摘要:

Human and pig cystic and pig hepatic arteries were suspended in tissue baths and the effect of α‐adrenoceptor selective drugs, prostaglandin F2α(PGF2α) and vasopressin were investigated. Prazosin fulfilled the criteria for competitive antagonism in concentrations 10‐9‐10‐7M. The pA2‐values were 9.53 in human cystic, 9.74 in pig cystic, and 9.57 in pig hepatic artery. Rauwolscine had no significant effect in the different arteries. In human cystic artery noradrenaline had significantly (P<0.05) higher Emaxand pEC50‐values (135% of the preceding K+‐induced contraction and 6.4, respectively) compared with pig cystic (106% and 5.7, respectively) and pig hepatic artery (116% and 5.9, respectively). Vasopressin had no effect in the cystic arteries, whereas it had a high potency (pEC50 was 8.5) but low intrinsic activity (Emaxwas 14%) in pig hepatic artery. Prostaglandin F2αhad a significantly higher Emaxin human than in pig arteries. No differences were found in pEC50‐values. This study indicates a similarity in pharmacological characteristics of some vasoactive drugs especially between pig cystic and hepatic arteries. If this is also true in man, the easily obtainable cystic artery can be used for screening the effect of drugs on

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00709.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Single dose intravenous and subcutaneous pharmacokinetics of recombinant human erythropoietin (rhEPO) has been determined in 6 chronic haemodialysis patients. Four patients, all on maintenance therapy with rhEPO, were consecutively treated both intravenously and subcutaneously with injections of rhEPO in a dose of 50 U/kg. Two previously untreated patients received 150 U/kg of rhEPO intravenously and subcutaneously. After intravenous injection of 50 U/kg of rhEPO a mean serum half‐life value of 5.4 ± 0.9 hr was found. The corresponding half‐life after injection of 150 U/kg was 7.6 hr. The peak concentration of serum EPO after subcutaneous injection was 12.5‐20 times lower than the corresponding intravenous Cmax. After administration of 150 U/kg subcutaneously the absorption of EPO was monitored to completion at 120 hr. The complete bioavailability of subcutaneous rhEPO after injection of 150 U/kg was 31.7%. Whether this low and protracted subcutaneous absorption of rhEPO is accounted for by either impeded absorption or partial skin degradation of rhEPO is not

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00710.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Autoradiography of male mice following inhalation of the radioactively labelled solvents, toluene, xylene, and styrene, revealed an accumulation of non‐volatile metabolites in the nasal mucosa and olfactory bulb of the brain. Since no accumulation occurred after benzene inhalation, it was assumed that the activity represented aromatic acids, which are known metabolites of these solvents. This was supported by the finding that also radioactive benzoic acid (main metabolite of toluene) and salicylic acid accumulated in the olfactory bulb. High‐performance liquid chromatography revealed that after toluene inhalation (for 1 hr), nasal mucosa and olfactory bulb contained mainly benzoic acid, with a strong accumulation in relation to blood plasma, and considerably less of its glycine conjugate, hippuric acid. After xylene inhalation, on the other hand, methyl hippuric acid dominated over the non‐conjugated metabolite, toluic acid. The results indicate a specific, possibly axonal flow‐mediated transport of aromatic acids from the nasal mucosa to the olfactory lobe of the brain. The toxicological significance of these results remains to be

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00711.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

A comparative study was carried out in the most TCDD‐resistant [Han/Wistar (H/W), LD50>3000 μg/kg] and the most TCDD‐susceptible [Long‐Evans (L‐E), LD50 about 10 μg/kg]rat strain to assess the significance of kinetic factors in TCDD toxicity. Young adult males of both strains were administered 5 μg/kg (1.9 μCi/kg)14C‐TCDD intraperitoneally. Four rats per strain were killed at 4 hr, 1, 4, 8, 16, and 32 days after exposure. A total of 22 tissues along with blood and serum were sampled for liquid scintillation counting. From half of the animals, daily urine and faeces were also analyzed. In addition, 3 rats per strain were given 50 μg/kg (19 μCi/kg)14C‐TCDD and prepared for whole‐body autoradiography after 1, 4 or 8 days. The livers of two rats per strain killed at 4 hr, 4 or 16 days, and the excreta from two rats of both strains collected on days 1‐4, 5‐8, 13‐16, and 29‐32 after exposure were analyzed for metabolites of TCDD by high pressure liquid chromatography. The label was mainly excreted in faeces as metabolites of TCDD, and the half‐life of elimination was 20.8 (L‐E) or 21.9 (H/W) days. A very similar overall distribution pattern was observed in both strains irrespective of dose, and the liver was the major site of accumulation. Practically all liver14C‐activity was found as the parent compound. Moderate strain‐related differences were observed in the thyroid, thymus, prostate, adrenals, and brown and white fat, where lower values were recorded in H/W rats. Site‐dependent variation was detected in the brain. The results do not support the view that TCDD metabolism or disposition would have a major impact on th

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00712.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The interaction between theophylline and verapamil was investigated in 7 healthy volunteers. Oral administration of verapamil in a dose of 120 mg t.i.d. for 7 days caused a significant inhibition of the elimination of theophylline (5 mg/kg intravenously). Theophylline clearance was reduced from 45.2 to 36.1 ml/hr/kg (20.1%; P<0.005). The apparent steady‐state volume of distribution of the drug was not influenced. The terminal half‐life of theophylline was increased from 6.80 to 8.23 hr (21.0%; P<0.001). Increased steady‐state plasma theophylline concentrations may thus be expected when verapamil is added to a drug regimen which includes theophy

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00713.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The distribution of disulfiram (Antabuse®) over erythrocyte cell membranes and the inhibitory action of the parent drug and its metabolites on a disulfiram sensitive erythrocyte isozyme of aldehyde dehydrogenase (ALDH) was investigated in intact and haemolyzed human erythrocytes. These studies showed that not only disulfiram but also its bis(diethyldithiocarbamato) copper complex (Cu(DDC)2) were distributed over the erythrocyte cell membranes. In addition, disulfiram was the only substance examined that inactivated erythrocyte ALDH, a reaction which was dependent on the concentration of disulfiram added

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00714.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

In spinal cords from normal mice,3H‐clonidine bound to α2‐adrenoceptors with an apparant Kdof 4.6 nM and capacity (Bmax) of 430 fmol/mg protein. The non‐hydrolyzable GTP analogue Gpp(NH)p was found to dose‐dependently reduce the binding of3H‐clonidine the effect of Gpp(NH)p being essentially maximal at 10‐4M. Gpp(NH)p was found to reduce the apparent affinity as well as the apparent number of binding sites for3H‐clonidine; the Kdof3H‐clonidine being 16 nM and the Bmax, 300 fmol/mg protein when 10‐4M of the nucleotide was present. In mice pretreated with the noradrenaline neurotoxin DSP4 for 14 days prior to assay, the specific binding of nearly saturating concentrations (10–30 nM) of3H‐clonidine was virtually the same as for control mice. However, for the DSP4 treated animals the down‐regulation of3H‐clonidine binding induced by 10‐4M Gpp(NH)p was significantly higher than for control mice. Thus, at a3H‐clonidine concentration of 10 nM the down‐regulation induced by Gpp(NH)p was 64.1±2.6% for the DSP4 versus 58.9±2.3% for the control mice (P<0.05). At a3H‐clonidine concentration of 30 nM the down‐regulation was 52.4±1.4% for DSP4 versus 41.8±4.1% for control mice (P<0.05). DSP4 pretreatment also potentiated the antinociceptive effect of intrathecal clonidine, as assessed by the tail‐flick and hot plate tests. It is suggested that the functional supersensitivity induced by DPS4 for clonidine is related to the increased sensitivity for guanine nucleotide regu

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00715.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Human proximal tubular cells were isolated and grown in culture for three passages. The proliferation of these cells were inhibited by the immunosuppressive drug cyclosporin A in dose dependent manner in the range of 250 to 2000 ng/ml growth medium. The cultures with low cell density were more sensitive to cyclosporin A compared to the cultures with high density, measured by the incorporation of3H‐thymidine. The toxic effect of cyclosporin A on cells isolated from patients treated with cyclosporin A, did not differ from cells isolated from normal tissue. The calcium channel blocker, verapamil, reversed the inhibitory effect of low concentrations of cyclosporin A on cell proliferation. The electron microscopy showed that cells treated with cyclosporin A, had severe morphological alterations with rounded mitochondria and giant vesicles in the cytoplasma. The results support the hypothesis that the toxic effect of cyclosporin A may be mediated through an increased Ca++influx into the proximal tubular cell

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00716.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The role of cytosolic anion binding proteins (glutathione S‐transferases) in the hepatic transport of bile acids remains controversial. To investigate whether increased levels of the hepatocyte total glutathione S‐transferase content were associated with changes in the release of bile acids from the hepatocyte, we measured the rate of release of radioactive bile acids in isolated hepatocytes from thyroidectomized, phenobarbital pretreated and untreated rats. The isolated hepatocytes were preincubated with either14C‐cholic acid or14C‐taurocholic acid, and the release rate of radiolabeled bile acids was determined. Hepatocyte total glutathione S‐transferase content was measured by rocket immunoelectrophoresis. The release rate of the radiolabeled bile acids was significantly (P<0.005) decreased in both hypothyroid and phenobarbital pretreated hepatocytes. The levels of total glutathione S‐transferase content were significantly (P<0.001) increased in the hepatocytes from both hypothyroid and phenobarbital pretreated animals. Our findings reveal a striking inverse relationship between the total glutathione S‐transferase content of the hepatocyte and the release rate of radiolabeled bile acids in isolated hepatocytes from two independent animal models. These observations support the hypothesis that cytosolic anion binding proteins (glutathione S‐transferases) may influence the net flux across the hepatocyte plasma membrane largely by

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00717.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Sleep effects of oral administration of the serotonin uptake inhibitor zimeldine to cats on 15 consecutive days was measured. On administration days 8 and 15 REM sleep and PGO activity were significantly reduced. The amount of SWS‐2 was not changed for the whole group, but a subgroup with low baseline values showed an increase during zimeldine administration. A REM sleep rebound was observed on withdrawal day 2, and NREM sleep PGO activity was increased on withdrawal day 5. The results indicate an increased serotonergic inhibition of PGO wave activity and REM sleep during chronic administration of zimeldin

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00718.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY