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B Mets

Publications and source records attributed to B Mets.

At least 37 records · Page 2Linked to original sources
PubMed1998

A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats.

Cocaine addiction and overdose have long defied specific treatment. To provide a new approach, the high-activity catalytic antibody mAb 15A10 was elicited using a transition-state analog for the hydrolysis of cocaine to nontoxic, nonaddictive products. In a model of cocaine overdose, mAb 15A10 protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion; a noncatalytic anticocaine antibody did not reduce toxicity. Consistent with accelerated catalysis, the hydrolysis product ecgonine methyl ester was increased >10-fold in plasma of rats receiving mAb 15A10 and lethal amounts of cocaine. In a model of cocaine addiction, mAb 15A10 blocked completely the reinforcing effect of cocaine in rats. mAb 15A10 blocked cocaine specifically and did not affect behavior maintained by milk or by the dopamine reuptake inhibitor bupropion. This artificial cocaine esterase is a rationally designed cocaine antagonist and a catalytic antibody with potential for medicinal use.

Animals↗
PubMed1997

Hepatic energy charge and adenine nucleotide status in rats anesthetized with halothane, isoflurane or enflurane.

BACKGROUND: Volatile anesthetics are known to have varying effects on hepatic oxygen supply in vivo and have been shown to depress hepatic mitochondrial respiration and so energy charge in vitro. However, the effect of halothane, isoflurane and enflurane on hepatic adenine nucleotide status in vivo has not been evaluated. METHODS: Ninety male rats were exposed to 40% oxygen (n = 22) or 40% oxygen in equipotent (1 MAC) concentrations of halothane (1%) (n = 23), isoflurane (1.4%) (n = 22) or enflurane (2%) (n = 23) for 2 hours. All animals were then administered intraperitoneal pentobarbital and anesthesia continued and laparotomy was performed. A liver biopsy was taken for determination of hepatocellular adenosine-5-triphosphate (ATP), adenosine-5-diphosphate (ADP) and adenosine-5-monophosphate (AMP) and computation of energy charge (EC) from ¿(ATP + 1/2ADP)+(ATP + ADP + AMP)¿ and total adenine nucleotides (TAN) from (ATP + ADP + AMP). After the biopsy the aorta was cannulated for blood sampling. RESULTS: Rats in each group were similar in weight, as well as acid base and blood gas status just after liver biopsy. Hepatic energy charge, ATP, ADP, AMP, and TAN levels were not different in animals receiving either halothane, isoflurane or enflurane when compared with those receiving only oxygen. CONCLUSION: One MAC of anesthesia for a period of 2 hours with the described volatile anesthetic agents did not affect adenine nucleotide status in vivo in rats.

Adenine Nucleotides↗
PubMed1996

Determination of cocaine, norcocaine, benzoylecgonine and ecgonine methyl ester in rat plasma by high-performance liquid chromatography with ultraviolet detection.

An isocratic high-performance liquid chromatographic method with ultraviolet detection at 235 nm is described for the determination of cocaine and its metabolites benzoylecgonine, norcocaine and ecgonine methyl ester in rat plasma, collected during toxicity studies. Following simultaneous solid-phase extraction of all analytes and the internal standard tropacocaine, cocaine, benzoylecgonine and norcocaine were separated on a C18 column. Ecgonine methyl ester and cocaine were separated on coupled cyanopropyl and silica columns, following derivatization of ecgonine methyl ester to p-fluorococaine. The extraction efficiencies of these compounds from plasma ranged from 78 to 87%, while the limits of detection ranged from 35 to 90 ng/ml. The assay was linear from 300 to 5000 ng/ml, and the within-day precision 2 to 8% over this concentration range.

Animals↗
PubMed1996

The role of catecholamines in cocaine toxicity: a model for cocaine "sudden death".

Sudden death associated with cocaine abuse is preceded by a state of agitated delirium. We postulated that release of catecholamines associated with this stress enhanced toxicity from cocaine. Thus we investigated the effect of catecholamine infusion [(epinephrine (7.25 ugml-1), norepinephrine (4.4 ugml-1) and dopamine (8.0 ugml-1), infused at 6 ml h-1] on the toxicity from concomitant infusion of cocaine (1 mg-kg-1 min-1). Two groups of rats were studied in order to isolate distinct toxicity endpoints: convulsions and respiratory arrest in conscious, and, circulatory arrest in anesthetized and ventilated rats. Catecholamines were administered at either full or 1/2 strength to establish a dose response effect on cocaine toxicity. Catecholamine infusion in a dose dependent fashion provoked earlier convulsions and respiratory arrest in conscious rats and circulatory arrest in anesthetized and ventilated rats. Despite lower cocaine cumulative dose administration, rats receiving catecholamines had similar plasma cocaine concentrations at the onset of convulsions and respiratory arrest compared to those with cocaine infusion alone. The data suggest that catecholamines enhance the convulsive, respiratory and circulatory toxicity of cocaine by a pharmacokinetic interaction.

Animals↗
PubMed1996

Early effects of total hepatectomy on haemodynamic state and organ uptake of catecholamines in the pig.

In a previous study, we showed that plasma concentrations of catecholamines were increased during the anhepatic phase in pigs. In this study, we investigated if a constant depth of anaesthesia would prevent these changes and, if not, if the changes were caused by impaired extraction of catecholamines. We measured arterial and venous pressures, heart rate and cardiac output in 10 anaesthetized pigs. Hepatic arterial and portal venous flows were measured. Blood for measurement of catecholamines was sampled from carotid and pulmonary arteries and portal, hepatic and renal veins. After a 2-h observation period, the liver was removed and the circulation reconstituted. Measurements were made and samples obtained for another 2 h. Catecholamine concentrations increased 2-10-fold after hepatectomy. Before hepatectomy, noradrenaline was extracted by the lung (mean extraction ratio 23 (SEM 8)%) and the liver (30 (11)%); after hepatectomy, there was extraction by the kidney (24 (12)%) but extraction by the lung (29 (8)%) was unchanged. Before hepatectomy, adrenaline was extracted predominantly by the kidney (73 (5)%) and the liver (70 (6)%), with minimal extraction by the lung; after hepatectomy, extraction by the lung increased (25 (4)%) and decreased slightly in the kidney (56 (6)%). While mean arterial pressure did not change, heart rate increased by approximately 50% and cardiac index declined (ns) within 2 h after hepatectomy. There was a sharp increase in pulmonary vascular resistance after removal of the liver and changes correlated with increases in arterial plasma concentrations of catecholamines.

Anesthesia, General↗
PubMed1995

Hepatic blood flow during reduced liver grafting in pigs. A comparison of controls and recipients of intact allografts.

Intraoperative changes in portal venous and hepatic arterial flow were compared in porcine recipients of reduced liver grafts with recipients of intact grafts and sham-operated controls. Control animals showed no significant changes in hepatic blood flow (measured with perivascular ultrasonic cuffs), heart rate, mean arterial pressure, cardiac output, acid/base balance, plasma sodium, potassium, glucose, or catecholamines. Recipients of intact or reduced grafts showed hypotension, reduced cardiac output, tachycardia, and increased systemic vascular resistance during the anhepatic phase, which lasted approximately 30 min. These changes returned to normal in recipients of intact grafts but in recipients of reduced grafts, levels returned only to 50-60% of baseline. After intact grafting, total liver blood flow and the portal and arterial components returned to baseline within 2 hr of revascularization, but after reduced grafting, hepatic arterial flow values remained depressed to 50-60% of baseline. Plasma epinephrine and norepinephrine were unaltered during control operation but increased 4- to 20-fold in recipients of all grafts. These returned towards baseline in all except recipients of reduced grafts, in which norepinephrine levels remained significantly elevated for the 4 hr of postoperative study. These data highlight persistent elevation of plasma norepinephrine after reduced liver grafting, which may have contributed to the diminished hepatic arterial flow. These results need to be confirmed in adult recipients of split liver grafts in whom grafts are comparatively small. In such patients receiving donor livers which have undergone prolonged storage, the effects of increased plasma norepinephrine levels upon donor agonal arterial spasm may be significant.

Animals↗
PubMed1995

Substance P level is increased in the cholesterol induced anaphylactoid reaction in the pig.

The role of substance P (SP) in cholesterol-induced anaphylactoid reaction was investigated in 13 Landrace pigs. Pigs were anesthetized with sodium thiopental and ventilation was controlled with 70% nitrous oxide in oxygen. A Swan-Ganz catheter and a carotid arterial line were placed to monitor the hemodynamic data. Group 1 pigs (control group, n = 5) each received 20 ml of intravenous (IV) colloid infusion solution (Haemaccel) and group 2 pigs (cholesterol group, n = 8) each received an IV injection of pure cholesterol emulsion (12 mg/kg) in 20 ml of Haemaccel. Blood samples for SP and histamine (H) levels were taken just before and for 10 min following the placebo, Haemaccel, and cholesterol injections. Urine samples were also collected just before and at 60 min following the injections for methyl histamine (MH) levels. Group 2 pigs (cholesterol) developed an anaphylactoid reaction as indicated by marked and significant hemodynamic changes. None of the group 1 (placebo) pigs developed an anaphylactoid reaction. Significant increases in blood SP and H levels (P < 0.05), and urine MH levels (P < 0.05) were seen in cholesterol-treated pigs (group 2), whereas no significant changes were seen in control pigs (group 1). Our results suggest that SP is involved in the cholesterol-induced anaphylactoid reaction in pigs.

Anaphylaxis↗
PubMed1995

Lethal toxicity from equimolar infusions of cocaine and cocaine metabolites in conscious and anesthetized rats.

We compared the lethal toxicity of cocaine with that of three of its metabolites to determine the contribution of these metabolites to the lethal potential from cocaine infusion. Equimolar quantities of cocaine, norcocaine, benzoylecgonine, and ecgonine methyl ester were infused in conscious rats to determine onset of convulsions and respiratory arrest. In addition, the convulsive and respiratory toxicity for cocaine and norcocaine were evaluated in anesthetized rats and their circulatory toxicity in anesthetized and ventilated rats. Norcocaine infusion resulted in earlier onset of convulsions and respiratory arrest in conscious rats than cocaine and earlier onset of circulatory arrest. Plasma concentrations of norcocaine and cocaine were not different at these times. Benzoylecgonine and ecgonine methyl ester were less potent convulsants and respiratory depressants than norcocaine and cocaine, with ecgonine methyl ester more respiratory depressant than benzoylecgonine. Pentobarbital anesthesia enhanced the respiratory depression and suppressed or delayed the onset of convulsions from norcocaine and cocaine infusion. Prolonged infusion of cocaine to circulatory arrest resulted in benzoylecgonine concentrations approximately 60%, and norcocaine concentrations approximately 5%, of the cocaine concentration, but no detectable ecgonine methyl ester formation. We conclude that although norcocaine, ecgonine methyl ester, and benzoylecgonine administered separately have lethal potential in massive dosages, death from cocaine overdose primarily results from the parent compound and not from metabolite formation.

Animals↗
PubMed1994

Alcohol pretreatment alters the metabolic pattern and accelerates cocaine metabolism in pigs.

We investigated whether alcohol pretreatment would affect the disposition and metabolic pattern of intravenously (i.v.) administered cocaine in pigs. Six pigs (Group A) received alcohol (1 g/kg/day) and six pigs (control; Group D) received an equal volume of isocaloric dextrose 44% in water for 10 days via an intragastric tube. On day 11, arterial samples were taken for five hours following an intravenous administration of cocaine hydrochloride (4 mg/kg). Plasma concentrations of cocaine and its major metabolites were analyzed by HPLC method. Significant decrease in plasma half-life (10 +/- 1.2 vs. 18.7 +/- 1.4 min), and significant increases in apparent volume of distribution (73 +/- 6 vs. 51 +/- 31) and clearance (5.37 +/- 0.6 vs. 1.82 +/- 0.1 l/min) were seen in alcohol pretreated pigs as compared with control pigs (P < 0.05). Significant increases in plasma concentrations of benzoylecgonine (P < 0.05), and insignificant differences in ecgonine methyl ester and norcocaine levels were seen between the two groups. Neither ecgonine nor cocaethylene was detected in the blood samples. Our data show that alcohol administration for ten days accelerated the elimination of i.v. administered cocaine and altered its metabolic pattern in pigs.

Animals↗
PubMed1994

Lidocaine extraction by the in vivo and isolated perfused pig liver.

Hepatic lidocaine elimination is increasingly being used to assess hepatic function. Although the isolated liver is extensively used as a model of in vivo function, it is necessary to determine whether this is a suitable model for in vivo lidocaine elimination. Fourteen male pigs (22-25 kg) were divided into two groups. Seven were anesthetized, and catheters and perivascular flow probes placed for transhepatic sampling and hepatic arterial and portal venous flow measurement. Sampling was performed at hourly intervals to determine hepatic function and plasma composition. Hepatic lidocaine elimination was determined during the second hour of a lidocaine infusion (1.41 mg.kg-1.min-1 for 10 min, then 0.165 m.kg-1.min-1), during which time the mean hepatic blood flow rates, plasma acid base status and body temperature were measured so that these could be emulated in the isolated perfused liver experiments. Seven male pigs were then anesthetized and the liver resected and cannulated for isolated liver perfusion. Hepatic arterial and portal venous blood flow and perfusate temperature were set to the mean in vivo values, and hepatic function and perfusate composition assessed at corresponding times. Hepatic lidocaine elimination was determined at a similar hepatic inflow whole blood concentration (+/- 5 micrograms.ml-1) to that in vivo over the second hour of lidocaine administration (40 mg bolus, then 2.8 mg.min-1). Lidocaine extraction ratio in vivo (0.61 +/- 0.04) [mean +/- SEM] and ex vivo (0.63 +/- 0.02) was similar, as was hepatic blood clearance (381 +/- 70 vs 363 +/- 16 ml.min-1) and hepatic blood intrinsic clearance (1132 +/- 280 vs 1069 +/- 109 ml.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1994

The effect of hepatectomy and plasma cholinesterase inhibition on cocaine metabolism and cardiovascular responses in pigs.

To determine the effects of total hepatectomy and inhibition of plasma cholinesterase activity on cocaine metabolism, we measured plasma concentrations of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, by high-performance liquid chromatography in three groups of male pigs. Pigs were anesthetized with sodium thiopental and lungs were ventilated with nitrous oxide in oxygen. A right carotid arterial cannula and an internal jugular venous catheter were then inserted for the administration of cocaine and for blood sampling. A Swan-Ganz catheter was inserted through the right internal jugular vein. Group 1 pigs underwent sham operation; group 2 and 3 pigs underwent hepatectomy and portocaval shunt. In addition, group 3 pigs were treated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor. After this preparation, pigs were given 4 mg/kg cocaine intravenously over 2 minutes. After cocaine injection, 4 ml blood was collected into heparinized test tubes containing 2.5% sodium fluoride for determination of cocaine and its metabolites at 2, 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes. We also measured hemodynamic responses after cocaine administration, including heart rate and rhythm, cardiac output, and arterial blood pressure. Data were analyzed by analysis of variance. Blood levels of cocaine and its metabolites were significantly different among the three groups (p < 0.05 by analysis of variance). Our results show that total hepatectomy was associated with a marked slowing of cocaine metabolism, absence of norcocaine, and increased benzoylecgonine levels when compared with the baseline values in the control pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of hypoxia on the hepatic metabolism of lidocaine in the isolated perfused pig liver.

The metabolism of lidocaine to monoethylglycinexylidide has been found useful as an indicator of liver function in association with liver transplantation. It has been postulated that this is due to the common effect of hypoxic damage on liver function and lidocaine metabolism. The effects of hypoxia on the elimination of lidocaine and the formation of monoethylglycinexylidide and on indexes of liver function were investigated with the isolated perfused pig liver preparation. This study was performed at similar hepatic effluent lidocaine concentrations of approximately 5 micrograms.ml-1 in normoxic (n = 7) and hypoxic (n = 8) livers of similar mass harvested from male Landrace x Large White pigs and perfused at standard unit hepatic flow rates. Whole blood lidocaine extraction ratio was 0.63 +/- 0.02 in normoxic livers (30% O2 at oxygenator inflow). It was significantly less (0.23 +/- 0.03) in livers subjected to hypoxia (2% O2 at oxygenator inflow), as were hepatic clearance (57.1 +/- 2.1 vs. 20.3 +/- 3.1 ml.min-1.100 gm-1), intrinsic clearance (1,706 +/- 182 vs. 284 +/- 53 ml.min-1.100 gm-1) and monoethylglycinexylidide formation as indicated by monoethylglycinexylidide/lidocaine ratios in the hepatic venous effluent (0.379 +/- 0.061 vs. 0.073 +/- 0.014) (p < 0.01). Hepatic oxygen consumption, adenine nucleotide status and bile flow were significantly impaired by hypoxia. Whereas perfusate potassium concentration increased early, AST levels showed delayed increases and ALT levels showed no changes. These changes correlated strongly with hepatic lidocaine elimination (p < 0.01). We conclude that lidocaine metabolism may be an early indicator of severe hepatic hypoxia.

Analysis of Variance↗
PubMed1993

Effect of lidocaine on in vivo hepatic function.

Lidocaine is administered to assess donor or recipient liver function during hepatic transplantation. This study was performed to determine whether lidocaine administered at a constant concentration affected hepatic function or had demonstrable effects on hepatocellular ultrastructure. Fourteen pigs were randomly allocated to receive either a two-stage infusion of lidocaine hydrochloride or of saline. Transhepatic blood samples were taken and ultrasonic portal venous and hepatic arterial blood flow readings made on animals anesthetized with isoflurane in nitrous oxide. Liver biopsies were taken for histological analysis and determination of adenine nucleotide status prior to and after 2 hr of the two-stage infusion. A mean systemic constant plasma lidocaine concentration of 5.9 micrograms/ml was achieved during the second hour of infusion. There were no differences between the two groups in a large number of indices of hepatic function and plasma composition prior to and during the second hour of the respective infusions. Hepatic blood flow was also similar at these times. On histological examination there were no electron microscopic changes that could be specifically attributed to the administration of lidocaine. However, there were progressive changes with time. This study suggests that in anesthetized pigs a constant lidocaine concentration of about 6 micrograms/ml has no detrimental effect on hepatic function. Progressive hepatic ultrastructural changes occurred that could not be attributed to the administration of lidocaine. These may be the result of anesthetic administered or the surgery performed.

Animals↗
PubMed1993

Comparison of in vivo and ex vivo porcine liver function using the same liver.

In vivo and ex vivo liver function was compared using the same livers to exclude interanimal variation in hepatic function. Six male pigs were anesthetized, and catheters and perivascular flow probes placed for transhepatic sampling and hepatic arterial and portal venous flow measurement. After a 2-h in vivo study period, the livers were resected and studied immediately afterwards for a further 2 h ex vivo as an isolated perfused preparation (Experiment A). Hepatic function in a further 6 pig livers (Experiment B) was studied ex vivo only for comparison with the ex vivo livers from Expt. A to determine whether the prior in vivo study had affected hepatic function. Despite using the same livers with similar total hepatic blood flows, (0.91 +/- 0.16 ml.g-1 x min-1) in vivo and (0.84 +/- 0.03 ml.g-1 x min-1) ex vivo, hepatic oxygen consumption (6.5 +/- 0.9 vs 2.6 +/- 0.2 ml O2 x 100 g-1), adenosine-5-triphosphate content (5.22 +/- 0.62 vs 4.14 +/- 0.71 microM.g liver-1) and bile flow (15.1 +/- 1.2 vs 6.0 +/- 1.0 ml.h-1) were initially less ex vivo and remained so throughout the study, while perfusate potassium (initially) (3.7 +/- 0.1 vs 6.4 +/- 0.3 meq.l-1), and aspartate aminotransferase (50 +/- 9 vs 76 +/- 5UL-1) was consistently higher than in vivo values. Initial hepatic energy charge (0.620 +/- 0.034 vs 0.552 +/- 0.061) and total adenine nucleotides 12.49 +/- 0.60 vs 11.66 +/- 0.62 microM.g liver-1) were not different and remained so subsequently.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1993

Lidocaine decay and hepatic extraction in the pig.

Plasma lidocaine decay after injection was studied in five anaesthetized pigs and fitted to a two compartment open model. Derived pharmacokinetic parameters were employed to rapidly achieve plateau concentrations within 60 min of starting a two stage infusion of lidocaine hydrochloride. Hepatic extraction and clearance of lidocaine at steady state were determined in 10 pigs by transhepatic sampling and measurement of hepatic arterial and portal venous blood flow using perivascular ultrasonic flow probes placed at laparotomy. These data were compared with similar studies performed in man as well as the sheep, dog, monkey and cat. The lidocaine extraction ratio of 0.60 in the pig was found to be similar to that determined by others in man.

Animals↗
PubMed1993

The effects of inhibition of plasma cholinesterase activity on systemic toxicity and blood catecholamine levels from cocaine infusion in pigs.

We investigated systemic effects and possible mechanisms for lethality of intravenously infused cocaine in spontaneously breathing and mechanically ventilated unconscious Landrace male pigs weighing about 26 kg (25.75 +/- 0.25 kg) that were pretreated with either saline solution (groups 1 and 3) or iso-ompa (tetraisopropyl pyrophosphoramide), a specific plasma cholinesterase inhibitor (groups 2 and 4). Pigs were made unconscious with sodium thiopental and ventilated with 70% nitrous oxide and 30% oxygen. A carotid arterial cannula and a Swan-Ganz catheter were inserted for hemodynamic monitoring. Pigs in groups 1 and 2 were then allowed to breathe spontaneously and groups 3 and 4 were mechanically ventilated. After obtaining a stable state, as judged by cardiovascular and respiratory parameters, the pigs were infused intravenously with cocaine hydrochloride (0.8 mg/kg/min) until the time of cardiac arrest. Respiratory and cardiovascular parameters, blood temperature, and sodium and potassium levels were monitored. The times of occurrence of respiratory arrests (RA), cardiac arrests (CA), and convulsions were recorded. Our results showed that RA is the primary cause of death in spontaneously breathing pigs and that mechanical ventilation significantly delayed the occurrence of CA (p < 0.05). Significant decreases in cardiac output, mean blood pressure, and heart rate as well as significant increases in systemic and pulmonary vascular resistances, central venous and pulmonary wedge pressures, and blood K+ levels were noted in mechanically ventilated pigs (p < 0.05). Variable hemodynamic responses were noticed in spontaneously breathing pigs. Our results also showed that no significant changes occurred in blood catecholamine levels when compared with baseline values associated with the infusion of toxic doses of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