodium valproate (VPA) during embryogenesis, we administered VPA to chick embryos and examined their social behaviors after hatching.

Methods and results

Embryos treated with VPA (35 μmol/egg) on day 14 were similar to controls for hatching date (day 21) and hatchlings' abilities, such as motor, imprinting, and surface righting. However, these VPA chicks on posthatching day 3 scored significantly low in the chick's social separation stress (SSS) test as follows. Aggregation test evaluated the speed of four chicks, individually isolated by a cardboard in a box, to aggregate upon removal of the cardboards. Belongingness test evaluated the speed of a chick isolated at a corner to join the group of three chicks placed at the opposite corner. Vocalization test for each chick was performed in an isolated corner by using a sound level meter. The results demonstrated that compared with controls, VPA chicks were significantly slow in aggregation (12.7?±?2.5 s vs. 2.9?±?0.9 s, p?=?0.006) and belongingness (3.6?±?0.28 s/40 cm vs. 2.6?±?0.14 s/40 cm, P?=?0.003) and weak in vocalization (13.4?±?2.8 dB/30 s vs. 26.7?±?1.3 dB/30 s, P?=?0.001), respectively. Weight of cerebellum of VAP chick was 15 % lighter than controls (P?=?0.004).

Conclusions

Chick embryos exposed to VPA during the last week of embryogenesis had impaired social behaviors in spite of normal mortar and imprinting ability. The present method will be a useful animal model for assessing the effects of environment during embryogenesis on social behaviors in later life.     

Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial

Purpose

We investigated whether acetaminophen, given at 2?g/day and 3?g/day might potentiate the anticoagulant effect of warfarin.

Methods

Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2?g/day or 3?g/day) or placebo.

Results

The mean maximal INR increase was 0.70?±?0.49 and 0.67?±?0.62 in patients receiving acetaminophen at 2?g/day and 3?g/day, respectively (P?=?0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R ²?=?0.36, P?R ²?=?0.46, P?R ²?=?0.563, P?Conclusion Acetaminophen, at 2?g/day or 3?g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting.     

Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced chronic injury in rats

Abstract

Context: Bovine pancreatic trypsin inhibitor (BPTI) has been reported to relieve liver ischemia-reperfusion-induced injury in rats.

Objective: This study was designed to determine whether the recombinant BPTI (rBPTI) can prevent the chronic liver injury induced by CCl₄ in rats.

Materials and methods: Fifty male Wistar rats were divided into five groups. Rats were treated with 40% CCl₄ at a dose of 2?ml/kg body weight twice a week subcutaneously for 12 weeks. In the 8th week, they were administered intraperitoneally with rBPTI (80 MU/kg), BPTI (80 MU/kg) or hepatocyte growth-promoting factor (pHGF; 100?mg/kg) daily for the next 4 weeks.

Results: rBPTI significantly prevented the disruption of liver function of alanine aminotransferase (ALT; 172.7?±?18.16 versus 141.2?±?15.28, p?=?0.003), aspartate aminotransferase (AST; 225.10?±?36.54 versus 170.06?±?27.14, p?=?0.007) and hydroxyproline (Hyp; 1.14?±?0.27 versus 0.62?±?0.17, p?=?0.001). rBPTI significantly decreased the level of thiobarbituric acid reactive substances (TBARS; 1.15?±?0.16 versus 0.87?±?0.15, p?=?0.003) and increased the activities of superoxide dismutase (SOD; 6.07?±?0.95 versus 7.75?±?1.12, p?=?0.007). rBPTI reduced the production of cytokines of IL-1β and TGF-β. The hepatocyte necrosis, fibrosis, fatty degeneration and inflammatory cell infiltration were ameliorated by rBPTI administration.

Conclusion: This study demonstrated that rBPTI exerted a hepatoprotective effect on chronic liver fibrosis induced by CCl₄, which suggests that rBPTI may have the potential application for chronic liver injury induced by drugs metabolism and toxic substances.     

Cis-resveratrol glucuronidation kinetics in human and recombinant UGT1A sources

1. It was hypothesized that cis-resveratrol glucuronidation contributes to a greater extent to in-vitro disposition of total resveratrol than previously assumed. To this end, the kinetic data for cis-resveratrol glucuronidation are reported.

2. Glucuronidation assays were conducted in human liver and intestinal microsomes and in uridine diphosphate-glucuronosyltransferases (UGTs) UGT1A1, UGT1A6, UGT1A9, and UGT1A10. Kinetic parameters were estimated for the major cis-resveratrol-3-O-glucuronide (cis-R3G). Substrate inhibition was observed with apparent V_max, K_m and K_i of 6.1?±?0.3/27.2?±?1.2 nmol min^?1 mg^?1, 415?±?48.1/989.9?±?92.8 and 789.6?±?76.3/1012?±?55.9?μM in human intestinal microsomes (HIMs) and UGT1A6, respectively (estimate?±?standard error (SE)). Biphasic kinetics were observed in human liver microsomes (HLMs), while sigmoidal kinetics were seen in UGT1A9 (V_max?=?11.92?±?0.2 nmol min^?1 mg^?1; K_m?=?360?μM; n?=?1.27?±?0.07). The 4′-O-glucuronide (cis-R4′G) exhibited atypical kinetics in HLM, HIM, UGT1A1, and UGT1A10. UGT1A9 catalysed cis-R4′G formation at high substrate concentrations (V_max?=?0.33?±?0.015 nmol min^?1 mg^?1; K_m?=?537.8?±?67.8?μM).

3. In conclusion, although the rates of formation of cis-R3G in HLM and UGT1A9 were higher than those for trans-R3G, the contribution to total resveratrol disposition could not be determined fully due to atypical kinetics observed.

     

CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers

Objectives

Pantoprazole is metabolized by cytochrome P450 2?C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated.

Methods

Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug.

Results

Carriers of CYP2C19*2/*2 (n?=?2) were characterized by higher, starting from 3.5?h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n?=?6) volunteers. In subjects with CYP2C19*17/*17 genotype (n?=?6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0?h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n?=?6) and CYP2C19*2/*17 (n?=?6) displayed concentration–time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ_z) by 83.3%, prolongation of terminal half-life (t_?) by 572%, a rise in area under the concentration–time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38?±?1.00?mg?h/L vs 3.00?±?1.02 mg?h/L, p?max (2.13?±?0.42?mg/L vs 1.61?±?0.35?mg/L, p?p?CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68?L/h) and the highest value in subjects with genotype *17/*17 (31.13?L/h).

Conclusion

These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.