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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    Pharmacology (Online)
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Blackwell Publishing

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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims: The present study investigates the effects of pregabalin (PGB), acetaminophen (ACET) and tenoxicam (TNX) administration in somatic and visceral nociception, using the tail flick test and the writhing test in mice. Methods: In the tail flick test, the substances were administered orally and the latency time response was recorded 15, 30, 60, 90 and 120 min after administration. In the writhing test, pain responses were scored every 5 min during a 30-min period after intraperitoneal injection of diluted acetic acid. Results: Our study demonstrated that oral administration of the combination PGB-ACET resulted in a stronger increase of latency reaction - statistically significant after 15 min compared to TNX and after 30 min compared to PGB in tail flick test. In the writhing test, the combination PGB-ACET, but also PGB-TNX, resulted in a stronger decrease of writhe numbers - statistically significant compared to the effects of the separate administration of each substance. This decrease was more intense in animals treated with the combination PGB-ACET than with PGB-TNX. Conclusion: These results suggest an antinociceptive activity which may be a consequence of the synergic action of the substances. © 2014 S. Karger AG, Basel.
    Pharmacology 07/2014; 93(5-6):253-259.
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    ABSTRACT: Background/Aims: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. The new compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent combining the peroxisome proliferator-activated receptor γ agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety. Methods: In vitro and in vivo characterization was performed by isometric tension recording, platelet function, bleeding time and detection of oxidative stress. Results: In vitro, CLC-3000 displayed more potent vasodilation than pioglitazone alone or classical nitrates. In vitro, some effects on oxidative stress parameters were observed. Authentic AEN or the AEN-containing linker CLC-1275 displayed antiaggregatory effects. In vivo treatment with CLC-3000 for 7 days did neither induce endothelial dysfunction nor nitrate tolerance nor oxidative stress. Acute or chronic administration of AEN increased the tail vein bleeding time in mice. Conclusion: In summary, the results of these studies demonstrate that CLC-3000 contains a vasodilative and antithrombotic activity that is not evident with pioglitazone alone, and that 7 days of exposure in vivo showed no typical signs of nitrate tolerance, endothelial dysfunction or other safety concerns in Wistar rats. © 2014 S. Karger AG, Basel.
    Pharmacology 06/2014; 93(5-6):203-215.
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    ABSTRACT: The duration of action of melatonin may be important for improvements in sleep efficiency in insomniacs. Ramelteon, a selective melatonin agonist, is primarily metabolized to the active metabolite M-II, which has a longer half-life and greater systemic exposure than ramelteon. Hence, M-II may contribute significantly to the hypnotic benefits of ramelteon. We assessed the ramelteon-like activity of M-II in vitro and in vivo using cats. Binding and functional studies in Chinese hamster ovary cells expressing human melatonin receptors (MT1 or MT2) revealed that M-II binds melatonin receptors with lower affinity (Ki: 114 and 566 pmol/l for MT1 and MT2, respectively) and has lower potency (IC50: 208 and 1,470 pmol/l for MT1 and MT2, respectively) compared with ramelteon. However, higher M-II doses significantly improved sleep in cats. Thus, M-II may contribute to the clinical efficacy of ramelteon. © 2014 S. Karger AG, Basel.
    Pharmacology 06/2014; 93(3-4):197-201.
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    ABSTRACT: Objective: To compare the hemodynamics after combined spinal-epidural anesthesia (CSEA) between decubitus and sitting positions in aged patients undergoing total hip replacement. Methods: A total of 80 aged patients who underwent CSEA for elective total hip replacement were randomly divided into a decubitus position group (group D) and a sitting position group (group S; each group with 40 patients). In group D, 10 mg of 0.5% bupivacaine were given into the subarachnoid space in decubitus position. In group S, 10 mg of 0.5% bupivacaine were given into the subarachnoid space in the sitting position, which was maintained for 1 min, after which the patients were in decubitus position. In both groups, the sensory block levels and changes in hemodynamics were assessed. Results: The mean arterial blood pressure was significantly higher in group S than in group D at each time point within 30 min after anesthesia. There were no significant differences in heart rate between the two groups at each time point. There was also no significant difference in the level of sensory block between the two groups 20 min after the administration of CSEA. Conclusion: For aged patients undergoing total hip replacement, CSEA is safer and more effective in the sitting position than in decubitus position. © 2014 S. Karger AG, Basel.
    Pharmacology 05/2014; 93(3-4):193-196.
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    ABSTRACT: Background: Angiogenesis is usually driven by inflammation. Matrix metalloproteinases MMP-3 and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 are implicated in vascular remodeling. TIMP-2 exhibits antiangiogenic properties. Statins show benefits that are additional to lipid lowering including pro- and antiangiogenic properties. Atherosclerotic lesions in the coronary arteries have been well studied, but less is known about the fine terminal branches of the myocardial vasculature. Methods: To examine this, we studied rosuvastatin (RSV) treatment in ApoE knockout (ApoE(-/-)) mice fed a high cholesterol (HC) diet. Hearts from ApoE(-/-) mice on a normal diet, HC diet and HC diet with RSV were harvested to determine MMP-3, MMP-9, TIMP-1, TIMP-2, vascular endothelial growth factor (VEGF)-A and estrogen receptor-α (ER-α) mRNA. Results: RSV inhibited TIMP-1 and TIMP-2 expression and enhanced myocardial VEGF-A and ER-α expression, independently of plasma lipid level changes, but had no effect on MMP-3 and MMP-9 expression. Conclusions: These modulations of TIMPs, VEGF and ER-α expression induced by RSV may act as local stimulating factors for arteriolar growth in the myocardium. © 2014 S. Karger AG, Basel.
    Pharmacology 05/2014; 93(3-4):178-184.
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    ABSTRACT: Background: The aim of this study was to characterize the anticonvulsant effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ) in combination with clobazam (CLB) in the mouse maximal electroshock-induced seizure (MES) model. Methods: The anticonvulsant interaction profile between 1-MeTHIQ and CLB in the mouse MES model was determined using an isobolographic analysis for parallel dose-response relationship curves. Results: Electroconvulsions were produced in albino Swiss mice by a current (sine wave, 25 mA, 500 V, 50 Hz, 0.2-second stimulus duration) delivered via auricular electrodes by a Hugo Sachs generator. There was an additive effect of the combination of 1-MeTHIQ with CLB (at the fixed ratios of 1:3, 1:1 and 3:1) in the mouse MES-induced tonic seizure model. Conclusions: The additive interaction of the combination of 1-MeTHIQ with CLB (at fixed-ratios of 1:3, 1:1 and 3:1) in the mouse MES model seems to be pharmacodynamic in nature and worth of considering in further clinical practice. © 2014 S. Karger AG, Basel.
    Pharmacology 05/2014; 93(3-4):172-177.
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    ABSTRACT: Background: Heme oxygenase-1 (HO-1) contributes to the pathogenesis of pulmonary fibrosis. However, the expression of HO-1 in fibroblasts under fibrotic conditions has not been studied. Methods: This study was conducted to investigate the expression of HO-1 in lung fibroblasts from mice and humans under fibrotic conditions by Western blot. Results: We found that the expression of HO-1 was significantly decreased in lung fibroblasts isolated from bleomycin-challenged mice in comparison with control mice. Transforming growth factor-β (TGF-β) inhibited HO-1 expression and induced differentiation in human lung fibroblasts. Pretreatment with nuclear factor-κB (NF-κB) activation inhibitor or knockdown of the NF-κB p65 subunit attenuated TGF-β-induced inhibition of HO-1 expression and differentiation in human lung fibroblasts. Similarly, lysophosphatidic acid (LPA) induced TGF-β expression and decreased HO-1 expression in human lung fibroblasts. Interestingly, pretreatment with neutralized anti-TGF-β antibody attenuated LPA effects in human lung fibroblasts. Conclusion: These data suggested that TGF-β inhibited HO-1 expression in human lung fibroblasts through activation of NF-κB. © 2014 S. Karger AG, Basel.
    Pharmacology 01/2014; 93(3-4):185-92.
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    ABSTRACT: Background and Purpose: The normal liver sinusoidal endothelium is thin and punctuated with fenestrations 50-200 nm in diameter that filter endobiotics and xenobiotics. Defenestration of the liver sinusoidal endothelium in old age and after pre-treatment with poloxamer-407 (P407) has been shown to prevent the transfer of small chylomicrons across the liver sinusoidal endothelium. The aim of this study was to investigate the impact of liver sinusoidal endothelium fenestrations on the hepatic uptake of the highly protein-bound drug diazepam. We hypothesized that defenestration will reduce the hepatic extraction of drugs which are highly bound to albumin. Methodology: The isolated perfused rat liver (IPRL) model and multiple indicator dilution technique were used to investigate the effect of fenestrations in the liver sinusoidal endothelium on the hepatic disposition of diazepam in old and young rats, and in young rats treated with P407 or vehicle. A bolus dose of (14)C-diazpeam and non-extracted tracers ((3)H-sucrose and Evans blue) was injected into the portal vein. The single-pass recovery of diazepam and markers and the apparent volume of distribution were determined. Results: Scanning electron microscopy confirmed reduced porosity of the liver sinusoidal endothelial cells in P407-treated rats and old rats compared to young and control rats. The fractional recovery of diazepam was significantly increased in P407-treated rats compared to controls (0.20 ± 0.16, n = 12, P407; 0.08 ± 0.05, n = 8, controls; p = 0.0029), and in old rats compared to young rats (0.15 ± 0.03, n = 11, old; 0.10 ± 0.02, n = 11, young; p = 0.0004) following a single pass. Conclusion: Defenestration due to age-related pseudocapillarization and treatment with P407 resulted in reduced hepatic extraction of diazepam after a single pass through the IPRL. These results highlight the importance of the liver sinusoidal endothelium in the ultrafiltration of highly protein-bound drugs, and may also provide an additional mechanism for reduced hepatic clearance of diazepam in conditions associated with defenestration.
    Pharmacology 01/2012; 90(5-6):233-41.
  • Pharmacology 01/2010; 86:168.
  • Pharmacology 01/2008; 81:259-265.
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    ABSTRACT: Alzheimer's disease is a complex and multifactorial neurodegenerative disease. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed at evaluating the effects of trans-resveratrol in the prevention of colchicine-induced cognitive impairment and oxidative stress in rats. Intracerebroventricular administration of colchicine (15 microg/5 microl) induced impaired cognitive functions in both the Morris water maze task and the elevated plus-maze task. Chronic treatment with resveratrol (10 and 20 mg/kg, p.o.) for a period of 25 days, beginning 4 days prior to colchicine injection, significantly improved the colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde (MDA) and nitrite levels and depletion of reduced glutathione (GSH) activity in the rat brains. It also showed a significant decrease in acetylcholinesterase activity. Besides improving cognitive dysfunction, chronic administration of resveratrol significantly reduced the elevated MDA and nitrite levels and restored the depleted GSH and acetylcholinesterase activity. Results of the present study indicated that trans-resveratrol has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress.
    Pharmacology 02/2007; 79(1):17-26.
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    ABSTRACT: To study whether rosiglitazone prevents the development of diabetic nephropathy through reduction of reactive oxygen species and its downstream signal transduction pathways. The rats were intraperitoneally injected with streptozotocin to induce diabetes, meanwhile the rats in the therapeutic groups were given rosiglitazone (5 or 20 mg/kg/day) for 4 weeks by intragastric administration. Blood glucose, serum lipid and creatinine, urinary albumin excretion were measured. Malondialdehyde content, the activities of nuclear factor-kappaB (NF-kappaB), antioxidant enzymes including Cu-Zn SOD and GSH-Px in kidney were also measured. In addition, the mRNA and protein expression of MCP-1 were semiquantitatively determined with PT-PCR and immunohistochemical staining respectively. No significant difference of blood glucose and lipid were found between diabetic rats and rosiglitazone treatment groups. The renal histopathology was improved significantly. The expressions of MCP-1 mRNA and protein, malondialdehyde level and the activity of NF-kappaB were decreased markedly in rats treated with high-dose rosiglitazone, but the activities of renal Cu-Zn SOD and GSH-Px increased significantly. Rosiglitazone treatment prevented glomerular injury in diabetic rats, which was closely related with its roles of reducing reactive oxygen species, NF-kappaB activation and MCP-1 expression in the early phase of diabetic nephropathy.
    Pharmacology 02/2007; 80(1):57-64.
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    ABSTRACT: The effects of antipsychotic drugs sulpiride and clozapine on morphine state-dependent memory of passive avoidance task were examined in mice. Post-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opioid (5 mg/kg). In animals where memory was impaired by post-training morphine, the administration of either sulpiride or clozapine before pre-test morphine reduced the improvement of memory produced by the opioid. Co-administration of sulpiride with clozapine did not potentiate their antagonistic response. In conclusion, the inhibition of improvement of memory retrieval by morphine treatment on the test day by the two dopamine receptor antagonists seems to be induced through two different receptor mechanisms.
    Pharmacology 02/2007; 79(3):149-53.
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    ABSTRACT: Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. The PPAR subfamily consists of three members: PPARalpha, PPARgamma, and PPARbeta/delta. Fibrates are acting via PPARalpha, and they are used as lipid-lowering agents. PPARgamma agonists reduce insulin resistance and have been used in the treatment of type 2 diabetes. As the knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including a novel role in the management of cardiovascular disorders (CVD). PPARalpha/gamma dual agonists are currently under development and hold considerable promise in the management of type 2 diabetes and provide an effective therapeutic option for treating the multifactorial components of CVD. Several experimental and clinical evidences elucidated the beneficial effects of PPAR ligands in prevention and treatment of various CVD. However, PPARalpha and PPARgamma agonists have been shown to be proinflammatory and proatherogenic in a few studies. Further, PPARgamma ligands have been noted to be involved in the pathogenesis of congestive heart failure. These controversial results obtained from a few studies created further complication in understanding the role of PPARs. The function of PPARdelta and its potential as a cardiovascular therapeutic target are currently under investigation. The present review focuses on the merits and limitations of PPAR agonists with regard to their use in CVD.
    Pharmacology 02/2007; 80(1):1-10.
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    ABSTRACT: Fluoxetine (FLX) has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. This study evaluated the effects of developmental FLX exposure on anxiety, depression, aggressivity and pain sensitivity of male and female mice pups. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Pups were submitted to open-field, forced swimming, elevated plus-maze, intruder-resident and hot plate tests at adolescence and adulthood. In male pups, exposure to FLX decreased ambulation at postnatal day (PND) 40 and tended (p=0.07) to increase the latency to the first attack in the intruder-resident test at PND 70, suggesting decreased impulsivity. In female pups, FLX exposure increased immobility time in the forced swimming test at both PND 30 and 70, which is interpreted as depressive-like behavior. In conclusion, our results suggest that maternal exposure to FLX during pregnancy and lactation results in enduring behavioral alterations in male and female pups throughout life.
    Pharmacology 02/2007; 80(1):49-56.
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    ABSTRACT: We have recently demonstrated that the combination of methadone and morphine enhances the ability of morphine to induce mu-opioid peptide (MOP) receptor endocytosis. As a result, rats receiving both drugs show reduced morphine tolerance and dependence. In the present study, we identify the biochemical basis for the protective effect of the drug combination. In rats treated with morphine alone, the inhibitory effect of DAMGO on forskolin-stimulated adenylyl cyclase activity was significantly reduced in a brain-region-selective manner. Importantly, these reductions were prevented in animals receiving the drug combination. We found that these changes were not due to alterations in MOP receptor density, or MOP receptor-G protein coupling, as no significant change in these parameters was observed. Together these data demonstrate that neither changes in receptor number nor function are required for morphine tolerance and dependence. Rather, brain-region-selective changes in adenylyl cyclase signal transduction are critical, and both these biochemical changes and the behavioral effects are prevented by facilitating endocytosis of the MOP receptor.
    Pharmacology 02/2007; 79(4):193-202.
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    ABSTRACT: Drug development, and especially that intended for central nervous system (CNS) disorders, still poses a challenge. We investigated both the use of bifunctional compounds designed for multiple targeting and enhanced CNS permeability, and of recombinant alpha-fetoprotein (AFP), a natural pregnancy-associated immunomodulating protein for the treatment of CNS inflammation. Bifunctional compounds showed a novel pharmacokinetic profile due to the conjugation, yet retained, and even improved pharmacodynamics. AFP was well tolerated and decreased various aspects of neuroinflammation, including disease severity, axonal loss and damage, T-cell reactivity, and antigen presentation. Our results show that both strategies may serve as future drug modalities.
    Pharmacology 02/2007; 79(1):42-9.
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    ABSTRACT: The ovariectomized (OVX) rat, as an established animal model of human osteoporosis, was adopted in the present experiment to study the protective effects of sodium daidzein sulfonate (SDS) on trabecular bone. Six-month-old Sprague-Dawley rats were sham-operated or ovariectomized. Five days later, the OVX rats were randomly assigned to one of three experimental groups and treated for 90 days with vehicle, 17beta-estradiol (E(2)) or SDS. Compared with OVX rats, SDS administration (15 mg/kg) prevented OVX-induced decrease in lumbar vertebral and femoral bone mineral density (BMD), and significantly increased bone mechanical strength parameters, including ultimate stress and elastic modulus. In the OVX group, the structure of trabecular plate in the femoral head was absorbed and became progressively thinner or was removed completely, accompanied by enlargement of marrow cavities and amalgamation of two or more marrow cavities. Administration of SDS and E(2 )prevented the change of trabecular bone microarchitecture induced by OVX, increasing the trabecular bone area and trabecular thickness, while decreasing the trabecular separation. These results indicate that SDS administration prevents OVX-induced decrease in BMD and bone mechanical strength, and has a moderate protective effect on the microarchitecture of trabecular bone in aged Sprague-Dawley rats.
    Pharmacology 02/2007; 79(3):129-36.
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    ABSTRACT: There are data that document the anti-inflammatory effect of enoxaparin (EP) and its possible antioxidant potential. This study was designed to search for the antioxidant mechanism(s) of EP directly on endothelial cells exposed to an oxidant stimulus. For this purpose cultured human endothelial cells were exposed to nontoxic concentrations of hydrogen peroxide in the presence or absence of EP, and the adhesion of monocytes, the expression of cell adhesion molecules and transcription factors possibly involved in the process were tested. Adhesion assays, ELISA and Western blot analysis revealed that EP reduced monocyte adhesion, ICAM-1 and P-selectin expression, decreased the nuclear levels of c-Jun and p65 proteins, and diminished the phosphorylation of c-Jun protein, MAPK p38 and JNK. Together, the data demonstrate the antioxidant effect of EP and the involvement of ICAM-1, P-selectin, MAPK p38, JNK and the transcription factors NF-kappaB and AP-1 in the mechanism of action of this drug.
    Pharmacology 02/2007; 79(3):154-62.

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