Similarity between platelet and blood-vessel reactivity.
Explore the source record for details and available documents.
Forearm↗
Biomedical subjects
J R Mitchell
Publications and source records attributed to J R Mitchell.
Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes.
Extracts of feverfew (Tanacetum parthenium) inhibited secretory activity in blood platelets and polymorphonuclear leucocytes (PMNs). Release of serotonin from platelets induced by various aggregating agents (adenosine diphosphate, adrenaline, sodium arachidonate, collagen, and U46619) was inhibited. Platelet aggregation was consistently inhibited but thromboxane synthesis was not. Feverfew also inhibited release of vitamin B12-binding protein from PMNs induced by the secretagogues formyl-methionyl-leucyl-phenylalanine, sodium arachidonate, and zymosan-activated serum. Feverfew did not inhibit the secretion induced in platelets or PMNs by the calcium ionophore A23187. The pattern of the effects of the feverfew extracts on platelets is different from that obtained with other inhibitors of platelet aggregation and the effect on PMNs is more pronounced than has been obtained with very high concentrations of non-steroidal anti-inflammatory agents.
Blood Platelets↗
Oxidation of hydrazine metabolites formed from isoniazid.
Studies in rats indicate that the metabolic activation of acetylhydrazine, a metabolite of isoniazid, is a critical determinant of the hepatotoxicity of isoniazid. As demonstrated in that model, the formation of 14CO2 after the administration of 14C-acetylisoniazid reflects the activity of the toxic pathway. A similar approach in man should make it possible to demonstrate the presence and to assess the quantitative importance of this toxifying pathway, and thus to evaluate its role in the pathogenesis of isoniazid hepatitis. We gave 300 mg isoniazid together with 10 microCi 14C-acetylisoniazid (12 mg) to 17 healthy subjects and determined the time course of the plasma concentrations of isoniazid, acetylisoniazid, acetylhydrazine, and diacetylhydrazine and of the exhalation of 14CO2. The time course of 14CO2 in breath closely paralleled the plasma concentration-time curve of acetylhydrazine but not those of acetylisoniazid or diacetylhydrazine, indicating that the 14CO2 originated directly from the metabolism of acetylhydrazine. The cumulative exhalation of 14CO2 increased with decreasing rate of acetylation of isoniazid, such that slow acetylators generated more 14CO2 than rapid acetylators. Simulation studies demonstrated that even if the data are corrected for the different formation of acetylisoniazid from isoniazid in slow and rapid acetylators, the slow acetylators still generated more 14CO2. The data therefore indicate that a substantial fraction of the acetylhydrazine formed from isoniazid passes through a pathway that has been shown in animals to generate highly reactive and hepatotoxic intermediates.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylation↗
Diet and arterial disease--the myths and the realities.
Explore the source record for details and available documents.
Adolescent↗
Rhesus diploid rabies vaccine (adsorbed): a new rabies vaccine using FRhL-2 cells.
The FRhL-2 cell line, a diploid line derived from the lung of a fetal rhesus monkey, was used to prepare a potent rabies vaccine by adapting the Kissling strain of rabies virus to FRhL-2 cells, growing the virus in quantity, inactivating the virus with beta-propiolactone, and concentrating the virus by adsorption to aluminum phosphate. High levels of antibody to rabies virus, induced by the vaccine in both guinea pigs and humans at 14 days after immunization, were determined to be IgG. Data from postexposure protocols with guinea pigs and simulated postexposure protocols in humans showed protection and antibody response even when rabies immune globulin was administered at the time of vaccination.
Animals↗
An investigation of the cause of accumulation of verapamil during regular dosing in patients.
