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 l-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 well with respiratory depression and miosis for l- 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 administered frequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

The interaction of (N-methyl-14C) morphine with purified human albumin and gamma globulin and with human plasma was studied by equilibrium dialysis. Morphine binds to albumin and, to a lesser extent, to gamma globulin, but probably does not bind to plasma lipoproteins. The per cent of drug bound to protein was dependent on protein concentration but independent of drug concentration in the therapeutic range of plasma morphine concentration. In this range, 34.0% to 37.5% of the drug is bound to human plasma, largely to the albumin fraction. This study is compared to an earlier one on the interaction of methadone with plasma proteins. It is likely that the lower lipid solubility of morphine compared to methadone is related to its decreased affinity for plasma proteins.

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 to 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.

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In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labor. This step is not easily identifiable with present methods designed to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties that make muscle more excitable and responsive and produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone and nitric oxide appear to have important roles in these processes. The progress of labor can be assessed noninvasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labor. EMG activity also increases substantially during preterm labor in humans and rats and may be predictive of preterm labor. A quantitative method for assessing the cervix is also described. A collascope estimates cervical collagen content from a fluorescent signal generated when collagen crosslinks are illuminated with an excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy and indicates that cervical softening occurs progressively in the last one-third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy and indicate controls and treatments.