Showing papers in "Basic & Clinical Pharmacology & Toxicology in 2013"
TL;DR: The aim of this systematic MiniReview was to identify, assess and summarize the literature investigating the effect of pharmacist-led medication reviews in hospitalized patients, and to design research within this area using rigorous design, large sample sizes and comparable outcome measures for patient health outcomes.
Abstract: Suboptimal medication use may lead to morbidity, mortality and increased costs To reduce unnecessary patient harm, medicines management including medication reviews can be provided by clinical pharmacists Some recent studies have indicated a positive effect of this service, but the quality and outcomes vary among studies Hence, there is a need for compiling the evidence within this area The aim of this systematic MiniReview was to identify, assess and summarize the literature investigating the effect of pharmacist-led medication reviews in hospitalized patients Five databases (MEDLINE, EMBASE, CINAHL, Web of Science and the Cochrane Library) were searched from their inception to 2011 in addition to citation tracking and hand search Only original research papers published in English describing pharmacist-led medication reviews in a hospital setting including minimum 100 patients or 100 interventions were included in the final assessment A total of 836 research papers were identified, and 31 publications were included in the study: 21 descriptive studies and 10 controlled studies, of which 6 were randomized controlled trials The pharmacist interventions were well implemented with acceptance rates from 39% to 100% The 10 controlled studies generally show a positive effect on medication use and costs, satisfaction with the service and positive as well as insignificant effects on health service use Several outcomes were statistically insignificant, but these were predominantly associated with low sample sizes or low acceptance rates Therefore, future research within this area should be designed using rigorous design, large sample sizes and includes comparable outcome measures for patient health outcomes
145 citations
TL;DR: It is suggested that chronic and systemic TNF‐α inhibition reduced depression and anxiety‐like behaviour in the CMS model of depression in rats.
Abstract: Pro-inflammatory cytokines have been proposed to be associated with the pathogenesis of depression. Consistent with this notion, several clinical observations have suggested the antidepressant efficacy of TNF-α inhibitors in patients with chronic inflammatory diseases. In this study, we evaluated the antidepressant and anxiolytic effects of chronic TNF-α inhibitor (infliximab, 5 mg/kg, i.p., weekly) administration in the chronic mild stress (CMS) model of depression. Rats were divided into three groups: saline-control (no stress), saline-CMS, and infliximab-CMS. Rats in the latter two groups were exposed to CMS for 8 weeks. Saline (former two groups) or infliximab was injected weekly during this period. After CMS, total locomotor activity, anxiety-like behaviour and depression-like behaviours were evaluated using automated locomotor activity cage, elevated plus maze (EPM), and sucrose preference (SPT) and forced swimming (FS) tests, respectively. As expected, the saline-CMS group exhibited higher depression-like behaviours in FS and SPT tests compared with the saline-control group. There were no differences between these two groups in terms of the anxiety-like behaviour or total locomotor activity. Infliximab reduced the depression-like behaviour of CMS rats compared with saline-CMS group, and anxiety-like behaviour of CMS rats compared with saline-CMS and saline-control groups. Our findings suggest that chronic and systemic TNF-α inhibition reduced depression and anxiety-like behaviour in the CMS model of depression in rats.
121 citations
TL;DR: Findings indicate that curcumin attenuates HFD‐induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic Steatosis.
Abstract: Curcumin is a well-known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes However, the effect of curcumin on hepatic lipid metabolism remains unclear The aim of this study was to examine the effects of curcumin on hepatic steatosis in high-fat/cholesterol diet (HFD)-induced obese mice Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 015% curcumin (HFD+C) for 11 weeks We found that curcumin significantly lowered the body-weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 005) The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD-induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 005) Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation Moreover, curcumin activated AMP-activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator-activated receptor alpha By contrast, curcumin suppressed the HFD-mediated increases in sterol regulatory element-binding protein-1, acetyl-CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression Taken together, these findings indicate that curcumin attenuates HFD-induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis
101 citations
TL;DR: It is indicated that d‐limonene has antioxidant potential in addition to its antidiabetic effect in experimental diabetes and thereby conferred protection against STZ‐induced diabetic rats.
Abstract: The aim of this study was to evaluate the protective effects of D-limonene on the levels of lipid peroxidation by-products and antioxidant defence systems in the plasma and tissues of normal and streptozotocin (STZ)-induced diabetes rats. The experimental diabetes was induced in rats by a single dose of STZ (40 mg/kg i.p.) injection, and treatment with D-limonene was continued for 45 days. After the treatment period, oxidative stress parameters such as lipid peroxidation by-products; enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase; non-enzymic antioxidants including reduced glutathione, Vitamins C and E were measured in the plasma and tissues of experimental rats. An increase in the levels of lipid peroxidation by-products and significant decrease in antioxidant enzymes were observed in untreated diabetic rats. Administration of D-limonene to diabetic rats for 45 days caused a significant reduction in the levels of lipid peroxidation by-products and an increase in the activities of antioxidant enzymes, when compared with the untreated diabetic group. There was no significant difference in normal treated groups, when compared with normal rats. Biochemical observations were substantiated with the help of histopathological examinations through its antioxidant properties and thereby conferred protection against STZ-induced diabetic rats. The result of this study indicates that D-limonene has antioxidant potential in addition to its antidiabetic effect in experimental diabetes.
95 citations
TL;DR: Administration of kolaviron and sulfasalazine ameliorated DSS‐induced colitis by increasing the antioxidant status decreased hydrogen peroxide and lipid peroxidation levels and attenuated the adverse effect of DSS on colon architecture.
Abstract: The beneficial effects of kolaviron, a natural biflavonoid from the seeds of Garcinia kola, have been attributed mainly to its antioxidant and anti-inflammatory effects. This study investigated these effects on dextran sulphate sodium (DSS)-induced ulcerative colitis in rats. Sulfasalazine served as standard reference in this study. Kolaviron and sulfasalazine were separately co-administered orally at 200 mg/kg and 500 mg/kg, respectively, to dextran sulphate sodium-exposed rats for 5 days. The result indicated that kolaviron or sulfasalazine significantly prevented DSS-induced body weight loss as well as the incidence of diarrhoea and bleeding in DSS-exposed rats. Kolaviron suppressed the DSS-mediated increase in colonic nitric oxide concentration and myeloperoxidase activity and significantly prevented the increase in inflammatory mediators, interleukin-1β and tumour necrosis factor alpha, in the colon of DSS-treated rats. The significant depletion in colonic antioxidant status in rats exposed to DSS alone was evident by marked reduction in colonic catalase and glutathione S-transferase activities as well as glutathione content, leading to elevated hydrogen peroxide and lipid peroxidation levels. Histopathologically, DSS alone resulted in severe epithelial erosion, total absence of goblet cells, destruction of the crypts, necrotic and distorted glands, accompanied by marked cellular mononuclear cells infiltration. However, administration of kolaviron and sulfasalazine ameliorated DSS-induced colitis by increasing the antioxidant status decreased hydrogen peroxide and lipid peroxidation levels and attenuated the adverse effect of DSS on colon architecture. In conclusion, the anti-colitis effect of kolaviron is related to its intrinsic anti-inflammatory and anti-oxidative properties.
86 citations
TL;DR: The results suggest that β‐CD might represent an important tool for improvement of analgesic and anti‐inflammatory profiles of (−)‐linalool and other water‐insoluble compounds, such as lipophilic monoterpenes or essential oils.
Abstract: Many plants produce (-)-linalool, a plant-derived monoterpene alcohol, including members of the Lamiaceae (mints) and Lauraceae family (laurels, cinnamon, rosewood). The anti-inflammatory and analgesic effects of (-)-linalool have been widely suggested for various studies. Poor chemical stability and short half-life restrain the clinical applications of some essential oil and monoterpenes, including (-)-linalool. However, β-cyclodextrin (β-CD) has been used to increase solubility and stability of lipophilic compounds and also to improve the pharmacological effects. In this study, the antinociceptive effect of (-)-linalool and (-)-linalool/β-CD was examined using the acetic acid writhing reflex, formalin and hotplate tests in rodents. (-)-Linalool and (-)-linalool/β-CD demonstrated strong antinociceptive activity in all the chemical- and heat-induced mice models (p < 0.01 or p < 0.001). These findings imply the involvement of both peripheral and central antinociceptive mechanisms. In peritonitis induced by carrageenan, isolated monoterpene or β-CD complex also reduced total leucocyte migration and TNF-α levels in peritoneal fluid. The inclusion complexes, (-)-linalool/β-CD, revealed that the antinociceptive effect was significantly (p < 0.01) improved when compared with (-)-linalool alone. Such results were unlikely to be provoked by any motor abnormality. Together, our results suggest that β-CD might represent an important tool for improvement of analgesic and anti-inflammatory profiles of (-)-linalool and other water-insoluble compounds, such as lipophilic monoterpenes or essential oils.
82 citations
TL;DR: The present observations disclose a novel effect of fumagillin, that is, stimulation of eryptosis, paralleled by Ca2+ entry, ceramide formation, phosphatidylserine exposure and decrease of cell volume.
Abstract: Fumagillin, a cyclohexane isolated from fungus Aspergillus fumigatus, has anti-infective and anti-cancer potency. Fumagillin is at least partially effective by inducing suicidal death or apoptosis. In analogy to apoptosis of nucleated cells, eryptosis is the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide. The present study explored whether fumagillin (5–100 μM) could stimulate eryptosis. To this end, [Ca2+]i was estimated from Fluo3 fluorescence, ceramide by utilizing specific antibodies, cell volume from forward scatter, phosphatidylserine exposure from annexin V binding and haemolysis from haemoglobin release. As a result, a 48-hr exposure to fumagillin significantly increased [Ca2+]i (≥10 μM), enhanced ceramide abundance (100 μM), triggered annexin V binding (≥10 μM) and decreased forward scatter (≥10 μM). Fumagillin exposure was followed by slight but significant increase of haemolysis. Removal of extracellular Ca2+ significantly blunted but did not abolish the effect of fumagillin (100 μM) on annexin V binding. The present observations disclose a novel effect of fumagillin, that is, stimulation of eryptosis, paralleled by Ca2+ entry, ceramide formation, phosphatidylserine exposure and decrease of cell volume.
67 citations
TL;DR: A detailed literature review found that respiratory, cardiovascular and certain neurological presentations are warning signs of severe neonicotinoid intoxication, and the amounts and concentration are not useful guides for the management of intoxicated patients.
Abstract: Neonicotinoids are a new class of insecticides widely applied for crop protection. These insecticides act as agonists at nicotinic acetylcholine receptors, which cause insect paralysis and death. The high specificity for receptors in insects was considered to possess highly selective toxicity to insects and relative sparing of mammals. However, an increasing number of cases of acute neonicotinoid poisoning have been reported in recent years. We reported a man who developed respiratory failure and shock after ingestion of neonicotinoid insecticide. A detailed literature review found that respiratory, cardiovascular and certain neurological presentations are warning signs of severe neonicotinoid intoxication. The amounts of ingested neonicotinoid insecticide and the plasma neonicotinoid concentration are not useful guides for the management of intoxicated patients. Supportive treatment and decontamination are the practical methods for the management of all neonicotinoid-poisoned patients.
58 citations
TL;DR: This study supports the use of sCAMs as potential biomarkers of endothelial activation in inflammatory conditions with a significant positive correlation between the levels of ICAM‐1 and sICAM‐ 1 and between the Levels of VCAM and sVCAM‐2 and sE‐selectin seems promising.
Abstract: Endothelial activation is a pivotal event in the development and progression of inflammation. Central to endothelial activation is the up-regulation of cellular adhesion molecules (CAMs) including E-selectin (CD62E), ICAM-1 (CD54), VCAM-1 (CD106) and PECAM-1 (CD31). These CAMs are also found in soluble forms (sCAMs). In this in vitro study of endothelial activation, we examined whether the levels of sCAMs correlate with the endothelial surface expression of CAMs in a dose-dependent and time-dependent manner. Such a correlation would support the use of sCAMs as surrogate markers for endothelial activation in inflammatory conditions. Human umbilical vein endothelial cells (HUVEC) were cultured with various concentrations of TNF-α for 8 hr and at a fixed concentration of TNF-α for various durations. The levels of soluble and surface-bound E-selectin, ICAM-1, VCAM-1 and PECAM-1 were quantified by flow cytometry. TNF-α stimulation increased CAM and sCAM expression in a dose-dependent and time-dependent manner. There was a significant positive correlation between the levels of ICAM-1 and sICAM-1 and between the levels of VCAM and sVCAM-1 in both the dose–response and time–response experiments. A positive correlation between the levels of E-selectin and sE-selectin was observed in the time–response experiment. This study supports the use of sCAMs as potential biomarkers of endothelial activation. In particular, the use of sICAM-1, sVCAM-1 and sE-selectin seems promising.
54 citations
TL;DR: It is confirmed that extreme metabolizers (poor and ultrarapid metabolizers) incur higher costs than similar patients with a normal metabolizer genotype, but this study shows that these excess costs can be reduced by pharmacogenetic testing.
Abstract: The effect of pharmacogenetic testing for CYP450 2D6 and 2C19 on treatment costs have not yet been documented. This study used Danish patient registers to calculate healthcare costs of treating patients with diagnoses within the schizophrenic spectrum for 1 year with or without pharmacogenetic testing for polymorphisms in the genes for the CYP2D6 and CYP2C19 enzymes. In a randomized, controlled trial, stratified with respect to metabolizer genotype, 104 patients were assigned to treatment based on pharmacogenetic testing and 103 patients to treatment as usual. Random exclusion of extensive and intermediate metabolizers was used to increase the frequency of extreme metabolizers (poor metabolizers and ultrarapid metabolizers for CYP2D6) to 20% in both groups. Cost differences were analysed at several levels including (i) overall healthcare expenditure, (ii) psychiatric hospital cost (iii) nonpsychiatric hospital cost, (iv) primary care spending and (v) pharmaceuticals. Statistically significant differences in costs of psychiatric care dependent on metabolizer status were found between intervention groups. Pharmacogenetic testing significantly reduced costs among the extreme metabolizers (poor metabolizers and ultrarapid metabolizers) to 28%. Use of primary care services and pharmaceuticals was also affected by the intervention.This study confirms earlier findings that extreme metabolizers (poor and ultrarapid metabolizers) incur higher costs than similar patients with a normal metabolizer genotype. However, this study shows that these excess costs can be reduced by pharmacogenetic testing. Pharmacogenetic testing for CYP2D6 and CYP2C19 could thus be considered as a means of curtailing high psychiatric treatment costs among extreme metabolizers.
51 citations
TL;DR: It is suggested that quercetin (Q), a flavonoid largely found in vegetable foods, with known anti-inflammatory and antioxidant properties, may have protective effects by improving liver integrity in NASH.
Abstract: Non-alcoholic steatohepatitis (NASH) is a frequent condition in obese patients that may progress to end-stage liver disease. This study was designed to evaluate the modulation of this condition by use of quercetin (Q), a flavonoid largely found in vegetable foods, with known anti-inflammatory and antioxidant properties, in the experimental model of non-alcoholic steatohepatitis (NASH) using a diet deficient in methionine and choline (MCD). Male C57BL6 mice were divided into four groups (n = 16): (i) Control plus vehicle (control ration plus carboxymethylcellulose 1% used as vehicle, CO + V); (ii) Control ration plus Q 50 mg/kg (CO + Q); (iii) MCD diet plus vehicle (NASH + V); and (iv) MCD diet plus Q (NASH + Q). Diets were administered for 4 weeks. At the end of the experimental period, liver alterations, bioindicators of oxidative stress and DNA damage were assessed. NASH was diagnosed in 100% of the mice that were fed the MCD diet. In addition, a significant increase in DNA damage in liver tissue from NASH + V group was observed in comparison with CO + V. The group NASH + Q showed a significant decrease in hepatic damage enzymes, lipoperoxidation, DNA damage and a lower degree of macrovesicular steatosis, ballooning and inflammatory process. These findings suggest that Q may have protective effects by improving liver integrity in NASH.
TL;DR: Together, the results provide first‐time evidence that this monoterpene attenuates orofacial pain at least, in part, through an activation of CNS areas, mainly retrosplenial cortex and periaqueductal grey.
Abstract: Citronellol (CT) is a monoterpenoid alcohol present in the essential oil of many medicinal plants, such as Cymbopogon citratus. We evaluated the antinociceptive effects of CT on orofacial nociception in mice and investigated the central pathway involved in the effect. Male Swiss mice were pretreated with CT (25, 50 and 100 mg/kg, i.p.), morphine (5 mg/kg, i.p.) or vehicle (saline + tween 80 0.2%). Thirty minutes after the treatment, we injected formalin (20 μl, 2%), capsaicin (20 μl, 2.5 μg) or glutamate (40 μl, 25 μM) into the right limb. For the action in the CNS, ninety minutes after the treatment, the animals were perfused, the brains collected, crioprotected, cut in a criostate and submitted in an immunofluorescence protocol for Fos protein. CT produced significant (p < 0.01) antinociceptive effect, in all doses, in the formalin, capsaicin and glutamate tests. The immunofluorescence showed that the CT activated significantly (p < 0.05) the olfactory bulb, the piriform cortex, the retrosplenial cortex and the periaqueductal grey of the CNS. Together, our results provide first-time evidence that this monoterpene attenuates orofacial pain at least, in part, through an activation of CNS areas, mainly retrosplenial cortex and periaqueductal grey.
TL;DR: Intravenous lipid emulsion was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid‐rich tissues, and in spite of the entrapment, there was no difference in haemodynamics between the groups.
Abstract: Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid(®) (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain amitriptyline concentration by 25% (p = 0.038) and amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial amitriptyline tissue distribution, was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.
TL;DR: Nicorandil protected cardiac tissues against doxorubicin cardiotoxicity as demonstrated from normalization of cardiac biochemical and oxidative stress parameters and amelioration of histopathological changes.
Abstract: Doxorubicin is a chemotherapeutic drug used to treat solid and haematopoietic tumours. Its use is limited by a major side effect of cardiotoxicity. It was reported that doxorubicin-induced cardiotoxicity is mediated through oxidative stress coupled with impaired NO bioavailability and NF-κB activation. Nicorandil, a mitochondrial ATP-dependent potassium (KATP ) channel opener, was reported to be cardioprotective on ischaemic myocardium. However, the effect of nicorandil against doxorubicin-induced cardiotoxicity has not yet been clarified. Accordingly, six groups of rats were used. The first three groups were injected with vehicle, nicorandil (3 mg/kg) orally and doxorubicin (a single intraperitoneal injection of 20 mg/kg), respectively. Group four was treated with nicorandil, whereas group five was treated with glibenclamide and then nicorandil starting 2 days before doxorubicin and continued for five consecutive days. Group six was treated with glibenclamide alone. At the end of the experiment, the rats were killed. Cardiac enzyme indexes were measured in serum. Heart tissues were processed for determination of nitrite/nitrate, NF-κB protein expression, glutathione (GSH), lipid peroxide (TBARS) levels and superoxide production. In addition to body-weight reduction, doxorubicin produced cardiotoxicity as indicated from the increase in lactate dehydrogenase (LDH), creatine kinase (CK) activities, TBARS, superoxide production, NF-κB expression and caspase-3 activity. Moreover, doxorubicin decreased GSH and nitrite/nitrate levels. Histopathological examination of doxorubicin-treated hearts revealed degenerative changes. On the other hand, nicorandil protected cardiac tissues against doxorubicin cardiotoxicity as demonstrated from normalization of cardiac biochemical and oxidative stress parameters and amelioration of histopathological changes. Glibenclamide, a blocker of the KATP channel, reversed most of the cardiac effects of nicorandil.
TL;DR: It is found that caspase‐3 and Bax/Bcl‐2 ratio, two hallmarks of apoptosis, were significantly decreased in the rats pre‐treated with U0126 and PD169316, 7 days after Aβ injection, which reinforces and extends the notion of the potential neuroprotective role of ERK and/or p38 inhibitors against the neuronal toxicity induced by Aβ.
Abstract: In the present study, we examined the effects of intracerebroventricular administration of extracellular signal-regulated protein kinase- (ERK) and p38-specific inhibitors, U0126 and PD169316, respectively, on apoptosis induced by amyloid beta (Aβ) in rats. To investigate the effects of these compounds, we evaluated intracellular signalling pathways of apoptosis, as well as inflammatory and antioxidant pathways, 7 and 20 days after Aβ injection. We found that caspase-3 and Bax/Bcl-2 ratio, two hallmarks of apoptosis, were significantly decreased in the rats pre-treated with U0126 and PD169316, 7 days after Aβ injection. This observation was in agreement with the results of immunostaining analysis of the hippocampus that showed decreased levels of terminal transferase dUTP nick end labelling positive cells in the hippocampus of U0126 and PD169316 pre-treated rats, compared with the Aβ-injected group. We also chased the changes in the levels of calpain-2 and caspase-12, two ER factors, in the Aβ-injected and treatment groups. Decreased levels of calpain-2 and caspase-12 in U0126 and PD169316 pre-treated rats confirmed the protective effects of these inhibitors. Furthermore, we studied the effect of two stress-sensing transcription factors, nuclear-related factor-2 (Nrf2) and nuclear factor-кB (NF-кB), in Aβ-injected as wells as U0126 and PD169316 pre-treated rats. U0126 and PD169316 activated Nrf2 and suppressed NF-кB pathways, 7 days after Aβ injection. These antioxidant and inflammatory pathways restored to the vehicle level within 20 days. Taken together, our findings reinforce and extend the notion of the potential neuroprotective role of ERK and/or p38 inhibitors against the neuronal toxicity induced by Aβ.
TL;DR: Analyzing associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose‐ and weight‐adjusted area under the total plasma level time curves (AUC) for propofol suggests that, compared to men, more rapid Propofol metabolism may occur in women – a factor that may contribute to the mentioned differences in the efficacy of prop ofol anaesthesia between male and female patients.
Abstract: Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.
TL;DR: It is suggested that active secretion by efflux transporters P‐glycoprotein (MDR1) and breast cancer resistance protein (BCRP) contributes to rivaroxaban clearance.
Abstract: Rivaroxaban is a novel factor 10a inhibitor, where hepatic metabolism and renal clearance account for its overall disposition. Renal impairment is known to increase rivaroxaban-associated bleeding risk in patients. As renal rivaroxaban clearance exceeds glomerular filtration rate, we suggested that active secretion by efflux transporters P-glycoprotein (MDR1) and breast cancer resistance protein (BCRP) contributes to rivaroxaban clearance. The ability of MDR1 and BCRP efflux transporters to mediate rivaroxaban transport in vitro was assessed in polarized cell monolayers. A significantly greater vectorial transport of rivaroxaban was observed in the basal to apical direction in Caco-2 cells, which was attenuated in the presence of the selective inhibitors. After oral administration of rivaroxaban (2 mg/kg), plasma concentrations did not significantly differ between wild-type and Mdr1a(def) or Bcrp(-/-) mice (n = 6 per group). However, rivaroxaban clearance was significantly reduced in Mdr1a/Mdr1b(-/-)/Bcrp(-/-) mice. Interestingly, rivaroxaban brain-to-plasma ratio did not differ in mice lacking only Mdr1a or Bcrp, but more than two times higher in the Mdr1a/Mdr1b(-/-)/Bcrp(-/-) mice. Rivaroxaban is a shared substrate of MDR1 and BCRP. In vivo, MDR and BCRP function synergistically to modulate rivaroxaban disposition and appear to be particularly relevant to limiting its central nervous system entry. These data have important implications for safety and efficacy of anticoagulation therapy with rivaroxaban as many drugs in clinical use are known MDR1 inhibitors and loss-of-function polymorphisms in BCRP are common.
TL;DR: The data suggest that protocatechuic acid may be a candidate therapy for stroke recovery by promoting angiogenesis via a programmed PI3K/Akt/eNOS/VEGF signalling axis.
Abstract: In this study, we sought to elucidate whether protocatechuic acid contributes to induce angiogenesis as well as its mechanisms. To this end, we examined the role of protocatechuic acid on human brain microvascular endothelial cell line (HBMEC) proliferation, invasion and tube formation in in vitro. For the study of mechanisms involved, the phosphoinositide 3 kinase (PI3K)-Akt inhibitor LY294002, the endothelial nitric oxide synthase (eNOS) inhibitor L-NAME, vascular endothelial growth factor (VEGF), antagonist sFlt-1 and VEGF receptor blocker SU-1498 were used. Proliferation of HBMEC was tested by MTT. Scratch adhesion test was used to assess the ability of invasion. A Matrigel tube formation assay was performed to test capillary tube formation ability. PI3K-Akt-eNOS-VEGF pathway activation in HBMEC was tested by Western blot. Our data suggested that protocatechuic acid induces angiogenesis in vitro by increasing proliferation, invasion and tube formation. VEGF expression was increasing by protocatechuic acid and counteracted by VEGF antagonist sFlt-1, LY294002 and L-NAME in HBMEC. Tube formation was increased by protocatechuic acid and counteracted by VEGF receptor blocker-SU1498, LY294002 and L-NAME. These data suggest that protocatechuic acid may be a candidate therapy for stroke recovery by promoting angiogenesis via a programmed PI3K/Akt/eNOS/VEGF signalling axis.
TL;DR: GA functions as a non‐competitive inhibitor of ABCB1 by directly inhibiting and reducing its expression levels by promoting protein degradation through post‐translational proteasome pathway, suggesting that GA functions as an anti‐multidrug‐resistant agent.
Abstract: Gambogic acid (GA) is known for its anti-cancer activity in a phase II clinical trial. However, the detailed molecular mechanisms of its anti-multidrug resistance remain unclear. The present study was designed to study the relationship between GA and multidrug-resistant protein ATP-binding cassette transporter B1 (ABCB1). GA dose dependently inhibited ABCB1 activity levels in the in vitro Pgp-Glo assay system and increased the cellular accumulation of ABCB1 substrate adriamycin. Although GA had no significant influence on ABCB1 mRNA in the real-time PCR assay, Western blot detection indicated the compound reduced ABCB1 protein levels. Further study showed the proteasome inhibitor MG-132 reversed the GA-decreased ABCB1 level and prolonged half-life of ABCB1. It was also found that GA coordinated with other anti-cancer drugs (such as adriamycin, docetaxel, verapamil and protopanaxadiol) to enhance cellular cytotoxicity on human epithelial cancer cell lines with higher ABCB1 expression levels. These data suggest that GA functions as a non-competitive inhibitor of ABCB1 by directly inhibiting and reducing its expression levels by promoting protein degradation through post-translational proteasome pathway. The results of this study will aid in the understanding of the synergistic effects of combining GA with other drugs as a new anti-multidrug-resistant agent.
TL;DR: This study explored whether dermaseptin modifies [Ca2+]i and elicits eryptosis, an effect at least partially due to entry of extracellular Ca2+.
Abstract: Dermaseptin, an antimicrobial peptide participating in the host defence against pathogens, interacts with the membrane of target cells, leading to membrane permeabilization and eventual cell lysis. Dermaseptin has previously been shown to trigger haemolysis. Prior to haemolysis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling leading to phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increase in cytosolic Ca2+ activity [(Ca2+)]i and formation of ceramide. This study explored whether dermaseptin modifies [Ca2+]i and elicits eryptosis. Cell volume has been estimated from forward scatter, phosphatidylserine exposure from annexin-V binding, haemolysis from haemoglobin release, ceramide formation from binding of fluorescent antibodies and [Ca2+]i from Fluo3-fluorescence. A 48-hr exposure to dermaseptin (50 μM) was followed by a significant increase in [Ca2+]i, a significant increase ceramide abundance, a significant decrease in forward scatter and a significant increase in annexin-V binding. The annexin-V binding after dermaseptin treatment was significantly blunted but not abrogated in the nominal absence of extracellular Ca2+. Dermaseptin triggers eryptosis, an effect at least partially due to entry of extracellular Ca2+.
TL;DR: The overall data conclude that chemotherapeutic efficacy of baicalein (BE) might have strong mitochondria protective and restoration capacity in sub‐cellular level against lung carcinogenesis in Swiss albino mice.
Abstract: Our current study aimed to evaluate the chemotherapeutic efficacy of baicalein (BE) in Swiss albino mice, which is exposed to benzo(a)pyrene [B(a)P] for its ability to alleviate mitochondrial dysfunction and systolic failure. Here, we report that oral administration of B(a)P (50 mg/kg body weight)-induced pulmonary genotoxicities in mice was assessed in terms of elevation in reactive oxygen species (ROS) generation and DNA damage in lung mitochondria. MDA-DNA adducts were formed in immunohistochemical analysis, which confirmed nuclear DNA damage. mRNA expression levels studied by RT-PCR analysis of voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT) were found to be significantly decreased and showed a marked increase in membrane permeability transition pore (MPTP) opening. Accompanied by up-regulated Bcl-xL and down-regulated Bid, Bim and Cyt-c proteins studied by immunoblot were observed in B(a)P-induced lung cancer-bearing animals. Administration of BE (12 mg/kg body weight) significantly reversed all the above deleterious changes. Moreover, assessment of mitochondrial enzyme system revealed that BE treatment effectively counteracts B(a)P-induced down-regulated levels/activities of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase, cytochrome-C-oxidase and ATP levels. Restoration of mitochondria from oxidative damage was further confirmed by transmission electron microscopic examination. Further analysis of lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, reduced glutathione, vitamin E and vitamin C in lung mitochondria was carried out to substantiate the antioxidant effect of BE. The overall data conclude that chemotherapeutic efficacy of BE might have strong mitochondria protective and restoration capacity in sub-cellular level against lung carcinogenesis in Swiss albino mice.
TL;DR: It is demonstrated that ritonavir is able to block prasugrel CYP3A4 bioactivation and this CYP‐mediated drug–drug interaction might lead to a significant reduction of pr asugrel efficacy in HIV‐infected patients with acute coronary syndrome.
Abstract: The new anti-aggregating agent prasugrel is bioactivated by cytochromes P450 (CYP) 3A and 2B6. Ritonavir is a potent CYP3A inhibitor and was shown in vitro as a CYP2B6 inhibitor. The aim of this open-label cross-over study was to assess the effect of ritonavir on prasugrel active metabolite (prasugrel AM) pharmacokinetics in healthy volunteers. Ten healthy male volunteers received 10 mg prasugrel. After at least a week washout, they received 100 mg ritonavir, followed by 10 mg prasugrel 2 hr later. We used dried blood spot sampling method to monitor prasugrel AM pharmacokinetics (C(max) , t(1/2) , t(max) , AUC(0-6 hr) ) at 0, 0.25, 0.5, 1, 1.5, 2, 4 and 6 hr after prasugrel administration. A 'cocktail' approach was used to measure CYP2B6, 2C9, 2C19 and 3A activities. In the presence of ritonavir, prasugrel AM C(max) and AUC were decreased by 45% (mean ratio: 0.55, CI 90%: 0.40-0.7, p = 0.007) and 38% (mean ratio: 0.62, CI 90%: 0.54-0.7, p = 0.005), respectively, while t(1/2) and t(max) were not affected. Midazolam metabolic ratio (MR) dramatically decreased in presence of ritonavir (6.7 ± 2.6 versus 0.13 ± 0.07) reflecting an almost complete inhibition of CYP3A4, whereas omeprazole, flurbiprofen and bupropion MR were not affected. These data demonstrate that ritonavir is able to block prasugrel CYP3A4 bioactivation. This CYP-mediated drug-drug interaction might lead to a significant reduction of prasugrel efficacy in HIV-infected patients with acute coronary syndrome.
TL;DR: Methylphenidate exposure during pregnancy does not appear to be associated with a substantially (i.e. more than twofold) increased risk of congenital malformations, and children exposed to methylphenidate in utero during first trimester were identified.
Abstract: Methylphenidate is a centrally acting sympathomimetic used for the treatment of attention deficit/hyperactivity disorder in children and adolescents and for narcolepsy in adults. Despite the growing use among adult women, no reliable data on the prevalence of use during pregnancy have been published, and safety during pregnancy has not been established. We systematically reviewed available data on birth outcome after human in utero exposure to methylphenidate. Systematic searches in PubMed/Embase were performed from origin to August 2012, and data from Michigan Medicaid recipients, The Collaborative Perinatal Project and the Swedish Birth Registry were evaluated. Excluding three case reports, a total of 180 children exposed to methylphenidate in utero during first trimester were identified, among whom, four children with major malformations were observed. Methylphenidate exposure during pregnancy does not appear to be associated with a substantially (i.e. more than twofold) increased risk of congenital malformations.
TL;DR: In this article, the pharmacological profile of a new α2C-selective AR antagonist ORM-10921 has been reported, which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK-801.
Abstract: The α2-adrenoceptors (ARs) are important modulators of a wide array of physiological responses As only a few selective compounds for the three α2-AR subtypes (α2A , α2B and α2C ) have been available, the pharmacological profile of a new α2C-selective AR antagonist ORM-10921 is reported Standard in vitro receptor assays and antagonism of α2, and α1-AR agonist-evoked responses in vivo were used to demonstrate the α2C-AR selectivity for ORM-10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK-801 The Kb values of in vitro α2C-AR antagonism for ORM-10921 varied between 0078-12 nM depending on the applied method The selectivity ratios compared to α2A-AR subtype and other relevant receptors were 10-100 times in vitro The in vivo experiments supported its potent α2C-antagonism combined with only a weak α2A-antagonism In the pharmacodynamic microdialysis study, ORM-10921 was found to increase extracellular dopamine levels in prefrontal cortex in the baseline conditions In the behavioural tests, ORM-10921 displayed potent antidepressant and antipsychotic-like effects in the forced swimming test and prepulse-inhibition models analogously with the previously reported results with structurally different α2C-selective AR antagonist JP-1302 Our new results also indicate that ORM-10921 alleviated the NMDA-antagonist-induced impairments in social behaviour and watermaze navigation This study extends and further validates the concept that α2C -AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α2C-antagonism to treat such disorders
TL;DR: The eudesmol isomers herein investigated are able to reduce cell proliferation and to induce tumour cell death by caspase‐mediated apoptosis pathways in human hepatocellular carcinoma HepG2 cells.
Abstract: Eudesmols are naturally occurring sesquiterpenoid alcohols that present cytotoxic effect to cancer cells. Herein, all eudesmol isomers displayed cytotoxicity to different tumour cell lines. a-Eudesmol showed IC50 values ranging from 5.38 1.10 to 10.60 1.33 lg/mL for B16-F10 and K562 cell lines, b-eudesmol showed IC50 values ranging from 16.51 1.21 to 24.57 2.75 lg/mL for B16-F10 and HepG2 cell lines, and c-eudesmol showed IC50 values ranging from 8.86 1.27 to 15.15 1.06 lg/mL for B16-F10 and K562 cell lines, respectively. In addition, in this work, we studied the mechanisms of cytotoxic action of eudesmol isomers (a-, b- and c-eudesmol) in human hepatocellular carcinoma HepG2 cells. After 24-hr incubation, HepG2 cells treated with eudesmol isomers presented typical hallmarks of apoptosis, as observed by mor- phological analysis in cells stained with haematoxylin-eosin and acridine orange/ethidium bromide. None of eudesmol isomers caused membrane disruption at any concentration tested. Moreover, eudesmol isomers induced loss of mitochondrial membrane potential and an increase in caspase-3 activation in HepG2 cells, suggesting the induction of caspase-mediated apoptotic cell death. In conclusion, the eudesmol isomers herein investigated are able to reduce cell proliferation and to induce tumour cell death by caspase-mediated apoptosis pathways. The essential oil (300 mg) was fractionated by silica gel 60 (0.063- 0.200 mm; Merck, Darmstadt, Germany) column chromatography (1.5 9 43.0 cm) using petroleum ether with increasing amounts of CH2Cl2 (0%, 5%, 10%, 20%, 50% and 80%) followed by CH2Cl2 with increasing amounts of EtOAc (0%, 5%, 10%, 20% and 50%) as
TL;DR: It is shown that silymarin has the ability to inhibit T cell proliferation and pro‐inflammatory cytokine secretion in vitro and might be a valuable drug in therapeutic situations in which immunosuppression is required.
Abstract: Silymarin, a polyphenolic flavonoid derived from milk thistle (Silybum marianum), is known to have anti-inflammatory, hepatoprotective and anticarcinogenic effects. In this study, the in vitro immunomodulatory effect of silymarin was investigated using human CD4+ T cells. Peripheral blood mononuclear cells (PBMC) from healthy individuals were activated with anti-CD3 (5 μg/ml) plus anti-CD28 (2 μg/ml) and treated with 10, 50 and 100 μM silymarin. Cells were incubated 72 hr for proliferation assay using MTT and for viability analysis using PI staining and flow cytometry. Naive CD4+ T cell was also isolated from PBMC, activated with PHA/anti-CD28 and treated with 100 μM silymarin for 72 hr. MAPKs' activity of cell lysate from activated naive CD4+ T cells was assessed using an ELISA-based MAPKinase activity kit, and Th1/Th2/Th17-related cytokine expression was determined by Multi-analyte ELISA array kit. Results indicated a significant inhibition in proliferation of activated PBMC after 48-hr incubation with 100 μM silymarin without causing cell death. Moreover, MAPKs' activity (ERK1/2 and P38) and Th1-related cytokines (IL-2, TNF-α, IFN-γ) were significantly reduced in silymarin-treated cells compared with control after 72 hr. This study shows that silymarin has the ability to inhibit T cell proliferation and pro-inflammatory cytokine secretion in vitro. Furthermore, silymarin is able to inhibit ERK1/2 and P38 pathway activation in T cells stimulated through TCR engagement, a property that is likely associated with its ability to inhibit T cell proliferation and cytokine secretion. Therefore, silymarin, as an immune-response modifier, might be a valuable drug in therapeutic situations in which immunosuppression is required.
TL;DR: The role of TSPs in cardiac remodelling, remodelling after myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis is emphasized and further investigation is encouraged to validate them as potential cardiovascular drug targets.
Abstract: The thrombospondin (TSP) family consists of five multimeric, multidomain calcium-binding glycoproteins that act as regulators of cell-cell and cell-matrix associations as well as interact with other extracellular matrix molecules affecting their function. Increasing interest on cardiac TSP-1, TSP-2 and TSP-4 has emerged, and they have been studied in cardiac hypertrophy, myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis. The aim of this MiniReview is to summarize the current knowledge on each TSP in various cardiovascular pathologies. We specifically emphasize the role of TSPs in cardiac remodelling and evaluate TSPs as potential cardiovascular drug targets. Thrombospondin-1 (TSP-1) is the most studied TSP, being antiangiogenic and able to activate transforming growth factor-β. The functions of TSP-2 and TSP-4 are linked in maintaining the composition of the matrix of the hypertrophied heart, whereas there is very little knowledge on cardiac TSP-3 and TSP-5. TSP-1, TSP-2 and TSP-4 have been shown to affect cardiac remodelling in vivo, for example, by modulating matrix metalloproteinase and transforming growth factor-β activity, collagen synthesis, myofibroblast differentiation, cell death and stretch-mediated augmentation of cardiac contractility. The detrimental role for TSPs in cardiovascular pathophysiology has been clearly demonstrated in knockout mouse models, and augmentation of TSP signalling in the heart during stress and haemodynamic overload might be beneficial. In conclusion, the role of TSP-1, TSP-2 and TSP-4 in cardiac hypertrophy, remodelling after myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis encourages further investigation to validate them as potential drug targets.
TL;DR: Results indicate that BpirLAAO‐I induces apoptosis and potentiates IM effect on BCR‐ABL+ cells.
Abstract: Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of Philadelphia chromosome and by BCR-ABL1, which encodes the BCR-ABL oncoprotein. Although imatinib mesylate (IM) is effective for CML treatment, patients in accelerated and blastic phases of the disease are often refractory to this therapy, and there are also cases of IM resistance in patients in the chronic phase. Therefore, potential new drugs are being investigated to improve the efficiency of the therapy of CML such as snake venoms and their compounds. In this investigation, Bothrops pirajai L-amino acid oxidase (BpirLAAO-I) effect on normal peripheral blood mononuclear cells (PBMC) and on BCR-ABL+ cell line was assessed to explore its potential against leukaemic cells. MTT viability assay, lymphocyte subsets quantification and cell activation markers expression were performed to evaluate BpirLAAO-I effect on normal PBMC. The effect of BpirLAAO-I on HL-60 and HL-60.BCR-ABL cell lines was assessed by apoptosis detection. BpirLAAO-I was able to induce apoptosis in HL-60 and HL-60.BCR-ABL cell lines in a dose-dependent manner, promoted caspases 3, 8 and 9 activation and enhanced IM effect while not affecting the viability of normal cells. In addition, BpirLAAO-I promoted immune cells activation and lymphocytes subsets changes on normal PBMC. The results indicate that BpirLAAO-I induces apoptosis and potentiates IM effect on BCR-ABL+ cells.
TL;DR: It is indicated that TRPM7 channel modulates intestinal motility and regulates the pathophysiology of human gastric and breast adenocarcinoma cells and should be considered a potential target for the treatment of gut motor disorders and gastrics and breast cancer.
Abstract: Transient receptor potential melastatin 7 (TRPM7) plays a role in a number of physiological and pharmacological functions in variety of cells. The aim of this study was to clarify the role for TRPM7 channels and the effect of waixenicin A on the pacemaking activity of interstitial cells of Cajal (ICCs) and on the cell viability of the human gastric and breast adenocarcinoma cell lines, AGS and MCF-7, respectively. Waixenicin A decreased the amplitude of pacemaker potentials in cultured ICC clusters and inhibited TRPM7 currents, but had no effect on Ca2+-activated Cl− conductance (ANO1). Furthermore, waixenicin A was found to inhibit the growth and survival of AGS and MCF-7 cells. These findings indicate that TRPM7 channel modulates intestinal motility and regulates the pathophysiology of human gastric and breast adenocarcinoma cells. These findings suggest that TRPM7 channel be considered a potential target for the treatment of gut motor disorders and gastric and breast cancer.
TL;DR: The effects of selenium on H2O2‐induced TRPM2 channel currents in the Chinese hamster ovary (CHO) cell line are investigated using patch‐clamp and fura‐2 fluorescence imaging techniques.
Abstract: It has been recently reported that the essential antioxidant element selenium has protective effects on cytosolic Ca 2+ levels in cell lines. However, the effects of selenium on like transient receptor potential melastatin 2 (TRPM2) in response to oxidative stress (H2O2) are not well understood. We investigated the effects of selenium on H2O2-induced TRPM2 channel cur- rents in the Chinese hamster ovary (CHO) cell line using patch-clamp and fura-2 fluorescence imaging techniques. The CHO cell line was incubated in the presence of selenium for 36-48 hr before patch-clamp and Ca 2+ signalling analysis. Selenium was also applied internally in the cells by patch pip- ette. H2O2-induced TRPM2 currents were completely inhibited in cells with selenium applied extracellularly. Intracellular selenium, as well as 2-aminoethoxydiphenyl borate (2-APB) and N-(p-amylcinnamoyl) anthranilic acid (ACA) also inhib- ited the H2O2-induced TRPM2 currents. However, extracellu- lar selenium incubation induced lower block of H2O2-induced TRPM2 currents as compared to intracellular selenium. The data with selenium would support the idea that H2O2 acts by initiating a metabolic cascade resulting in the production of cytosolic factors such as oxidative stress and ADP-ribose that are responsible for the activation of TRPM2 channel activity. Lipid peroxidation levels were decreased by selenium incuba- tion although glutathione peroxidase activity and reduced glu- tathione levels increased. In conclusion, selenium supplementation in the transfected CHO cell line seems to have protective effects on the H2O2- induced increase in Ca 2+ influx and oxidative stress through regulation of TRPM2 channels. These findings suggest that selenium might be used in the treatment of cellular oxidative toxicity involving TRPM2 channel activation.