Influence of NADPH oxidase inhibition on oxidative stress parameters in rat hearts

BackgroundThe aim of this study was to assess whether apocynin, an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase blocker, influences lipid peroxidation TBARS, hydrogen peroxide (H₂O₂) content, protein level, heart edema, tumor necrosis factor a (TNF-α) concentration or the glutathione redox system in heart homogenates obtained from endothelin 1 (ET-1)-induced oxidative stress rats.MethodsExperiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (3 μg/kg b.w., iv); Group III: apocynin (5 mg/kg b.w., iv) administered half an hour before saline; Group IV: apocynin (5 mg/kg b.w., iv) administered half an hour before ET-1 (3 μg/kg b.w., iv).ResultsInjection of ET-1 alone showed a significant (p < 0.001) increase in thiobarbituric acid reactive substances (TBARS) and the hydrogen peroxide level (p < 0.01) vs. control, as well as a decrease (p < 0.001) in the GSH level. Apocynin significantly decreased TBARS (p < 0.001) and H₂O₂ (p < 0.05) level (vs. control) as well as improved protein level (p < 0.001) in the heart. Apocynin also prevented ET-1-induced heart edema (p < 0.05). The presence of ET-1 increased the concentration of TNF-α (p < 0.05) while apocynin decreased it (p < 0.05). Our results indicate that ET-1 may induce oxidative stress in heart tissue by reducing the GSH/GSSG ratio, stimulating lipid peroxidation and increasing TNF-α concentration. Apocynin diminished these measures of oxidative stress and TNF-α.ConclusionET-1-induced formation of ROS in the heart is at least partially regulated via NADPH oxidase.     

Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: Changes in urinary pyrroles levels and motor activity performance

The interference of N-acetylcysteine (NAC) on 2,5-hexanedione (2,5-HD) neurotoxicity was evaluated through behavioral assays and the analysis of urinary 2,5-HD, dimethylpyrrole norleucine (DMPN), and cysteine-pyrrole conjugate (DMPN NAC), by ESI-LC–MS/MS, in rats exposed to 2,5-HD and co-exposed to 2,5-HD and NAC.Wistar rats were treated with 4 doses of: 400 mg 2,5-HD/kg bw (group I), 400 mg 2,5-HD/kg bw + 200 mg NAC/kg bw (group II), 200 mg NAC/kg bw (group III) and with saline (group IV). The results show a significant decrease (p < 0.01) in urinary DMPN and free 2,5-HD, a significant increase (p < 0.01) in DMPN NAC excretion, and a significant recovery (p < 0.01) on motor activity in rats co-exposed to 2,5-HD + NAC, as compared with rats exposed to 2,5-HD alone. Taken together, our findings suggest that at the studied conditions NAC protects against 2,5-HD neurotoxicity and DMPN may be proposed as a new sensitive and specific biomarker of 2,5-HD neurotoxicity in animals treated with a toxic amount of 2,5-hexanedione.     

The beneficial effects of ozone therapy in acetaminophen-induced hepatotoxicity in mice

Background

The aim of the present study was to determine the therapeutic effects of medical ozone therapy on acute acetaminophen (APAP)-induced hepatotoxicity which were not clearly demonstrated in prior studies.

Caffeic acid treatment alters the extracellular adenine nucleotide hydrolysis in platelets and lymphocytes of adult rats

This study evaluated the effects of caffeic acid on ectonucleotidase activities such as NTPDase (nucleoside triphosphate diphosphohydrolase), Ecto-NPP (nucleotide pyrophosphatase/phosphodiesterase), 5′-nucleotidase and adenosine deaminase (ADA) in platelets and lymphocytes of rats, as well as in the profile of platelet aggregation. Animals were divided into five groups: I (control); II (oil); III (caffeic acid 10 mg/kg); IV (caffeic acid 50 mg/kg); and V (caffeic acid 100 mg/kg). Animals were treated with caffeic acid diluted in oil for 30 days. In platelets, caffeic acid decreased the ATP hydrolysis and increased ADP hydrolysis in groups III, IV and V when compared to control (P < 0.05). The 5′-nucleotidase activity was decreased, while E-NPP and ADA activities were increased in platelets of rats of groups III, IV and V (P < 0.05). Caffeic acid reduced significantly the platelet aggregation in the animals of groups III, IV and V in relation to group I (P < 0.05). In lymphocytes, the NTPDase and ADA activities were increased in all groups treated with caffeic acid when compared to control (P < 0.05). These findings demonstrated that the enzymes were altered in tissues by caffeic acid and this compound decreased the platelet aggregation suggesting that caffeic acid should be considered a potentially therapeutic agent in disorders related to the purinergic system.     

