Cardiovascular System Toxicity Research Articles

Bupivacaine Protein Binding in the Term Parturient

DENSON, D. D.; COYLE, D. E.; THOMPSON, G. A.; SANTOS, D.; TURNER, P. A.; MYERS, J. A.; KNAPP, R. Author Information

Purification and partial characterization of Flavotoxin A.

A heat-resistant, low-molecular-weight toxin was isolated from semisolid potato dextrose agar medium after inoculation with Flavobacterium farinofermentans sp. nov., which was isolated from fermented corn meal that caused some outbreaks of food poisoning in China. The toxin was purified by solvent partition, Sephadex LH-20 gel filtration, and C-18 reversed-phase column chromatography. Thin-layer chromatography and high-pressure liquid chromatographic methods were developed for the identification and analysis of the toxin. The purified toxin exhibited a single spot in thin-layer chromatography and a single peak in high-pressure liquid chromatography and had adsorption maxima at 232 and 267 nm. Mass spectral analysis indicated a molecular weight of 169 with an experimental formula of C9H13O3. The 50% lethal dose of purified toxin in mice (oral) was less than 6.84 mg/kg, but greater than 0.68 mg/kg. Postmortem examination showed that the mice died of some type of neurological and cardiovascular system toxicity. The name Flavotoxin A is being assigned to the toxin.

Bupivacaine protein binding in the term parturient: effects of lactic acidosis.

The effects of lactic acidosis on bupivacaine serum protein binding was studied in a group of term parturients and a group of nonpregnant female control subjects. Groups were matched in age and health. Distribution characteristics of bupivacaine in pregnancy were determined. Bupivacaine protein binding was best characterized by the model for two classes of binding sites in all studies. The parturients exhibited a lower capacity for the high-affinity, low-capacity (alpha 1-acid glycoprotein) site and higher affinity for the low-affinity, high-capacity (albumin) site. Lactic acidosis decreased the affinity constant for the high-affinity, low-capacity site in the control group but did not change binding characteristics in the parturients. Free concentration of bupivacaine (Cu) was elevated at low total bupivacaine concentrations (Ct) (less than 10 micrograms/ml). No differences in Cu were detected at concentrations in the cardiotoxic range (greater than 20 micrograms/ml). The Cu values predicted by the estimated binding parameters from in vitro experiments were compared with actual Cu measured in nine parturients at delivery; they correlated significantly (r = 0.94). Distribution changes for bupivacaine in the parturients were consistent with known physiologic changes in body composition associated with pregnancy. Alterations that occur in serum protein binding during pregnancy should not result in increased risk of central nervous system or cardiovascular system toxicity since these alterations do not increase free tissue concentration.

Toxicity and distribution of lidocaine in nonasphyxiated and asphyxiated baboon fetuses.

The dosage and blood concentration of lidocaine required to produce central nervous and cardiovascular system toxicity in both nonasphyxiated and asphyxiated fetuses were determined in ten pregnant baboons with fetuses of average gestation of 158 days (term, 185 days). Lidocaine was infused into the fetal jugular vein until cardiac arrest occurred, following which fetal brain, heart, lungs liver and kidneys were obtained. Mean dosage and blood concentration of lidocaine associated with seizures were 9.4 mg/kg and 15.2 micrograms/ml, respectively, in the nonasphyxiated fetuses, and 3.9 mg/kg and 5.6 micrograms/ml, respectively, in the asphyxiated ones. The dosage and blood concentration of the drug required to produce cardiac arrest were significantly higher in the nonasphyxiated group (35 mg/kg and 269 micrograms/ml, respectively) compared to the sphyxiated group (9 mg/kg and 40 micrograms/ml, respectively). Tissue-plasma ratios of lidocaine were significantly higher (P less than 0.05) in the brain, heart, and liver of the asphyxiated fetuses as compared with the nonasphyxiated ones. The relative proportion of the injected dose found in the organs was also higher (P less than 0.05) in the asphyxiated group. These results indicate that the increased sensitivity of the asphyxiated fetus to lidocaine may be related in part to a greater uptake of local anesthetics by the fetal organs.