The accumulation of verapamil during regular dosing conditions was studied. Plasma concentrations of verapamil (V) and norverapamil (NV) were measured as were urinary concentrations of verapamil, norverapamil, and four other N- and O-dealkylated metabolites in nine patients after an initial single dose and after chronic oral verapamil administration to steady-state plasma concentrations. Indocyanine green (ICG) clearance was determined immediately prior to the initial verapamil dose and prior to the verapamil washout from regular dosing. An approximately two-fold accumulation of V had occurred during regular dosing. The area under the plasma concentration-time curve (AUC1) after the first dose was 417.4 +/- 276.7 ng ml-1 h (mean +/- s.d.) and increased to 786.5 +/- 54 ng ml-1 h (P less than 0.01) during one dosage interval at steady-state (AUCss). NV also tended to accumulate from an AUC1 of 552.6 +/- 411 to an AUCss 668.7 +/- 332 ng ml-1 h (P less than 0.09). The ratio of AUC-V to AUC-NV was unchanged. The verapamil elimination half-life (t 1/2) increased from 8.4 +/- 4.2 to 12.0 +/- 3.6 h (P less than 0.01) whereas the norverapamil t 1/2 was unchanged. ICG clearance was unchanged. Urinary excretion of NV increased slightly but the ratio of urinary V/NV concentrations was not significantly altered nor was the ratio of four other metabolites to verapamil or the ratio of the combined o-demethylated to the N-dealkylated metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Distribution and retention of spermatozoa with acrosomal and nuclear abnormalities in the cow genital tract.
Two experiments were conducted to evaluate the fate of sperm following uterine insemination. In Exp. I, five pairs of Holstein cows were inseminated with egg yolk-Tris extended semen (approximately 1.0 X 10(9) sperm; .5 ml) from five ejaculates from a single bull that had high levels (approximately 70%) of morphologically abnormal sperm. Cows were slaughtered 12 h after insemination. The genital tracts were removed and promptly clamped into defined regions. Sperm were recovered by flushing with 2.9% sodium citrate buffer. Proportions of abnormal sperm in the various regions were compared with those in the inseminate. Sperm numbers were also determined from each region. Regions of the tract varied in number of sperm (P less than .001), proportions of knobbed acrosomes (P less than .001), tapered heads (P less than .001), protoplasmic droplets (P less than .001), tail abnormalities (P less than .029) and total abnormalities (P less than .002). A total of 63.5 +/- 6.4 X 10(6) sperm was recovered. These sperm were distributed throughout the tract as follows: vagina, 91.8%; cervix, 5.4%; uterine horns, 2.7%, and uterotubal junctions-isthmi, .04%. No sperm were recovered from ampullae. Because retrograde movement of sperm from the uterus occurred in Exp. I, we conducted Exp. II to determine the extent of sperm loss from the genital tract following insemination. Three pairs of Holstein cows were inseminated with .42 X 10(9) sperm (.5 ml; egg yolk-Tris extender) from the same bull used in Exp. I (three ejaculates). All discharged mucus and urine was collected for 12 h after insemination for recovery of sperm. Aspirates (approximately 1 ml) of mucus from the vagina were evaluated during the 12-h post-insemination period for numbers of sperm and leucocytes. Sperm were also recovered from the tract following slaughter (approximately 12 h) to determine retention. Overall, 73 +/- 3.7% of inseminated sperm were recovered. Components were: inseminate lost from the genital tract in discharged mucus, 60 +/- 4.6%; lost in urine, .06 +/- .02%; aspirated from the vagina, 4.4 +/- 1%; adhered to equipment, 1.3 +/- .3%, and retained in the genital tract, 6.5 +/- 1.6%. Predicted numbers of sperm contained in discharged mucus 2 h post-insemination were greater (P less than .009) than at subsequent hours.(ABSTRACT TRUNCATED AT 400 WORDS)
Acrosome↗
Oxidant stress and hepatic necrosis in rats treated with diquat.
Although diquat produces massive oxidant stress in both Fischer and Sprague-Dawley rats, the Fischer rats sustain hepatic necrosis and the Sprague-Dawley rats do not. A previous example of probable hepatic necrosis produced by an oxidant stress-generating compound was demonstrated in animals in which glutathione peroxidase activity had been decreased by a dietary deficiency of selenium. In the present study the susceptible Fischer rats had hepatic peroxidase activities equal to the resistant Sprague-Dawley rats. Hepatotoxic doses of diquat did not diminish hepatic glutathione peroxidase or reductase activities or hepatic content of ascorbic acid, NADPH or protein sulfhydryls. Hepatic nonprotein sulfhydryls were decreased by 50% but recovered to control values by 6 h. Biliary excretion of oxidized glutathione in the Fischer rat after administration of diquat was 4 times that observed after administration in Sprague-Dawley rats. The diquat-induced peroxidation of hepatic lipids was indicated by small increases in the 11-, 12-, and 15-hydroxyeicosatetraenoic acids, as quantitated by a new gas chromatography-mass spectrometry assay. Thus, acute lethal injury caused by redox cycling compounds that generate reactive oxygen species does not exhibit a number of the biochemical alterations in vivo that occur with cell death produced by similar compounds in isolated hepatocyte systems.
Alanine Transaminase↗
Effects of N-acetylcysteine on the disposition and metabolism of acetaminophen in mice.
N-acetylcysteine is the drug of choice for the treatment of acetaminophen poisoning, yet the mechanism of protection in vivo is unknown. Prevention of liver injury could result from decreased production of the toxic intermediate(s), from increased capacity to detoxify the toxic intermediate(s) or from increased ability of the tissue to withstand or even repair the molecular damage caused by the toxic species. Treatment of mice with N-acetylcysteine (1200 mg/kg p.o.) was found to prevent the hepatic damage caused by 1000 mg/kg p.o. of acetaminophen. Possible mechanisms for this hepatoprotective effect were examined by measurement at different time points of acetaminophen and its metabolites in plasma, urine, bile and whole-body homogenates and by evaluation of the changes in these parameters caused by treatment with N-acetylcysteine. A high-pressure liquid chromatographic method was developed to measure the majority urinary metabolites of acetaminophen and was validated by desorption chemical ionization mass spectral analysis of individual metabolites. Minimal differences in the concentration of unchanged acetaminophen and metabolites in whole-body homogenates at 4, 6 and 24 hr postdose were noted for N-acetylcysteine-treated vs. vehicle-treated mice. These results are incompatible with a decreased formation of the toxic species secondary to delayed acetaminophen absorption from the gastrointestinal tract or with an increased clearance of acetaminophen via nontoxic pathways such as sulfation as plausible mechanisms for the observed hepatoprotection.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice.
Experiments were designed to test whether the protective effect of N-acetylcysteine against acetaminophen hepatotoxicity precedes arylation of tissue or whether protection occurs after arylation of tissue. Investigation of potential postarylation actions showed that N-acetylcysteine was unable to attenuate the liver necrosis caused by acetaminophen or several other hepatotoxins that act through chemically reactive metabolites. Furthermore, varying the time and route of N-acetylcysteine treatment indicated that the late protection against acetaminophen mortality probably was a consequence of pharmacokinetic factors rather than postarylation intervention in the process of cell death. The antidote was found to inhibit covalent binding of acetaminophen by about 70% when N-acetylcysteine protected against liver necrosis. Treatment regimens that had no effect upon covalent binding also had no effect on acetaminophen hepatotoxicity. Previous failures to detect this relationship apparently occurred because of a failure to consider biological events important in the pathophysiology of acetaminophen-induced necrosis, particularly the marked intrahepatic hemorrhage and vascular congestion with liver engorgement by protein and fluid. These results support the hypothesis that sulfhydryl nucleophiles such as N-acetylcysteine act primarily through prearylation mechanisms to decrease the amount of reactive metabolite available for initiation of hepatic injury.
Acetaminophen↗
ATP-dependent calcium uptake by rat liver plasma membrane vesicles. Effect of alkylating hepatotoxins in vivo.
Lethal cell injury from hepatotoxic drugs has been postulated to result from an alteration in cell Ca2+ homeostasis. ATP-dependent Ca2+ uptake by the plasma membrane has a sulfhydryl-dependent functional moiety and, therefore, could be vulnerable to chemically reactive drug intermediates. Thus, alkylating hepatotoxins given in vivo were examined for their ability to inhibit Ca2+ accumulation by plasma membrane vesicles isolated from livers of adult male rats. ATP-dependent Ca2+ accumulation was decreased 62% by bromobenzene, 76% by acetaminophen, and 92% by CCl4. Mitochondrial Ca2+ uptake was minimally affected by the toxins, and only CCl4 affected Ca2+ accumulation by liver microsomes. The effect of acetaminophen on plasma membrane Ca2+ uptake was apparent as early as 45 min postdose. Depletion of protective intracellular GSH by diethyl maleate treatment (400 mg/kg) alone minimally decreased control plasma membrane uptake activity, although the GSH depletion markedly potentiated the effect of acetaminophen on the plasma membrane and on necrosis. Alkylation of sites on the plasma membrane may be a key chemical-macromolecule interaction in drug-induced liver necrosis, and inhibition of plasma membrane Ca2+ regulation may provide a connecting link between the alkylation hypothesis and the perturbed Ca2+ homeostasis hypothesis of lethal cell injury.
Acetaminophen↗
Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans.
The plasma concentrations of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine and diacetylhydrazine, were measured by gas chromatography-mass spectrometry in 12 healthy subjects after the ingestion of 300 mg of isoniazid. The area under the plasma concentration-time curve of acetylisoniazid and diacetylhydrazine increased with increasing rate of acetylation of isoniazid. In contrast, the area under the plasma concentration-time curve of acetylhydrazine, the postulated precursor of a toxic metabolite formed from isoniazid, was greater in slow acetylators. This occurred even though rapid acetylators generated more acetylisoniazid and thus more acetylhydrazine from isoniazid, because the rapid acetylators also acetylated acetylhydrazine faster to diacetylhydrazine than did the slow acetylators. Due to this complex relationship between area under the plasma concentration-time curve of acetylhydrazine and the rate of isoniazid acetylation (i.e., a faster rate of formation of acetylhydrazine is accompanied by a faster clearance to diacetylhydrazine), the rate of acetylation of isoniazid minimally influences the exposure of most patients to acetylhydrazine. This pharmacokinetic analysis, however, also shows that the apparent plasma half-life of acetylhydrazine is about five times longer than the plasma half-life of isoniazid, and thus repeated doses of isoniazid should lead to an accumulation of acetylhydrazine in the slowest acetylators in which the plasma half-life of acetylhydrazine is 20-plus hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylation↗
Spontaneous platelet aggregation in whole blood: dependence on age and haematocrit.
Explore the source record for details and available documents.
Adolescent↗
Low circulating vitamin K levels and fractured femur.
Explore the source record for details and available documents.
Femoral Fractures↗
Home care for patients with suspected myocardial infarction: use made by general practitioners of a hospital team for initial management.
Two hundred and sixty three general practitioners were offered the use of a hospital based service consisting of a medical senior house officer, a nurse attached to a coronary care unit, and a specially equipped ambulance estate car to help with the initial management of patients with suspected myocardial infarction who might be suitable for home care. One hundred and sixty nine general practitioners registered as potential users of this service; during 22 months they called the hospital team to see 271 patients, 235 of whom the team suspected had indeed suffered a myocardial infarction. During the same period, however, these general practitioners also admitted 317 patients with suspected myocardial infarction directly to hospital. Other general practitioners admitted 323 patients and deputising doctors 258. A further 529 patients with suspected infarction were admitted without the intervention of a general practitioner. Of the patients seen by the team, 54 required immediate admission to hospital; 17 of the remaining patients who initially appeared suitable for home care later required admission to hospital. In a large city such as Nottingham the provision of hospital based facilities to help general practitioners with home management is unlikely to make an appreciable impact on the overall pattern of care of patients with suspected myocardial infarction.
Aged↗
Hyperimmunoglobulinaemia D and periodic fever.
Explore the source record for details and available documents.
Adult↗
Effectiveness of speech therapy for aphasic stroke patients. A randomised controlled trial.
Aphasic stroke patients were randomly allocated to either a speech therapy group receiving treatment twice a week for 24 weeks or a no-treatment control group. Patients in both groups improved and there were no significant differences in language recovery between the 104 patients allocated to the treatment group and the 87 allocated to the no-treatment group. This treatment regimen, which is representative of clinical practice, is ineffective for most aphasic stroke patients.
Acute Disease↗