Pharmacology (PHARMACOLOGY )

Publisher: Blackwell Publishing


This journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes. ëPharmacologyí is an international forum to present and discuss current perspectives in drug research.

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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandin (PG) E2 has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). E-type prostanoid (EP) receptor 4 is known to confer inhibitory signals to eosinophils and monocytes, amongst others. In this study, we investigated whether the responsiveness of eosinophils and monocytes to PGE2 and EP4 receptor activation is altered in AERD patients. While the expression of the EP4 receptor in eosinophils was unaltered in AERD patients, inhibition of eosinophil chemotaxis by PGE2 or the EP4 agonist CAY10598 was less pronounced in AERD patients as compared to healthy control subjects. In monocytes, we found no changes in basal or lipopolysaccharide (LPS)-stimulated PGE2 synthesis, but the response to EP4 receptor activation with respect to inhibition of LPS-induced tumor necrosis factor-α release was reduced in AERD patients, especially in the presence of aspirin (acetylsalicylic acid). Our data point towards a decreased sensitivity of inhibitory EP4 receptor that may play a role in AERD. © 2014 S. Karger AG, Basel.
    Pharmacology 12/2014; 94(5-6):280-286.
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    ABSTRACT: The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and β-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and β-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and β-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and β-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway. © 2014 S. Karger AG, Basel.
    Pharmacology 12/2014; 94(5-6):287-295.
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    ABSTRACT: Background: Recent studies have suggested that some single nucleotide polymorphisms (SNPs) in the human µ-opioid receptor gene (OPRM1) affect the postoperative analgesic efficacy of opioids and their side effects. In this study, we assessed the association between SNPs in the OPRM1 gene and intraoperative remifentanil consumption as well as perioperative side effects during gynecological hysteroscopic surgery in women from Northern China. Methods: We analyzed 178 women undergoing gynecological hysteroscopic surgery. SNP genotyping was performed using the SNaPshot method. The state anxiety index (SAI) and pressure pain threshold (PPT) of all patients were assessed preoperatively. Monitored anesthesia care was maintained by the intravenous infusion of remifentanil. Intraoperative remifentanil usage and perioperative side effects were recorded. Statistical analyses were performed using SPSS software. Results: Patients carrying one or two copies of the minor allele (G allele) of rs558025 required significantly more intraoperative remifentanil than patients without the minor allele (p = 0.001, corrected p = 0.006). There were no significant associations between the six SNPs and various clinical characteristics. No significant associations between the six SNPs and PPT or SAI were found in our study. Conclusions: SNP rs558025 in the OPRM1 gene was associated with intraoperative remifentanil consumption during gynecological hysteroscopic surgery in our subjects. © 2014 S. Karger AG, Basel.
    Pharmacology 12/2014; 94(5-6):273-279.
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    ABSTRACT: Objective: Advanced glycation end products (AGEs) play a pivotal role in the initiation and progression of osteoarthritis (OA). Peroxisome proliferator-activated receptor-γ (PPARγ) has been shown to exhibit anti-inflammatory and anticatabolic properties and to be protective in animal models of OA. This study was aimed to investigate the possible protective effect of the PPARγ agonist pioglitazone on AGE-induced chondrocyte damage. Methods: Cultured chondrocytes were stimulated with AGEs in the presence or absence of an antibody against the receptor for AGEs (anti-RAGE), an inhibitor of NF-κB (pyrrolidine dithiocarbamate) and pioglitazone. The RNA expression levels of TNF-α, matrix metalloproteinase (MMP)-13 and PPARγ were detected by RT-PCR. The expression of nuclear p65 was determined by Western blot analysis. Results: Upregulation of TNF-α and MMP-13 as well as downregulation of PPARγ were induced by AGEs in a time- and dose-dependent manner. The maximum effect was induced by 100 μg/ml AGEs. This effect can be inhibited by anti-RAGE. Pioglitazone dose-dependently inhibited the expression of TNF-α and MMP-13 induced by AGEs, which was combined with the inhibition of nuclear p65 expression. Conclusion: The PPARγ agonist pioglitazone modulates TNF-α and MMP-13 expression in cultured rabbit chondrocytes via NF-κB signaling. It indicates that pioglitazone may have therapeutic potential in OA. © 2014 S. Karger AG, Basel.
