Lester C. Mark

Cytochromes P‐450 and bs in human liver microsomes

Cytochromes P‐450 and b, have been demonstrated in human liver microsomes. The carbon monoxide and ethyl isocyanide difference spectra of cytochrome P‐450 in human liver are similar to those observed with rat or rabbit liver. The kinetic properties of 3,4‐benzpyrene hydroxylase in human liver have been determined.

Intravenous thiobarbiturate anesthesia for cesarean section.

A strictly controlled thiobarbiturate–succinylcholine–oxygen sequence, with thiobarbiturate dosage 4-7 mg/kg, seems safe for elective cesarean section. Two hundred and forty-eight patients were divided into four groups, which received 4, 5⅓ 6⅓ or 8 mg/kg of thiobarbiturate, respectively. Blood samples for barbiturate analysis were drawn at birth from the maternal antecubital vein and the umbilical artery and vein. Apgar scores were good (7-0) in 75-90 per cent, and fair (4-6) in 6-19 per cent, of infants in the first three groups, but only 60 per cent good, 34 per cent fair, after 8 mg/kg. Amniotic or other fluid had accumulated in the oropharynxes of most infants with low scores. Factors combining to protect the fetal brain against massive invasion by thiobarbiturale from the mother include: swift decline of drug concentrations in maternal blood; nomhomogeneity of blood in the intervillous space; absence of a maternalfetal capillary bed; hepatic extraction of drug from umbilical venous blood; progressive dilution; extensive shunting in the fetal circulation.

Tissue Thiopental Concentrations in the Fetus and Newborn

The distribution of thiopental was studied in tissues and organs of anencephalic human neonates and in fetal guinea pigs. The drug was administered by intermittent intravenous injections to the mother or by a single injection into the guinea pig fetus via the umbilical vein. High concentrations were found in the fetal liver, especially following direct injection into the fetus, in which case as much as 50 per cent of the dose could be accounted for in this organ. These findings document the importance of the fetal liver in preventing the fetal brain from being exposed to high concentrations of thiopental administered to the mother.

Metabolic studies with deuterated phenobarbital.

Isotope effects iii the metabolism of phenobarbital with dogs and rats were investigated using phenoharhitnlp-d (11) and phenobarbital-p-d-ethyl-& (111). The deuterated compounds were synthesized via benzvl-p-d cyanide prepared from toluene-p-d. This intermediate was utilized in the subsequent s t e p of the synthesiq except that for 111, ethyl-dr iodide was incorporated into the ethylcyanophenyl acetate preciirsor. Purity and extent of deuterium labeling was established by several analytical criteria. I t was foitnd that the apparent rate of plasma drug level decay for all three compounds was the same, which suggests that the riipture of the p a w C-H bond is not rate limiting in the metabolism of phenobarbital. On the other hand, a 13-26T exchange of the p-deuterium vthstituent was observed in civo, which on the basis of a postulated two-step mechanism leads to a product isotope effect of 4-8. The sedative effective of the three compounds was found to be similar.

Pharmacologic and Physiologic Aspects of Anesthesiology

DURING the six years since our last report of progress in the field of anesthesiology1 there have been important advances in the acquisition of scientific information and in the application of this...

Studies with Thiohexital, an Anesthetic Barbiturate Metabolized with Unusual Rapidity in Man

Thiohexital, a des-methyl-thio analog of methohexital, has been found to be the most rapidly metabolized intravenous barbiturate yet studied in man. It is more highly bound to plasma proteins than are thiopental and methohexital. The uptake by human adipose tissue, studied in vivo by means of serial biopsies, was considerably less than the uptake of thiopental. An analysis which correlates clinical features of the drug with physicochemical and metabolic factors is presented. It appears that a more rational approach to drug design based on these considerations would lead to a superior anesthetic barbiturate.

Placental Transfer of Drugs and their Distribution in Fetal Tissues

The passage of drugs and other foreign chemicals across the placenta and their distribution into and ultimate removal from fetal tissues are influenced by a variety of factors. Obviously of prime significance are the physicochemical properties of the compound in question. Equally important, however, are the pertinent anatomic features of and hemodynamic and pharmacokinetic events within the maternal circulation, the placenta and the fetus. The present chapter will concentrate on these fundamental principles. For more detailed analysis of some individual drug groups, the interested reader is directed to excellent reviews by Marx (1961), Moya and Thorndike (1962), Moya and Smith (1965) and Adamsons and Joelsson (1966).

Passage of thiopental and barbital into ocular and cerebrospinal fluids of dog.

Summary Experiments with dogs have shown that thiopental enters ocular fluid and spinal fluid more rapidly than barbital does. This is probably due to the higher lipid solubility of the thio barbiturate. The authors thank Drs. Bernard B. Brodie and J. J. Burns for helpful criticism.

Passage of Barbital into Cerebrospinal Fluid.

Summary Experiments in dogs have shown that barbital passes slowly into the brain and even more slowly into cerebrospinal fluid. It is possible that the blood cerebrospinal fluid barrier and blood brain barrier are similar for this drug.