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Biomedical subjects

K M Knights

Publications and source records attributed to K M Knights.

At least 37 records · Page 2Linked to original sources
PubMed1988

The stereospecific incorporation of fenoprofen into rat hepatocyte and adipocyte triacylglycerols.

The formation of triacylglycerols containing fenoprofen was studied in rat isolated adipocytes and hepatocytes incubated with [3H]glycerol and R or S fenoprofen. In both hepatocytes and adipocytes there was a high-affinity enzymatic process for the synthesis of triacylglycerol containing fenoprofen which was stereospecific for the R enantiomer. The apparent Km values for R fenoprofen were 1.0 microM in adipocytes and 2.8 microM in hepatocytes. These results are consistent with the proposed stereospecific formation of R-2-arylpropionyl-CoA thioesters resulting in the stereospecific formation of R-tri-acylglycerol at clinically relevant unbound fenoprofen concentrations. In isolated hepatocytes, but not adipocytes, a second low-affinity enzymatic process for the synthesis of triacylglycerol containing fenoprofen was also observed. However, this process (Km = 3780 microM) occurred at concentrations much higher than those found in man with usual doses.

Adipose Tissue↗
PubMed1988

A radioisotopic assay of picomolar concentrations of coenzyme A in liver tissue.

A single-step enzyme assay using [14C]palmitic acid and bacterial acyl-coenzyme A synthetase (EC 6.2.1.3) is described for the determination of reduced coenzyme A (CoASH) levels in liver samples. Use of this technique provides a rapid and accurate determination of CoASH in the range 1-250 pmol. Application of the method to the quantitation of CoASH in samples of human liver tissue and rat liver homogenate, isolated hepatocytes, and mitochondria is described.

Animals↗
PubMed1988

Halothane induced hepatic necrosis in rats: the role of in vivo lipid peroxidation.

Hepatic damage was induced in phenobarbitone pretreated male Fischer 344 rats by the administration of 1% halothane in 14% oxygen for either 1 or 2 hours. Ethane production during the exposure period was not significantly different between the halothane and non-halothane exposed groups. Animals were sacrificed 1, 2, 6 and 24 hrs from commencement of anaesthesia and the hepatic microsomal fraction analyzed for diene conjugates, lipid hydroperoxides, total lipid content and fatty acid composition. Animals exposed to halothane and sacrificed at 2 and 24 hrs had significantly elevated levels of diene conjugates (P less than 0.05), while lipid hydroperoxide concentration and serum alanine aminotransferase increased in only those animals sacrificed at 24 hrs. Alterations in total lipid content and hepatic microsomal fatty acid composition were not observed in animals sacrificed after 1 and 2 hrs. A significant reduction in total lipid and arachidonic acid content occurred only in those animals sacrificed 24 hrs after exposure, however a concomitant increase in the saturated fatty acid fraction was not observed. It is proposed that alterations in fatty acid composition in vivo and evidence of lipid peroxidation occur as a result of cell death rather than an initiating event in halothane induced hepatic necrosis in rats.

Alanine Transaminase↗
PubMed1987

Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations.

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.

Alanine Transaminase↗
PubMed1987

A randomized prospective controlled study of the metabolism and hepatotoxicity of halothane in humans.

In a randomized prospective controlled study in humans, the metabolism and hepatic effects of a single administration of halothane were compared with enflurane and meperidine. Pre- and postoperative antipyrine pharmacokinetics, intraoperative indocyanine green clearance, liver histology, and postoperative liver function tests were determined in 24 patients undergoing abdominal surgery who were randomly allocated to receive either halothane (0.5%, group I), enflurane (0.8%, group II), or meperidine (group III) as a supplement to a common basal anesthetic regimen consisting of thiopental, nitrous oxide/oxygen/muscle relaxant. In addition, end-tidal concentrations of the volatile reductive metabolites of halothane, chlorodifluoroethylene (CDF), and chlorotrifluoroethane (CTF) were determined in group I patients and serum and urinary inorganic fluoride were determined in both group I and II patients. Indocyanine green clearance was measured before anesthesia (stage I), during basal anesthesia (stage II), in the presence of surgical stimuli (stage III), and after introduction of the selected anesthetic agent (stage IV). CDF and CTF were detectable within 20 min of the start of halothane anesthesia in every patient receiving halothane. Peak serum fluoride concentrations occurred at 2 and 24 hr in the enflurane and halothane groups, respectively, whereas urinary fluoride excretion was elevated postanesthesia in the enflurane group only. There was no difference between the pre- and postoperative disposition of antipyrine in group II or III, but after anesthesia, antipyrine clearance was significantly decreased (P less than 0.02) and plasma half-life increased (P less than 0.05) in group I patients (halothane). Concentrations of serum alanine aminotransferase (ALT) and bilirubin were significantly elevated (P less than 0.5) postoperatively in groups I and II but unchanged from preoperative values in group III patients. Three of the 24 liver biopsies taken at the end of stage IV showed several foci of acute liver cell necrosis; of these, two patients were from group I and one from group II. There were no significant differences in liver cell morphology (P greater than 0.5) in biopsies taken at the end of stage IV compared with biopsies at the end of stage III, from groups I and II. The results of this study show that reductive metabolism of halothane occurs routinely in patients undergoing halothane anesthesia under conditions of normoxia. This may be the cause of the changes in antipyrine clearance after halothane anesthesia.

Antipyrine↗
PubMed1987

Halothane hepatitis in an animal model: time course of hepatic damage.

The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage. Liver tissue was obtained immediately at post-mortem for histological examination. Serum ALT was increased at the end of the anaesthetic period, i.e. 2 h, with peak levels occurring at 12-24 h and remaining elevated for 3 days after exposure. Minor changes in liver histology were evident at 2 h in 50% of the animals and by 6 h all animals had mild hepatic injury. The extent of the necrosis was maximal at 24 h and this was sustained until 3 days. By 5 days after exposure minimal evidence of liver damage was observed and animals killed at 30 days had morphologically normal livers. Elevation of serum ALT or changes in liver histology were not observed in other treatment groups. The early onset of damage at 2-6 h is in keeping with direct hepatotoxicity associated with the biotransformation of halothane.

Alanine Transaminase↗
PubMed1986

Benoxaprofen induced toxicity in isolated rat hepatocytes.

The toxicity of benoxaprofen, a non-steroidal anti-inflammatory compound was investigated using rat hepatic microsomal and isolated hepatocyte suspensions. In microsomes, benoxaprofen produced a Type I binding spectra and competitively inhibited (ki 380 microM) the oxidative metabolism of aminopyrine. Marked toxicity was observed following incubation of benoxaprofen with isolated hepatocytes from either untreated, phenobarbitone (PB) or 3-methylcholanthrene (3-MC) pretreated male rats. In untreated hepatocytes increases in the intracellular lactate/pyruvate (L/P) ratio and alanine aminotransferase (ALT) release were related to the benoxaprofen concentration and duration of incubation. Alterations in L/P ratio preceded the release of cytosolic ALT and at 4 h a well defined dose-response relationship existed between the benoxaprofen concentration and the observed increases in the L/P ratio and ALT release. Pretreatment of animals with either PB or 3-MC did not affect the temporal nature nor the magnitude of the hepatocyte response to benoxaprofen. In addition, inhibitors of cytochrome P-450 isozymes (SKF-525A, metyrapone and alpha-napthoflavone) were ineffective with regard to modifying the observed toxicity. The results of this study suggest that hepatic cytochrome P-450 mediated metabolism may not be implicated in the toxicity of benoxaprofen in isolated hepatocytes. However, alterations in the cellular redox state and evidence of plasma membrane bleb formation suggest that benoxaprofen may uncouple oxidative phosphorylation and disturb intracellular calcium ion homeostasis.

Alanine Transaminase↗
PubMed1986

Interaction of benoxaprofen with rat erythrocytes: effects on oxidative metabolism and membrane ATPase activities.

Incubation of rat erythrocytes with benoxaprofen resulted in increased glucose utilization, lactate production, depletion of cellular ATP and significant haemolysis. In isolated red cell membranes, benoxaprofen produced a dose related stimulation of both Ca2+ dependent and Ca2+ independent ATPase activities. Coincubation of either erythrocytes or red cell membranes with cysteine ameliorated the effects of benoxaprofen. A possible association exists between the mechanism of the reported anti-inflammatory activity of benoxaprofen and its cellular toxicity.

Adenosine Triphosphatases↗
PubMed1981

A rapid gas-liquid chromatographic determination of antipyrine clearance in the rat.

The assay procedure described in this paper allows the calculation of pharmacokinetic data of antipyrine disposition to be obtained from a single animal with minimal disturbance in hematocrit. A sample volume (100 microliters) allows the repeated use of the same rat for studies of hepatic drug metabolism. The lower limit of sensitivity is 5 micrograms/ml, with a range of linearity extending to 100 micrograms/ml. This allows for various dosing regimens. The GLC assay is rapid and accurate as shown by comparison with previously published values for the half-life of antipyrine in rats.

Animals↗
PubMed1979

Blood carbon dioxide tension changes during hysteroscopy.

During hysteroscopy the uterus may be distended with carbon dioxide (CO2), nitrous oxide (N2O), or Hyskon (a high molecular weight dextran). An initial study in 27 patients (group 1) using arterialized venous blood samples demonstrated rises in carbon dioxide tension (PCO2) when N2O was insufflated by using a laparoscopy insufflating device--a constant-pressure, variable-volume gas source. Cardiovascular collapse occurred in one patient in this group, most probably as a result of macropulmonary emboli of N2O. The rise in PCO2 is accounted for by an increase in physiologic dead space. In another 24 patients (group 2) the gaseous media were introduced by using a constant-volume, variable-pressure gas source; this resulted in minimal changes in arterial PCO2. The choice of whether a gaseous or liquid distending medium is used for hysteroscopy is governed by the state of the endometrium. If a gaseous medium is indicated, then CO2 is preferable to N2O and should be introduced with a constant-volume, variable-pressure gas source.

Carbon Dioxide↗
PubMed1977

Metabolism of 14C-labelled alphaxalone in man.

The metabolism of 14C-labelled alphaxalone, dispensed as Althesin, was studied in normal patients, patients with obstructive jaundice and patients with chronic renal disease and anuria. The radioactive label was removed rapidly from the plasma following i.v. administration. The major portion of the label was excreted in the urine. In patients with normal renal function 14C-labelled alphaxalone is probably taken up by the liver, metabolized to a more polar compound and excreted in the urine; a small amount is excreted in the bile. In the patient with anuria, hepatic uptake appears to be relatively normal and the length of action of Althesin is not prolonged. It is assumed that in such patients the eventual route of excretion is via the bile and faeces.

Alfaxalone Alfadolone Mixture↗
PubMed1977

Enflurane (Ethrane) anaesthesia in man. Metabolism and effects on biochemical and haematological variables.

In 10 patients serum inorganic fluoride increased to a mean peak value of 16 micronmol.litre--1 after 2 h of enflurane anaesthesia. Four days after anaesthesia, serum inorganic fluoride had decreased to the values before operation. The maximum daily inorganic fluoride excretion in urine (UFV) did not exceed 200 micronmol.litre--1. In a group of 20 patients routine biochemical and haematological variables were measured before and after enflurane anaesthesia. There were only minor changes in these variables, attributable to the surgical procedure. It is concluded that renal dysfunction is unlikely to follow enflurane anaesthesia in patients with previously normal hepatic and renal function.

Anesthesia, Inhalation↗