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1.	Bergdahl, Andreas, et al. (author) Lovastatin Induces Relaxation and Inhibits L-Type Ca2+ Current in the Rat Basilar Artery. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:3, s. 128-134 Journal article (peer-reviewed)abstract Statins inhibit cholesterol biosynthesis and protect against ischaemic stroke. It has become increasingly apparent that the beneficial effects of statin therapy may extend beyond lowering of serum cholesterol. The present study was done to explore possible pleiotropic statin effects at the level of the cerebral vascular smooth muscle. Lovastatin, lovastatin acid, simvastatin and pravastatin, were added to segments of the rat basilar artery and effects on contraction and Ca2+ handling were examined. Pravastatin had no effect on contraction. Simvastatin, lovastatin, and, to a lesser degree, lovastatin acid, caused relaxation (IC50=0.8, 1.9 and 22 μmol/l) of both intact and denuded arteries precontracted with 5-HT or high-K+. This effect was not reversed by mevalonate, suggesting that it was not related to cholesterol or isoprenoid metabolism. Relaxation was associated with a reduction of the intracellular Ca2+ concentration measured with Fura 2 and with a reduced Mn2+ quench rate, suggesting a direct effect on ion channels in the smooth muscle cell membrane. Current measurements in isolated and voltage clamped basilar artery muscle cells demonstrated that both lovastatin and lovastatin acid inhibit L-type Ca2+ current. We propose that lipophilicity is an important factor behind the effects of statins on vascular tone and that Ca2+ current inhibition is the likely mechanism of action.
2.	Bergdahl, Ingvar A., et al. (author) Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human erythrocytes 1997 In: Basic and Clinical Pharmacology and Toxicology. - : Wiley. - 0901-9928. ; 81:4, s. 153-158 Journal article (peer-reviewed)abstract Over 99% of the lead present in blood is usually found in erythrocytes. To investigate the nature of this selective accumulation of lead in erythrocytes, the specific binding of lead to proteins in human erythrocytes was studied using liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC-ICP-MS). The principal lead-binding protein had a mass of approximately 240 kDa, and adsorption to specific antibodies showed that protein was delta-aminolevulinic acid dehydratase (ALAD). Thus, the previous notion that lead in erythrocytes was bound primarily to haemoglobin has to be revised. Furthermore, in lead-exposed workers, the percentage of lead bound to ALAD was influenced by a common polymorphism in the ALAD gene. Specifically, in seven carriers of the ALAD2 allele, 84% of the protein-bound lead recovered was bound to ALAD compared to 81% in seven homozygotes for the ALAD1 allele whose erythrocytes were matched for blood-lead concentration. The small difference was statistically significant in Wilcoxon matched-pairs signed-rank test (P = 0.03). No ALAD allele-specific difference in ALAD-bound lead was found among 20 unexposed controls. Perhaps the difference in ALAD-bound lead can provide an explanation for the previously reported finding of higher blood-lead levels among carriers of the ALAD2 allele than among ALAD1 homozygotes in lead-exposed populations.
3.	Chen, D, et al. (author) Gastric phenotypic abnormality in cholecystokinin 2 receptor null mice 2002 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 91:6, s. 375-381 Journal article (peer-reviewed)abstract Gastrin, released from antral G-cells, plays an important role in the regulation of gastric acid secretion and is trophic for the stomach, The cholecystokinin type 2 (CCK)(2) receptor (previously referred to as CCK-B/gastrin receptors) is expressed in both parietal cells and ECL cells in the oxyntic mucosa of stomach. Gastric phenotypic abnormality has been observed in CCK2 receptor null (gene knock-out) mice. Such mice displayed markedly impaired gastric acid secretion, atrophy of the oxyntic mucosa and hypergastrinaemia. The impaired acid secretion may be the result of a reduced parietal cell mass, a reduced proportion of actively secreting parietal cells (with secretory canaliculi), and a replacement of ECL cells by histamine-free ECL-like cells. The ECL-like cells, observed in the CCK2 receptor null mice, lacked the hallmark features of wild-type ECL cells, i.e. histamine and cytoplasmic secretory vesicles. However, they had the features of endocrine cells, such as the content of pancreastatin (a fragment of chromogranin A), with cytoplasmic small dense-core granules and microvesicles. We propose that the replacement of ECL cells by ECL-like cells in the mutant mice reflects an altered differentiation of the same precursors that develop into ECL cells in wild-type mice. Thus, studies of CCK2 receptor null mice demonstrate the importance of the receptor in the regulation of gastric acid secretion and in the differentiation of ECL cells in the oxyntic mucosa of stomach.
4.	Ericsson, Peter, et al. (author) ECL Cell Histamine Mobilization Studied byGastric Submucosal Microdialysis in Awake Rats:Methodological Considerations. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:2, s. 57-65 Journal article (peer-reviewed)abstract The ECL cells are endocrine/paracrine cells in the acid-producing part of the stomach. They secrete histamine in response to circulating gastrin. Gastric submucosal microdialysis has been used to study ECL-cell histamine mobilization in awake rats. In the present study we assess the usefulness and limitations of the technique. Microdialysis probes were implanted in the gastric submucosa. Histological analysis of the stomach wall around the probe revealed a moderate, local inflammatory reaction 1-2 days after implantation; the inflammation persisted for at least 10 days. Experiments were conducted 3 days after the implantation. The "true" submucosal histamine concentration was determined by perfusing at different rates (the zero flow method) or with different concentrations of histamine at a constant rate (the no-net-flux method): in fasted rats it was calculated to be 87±5 (means±S.E.M.) nmol/l and 76±9 nmol/l, respectively. The corresponding histamine concentrations in fed rats were 93±5 and 102±8 nmol/l, respectively. With a perfusion rate of 74 mul/hr the recovery of submucosal histamine was 49%, at 34 mul/hr the recovery increased to 83%. At a perfusion rate below 20 mul/hr the microdialysate histamine concentration was close to the actual concentration in the submucosa. The ECL-cell histamine mobilization was independent of the concentrations of Ca2+ in the perfusion medium (0-3.4 mmol/l Ca2+). In one experiment, histamine mobilization in response to gastrin (10 nmol/kg/hr subcutaneously) was monitored in rats pretreated with prednisolone (60 mg/kg) or indomethacin (15 mg/kg). The two antiinflammatory agents failed to affect the concentration of histamine in the microdialysate either before or during the gastrin challenge, which was in accord with the observation that the inflammatory reaction was modest and that inflammatory cells were relatively few around the probe and in the wall of the probe. In another experiment, rats were given aminoguanidine (10 mg/kg) or metoprine (10 mg/kg) 4 hr before the start of gastrin infusion (5 nmol/kg/hr intravenously). Metoprine (inhibitor of histamine N-methyl transferase) did not affect the microdialysate histamine concentration, while aminoguanidine (inhibitor of diamine oxidase) raised both basal and gastrin-stimulated histamine concentrations. We conclude that microdialysis can be used to monitor changes in the concentration of histamine in the submucosa of the stomach, and that the inflammatory reaction to the probe is moderate and does not affect the submucosal histamine mobilization.
5.	Kugelberg, Fredrik C., et al. (author) Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats 2002 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 90:6, s. 303-310 Journal article (peer-reviewed)abstract The spontaneous open-field behavioural effects of 10 days of chronic treatment with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100 mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered subcutaneously by implanted osmotic pumps) were examined in rats. Central and peripheral arena locomotor and rearing activities were recorded simultaneously, and the data were assessed during the first hour as well as during the following 24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg daily exhibited lower peripheral locomotor and rearing activities than the other groups during the first test hour. The ratio between central and peripheral activity increased in a dose-dependent non-proportional manner during the first test hour, indicating a general increase in the central arena activity exerted by the rats when treated with citalopram. No major differences were observed between any of the four groups in overall behavioural activities over the 24-hr period. This study indicated that the open-field locomotor and rearing behaviours in normal rats were affected by increasing doses of racemic citalopram, particularly during the first hour of adaptation.
6.	Oberg, M, et al. (author) Subchronic toxicity of Baltic herring oil and its fractions in the rat I: Fractionation and levels of organohalogen pollutants 2002 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 91:5, s. 220-231 Journal article (peer-reviewed)abstract Baltic herring (Clupea harengus) oil was extracted and fractionated. To examine the contribution to toxicity and biological effects of different halogenated organic pollutants, the herring oil and the fractions were mixed into pelleted food and given to Sprague-Dawley female rats at three levels, corresponding to a human intake of 1.6, 8.2 and 34.4 kg fish per week. Herring oil, its fractions, as well as liver tissues from exposed rats, were analyzed for: eight chlorinated biphenyls, all 2,3,7,8-substituted chlorinated dibenzo-p-dioxins and dibenzofurans, hexachlorocyclohexanes, hexachlorobenzene, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), DDT-metabolites, three brominated diphenylethers as well as extractable organically bound chlorine and halogenated fatty acids. A bioassay (EROD) was used for measuring the dioxin-like enzyme induction activity. Nordic Sea lodda (Mallotus villosus) oil was used as a nutritionally equivalent control, with much lower levels of halogenated organic pollutants. A full toxicological subchronic examination is reported in the following paper (Stern et al. 2002). In this study, we report that the fractionation procedure resulted in a substantial reduction of most of the pollutants in the triacylglycerol fraction, and a pronounced enrichment of most of the pollutants into the two other fractions. However, all contaminants were present at some levels in all of the fractions. The concentrations of organoltalogens found in this study were representative for Baltic herring during the mid-1990s. Rat liver tissue showed similar residue patterns as the diet, with the exception of chlorinated dibenzo-p-dioxin and dibenzofuran congeners that had a higher liver retention than pesticides, chlorinated biphenyls and brominated diphenylethers.
7.	Sjöberg, Trygve, et al. (author) Postjunctional α-adrenoceptors in human superficial epigastric arteries and veins. 1987 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 60:1, s. 43-50 Journal article (peer-reviewed)
8.	Green, Henrik, et al. (author) Spontaneous Reversal of P-Glycoprotein Expression in Multidrug Resistant Cell Lines 2003 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 93:6, s. 297-304 Journal article (peer-reviewed)abstract Increased expression of P-glycoprotein encoded by the mdr-1 gene is a well-characterised mechanism for resistance to cancer chemotherapeutic drugs in cell lines. However, the P-glycoprotein expression after removal of the selection pressure has not fully been elucidated. The stability of P-glycoprotein expression in the presence (+) and absence (-) of vincristine (30 or 150 nM) was studied in multidrug resistant K562 cell lines (VCR30+, VCR150+, VCR30- and VCR150-) for 11 months. The P-glycoprotein protein and mdr-1 mRNA levels were determined at regular intervals using flow cytometry and real-time PCR, respectively. Chemosensitivity to a panel of antineoplastic drugs was measured using an MTT assay. The presence of vincristine (VCR30+ and VCR150+) resulted in high and stable levels of P-glycoprotein and mdr-1 mRNA during the whole period compared to wild type. As for the VCR30- and VCR150- subcultures, the expressions of P-glycoprotein and mdr-1 mRNA were stable for five months, and then the levels decreased rapidly. Concomitantly, the sensitivity to drugs known as P-glycoprotein substrates was restored. In conclusion, resistant cells growing in the presence of the inducing drug have a stable P-glycoprotein expression and resistance level, but removing the inducing drug may result in a sudden and rapid lowering of P-glycoprotein and mdr-1 mRNA levels as long as five months after drug withdrawal.
9.	Barg, Sebastian (author) Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 92:1, s. 3-13 Research review (peer-reviewed)abstract In pancreatic B- and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca2+-influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca2+-influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (<1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further "priming" for release by several ATP- and Ca2+-dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca2+-channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.