Adenosine deaminase activity and immunoglobulin levels as potential systemic biomonitors of occupational hazards and health status in municipal solid waste management workers

Immune status of waste management workers (WMW) with underlying systemic inflammation was assessed to identify useful immune-related biomarkers of occupational health and safety. Clinical history of WMW revealed high prevalence of respiratory symptoms alongside gastrointestinal and musculoskeletal complaints relative to control. Systemic inflammation, characterized by significant (p < 0.001) elevation of erythrocyte sedimentation rate and C-reactive protein, was associated with marked increase in concentration and prevalence of IgA (p < 0.05), IgG (p < 0.01) and adenosine deaminase activity (ADA) (p < 0.01) in WMW. Haematological changes include significant (p < 0.01) increase in lymphocytes, monocytes and total leukocytes. Eosinophils also increased significantly (p < 0.001) while haemoglobin, packed cell volume and neutrophil decreased significantly (p < 0.05). Receiver operating characteristic curve and multivariate analyses revealed ADA (p < 0.002) and IgG (p < 0.05) as important immune markers respectively for assessing sub-clinical effects of occupational exposure. Our data suggest ADA and IgG as useful immune health and safety indicators in WMW.     

A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25–50 mg) in patients with major depressive disorder

A randomised placebo-controlled “dose relation study” was conducted in 549 patients who met the criteria for major depressive disorder, to evaluate the efficacy and safety of three doses regimens of agomelatine during 6 weeks: low fixed dosage (10 mg/day, n=133), fixed dosage (25 mg/day, n=138) and a flexible dosage with up-titration in case of insufficient improvement at week 2 (25–50 mg/day, n=137). At last post-baseline assessment, there were significant and incremental placebo-agomelatine differences on mean HAM-D₁₇ total scores in favour of each agomelatine dose regimen (2.46±0.76 points, p=0.001 at 10 mg; 4.71+0.75 points, p<0.0001 at 25 mg and 4.92±0.76 points, p<0.0001 at 25–50 mg) with statistically significant differences between 25 mg and 25–50 mg dose regimens compared to the 10 mg dose. The response rate according to HAM-D₁₇ was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.1% at 10 mg p=0.005; 25.9% and 27.4% respectively at 25 mg and 25–50 mg, p<0.0001). The benefit of agomelatine was demonstrated in the subgroup of severely depressed patients in the 25 mg and 25–50 mg/day regimens. Consistent clinical response according to CGI variables and better social functioning were found in patients receiving agomelatine. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. This study provides evidence of a dose effect for agomelatine between 10 mg and the therapeutic dose regimen of agomelatine 25–50 mg: the efficacy of the higher dose regimens being more efficacious than the lowest (10 mg) daily dose. The data support a definitive statement regarding the utility of 25 mg as the threshold dose for initiating agomelatine in depressed patients.     

Assessment of toxicological effects of blood microsampling in the vehicle dosed adult rat

Historically, satellite groups are often used for rodent toxicokinetic profiling because of the haematological consequences of blood sampling. If microsampling is shown to be toxicologically benign, its adoption in rat studies would enable comparison of exposure and toxicity in individual animals (as happens in non-rodent studies) as well as obviating need for satellite groups.MethodsGroups of 10 male (200–300 g) and female (150–250 g) rats aged 10 weeks were vehicle dosed and either left unsampled, conventional blood volume sampled (6 × 200 μL) or microsampled (6 × 32 μL) on Days 1 and 14. At termination on Day 15, clinical pathology plus liver and spleen weights and histopathology were obtained.ResultsAll clinical pathology parameters were within background range. However, compared to unsampled controls, conventional volume sampled rats showed a statistically significant (p < 0.001) decrease in haemaglobin, haematocrit and red blood cell count, an increase in reticulocytes (at least p < 0.01), increased AST and GLDH and, in males only, an increase in monocytes and neutrophils. In contrast, microsampled animals showed no changes except for a slight, toxicologically insignificant decrease in haemoglobin concentration (15.0 g/dL compared to the unsampled group mean of 14.4 g/dL) in females (p < 0.05) and a small increase in monocytes (p < 0.05) in males.ConclusionMicrosampling of adult rats is possible without adverse toxicological consequences.     

Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice

The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively. Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0.001), body weight (p < 0.01), circulating insulin and LDL-cholesterol (p < 0.001) and improved insulin sensitivity (p < 0.001) as well as oral and intraperitoneal (p < 0.001) glucose tolerance. Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls. In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle. Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0.001) elevated pancreatic glucagon content. Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0.001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1. Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0.05), body weight (p < 0.05 to p < 0.01), circulating glucose (p < 0.05 to p < 0.01) and insulin (p < 0.05 to p < 0.001) and improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Notably, these beneficial effects were still evident 18 days following cessation of treatment. These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes.     

Potential anti-inflammatory effect of Leea macrophylla Roxb. leaves: A wild edible plant

Leea macrophylla (Leeaceae) is a wild edible plant with ethomedicinal importance as anti-inflammatory agent. However, no systematic studies on its anti-inflammatory activity and mechanisms have been reported. Present study was undertaken to evaluate anti-inflammatory activity of methanol extract of L. macrophylla leaves. Phytochemical investigation revealed presence of sterols, triterpenoids and ascorbic acid in extract. Methanol extract inhibited lipopolysaccharide stimulated production of inflammatory mediators viz. prostaglandin E2, tumor necrotic factor-α, interleukin-6 and interleukin-1β in vitro in mouse peritoneal macrophages. Additionally, the in vivo anti-inflammatory activity of this extract was evaluated by using carrageenan induced paw edema and cotton pellet granuloma assays in experimental rats. Oral administration of extract (100 and 200 mg/kg) exhibited dose dependant inhibition of carrageenan induced inflammation (p < 0.05) and the reduction of the granuloma tissue formation (p < 0.05–0.01). The extract (100 and 200 mg/kg, orally) exhibited significant central and peripheral analgesic activity in hot-plate test (p < 0.01) and acetic acid induced writhing test (p < 0.05–0.01) respectively in experimental mice. Treatment with extract (100 and 200 mg/kg, orally) significantly reduced the yeast provoked elevated body temperature (p < 0.05–0.01) in experimental rats. These results confirmed the traditional anti-inflammatory indication of L. macrophylla leaves.     

Solid lipid nanoparticles as anti-inflammatory drug delivery system in a human inflammatory bowel disease whole-blood model

Standard treatment for inflammatory bowel diseases (IBD) necessitates frequent intake of anti-inflammatory and/or immunosuppressive drugs, leading to significant adverse events.To evaluate the role solid lipid nanoparticles (SLN) play as drug delivery system in enhancing anti-inflammatory activity for drugs such as dexamethasone and butyrate in a human inflammatory bowel diseases whole-blood model. ELISA assay and the peripheral blood mononuclear cell (PBMC) cytokine mRNA expression levels were evaluated by quantitative SYBR Green real-time RT-PCR to determine the IL-1β, TNF-α, IFN-γ and IL-10 secretion in inflammatory bowel diseases patients’ PBMC culture supernatants. There was a significant decrease in IL-1β (p < 0.01) and TNF-α (p < 0.001) secretion, whilst IL-10 (p < 0.05) secretion significantly increased after cholesteryl butyrate administration, compared to that of butyrate alone at the highest concentration tested (100 μM), at 24 h exposure. There was a significant decrease in IL-1β (p < 0.01), TNF-α (p < 0.001) and IL-10 (p < 0.001) secretion after dexamethasone loaded SLN administration, compared to dexamethasone alone at the highest concentration tested (250 nM) at 24 h exposure. No IFN-γ was detected under any conditions and no cytotoxic effects observed even at the highest concentration tested.The incorporation of butyrate and dexamethasone into SLN has a significant positive anti-inflammatory effect in the human inflammatory bowel disease whole-blood model.     

