Pharmacology &amp Toxicology (Pharmacol Toxicol )


Pharmacology & Toxicology is an independent journal, publishing original scientific research in all fields of experimental pharmacology and toxicology, including biochemical, cellular and molecular pharmacology and toxicology. Manuscripts on clinical pharmacology and its aspects, pharmacodynamics and pharmacokinetics, are also accepted.

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    Pharmacology & Toxicology website
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    Pharmacology and toxicology
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Publications in this journal

  • Pharmacology &amp Toxicology 01/2012;
  • Pharmacology &amp Toxicology 05/2009; 15(4):384 - 394.
  • Pharmacology &amp Toxicology 05/2009; 15(4):373 - 383.
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    ABSTRACT: Of the known biochemical actions of caffeine, only inhibition of adenosine receptors occurs at concentrations achieved during normal human consumption of the drug. Under normal physiological conditions, adenosine is present in sufficient concentrations to activate A1 and A2a receptors. Via actions on A, receptors, adenosine decreases neuronal firing and the release of neurotransmitters. The exact mechanisms are not known, but several possibilities are discussed. Via actions on A2a receptors, adenosine - and hence caffeine - can influence dopaminergic neurotransmission. Caffeine can induce rapid changes in gene expression and, somewhat later, marked adaptive changes. These include antiepileptic and neuroprotective changes. Thus, caffeine has a number of central effects directly or indirectly related to adenosine receptors. Some of these are potentially useful, and drug development based on the actions of caffeine should be interesting.
    Pharmacology &amp Toxicology 03/2009; 76(2):93 - 101.
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    ABSTRACT: A previous study has demonstrated that the urinary level of 6 β-hydroxycortisol is a marker of liver CYP3A content after induction by rifampicin. To put in evidence an eventual genetic polymorphism for this cytochrome, the frequency distribution of 6 β-hydroxycortisol excretion was investigated in 102 healthy Caucasians before and after 6 days of oral rifampicin administration (600 mg daily). After rifampicin treatment, a wide interindividual distribution was observed but no clear bimodality. Moreover the mean 6 β-hydroxycortisol level was higher in women (n = 38) than in men (n = 64). These observations do not favour the existence of a CYP3A genetic polymorphism based on 6 β-hydroxycortisol excretion but evoke a sexual dimorphism. However, CYP3A is composed of at least four enzymes and as the enzyme(s) responsible for Cortisol 6 β-hydroxylation is (are) not perfectly known, it can not be excluded that a genetic polymorphism does exist for one enzyme of this family.
    Pharmacology &amp Toxicology 03/2009; 71(4):258 - 261.
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    ABSTRACT: In Denmark the official dietary guidelines and food recommendations are expressed in the Five Dietary Advices and the Danish food circle. Such guidelines are entirely different from recommendations on nutrient intakes, which are expressed in terms of exact values and established through a more formal procedure.Some of the most fundamental principles for food recommendations given to the public are that they are perceived as consistent and based on a firm consensus, and that their relevance and translation into practical action is obvious to the public. When the situation in Denmark is compared to these principles the main issue turns out to be neither lack of consistency in recommendations issued by government agencies and voluntary health organisations, nor is it lack of consensus among the experts about the fundamental messages of the guidelines. A more important problem is that the public does not distinguish between formal recommendations from authorized sources, and a variety of advices from other sources as well as non-formal comments from individual scientists. A cause of serious concern is the fact that the Danish public seems to lack a realistic picture of what the dietary guidelines imply in terms of foods. A number of contradictions is built into the process of communicating dietary recommendations effectively to the public. These can only be solved if the process is planned on a long-term basis.
    Pharmacology &amp Toxicology 03/2009; 72(s1):144 - 147.
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    ABSTRACT: Racemic dimercaptosuccinic acid (DMSA) was found more efficient than the meso-isoform in enhancing the removal of mercury in rats. However. racemic-DMSA has recently been found more toxic. The efficiency of combined oral treatment with the two isoforms of DMSA for removal of mercury has now been evaluated. Female albino rats were treated orally for four days with meso- (M) and/or racemic- (R) DMSA (1 mmol/kg each), five days after a single intraperitoneal administration of 203Hg with 0.5 mg HgCl2/kg. The animals were divided into six groups according to the number of treatments with each isomer: control (untreated), 4M, 1R + 3M, 2R + 2M, 3R+1M, and 4R. Whole body, kidney, liver and brain mercury contents were measured nine days after 203Hg administration. In all treated groups retention in the whole body and kidneys was greatly reduced. The groups treated with racemic-DMSA, regardless of the number of doses, showed a greater removal of mercury than the group treated with meso-DMSA alone (4M). All treatments were less efficient in reducing liver retention, and the brain retention was not affected. It was concluded that even a single application of the more toxic racemic-DMSA during a four-day oral treatment regimen is sufficient to improve the removal by meso-DMSA of mercury from rats.
    Pharmacology &amp Toxicology 03/2009; 81(5):242 - 244.
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    ABSTRACT: Two progesterone metabolites 3-hydroxy-5-pregnan-20-one (5-) and 3-hydroxy-5β-pregnan-20-one (5-β) were investigated for anaesthetic potency in male rats with an EEG-threshold method. Dose rate curves were obtained by infusing 5- and 5β intravenously with different rates until an EEG-criterion (a burst suppression of one sec. or more, the “silent second”) was seen in the EEG. The potency of the investigated drugs has been estimated by comparing threshold doses at optimal infusion rates. 5- and 5-β were tested on both young (44 to 46 days) and adult (109 to 118 days) rats. The relation between age and the anaesthetic sensitivity of 5-β was tested by weekly threshold determinations. 5- and 5-β infused separately with different infusion rates gave almost V-shaped dose rate curves. The optimal infusion rate was in all age groups 2 mg/kg/min. In young rats 5- (6.7 mg/kg) was more potent than 5-β (8.9 mg/kg). In adult rats the sensitivity was increased but the relation in potency between 5- (5.1 mg/kg) and 5-β (6.6 mg/kg) was unchanged. With 5-β the main change in this age-related increase in anaesthetic sensitivity was seen between 49 and 70 days of age. Both 5- and 5-β exhibited an excitatory action seen as jerks during induction of the EEG-criterion.
    Pharmacology &amp Toxicology 03/2009; 61(1):42 - 47.
  • Pharmacology &amp Toxicology 03/2009; 78(s1):1 - 26.
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    ABSTRACT: Repeated administration of cocaine to animals results in sensitization to several reactions to the drug, including seizures and mortality. These consequences are thought to be related to the pathology that develops in humans abusing cocaine. Previous studies implied the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors in cocaine-induced toxicity, and recent studies documented a role for nitric oxide in NMDA-receptor mediated neurotoxicity. The present study was undertaken to determine whether nitric oxide synthase inhibitors block the development of sensitization to the toxic effects of cocaine in mice. Repeated administration of cocaine (45 mg/kg/day; intraperitoneally) to Swiss Webster mice, for 7 days, resulted in a progressive increase in the duration of the convulsive response to cocaine, an increase in the number of animals that had seizures, and augmentation in lethality rate. Pretreatment with NG–nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/day; intraperitoneally) or NG–nitro-L-arginine (NO-Arg; 25 mg/kg/day; intraperitoneally) completely abolished the sensitization to the convulsive and lethal responses to cocaine. Receptor binding assays indicated first, that pretreatment with L-NAME apparently diminished cocaine-induced upregulation of cortical NMDA receptors, and second, that the effects of the nitric oxide synthase inhibitors tested are not mediated via a direct interaction of the drugs with the phencyclidine/NMDA receptor complex. Taken together, the present study suggests an important role for nitric oxide in the development of sensitization to the toxic effects of cocaine, and further supports the relationship between NMDA-receptor mediated neurotoxicity and nitric oxide.
    Pharmacology &amp Toxicology 03/2009; 74(3):162 - 166.
  • Pharmacology &amp Toxicology 03/2009; 61(s3):1 - 55.
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    ABSTRACT: Application of autometallography (AMG) to histological material from humans and animals exposed to gold, silver and mercury has made it possible to localize these heavy metals at light and electron microscopic levels. Because of high sensitivity of the technique, traces of the three metals have been demonstrated in tissues and cells that had previously not been suspected of containing metals. A chelatable pool of zinc in the synaptic vesicles of the zinc-positive neurones can be demonstrated by AMG in the brain. The well defined staining pattern can be used to estimate volumes of cortical subdivisions. Volumetric studies based on autometallographic differentiation of cortical regions have provided valuable information about the effects of different toxicants. AMG can be combined with new quantitative methods, such as electron energy loss spectroscopy (EELS), electron probe X-ray microanalysis (EPMA) and laser microprobe mass analysis (LAMMA), to enhance detection of AMG metal catalysts with these techniques.
    Pharmacology &amp Toxicology 03/2009; 68(6):414 - 423.
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    ABSTRACT: The antidotal efficacies of chelators during acute cadmium intoxication has previously been examined in experiments where both a soluble cadmium salt and the chelator were administered parenterally. In the present study, PA, DMSA and related compounds were studied as oral antidotes during oral CdCl2 intoxication. According to the antagonistic effects noted on mortality, peristaltic toxicity and intestinal cadmium uptake, the relative efficacies of the compounds tested were: DMSA > PAD > DMPS > MSA > PA > NAPA. None of the chelators induced major changes in the organ distribution of absorbed cadmium, in particular no increased cerebral deposition of cadmium. This study indicates that, in oral cadmium intoxication in humans, orally administered DMSA would be likely to offer protection against the local toxicity of cadmium in the gastrointestinal tract as well as to reduce the risk of systemic toxicity of absorbed cadmium.
    Pharmacology &amp Toxicology 03/2009; 63(5):386 - 389.
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    ABSTRACT: Felodipine, a potent dihydropyridine calcium antagonist with a pronounced vascular selectivity, was given intravenously (0.006-0.025 μmol kg−1) to anaesthetized, open-chest dogs with denervated hearts. The result was a dose-dependent decrease in mean arterial pressure (MAP) and total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and left ventricular end-diastolic pressure remained relatively unchanged. Cardiac tension work (TTI) and oxygen consumption (MVO2) were reduced, probably due to the decrease in afterload. The relative reduction of the coronary vascular resistance (CVR) was greater than that of TPR. The hypotensive effect of verapamil (0.05-0.20 μmol kg−1) was small and MAP decreased mainly via a decrease in HR and SV. Higher doses of verapamil which induced vasodilatation could not be given without the development of complete atrio-ventricular dissociation. Hydralazine (11-45 μmol kg−1) decreased TPR and CVR in parallel but the decrease in MAP was partly counteracted by a powerful increase in HR, SV and cardiac inotropy which was associated with elevated catecholamine levels in plasma. When MAP and HR were maintained constant by means of aortic balloon inflation and atrial pacing, felodipine markedly increased coronary blood flow and coronary sinus oxygen saturation while SV, TTI, inotropy and MVO2 remained relatively unchanged. It is concluded that felodipine markedly dilates peripheral resistance vessels, and in particular those in the coronary vascular bed, without any cardiodepressant effects.
    Pharmacology &amp Toxicology 03/2009; 68(4):310 - 315.
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    ABSTRACT: N-nitrosooxprenolol (NO-oxprenolol) might be formed in the stomach of patients taking the β-adrenergic blocking drug, oxprenolol. This nitroso derivative has previously been shown to induce DNA damage and repair in both rat and human cultured hepatocytes. The results of the present study show that in the presence of co-cultured rat hepatocytes, 0.03 mM NO-oxprenolol produced a significant increase in the frequency of 6-thioguanine-resistant but not of ouabain-resistant mutants. No mutagenic activity was detected in the absence of metabolic activation. In mice, NO-oxprenolol (1 g/kg) increased the incidence of micronucleated cells in the liver but not in the bone marrow and the spleen. These results suggest that NO-oxprenolol, consistent with its chemical nature of nitrosamine, is biotransformed into short-lived reactive species.
    Pharmacology &amp Toxicology 03/2009; 71(2):154 - 158.
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    ABSTRACT: In order to study the effects of nicotine on liver, groups of rats were given nicotine doses that simulated those seen in chronic smoking (54 and 108 μmol/l of nicotine) for 10 days. A subgroup was also given a single subcutaneous injection of 6 g/kg of carbon tetrachloride (CCl4) shortly before the animals of the group were killed. Histology demonstrated a significant hepatotoxic effect in the group receiving 108 μmol/l of nicotine when compared with the control group in the form of fatty change, focal or confluent necrosis and dark-cell change. The effects in pregnant rats were less severe. Carbon tetrachloride alone induced significant fatty change and focal necrosis in non-pregnant rats but not in pregnant rats. Nicotine also aggravated the CCl4 induced pathological changes in livers of both non-pregnant and pregnant animals. Thus nicotine alone, when given at a concentration of 108 μmol/l, exerted hepatotoxic effects; the alkaloid also aggravated the hepatotoxicity of CCl4. Pregnant rats were more resistant to the hepatotoxic effects produced by nicotine and CCl4.
    Pharmacology &amp Toxicology 03/2009; 77(3):225 - 230.
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    ABSTRACT: This investigation was aimed to study the effect of magnesium on 1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP)–induced neurotoxicity in mice. Four groups of mice were given magnesium sulfate (MgSO4.7H2O) in drinking water at four different concentrations of 0.0 g/l (control), 2.5 g/l (low), 5.0 g/l (medium) and 10.0 g/l (high) respectively for a period of 16 weeks; these animals also received MPTP (30 mg/kg, intraperitoneally daily) during the last five days of Mg treatment. Other four groups of mice were given similar dose regimen of MgSO4 but received injections of saline instead of MPTP. Seventy–two hr after the last dose of MPTP, neurobehavioural studies including locomotor activity, pole climbing test and heat nociception test were performed and striata were collected for the analysis of dopamine. The results of this study show that treatment of mice with MgSO4 or MPTP individually has no effect on their behaviour. Concomitant administration of low dose of MgSO4 (2.5 g/l) along with MPTP produced increase in motor activity and latency to heat stimuli; whereas medium and high doses of MgSO4 in combination with MPTP produced opposite (as compared to low dose) effects resulting in a decrease in motor activity and latency to heal stimuli and increase in pole climbing time. However, MgSO4 dose–dependently exacerbated MPTP–induced depletion of striatal dopamine. The mortality was drastically increased (30–55%) in the animals receiving combined treatments of MPTP and MgSO4 as compared to the mice treated with MPTP alone (12%). This study clearly points towards the ability of MgSO4 to modify MPTP–induced neurotoxicity.
    Pharmacology &amp Toxicology 03/2009; 82(5):218 - 222.
  • Pharmacology &amp Toxicology 03/2009; 72(s1):176 - 179.
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    ABSTRACT: The distribution of approximately equipotent doses of 14C-labelled clodronate (0.1 mmol/kg), etidronate (0.1 mmol/kg), and amidronate (0.015 mmol/kg), and also an equimolar dose of amidronate (0.1 mmol/kg), was studied in mice by measuring the 14C-activities in various tissues up to 360 days after a single intravenous injection. With the higher dose of amidronate the distribution could be, however, monitored only for 7 days because of the toxicity of the drug. The results indicate that there are major differences in the deposition of the bisphosphonates into soft tissues, while the disappearance from plasma and incorporation into bone are quite similar in terms of percentage of dose per g of tissue. However, the binding capacity of bone for clodronate and etidronate is many times greater than that for amidronate expressed as nmol of the drug per g of tissue. Amidronate deposits in the spleen and liver of mice, when injected in saline, whereas clodronate and etidronate do not. This agrees with the suggestion that amidronate, but not the other two, can interfere with the mononuclear phagocyte system of spleen and liver.
    Pharmacology &amp Toxicology 03/2009; 66(4):294 - 298.
  • Pharmacology &amp Toxicology 03/2009; 66(s3):144 - 148.

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