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Biomedical subjects

B R Brown

Publications and source records attributed to B R Brown.

At least 55 records · Page 3Linked to original sources
PubMed1987

Adverse effects of volatile anaesthetics.

The volatile inhalation anaesthetics have been implicated in a variety of adverse viscerotoxic reactions. In general, they have been proven to produce very few non-predicted toxicities. Hepatitis caused by halothane now seems to be the only major problem in this regard with these drugs in current practice. The evidence is convincing that this reaction is based initially on biotransformation. Thus decreases in the amount of biotransformation and lessened production of reactive metabolic products would theoretically produce a safer anaesthetic. While not perfect in all circumstances, enflurane and isoflurane come close to achieving the goal of decreased adverse viscerotoxic events.

Anesthesia, Inhalation↗
PubMed1987

Clinical pharmacokinetics of the inhalational anaesthetics.

At present, the most widely used inhalational anaesthetics are the halogenated, inflammable vapours halothane, enflurane, isoflurane and the gas nitrous oxide. The anaesthetic effect of these agents is related to their tension or partial pressure in the brain, represented at equilibrium by the alveolar concentration. The minimum alveolar concentration for a specific agent is remarkably constant between individuals. The uptake and distribution of inhalational anaesthetics depends on inhaled concentration, pulmonary ventilation, solubility in blood, cardiac output and tissue uptake. Inhalational anaesthetics are mainly eliminated by pulmonary exhalation, but significant amounts of halothane are removed by hepatic metabolism. Inhalational agents currently in use have acceptable pharmacokinetic characteristics, and clinical acceptance depends on their potential for adverse effects. Induction of anaesthesia with halothane is rapid and relatively pleasant and it is the agent of choice for paediatric anaesthesia. Between 20 and 50% is metabolised, and the parent drug is a potent inhibitor of drug metabolism. Post-operatively enzyme induction may follow. The major disadvantages of halothane are myocardial depression, propensity to evoke cardiac arrhythmias and the rare but serious halothane hepatitis. Induction and recovery from enflurane anaesthesia is rapid. Metabolism accounts for 5 to 9% of the elimination. The metabolic product inorganic fluoride may in rare cases cause renal toxicity. Enflurane is a weak inhibitor of drug metabolism at anaesthetic concentrations. Enflurane depresses circulation more than halothane by reducing both myocardial contractility and systemic vascular resistance, but cardiac rhythm is stable. Enflurane anaesthesia may, unlike the other agents, induce epileptic activity. Enflurane is widely used as replacement for halothane in adults. Despite its low blood-gas solubility, the airway irritability of isoflurane precludes a faster induction of anaesthesia than with halothane. Isoflurane is almost resistant to biodegradation. Myocardial contractility is maintained during isoflurane anaesthesia and cardiac rhythm is stable except for the occurrence of tachycardia in some patients. Isoflurane is the inhalational agent of choice for neurosurgical operations. Sevoflurane is an experimental ether vapour: induction and recovery is fast and pleasant. It is metabolised to the same extent as enflurane and subnephrotoxic concentrations of inorganic fluoride may result. Sevoflurane has fewer respiratory and cardiovascular depressant effects than halothane and may be a future alternative for paediatric anaesthesia.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesia, Inhalation↗
PubMed1987

Characterization of a halothane-induced humoral immune response in rabbits.

An animal model of halothane-induced liver injury has been developed in the rabbit to study the production of humoral immunity towards a biotransformation intermediate of halothane. Rabbits exposed many times to halothane in a 75% O2/25% N2 atmosphere produce an antibody that cross-reacts with the trifluoroacetyl moiety of trifluoroacetylated rabbit serum albumin (TFA-RSA). The generation of this halothane-induced immunogen is dependent upon high oxygen tension as shown by the minimal anti-TFA antibody response seen in rabbits exposed to halothane in a 14% O2/86% N2 atmosphere. In addition, halothane exposure of rabbits specifically immunized with the metabolite-carrier complex, TFA-RSA, induces a secondary antibody response toward the immunogen. In rabbits, either immunized with TFA-RSA or not, multiple halothane exposures induce populations of antibodies with varying specificities. Evidence suggests that predominance of the metabolic intermediate, the ensuing immunogen, and the subsequent antibody response depends upon the oxygen tension during successive exposures to halothane. These successive exposures could potentially generate many different immunogens resulting in varied antibody specificities.

Animals↗
PubMed1987

The outpatient and ENT surgery.

Rules for admission of the ENT surgical patient into the ambulatory surgery scene are being relaxed as time and experience accrues. The anesthesiologist will probably be far freer in the use of the sympathetic amine epinephrine and cocaine. Thus, careful examination of all facets of the patient's history, clinical examination, drug intake, and laboratory studies must be synthesized in the determination of whether the cardiovascular system can tolerate the stimulation. Appropriate counter measures must be at hand just as for the inpatient situation.

Age Factors↗
PubMed1987

Halothane hepatotoxicity in guinea pigs.

A recently reported animal model of halothane-associated hepatotoxicity in males of a colored strain of guinea pig was further characterized as to possible sex and strain specificity in outbred albino Amana, inbred albino Hartley, inbred colored strain 2, and inbred colored strain 13 guinea pigs. Exposure to 1% halothane for 4 hr in 21% O2 proved to be hepatotoxic in both sexes. Forty-eight hours after halothane exposure fatty vacuolization of hepatocytes was present in all animals. Histologically identifiable hepatic necrosis occurred in 60% of the guinea pigs exposed, along with concomitant increases in SGPT. Approximately one half of these responding animals had extensive centrilobular necrosis, which was still present 96 hr after halothane exposure. Females of the inbred strain 2 and males and females of strain 13 were the most susceptible to halothane-induced hepatic necrosis whereas the inbred Hartley strain was almost totally refractory to necrosis. Outbred Amana and male inbred strain 2 animals exhibited an intermediate hepatotoxic response. Comparison of the halothane-associated hepatic lesion with that induced by anoxic/ischemic mechanisms, (exposure to low (8%) oxygen during 1.7% enflurane anesthesia) showed obvious differences in the morphology of the hepatic necrosis and the apparent time course of lesion development. This guinea pig model of halothane-associated hepatotoxicity appears to be superior to previous animal models in that no pretreatment of the guinea pigs is required, both sexes are affected, and the resulting hepatic lesion is more persistent.

Animals↗
PubMed1986

Oxygen concentrations required for reductive defluorination of halothane by rat hepatic microsomes.

The free oxygen concentrations required for reductive defluorination of halothane by rat hepatic microsomes from control and phenobarbital- (PB) and polychlorinated biphenyl-(PCB) treated animals were determined. Halothane-exposed microsomes from treated rats generated measurable levels of fluoride ion after 30 min incubations with oxygen concentrations of 5% or less. Microsomes from control animals produced fluoride only if the free oxygen concentration was 2% or less. During anoxic (0% oxygen) incubations, defluorination rates of 2.10 +/- 0.17, 5.55 +/- 0.38, and 5.46 +/- 0.30 nmol fluoride X mg protein-1 X 30 min-1 were observed for microsomes from control, PB, and PCB rats, respectively. Normalizing the maximal rates of defluorination to the microsomal cytochrome P-450 content yielded values of 5.14 +/- 1.40, 3.70 +/- 0.15, and 2.38 +/- 0.26 nmol fluoride X nmol cytochrome P-450-1 X 30 min-1 for control, PB, and PCB microsomes, respectively. Oxygen concentrations required for reductive metabolism of halothane by isolated rat hepatic microsomes are close to normal physiologic free oxygen concentrations of 4-5% reported for centrilobular areas of the rat liver. Thus even slight reductions in hepatic oxygenation during anesthetic exposure could lead to enhanced reductive biotransformation, an observation found in rat models of halothane-associated hepatic injury. The large differences among the treatment groups in the rates of fluoride ion generated per nanomole cytochrome P-450 indicate that enzyme induction regimens disproportionately increase those isozymes of hepatic cytochrome P-450 that are not involved with the reductive defluorination of halothane.

Animals↗
PubMed1985

Comparison of the requirements for hepatic injury with halothane and enflurane in rats.

A rat model of enflurane-associated hepatotoxicity was compared with the halothane-hypoxia (HH) model (adult male rats, phenobarbital induction, 1% halothane, 14% O2, for 2 hr). The enflurane-hypoxia heating (EHH) model involved exposing phenobarbital-pretreated male adult rats to 1.5-1.8% enflurane at 10% O2 for 2 hr with external heating to help maintain body temperature. Exposure to either anesthetic without temperature support led to a decrease in body temperature of 7-9 degrees C, while heating the animals during anesthesia resulted in only a 0.5-2 degree decrease. Reducing the oxygen tension to 10% O2 combined with heating the animals during exposure produced significant decreases in the oxidative metabolism of both halothane and enflurane as compared to exposures of 14% O2. The same conditions also caused a significant increase in the reductive metabolism of halothane, indicating that a severe hepatic hypoxia or anoxia occurs during anesthesia at 10% O2 with external heating. The time course of lesion development in the HH model paralleled results obtained with an oral dose of CCl4: gradual progression of necrosis up to 24 hr. EHH resulted in a classic hypoxic/anoxic injury with elevated serum glutamate pyruvate transaminase values and a watery vacuolization of centrilobular hepatocytes immediately after exposure. The HH model required phenobarbital pretreatment of the rats for expression of hepatic injury; EHH did not. Heating of the animals during anesthesia exposure was necessary for enflurane-induced hepatoxicity but had little effect on the HH model. Exposure to 5% O2 without anesthetic mimicked EHH in both requirements for and type of hepatic injury.

Anesthesia, Inhalation↗
PubMed1984

The involvement of endotoxin in halothane-associated liver injury.

Since endotoxin, lipopolysaccharides (LPS), have been implicated as a causative factor in the development of hepatic necrosis in rats exposed to hepatotoxic levels of several chemical agents, the role of LPS in the halothane-hypoxia (HH) model of hepatic damage in male Sprague-Dawley rats was investigated. When injected intravenously immediately after halothane anesthesia, a subnecrotic dose of LPS (0.5 mg/kg; Escherichia coli 026:B6) was found to markedly potentiate HH-induced hepatic necrosis. Pretreatment of the animals with the antiendotoxin agent, lactulose, prior to exposure to halothane reduced the hepatic damage normally seen from HH. A possible mechanism of LPS-induced potentiation was indicated by changes in hepatic calcium levels at 24 h after treatment. Endogenous LPS may play a role in HH-induced hepatic necrosis, and the mechanism of LPS-induced potentiation may be due to an LPS-related membrane dysfunction.

Anesthesia↗
PubMed1983

Cognitive and psychosocial differences between I and E locus of control aged persons.

An abbreviated version of Rotter's Locus of Control (LOC) Scale was administered to 437 elderly subjects living in a variety of settings in an urban community. The group (n = 199) which scored below the median (internal orientation) was compared with the group (n = 238) which scored at or above the median (external orientation) on an array of 37 cognitive and psychosocial variables. Significant differences, mostly favoring the internal subjects, were found on 13 of the variables, suggesting relatively better self-reported health status, cognitive, and personal-social functioning on their part. These results are in general agreement with most other reports dealing with the relationships between LOC responses of the aged and their psychosocial functioning. Step-wise multiple regression analysis of the intercorrelations among the 37 variables and LOC show only seven are significant and these account for no more than 13 percent of the variance. The overall impression is that LOC has a reliable relationship to limited aspects of cognitive and psychosocial functioning, but that the power of its predictive effectiveness is still quite limited.

Aged↗
PubMed1981

Halogenated analgesics and hepatotoxicity.

The otherwise safe and useful anaesthetic halothane has been suspected of producing the occasional complication of hepatic necrosis, ascribed either to a drug allergy or to biotransformation to reactive intermediates. Several characteristics, such as middle age, obesity and multiple administrations of the anaesthetic, seem to put the patient at higher risk. The diagnosis of anaesthetic-induced jaundice is still one of exclusion, however, and this rare problem is felt to be overdiagnosed.

Anesthetics↗
PubMed1981

Azido analogs of acridine: photoaffinity probes for frameshift mutagenesis in Salmonella typhimurium.

In order to identify a photoaffinity probe for 9-aminoacridine frameshift mutagenesis, 20 azido analogs of acridine were synthesized and tested in Ames' Salmonella tester strains, TA1535, TA1537, TA1538 and their corresponding excision-repair-coefficient strains TA1975, TA1977 and TA1978, to determine their mutagenicity and toxicity relative to 9-aminoacridine. The substituent-mutagenicity patterns observed for these compounds agree very well with those obtained previously for non-azidoacridines. The results presented here show that the 2-azido-analog of 9-aminoacridine demonstrates biological activity similar to 9-aminoacridine prior to photolytic activation. With light activation, however, the 9-amino-2-azido derivative becomes more effective at producing frameshift mutations characteristic of 9-aminoacridine. Furthermore, this photolytic enhancement of mutagenesis appears to be due to the repairable lesion suggesting that covalent attachment of the drug occurs.

Acridines↗
PubMed1981

Factors affecting the formation of chlorotrifluoroethane and chlorodifluoroethylene from halothane.

Since CF3CH2Cl and CF2CHCl are probably the products of reactive intermediates formed during the reductive metabolism of halothane (CF3CHClBr), factors affecting their in vitro and in vivo formation were investigated. In vitro studies with rat hepatic microsomes showed that CF3CH2Cl and CF2CHCl are produced by cytochrome P-450 mediated reductive pathways which were inhibited by the presence of CO. Under conditions of exposure known to promote halothane hepatotoxicity in phenobarbital treated rats (1 per cent halothane, 14 per cent oxygen), the hepatic and blood concentrations of the volatile metabolites were enhanced. Central venous levels of the volatile metabolites were much higher than he concentration in peripheral vessels. The CF3CH2Cl/CF2CHCl ratio in blood was approximately three, whereas the ratio in vitro was almost unity. Liver levels of the two volatile metabolites greatly exceeded the blood levels, but interestingly they were present in equivalent concentrations. The differences in the ratio of CF3CH2Cl to CF2CHCl may be explained by the fact that CF2CHCl is further degraded under oxidative conditions, whereas CF3CH2Cl appears relatively stable. Measurement of these metabolic products in patients undergoing halothane anesthesia may permit rapid detection of an unusually high level of halothane biotransformation along its hepatotoxic pathway.

Animals↗
PubMed1981

Extrahepatic biotransformation of halothane and enflurane.

The rates of biotransformation of halothane and enflurane by rabbit kidney and lung microsomal preparations were compared t the hepatic microsomal biotransformation of these agents. All three microsomal preparations (pulmonary, renal, and hepatic) were found capable of performing oxidative demethylation reactions as well as epoxidation. This was evidenced by the ability of these three microsomal preparations to metabolize benzphetamine, methoxyflurane, and trichloroehylene. Only the liver microsomal preparations were capable of defluorinating enflurane at any appreciable rate (6 +/- 3 pmoles/min/mg of microsomal protein). The three microsomal preparations performed reductive biotransformation of halothane, and the liver microsomes produced more than 3 times as much product as the other tissues. Pulmonary and renal microsomal preparations metabolized halothane reductively about equally. Differences in the solubility of halothane and enflurane in the rabbit pulmonary and hepatic microsomes were not found to be a cause of the differences in biotransformation in these two organs. Extrahepatic biotransformation may be an important factor in the disposition of volatile anesthetics.

Anaerobiosis↗