The comparative effects of perindopril and catechin on mesangial matrix and podocytes in the streptozotocin induced diabetic rats

BackgroundHyperglycemia and advanced glucose end substance (AGE) are responsible for excessive reactive oxygen species (ROS) production, which causes oxidative stress in diabetes mellitus. Oxidative stress and high blood pressure may cause injury and glomerulosclerosis in the kidney. End-stage kidney failure induced by glomerulosclerosis leads to microalbuminuria (Ma) in diabetic nephropathy. We investigated the effects of an angiotensin converting enzyme inhibitor (ACEI), perindopril, and an antioxidant, catechin, on podocytes and the glomerular mesangial matrix in experimental diabetic nephropathy using ultrastructural visualization and immunohistochemical staining.MethodsWe compared 5 groups of male adult Wistar albino rats: a control group, an untreated diabetic group, and diabetic groups treated with perindopril, catechin, or catechin + perindopril.ResultsBlood glucose values in all diabetic groups were significantly higher than in the control group (p < 0.001). The body weight in all diabetic groups was significantly lower than in the control group (p < 0.001, p < 0.05). The kidney weight in the catechin + perindopril-treated diabetic group was significantly lower than in the untreated diabetic group (p < 0.001). In all treated diabetic groups, Ma levels decreased significantly (p < 0.001). Mesangial matrix and podocyte damage increased in the untreated diabetic group, but the group treated with catechin + perindopril showed less damage. TGF-beta 1 immunostaining was significantly lower in the catechin-treated and perindopril-treated groups than in the untreated diabetic group (p < 0.001). Catechin was more effective than ACEI in preventing podocyte structure. Podocytes appeared to be the first cells affected in diabetes mellitus. When exposed to hyperglycemia, podocytes caused the mesangial matrix to expand.ConclusionsCatechin and perindopril were more effective in preventing renal corpuscle damage when administered together.     

Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese

Manganese (Mn) can cause manganism, a neurological disorder similar to Parkinson’ Disease (PD). The neurobehavioral and neuroinflammatory end-points in the Mn post exposure period have not been studied yet. Rats were injected on alternate days with 8 doses of MnCl₂ (25 mg/kg) or saline, then euthanized 1, 10, 30 or 70 days following the last dose. Whole-blood (WB) (p < 0.05), urine (p < 0.05) and brain cortical (p < 0.0001) Mn levels were significantly increased 24 h after the last dose. Decreases in the rats’ ambulation were noted 1, 10 and 30 days after the last Mn dose (p < 0.001; p < 0.05; p < 0.001, respectively) and also in the rearing activity at the four time-points (p < 0.05). Cortical glial fibrillary acid protein immunoreactivity (GFAP-ir) was significantly increased at 1, 10, 30 (p < 0.0001) and 70 (p < 0.001) days after the last Mn dose, as well as tumor necrosis α (TNF-α) levels (p < 0.05) but just on day 1. Taken together, the results show that, during the 70-day clearance phase of Mn, the recovery is not immediate as behavioral alterations and neuroinflammation persist long after Mn is cleared from the cortical brain compartment.     

Elucidation of protective efficacy of Pentahydroxy flavone isolated from Madhuca indica against arsenite-induced cardiomyopathy: Role of Nrf-2, PPAR-γ, c-fos and c-jun

BackgroundMadhuca indica J. F. Gmel. (Sapotaceae) is widely used ethnobotanically as anti-diabetic, antipyretic, hepatoprotective, anti-inflammatory and analgesic. It was shown to possess potent anti-apoptotic property.The aim of the studyTo evaluate the possible mechanism of action of isolated phytoconstituent from Madhuca indica Leaves methanolic extract (MI-ALC) on arsenic-induced cardiotoxicity in rats.Materials and methodsThe 3,5,7,3′,4′-Pentahydroxy flavone (QTN) was isolated and characterized by using HPTLC, ¹H NMR, and LC–MS from MI-ALC. QTN (5, 10 and 20 mg/kg, p.o.) was administered in arsenic intoxicated rats (5 mL/kg, p.o.) for 28 days and evaluated for various behavioral, biochemical, molecular and ultra-histological changes.ResultsTreatment with QTN (10 and 20 mg/kg, p.o.) significantly inhibited (p < 0.05) arsenic-induced electrocardiographic, hemodynamic and left ventricular function alterations. Elevated levels of cardiac markers (LDH, CK-MB, AST, ALT, and ALP), altered lipid metabolism (total cholesterol, triglyceride, LDL, HDL, and VLDL) was significantly restored (p < 0.05) by QTN. It also significantly inhibited (p < 0.05) altered cardiac oxido-nitrosative stress, Na-K-ATPase level and mitochondrial enzymes (I–IV) activity after arsenite administration. QTN significantly increased (p < 0.05) myocardial Nrf-2, PPAR-γ and significantly decreased (p < 0.05) myocardial c-fos and c-jun mRNA expressions. Flow cytometric analysis showed that treatment with QTN (10 and 20 mg/kg) significantly inhibited (p < 0.05) arsenite-induce ROS and apoptosis. It also reduced ultra-histological aberrations induced by sodium arsenite.ConclusionAdministration of 3,5,7,3′,4′- Pentahydroxy flavone (i.e. Quercetin (QTN)) isolated from MI-ALC showed significant protection against arsenic-induced oxido-nitrosative stress and myocardial injury via modulation of Nrf2, PPAR-γ, and apoptosis.     