10.	Björkqvist, Maria, et al. (author) Effects of CCK2 receptor blockade on growth parameters in gastrointestinal tract and pancreas in rats 2001 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 89:4, s. 208-213 Journal article (peer-reviewed)
11.	Claeson, Per, et al. (author) Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol : A Comparison with Nimodipine in the Isolated Rat Aorta 1991 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 69:3, s. 173-177 Journal article (peer-reviewed)abstract Abstract: (+)‐T‐Cadinol is a sesquiterpene with smooth muscle relaxing properties. In the isolated rat aorta, T‐cadinol relaxed contractions induced by 60 mM K+ in a concentration‐dependent fashion. The dihydropyridine calcium antagonist nimodipine was approximately 4,000 times more potent than T‐cadinol. While both drugs nearly abolished the K+‐induced contractions, they only partially relaxed contractions induced by phenylephrine. The relaxation induced by T‐cadinol and nimodipine in K+‐contracted aortic rings, was completely reversed by the calcium channel activator Bay K8644. In aortic preparations partially depolarized by 20 mM K+, Bay K8644 induced a concentration‐dependent contraction. Nimodipine shifted the Bay K8644 concentration‐response curve to the right in a parallel manner, consistent with a competitive mode of inhibition. T‐cadinol at concentrations less than 10−3.5 M also produced a right‐ward shift of the Bay K8644 concentration‐response curve with a maintained maximum response. However, the highest T‐cadinol concentration used (10−3.5 M) significantly reduced the maximum response. In conclusion, although T‐cadinol and nimodipine display marked structural differences, their pharmacological profiles of action have several features in common, suggesting that T‐cadinol is a calcium antagonist, possibly interacting with the dihydropyridine binding sites on the calcium channels. 1991 Nordic Pharmacological Society
12.	Kjellstrand, Per, et al. (author) Tolerance during inhalation of organic solvents 1990 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 66:5, s. 409-414 Journal article (peer-reviewed)
13.	Kotarsky, Knut, et al. (author) Progress in methodology improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:6, s. 249-258 Research review (peer-reviewed)abstract Seven-transmembrane G-protein-coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified. These receptors are referred to as "orphan" receptors. A pre-requisite for the identification of ligands activating orphan receptors is powerful assay systems. Until now, reporter gene assays have not been in common use in this process. Here, we summarize our development of improved reporter gene assays. We optimized reporter gene assays in respect of (i) the promoter region of the construct, (ii) the reporter enzyme used, (iii) and the assay procedure. Furthermore, an unique fluorescence-based clone selection step was introduced, allowing rapid selection of the most sensitive reporter cell clones when establishing stable reporter cell lines. Mathematical formulae are provided to enable a simple and reliable comparison between different cell lines, when tested with a compound of interest. The resulting reporter cell lines responded in a very sensitive way to the stimulation of various test receptors. The reporter system was termed HighTRACE® (high-throughput reporter assay with clone election). Its high assay quality makes it suitable as a primary screening tool. Ligands for two recently unknown 7TM receptors were identified using the HighTRACE® system i.e., two cell surface free fatty acid receptors, GPR40 (FFA1R) and GPR43 (FFA2R). The identification was accomplished using a reverse pharmacology approach.
14.	Pessah-Rasmussen, H, et al. (author) Human fibroblasts lacking trans-stilbene oxide active glutathione transferase exhibit increased cell death when exposed to polycyclic aromatic hydrocarbons 1992 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 70:5 Pt 1, s. 5-361 Journal article (peer-reviewed)abstract Glutathione transferases (GST) are detoxifying enzymes who act with many endogenous and exogenous substances such as polycyclic aromatic hydrocarbons (PAH). The GST activity towards trans-stilbene oxide (GST-tSBO) is inherited in an autosomal dominant fashion and can be separated in high (GST-positive) and low (GST-negative) phenotypes when measured in blood. Human fibroblast cultures were established from males matched for age, smoking habits and clinical manifestations of atherosclerosis. Matched pairs of GST-negative and GST-positive fibroblasts were studied. There was a very strong correlation between the levels of GST-tSBO in peripheral blood and in cultured fibroblasts within the same individual. When fibroblasts were exposed to benzo(a)pyrene (BP) or dimethylbenzanthracene (DMBA) GST-negative cells produced relatively more collagen than GST-positive cells. GST-negative fibroblasts showed a greater cell death than GST-positive fibroblasts as well among controls as after exposure to PAH. It is concluded that lack of GST-tSBO is easily discriminated in cultured skin fibroblasts. GST-negative and GST-positive fibroblasts showed different susceptibility towards some toxic stimuli that might be of importance in atherogenesis.
15.	Ruzicka, Hana, et al. (author) Pharmacokinetics and antidiuretic effect of high-dose desmopressin in patients with chronic renal failure. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 92:3, s. 137-142 Journal article (peer-reviewed)
16.	Waldeck, Bertil (author) Three-dimensional pharmacology, a subject ranging from ignorance to overstatements. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:5, s. 203-210 Research review (peer-reviewed)abstract Stereoselectivity has been known to play a role in drug action for 100 years or more. Nevertheless, chiral drugs have been developed and used as racemates, neglecting the fact that they comprise mixtures of two or more compounds which may have quite different pharmacological properties. A very limited access to pure enantiomers in the past has been responsible for this unsatisfactory state of affairs. During the last 20 years, significant achievements have made it possible to perform stereoselective synthesis and analysis. Today, novel chiral drugs are as a rule developed as single enantiomers. Yet, studies of old racaemic drugs are still designed, performed and published without mention of the fact that two or more compounds are involved. In recent years, a number of old racaemic drugs have been re-evaluated and re-introduced into the clinical area as the pure, active enantiomer (the eutomer). While in principle correct, the clinical benefit of this shift from a well established racaemate to a pure enantiomer often seems to be limited and sometimes exaggerated. Racaemic drugs with a deleterious enantiomer that does not contribute to the therapeutic effect (the distomer), may have been sorted out in the safety evaluation process. However, in the future any pharmacological study of racaemic drugs must include the pure enantiomers. This will generate new, valuable information on stereoselectivity in drug action and interaction
17.	Xu, C B, et al. (author) Interactions between cultured bovine arterial endothelial and smooth muscle cells : effects of injury on the release of growth stimulating and growth inhibiting substances 1991 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 69:3, s. 195-200 Journal article (peer-reviewed)abstract Dimethylsulfoxide-soluble particles (DSP) from cigarette smoke and ultraviolet light caused a low degree (cell death less than 30%) and high degree (cell death 60-90%) injury to bovine arterial endothelial cells and smooth muscle cells in culture. Conditioned medium from low degree injured endothelial cells and smooth muscle cells generally inhibited DNA synthesis in new smooth muscle cells or endothelial cells while high degree injury increased DNA synthesis in new cells. Specifically, the growth stimulating activity from endothelial cells was decreased after low degree injury but increased after high degree. UV light released more growth stimulating substances from smooth muscle cells after both low and high degree injury. The release of growth inhibiting substances was dependent on both cell kind and degree of injury. In co-culture low and high degree DSP injury to endothelial cells inhibited smooth muscle cell proliferation, which was in contrast to the effect of conditioned medium from high degree injured endothelial cells. Conditioned medium from endothelial cells treated with LDL and glucose inhibited DNA synthesis in smooth muscle cells. It is concluded that injury to endothelial cells or smooth muscle cells will modify the release of growth inhibiting and growth stimulating activity and that this release will depend on cell kind as well as degree and kind of the injurious stimulus.
18.	Adding, LC, et al. (author) Gadolinium chloride inhibition of pulmonary nitric oxide production and effects on pulmonary circulation in the rabbit 1998 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 83:1, s. 8-15 Journal article (peer-reviewed)
19.	Ahlenius, S (author) Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs 1999 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 84:5, s. 193-196 Journal article (peer-reviewed)
20.	Auberson, S, et al. (author) Different ion channel control pH6-induced bronchoconstriction and calcitonin gene-related peptide release in the guinea-pig lung 1999 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 84:4, s. 181-186 Journal article (peer-reviewed)
21.	Bannenberg, GL, et al. (author) Stretch-induced stimulation of lower airway nitric oxide formation in the guinea-pig: inhibition by gadolinium chloride 1997 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 81:1, s. 13-18 Journal article (peer-reviewed)
22.	Bergqvist, PBF, et al. (author) Elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy 1997 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 80:4, s. 187-190 Journal article (peer-reviewed)
23.	Carlsson, Carina, et al. (author) 2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia 2003 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 93:4, s. 156-168 Journal article (peer-reviewed)abstract 2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.
24.	Dahlin, KL, et al. (author) Amitriptyline-induced release of endothelin-1 in isolated perfused and ventilated rat lungs 1999 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 85:6, s. 288-293 Journal article (peer-reviewed)
25.	Enoksson, S, et al. (author) Forskolin potentiates isoprenaline-induced glycerol output and local blood flow in human adipose tissue in vivo 1997 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 81:5, s. 214-218 Journal article (peer-reviewed)
26.	Fowler, Christopher, et al. (author) Pharmacological properties of cannabinoid receptors in the avian brain : similarity of rat and chicken cannabinoid1 receptor recognition sites and expression of cannabinoid2 receptor-like immunoreactivity in the embryonic chick brain 2001 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 88:4, s. 213-222 Journal article (peer-reviewed)
27.	Johansson, Maria, et al. (author) Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones 1998 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 83:5, s. 225-230 Journal article (peer-reviewed)abstract The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.
28.	Lind, Anna-Britta, et al. (author) Gene expression of cytochrome P450 1B1 and 2D6 in leukocytes in human pregnancy 2003 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 92:6, s. 295-9 Journal article (peer-reviewed)abstract We investigated the influence of human pregnancy on gene expression of two cytochrome P450 enzymes in white blood cells. Cytochrome P450 1B1 (CYP1B1) catalyses oestradiol 4-hydroxylation, and may participate in the endocrine regulation of oestrogens. Cytochrome P450 2D6 (CYP2D6) metabolises many commonly used drugs, and previous studies have suggested that it is induced during pregnancy. CYP1B1 and CYP2D6 were therefore considered to be of interest in human pregnancy. As it is not ethically possible to take liver biopsies from healthy mothers during pregnancy, easily accessible cells that express the genes were used as a surrogate tissue. White blood cells were collected from eighteen pregnant women, and were used to measure CYP1B1 and CYP2D6 ribonucleic acid (RNA). The analysis was repeated after pregnancy, the women, thus, serving as their own controls. Real-time reverse transcriptase - polymerase chain reaction methods were used with 18S ribosomal RNA as an internal control. A slight, but not significant, increase in gene activity of CYP1B1 was detected during pregnancy. Expression of CYP2D6 in blood was extremely low, and induction of CYP2D6 during pregnancy could not be confirmed. In conclusion, gene expression of CYP1B1 and CYP2D6 in leukocytes was not significantly up-regulated in the third trimester of pregnancy, but a trend indicating an altered metabolism during pregnancy was detected.
29.	Luurila, S., et al. (author) Pharmacokinetics of bisphosphonates in rabbits 1999 In: Pharmacology and Toxicology. - : Blackwell Munksgaard. - 0901-9928 .- 1600-0773. ; 84:1, s. 24-28 Journal article (peer-reviewed)abstract Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The 14C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P<0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P=0.016). At 24 hr, plasma concentration of tiludronate was 12 ± 6.6%, of etidronate 18 ± 2.5%, of clodronate 0.8 ± 0.2%, and of pamidronate 1.4 ± 0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC(0-24hr) for tiludronate and etidronate was 9-11 times larger than for clodronate. AUC(0-24hr) for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9- 15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2-1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of filudronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates.
30.	Magnusson, O, et al. (author) Prolonged treatment with the atypical antipsychotic agent remoxipride reduces extracellular glutamate levels in the striatum of freely moving rats 1997 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 81:1, s. 53-56 Journal article (peer-reviewed)
31.	Naidu Sjöswärd, Kerstin, 1938-, et al. (author) Metabolism of salbutamol differs between asthmatic patients and healthy volunteers 2003 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 92:1, s. 27-32 Journal article (peer-reviewed)abstract Patients with asthma are a target group for medication with β2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries β2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 μg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.
32.	Salmi, P, et al. (author) Evidence for functional interactions between 5-HT1A and 5-HT2A receptors in rat thermoregulatory mechanisms 1998 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 82:3, s. 122-127 Journal article (peer-reviewed)
33.	Stern, Natalia, et al. (author) Subchronic toxicity of Baltic herring oil and its fractions in the rat II : Clinical observations and toxicological parameters. 2002 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 91:5, s. 232-244 Journal article (peer-reviewed)abstract This study aimed to increase the knowledge about the toxicity of fish-derived organohalogen pollutants in mammals. The strategy chosen was to separate organohalogen pollutants derived from Baltic herring (Clupea harengus) fillet, in order to obtain fractions with differing proportions of identified and unidentified halogenated pollutants, and to perform a subchronic toxicity study in rats, essentially according to the OECD guidelines, at three dose levels. Nordic Sea lodda (Mallotus villosus) oil, with low levels of persistent organohalogen pollutants, was used as an additional control diet. The toxicological examination showed that exposure to Baltic herring oil and its fractions at dose levels corresponding to a human intake in the range of 1.6 to 34.4 kg Baltic herring per week resulted in minimal effects. The spectrum of effects was similar to that, which is observed after low-level exposure to pollutants such as chlorinated dibenzo-p-dioxins and dibenzofurans (CDD/F) and chlorinated biphenyls, despite the fact that these contaminants contribute to a minor part of the extractable organically bound chlorine (EOCl). The study confirmed previous findings that induction of hepatic ethoxyresorufin deethylase (EROD) activity takes place at daily intake levels 0.15 ng fish-derived CDD/F-TEQs/kg body weight. The study also demonstrated that hepatic vitamin A reduction takes place at somewhat higher daily exposure levels, i.e. 0.16–0.30 ng fish-derived CDD/F-TEQs/kg body weight. Halogenated fatty acids, the major component of EOCl, could not be linked to any of the measured effects. From a risk management point of view, the study provides important new information of effect levels for Ah-receptor mediated responses following low level exposure to organohalogen compounds from a matrix relevant for human exposure.
34.	Laine, K, et al. (author) A screening study on the liability of eight different female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes 2003 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 93:2, s. 77-81 Journal article (peer-reviewed)
35.	Abelson, Klas, et al. (author) Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats 2002 In: Pharmacology and Toxicology. - : Blackwell. - 0901-9928 .- 1600-0773. ; 90:4, s. 187-192 Journal article (peer-reviewed)abstract Abstract:Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10–300 μg/kg) and atropine (0.1, 10, 5000 μg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2–C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 μg/kg), or subcutaneously with oxotremorine (30, 100, 300 μg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 μg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 μg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.
36.	BAGER, Y, et al. (author) Interaction of 3,4,5,3',4'-pentachlorobiphenyl and 2,4,5,2',4',5'-hexachlorobiphenyl in promotion of altered hepatic foci in rats 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 77:2, s. 149-154 Journal article (peer-reviewed)
37.	BECK, O, et al. (author) Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 77:5, s. 323-326 Journal article (peer-reviewed)
38.	BOLME, P, et al. (author) Malnutrition and pharmacokinetics of penicillin in Ethiopian children 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 76:4, s. 259-262 Journal article (peer-reviewed)
39.	BRONNER, U, et al. (author) Metabolism is an important route of pentamidine elimination in the rat: disposition of 14C-pentamidine and identification of metabolites in urine using liquid chromatography-tandem mass spectrometry 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 77:2, s. 114-120 Journal article (peer-reviewed)
40.	DOCK, L, et al. (author) Metabolism of mercury in hamster pups administered a single dose of 203Hg-labeled methyl mercury 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 76:1, s. 80-84 Journal article (peer-reviewed)
41.	FREDHOLM, BB (author) Astra Award Lecture. Adenosine, adenosine receptors and the actions of caffeine 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 76:2, s. 93-101 Journal article (peer-reviewed)
42.	Fredholm, BB, et al. (author) Effects of ethanol and acetate on adenosine production in rat hippocampal slices 1996 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 79:3, s. 120-123 Journal article (peer-reviewed)
43.	FREDHOLM, BB (author) Purinoceptors in the nervous system 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 76:4, s. 228-239 Journal article (peer-reviewed)
44.	Hasselstrom, J, et al. (author) Disposition and analgesic effects of systemic morphine, morphine-6-glucuronide and normorphine in rat 1996 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 79:1, s. 40-46 Journal article (peer-reviewed)
45.	Håkansson, H., et al. (author) In vivo and in vitro toxicity of fractionated fish lipids, with particular regard to their content of chlorinated organic compounds 1991 In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 69:6, s. 459-471 Journal article (peer-reviewed)abstract Six different lipid matrices (the intact lipid (IL), four lipid fractions with different polarity, and the free fatty acids (FFAs) obtained by hydrolysis of the triacylglycerol (TAG) containing fraction) were obtained from salmon (Salmo salar) and eel (Anguilla anguilla), each collected at a contaminated and a comparatively uncontaminated catch site along the coast of Scandinavia. The lipid matrices were studied in toxicological test systems representing various biological functions of different organ systems from several species and trophic levels. The results were evaluated with particular respect to the concentrations of extractable organically bound chlorine (EOCl) in the matrices tested. In some test systems, the specimens with a higher EOCl concentration appeared to be more toxic. For example, the TAG containing fraction (F2) from Idefjord eel, having a higher EOCl content than F2 from Oslofjord eel, reduced the number and hatchability of eggs laid by zebrafish. Both IL and F2 of Idefjord eel increased mortality and reduced the oxygen/nitrogen-ratio in blue mussels. Non-polar compounds (F1) from Bothnian Sea salmon induced 7-ethoxyresurofin O-deethylase (EROD) activity in rainbow trout hepatocytes, whereas F1 from Senja salmon did not. F1 from Bothnian Sea salmon also reduced the number of T-cells in foetal mouse thymus anlagen in vitro compared with the cell number in anlagen exposed to F1 from Senja salmon. A positive correlation between EOCl concentration and test response was found for EROD activity in rainbow trout hepatocytes and for ATP-leakage in Erlich ascites tumour cells when testing the phospolipid containing fraction (F4). However, in most test systems the fish oils, irrespective of EOCl content, were of low toxicity, and the observed effects need to be verified in future studies.
46.	Kato, Y, et al. (author) Inhibition of cell-cell communication by commercial chlorinated paraffins in rat liver epithelial IAR 20 cells 1996 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 79:1, s. 23-28 Journal article (peer-reviewed)
47.	Lastbom, L, et al. (author) Hexamethylene diisocyanate (HDI)-induced lung impairment: studies in isolated perfused and ventilated guinea pig lungs 1997 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 81:2, s. 85-89 Journal article (peer-reviewed)
48.	Marandi, T, et al. (author) Debrisoquin and S-mephenytoin hydroxylation phenotypes and CYP2D6 genotypes in an Estonian population 1996 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 78:5, s. 303-307 Journal article (peer-reviewed)
49.	NISELL, M, et al. (author) Nicotine dependence, midbrain dopamine systems and psychiatric disorders 1995 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 76:3, s. 157-162 Journal article (peer-reviewed)
50.	Nordenhall, K, et al. (author) Cross-fostering study of methyl mercury retention, demethylation and excretion in the neonatal hamster 1998 In: Pharmacology & toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 82:3, s. 132-136 Journal article (peer-reviewed)

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