Parental pre-pregnancy BMI is a dominant early-life risk factor influencing BMI of offspring in adulthood.

OBJECTIVE: We examined parental and early-life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22. METHODS: Data were analysed on 1355 participants from the Western Australian Pregnancy Cohort (Raine) Study, with anthropometry collected during pregnancy, at birth, one year and at three yearly intervals thereafter. Multivariate analyses and cross-sectional logistic regression quantified the timing and contribution of early-life risk factors for overweight and obesity in young-adulthood. RESULTS: At five years of age 12.6% of children were overweight and 5.2% were obese. By early adulthood, the prevalence of obesity had increased to 12.8%, whilst overweight remained relatively stable at 14.2% (range from early childhood to adulthood 11-16%). Parental pre-pregnancy body mass index (BMI) was the strongest determinant of adult offspring BMI. Although rapid first year weight gain was associated with increased offspring BMI, the impact of first year weight-gain diminished over childhood, whilst the impact of parental BMI increased over time. CONCLUSIONS: Parental pre-pregnancy BMI and rapid early-life weight gain predispose offspring to obesity in adulthood.

Maternal and umbilical cord androgen concentrations do not predict digit ratio (2D:4D) in girls: a prospective cohort study.

Digit ratio (2D:4D) is widely used as a marker of prenatal androgen exposure. However, there are no published prospective studies where prenatal androgen exposure has been measured and correlated with digit ratio in adult life. We aimed to establish the prospective relationship between prenatal androgen exposure in the second and third trimesters of pregnancy (as measured by maternal circulating androgen concentrations and umbilical cord androgen concentrations) and digit ratio in adolescent girls. Androgen concentrations (testosterone, free androgen index, androstenedione, DHEAS) and sex hormone binding globulin (SHBG) were measured in stored plasma samples from pregnant mothers at 18 (n=118) and 34/36 (n=114) weeks of gestation and in cord blood (n=82) from the Western Australian Pregnancy (Raine) Cohort Study (www.rainestudy.org.au). Digit ratio was measured in 244 female offspring from this cohort at age 14-16 years. Only one borderline statistically significant correlation between maternal circulating androstenedione levels at 18 weeks of gestation and left hand digit ratio was seen. No other statistically significant relationship between maternal androgen concentrations or umbilical cord androgen concentrations and digit ratio in adolescence were observed. These findings suggest that variation in 2D:4D in girls is not established as a result of testosterone concentrations in the second and third trimesters. We conclude that prenatal androgen exposure as measured by maternal circulating androgen concentrations at 18 and 34/36 weeks of gestation or in the umbilical cord at birth may not predict digit ratio in girls.

The relationship between maternal and umbilical cord androgen levels and polycystic ovary syndrome in adolescence: a prospective cohort study.

CONTEXT: The prenatal antecedents of polycystic ovary syndrome (PCOS) are not known, but prenatal androgen exposure is thought to contribute. This has not previously been investigated in large prospective studies of normal human pregnancy. OBJECTIVE: The aim of the study was to establish the prospective relationship between early life androgen exposure and PCOS in adolescence. DESIGN AND SETTING: A prospective cohort study was conducted in the general community. PATIENTS OR OTHER PARTICIPANTS: A total of 2900 pregnant women were recruited at 18 wk gestation. Prenatal androgen exposure was measured from maternal blood samples (at 18 and 34-36 wk) and umbilical cord blood. Timed (d 2-5 menstrual cycle) blood samples were collected, clinical hyperandrogenism was assessed, and transabdominal ultrasound examination of ovarian morphology was performed in 244 unselected girls from the Raine cohort aged 14-17 yr. MAIN OUTCOME MEASURE(S): We examined the relationship between early life androgen exposure and PCOS in adolescence. RESULTS: We did not observe a statistically significant relationship between early life androgen exposure and PCOS in adolescence. CONCLUSIONS: This is the first prospective study to evaluate the relationship between prenatal androgen exposure and PCOS in adolescence in normal pregnancy. Our findings do not support the hypothesis that maternal androgens, within the normal range for pregnancy, directly program PCOS in the offspring.

Organizational role for pubertal androgens on adult hypothalamic-pituitary-adrenal sensitivity to testosterone in the male rat.

The inhibitory effect of androgens on the hypothalamic-pituitary-adrenal (HPA) axis in basal and stress conditions in adult male rats is well documented. Major sex-related neuroendocrine changes take place during puberty. There is a robust rise in production and secretion of gonadal steroids, which is thought to underlie numerous neural and behavioural changes brought on after puberty. The present study investigated the effect of the pubertal rise in gonadal steroid levels on the subsequent adult corticosterone profile, particularly the sensitivity of the adult HPA axis to testosterone. Animals were castrated either prepubertally (28 days) or in adulthood (11 weeks) and adult animals were subsequently treated with subcutaneous implants containing either testosterone or cholesterol. Using an automated blood sampling system, blood was collected from each freely moving, conscious rat every 10 min (i) over a 24 h period; (ii) in response to 10 min of noise stress, and (iii) following an immunological challenge with lipopolysaccharide (LPS). Analysis revealed that testosterone treatment did not significantly affect overall corticosterone release over the 24 h period in adult animals castrated before puberty in contrast to animals castrated in adulthood in which testosterone significantly suppressed corticosterone secretion. Following either a noise stress or LPS injection, testosterone treatment did not affect the hypothalamic or adrenal stress response in animals castrated prepubertally. Testosterone significantly suppressed the corticotrophin-releasing hormone and arginine vasopressin mRNA as well as the corticosterone response to LPS in castrated animals that had had their testes intact over puberty. These data provide evidence that puberty is a critical organizational period during which rising levels of gonadal steroids programme the sensitivity of the adult HPA axis to gonadal steroids in adulthood.

Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion.

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.

Diurnal variation in the responsiveness of the hypothalamic-pituitary-adrenal axis of the male rat to noise stress.

Basal activity of the rat hypothalamic-pituitary-adrenal (HPA) axis is highly dynamic and displays both circadian and ultradian rhythmicity in corticosterone secretion. This study investigated the relationship between basal corticosterone pulsatility and the corticosterone response to noise during the early light phase when there are no endogenous corticosterone pulses and during the early dark phase when there are hourly pulses of corticosterone. An automated blood sampling system was used to collect blood in conscious male rats at 5-min intervals before, during and after exposure to 10-min periods of white noise (104 dB). Behavioural responses to noise were also monitored during these periods. During the early light phase (morning), there was a consistent corticosteroid response to noise with corticosterone concentrations rising rapidly and reaching peak values 10-15 min after the noise had ceased, following which circulating concentrations declined at a rate comparable to the hormones half-life. A second noise stress, 80 min later, resulted in adaptation of the corticosterone response. During the early dark phase (evening), the corticosterone response to the noise was similar to that seen in the morning, although there was no adaptation to a second stimulus. During the evening, the inhibition of endogenous HPA activity after the sound was limited to 40 min following stress.

Postnatal masculinization alters the HPA axis phenotype in the adult female rat.

The ability of postnatal testosterone propionate (TP) to masculinize both behaviour and gonadal cyclicity in the female rat is well documented. We have investigated whether postnatal androgen also has an organizational effect on another sexually dimorphic neuroendocrine system--the hypothalamo-pituitary-adrenal (HPA) axis. Female rats were exposed to a single injection of testosterone propionate (TP) or oil within 24 h of birth. As adults, rats were either ovariectomized and given 17beta-oestradiol replacement (OVXE2) or sham ovariectomized with cholesterol implants (SHOVX). An automated sampling system collected blood from unanaesthetized adult female rats every 10 min over a 24-h period, during a mild psychological stress (noise) and following an immunological lipopolysaccharide stress (LPS). Neonatal TP-treated SHOVX rats had a significant reduction in the number, height, frequency and amplitude of corticosterone pulses over the basal 24-h period, compared to both the neonatal oil-treated and TP-treated OVXE2 animals. The corticosterone response to both noise and LPS was also significantly decreased for the TP-treated SHOVX females. Three hours post-LPS administration, TP females had significantly lower values of paraventricular nucleus (PVN) corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and anterior pituitary proopiomelanocortin (POMC) mRNAs and greater PVN glucocorticoid receptor (GR) mRNA expression compared to the oil-treated controls. E2 replacement in adult TP rats normalized all the mRNA levels, except for PVN GR mRNA which did fall towards the levels of the oil-control animals. A single injection of TP within 24 h of birth disrupts the development of the characteristic female pattern of corticosterone secretion and the normal female HPA response to stress, resulting in a pattern similar to that seen in males. These effects can be reversed by E2 treatment in the adult TP female rat.

Organizational role for testosterone and estrogen on adult hypothalamic-pituitary-adrenal axis activity in the male rat.

Organizational effects of testosterone during a critical period of neonatal life have major irreversible effects on adult sexual behavior. We have investigated whether perinatal androgen changes also affect another major sexually differentiated system, the hypothalamo-pituitary-adrenal axis. This was assessed in male rats who had been exposed to perinatal flutamide or 1,4,6-androstatriene-3,17-dione (ATD). Once the animals reached adulthood, an automated sampling system was used to collect blood from freely moving animals at 10-min intervals over 24 h, followed by a noise stress and then the administration of lipopolysaccharide (LPS). Perinatal flutamide- and ATD-treated rats not only had higher mean corticosterone levels and increased frequency and amplitude of corticosterone pulses over the 24 h compared with vehicle-injected controls, but they also showed markedly increased corticosterone responses to both noise and LPS. All parameters of increased hypothalamo-pituitary-adrenal activity resembled the normal physiological state of the intact adult female rather than that of the intact adult male rat. Furthermore, 3 h after LPS administration, both flutamide- and ATD-treated animals had markedly higher levels of corticotropin-releasing factor mRNA in the parvocellular paraventricular nucleus (PVN) and proopiomelanocortin mRNA in the adenohypophysis. Flutamide-treated rats also had a greater level of PVN arginine vasopressin mRNA. PVN glucocorticoid receptor mRNA levels were significantly lower in both the flutamide- and the ATD-treated male rats. These data highlight the importance of perinatal exposure to both testosterone and estrogen(s) on the development of a masculinized circadian corticosterone profile and stress-induced hypothalamo-pituitary-adrenal axis activity in the adult male rat.

Gonadectomy reverses the sexually diergic patterns of circadian and stress-induced hypothalamic-pituitary-adrenal axis activity in male and female rats.

Enhanced corticosterone release by female compared to male rats under basal and stress conditions is well documented. The demonstration that gonadectomy enhances stress-induced corticosterone secretion in male rats, but reduces such levels in female rats, suggests a causal association between gonadal steroids and corticosterone release. The present study examined the corticosterone profile of sham gonadectomized and gonadectomized female and male rats under basal and stress conditions. An automated sampling system collected blood from each freely moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide, LPS). Plasma was analysed for corticosterone content using radioimmunoassay. Castration resulted in a significant increase in basal corticosterone release compared to the sham-castrated male rats. Pulsar analysis revealed a significant two-fold increase in the number of corticosterone pulses over 24 h. Corticosterone increases in response to noise stress and to LPS injection were enhanced following castration. Conversely, ovariectomy resulted in a two-fold reduction in the number of corticosterone pulses as well as the stress response compared to sham-ovariectomized female rats. Arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary were analysed post-LPS administration by in situ hybridization. Significantly higher values were found for AVP, CRH and POMC mRNAs examined for sham females and castrated males compared to sham males and ovariectomized females. This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness. The present results extend these observations to the regulation of the dynamic pattern of corticosterone release under basal conditions and suggests that this alteration in pulsatility is important for the differences in stress responsiveness when comparing males and females.

Gonadal steroid replacement reverses gonadectomy-induced changes in the corticosterone pulse profile and stress-induced hypothalamic-pituitary-adrenal axis activity of male and female rats.

We investigated the effects of gonadal hormone replacement on the pulsatile parameters underlying basal circadian corticosterone secretion in castrated male and ovariectomized female rats using an automated sampling system. Blood was collected from freely moving, unanaesthetized rats every 10 min over a 24-h period and sampling was continued during a noise stress and after lipopolysaccharide (LPS) administration. Castrated male rats had markedly higher corticosterone levels than intact controls. This was reflected by increased number and frequency of pulses in addition to an increase in the pulse height and amplitude under both basal circadian and stress conditions. Hormone replacement with either testosterone or dihydrotestosterone returned these corticosterone levels and circadian profile to those found in intact males, confirming an androgen-mediated effect. Ovariectomized females had significantly lower basal and stress-induced corticosterone levels with lower frequency and amplitude of corticosterone pulses than intact females. 17beta-oestradiol replacement returned basal levels, pulsatile measurements and stress-induced corticosterone levels to those found in intact females. Three hours post-LPS administration, castrated males demonstrated significantly higher values of parvocellular paraventricular nucleus (PVN) arginine vasopressin and corticotrophin-releasing factor and anterior pituitary pro-opiomelanocortin mRNA while ovariectomized females showed significantly lower levels of all three transcripts compared to intact controls. PVN glucocorticoid receptor mRNA levels 3 h post-LPS administration were significantly decreased in castrated males and significantly increased in ovariectomized female rats. Replacement of gonadal steroids resulted in a return to the levels found in intact controls after LPS. Gonadal steroid replacement is sufficient to reverse changes in the pulsatile characteristics of corticosterone release after gonadectomy. In addition, gonadal steroid replacement reverses stress-induced alterations in hypothalamic-pituitary-adrenal (HPA) activity. These data demonstrate a major contribution of gonadal steroids to the regulation of HPA axis activity and to the pulsatile characteristics of corticosterone release.

Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: sexual dimorphism and changes across the estrous cycle.

