摘要:

The vitamin K‐dependent clotting factors II, VII, IX, and X are proteins which undergo γ‐carboxylation of specific glutamic acid residues prior to secretion from the liver. These unique Ca2+binding amino acids allow the interaction of the proteins with cell surface phospholipids, a function that is crucial for expression of full procoagulant activity of the proteins. The N‐terminal region of the molecule contains the γ‐carboxylation sites and is termed the Gla‐domain. A preliminary observation in rats suggested that mineralized bone accumulated activated recombinant FVII (rFVIIa: NovoSeven™) as well as the non‐activated, single chain rFVII. The present study investigated the role of the Gla‐domain in the accumulation of rFVII in bone, as well as the influence of the activation state of FVII on this phenomenon. Rats were treated with125I‐labelled rFVII, rFVIIa, Gla‐domainless rFVIIa, factor IX, iodide, or recombinant human growth hormone (rhGH). Following sacrifice, radioactivity was measured in mineralized bone, among other tissues. Following administration of125I‐radiolabelled rFVII, rFVIIa and factor IX, but not Gla‐domainless rFVIIa, iodide or rhGH, extensive sequestration occurred in endochondrally as well as intramembranously ossified bones. The results indicate that the proteins containing a Gla‐domain, and only these, are sequestered in bone. Additionally, the normally occurring form of FVII in the circulation, the single‐chain FVII, exhibited similar kinetics in rat bone and plasma, as the two‐chain rFVIIa. The half‐life of rFVII/rFVIIa in mineralized bone was between 3 and 4 days, implying that significant bone accumulation of the factor will take place at steady state. However, the approach to steady state takes more than 2 weeks and the absolute amounts of accumulated rFVII are negligible with respect to bone matrix structure and function. Besides not being sequestered in bone,125I‐labelled Gla‐domainless rFVIIa was present in larger amounts than rFVIIa in kidney tissue due to the charge and size properties of the molecule. In conclusion, accumulation in mineralized bone of the vitamin K‐dependent clotting factors seems to depend on the presence of a Ca2+‐binding Gla‐domain. The physiological implications of the phenomenon remain speculative at present but in theory, the bone compartment could be a storage site for e.g. factors VII and IX in dynamic equilibrium with t

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01549.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The 5HT‐antagonistic effect of drugs in man is difficult to study because of side effects to 5HT. Ergotamine, however contracts human arteries, probably by acting on 5HT receptors. This effect can be antagonizedin vitroby the 5HT antagonist ICI 169,369. After an initial ergotamine challenge to select responders to ergotamine, 10 selected volunteers were given in a double blind study an oral dose of either placebo, 30 mg or 120 mg of ICI 169,369. After 2 hr an intravenous dose of 0.5 mg ergotamine tartrate was given. From 6 to 8 hr after the administration, ergotamine caused a mean decrease in the toe‐arm systolic gradient, measured by strain‐gauge plethysmography of 32 mmHg (P<0.001), which was not influenced by either 30 mg or 120 mg ICI 169,369 (P<0.4). The most likely explanation for our inability to detect any effect of ICI 169,369 on blood pressure changes, induced by ergotamine may be high binding (99%) of ICI 169,369 to plasma proteins. There was, however, indication of aper sevasodilatory effect of ICI 169,369 since the dose of 120 mg increased the toe‐arm systolic gradient by 4

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01550.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The muscle relaxant atracurium is known to undergo extrahepatic degradation via Hofmann elimination and ester hydrolysis. The purpose of the present study was to evaluate the effects of atracurium on hepatic P450‐dependent enzyme activities. Thirty‐two male Sprague‐Dawley rats were anaesthetized, mechanically ventilated, and randomly allocated to one of four study groups: group 1 received saline, group 2 atracurium, group 3 vecuronium, and group 4 pancuronium intravenously for a period of 3 hr. Equipotent doses of the muscle relaxants were applied; the doses had been obtained in a pilot study using evoked electromyography. At the end of the study period, the livers were removed and analyzed. All three muscle relaxants may lead to inhibition of hepatic drug metabolism. Atracurium influences hepatic P450, although it is predominantly degraded in extrahepatic tissues. Further studies are needed to evaluate the contribution of the major metabolite laudanosine to this inhibitory a

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01551.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Two methods of determining concentration‐response curves were compared in isolated endothelium‐intact mesenteric arterial rings from Wistar rats: arterial contractile and relaxation responses were elicited by adding compounds cumulatively or introducing a single concentration at a time (non‐cumulative method). The contractile responses induced by high concentrations of K+(20‐125 mM) were comparable between the two methods, whether or not the responses were elicited in the presence of phentolamine (10 μM) and atenolol (10 μM). Noradrenaline (1 nM ‐ 10 μM) likewise induced similar contractions regardless of method of administration, the only exception being the highest concentration (100 μM) which produced lower contractile force when added directly upon resting tension than after cumulative administration. This difference was abolished by atenolol (10 μM). Arterial smooth muscle relaxations induced by endothelium‐dependent (acetylcholine 1 nM ‐ 10 μM) and ‐independent agents (nitroprusside 1 nM ‐ 1 μM, isoprenaline 10 nM ‐ 100 μM) were similar whether the relaxants were added in a cumulative fashion or in a single concentration introduced upon each precontraction. Thus, cumulative and non‐cumulative administration of contractile and relaxing agents give quite comparable results. We conclude that the cumulative method is a reliable and time‐saving way of studying vascular

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01552.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Paraquat (30‐70 mg/kg intraperitoneally) caused typical shaking behaviour in rats in a dose‐dependent manner. Myoclonus also appeared after the shaking behaviour in several rats treated with the highest dose of paraquat. Morphine (5 mg/kg intraperitoneally, 30 min. before paraquat) significantly reduced the frequency of shaking behaviour. The alleviation by morphine disappeared when naloxone (1.5 mg/kg intraperitoneally 15 min. after morphine) was coadministered. Although there was no histological change in brain slices of paraquat‐treated rats (70 mg/kg intraperitoneally), the fluorescein uptake into brain was increased by the treatment. Morphine prevented the increase of fluorescein uptake, but naloxone failed to antagonize this effect. On the other hand, intracerebroventricularly administered paraquat (25.7 μg/rat) caused tremor in all rats, but not shaking behaviour nor myoclonus. These findings suggest that paraquat administered systemically as well as centrally may be toxic to the brain. Although the actions of paraquat on the brain seem to be complicated, opioid receptors may play a role in the a

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01553.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The effect of a GABA transaminase inhibitor, gamma‐vinyl GABA, on the voluntary alcohol consumption of alcohol‐preferring AA rats produced by selective breeding for high alcohol preference, was studied. The rats were first trained to voluntarily drink 10% (v/v) ethanol solution until their ethanol consumption stabilized. Gamma‐vinyl GABA (100, 200 or 500 mg/kg) was then injected intraperitoneally in three groups of rats, with saline‐injected animals serving as a control group. The rats continued to have a free choice between 10% ethanol and plain tap water for five days after the injection, and their ethanol, water and food consumptions were measured daily. Gamma‐vinyl GABA decreased ethanol consumption by the rats in a dose‐dependent way. The consumption remained significantly decreased for three days in the two groups receiving the highest doses, with only a small concomitant tendency to decreased food intake. The results suggest that an increase in brain GABA concentration decreases alcohol drinking, possibly through potentiation of the pharmacological action

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01554.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

(+)‐Terodiline was given orally (25 mg) and intravenously (12.5 mg) to eight healthy volunteers. The pharmacokinetics of (+)‐terodiline could be described by a one compartment model. The lag time of absorption was 0.6 ± 0.5 hr (mean ± S.D.), the absorption half‐life 0.9 ± 0.5 hr, the time to maximum serum concentration 5.6 ± 2.2 hr and the corresponding maximum serum concentration 62 ± 22 μg/1. The volume of distribution was found to be 372 ± 84 1, the systemic clearance 86 ± 29 ml/min., the mean residence time 81 ± 38 hr and the observed terminal half‐life of elimination 56 ± 26 hr. The urinary excretion of the intravenous dose was 12 ± 6% and the renal clearance 10 ± 5 ml/min. The bioavailability of (+)‐terodiline was 93 ± 19%. The present results indicate that (+)‐terodiline as well as the racemate can be characterized as low clearance long half‐life drugs. One subject was a poor hydroxylator of debrisoquine and exhibited a 3‐fold decrease in clearance and increase in half‐life of (+)‐terodiline relative to extensive metabolizers. Observed pharmacological effects were mild accomodation disturbances and dry mouth, i.e. the same effects as those that may be seen at a corresponding dose of terod

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01555.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The capacity of stearic, monochlorostearic, dichlorostearic and oleic acids to cause membrane damage was measured as their ability to induce leakage of adenosine triphosphate (ATP) from mammalian tumour cellsin vitro.Chlorinated stearic acids, and oleic acid, caused ATP leakage at lower concentrations than normal stearic acid. The membrane disturbing properties are suggested to be a result of the different molecular geometries of the chlorinated stearic acids, and oleic acid, compared to non‐chlorinated stearic aci

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01556.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The toxicokinetic properties of C8 and C10 1‐alkenes and iso‐alkanes have been investigated in rats during inhalation of 100 p.p.m. of the single hydrocarbons for 3 days, 12 hr/day. The concentration of hydrocarbon was measured in blood, brain, liver, kidneys and perirenal fat at days 1, 2 and 3, immediately after exposure and 12 hr after exposure on day 3. The 1‐alkenes showed an efficient absorption to blood combined with extensive accumulation in organs, compared to the iso‐alkanes. The concentration of 1‐alkenes and iso‐alkanes in blood, brain, liver and fat increased with increasing number of carbon atoms. The C9 and C10 1‐alkenes and iso‐alkanes showed increasing concentration in fat during the exposure period and high concentrations 12 hr after cessation of exposure. The extensive accumulation in both blood and organs of 1‐alkenes compared to any of the other groups of hydrocarbons may have a toxicologic relevance. Products which contain 1‐alkenes should be handled carefully to minimize the risk of

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01557.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Most models for the study of the mechanism of intestinal absorption of Cadmium (Cd) have been using intestinal tissuein vitroorin situ.Thein vivoexperiments reported in this article were performed in an attempt to localize the site for gastrointestinal absorption of cadmium chloride during natural physiological conditions by oral exposure of mice to109Cd‐labelled CdCl2. Independent of exposure via drinking water or oral administration of a single dose, Cd was primarily deposited in the most proximal duodenum. Thus the present study as well as others indicate that absorption takes place in the proximal part of the intestine. Absorbed Cd is initially transported to the liver and deposited before being redistributed and accumulated in the kidneys. In this experimental model, dietary tetraethylthiuram disulfide exposure was shown to change the intestinal labelling profile and increase the whole‐body retention as well as the intestinal deposition of

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01558.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY