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 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: 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.
  • Pharmacology &amp Toxicology 03/2009; 66(s3):144 - 148.
  • Pharmacology &amp Toxicology 03/2009; 61(s3):1 - 55.
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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.
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    ABSTRACT: The sympathoinhibitory effects of ketanserin were investigated in the spontaneously hypertensive rat. In conscious rats ketanserin (0.1–10.0 mg/kg intravenously caused dose-related reductions in blood pressure and heart rate (carotid artery). The heart rate reduction was prevented by chemical sympathectomy (reserpine) and in anaesthetized rats the heart rate reduction was correlated to a reduction in the directly recorded preganglionic sympathetic activity in the left renal nerve. Ketanserin had no presynaptic effects on the sympathetic nerve terminals as evidenced by the lack of effect on the tachycardia induced by electrical stimulation of the sympathetic outflow in pithed rats. In rats, catecholamine-depleted by reserpine, the heart rate reduction was prevented, and in atropine-pretreated animals there was a partial blockade of the bradycardic effect. We conclude that the lack of reflexogenic tachycardia in response to the hypotension induced by ketanserin treatment is partly due to a preganglionic inhibition of sympathetic nerve activity.
    Pharmacology &amp Toxicology 03/2009; 64(4):352 - 355.
  • Pharmacology &amp Toxicology 03/2009; 72(s1):176 - 179.
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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: 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.
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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.
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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: The pathophysiologic effects of anatoxin-a(s) from the cyanobacterium Anabaena flos-aquae NRC-525-17 were investigated in anaesthetized adult male Sprague Dawley rats given the toxin by continuous intravenous infusion until death. Rats (n=6) pretreated with atropine sulfate (50 mg/kg) intraperitoneally survived significantly longer (P<0.05) than non-atropinized rats (n = 6), suggesting that the muscarinic effects of anatoxin-a(s) were important in the lethal syndrome. In contrast to rats only given toxin, rats that were pretreated with atropine had a decrease in heart rate and mean blood pressure that followed profound reductions in respiratory tidal and minute volume, suggesting that neuromuscular blockade of the muscles of respiration was the cause of death. Even when survival time of rats was increased by pretreatment with atropine, phrenic nerve amplitude increased, indicating a lack of a depressive effect of anatoxin-a(s) on central mediation of respiration. Rats (n=3) continuously ventilated during toxin infusion survived a dose more than 4 fold greater than a consistently lethal dose of the toxin. Thus, the cardiovascular effects of anatoxin-a(s) alone could not account for the death of rats. Electromyographic activity recorded from the diaphragms of rats (n=5) during continuous toxin administration revealed an increase in muscular electrical activity that became more random and finally decreased prior to death, suggesting a toxin-induced neuromuscular blockade in vivo which ultimately was the cause of death of the anatoxin-a(s) dosed rats.
    Pharmacology &amp Toxicology 03/2009; 67(2):151 - 155.
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    ABSTRACT: All guidelines recommend short-acting inhaled β2-adrenoceptor agonists as the first-line drugs in acute asthma attacks and inhaled corticosteroids as the drugs of choice when regular daily treatment is needed. Short-acting inhaled β2-adrenoceptor agonists are not effective in reducing nocturnal awakenings because of their short duration of action. In addition there has been an intense debate about the regular use of these drugs. This debate is reviewed. They shold only be used on "as needed basis". The Swedish guidelines for the treatment of asthma were the first to recommend the new long-acting inhaled β2-adrenoceptor agonists at relatively early stage of the illness (800 μg daily of inhaled corticosteroids). Two recently completed large multicentre studies with salmeterol in asthmatics support this opinion. Both studies showed a better asthma control with a combination of a low inhaled steroid dose and salmeterol compared to a doubling of the steroid dose. In most asthmatic patients, still symptomatic on inhaled steroids doses 400 to 800 μg daily, a test of the addition of inhaled salmeterol is recommended. The steroid dose can be kept low and safe. However, asthmatic patients with either frequent or severe exacerbations should primarily have their steroid dose increased.
    Pharmacology &amp Toxicology 03/2009; 78(1):3 - 11.
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    Pharmacology &amp Toxicology 03/2009; 63(1):1 - 7.
  • Pharmacology &amp Toxicology 03/2009; 66(s4):1 - 31.
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    ABSTRACT: Simultaneous computer modelling of control and guanfacine-masked [3H]-MK 912 saturation curves as well as guanfacine competition curves revealed that both α2A- and α2C-adrenoceptor subtypes were present in the guinea pig cerebral cortex. The Kd value of [3H]-MK 912 determined for the α2A-subtype was 403 pM and for the α2C-subtype 79.8 pM; the receptor sites showing capacities 172 and 19.5 fmol/mg protein, respectively. The Kds of guanfacine were 20 and 880 nM for the α2A- and α2C-adrenoceptor, respectively. In the guinea pig kidney [3H]-MK 912 bound to a single saturable site with Kd 8.34 nM and capacity 285 fmol/mg protein, the site showing pharmacological properties like an α2B-adrenoceptor. Binding constants of 22 compounds for the three guinea pig α2-adrenoceptor subtypes were determined by computer modelling competition curves using for the cerebral cortex a “3-curve assay”, for the kidney an “1-curve assay”, and using [3H]-MK 912 as labelled ligand. Of the tested drugs guanfacine and BRL 44408 were found to be clearly α2A-selective. Spiroxatrine, yohimbine, rauwolscine and WB 4101, as well as [3H]-MK 912 itself, were found to be α2C-selective. The most selective compounds for α2B-adrenoceptors, when compared to α2A-adrenoceptors, were ARC 239 and prazosin. In the guinea pig kidney [3H]-p-aminoclonidine bound to α2-adrenoceptors as well as to non-adrenergic imidazoline sites. The α2-adrenoceptors could be completely blocked using 10 μM (-)-adrenaline without the non-adrenergic sites being affected. During these conditions the analysis of combined saturation and competition studies using labelled and unlabeled p-aminoclonidine with computer modelling revealed that the ligand labelled two different sites with Kds of 310 and 47,000 nM, respectively. Competition curves of 16 compounds for the non-adrenergic [3H]-p-aminoclonidine sites were shallow and resolved into two-site fits. For the high affinity [3H]-p-aminoclonidine site the highest affinities were shown by 1-medetomidine, UK-14,304, guanabenz and detomidine; the Kds of these drugs ranging 26–72 nM. All drugs tested showed low but varying affinities for the low affinity [3H]-p-aminoclonidine site. These data indicated that the [3H]-p-aminoclonidine binding sites of the guinea pig kidney are grossly different from the [3H]-idazoxan binding I2-receptors previously demonstrated also to be present in the guinea pig kidney.
    Pharmacology &amp Toxicology 03/2009; 76(6):353 - 364.