George D. Olsen

Morphine and phenytoin binding to plasma proteins in renal and hepatic failure.

The binding of morphine and phenytoin to plasma proteins was examined in healthy subjects and in patients with renal and hepatic failure. In the uremic patients without hepatic failure, morphine binding was dependent on the concentration of total serum proteins and albumin, but not the severity of renal failure as measured by creatinine clearance. Binding of phenytoin, however, was dependent on the degree of renal failure and albumin concentration, but not on total serum protein concentration. Renal transplant in 1 patient restored the binding of both drugs to a value within the normal range. The combination of hypoalbuminemia and hyperbilirubinemia resulted in the greatest impairment of binding for both drugs. It is concluded that patients with uremia, jaundice, hypoalbuminemia, particularly in combination, are sensitive to usual clinical doses of morphine, at least in part, because of decreased binding to plasma proteins.

Clinical eftects and pharmacokinetics of racemic methadone and its optical isomers

The respiratory and pupillary effects of oral l‐, d‐, and d,l‐methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half‐life of drug in blood was 22 hr for racemic methadone, 24 hr for 1‐methadone, and 25 hr for d‐methadone. The effects of d‐methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l‐methadone and 15 mg of d,l‐methadone induced intense and sustained respiratory depression and miosis. The changes induced by l‐methadone were of longer duration than those of d,l‐methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated weil with respiratory depression and miosis for 1‐ and d,l‐methadone. The potency ratio of l‐methadone to d,l‐methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l‐methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l‐Methadone administeredfrequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

Methadone binding to human plasma proteins

The interaction of L‐(1‐3H) methadone with solutions of purified human gamma globulin and with human plasma was studied by equilibrium dialysis. The per cent of methadone bound to gamma globulin was dependent on drug and protein concentration. In the normal range of serum gamma globulin concentration and the therapeutic range of plasma methadone concentration, gamma globulin bound 13.4% to 17.4% ot the total drug concentration. The binding of methadone to plasma from 2 healthy male volunteers, nontolerant to narcotic analgesics, was dependent on drug concentration. Methadone bound to plasma proteins decreased from 87.3% to 83.7% as drug concentration increased in the therapeutic range. This small decrease is most likely due to decreased binding by the gamma globulin fraction since albumin binding is constant in this range. The data in this study, as weil as a previous study with albumin, suggest that methadone may also bind to other plasma proteins such as beta, alpha‐I, and alpha‐2 globulins.

Ventilatory response to carbon dioxide of infants following chronic prenatal methadone exposure

Nine infants chronically exposed to methadone in utero were studied from birth to 7 weeks of age (66 studies). The maternal dose of methadone/HCl during the third trimester ranged from 14 to 70 mg orally once a day. The mean (range) of serum methadone t 1/2 in the neonates was 53 hours (22 to 113). In the first four days of life the methadone-exposed infants had a significantly (P less than 0.005) decreased sensitivity to carbon dioxide compared to control infants as measured by the slope of the ventilatory response curve. The mean slope +/- SD for the methadone-exposed infants, 10.4 +/- 7.7 ml/minute/kg mm Hg, was one third that of the control group (30.0 +/- 9.9 ml/minute/kg/mm Hg). Total ventilation, respiratory frequency, oxygen consumption, and end-tidal PCO2 were not significantly different in the two groups. The depressed ventilatory response to carbon dioxide persisted for an average of 15 days and lasted as long as 31 days in one infant. The time required to achieve a normal slope was not related to the size of the maternal methadone dose, to neonatal serum methadone t 1/2, or to the severity of and therapy for methadone withdrawal. If this abnormality in sensitivity to carbon dioxide persists beyond the neonatal period in some infants, it may contribute to the increased incidence of the sudden infant death syndrome among infants exposed to methadone in utero. Measurement of the ventilatory response to carbon dioxide may be clinically useful to determine which of these infants are at risk for SIDS.

Gentamicin binding to serum and plasma proteins.

Gentamicin binding to serum proteins was studied by equilibrium dialysis at 37°C and pH 7.4 in the presence of both physiologic and adjusted concentrations of ionized calcium and magnesium. The percentage of bound drug was inversely related to the concentration of these two divalent cations, ranging from 27% bound with no calcium and magnesium present to 17% bound in the presence of four times physiologic concentrations. No significant difference in the extent of drug‐protein binding was noted in a comparison of sera from healthy and uremic subjects. Heparin also was found to affect gentamicin binding. Increasing heparin concentration in serum increased apparent gentamicin‐protein binding to 34% in the presence of physiologic amounts of calcium and magnesium. Buffered heparin solutions without plasma proteins bound up to 65% of total drug concentration. Gentamicin‐protein binding may have implications regarding pharmacokinetics and renal cortical uptake.

Presence of hemoglobin messenger ribonucleoprotein in a reticulocyte supernatant fraction

Abstract A study is made of globin messenger ribonucleic acid (mRNA) distribution in a rabbit reticulocyte lysate. Ribonucleic acid with the electrophoretic mobility of globin mRNA is found not only in polyribosomes but also in a ribonucleoprotein complex which sediments at 15 S. Such presumptive mRNA is not found in single ribosomes or in the subribosomal particle fraction. Further evidence that the 15-S ribonucleoprotein contains globin mRNA is obtained using a protein synthesizing extract from embryonic muscle. Addition of 15-S complex to the extract specifically stimulates incorporation of radioactive amino acids into material which cochromatographs with carrier hemoglobin and which coprecipitates with the carrier hemoglobin upon addition of anti-hemoglobin antiserum.

Respiratory and ventilatory effects of methadone in healthy women

The effects of oral methadone on respiration, ventilation, pupillary diameter, and plasma concentrations of estrone, estradiol, and progesterone were investigated in healthy nonpregnant women, 21 to 29 yr old. All women were in the follicular phase of the menstrual cycle. The study design was a randomized, double‐blind, placebo‐controlled trial. Six women received 15 mg methadone · HCl, and six received placebo. Alveolar ventilation and oxygen consumption before treatments correlated with plasma progesterone concentration (r2 = 0.85 and 0.68) but the slope and x‐intercept of the ventilatory response to carbon dioxide curve did not. Female sex steroids in plasma were not affected by methadone. Mean elimination half‐life of methadone from serum was 19 hr. Methadone‐induced respiratory depression and miosis lasted more than 48 hr. The intensity of these changes was a linear function of the logarithm of the serum methadone concentration. Plasma progesterone concentration is an important determinant of resting ventilation and metabolism in the follicular phase of the menstrual cycle but endogenous progesterone does not protect women from the respiratory depressant effects of methadone.

New gas chromatographic assay for the quantification of methadone : Application in human and animal studies

Abstract A new gas chromatographic assay utilizing 2-dimethylamino-4,4-diphenyl-5-nonanone as the internal standard was developed for the quantification of methadone. The method involved extraction of methadone with 1-chlorobutane from tissue at pH 9.8, re-extraction of an aliquot of the organic solvent with 0.5 M sulphuric acid, alkalinization and final extraction into chloroform. The assay was used to determine the concentration of methadone (i) in whole blood samples from a normal volunteer following a single 9.4-mg oral dose of d -methadone hydrochloride, (ii) in whole blood, saliva and gastric juice from a methadone addict maintained on 90 mg of dl -methadone hydrochloride per day, (iii) in mouse liver microsomes incubated with methadone, and (iv) in the perfusate of the isolated perfused rat liver.

Respiratory and hemodynamic effects of methadone in pregnant women.

Minute ventilation, end-tidal PCO2, O2 and CO2 concentrations in expired air, pulse rate and arterial blood pressure were measured in the last half of pregnancy in eight women taking methadone daily. Measurements were made with the subjects seated at rest, during the steady state of 50-watt bicycle exercise, and during recovery. Calculations of O2 consumption. CO2 production, alveolar ventilation and oxygen debt were made. Studies were repeated in five subjects postpartum. Methadone diminishes the normal hyperventilation of pregnancy and its effect persists for more than 24 h. When comparisons are made of pregnant and postpartum values, some respiratory stimulation during pregnancy is apparent. Maternal oxygen debt following standard exercise during pregnancy is diminished after the daily dose of methadone and the maternal heart rate response to exercise is diminished concurrently. The maternal hypoventilation induced by methadone and maintained during exercise may be relevant to the low birth weights and high incidence of sudden infant death syndrome observed by others in the offspring of methadone-dependent women.