Prenatal androgen blockade accelerates pubertal development in male rhesus monkeys.

Aspects of the prenatal environment, including steroid hormones, modulate the timing of puberty onset in many mammalian species. This study tested whether prenatal androgen manipulations altered pubertal development in male rhesus macaques (Macaca mulatta). Pregnant females received testosterone enanthate (TE), the androgen receptor blocker flutamide, or vehicle during one of two periods of gestation, and their male offspring were observed for morphological, endocrine, and behavioral development from 3 to 4.5 years of age. Males exposed to flutamide early in gestation had a greater response to exogenous GnRH prepubertally, and greater testes volume, elevated testosterone, and elevated LH at age 3.5 than did control subjects. Males exposed to flutamide late in gestation also had greater testes volumes at age 3.5 than did control males. However, these differences between flutamide treated males and control males did not persist postpubertally. By 4.5 years of age, development in control males had reached comparable levels to that of flutamide-treated males. Late gestation treatment with TE had no effect on morphological pubertal development but early TE treatment altered some aspects of endocrine function during puberty. None of the prenatal androgen manipulations affected sexual behavior. These findings suggest that prenatal androgens, in conjunction with social factors, masculinize pubertal timing in rhesus monkey males.

Halo polarization profiles and sampled ice crystals: observations and interpretation.

Simultaneous two-wavelength polarization and radiance distributions have been obtained for 22 degrees parhelia in four Antarctic ice-crystal swarms that extended to ground level. Samples of crystals that produced these parhelia were collected and replicated. The wavelength dependence of the width of the halo polarization peak agrees with Fraunhofer diffraction theory, indicating that the broadening of the halos is caused primarily by diffraction. However, the observed broadening is much more than predicted from the size distribution of the replicated crystals. From one halo display to the other, the ratio of observed/predicted broadening is erratic, suggesting size-dependent collection efficiency in the sampling. This would imply that, for South Pole conditions, halo polarimetry (or even photometry) is a more reliable method for crystal size determination than actual sampling. It also implies that shapes of the sampled crystals need not necessarily be representative for the shapes of the halo-making crystals in the swarm. Our previous hypothesis [Appl. Opt. 33,4569 (1994)], that a spread of interfacial angles is the dominating cause of halo broadening, has proved untenable.

Timing of prenatal androgen exposure: anatomical and endocrine effects on juvenile male and female rhesus monkeys.

Prenatal androgen shapes genital differentiation. In humans, genital anatomy determines sex of rearing and subsequent behavioral development. Rhesus monkey genital anatomy and neuroendocrine function are sexually differentiated, and behavioral development occurs in a complex social environment. We investigated prenatal hormonal influences on sexual differentiation by suppressing or increasing androgens in male and female rhesus monkeys. Pregnant multiparous female rhesus monkeys received 35-40 days of testosterone enanthate (TE) treatment, androgen antagonist (flutamide, FL) treatment, or vehicle starting on gestation day (GD) 35 or 40 (early) or GD 110 or 115 (late). Exogenous androgen increased neonatal LH secretion in females when given early and altered female genital differentiation when administered either early or late. TE treatment, early or late in gestation, had no measurable effects on male genital differentiation or neuroendocrine function. Early FL treatment, however, radically altered male genital differentiation, producing in two cases males with a urethral opening separate from the glans. In females, early FL treatment produced detectable alterations in genitalia consistent with a reduced exposure to prenatal androgen, suggesting that female rhesus monkeys are naturally exposed prenatally to meaningful levels of T. Late FL treatment reduced male penis size and increased neonatal T secretion, but had no effect in females. This is the first study to block endogenous prenatal testosterone in rhesus monkeys, thereby altering sexual differentiation. These findings illustrate the complexity of prenatal influences on anatomical and neuroendocrine development. The relationship between the anatomical changes reported here and sex differences in behavior is currently under investigation.

Comparison of a neural network approach with five traditional methods for predicting creatinine clearance in patients with human immunodeficiency virus infection.

STUDY OBJECTIVE: To compare the results of an artificial neural network approach with those of five published creatinine clearance (Cl(cr)) prediction equations and with the measured (true) Cl(cr) in patients infected with the human immunodeficiency virus (HIV). DESIGN: Six-month prospective study. SETTINGS: Two university medical centers. PATIENTS: Sixty-five HIV-infected patients: 18 relatively healthy outpatients and 47 inpatients. INTERVENTIONS: All subjects had urine collected for 24 hours to determine Cl(cr). MEASUREMENTS AND MAIN RESULTS: The 16 input variables were age, ideal body weight, actual body weight, body surface area, height, and the following blood chemistries: sodium, potassium, aspartate aminotransferase, alanine aminotransferase, red blood cell count, platelet count, white blood cell count, glucose, serum creatinine, blood urea nitrogen, and albumin. The only output variable was Cl(cr). A training set of 55 subjects was used to develop the relationship between input variables and the output variable. The trained neural network was then used to predict Cl(cr) of a validation set of 10 subjects. Mean differences between predicted Cl(cr) and actual Cl(cr) (bias) were 4.1, 28.7, 29.4, 26.0, 31.8, and 55.8 ml/min/1.73 m2 for the artificial neural network, Cockcroft and Gault, Jelliffe 1, Jelliffe 2, Mawer et al, and Hull et al methods, respectively. CONCLUSION: The accuracy of predicting Cl(cr) in subjects with HIV infection by the artificial neural network is superior to that of the five equations that are currently used in clinical settings.

Pharmacokinetics of morphine sulfate in patients with burns.

Morphine sulfate (MS) pharmacokinetics was evaluated in seven patients with a mean body surface area burn of 21.5% to ascertain a rational basis for the management of pain in patients with burns. Treatments included a MS constant rate infusion followed by an oral MS solution (MS-OS) (5 to 15 mg administered every 3 hours) and then a 30 mg MS-controlled release tablet (MS-CR) every 8 hours. Each treatment was separated by a washout period when sampling of morphine was done. The apparent terminal half-life for MS-OS was 3 hours, which is similar to that of patients without burns, but the apparent terminal half-life for the MS-CR in patients with burns was substantially longer at 14.7 hours. The mean time to reach peak concentration for MS-CR was delayed relative to MS-OS 1.4 versus 0.5 hours, and the peak concentration was attenuated. The mean release time of the MS for the CR tablet is about 15 hours. The renal clearances of the MS-CR (114 ml/min) and MS-OS (147 ml/min) were less than the measured creatinine clearance (177 ml/min) but greater than the creatinine clearance (106 ml/min) predicted for a healthy individual. The prolonged release of MS-CR makes the MS-CR a good choice in the management of pain in patients with burns on an 8- to 12-hour dosing schedule, even though the patient might exhibit an increased clearance.

Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not confined to a congeneric series.

Many attempts have been made to describe quantitative structure-pharmacokinetic relationships within a congeneric series of drug molecules. The goal is to develop a predictive relationship that could predict in vivo results for other drugs within that series. These studies typically evaluate pharmacokinetic parameters that are reflective of both distribution and elimination processes. This work utilizes the results from 17 noncongeneric drugs reported in 18 pharmacokinetic studies. The objective was to determine if drug distribution parameters that were independent of elimination could be predicted from easily measured physicochemical parameters with a data base that included a wide variety of drugs that were not congeners of one another. Regression models utilizing a linear and a quadratic response surface were used to predict the various distribution parameters from physicochemical parameters, including molecular weight, intrinsic solubility, alcohol solubility, protein binding, and the distribution coefficient. Analogous to the extent of absorption, the extent of drug distribution can be predicted reasonably well by the probability that the drug will distribute into the peripheral system before being eliminated and by the volume of distribution at steady state. The duration of distribution, analogous to the rate of absorption, can be predicted by the mean transit time through the peripheral system the mean residence time of the drug in the peripheral system and the intrinsic mean residence time in the peripheral system. The ability to use statistical models to approximate drug distribution parameters without the constraints of working within a congeneric series provides some valuable opportunities.

Effect of aspirin and sulindac on methotrexate clearance.

The pharmacokinetics of low dose methotrexate (MTX) were evaluated in 12 rheumatoid arthritis patients in the presence and absence of steady-state levels of salicylic acid (ASA) and sulindac (SU). Using a Latin square design, patients were given MTX plus ASA (mean 3.4 g/day), MTX plus SU (mean 400 mg/day), or MTX alone. On a background of at least one year of regular MTX therapy, patients received 10 mg/m2 MTX iv (mean 17.8 mg) given after at least 2 weeks of treatment with each of the above regimens. Plasma concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were measured using HPLC. No differences in MTX clearance (Cl) were found comparing MTX alone, MTX + ASA, and MTX + SU. However, if one particular subject that had a very low clearance when receiving MTX alone was excluded, there was a statistically significant decrease in MTX clearance when either ASA or SUL were present. It is also noteworthy that ASA significantly increased the exposure of the subject to 7-OH-MTX and, to a lesser extent, so did sulindac. Since 7-OH-MTX has been shown to be an active metabolite when given for cytotoxic effects at higher doses and because it has been show to be nephrotoxic at doses a thousand-fold greater than used in rheumatoid arthritis, nonsteroidal anti-inflammatory drugs should be used cautiously with MTX until further large scale safety studies are conducted. The data indicate that if a clinically significant interaction were to occur, ASA is more likely than SU to interact with MTX.

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients.

The pharmacokinetics and bioavailability of low-dose methotrexate (MTX) (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received 10 mg/m2 (to the nearest 2.5 mg) of MTX in a single oral dose and a single intravenous (iv) dose one week apart. Serum concentrations for this low-dose regimen were monitored using a radiochemical ligand binding assay. The results indicate the MTX is cleared from the plasma at a rate of 84.6 mL/min/m2. The terminal half-life was approximately 6 h. The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2, respectively. The mean residence time in the body, in the systemic circulation, and in the periphery were estimated to be 4.7, 3.0, and 1.7 h, respectively, with a peripheral single-pass mean transit time of 6.0 h and an intrinsic mean residence time in the periphery of 7.9 h. The mean absorption time was 1.2 h and the oral bioavailability was 0.70. The ratio of synovial fluid concentration to serum concentration 4 and 24 h after a dose was found to be approximately 1.0, indicating that at least within that time range serum and synovial fluid concentrations are approximately equal. Because of conflicting results and insufficient data from previous high-dose pharmacokinetic studies, it is difficult to say whether or not low-dose MTX pharmacokinetics differs from those of high-dose MTX.

Gold pharmacokinetics in breast milk and serum of a lactating woman.

During 20 weeks of aurothioglucose therapy, gold in a mother's serum and breast milk and her nursing infant's serum and urine were measured. The mother's steady state plasma gold was 4.05 mg/l; it was 0.041 mg/l in breast milk. Only 0.0255 mg gold appeared in the breast milk/24 h. We calculated that only 0.1785 mg gold (0.71% of the weekly dose) would appear in the breast milk over a week. No gold (less than 5 X 10(-7) mg/l) was found in the infant's plasma or urine. It is very unlikely that more than minute amounts of gold are absorbed from the mother's breast milk when breast feeding an infant.

Drug therapy considerations in the elderly.

The growing elderly population receives an increasing proportion of the prescriptions dispensed each year. There are a number of problems associated with drug therapy in the elderly. This article reviews some of the pharmacological factors, which may change with increasing age, including absorption, transportation, tissue localization, receptor sites, homeostasis, excretion and metabolism, and which in turn may alter the action of a drug. Suggestions are made regarding the treatment of elderly patients.