Immunomodulatory effect of diethylcarbamazine citrate plus filarial excretory–secretory product on rat hepatocarcinogenesis

Diethylcarbamazine citrate (DEC) had a significance in anti-filarial chemotherapy, while excretory–secretory product (ES) is released from adult filarial females. The target of the current study was to examine the immunomodulatory effect of DEC, Setaria equina ES or a combination of them on rat hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN). In vitro effect of combined DEC and ES or ES alone on lipopolysaccharide (LPS)-stimulated rat peripheral blood mononuclear cells (PBMCs) was tested through IFN-γ assay in culture supernatants. In addition, single or repeated doses of DEC, ES or DEC + ES have been applied in white albino rats to test the effect on HCC. Levels of IFN-γ and anti-ES IgG antibodies in rat serum were assayed using ELISA. Hemolytic complement activity (CH₅₀) was determined in serum while the concentration of nitric oxide (NO) was assayed in liver tissue. The infiltration of NK cells as well as the expression of MHC Iproliferating cell nuclear antigen (PCNA), inducible NO synthase (iNOS), Bcl2 and p53 were determined using immunohistochemistry. There was a dose-dependent increase in IFN-γ after in vitro exposure to DEC + ES. Repeated ES doses increased NO concentration (p < 0.05) and expression of iNOS but reduced CH₅₀ (p < 0.001), while repeated DEC + ES doses could increase anti-ES IgG (p < 0.01), IFN-γ level (p < 0.05) and NK cell infiltration. The same treatments could also reduce the expression of MHC I expression, PCNA, Bcl2 and p53. This study has shown immunomodulatory and protective effects of DEC + ES repeated doses on rat HCC.     

Exposure of mice to benzo(a)pyrene impairs endometrial receptivity and reduces the number of implantation sites during early pregnancy

Benzo(a)pyrene (BaP) is a ubiquitous environmental pollutant. Studies have demonstrated it to be an endocrine-disrupting chemical that can cause adverse effects on the female reproductive system. However, the effect of BaP on early pregnancy has not been reported. We investigated the effect of BaP on endometrial receptivity and embryo implantation. Pregnant mice were dosed with BaP at 0.2, 2 and 20 mg/kg/day from day 1 (D1) to day 5 (D5) of gestation. Exposure to BaP impaired the morphology of the endometrium and decreased the number of implantation sites (p_0.2 = 0.006, p₂ = 0.167, p₂₀ = 0.003). Levels of estrodiol (p < 0.001, for three treatment group compare with control group) and progesterone-4 in plasma were elevated in BaP-treatment groups (p_0.2 < 0.001, p₂ < 0.001, p₂₀ = 0.032). Expression of estrogen receptor-α was up-regulated (p_0.2 = 0.002, p₂ = 0.131, p₂₀ = 0.024) whereas expression of the progesterone receptor was down-regulated (p_0.2 < 0.001, p₂ = 0.064, p₂₀ = 0.021). Levels of receptivity-related genes HoxA10 (p_0.2 < 0.001, p₂ = 0.135, p₂₀ < 0.001) and E-cadherin (p_0.2 = 0.002, p₂ = 0.624, p₂₀ = 0.137) were changed by BaP. These results revealed that BaP can disrupt the balance of estrogen and progesterone, influence expression of their receptors and downstream related genes, lead to changes in endometrium receptivity, and reduce of the number of implantation sites.     

Dietary fatty acid content influences the expression of genes involved in the lipid turnover and inflammation in mouse colon and spleen

BackgroundDietary interventions can improve gastrointestinal (GI) symptoms. We determined the effects of fatty acids (FAs) supplementation with medium- and long-chain saturated FAs on mouse GI motility and correlated them with the expression of genes for free FA receptors (FFAR)1-4, FA binding protein 4 (FABP4) and inflammation.MethodsForty-eight BalbC were assigned to: standard diet (STD), diet rich in medium-chain saturated FAs (COCO) and long-chain saturated FAs (HF) (7% by weight). Body weight (BW) and food intake (FI) were monitored for 8-weeks. GI motility was determined by fecal pellet output (FPO) and colon bead expulsion tests. FABP4 inhibitor, BMS309403 (1 mg/kg, ip) was injected to half of each group 2 days/week. mRNA expression of FABP4, (FFAR)1-4, and pro-inflammatory cytokines were measured in colonic and splenic tissues using real-time PCR.ResultsCOCO and HF decreased FI. COCO accelerated overall GI transit (p < 0.05). COCO increased the mRNA expression of FFAR2 (p < 0.001) and TNFα (p < 0.01); HF increased the expression of FABP4 and FFAR4 (p < 0.05), and FFAR2 (p < 0.001) in the colon, and decreased FFAR1 and FFAR4 (p < 0.001), TNFα (p < 0.01) and IL-1β (p < 0.05) in splenic tissues. BMS309403 decreased the FI and delayed colonic transit in STD+BMS and COCO+BMS vs. STD (p < 0.05). HF+BMS increased colonic expression of FFAR3 (p < 0.01), TNFα (p < 0.01), IL-6 (p < 0.01), and reduced FFAR4 (p < 0.05); COCO + BMS decreased TNFα (p < 0.01).ConclusionDiversification in the dietary lipid content affected GI motility in mice and the expression of FFARs and pro-inflammatory cytokines in vivo.     

Nimodipine can improve cerebral metabolism and outcome in patients with severe head trauma

In the present study, the effect of nimodipine was investigated in a patient with severe head trauma. Nimodipine was administered into the peripheral vein to prevent secondary neuronal damages in patients. The five patients in control group were treated according to the standard procedures without nimodipine. Other five patients in nimodipine group were treated with standard procedures plus nimodipine. Cerebral perfusion pressure (CPP), intracranial pressure (ICP), jugular venous oxygen saturation (SjvO₂), jugular lactate and glucose levels were measured. Additionally, all patients were evaluated with Glascow outcome score (GOS) before discharge. It was found that CPP (p < 0.05) and SjvO₂ (p < 0.05) were significantly higher; but, ICP (p < 0.001), jugular lactate (p < 0.05) and jugular glucose (p < 0.05) were lower in nimodipine than that of control groups. Again, GOS values were significantly higher in nimodipine than that of control groups (p < 0.05). Results of this study revealed that nimodipine can improve cerebral metabolism and outcome in patient with severe head trauma. Thus, nimodipine may be considered as a protective agent against severe head trauma related neuronal injuries.     

Reporting of cigar use among adolescent tobacco smokers

IntroductionWith the changing landscape of tobacco products, the divide between cigarettes and cigars is obscured, so understanding adolescent reporting of cigar use is needed to improve best practices for surveillance, screening, and prevention/intervention. This study examined adolescents' reported cigar use and correlates of use.MethodsParticipants (N = 186) were 13–17 year old tobacco users participating in a prospective study of adolescent smoking behaviors. Measurement occurred at baseline and 24-months, and included demographics, nicotine dependence, tobacco use, and quit attempts. Cigar use was assessed as, “have you smoked a cigar in the last 30 days” and by brand specific use in the past 30 days.FindingsCigar use was reported by 51 adolescents (27%), and increased to 76 (41%) when identifying by brand name. African Americans (32%) were more likely to smoke cigars than whites (10%, p < .01), Asian/Pacific Islanders (3%, p = .04), and multiracial participants (24%, p = .05). Cigarette-only users smoked more per day (p = .04) and had higher cotinine levels (p = .05) than cigar users. Number of prior quit attempts (p = .84) did not differ by group. Group differences in addiction were found between cigar users and cigarette only users (p < .01). At 24 months, more baseline cigar users were tobacco abstinent than cigarette only users (16% versus 7%, p < 0.01, respectively).ConclusionsAssessment of brand-specific cigars nearly doubled the reporting among adolescent users. Cigar users differed from cigarette-only users in consumption and likelihood of abstinence at 24-months. For more accurate surveillance and to inform treatment considerations, surveys of adolescent tobacco use should include cigars, including brand names, in the assessment strategy.     

First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo

The response to centrally acting drugs is highly variable between individuals and does not always correlate with plasma drug levels. Drug-metabolizing CYP enzymes in the brain may contribute to this variability by affecting local drug and metabolite concentrations. CYP2D metabolizes codeine to the active morphine metabolite. We investigated the effect of inhibiting brain, and not liver, CYP2D activity on codeine-induced analgesia. Rats received intracerebroventricular injections of CYP2D inhibitors (20 μg propranolol or 40 μg propafenone) or vehicle controls. Compared to vehicle-pretreated rats, inhibitor-pretreated rats had: (a) lower analgesia in the tail-flick test (p < 0.05) and lower areas under the analgesia-time curve (p < 0.02) within the first hour after 30 mg/kg subcutaneous codeine, (b) lower morphine concentrations and morphine to codeine ratios in the brain (p < 0.02 and p < 0.05, respectively), but not in plasma (p > 0.6 and p > 0.7, respectively), tested at 30 min after 30 mg/kg subcutaneous codeine, and (c) lower morphine formation from codeine ex vivo by brain membranes (p < 0.04), but not by liver microsomes (p > 0.9). Analgesia trended toward a correlation with brain morphine concentrations (p = 0.07) and correlated with brain morphine to codeine ratios (p < 0.005), but not with plasma morphine concentrations (p > 0.8) or plasma morphine to codeine ratios (p > 0.8). Our findings suggest that brain CYP2D affects brain morphine levels after peripheral codeine administration, and may thereby alter codeine's therapeutic efficacy, side-effect profile and abuse liability. Brain CYPs are highly variable due to genetics, environmental factors and age, and may therefore contribute to interindividual variation in the response to centrally acting drugs.     

Influence of specific endothelin-1 receptor blockers on hemodynamic parameters and antioxidant status of plasma in LPS-induced endotoxemia

BackgroundThe potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of plasma oxidative stress seen in sepsis. The selective endothelin receptor blockers BQ123 andBQ788 were used to investigate the importance of selective endothelin receptor blockage in modulating oxidative stress during endotoxemia.MethodsThe study was performed on male Wistar rats (n = 6 per group) divided into groups: (1) saline, (2) lipopolysaccharide (LPS) (15 mg\kg)-saline, (3) BQ123 (0.5 mg\kg)-LPS, (4) BQ123 (1 mg\kg)-LPS, (5) BQ788 (3 mg\kg)-LPS. The endothelin receptor type A (ETA-R) or type B (ETB-R) antagonist was injected intravenously 30 min before LPS administration. Blood pressure was monitored and blood was taken before, 90 min and 300 min after saline or LPS administration.ResultsInjection of LPS alone resulted in a decrease in mean arterial pressure (MAP) (p < 0.05), a decrease in ferric reducing ability of plasma (FRAP) value (p < 0.01) and a marked increase in plasma tumor necrosis factor α (TNF-α) and thiobarbituric acid reactive substances (TBARS) (p < 0.001, p < 0.001, respectively). Administration of BQ123 before LPS administration deteriorated MAP in a dose dependent way. Moreover, BQ123 (1 mg\kg) decreased plasma level of TBARS and TNF-α (p < 0.01 and p < 0.05, respectively) and increased FRAP value (p < 0.001). On the contrary, BQ788 prevented LPS-induced decrease in MAP (p < 0.001) and led to a significant reduction in plasma TBARS concentration (p < 0.01).ConclusionOur study showed that blockage of ETB-R during endotoxemia improved blood hemodynamics and decreased plasma lipid peroxidation. Blockage of ETA-R improved plasma antioxidant status and decreased lipid peroxidation and TNF-a production, but it deteriorated hemodynamic conditions.