ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00588.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00589.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00590.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:To further clarify the mode of action of estramustine, the influence on macromolecular synthesis in the human prostatic tumour cell line 1013L was investigated. Cell treatment with estramustine, nor‐nitrogen mustard and tauromustine, followed by radioactive nucleotide and leucine incorporations, as a measure of RNA, DNA and protein labelling, were carried out. The initial effect of estramustine clearly differed from that obtained after treatment with nor‐nitrogen mustard and tauromustine. No inhibition of DNA synthesis was found whereas an inhibition of overall RNA synthesis was predominant. Adaption of an established RNA separation method was used in an indepth study of RNA labelling after estramustine treatment. An inhibition of 29S, 18S and 4–7S RNA was found after estramustine treatment, indicating disturbances in either RNA processing or RNA transport. The lack of 45S RNA labelling additionally indicates pre‐ribosomal inh

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00591.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:The myocardial accumulation of pinacidil showed one‐compartment characteristics with a half‐time of 1.11 min., whereas the disposition followed three‐compartment kinetics with half‐times for the relevant two redistributory and the terminal phases of 0.39, 1.51 and 5.44 min., respectively. At a steady‐state drug concentration in the perfusate of 6.12 nmol ml−1, the average concentration of pinacidil in the myocardium was 20.6 nmol g−1. The accumulated amount could predictically be referred with 57% to a central and 31 and 12% to two peripheral (deeper) drug pools. The pharmacodynamic effects of pinacidil in the isolated perfused rabbit heart were studied at stepwise increasing concentrations from 0.15 to 100 μM. Coronary flowrate increased initially up to 24.5% at 1.5 μM pinacidil and then gradually decreased. Amplitude and velocity of contraction were both inhibited in a biphasic way up to 92.7 and 94.1%, respectively. Apparent dynamic steady states developed within 13–15 min. The computer‐derived inhibitory Em‐values related to the first phase were 49.2 and 52.4% and those related to the second phase were 111.7 and 108.3%, respectively. Heart frequency decreased monophasically and exhibited an inhibitory Em‐value of 19.6%. Oxygen consumption decreased at pinacidil concentrations higher than 15 μM and the Em‐value was 69.7%. The frequency‐corrected QT‐interval decreased biphasically and the related inhibitory Em‐values were 8.6 and 58.7%. The QRS‐interval did not change and the PQ‐interval only showed a minor increase at the highest pinacidil concentration. Our findings are compatible with the concept of pinaci

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00592.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:Guanethidine sulphate 40 mg/kg was administered intraperitoneally daily for 14 days to normal Lewis rats and athymic nude rats of a Lewis background (rnu/rnu). Histological examination of the superior cervical ganglia demonstrated a pronounced chromatolysis of the neurones and a loss of the major part of the nerve cells accompanied by an increased number of small mononuclear inflammatory cells. The extent of chromatolysis and nerve cell death induced by guanethidine did not differ between normal and nude rats, whereas the increase of the number of mononuclear cells was lower in the nude rats than in the normal rats (163 and 268 per cent respectively of the saline treated controls, P<0.01). Since guanethidine induced nerve cell death in the T‐cell deficient nude rat to the same extent as in normal rats, it is concluded, that the effect is caused by either a thymus‐independent immune‐response or by a direct toxic e

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00593.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:An anaesthetic dose (40 mg/kg) of sodium pentobarbital (SP) was administered intragastrically to adult, fasted male rats at total dosing volumes of 1, 2, or 3 ml. Area under the plasma concentration‐time curve did not differ for the various dosing volumes. During the initial (rapid) phase of gastric emptying all solutions containing drug appeared to empty at a faster rate than distilled water (2 ml). However, solutions containing drug emptied much more slowly than water during the terminal (slow) phase of gastric emptying. Drug solutions moved along the small intestine at approximately the same rate as distilled water. SP significantly lowered rectal temperature and slowed the propagation velocity of the migrating myoelectric complex (MMC) recorded from four serosal electrodes chronically implanted along the proximal small intestine. In addition, the drug significantly decreased the rate of MMC recurrence, extended the duration of MMC phases, and decreased slow wave frequency at all sites monitored. The results suggest that: 1) the relative oral bioavailability of sodium pentobarbital is not influenced by dosing volume within the range tested, 2) the various dosing volumes of SP tested moved through the gastrointestinal tract at an equal rate, and 3) orally administered SP significantly decreases the propagation velocity and periodicity of the MMC in the small intestin

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00594.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:In a double‐blind and cross‐over study 12 healthy subjects took temazepam 20 mg in two different formulations (soft gelatine capsule or uncoated tablet) and matched placebo at one‐week intervals. Plasma temazepam concentrations at 0.5, 1, 2, 3, 8, 12 and 24 hours after treatment were analyzed by gas chromatography. Psychomotor performance was measured objectively (digit symbol substitution, letter cancellation, Maddox wing test) and subjectively (visual analogue scales) before the drug intake and 1, 2 and 3 hours later and the plasma benzodiazepine concentrations were analyzed also by radioreceptor bioassay. The two different formulations were compared in pharmacokinetic and pharmacodynamic terms, and the gas chromatographic and radioreceptor assays were compared. The soft gelatine capsule produced higher peak plasma concentrations than the uncoated tablet. The computed AUCs and elimination half‐lives proved to be similar after either formulation. A satisfactory correlation between the bioassayed benzodiazepine concentrations and chemically assayed temazepam was shown. In pharmacodynamic terms the results suggest a shorter and somewhat smaller subjective response for the capsule than for the tabl

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00595.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:A murine foetal thymus organ culture system was employed to screen a number of immunotoxic chemicals for direct thymus toxicity. The toxic effects caused by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and its congeners on the system used had previously been shown to be similar to those causedin vivoon lymphoid development. The most potent compound tested was the corticosteroid fluocinolone acetonide, which caused a 50% inhibition of lymphoid development (EC50) at a concentration of 5 × 10−11M. The EC50 of TCDD was around 5 × 10−10M while that of 4 β‐phorbol 12‐myristate 13‐acetate (TPA) was ca 10−7M. TCDD and its congeners are believed to act via binding to theAhreceptor. Other known or presumed ligands of this receptor, which are potent inducers of P1‐450 (P‐448) ‐dependent polysubstrate monooxygenase activities, were considerably less toxic with EC50 levels varying between 10−5M (7,12‐dimethylbenz(α‐) antracene, α‐naphthoflavone, benzo(α)pyrene) and 10−4M (β‐naphthoflavone and 3‐methylcholantrene). Dinaphtho/2,3‐b,5,6‐b/dioxin and indolo/2,3‐b/carbazole showed toxicity at 5 × 10−6− 10−5M and 5 × 10−5M respectively. TCDD, TPA, and fluocinolone showed additive effects when added two by two in different combinations. Thus fluocinolone, known to counteract the toxicity and epidermal growth factor (EGF) cell‐surface receptor‐decreasing activity caused by TPA in other cell typ

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00596.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Abstract:Two genetically distinct substrains of the Wistar rat (RR and rr) were used to study the tissue distribution of the inducibility of aldehyde dehydrogenase (ALDH). The RR substrain is responsive to phenobarbital (PB), as far as the induction of the hepatic ALDH activity is concerned, whereas the rr substrain is deprived of this biochemical property. Both substrains, however, respond to treatment with methylcholanthrene (MC), exhibiting a uniform increase of the ALDH activity in the liver. It is known that PB and MC induce two different isozymes of the hepatic cytosol. The effect of PB (1 g/l in drinking water, for 12 days) on the inducibility of ALDH in extrahepatic tissues was examined in the RR substrain. On the contrary, MC was given (50 mg/kg x 4, intraperitoneally) to rr animals. The activity of ALDH was found to be induced by PB in the liver and the intestinal mucosa, when measured with NAD and propionaldehyde (P/NAD) or phenylacetaldehyde (Ph/NAD). An increase of the activity was also noticed when ALDH was measured with NADP and benzaldehyde (B/NADP). In rr animals, MC induced the B/NADP activity in the liver, the intestinal mucosa, the kidneys, the lungs, the spleen, the brain, the urinary bladder and the heart. The effect of MC on various tissues was less distinct, when ALDH was measured as P/NAD or Ph/NAD activity. It is concluded, that PB and MC not only induce different types of ALDH activity, but they also reveal differences in the tissue distribution of the inducibility of ALDH.

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1989.tb00597.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY