Fundamental and Clinical Pharmacology via MedWorm.com

Deoxyuridine analog nucleotides in deoxycytidine analog treatment: secondary active metabolites?

Fundamental and Clinical Pharmacology — Fri, 26 Feb 2010 00:00:00 +0100

This article reviews the literature on the formation and pharmacological activity of deaminated dCa nucleotides. Most dCa's are rapidly deaminated into deoxyuridine analogs (dUa's) which are only slowly phosphorylated and therefore relatively inactive. dUa nucleotides are, however, also formed via deamination of dCa monophosphates by deoxycytidine monophosphate deaminase (dCMPD). dUa-monophosphates can interact with thymidylate synthase (TS), whereas dUa-triphosphates are incorporated into nucleic acids and interfere with polymerases. Administration of dCa's as monophosphate prodrugs or co-administration of the cytidine deaminase inhibitor tetrahydrouridine (THU) does not prevent dUa nucleotide formation which is, on the other hand, influenced by the dose and dCMPD activity. Taken together...

Complement receptor 3 (CD11b/CD18) is implicated in the elimination of β-amyloid peptides

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

Microglia are the professional phagocytes of the brain and express phagocytic receptors such as complement receptor 3 (CR3 or CD11b/CD18). Using mimics of the amyloid deposit made of heat-killed yeasts coated with either A[beta] 1-40 or A[beta] 1-42, we were able to study how microglia interacted with and ingested these particles in vitro. We have shown previously that the low density lipoprotein receptor-related protein (LRP) is largely implied in the phagocytosis of A[beta] 1-42-opsonized heat-killed yeasts and partly in that of A[beta] 1-40-opsonized heat-killed yeasts. Here, we report that antibodies against CD11b or CD18 reduced the uptake of the artificial amyloid deposit by microglial cell showing that CR3 is involved in the mechanism. Moreover, a concomitant inhibition of LRP and C...

Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

The present study is designed to assess the mitochondrial status during benzo(a)pyrene (B(a)P)-induced lung carcinogenesis in Swiss albino mice and to reveal the modulatory effect of hesperidin over it. B(a)P (50 mg/kg body weight)-induced mitochondrial abnormalities was evident from alterations in mitochondrial lipid peroxides, antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin E, and vitamin C), major tricarboxylic acid (TCA) cycle enzyme activities (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, alpha-ketoglutarate dehydrogenase), electron transport chain (ETC) complexes activities and ATP levels. Ultrastructural changes in lung mitochondria were also in acco...

Angiogenic targets for potential disorders

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

This review shall familiarize the readers with various fundamental aspects of angiogenesis. Angiogenesis is a feature of a limited number of physiological processes like wound healing, ovulation, development of the corpus luteum, embryogenesis, lactating breast, during immune response, and during Inflammation. It is driven by a cocktail of growth factors and pro-angiogenic cytokines and is tempered by an equally diverse group of inhibitors of neovascularization. The properties and biological functions of angiogenic growth factors such as VEGF, FGF-2, nitric oxide, MMP, angiopoietin, TGF-[beta] as well as various inhibitors such as angiostatin, endostatin, thrombospondin, canstatin, DII4, PEDF are discussed in this review with respect to their impact on angiogenic process. In recent years, ...

French summaries of product characteristics: content in relation to therapeutic monitoring of psychotropic drugs

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

The prescription information (summary of product characteristics, SPC) is compiled by the pharmaceutical industry as required by the national regulatory authorities. They vary in their content about the properties of drugs and about the usefulness of therapeutic drug monitoring (TDM) in the blood of patients. Based on a previous study carried out in Germany, the degree of agreement of French SPC for 59 psychotropic drugs with the existing medico-scientific evidence in the area of TDM was examined using a recently developed instrument. A summary score of SPC content (SPCC) related to TDM (SPCCTDM) has been calculated and compared with the level of recommendation of TDM of the AGNP-TDM expert group consensus guidelines for TDM in psychiatry [AGNP: Arbeitsgemeinschaft für Neuropsychopharmako...

Regulation of drug transporter mRNA expression by interferon-γ in primary human hepatocytes

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

Interferon (IFN)-[gamma] is known to downregulate expression of drug detoxifying proteins such as cytochromes P-450 (CYPs) in human hepatocytes. The present study was designed to determine whether IFN-[gamma] may also impair expression of influx and efflux drug transporters, which constitute important determinants of the liver detoxification pathway. Exposure of primary human hepatocytes to 10 ng/mL IFN-[gamma] was found to downregulate mRNA levels of sinusoidal influx transporters such as sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide (OATP) 2B1, OATP1B1, and OATP1B3. IFN-[gamma] concomitantly reduced mRNA expression of drug efflux pumps such as multidrug resistance gene 1, multidrug resistance protein (MRP) 2, MRP3, breast cancer resistance protein...

Vitamin use among children attending a Canadian pediatric emergency department

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

Increasing use of vitamins has been documented worldwide in children and adolescents, and potential for vitamin[ndash]drug interactions exists. The aim of this study was to identify vitamin use by children visiting a pediatric emergency department (ED). A survey of parents and/or patients 0[ndash]18 years was conducted at a large pediatric ED in Canada. A total of 1804 families were interviewed. The main outcome measure was prevalence of vitamin use by children in the preceding 3 months. A third (32.3%) of the patients in our cohort had used vitamins in the preceding 3 months, and 48% of them were taking vitamins daily. Over 8% of all children used vitamins within the last 24 h. The use of vitamins was higher with older patient and parental age (P < 0.001), chronic patient illness (P < 0.0...

Gender differences in the cardiovascular effects of sex hormones

Fundamental and Clinical Pharmacology — Mon, 22 Feb 2010 00:00:00 +0100

Over the last decade, compelling evidence supports the idea that the different impact of cardiovascular disease (CVD) and the differences in vascular biology in men and women may be, at least in part, related to the cardiovascular and metabolic effects of sex steroid hormones. Indeed, androgens and oestrogens influence a multitude of vascular biological processes and their cardiovascular effects are multifaceted. While in women the effects of androgens mainly depend upon oestrogens' levels and, ultimately, upon the estradiol/testosterone ratio, the effects of androgens in men mostly relate to their aromatization into oestrogens. Oestrogens exert potential beneficial effects on the cardiovascular system in both sexes. In women, the effect of oestrogens, alone or in association with progesti...

Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson's disease

Fundamental and Clinical Pharmacology — Sat, 13 Feb 2010 00:00:00 +0100

Gait disorders form one component of the axial disorders observed in Parkinson's disease (PD). Indeed, short steps with a forward-leaning stance are diagnostic criteria for PD in the early stages of the condition. Gait disorders also represent a major source of therapeutic failure in the advanced stages of PD (with the appearance of freezing of gait and falls) because they do not respond optimally to the two hand late-stage therapeutics [ndash] levodopa and electrical subthalamic nucleus (STN) stimulation. The late onset of doparesistance in these disorders may be linked to propagation of neurodegeneration to structures directly involved in gait control and to non-dopaminergic neurotransmitter systems. The coeruleus locus (a source of noradrenaline) is rapidly and severely affected, leadin...

(E)-2-benzylidene-4-phenyl-1,3-diselenole has antioxidant and hepatoprotective properties against oxidative damage induced by 2-nitropropane in rats

Fundamental and Clinical Pharmacology — Fri, 05 Feb 2010 00:00:00 +0100

The in vitro effect of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) was evaluated through iron/EDTA-induced thiobarbituric acid reactive species (TBARS) and reactive species (RS) determinations as well as of the scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical quantification. BPD at the concentrations of 10 and 50 [mu][Mu] decreased RS and TBARS levels, respectively. The antioxidant activity was not related to the scavenging DPPH radical mechanism. A second objective of this study was to investigate the hepatoprotective action of BPD, administered by oral route, against oxidative damage induced by 2-nitropropane (2-NP) (100 mg/kg of body weight) in liver of rats. At the dose of 50 mg/kg, BPD protected against the increase in aspartate aminotransferase (AST), alanine aminotransfe...

Hepatoprotective, antinociceptive and antioxidant activities of cimetidine, ranitidine and famotidine as histamine H2 receptor antagonists

Fundamental and Clinical Pharmacology — Thu, 14 Jan 2010 00:00:00 +0100

The antioxidant, antinociceptive and hepatoprotective effects of H2 receptor blockers were examined with different experimental models. Antioxidant activities were determined by employing various in vitro assay systems such as 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical-scavenging activity assays, reducing power determination assays, nitric oxide-scavenging activity assays and hydrogen peroxide-scavenging activity assays. Antinociceptive effects were determined using the hot plate test in mice. The hepatoprotective effects of cimetidine, ranitidine and famotidine against hepatotoxicity induced by carbon tetrachloride (CCl4) were determined by measuring the levels of serum enzymes alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities in mice. W...

Insight into pain-inducing and -related gene expression: a challenge for development of novel targeted therapeutic approaches

Fundamental and Clinical Pharmacology — Tue, 12 Jan 2010 00:00:00 +0100

The multidimensional issue of pain in relation to the need for efficient treatment has been the focus of extensive research. Gaining insight into the molecular mechanisms of pain and identifying specific genes and proteins as possible drug targets is strongly required considering that not all patients can be adequately treated with the currently available drugs. This up-to-date review aimed to summarize the findings of recent proteomic and genomic approaches in different types of pain to comment on their potential role in pain signaling pathways and to evaluate their possible contribution to the development of novel and possibly more targeted pain therapeutic strategies. Although pain treatment strategies have been greatly improved during the past century, no ideal targeted pain treatment ...

Lack of association between schizophrenia and polymorphisms in dopamine metabolism and transport genes

Fundamental and Clinical Pharmacology — Wed, 23 Dec 2009 00:00:00 +0100

We investigated the relationship between several functional polymorphisms in genes coding for dopamine metabolism and transport enzymes (MAO-A VNTR; MAO-A 941T>G; DAT VNTR; DAT -67A/T; CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*6) and the frequency of schizophrenia. Participants in the study were 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls. Genomic DNA was isolated from whole blood and genotyped by several methods. However, there was no association between schizophrenia and the alleles, genotypes or diplotypes that were studied or their interactions. Polymorphisms in genes coding for dopamine metabolism and transport enzymes did not predispose to or protect from schizophrenia and related disorders. (Source: Fundamental and Clinical Pharmacology...

The effect of insulin in combination with selenium on blood glucose and GLUT4 expression in the cardiac muscle of streptozotocin-induced diabetic rats

Fundamental and Clinical Pharmacology — Thu, 17 Dec 2009 00:00:00 +0100

We evaluated the effect of a combination of low doses of insulin (1 U/kg/day) and selenium (180 [mu]g/kg/day) on general physiological parameters and the level of glucose transporter (GLUT4) in the cardiac muscle of streptozotocin-induced diabetic rats. Diabetic rats were treated with insulin, selenium and a combination of insulin and selenium for 4 weeks. The levels of blood glucose and hemoglobin A1c were estimated; the level of the GLUT4 in the cardiac muscle was examined by immunoblotting and immunohistochemistry. Insulin in combination with selenium could significantly lower blood glucose and HbA1c levels and could restore disturbances in GLUT4 level in the cardiac muscle. The treatment with insulin was only partially effective in the restoration of diabetic alterations. We conclude t...

Animal models of neuropathic pain

Fundamental and Clinical Pharmacology — Thu, 17 Dec 2009 00:00:00 +0100

Animal models are pivotal for understanding the mechanism of neuropathic pain and development of effective therapy for its optimal management. A battery of neuropathic pain models has been developed to simulate the clinical pain conditions with diverse etiology. The present review exhaustively discusses the methodology, behavioral alterations, limitations, and advantages of about 40 different animal models of neuropathic pain along with their modifications. Development of these models has contributed immensely in understanding the chronic pain and underlying peripheral as well as central pathogenic mechanisms. Furthermore, research has resulted in the development of new therapeutic agents for neuropathic pain management, and the preclinical data obtained using these animal models have been...

Effects of trimetazidine, a partial inhibitor of fatty acid oxidation, on ventricular function and survival after myocardial infarction and reperfusion in the rat

Fundamental and Clinical Pharmacology — Thu, 17 Dec 2009 00:00:00 +0100

In this study, we tested whether chronic pre-MI administration of TMZ would be beneficial during and after acute MI. Two-hundred male Wistar rats were studied in four groups: sham + TMZ diet (n = 20), sham + control diet (n = 20), MI + TMZ diet (n = 80), and MI + control diet (n = 80) splitted into one short-term and one long-term experiments. Sham surgery consisted of a thoracotomy without coronary ligation. MI was induced by coronary occlusion followed by reperfusion. Left ventricle (LV) function and remodeling were assessed by serial echocardiography throughout a 24-week post-MI period. LV remodeling was also assessed by quantitative histological analysis of post-MI scar formation at 24 weeks post-MI. During the short-term experiment, 10/80 rats died after MI, with no difference between...

Hepatic effects of flunixin-meglumin in LPS-induced sepsis

Fundamental and Clinical Pharmacology — Thu, 17 Dec 2009 00:00:00 +0100

The aim of this study was to evaluate the actions of the non-steroidal anti-inflammatory drug flunixin-meglumin (FM) on the changes caused by lipopolysaccharide (LPS)-induced sepsis in the rat liver. Eight groups of five adult male Wistar rats were analysed: (1) saline injected (controls), (2) FM treated with 1.1 mg/kg, (3) FM treated with 2.2 mg/kg, (4) LPS-injected (10 mg/kg), (5) LPS-injected with 1.1 mg/kg FM pretreatment, (6) LPS-injected with 2.2 mg/kg FM pretreatment, (7) LPS-injected with 1.1 mg/kg FM post-treatment and (8) LPS-injected with 2.2 mg/kg FM post-treatment. All drugs were intraperitoneally injected. The following parameters were evaluated: plasma levels of hepatic enzymes and urea, hepatic histological characteristics, antioxidant enzymes and several metabolic fluxes. ...

Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline

Fundamental and Clinical Pharmacology — Thu, 17 Dec 2009 00:00:00 +0100

Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting [alpha]-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six [alpha]-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six [alpha]-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these [alpha]-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of [alpha]-adrenoceptor subtypes in human nasal mucosa was: [alpha]2A > [alpha]1A [ge] [alpha]2B > [alpha]1D [ge] [alpha]2C >> [alpha]1B. Oxymetazoline and xylometaz...

Antispasmodic effects of essential oil of Pterodon polygalaeflorus and its main constituent β-caryophyllene on rat isolated ileum

Fundamental and Clinical Pharmacology — Fri, 11 Dec 2009 00:00:00 +0100

This study investigates the effects of essential oil of Pterodon polygalaeflorus (EOPP) and [beta]-caryophyllene ([beta]-CAR). EOPP and [beta]-CAR relaxed the basal tone of ileum smooth muscle in a concentration-dependent manner (IC50s = 394.35 ± 62.12 and 68.65 ± 9.51 [mu]g/mL respectively), an effect that was unaltered by hexamethonium, L-nitroarginine methyl ester or indomethacin. Both EOPP and [beta]-CAR evoked a concentration-dependent relaxation of ileum pre-contracted with KCl with an IC50 value of 107.78 ± 10.47 and 17.35 ± 0.75 [mu]g/mL, respectively. EOPP and [beta]-CAR inhibited the contractions induced by acetylcholine (ACh) and by KCl. In ileal preparations, the CaCl2-induced contractions were reduced by EOPP (300 [mu]g/mL) and [beta]-CAR (100 [mu]g/mL). Furthermore, CaCl2...

Effects of induced hyperthermia on pharmacokinetics of ropivacaine in rats

Fundamental and Clinical Pharmacology — Fri, 11 Dec 2009 00:00:00 +0100

Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 °C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentr...

Antagonist-D2S-dopamine receptors interactions in intact Chinese recombinant ovary cells

Fundamental and Clinical Pharmacology — Thu, 10 Dec 2009 00:00:00 +0100

D2-type dopamine receptors are major recognition sites for antipsychotic drugs. There are two splice variants: D2S and D2L with an additional 29 amino acid sequence in the third intracellular loop. Only little comparative information is hitherto available about their pharmacological properties and none of these studies dealt with intact cell systems. This prompted us to investigate the binding properties of [3H]-raclopride, a hydrophilic benzamide, and [3H]-spiperone, a highly hydrophobic butyrophenone, to intact CHO cells expressing recombinant human D2L-receptors. Presently, we have repeated and extended this experimental approach to the human D2S-receptors in the same cell system. Except for a slower dissociation of [3H]-spiperone from D2S, the binding properties of these and other anta...

'Multiple action fixed combination. Present or future?'

Fundamental and Clinical Pharmacology — Fri, 04 Dec 2009 00:00:00 +0100

Cardiovascular disease (CVD) is the most common cause of death in Western countries and will continue to be so in upcoming years. A close correlation has been demonstrated among CVD, stroke, ischemic heart disease, renal failure and a number of modifiable risk factors. As cardiovascular (CV) risk factors commonly co-exist, high-risk patients with hypertension, obesity and diabetes may well benefit from a multiple action combination of CV agents with synergistic efficacy. Control of blood pressure (BP) and the other CV risk factors is still far from the optimal rates and achievement of internationally accepted goals must be imperative. The benefits of achieving these goals, including significant reductions in CV morbidity and mortality, are well documented. Thus, a rigorous effort to improv...

Proconvulsant potential of cyproheptadine in experimental animal models

Fundamental and Clinical Pharmacology — Thu, 03 Dec 2009 00:00:00 +0100

In epileptic patients cyproheptadine is frequently prescribed as an appetite stimulant for the treatment of anorexia associated with anti-epileptic drugs and for the management of 'serotonin syndrome' in depressed epileptic patients. However, the study of serotonergic and histaminergic pathway shows that the decreased neurotransmission of serotonin and histamine in the brain reduces seizures threshold. Since, cyproheptadine interferes with these pathways via antagonizing subtypes of 5-HT1/2 receptors and H1 receptor, therefore the present study was undertaken to investigate its effect on seizures threshold, so as to substantiate its use in epileptics. In the present study convulsions were induced in mice by, maximum electroshock (MES), picrotoxin, and pentylenetetrazol (PTZ). Cyproheptadin...

The polypill in the primary prevention of cardiovascular disease

Fundamental and Clinical Pharmacology — Fri, 27 Nov 2009 00:00:00 +0100

Coronary heart disease (CHD) and stroke are the most common causes of death worldwide. The polypill, a multi-component tablet or capsule designed to reduce several cardiovascular causal risk factors simultaneously, has the potential to reduce the incidence of heart attacks and stroke by about 80%, the precise reduction depending on the formulation of the polypill and adherence to preventive treatment. The full public health impact can only be realized if the polypill is used to prevent first cardiovascular disease events, because most heart attacks and strokes are first events. A simple and effective method of selecting who should be offered the polypill is needed. Even though serum cholesterol and blood pressure are important causes of CHD and stroke and lowering them has a large preventi...

Acute generalized exanthematous pustulosis (AGEP) induced by cefotaxime

Fundamental and Clinical Pharmacology — Wed, 18 Nov 2009 00:00:00 +0100

We report a case of acute generalized exanthematous pustulosis (AGEP) after cefotaxime use confirmed by a positive patch test. A 30-year-old woman received cefotaxime, fosfomycin and ciprofloxacin for sinusitis. Twelve days after drug initiation, she developed an extending pustular erythema associated with fever. Laboratory investigations showed marked leukocytosis. His blood chemistry was normal. The histological examination showed parakeratosis, spongiosis and nonfollicular intra-epidermal pustules consistent with AGEP. All medications were withdrawn. The symptoms resolved within 11 days after cefotaxime discontinuation. Patch tests were positive to cefotaxime after 48 h, while ciprofloxacin and fosfomycin yielded negative findings. Based on the Naranjo algorithm, it is probable that AGE...

Serum brain-derived neurotrophic factor and platelet activation evaluated by soluble P-selectin and soluble CD-40-ligand in patients with acute myocardial infarction

Fundamental and Clinical Pharmacology — Tue, 10 Nov 2009 00:00:00 +0100

The objective of this study was to evaluate the relationship between BDNF, functional parameters and biological markers associated with inflammatory processes and platelet activation. BDNF serum levels were assessed in patients with acute myocardial infarction (MI) (n = 20) or stable angina pectoris (SAP) (n = 20) who underwent coronary angiography. Serum levels of IL-6, MCP1, sVCAM, soluble CD-40-ligand (sCD40L) and soluble P-selectin (sP-selectin) were measured simultaneously by flux cytometry. Median BDNF levels were higher in the MI than in the SAP group (1730 vs. 877 pg/mL, respectively; P = 0.025). In MI patients, we observed a significant correlation between BDNF and sP-selectin (r = 0.58, P = 0.023), although we found a non-significant trend between BDNF and sCD40L (r = +0.35, P = ...

Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission

Fundamental and Clinical Pharmacology — Tue, 10 Nov 2009 00:00:00 +0100

Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol present in the essencial oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. This work presents the behavioral effects of carvacrol in animal models of elevated plus maze (EPM), open field, Rotarod and barbiturate-induced sleeping time tests in mice. Carvacrol (CVC) was administered orally, in male mice, at single doses of 12.5; 25 and 50 mg/kg while diazepam 1 or 2 mg/kg was used as standard drug and flumazenil (2.5 mg/kg) was used to elucidate the possible anxiolytic mechanism of CVC on the plus maze test. The results showed that CVC, at three doses, had no effect on the spontaneous motor activity in the Rotarod test nor in the number of squares crossed in the open-field test. Ho...

Non-competitive interaction between raclopride and spiperone on human D2L-receptors in intact Chinese hamster ovary cells

Fundamental and Clinical Pharmacology — Tue, 10 Nov 2009 00:00:00 +0100

We recently investigated the binding properties of the antagonists [3H]-raclopride and [3H]-spiperone to intact Chinese hamster ovary cells expressing recombinant human D2long-dopamine receptors (CHO-D2L cells). Compared with saturation binding with [3H]-raclopride, raclopride reduced [3H]-spiperone binding with to low potency in competition binding experiments. The present findings illustrate the ability of spiperone to inhibit [3H]-raclopride binding non-competitively. While raclopride only decreases the apparent KD of [3H]-raclopride in saturation binding experiments, spiperone only decreases the number of sites to which [3H]-raclopride binds with high affinity. Also, while the IC50 of raclopride depends on the concentration of [3H]-raclopride in competition experiments, this is not the...

Fatal liver injury associated with clopidogrel

Fundamental and Clinical Pharmacology — Fri, 06 Nov 2009 00:00:00 +0100

We report a serious liver injury with fatal outcome in a 63-year-old man developed 19 days after starting clopidogrel for percutaneous coronary stenting. (Source: Fundamental and Clinical Pharmacology)

Pharmacological doses of vitamin A increase caspase-3 activity selectively in cerebral cortex

Fundamental and Clinical Pharmacology — Wed, 04 Nov 2009 00:00:00 +0100

Vitamin A exerts a wide range of physiological roles from embryonic to adulthood stages of the mammalian life. However, there is a great concern regarding the deleterious effects of vitamin A use even therapeutically. It was shown that vitamin A induces behavioral impairments, for instance, anxiety-like behavior and depression, in experimental animals and humans. Caspases are enzymes associated with cell death; however, there is a role for such enzymes also in synaptic plasticity. Then, based on previously published data, we have investigated the effects of vitamin A supplementation at clinical doses (1000[ndash]9000 IU/kg/day) for 28 days on caspase-3 and caspase-8 activities in adult rat cerebral cortex, cerebellum, striatum, and hippocampus. Furthermore, we have quantified TNF-[alpha] l...

Toxicological evaluation of azumolene after repeated intraperitoneal administration in rats

Fundamental and Clinical Pharmacology — Tue, 03 Nov 2009 00:00:00 +0100

In conclusion, Az is a safe compound for long-term administration, but does cause a mild, reversible reaction in skeletal muscle and kidney. (Source: Fundamental and Clinical Pharmacology)

Thrombin-stimulated proliferation is mediated by endothelin-1 in cultured rat gingival fibroblasts

Fundamental and Clinical Pharmacology — Sat, 31 Oct 2009 00:00:00 +0100

In this study, using cultured rat gingival fibroblasts, we investigated whether thrombin-induced proliferation of gingival fibroblasts is mediated by ET-1. Thrombin-induced proliferation (0.05[ndash]2.5 U/mL). Proliferation was also induced by a PAR1-specific agonist (TFLLR-NH2, 0.1[ndash]30 [mu]m), but not by a PAR2-specific agonist (SLIGRL-NH2). Thrombin (2.5 U/mL) induced an increase in immunoreactive ET-1 expression, which was inhibited by cycloheximide (10 [mu]g/mL), and an increase in preproET-1 mRNA expression, as assessed by reverse transcription polymerase chain reaction. TFLLR-NH2 increased ET-1 release into the culture medium in both a concentration (0.01[ndash]10 [mu]m)- and time (6[ndash]24 h)-dependent manner, as assessed by solid phase sandwich enzyme-linked immunosorbent as...

The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes

Fundamental and Clinical Pharmacology — Tue, 20 Oct 2009 23:00:00 +0100

The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty-three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild-type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild-type genotype. G2677T/A: The car...

Perception of risk of adverse drug reactions: a 3-year follow-up of a cohort of medical students

Fundamental and Clinical Pharmacology — Tue, 20 Oct 2009 23:00:00 +0100

Previous studies have pointed out the question of effective training and information to health professionals on pharmacovigilance. The lack of training is known to induce inadequate use of drugs and noncompliance of patients. Pharmacology teaching is performed in the third year of medical studies at the Toulouse Faculty of Medicine. The aim of the study was to investigate the perception of risk of adverse drug reactions (ADRs) by medical students at the end of the one year pharmacology course and two years later, after clinical training period. Sixty-seven students were interviewed in May 2005 and in October 2007. Visual analogue scales were used to define a score of perceived risk of ADRs associated with each drug class (ranking from 0 to 10) before and after pharmacology training. The dr...

Anti-arthritic effect of scopoletin, a coumarin compound occurring in Erycibe obtusifolia Benth stems, is associated with decreased angiogenesis in synovium

Fundamental and Clinical Pharmacology — Tue, 20 Oct 2009 23:00:00 +0100

In conclusion, scopoletin is capable of ameliorating clinical symptoms of rat adjuvant-induced arthritis, by reducing numbers of new blood vessels in the synovium and the production of important endogenous angiogenic inducers. Therefore, this compound may be a potential agent for angiogenesis-related diseases and could serve as a structural base for screening more potent synthetic analogs. (Source: Fundamental and Clinical Pharmacology)

Reduced elimination clearance of micafungin in rats with cholestatic hyperbilirubinemia

Fundamental and Clinical Pharmacology — Tue, 20 Oct 2009 23:00:00 +0100

We examined whether the pharmacokinetic disposition of micafungin (MCFG), an echinocandin class antifungal agent, is altered in hyperbilirubinemia using a rat model prepared by bile duct ligation (BDL). Serum bilirubin levels were increased depending upon the duration of BDL. The elimination rate constant and total body clearance (CLtot) of MCFG were reduced by 24% and 16%, respectively, after BDL for 1 h, but there was no significant change in the apparent volume of distribution at steady-state. The degree of reduction in the CLtot was much greater 7 days after BDL as compared with that 1 h after BDL (44% vs. 16%). However, the proportion of the biliary clearance in the CLtot was about 10%. This is similar to the extent of decrease in the CLtot by occlusion of the bile duct, demonstrating...

Drug reimbursement and GPs' prescribing decisions: a randomized case-vignette study about the pharmacotherapy of obesity associated with type 2 diabetes: how GPs react to drug reimbursement

Fundamental and Clinical Pharmacology — Mon, 12 Oct 2009 23:00:00 +0100

This study sought to identify the effect of drug reimbursability [ndash] a decision made in France by the National Authority for Health [ndash] on physicians' prescribing practices for a diet drug such as rimonabant, approved for obese or overweight patients with type-2 diabetes. A cross-sectional survey of French general practitioners (GPs) presented a case-vignette about a patient for whom this drug is indicated in two alternative versions, differing only in its reimbursability, to two separate randomized subsamples of GPs in early 2007, before any decision was made about reimbursement. The results indicate that (i) more than 20% of GPs in private practice would be willing to prescribe a non-reimbursed diet drug for patients with obesity complicated by type 2 diabetes; (ii) the number of...

No effect of CYP450 and P-glycoprotein on hydroxyurea in vitro metabolism

Fundamental and Clinical Pharmacology — Thu, 08 Oct 2009 23:00:00 +0100

Our objectives were (1) to study the HU metabolism via human cytochromes and (2) to test if HU is a substrate of P-gp. HU metabolism was investigated by determining the appearance of urea and HU decreasing upon incubation with human liver microsomes. Quantification was determined using HPLC coupled with UV-detection at 449 nm. Our method was linear between 5 and 1000 [mu]m, precise (coefficients of variation ranging from 1.7 to 9.9%), accurate (97.7[ndash]103.9%). The limit of quantification was 7 [mu]m. The ATPase activity of human P-gp membranes was determined by measuring inorganic phosphate liberation. HU and urea measurements in microsomes were not different between 0 and 60 min whatever HU concentration used from 30 to 300 [mu]m. The presence of NADPH in the medium has no effect on H...

The challenge of polypharmacy in cardiovascular medicine

Fundamental and Clinical Pharmacology — Thu, 08 Oct 2009 23:00:00 +0100

Albeit great efforts in reducing the burden of cardiovascular diseases (CVD), their prevalence continues to grow worldwide. Among the causes for this rising burden, the upcoming pandemic of obesity and diabetes further enhances the estimates of CV mortality and healthcare costs over the next decades. Nevertheless, advances in CVD treatment has increased life-expectancy, and future perspectives announce a growing aging population, with increasing comorbid conditions predisposing to CVD. Despite the emphasis on primary prevention, CV risk factors are still poorly controlled and a further need for CV drugs is upcoming. In chronic CVD such as hypertension, ischemic heart disease (IHD) and heart failure, the progressive use of multiple drugs is common and is recommended by international guideli...

The evolving story of the RAAS in hypertension, diabetes and CV disease – moving from macrovascular to microvascular targets

Fundamental and Clinical Pharmacology — Thu, 08 Oct 2009 23:00:00 +0100

The phylogenetically old renin-angiotensin-system (RAS) was originally described as a circulating hormonal system and a main cardiovascular regulator. However, there also exist 'local RASs' which are situated in cardiovascular as well as non-cardiovascular tissues where they are involved in physiological and patho-physiological processes such as inflammation, fibrosis, proliferation or apoptosis. Local RASs are activated in diabetes, preferentially in organs affected by hyperglycaemic injury such as the kidney or the retina. Increased renal or retinal Ang II levels may contribute to diabetic tissue injury in two ways: (i) by stimulating the angiotensin AT1-receptor and downstream pathological chains of events and (ii) by bidirectional interaction with the 'classical' hyperglycaemia-induced...

The ultrastructural and biochemical evidences of the beneficial effects of chronic caffeic acid phenethyl ester and melatonin administration on brain and cerebellum of aged rats

Fundamental and Clinical Pharmacology — Thu, 08 Oct 2009 23:00:00 +0100

Nervous system is highly vulnerable to the deleterious effects of age-related oxidative stress. A large body of researches has consistently confirmed the implication of free radicals both in normal cerebral ageing and ageing-related pathologies. In the present study, in addition to the light and electron microscopic pictures of brain and cerebellum of young, old and antioxidant administered old Sprague[ndash]Dawley rats, pro-oxidant status was evaluated in terms of measurements of total glutathione, lipid peroxidation (malondialdehyde) and activities of superoxide dismutase, catalase and glutathione peroxidase. Taking the results together, we suggest that supplemental administration of caffeic acid phenethyl ester and melatonin is beneficial in delaying age-related cellular damage in nervo...

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

Fundamental and Clinical Pharmacology — Wed, 23 Sep 2009 23:00:00 +0100

In conclusion, this study shows that the additive effect of the combined application of theophylline's major metabolites on the rabbit gastrointestinal tract plays a major role in the final response of the intestine, and a minor one in the final responses of the gastric regions, while both the parent drug and the metabolites contribute to the final responses of the oesophagus and LOS. (Source: Fundamental and Clinical Pharmacology)

Ribavirin therapeutic drug monitoring: why, when and how?

Fundamental and Clinical Pharmacology — Wed, 23 Sep 2009 23:00:00 +0100

Recent studies suggest the potential interest of ribavirin therapeutic drug monitoring to improve sustain virological response rate in hepatitis C virus-infected patients. The present review details the pharmacokinetic properties of ribavirin, suggesting that it may be a good candidate for therapeutic drug monitoring, the different possible strategies and the analytical methods that could be employed. (Source: Fundamental and Clinical Pharmacology)

Medicine or ecstasy? The importance of the logo

Fundamental and Clinical Pharmacology — Tue, 15 Sep 2009 23:00:00 +0100

Some pharmaceutical tablets have an appearance that resembles that of ecstasy (a logo and often a name referring to it, a given shape and/or a colour). These are sometimes sold in the street as 'ecstasy'. In order to assess the knowledge of this phenomenon, surveys were conducted among designer drug users (DDUsers), pharmacists and pharmaceutical firms. Three surveys were conducted: the first one was conducted among DDUsers by means of an anonymous questionnaire; the second one consisted of a 1-month postal survey within a network of 155 community pharmacies in the Aquitaine region, Southwestern France and the third one consisted of a postal questionnaire sent to 71 pharmaceutical firms. Nineteen users, 77 pharmacists and 25 pharmaceutical firms participated in the surveys. All DDUsers kne...

Deletion of the inducible nitric oxide synthase gene reduces peripheral morphine tolerance in a mouse model of chronic inflammation

Fundamental and Clinical Pharmacology — Mon, 14 Sep 2009 23:00:00 +0100

The implication of inducible nitric-oxide synthase (iNOS) on peripheral tolerance to morphine was evaluated in wild-type (WT) and iNOS knockout mice. Chronic inflammation was induced by subplantar (s.p.) injection of Complete Freund's Adjuvant (CFA), and morphine tolerance by subcutaneous implantation of a 75 mg morphine-pellet. Withdrawal was assessed after the intraperitoneal injection of 2 mg/kg naloxone. Antinociception was assessed (Randall-Selitto test) 5 min after a fixed dose of s.p. morphine (16 [mu]g). In the absence of inflammation, s.p. morphine did not induce antinociception, while during CFA-inflammation produced 47.4 ± 0.8 and 38.8 ± 2.7% inhibitions respectively, in each genotype (P < 0.05). In morphine-tolerant mice with CFA-inflammation, no antinociception could be elic...

CHICAGO, PERISCOPE and PROactive: CV risk modification in diabetes with pioglitazone

Fundamental and Clinical Pharmacology — Wed, 09 Sep 2009 23:00:00 +0100

Recent trials of intensive glycaemic control in patients with type 2 diabetes and its impact on cardiovascular disease have led to confusion and speculation amongst physicians. The Action to Control Cardiovascular Risk in Diabetes Study was terminated early because of a significant excess all-cause mortality in the intensively-treated group. Furthermore the ADVANCE and VADT trials did not demonstrate cardiovascular benefit with more intensive glycaemic control. Against this background, it is pertinent to re-visit and critically appraise the results of the PROactive study which examined the effects of the thiazolidinedione, pioglitazone, on cardiovascular end-points in a large, randomized, placebo-controlled clinical trial in type 2 diabetic patients with symptomatic disease. PROactive has ...

The effect of nitroglycerin tolerance on oxidative stress and anaerobic sulfur metabolism in rat tissues

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

In conclusion, the results obtained in the liver and kidney confirm the involvement of oxidative stress in the pathomechanism of GTN tolerance, and reveal the diverse effects of this phenomenon on the [gamma]GT and GST activity and SNT level in both organs. We observed for the first time that GTN tolerance could be accompanied by the disruption of hepatic anaerobic cysteine metabolism, associated with sulfane sulfur and rhodanese activity. (Source: Fundamental and Clinical Pharmacology)

Thioctic acid protects against carrageenan-induced acute inflammation in rats by reduction in oxidative stress, downregulation of COX-2 mRNA and enhancement of IL-10 mRNA

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

In this study, the protective role of the known antioxidant, thioctic acid, in carrageenan-induced acute inflammation in rats was assessed and was compared to the reference non-steroidal anti-inflammatory drug (NSAID) indomethacin. In addition, the roles of oxidative stress, nitric oxide (NO), inducible cyclooxygenase isoform (COX-2) and interleukin (IL)-10 mRNA expressions in thioctic acid-induced effects were also investigated. Inflammation was induced by injection of 0.1 ml of 1.5% carrageenan into the plantar side of right hind paws of the rats. Thioctic acid (50, 100 or 200 mg/kg), indomethacin (10 mg/kg), DMSO and saline were injected i.p. 2 h before carrageenan injection. The percentage increase in paw weight was calculated. Frozen hind paw were used for estimation of lipid peroxide...

Ethanol-induced relaxation of mouse esophagus: subcellular mechanisms

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

Ethanol (164 mm) produced reproducible relaxations in isolated mouse esophageal strips. Hexamethonium (10[ndash]500 [mu]m), a ganglionic blocking agent, and lidocaine (10[ndash]100 [mu]m), a local anesthetic agent, failed to affect the relaxations induced by ethanol in the mouse esophagus. Although verapamil (10[ndash]500 [mu]m), a selective blocker of L-type Ca2+ channels, failed to affect the relaxations to ethanol, ruthenium red (10[ndash]100 [mu]m), a selective blocker of ryanodine receptors (intracellular Ca2+ channels), and cyclopiazonic acid (1[ndash]10 [mu]m), a selective blocker of sarcoplasmic reticulum Ca2+ ATPase (SERCA), significantly inhibited these relaxations. In addition, tetraethylammonium (10[ndash]100 [mu]m), a potassium-selective ion channel blocker and N[omega]-nitro-...

Effects of β-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

[beta]-Aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this [beta]-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts cause...

Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

Two 5HT1A receptor agonists and chlordiazepoxide were examined in open-field, elevated plus maze, and emergence tests. At doses with no effect in the open-field, chlordiazepoxide increased open and open/total arm visits as well as open arm duration in the elevated plus maze, whereas 5HT1A receptor agonists showed an anxiolytic response on a single measure. The anxiolytic action of chlordiazepoxide was limited to the less active BALB/c strain. Unlike the 5HT1A receptor agonists, chlordiazepoxide was also anxiolytic in the emergence test, once again only in BALB/c and not C57BL/6J mice. Significant correlations were found between emergence latencies and specific indicators of anxiety in the elevated plus-maze in chlordiazepoxide-treated but not in mice treated with buspirone and 8-OH-DPAT. T...

Evaluation of various gentamicin dosage regimens in geriatric patients: a simulation study

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

The aim of this simulation study was to evaluate the ability of three regimens proposed in official French recommendations for gentamicin to hit defined pharmacokinetic (PK) and pharmacodynamic targets in a population of elderly patients. The first drug regimen tested consisted of a loading dose of 1 mg/kg and a maintenance dose weighted by creatininemia, every 8 h. The second regimen consisted of a fixed dose of 1 mg/kg at various intervals of time, calculated from creatinine clearance. The last regimen was a fixed dose of 3 mg/kg once a day. All regimens were for 5 days. We used a bicompartmental PK model and implemented a Monte Carlo simulation to generate a large sample of geriatric subjects. The analysis examined three ranges of creatinine clearance. Simulations showed that for the tw...

Antithrombotic therapy for heart failure in sinus rhythm

Fundamental and Clinical Pharmacology — Thu, 03 Sep 2009 23:00:00 +0100

Although the risk of thromboembolism in chronic heart failure is high even in the absence of atrial fibrillation, the risk to benefit ratio of anticoagulation vs. antiplatelet therapy or no antithrombotic therapy is poorly defined in this population. Post hoc analysis of large therapeutic heart failure trials has estimated the risk of thromboembolism to be between 1 and 4.5%. However, most of these studies have included some patients with atrial fibrillation, and thromboembolism was not a predefined endpoint. At present, the evidence for either anticoagulation or antiplatelet therapy is limited and the results from current large-scale randomized studies are awaited. From the randomized studies carried out thus far, there is a beneficial trend in favour of anticoagulation therapy, with less...

Gender differences in the treatment of chronic ischemic heart disease: prognostic implications

Fundamental and Clinical Pharmacology — Sun, 30 Aug 2009 23:00:00 +0100

Despite the relatively high prevalence of coronary artery disease in women, there are little data on the investigation and treatment of ischemic heart disease in this population. In the last couple of decades authors have addressed health problems in minorities, including women. The great majority of these studies included the acute coronary syndrome population but most recent ones have focused on the management of stable angina from a gender perspective. Many of those studies showed that there are inequities between genders regarding the care of patients with ischemic heart disease. Although little is known about the prognostic implications of such differences, studies have shown that suboptimal treatment in women leads to poor clinical outcomes. Gender-specific and both epidemiological a...

Effect of two oral doses of 17β-estradiol associated with dydrogesterone on thrombin generation in healthy menopausal women: a randomized double-blind placebo-controlled study

Fundamental and Clinical Pharmacology — Sat, 29 Aug 2009 23:00:00 +0100

Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17[beta]-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17[beta]-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation proce...

Correlation of seizures and biochemical parameters of oxidative stress in experimentally induced inflammatory rat models

Fundamental and Clinical Pharmacology — Sat, 29 Aug 2009 23:00:00 +0100

The role of oxidative stress in the pathogenesis of various conditions including epilepsy, inflammatory bowel disease and rheumatoid arthritis is evolving. The aim of this study was to find out the correlation between various inflammatory models with seizures and antioxidant parameters. Fifty-four male rats were divided into three groups of colitis, adjuvant arthritis and cotton wool granuloma (CWG). Each group had three subgroups of control, model and treatment. Thalidomide was used as treatment in colitis and arthritis group, whereas etoricoxib was used in CWG group. In colitis and arthritis groups, thalidomide was administered for 3 and 17 days, respectively, whereas etoricoxib was administered for 7 days in CWG group. At the end of treatment protocols, a subconvulsive dose of pentylene...

Adaptive designs for Phase I dose-finding studies

Fundamental and Clinical Pharmacology — Sun, 23 Aug 2009 23:00:00 +0100

This article discusses the current atmosphere and attitude towards adaptive designs and focuses on the influence of Bayesian approaches. (Source: Fundamental and Clinical Pharmacology)

Stereoselective renal tubular secretion of cetirizine enantiomers – initial plasma and urine data analysis may hold the key

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

(Source: Fundamental and Clinical Pharmacology)

Protective effect of quercetin, a polyphenolic compound, on mouse corpus cavernosum

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

Flavonoids are plant-based phenolic compounds, and quercetin is the most abundant dietary member of this family. One of the most important characteristics of quercetin is its antioxidant property. The aim of this study was to investigate antioxidant effects of quercetin on corpora cavernosa of mice. Corpora cavernosa were isolated in organ baths, precontracted with phenylephrine (0.5 [mu]m) and relaxant responses were mediated by acetylcholine (0.1[ndash]1 [mu]m), electrical field stimulation (EFS, 1[ndash]16 Hz, 0.5 ms, 30 V) or acidified sodium nitrite (a NaNO2, 0.5 mm). Superoxide anion generators; pyrogallol (50 [mu]m), hydroquinone (100 [mu]m), LY 83583 (6-Anilinoquinolin-5,8-quinone, 10 [mu]m) and superoxide dismutase (SOD) inhibitor; diethyldithiocarbamic acid (DETCA, 8 mm) were use...

Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

In conclusion our study augments existing data on transporter expression in the lactating mammary gland. These data should facilitate investigations into lactation-stage dependent changes in drug or nutrient milk-to-serum concentration ratios, the potential for drug[ndash] or disease[ndash]transporter interactions, and mechanistic studies of transporter function in the lactating mammary gland. (Source: Fundamental and Clinical Pharmacology)

Authors' reply

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

(Source: Fundamental and Clinical Pharmacology)

Paroxetine inhibited the relaxations induced by EFS in mice corpus cavernosum: is it a NOS inhibition?

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

Selective serotonin reuptake inhibitors are used in the treatment of psychiatric disorders but are associated with high incidence of sexual dysfunction such as ejaculation disorders by sertraline and fluoxetine, erection disorders by paroxetine. The aim of this study is to evaluate the effects of paroxetine, sertraline and fluoxetine on relaxation of smooth muscle of corpus cavernosum on the basis of nitric oxide (NO). Male mice were killed by cervical dislocation and their penile tissues were immediately removed. The tissues were incubated in organ baths containing Krebs solution at 37°C and bubbled with 95% O2 and 5% CO2. The corpus cavernosum strips were contracted with 10[minus]5 m phenylephrine (PHE) and relaxed with either paroxetine, sertraline, fluoxetine (10[minus]8[ndash]10[minu...

Pharmacogenetic of response efficacy to antipsychotics in schizophrenia: pharmacodynamic aspects. Review and implications for clinical research

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

We present this gene-by-gene approach while detailing the features of the polymorphisms being studied (functionality, linkage disequilibrium) and the features of the studies (studied treatment(s), prospective/retrospective study, pharmacological dosage). We discuss the heterogeneity of the results and their potential clinical implications and extract methodological suggestions for the future concerning phenotype characterization, genotypes variants studied and methodological and statistical approach. (Source: Fundamental and Clinical Pharmacology)

Unravelling the complex dissociation of [3H]-rimonabant from plated CB1 cannabinoid receptor-expressing cells

Fundamental and Clinical Pharmacology — Thu, 20 Aug 2009 23:00:00 +0100

The dissociation profile of the antagonist [3H]-rimonabant from recombinant CB1 cannabinoid receptors expressed in plated HEK293 cells followed a complex pattern when measured in medium only. After a rapid decline, the specific binding levelled off at about 20% below the initial value. To unravel the responsible mechanism(s), we examined the relative contribution of binding to cells and walls of the culture wells respectively. Washout was also performed in the presence of an excess of unlabelled ligand and/or bovine serum albumin (BSA). The findings suggest that dissociated [3H]-rimonabant molecules not only undergo rebinding to the same or neighbouring receptors but also partition in the cell membranes and fix to the walls. As these non-receptor associations still occur in presence of unl...

Quercitrin, a bioflavonoid improves glucose homeostasis in streptozotocin-induced diabetic tissues by altering glycolytic and gluconeogenic enzymes

Fundamental and Clinical Pharmacology — Mon, 17 Aug 2009 23:00:00 +0100

The present study is an investigation into the role of quercitrin on carbohydrate metabolism in normal and streptozotocin (STZ)-induced diabetic rats. Administration of STZ leads to a significant increase (P < 0.05) in fasting plasma glucose and a decrease in insulin levels. The content of glycogen is significantly decreased (P < 0.05) in liver and muscle, but increased in the kidney. The activity of hexokinase decreased whereas the activities of glucose 6-phosphatase and fructose 1,6-bisphosphatase significantly increased (P < 0.05) in the tissues. Oral administration of quercitrin (30 mg/kg) to diabetic rats for a period of 30 days resulted in significant (P < 0.05) alterations in the parameters studied but not in normal rats. A decrease of plasma glucose and increase in insulin levels w...

Selecting healthy volunteers in specific populations: a retrospective analysis of clinical and laboratory screening

Fundamental and Clinical Pharmacology — Sun, 16 Aug 2009 23:00:00 +0100

Healthy volunteers must undergo a medical examination before enrolment in a clinical trial. An increasing number of trials include specific populations designed to match the target populations of the drugs tested. Our study aimed at evaluating which investigations are the most appropriate in different sub-populations of healthy volunteers. Data from 350 healthy volunteers who attended our Research Center from 1997 to 2004 were retrospectively analysed. Volunteers were distributed into five sub-populations: young men, senior men, overweight men, young women, postmenopausal women. The screening procedure comprised a review of medical history, physical examination, electrocardiogram and laboratory tests. Ineligibility criteria were classified as non-medical causes, protocol specific medical c...

Pre-medication and renal pre-conditioning: a role for alprazolam, atropine, morphine and promethazine

Fundamental and Clinical Pharmacology — Sun, 16 Aug 2009 23:00:00 +0100

This study suggested a protective effect of these pre-medication drugs on I/R injury. Although obvious studies are required, these findings may lead to effective therapies against I/R injury. (Source: Fundamental and Clinical Pharmacology)

Antihypertensive drugs and risk of venous thromboembolism: results from the EDITH case–control study

Fundamental and Clinical Pharmacology — Sun, 16 Aug 2009 23:00:00 +0100

This report from a hospital-based case[ndash]control study included 785 cases with confirmed unprovoked VTE and their 785 age- and sex-matched controls. Cases and controls were asked for drug exposure in a one-to-one standardized interview using the same questionnaire. Drug exposure was defined as current use of drugs at admission with onset at least 1 week ago. Three hundred and eighty-four out of 785 cases (48.9%) and 379 out 785 controls (48.3%) reported that they were currently using at least one antihypertensive drug. Among all antihypertensive therapies, only angiotensin II receptor blockers were significantly associated with a reduced risk for VTE: adjusted conditional odds ratio (OR) 0.45 (95% CI, 0.29[ndash]0.70). In this hospital-based case[ndash]control study, a preventive role ...

Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: which drugs for which patients?

Fundamental and Clinical Pharmacology — Thu, 13 Aug 2009 23:00:00 +0100

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potent...

Haplotype structure and allele frequencies of CYP2B6 in Spaniards and Central Americans

Fundamental and Clinical Pharmacology — Thu, 13 Aug 2009 23:00:00 +0100

This study was aimed to investigate the potential differences in allele frequencies of the CYP2B6 gene between Spaniards and Central Americans. Three single nucleotide polymorphisms of the CYP2B6 gene 516 G>T, 785 A>G and 1459 C>T were assayed by a polymerase chain reaction in 180 Spaniards and 182 Central Americans. The allele frequencies for CYP2B6*1, CYP2B6*4, CYP2B6*5, CYP2B6*6, CYP2B6*9 in Spaniards and Central Americans were 0.593 and 0.642, 0.062 and 0.073, 0.113 and 0.030, 0.215 and 0.230, 0.014 and 0.023, respectively. CYP2B6*5 was less prevalent among Central Americans than in Spaniards (P < 0.001). In comparison to other previously studied populations, the CYP2B6*5 allele frequency among Spaniards was similar to other Caucasian or African groups, and higher than that in Asian po...

Protective effect of p-methoxyl-diphenyl diselenide in lethal acute liver failure induced by lipopolysaccharide and d-galactosamine in mice

Fundamental and Clinical Pharmacology — Thu, 13 Aug 2009 23:00:00 +0100

In this study, no alteration in ascorbic acid levels was observed in livers of mice exposed to LPS/d-GalN. Glutathione-S-transferase (GST) activity was stimulated by LPS/d-GalN exposure and p-methoxyl-diphenyl diselenide, at all doses, protected against this alteration. p-Methoxyl-diphenyl diselenide was effective in ameliorating inhibition of catalase activity induced by LPS/d-GalN exposure. Histological data showed that sections of livers from LPS/d-GalN-treated mice presented massive hemorrhage, inflammatory cells and necrosis. p-Methoxyl-diphenyl diselenide significantly attenuated LPS/d-GalN-induced hepatic histopathological alterations. Based on the results, we suggest the hepatoprotective effect of p-methoxyl-diphenyl diselenide on acute liver injury induced by LPS/d-GalN exposure i...

Effect of chronic pre-treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion

Fundamental and Clinical Pharmacology — Thu, 13 Aug 2009 23:00:00 +0100

Impaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient's morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia-induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia[ndash]reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham-operated animals (n = 1...

Combined therapy in the treatment of dyslipidemia

Fundamental and Clinical Pharmacology — Thu, 13 Aug 2009 23:00:00 +0100

This systematic review analyses the efficacy, tolerability and safety of combinations of different medicines used to treat dyslipidemias in clinical practice. A PubMed search up to January 2009, was conducted to identify relevant studies. Criteria used to identify studies included (1) English language, (2) published studies with original data or meta-analyses in peer-reviewed journals. Although statin treatment is a mainstay of dyslipidemia management today, complementary effects of other lipid-lowering and/or HDL-cholesterol-raising therapies might substantially increase the clinical benefits not only in the small minority of patients with severe dyslipidemias but in others as well. These therapies include combinations with bile acid sequestrants (cholestyramine, colestipol, colesevelam),...

Lasting reduction of postsurgical hyperalgesia after single injection of botulinum toxin type A in rat

Fundamental and Clinical Pharmacology — Thu, 13 Aug 2009 23:00:00 +0100

A single injection of low doses of botulinum toxin type A (3.5 U/kg) completely abolished secondary mechanical hyperalgesia throughout its duration in a model of post surgical pain after gastrocnemius incision in rat. (Source: Fundamental and Clinical Pharmacology)

Effect of soybean administration on the pharmacokinetics of carbamazepine and omeprazole in rats

Fundamental and Clinical Pharmacology — Wed, 12 Aug 2009 23:00:00 +0100

Influence of soybean administration on the bioavailability of carbamazepine and omeprazole was studied after single dose administration of soybean (10 g/kg p.o.) or after chronic administration of soybean (50% w/w mixed with normal feed) for 15 days in rats. Carbamazepine was administered orally at a dose of 10 mg/kg and omeprazole at a dose of 20 mg/kg. Soybean decreased the bioavailability of carbamazepine after both single dose and chronic administration. It produced a significant decrease in Cmax, Tmax, AUC0[ndash]t of carbamazepine after single dose administration and increased the plasma clearance and Vd along with decrease in Cmax, Tmax, AUC0[ndash]t and AUC0[ndash][infin] after chronic administration. On the contrary, soybean administration increased the bioavailability of omeprazo...

Vasorelaxant effects of the monoterpenic phenol isomers, carvacrol and thymol, on rat isolated aorta

Fundamental and Clinical Pharmacology — Wed, 12 Aug 2009 23:00:00 +0100

In conclusion, thymol and carvacrol induced an endothelium-independent relaxation in rat isolated aorta, an effect that seems mediated through some mechanisms probably involving a transduction pathway between Ca2+ release from sarcoplasmic reticulum and/or regulation of the Ca2+ sensitivity of the contractile system. Moreover, it's conceivable that thymol and carvacrol, at low concentrations, block the Ca2+ influx through the membrane. (Source: Fundamental and Clinical Pharmacology)

Association between inosine triphosphate pyrophosphohydrolase deficiency and azathioprine-related adverse drug reactions in the Chinese kidney transplant recipients

Fundamental and Clinical Pharmacology — Wed, 12 Aug 2009 23:00:00 +0100

This study demonstrates that ITPA activity reduced in patients with 94C>A mutation (P < 0.01). Patients with ITPA 94C>A homozygous allele are at high risk to develop AZA-related gastrointestinal toxicity and flu-like symptoms (P < 0.01). TPMT wild-type/ITPA variant (homozygote) is closely related to the AZA-induced side effects (P < 0.01). (Source: Fundamental and Clinical Pharmacology)

Combined therapy in the treatment of hypertension

Fundamental and Clinical Pharmacology — Wed, 12 Aug 2009 23:00:00 +0100

The majority of patients with hypertension need at least two antihypertensive agents to achieve blood pressure (BP) objectives. As current European guidelines for the treatment of arterial hypertension recommend, combined therapy is required when monotherapy fails and as a first-line treatment in certain situations, such as subjects at high or very high cardiovascular risk, markedly elevated BP values, or when lower targets are required ( (Source: Fundamental and Clinical Pharmacology)

Medical and non-medical direct costs of chronic low back pain in patients consulting primary care physicians in France

Fundamental and Clinical Pharmacology — Tue, 11 Aug 2009 23:00:00 +0100

A retrospective, observational, cohort study in primary care. To determine the total direct medical and non-medical cost of chronic low back pain (LBP) in France and its associated factors. Chronic LBP affects 5[ndash]10% of the population its burden in France is unknown. Ninety-eight randomly selected general practitioners included 796 adult patients with chronic LBP between October 2001 and December 2002. Direct costs due to physician visits, investigations, medications, hospitalizations, and other medical and non-medical resource use were collected for the 6 months prior to study visit. Costs both reimbursed and not by the French health insurance system were considered. Quality of life (QoL) and disease severity were measured using Short Form (SF)-8 and Roland-Morris disability question...

Ellagic acid and its methyl-derivatives inhibit a newly found nitratase activity

Fundamental and Clinical Pharmacology — Tue, 11 Aug 2009 23:00:00 +0100

We presently found that ellagic acid (EA) and its methylated derivatives, 4,4'O-methyl- and 3,3'O-methyl-ellagic acids (MeEA1 and MeEA2, respectively), amphipathic phenolic components of certain fruits and beverages, were also able to inhibit this activity, with a total inhibition for EA and a 60% inhibition for MeEA1 and MeEA2. EA exhibited the highest affinity for protein plasma, whereas a higher affinity of MeEA1 and MeEA2 (with MeEA1 > MeEA2) than EA was found for lipoprotein fractions, suggesting that the inhibition-driving property is protein affinity. As a result of this nitratase-inhibition property EA and its natural metabolite MeEA2 may have a beneficial role in special physiopathological conditions. (Source: Fundamental and Clinical Pharmacology)

Droperidol and ondansetron in vitro electrophysiological drug interaction study

Fundamental and Clinical Pharmacology — Tue, 11 Aug 2009 23:00:00 +0100

Droperidol and ondansetron are potent anti-emetic agents which are often administered together. Although both drugs prolong QT interval in man by inhibition of Human Ether-a-go-go Related Gene-coded potassium channels, only droperidol was tested using more integrated experimental models. Therefore, we studied the effects of both compounds and their combination on action potentials (AP) of rabbit Purkinje fibers using conventional intracellular glass microelectrode. Purkinje fibers, driven at 1 Hz, were exposed to increasing concentrations (from 0.001 to 10 [mu]m) of droperidol (n = 7) or ondansetron (n = 8) at 30 min intervals at 36.5°C. Other fibers were exposed to a constant droperidol concentration (0.1 [mu]m) alone (n = 7) or together with the same increasing concentrations of ondanse...

The comparison of the effects of anesthetic doses of ketamine, propofol, and etomidate on ischemia–reperfusion injury in skeletal muscle

Fundamental and Clinical Pharmacology — Tue, 11 Aug 2009 23:00:00 +0100

In conclusion, ketamine, propofol, and etomidate, with anesthetic doses, denoted efficacious effects on IRI; hence the drugs might be preferred in certain operations with the risk of IRI. (Source: Fundamental and Clinical Pharmacology)

Aspirin in the secondary prevention of cardiovascular disease: an update of the APTC meta-analysis

Fundamental and Clinical Pharmacology — Tue, 11 Aug 2009 23:00:00 +0100

We updated the 2002 Antiplatelet Trialists' Collaboration meta-analysis of antiplatelet therapy to assess the effects of aspirin alone in the secondary prevention of different types of thrombotic arterial disease. Results of randomized, placebo-controlled trials of aspirin in patients with confirmed cardiovascular disease were abstracted and synthesized by the Mantel[ndash]Haenszel method. We defined three cardiovascular disease groups according to the qualifying disease at entry: coronary artery disease (CAD), cerebrovascular disease (CRVD), and peripheral arterial disease (PAD). Results are given as odds ratios (OR) and 95% confidence intervals (95% CI). Compared with placebo, aspirin decreased significantly the risk of all-cause death in CAD and CRVD (OR = 0.80, 95% CI 0.75[ndash]0.86 a...

Molecular aspects of ischaemic postconditioning

Fundamental and Clinical Pharmacology — Wed, 05 Aug 2009 23:00:00 +0100

Preconditioning, a well established phenomenon had been used since 1980s to attenuate ischaemia-reperfusion induced injury. However, inability to predict the onset of ischaemia in clinical settings led to the discovery of a new concept of postconditioning (PoCo), in 2000s whereby brief repetitive cycles of ischaemia with intermittent reperfusion followed by prolonged ischaemia-elicited tissue protection. There is an impressive array of molecular mechanisms contributing to PoCo-mediated tissue-protection, which include triggers like adenosine (ADO), opioid, erythropoietin (EPO), endogenous nitric-oxide, reactive oxygen species, acetylcholine, tissue factors, pro-inflammatory cytokines and bradykinin; mediators like reperfusion injury salvage kinase pathways including phosphoinositide-3-kina...

Recurrent dysosmia induced by pyrazinamide

Fundamental and Clinical Pharmacology — Wed, 05 Aug 2009 23:00:00 +0100

We report a case of reversible olfactory disorder related to pyrazinamide in a woman, with a positive rechallenge. The patient presented every day a sensation of smelling something burning 15 min after drug intake. Dysosmia disappeared completely after pyrazinamide withdrawal and recurred after its rechallenge. The case was reported to the Tunisian Centre of Pharmacovigilance. (Source: Fundamental and Clinical Pharmacology)

Non-adrenergic non-cholinergic inhibition of gastrointestinal smooth muscle and its intracellular mechanism(s)

Fundamental and Clinical Pharmacology — Wed, 05 Aug 2009 23:00:00 +0100

Relaxation of gastrointestinal smooth muscle caused by release of non-adrenergic non-cholinergic (NANC) transmitters from enteric nerves occurs in several physiologic digestive reflexes. Likely candidate NANC inhibitory agents include nitric oxide (NO), adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), carbon monoxide (CO), protease-activated receptors (PARs), hydrogen sulfide (H2S), neurotensin (NT) and beta-nicotinamide adenine dinucleotide ([beta]-NAD). Multiple NANC transmitters work in concert, are pharmacologically coupled and are closely coordinated. Individual contribution varies regionally in the gastrointestinal tract and between species. NANC inhibition of gastrointestinal smooth muscle involves several int...

Gastroprotection of (-)-α-bisabolol on acute gastric mucosal lesions in mice: the possible involved pharmacological mechanisms

Fundamental and Clinical Pharmacology — Sun, 02 Aug 2009 23:00:00 +0100

In conclusion, gastroprotective effect on ethanol and indomethacin-induced ulcer promoted by (-)-[alpha]-bisabolol may be associated with an increase of gastric sulfydryl groups bioavailability leading to a reduction of gastric oxidative injury induced by ethanol and indomethacin. (Source: Fundamental and Clinical Pharmacology)

Pharmacokinetics and safety of olmesartan medoxomil in combination with either amlodipine or atenolol compared to respective monotherapies in healthy subjects

Fundamental and Clinical Pharmacology — Thu, 30 Jul 2009 23:00:00 +0100

The aim of this study was to investigate any influence on olmesartan plasma pharmacokinetics from amlodipine or atenolol. We analysed pharmacokinetics and safety of olmesartan medoxomil in combination with either amlodipine or atenolol compared to respective monotherapies in two separate studies. In one study, 18 subjects received once daily treatment for 7 days with olmesartan medoxomil 20 mg alone or with amlodipine 5 mg or amlodipine 5 mg alone. In the other study, atenolol 50 mg once daily replaced amlodipine. Concentration vs. time profiles for olmesartan monotherapy were similar to combination therapy. Mean olmesartan AUCss,[tau] for olmesartan alone and with amlodipine were 2439 and 2388 ng h/mL and for olmesartan alone and with atenolol were 2340 and 2247 ng h/mL. Corresponding olm...

Pharmacokinetics of rituximab associated with CHOP chemotherapy in B-cell non-Hodgkin lymphoma

Fundamental and Clinical Pharmacology — Tue, 28 Jul 2009 23:00:00 +0100

The pharmacokinetics of rituximab administered alone at a dose of 375 mg/m2 once a week have been widely studied but few data are available for the administration of rituximab in combination with other agents. We carried out a pilot pharmacokinetic study in 10 patients with B-cell non-Hodgkin lymphoma treated with rituximab associated with chemotherapy on a three-weekly basis. Patients received four courses of rituximab (375 mg/m2) associated with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) at 21-day intervals. Blood samples were collected from each patient at selected times throughout the treatment period and analysed using a validated enzyme-linked immunosorbent assay. The nonmem software was used to obtain population and post hoc estimates of rituximab pharmacokineti...

Early worsening heart failure in patients admitted with acute heart failure – a new outcome measure associated with long-term prognosis?