摘要:

Abstract:Rat liver parenchymal cells were isolated from normal and barbiturate pretreated rats. Cells from untreated animals were exposed to penicillin over a concentration range from 0.14 mM to 14.0 mM (50–5000 μg/ml). An inhibition of the incorporation of14C valine into stationary and medium proteins, ranging from 23% at 0.28 mM to 90% at 14.0 mM, was observed. The effect of a single dose penicillin (1.4 mM) on protein incorporation, enzyme leakage and viability was compared to the effect of paracetamol (6.6 mM) and tertiary butanol (10.9 mM). In these concentrations paracetamol and penicillin both inhibited the incorporation of valine into cell and medium protein in hepatocytes from untreated rats. Tertiary butanol showed no such effect. No drug affected the viability or the leakage of enzymes from the hepatocytes. In cells from barbiturate treated animals both paracetamol, penicillin and tertiary butanol had a significant inhibitory effect on the incorporation of radioactive labelled precursor into cell and medium proteins, but no effect on the leakage of enzymes or viability. The ratio between labelled medium and cell proteins was 31% lower in suspensions of control cells from barbiturate treated animals than in cells from untreated rats. It was concluded that penicillin may exert marked effects on protein metabolism in the frequently used isolated rat hepatocyte system, esspecially if the drug concentration well exceeds the usual cell culture concentration of 30–60

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb00995.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:The cytotoxicity of N‐hydroxyparacetamol (N‐OH‐pHAA), a postulated proximate metabolite of the hepatotoxic and nephrotoxic analgesic paracetamol, was studied in suspensions of hepatocytes isolated by collagen‐perfusion of livers of male rats. Incubation of cells with 0.25–2.0 mM N‐OH‐pHAA led after 3–5 hours to increased cell permeability measured by increased trypan blue uptake, increased NADH penetration or leakage of prelabelled51Cr. N‐OH‐pHAA rapidly depleted cellular glutathione, 16% of initial levels were seen after 30 min. incubation.3H‐N‐OH‐pHAA bound covalently to cellular proteins in a time‐ and concentration‐dependent manner, considerably higher binding rates were seen with boiled cells compared to intact cells. Pretreatment of animals with the cytochrome P‐450 inducer phenobarbital did not affect N‐OH‐pHAA cytotoxicity or covalent binding, whereas the cytochrome P‐450 inhibitor metyrapone inhibited both cytotoxicity and binding. Lipid peroxidation in hepatocytes could be seen as a late event after a limited range of N‐OH‐pHAA concentrations. In contrast, lipid peroxidation was an early event in cells exposed to carbon tetrachloride. A minimal exposure time of 30 min. of the hepatocytes to N‐OH‐pHAA was sufficient to eli

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb00996.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:The effect of inhibitors of toxicity of N‐hydroxyparacetamol(N‐OH‐pHAA), a postulated proximate metabolite of paracetamol, was studied in isolated rat hepatocytes. Additions of ascorbate, menadione, thiol‐containing amino acids and glutathione (GSH) led to an increased stability of N‐OH‐pHAA, reduced the covalent binding of N‐OH‐pHAA to cellular protein and decreased GSH depletion caused by N‐OH‐pHAA. Two to three hours elapsed after a 30 min. exposure of the cells to N‐OH‐pHAA before the cells responded with increased cell permeability. Ascorbate, acetylcysteine, GSH and promethazine were capable of inhibiting this second phase of N‐OH‐pHAA cytotoxicity in addition to their effects during the initial exposure phase. In contrast, the anti‐oxidant tocopherole and phenacetin were only effective during the second phase. Increasing the incubation medium pH during the second phase of N‐OH‐pHAA mediated cellular damage resulted in decreases in cytotoxicity. Lipid peroxidation, as measured by accumulation of thiobarbituric acid reactive metabolites, did not seem to be directly correlated with cytotoxicity, since cysteamine or higher concentrations of N‐OH‐pHAA inhibited lipid peroxidati

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb00997.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:The effect of eight penicillins on the mucociliary activity of rabbit trachea was testedin vitro.Carbenicillin and ampicillin had a minor inhibitory effect. Penicillin G and V and pheneticillin were a little more ciliestatic. Propicillin, cloxacillin and dicloxacillin were most toxic. The mucociliary toxicity increased with increasing lipophilicity of the penicillins and correlated well with their known neurotoxicin vivoeffects.

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb00998.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:Sprague‐Dawley rats were exposed, by inhalation, to toluene and dichloromethane (500, 1,500 or 3,000 p.p.m.) and to benzene (1,500 p.p.m.) for three days. Toluene and benzene increased the concentration of liver microsomal cytochrome P‐450. A dose dependent increase in thein vitroliver microsomal formation of several metabolites of biphenyl and benzo(a)pyrene was observed for both dichloromethane and toluene. At the highest dose‐level the increase in thein vitroformation of benzo(a)pyrene‐7,8‐dihydrodiol was more than threefold for both dichloromethane and toluene whereas the formation of benzo(a)pyrene‐4,5‐dihydrodiol increased more than five‐fold following exposure to toluene but less than two‐fold after exposure to dichloromethane. Our results suggest that dichloromethane and toluene can modify the metabolism and thereby the toxicity of other environme

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb00999.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:The ability of some xanthine derivatives to relax the trachea, contracted by pilocarpine, and to increase the force of contraction of directly stimulated skeletal muscles from the guinea‐pig was studiedin vitro.No relationship was found between these two effects. Relaxation of the trachea occurred at lower concentrations and with a different order of potency as compared with the effects on the slow‐contracting soleus muscle or on the fast‐contracting extensor digitorum longus. One of the compounds, IBMX, 1‐methyl‐3‐isobytylxanthine, showed an isoprenaline‐like effect on the soleus muscle i.e. it depressed the force and fusion of subtetanic contractions. The relaxing effect of theophylline and IBMX on the trachea was additive to that of terbutaline but no clear potentiation was observed. The depression of the contractions of the soleus muscle elicited by terbutaline was reinforced by IBMX but not by theophylline. Theophylline in concentrations which used alone enhanced the contractions of the soleus muscle inhibited the effect of terbutaline. We conclude that the relative contribution of the various effects of xanthine derivatives differs from compoun

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb01000.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:We have previously reported a consistent decrease of peripheral‐central systolic blood pressure (SBP) gradients after ergotamine. SBP was measured with cuffs and it is unknown whether measured values reflect changes of intra‐arterial SBP or increase of vessel wall tone beneath the cuffs. We hence studied the effect of ergotamine tartrate 0.5 mg intravenously on finger‐arm systolic gradients after the following procedures: Infiltration around finger arteries with papaverine (n = 2) and dihydralazine (n=3), occlusion of blood supply to a finger by an inflated cuff before and 2 hours after ergotamine (n = 6). A normal reduction in finger‐arm systolic gradients was seen. The ergotamine‐induced decrease of peripheral SBP must therefore be due to a fall in peripheral intra‐arterial SBP i.e. to contraction of arteries proximal to the digital arteries. Intra‐arterial injection of 10 μg ergotamine tartrate caused similar decrease in finger‐arm systolic gradients as intravenous administration of 0.5 mg (n= 1) indicating a periphera

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb01001.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:The pharmacokinetics of lorazepam after 0.03 mg/kg intravenous administration was investigated in 14 surgical patients (nasal surgery under local anaesthesia) ranging in age from 25 to 86 years (8 males and 6 females). No statistically significant changes in the kinetics of lorazepam associated with the aging process were found. In these premedicated patients a slow onset of the drug action of lorazepam was assessed both subjectively and objectively with no apparent relationship to the age. These findings are of potential clinical importance, because it is highly desirable to use drugs for which age‐related alterations are of minimum degree. In 5 male patients undergoing surgery with cardiopulmonary bypass, lorazepam disappeared from the plasma after a single 4 mg intravenous injection with an apparent comparable half‐life (10.0 ± 3.2 min.) to that of the above mentioned surgical patients. The concentrations of both unconjugated and conjugated lorazepam dropped abruptly at the start of extracorporeal circulation followed by an increase in the postperfusion period. After this peak effect the mean apparent half‐life of lorazepam was 15.1 ± 5.8 hours indicating no great change in its elimination in comparison with patients operated under local anaesthesia (half‐life 12.1 ± 3.7 hours). Pharmacokinetically, lorazepam appears to be a useful agent in connection with cardiopulmonary bypass

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb01002.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:Metronidazole (500 mg) was infused over 20 min. to five patients. At the end of the infusion blood samples were drawn at brief intervals. After subsequent metronidazole analysis the curve plotted for the elimination of the drug showed a bi‐exponential profile. Mean peak serum concentrations reached 15 μg per ml. At the end of the distribution phase, which was 20 to 30 min. after the infusion, the concentration had fallen to 10 μg per ml. A two‐compartment model was used to calculate the kinetic parameters. The elimination half‐life ranged from 4.7 to 15.8 hours, the total clearance from 43 to 193 ml per min., and the peripheral distribution volume from 41.5 to 79.1 1. The areas under the serum level curves exhibited a four‐fold variation, due to differences in either metabolism or elimina

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb01003.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

Abstract:Lung uptake of lidocaine was studied in anaesthetized Swedish landrace pigs using the double indicator dilution method with indocyanine green dye as i ntravascular marker. The pigs were given infusions of sodium bicarbonate or hydrochloric acid to arterial blood pH in the range 7 to 8. Lung uptake of lidocaine was found to correlate statistically significant (P<0.05) with pH. Lung uptake in the first injection before the infusion of acid or base, was 42 ± 4 (X̄ ± S.E.M.)%. The uptake was not found to correlate to cardiac output. The conclusion from this work is therefore that lung uptake of xenobiotic amines in part is dependent on blood

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1982.tb01004.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY