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S J Norman

Publications and source records attributed to S J Norman.

10 recordsLinked to original sources
PubMed1992

The effects of platelet-activating factor on the output of prostaglandins from the guinea-pig uterus.

Platelet-activating factor (PAF) significantly increased the output of prostaglandin (PG) F2 alpha from the guinea-pig uterus during the mid-cycle phase (Days 6-10), but only had a small, non-significant stimulatory effect on the outputs of PGE2 and 6-keto-PGF1 alpha. PAF significantly increased the outputs of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha from the guinea-pig uterus during the later phase of the cycle (Days 15-17). Lack of extracellular calcium did not affect the stimulatory effect of PAF on uterine PG output. However, TMB-8 (an intracellular calcium antagonist) prevented the increases in uterine PG output produced by PAF at both phases of the cycle. These results suggest that the stimulatory effect of PAF on uterine PG output in the guinea-pig is dependent upon the mobilization of intracellular calcium but is not dependent upon the uptake of extracellular calcium. Also, the weak stimulatory effect of PAF on PGE2 output from the uterus during the mid-cycle phase indicates that, if PAF is involved in implantation in guinea-pigs, it probably does not act via PGE2. Also, the lack of an inhibitory effect of PAF on uterine PGF2 alpha synthesis and release suggests that PAF is not the anti-luteolytic factor produced by the guinea-pig conceptus during early pregnancy.

Animals↗
PubMed1988

The interaction of omeprazole with rat liver cytochrome P450-mediated monooxygenase reactions in vitro and in vivo.

The effect of omeprazole on cytochrome P450-mediated monooxygenase reactions was assessed in rat liver S9 utilising ethylmorphine-N-demethylase (EM) and ethoxycoumarin-O-deethylase (ECOD) activities. The inhibition of EM by omeprazole was judged to be predominantly reversible in mechanism. The average Ki for omeprazole was 40 +/- 27 microM with EM and 76 +/- 6 microM with ECOD in four separate rats. In preparations of rat hepatocytes the intrinsic clearance of diazepam was decreased substantially by 50 microM omeprazole (average inhibition 73%). In comparison 50 microM cimetidine inhibited the intrinsic clearance of diazepam by 50%. The relationship between these two in vitro models for drug interactions is discussed in the context of previously published drug inhibition data. Moreover, repeated administration of omeprazole to adult male rats (500 mg.kg-1, 14 days, p.o.) resulted in statistical increases in liver weight, cytochrome P450 and ECOD activity. Thus omeprazole interacts with the mixed function oxidase system in vitro and in vivo.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1985

The effect of cimetidine and ranitidine on paracetamol glucuronidation and sulphation in cultured rat hepatocytes.

Cimetidine and ranitidine have been investigated for their ability to inhibit conjugation reactions in cultures of rat hepatocytes. Neither compound had any appreciable effect on rates of paracetamol sulphation. However, both cimetidine and ranitidine inhibited the glucuronidation of paracetamol in a dose-dependent manner. No adverse effects on cellular viability were noted utilizing enzyme leakage (lactic dehydrogenase) or protein synthesis measurements. The kinetics of inhibition by ranitidine were studied in more detail. At 0.25 mM ranitidine, the inhibition appeared to be purely competitive. However, at higher concentrations decreases in Vappmax were noted suggesting a more complex mechanism of inhibition. The relevance to inhibition in vivo by cimetidine and ranitidine and possible interactions between paracetamol and these histamine H2-receptor antagonists are discussed.

Acetaminophen↗
PubMed1985

Primary cultures of adult rat hepatocytes--a model for the toxicity of histamine H2-receptor antagonists.

Oxmetidine, a potent histamine H2-receptor antagonist, is cytotoxic to primary cultures of adult rat hepatocytes. The criteria of cellular injury included leakage of cytoplasmic enzymes into the culture medium, inhibition of protein synthesis and measurement of oxygen consumption by freshly isolated hepatocytes. These parameters were correlated with morphological changes in the cells as judged by inverted phase-contrast microscopy. In contrast, two other histamine H2-receptor antagonists, cimetidine and ranitidine, caused only minor changes in these parameters of cytotoxicity. The extent of injury observed with oxmetidine was both time and concentration dependent and was similar in hepatocytes maintained in culture for 2, 24 or 48 h. Prior treatment of rats with phenobarbital or beta-naphthoflavone did not influence oxmetidine-induced cytotoxicity. Inhibitors of cytochrome P-450-mediated monooxygenase activity had little effect on oxmetidine-induced injury with the exception of metyrapone, which was shown to inhibit the observed cytotoxicity by a mechanism other than inhibition of monooxygenase activity. In contrast, the injury could be potentiated by L-ethionine, an antimetabolite which reduces cellular ATP levels, suggesting that oxmetidine induces cytotoxic effects as a consequence of an interaction with intermediary energy metabolism.

Animals↗
PubMed1976

Cell-specific defect in monocyte function during tumor growth.

Inbred DA rats bearing a syngeneic 7,12-dimethylbenz[a]anthracene-induced neoplasm had an early impairment of chronic inflammation as measured by the numbers of monocytes elicited in a 3-day peritoneal exudative response to a sterile peptone injection. Furthermore, an advanced malignant tumor was associated with a complete block in the rats' capacity to mobilize monocytes, despite the fact that white blood cell counts on peripheral blood showed increased numbers of monocytes and polymorphonuclear leukocytes (PMN) during tumor growth. In contrast to the defect in chronic inflammation, a normal or increased acute inflammatory reponse was observed during tumor growth as measured by the 9-hour peritoneal PMN response to a sodium caseinate injection. Quantitative chemotaxis measurements in vitro made with these same peritoneal exudate cells revealed severe impairment of marcophage chemotaxis but normal migration of PMN. Generation of macrophage chemotactic signals from blood of rats with advanced tumors was not impaired. Since the resident cells of the peritoneal cavity were, chemotactically, a poor-responding population, this defective response in vitro appeared to correlate with the cell defect observed in vivo in the monocyte inflammatory response to peptone.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1973

Measurement of antibody-reactive toxin antigen during experimental staphylococcal B enterotoxemia.

Staphylococcal enterotoxin B (SEB) injected intravenously is rapidly cleared from the circulation and deposited in tissues. Type-specific antiserum administered after toxin has left the circulation can influence the course of enterotoxemia, and this observation suggests that toxin antigens may either be returned to the circulation or reside on cell surfaces readily available to antibody. If SEB toxin or its fragments regain access to the extracellular space, they might react with circulating antibody and be detected and quantitated by the reduction in antibody titer. Accordingly, 1 h after toxin or saline injection, animals were given type-specific enterotoxin B antiserum, and the difference in titers between the animals was used to compute the amount of enterotoxin immediately available to antibody. Further, by measuring differences in titers over a 48-h period, an estimate was made of the amount of SEB antigen that gained access to antibody. The data indicate that rats, which are relatively resistant to the lethal effects of enterotoxin, clear toxin from the circulation promptly and that very little toxin reenters the circulation. Monkeys, who are highly susceptible to SEB, also clear toxin promptly. However, in contrasts to rats, monkeys have greater quantities of SEB immediately available to antibody and in addition return significant quantities of toxin antigens to the extracellular space.

Animals↗
PubMedDate not supplied

The antipyrine breath test in the rat: a pharmacokinetic model.

Breath tests have been widely advocated for use as non-invasive probes of mixed function oxidase activity in vivo. A catenary sequence of events begins with demethylation and results in the exhalation of 14CO2. Intermediates in this chain include formaldehyde and formate. In this current study [14C]-antipyrine, [14C]-formaldehyde and [14C]-formate have been administered to rats. The data from these one carbon intermediates lead to the conclusion that demethylation is not the rate-limiting step in the antipyrine breath test in the rat. The resultant 14CO2 exhalation rate time profiles have been used to derive a compartmental pharmacokinetic model for the antipyrine breath test in the rat. The simplest catenary model (Antipyrine----formaldehyde----formate----CO2) did not adequately describe the observed data. A compartment in equilibrium with the central compartment for formate was needed to characterize fully the observed data. The derived compartmental model was able to predict qualitatively the effects of phenobarbitone induction on the antipyrine breath test. The quantitative agreement between the model prediction and the observed data could be improved by incorporating the changes in one carbon metabolism produced by phenobarbitone.

Animals↗
PubMedDate not supplied

Metabolism of temelastine (SK&F 93944) in hepatocytes from rat, dog, cynomolgus monkey and man.

A species comparison of the metabolic pathways of temelastine has been made using hepatocyte preparations from rat, dog, cynomolgus monkey, and man. Metabolites and unchanged temelastine were separated by HPLC and were compared with authentic standards by retention. The characteristic UV spectra of SK&F 93944 and its metabolites aided in the preliminary identification of metabolites in hepatocyte incubates, subsequently confirmed by liquid chromatography/mass spectrometry (LC/MS). The metabolic profile of temelastine is complex, both in vivo and in vitro, but all of the metabolites identified unambiguously from in vivo studies have also been demonstrated in vitro. Moreover, the time-dependent nature of the metabolic profile has been investigated in rat hepatocytes. Marked differences in the rate of production, extent of accumulation, and distribution between cells and culture medium have been observed for specific metabolites. Species differences in the metabolism of temelastine by rat, dog, cynomolgus monkey, and human hepatocytes have been observed. In particular, SK&F 94224 (a hydroxylated metabolite of temelastine) was not detected in human hepatocyte incubations at appreciable concentrations, but was present in varying amounts in the other species and especially in incubations from dog hepatocytes. Temelastine N-glucuronide was not detected in the rat hepatocyte system but was present to a modest or significant extent in hepatocyte incubations from dog, cynomolgus monkey, and man.

Animals↗
PubMedDate not supplied

Diazepam metabolism in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man.

Diazepam metabolism has been investigated in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man. The metabolite profile obtained by HPLC analysis of the culture medium indicated that substantial differences exist corresponding to known species differences in the metabolite profile of diazepam in vivo. These differences were attributed to a combination of the rate at which a metabolite was formed and the rate at which it is removed from the medium by further metabolism. The intrinsic clearance of nordiazepam in hepatocytes from each of the species exhibited the most marked species variation (rat much greater than guinea pig greater than rabbit greater than human greater than dog). Species that exhibited a high intrinsic clearance for nordiazepam were also those species that exhibited significant hydroxylation at the 4'-site of the molecule. The disappearance of diazepam was rapid in rat, dog, and guinea pig hepatocytes, but slow in human hepatocytes. Moreover, rat and human hepatocytes exhibited different saturability of diazepam clearance with respect to diazepam concentration accounting, at least in part, for the different rates of diazepam metabolism in the different species. These results support the value of hepatocytes in drug metabolism studies and especially in studies of species differences in metabolism.

Adult↗