    Pharmacology 12/2014; 94(5-6):265-272.
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    ABSTRACT: Bronchodilators are the cornerstone of the treatment of chronic obstructive pulmonary disease (COPD). In particular, the most commonly used drugs are inhaled long-acting agents, including long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs). The combination of a LABA with a LAMA, i.e. of molecules characterized by different mechanisms of action, results in a synergistic enhancement of their clinical and functional effects. Therefore, this combined treatment can be implemented in a number of cases in which disease control is not adequately achieved by a single active agent such as a LABA or a LAMA. Several LABA/LAMA fixed-dose combinations, mainly made up of newly developed compounds, are currently in advanced phases of experimental evaluation. Within such a context, the aim of this review is to outline the pharmacological basis of dual bronchodilation as well as to discuss the results of the main trials carried out using the drug combination consisting of indacaterol and glycopyrronium, a LABA and a LAMA recently introduced in the treatment of COPD. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):249-258.
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    ABSTRACT: Recent data have shown strong chemopreventive and possibly cancer chemotherapeutic effects of green tea polyphenols and EGCG against breast cancer. This systematic review aims to synthesize data on the possible interaction of green tea catechins with breast cancer endocrine treatment. Electronic databases were searched with the appropriate search terms. Experimental trials suggest a synergistic interaction of green tea catechins with tamoxifen or raloxifene in the treatment of estrogen receptor-positive and estrogen receptor-negative breast cancer through estrogen receptor-dependent and -independent mechanisms. No evidence of an interaction of green tea catechins with aromatase inhibitors or fulvestrant has been reported. As green tea catechins are natural compounds with a rather favorable safety profile, the strategy of co-administrating green tea catechins with tamoxifen seems to be a rational approach in chemoprevention, adjuvant and metastatic breast cancer treatment that needs further investigation. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):245-248.
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    ABSTRACT: Aims: Chemerin is a novel adipokine that is closely associated with cardiovascular diseases and glucose homeostasis. This study aimed to investigate the effects of chemerin on insulin resistance in rat cardiomyocytes. Methods: Rat cardiomyocytes were treated with high concentrations of glucose and tumor necrosis factor-alpha (TNF-α), and chemerin and chemokine-like receptor 1 (CMKLR1) were measured by Western blot analysis. Then, the cardiomyocytes were treated with chemerin and insulin. Glucose uptake was evaluated using a fluorescence microplate reader. Western blot analysis was used to evaluate the phosphorylation of Akt, insulin receptor substrate-1, p38 mitogen-activated protein kinase (MAPK), as well as extracellular signal-regulated kinase (ERK)1/2. Results: Chemerin and CMKLR1 were found to be expressed in rat cardiomyocytes. Pretreatment with chemerin caused decreases in glucose uptake and phosphorylation of Akt in insulin-stimulated cardiomyocytes. Furthermore, chemerin activated the phosphorylation of p38 MAPK and ERK1/2 in insulin-stimulated cardiomyocytes. Inhibition of ERK partially rescued chemerin-induced insulin resistance. Conclusion: Chemerin is a novel adipokine that induces insulin resistance in rat cardiomyocytes in part through the ERK1/2 pathway. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):259-264.
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    ABSTRACT: Na(+)/Ca(2+) exchanger 1 (NCX1) is a plasma membrane transporter involved in regulating intracellular Ca(2+) concentrations. NCX1 is critical for Ca(2+) regulation in cardiac muscle, vascular smooth muscle and nerve fibers. However, little is known about the physiological role of NCX1 in gastrointestinal motility. To determine the role of NCX1 in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced responses in the longitudinal smooth muscle of the distal colon in smooth muscle-specific NCX1 transgenic mice (Tg). Tg show that NCX1 protein was overexpressed in the distal colon at a level twofold greater than that of endogenous NCX1. We found that the amplitudes of EFS-induced relaxation that persisted during EFS were greater in Tg than in wild-type mice (WT). Under the nonadrenergic, noncholinergic condition, the EFS-induced relaxation in Tg was also greater than that in WT. Inhibition of NO synthase, CO synthase, soluble guanylate cyclase (sGC), and protein kinase G (PKG) all attenuated the enhanced relaxation in Tg, demonstrating the importance of NCX1 in NO/sGC/PKG signaling. The action of NOR-1, an NO donor, induced enhanced relaxation in Tg compared with that in WT. Unlike NOR-1, pituitary adenylate cyclase-activating peptide and vasoactive intestinal peptide induced a similar relaxation in Tg compared with that in WT. In this study, we demonstrate that NCX1 plays an important role in smooth muscle motility in the mouse distal colon. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):230-238.
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    ABSTRACT: Background/Aims: Hypercholesterolemia is a major risk factor for coronary artery disease and probiotics have been suggested as tools to manage elevated cholesterol levels. Methods: The present study investigated the ability of the biotherapeutic agent Saccharomyces boulardii (Sb-Biocodex) to reduce the hypercholesterolemia induced by a 0.1% cholesterol-enriched diet in the hamster. Results: In a first experiment, chronic oral treatment with S. boulardii at 12 × 10(10) CFU/kg (3 g/kg) twice a day was started from the beginning of the cholesterol diet and continued for 14 days ('preventive protocol'). In the second experiment, S. boulardii was given 14 days after the beginning of the cholesterol diet when hypercholesterolemia had developed and continued for an additional 14 days ('curative protocol'). In the preventive protocol, administration of the yeast significantly reduced hypercholesterolemia (14%) induced by the cholesterol-enriched diet compared to the group receiving only the cholesterol diet. In the curative protocol, S. boulardii significantly reduced hypercholesterolemia (12%) induced by the cholesterol-enriched diet, too. Moreover, the yeast significantly decreased the serum triglyceride increase by 39%. Conclusion: S. boulardii possesses anti-hypercholesterolemic properties in the hamster worthy of further evaluation in clinical studies. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):239-244.
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    ABSTRACT: The aim of this study was to evaluate the relative pharmacokinetic (PK) and pharmacodynamic (PD) properties of a single dose of ponesimod, an oral and selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, in Japanese and Caucasian healthy subjects and explore the effects of sex on PK. Subjects received a single 40-mg dose of ponesimod in a single-centre, open-label, parallel-group study design. Ten Japanese and 10 Caucasian healthy subjects (age: 22-45 years, 1:1 sex ratio) participated in the study and were matched for body weight (±10%). Ponesimod concentration in plasma was determined by liquid chromatography tandem mass spectrometry, and PK parameters were obtained by non-compartmental analysis. Total lymphocyte count served as PD marker. Adverse events (AEs), laboratory values, electrocardiography (12-lead ECG), and vital signs were assessed for safety and tolerability. Administration of ponesimod resulted in similar PK parameters between the two ethnic groups, with a 16% higher exposure [AUC0-∞ of 7,368 ng ∙ h/ml (95% CI: 6,059-8,962) vs. 6,353 ng ∙ h/ml (4,950-8,154)] and a 17% longer terminal elimination half-life [32.9 h (30.1-36.0) vs. 28.1 h (23.4-33.6)] in Japanese compared to Caucasian subjects. Exposure was slightly higher in female subjects [7,488 ng ∙ h/ml (5,983-9,371)] than in male subjects [6,252 ng ∙ h/ml (5,031-7,771)]. The maximum mean lymphocyte count decrease from baseline, observed 6 h after receiving the dose in both groups, was similar in Japanese subjects (61.8%) and Caucasians (62.5%). The maximum mean heart rate (ECG) reduction from baseline was similar, with a difference of 4.2 bpm between Caucasian and Japanese subjects, observed 2.5 h after receiving the dose in both ethnic groups. There were no clinically relevant changes in other safety variables. No serious AEs were reported during the study. This study showed that the PK and PD profile of ponesimod was similar in Japanese and Caucasian subjects. No unexpected safety findings were reported. No dose adjustment is deemed necessary for Japanese subjects compared to Caucasians. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):223-229.
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    ABSTRACT: Background: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efflux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. Methods and Results: Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-β-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 μmol/l) or treated with 30 μmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor α, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. Conclusion: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):214-222.
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    ABSTRACT: Background: Morphine is co-administered with adjuvant drugs to treat pain, nausea, vomiting, dyspnoea and delirium in cancer patients. Aim of the Study: To investigate analgesic effects of morphine when co-administered with adjuvant drugs. Material and Methods: Two-month-old male Wistar rats received single morphine doses alone (0.45 and 0.9 mg/kg) or with midazolam (0.3 mg/kg), haloperidol (0.15 and 0.45 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), and hyoscine butylbromide (1.7 mg/kg) as single subcutaneous injections. Analgesia was measured by the tail-flick test after 15, 30, 45, 60, and 90 min of drug administration. In the case of significant analgesia enhancement, analgesic and sedative effects were explored in 3-, 5-, 6-, 8-, and 11-month-old rats. Results: Significant morphine (0.9 mg/kg) analgesia enhancement was observed 60 min after haloperidol (0.15 and 0.45 mg/kg) and hyoscine butylbromide co-administration. The addition of haloperidol to morphine significantly increased analgesia in 6-, 8- and 11-month-old rats while in the case of hyoscine butylbromide co-administration this effect was observed only in 11-month-old rats. Conclusions: Haloperidol and hyoscine butylbromide enhanced morphine analgesia. Future studies may explore the repeated administration of these drug combinations in rats and humans. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):207-213.
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    ABSTRACT: Objective: To investigate the efficacy, safety, and clinical benefit of prolonged-release trazodone (Trittico) in the treatment of major depressive disorder (MDD). Methods: In this study, 363 Chinese patients with MDD were randomized 1:1 to receive either prolonged-release trazodone (150-450 mg) or placebo treatment for 6 weeks. The primary efficacy measurement was the change of the 17-item Hamilton Depression Rating Scale (HAMD-17) total score from baseline to the end of the study. The secondary efficacy measurements were the response and remission rates, the Clinical Global Impression - Improvement of Illness (CGI-I) score at the end of the study, and the change of the HAMD-14 total score and quality of sleep [evaluated by the Pittsburgh Sleep Quality Index (PSQI) scale] during the study period. Results: The mean maximum daily dose was 273.11 mg for the trazodone group and 290.92 mg for the placebo group. At the end of the study, there was a significant difference between the two groups in the HAMD-17 change score (trazodone vs. placebo: -11.07 vs. -8.29, p < 0.001). Trazodone showed advantages at 1 week of treatment, and the effect lasted until the end of the study (week 6). The response and remission rates of the trazodone group were significantly higher than those in the placebo group (response rate: 59.6 vs. 37.2%, p < 0.001; remission rate: 35.5 vs. 22.2%, p = 0.005). The majority of the adverse reactions of trazodone were mild to moderate, and the most frequent adverse reactions (≥5%) were dizziness, dry mouth, somnolence, and nausea. Conclusions: Prolonged-release trazodone was more effective than placebo in MDD and was well tolerated. © 2014 S. Karger AG, Basel.
    Pharmacology 11/2014; 94(5-6):199-206.
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    ABSTRACT: Background/Aim: Hepatocyte growth factor (HGF) plays a role in the regeneration and protection of the kidney, but little information is available concerning the pharmacokinetics of therapeutic treatment with HGF. In this study, HGF was administered after the onset of renal injury, and pharmacokinetic analysis was performed simultaneously with an efficacious dose. Methods: For the study of pharmacodynamics, recombinant human HGF was intravenously administered to rats with glycerol-induced acute kidney injury (AKI). In the pharmacokinetic study, rats subjected to glycerol injection or renal ischemia-reperfusion were used as models of AKI, and rats subjected to 5/6 nephrectomy were used as models of chronic kidney disease (CKD). Results: After intravenous administration of HGF at doses of 0.5-2.0 mg/kg, the elevation of blood urea nitrogen was suppressed, indicating that HGF had a pharmacodynamic effect. However, no significant difference was seen in the pharmacokinetic parameters such as clearance, distribution volume and half-life between the normal, AKI and CKD groups. Conclusion: The intravenous administration of HGF after the onset of renal dysfunction exerted a pharmacological effect on AKI, and renal injury did not affect the clearance of plasma HGF. This unaffected profile may serve as a base for the safety of HGF during therapeutic administration. © 2014 S. Karger AG, Basel.
    Pharmacology 10/2014; 94(3-4):190-197.
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    ABSTRACT: Background/Aim: It has been believed that epigenetic changes play a critical role in schizophrenia through improper interaction between genome and environmental risk factors. The aim of this case-control study was to investigate the association of the promoter hypermethylation status of glutathione S-transferase T1 (GSTT1) and glutathione S-transferase P1 (GSTP1) genes with the risk of schizophrenia. Materials and Methods: Methylation-specific PCR was used to estimate DNA methylation in the blood of 80 patients with schizophrenia and 71 healthy controls. Results: Promoter hypermethylation analysis of GSTT and GSTP indicated a significant difference between individuals with methylated and unmethylated status [odds ratio (OR) = 0.339, 95% confidence interval (95% CI) = 0.14-0.8, p = 0.012 and OR = 0.308, 95% CI = 0.135-0.7, p = 0.005, respectively]. Conclusion: The present study supports the hypothesis that impairment in the promoter region of GSTT and GSTP genes by hypermethylation may increase the risk of schizophrenia. © 2014 S. Karger AG, Basel.
    Pharmacology 10/2014; 94(3-4):179-182.
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    ABSTRACT: Background/Aims: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. Methods: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. Results: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 μg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. Conclusion: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent. © 2014 S. Karger AG, Basel.
    Pharmacology 10/2014; 94(3-4):170-178.
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    ABSTRACT: Naftopidil, an α1-adrenoceptor blocker, induced apoptosis of human malignant pleural mesothelioma NCI-H2052 cells. Naftopidil upregulated the expression of tumor necrosis factor-α (TNF-α) mRNA in these cells. Naftopidil, alternatively, increased FasL secretion from NCI-H2052 cells, without affecting the expression of FasL mRNA and protein, and activated caspase-3 and -8 in NCI-H2052 cells. Naftopidil drastically suppressed tumor growth in mice inoculated with these cells. The results of the present study indicate that naftopidil induces apoptosis of NCI-H2052 cells by upregulating the expression of TNF-α and stimulating the secretion of FasL, a ligand for the death receptor Fas, both to activate caspase-8 and the effector caspase-3, leading to the suppression of NCI-H2052 cell proliferation in vivo. This raises the possibility that naftopidil could be developed as an effective drug for the treatment of malignant pleural mesothelioma. © 2014 S. Karger AG, Basel.
    Pharmacology 10/2014; 94(3-4):163-169.
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    ABSTRACT: Background and Purpose: There is a remarkable paucity of studies analyzing the role of the endothelium-derived relaxing factors on the vascular effects of organophosphates. This study was carried out to evaluate the vascular effects of malathion and the role of nitric oxide (NO) and prostacyclin (PGI2). Methods: Vascular reactivity measuring isometric forces in vitro ('organ chambers') and flow cytometry (cells loaded with DAF-FM DA) were used. Results: In rat thoracic aorta segments contracted with phenylephrine (Phe) (10(-7) mol/l), malathion (10(-10) to 10(-5) mol/l) induced concentration-dependent relaxation in arteries with intact endothelium (n = 7; p < 0.05). Malathion-mediated relaxation was blocked by N-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/l), a nonspecific NO synthase inhibitor, and/or indomethacin (10(-5) mol/l), a nonspecific cyclooxygenase inhibitor (n = 10, p < 0.05). In thoracic aorta rings, with and without endothelium, Phe (10(-10) to 10(-5) mol/l) evoked concentration-dependent contraction, which was reduced in the presence of malathion. In rings with or without endothelium, incubated with malathion, L-NAME and indomethacin, the Phe-induced contraction was restored. The role of NO was confirmed using flow cytometry. Malathion evokes endothelium-dependent relaxation through the M1 muscarinic receptor, since this relaxation was clearly blocked by atropine (M1 and M2 blocker) and pirenzepine (M1 blocker), but was less blocked by gallamine (M2 blocker) or 4-DAMP (M3 blocker). Conclusions: These findings suggest that the organophosphate compound effects on vascular reactivity depend of NO and PGI2. © 2014 S. Karger AG, Basel.
    Pharmacology 10/2014; 94(3-4):157-162.
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    ABSTRACT: Objective: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. Methods: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. Results: Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. Conclusions: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials. © 2014 S. Karger AG, Basel.
    Pharmacology 09/2014; 94(3-4):148-156.