Sexual dimorphism in the rat hypothalamic-pituitary-adrenal axis was investigated by determination of plasma corticosterone and immunoreactive (I-) ACTH in males and in females at each stage of the estrous cycle. A serial blood-sampling technique enabled assessment of covariation of the two hormones across the full circadian range of their concentrations within individual animals. Distinct diurnal rhythms in plasma corticosterone were evident in all rats, and the degree and timing of this rhythmicity, determined by cosinor analyses, did not vary with gender or cycle stage. There were, however, marked differences in absolute levels of corticosterone across the estrous cycle, with the average daily concentration (mesor) increasing progressively from a minimum at estrus (129 +/- 11 ng/ml) to a maximum 3 days later at proestrus (246 +/- 14 ng/ml). The mesor corticosterone value in male rats (102 +/- 21 ng/ml) was not different from that in estrous females, but was lower than that in females at all other stages of the cycle. In contrast, no gender- or cycle-related differences were detected in absolute levels of I-ACTH, although distinct diurnal rhythms, synchronous with those for corticosterone, were evident in all groups. Accordingly, a strong and positive within-rat relationship between plasma corticosterone and I-ACTH was observed in all groups, but there was a clear shift in the nature of this relationship across the estrous cycle, such that the slope (i.e. concentration of plasma corticosterone per unit concentration of I-ACTH) was minimal in males and estrous females and maximal in proestrous females. In conclusion, this study shows that the extent of sexual dimorphism in resting plasma corticosterone levels is dependent on estrous cycle stage, being absent at estrus and maximal at proestrus. Moreover, this variation in plasma corticosterone was not accompanied by corresponding changes in plasma I-ACTH, suggestive of cycle-related changes in responsiveness of the adrenal cortex to trophic stimulation.

The hypothalamic-pituitary-adrenal axis in rat pregnancy and lactation: circadian variation and interrelationship of plasma adrenocorticotropin and corticosterone.

The circadian variation in immunoreactive (I-) ACTH and corticosterone was studied at several stages throughout rat pregnancy and compared with those before pregnancy and during lactation. Serial blood samples were obtained from chronically cannulated, conscious rats at 2- to 3-h intervals beginning at 0800 h at diestrus of the cycle; on days 2, 6, 10, 14, 18, and 22 of pregnancy (term = day 23); and on day 4 of lactation. Plasma I-ACTH and corticosterone were determined in all samples, and indices of their circadian variation (acrophase, mesor, and amplitude) were derived by cosinor analyses within each rat. A circadian variation in corticosterone was clearly evident in all groups, with individual cosinor r2 values being consistently high. Plasma I-ACTH also exhibited distinct circadian variation up to day 14 of pregnancy, but the cosinor r2 value then fell (P < 0.05, by analysis of variance) and remained low during lactation. Mesor levels (midpoint of the derived circadian range) of I-ACTH fell (P < 0.05) by 34% to 20.6 +/- 2.4 pg/ml by day 2 of pregnancy; corticosterone also fell (P < 0.05) by 34% to 141 +/- 27 ng/ml, and both changes were due primarily to reductions in peak levels. I-ACTH mesors then remained effectively unchanged for the remainder of pregnancy, but mesor corticosterone increased progressively after day 10 to reach a maximum of 286 +/- 28 ng/ml by day 22, and this rise was due to elevations in both trough and peak corticosterone levels. Further changes occurred after parturition, with mesor I-ACTH increasing more than 2-fold between day 22 of pregnancy and day 4 of lactation, whereas mesor corticosterone declined by more than half over the same period. Plasma corticosterone and I-ACTH were positively associated within rats in all groups (P < 0.01), but the common slope of this association increased considerably after midgestation, indicative of higher corticosterone levels for a given concentration of I-ACTH. In summary, this study identifies marked changes in the hypothalamic-pituitary-adrenal axis during rat pregnancy and lactation. Although a circadian variation in corticosterone was observed throughout, that in plasma I-ACTH was evident early in pregnancy but declined after midgestation. Absolute concentrations of plasma I-ACTH and corticosterone fell in parallel early in pregnancy, but corticosterone subsequently increased without any change in I-ACTH.(ABSTRACT TRUNCATED AT 400 WORDS)

Production rate, metabolic clearance rate and uterine extraction of corticosterone during rat pregnancy.

This study examined changes in the blood concentration of corticosterone with the onset and progression of pregnancy in the rat. To identify the source of variation in blood corticosterone, the metabolic clearance rate (MCR) and production rate of corticosterone were also determined. Measurements were made in conscious rats (n = 4-7 per group) in the morning of dioestrus and days 5, 10, 16 and 22 of pregnancy (term = day 23). Corticosterone levels were 713 +/- 38 nmol/l (mean +/- S.E.M.) in non-pregnant rats, remained unchanged to day 10 of pregnancy, then increased to 1036 +/- 52 nmol/l by day 16 and remained high at day 22. The production rate of corticosterone appeared to increase during pregnancy from 25.6 +/- 1.7 mumol/day on day 10 to reach 36.3 +/- 3.3 mol/day on day 22, but this did not reach statistical significance (one-way ANOVA). The MCR of corticosterone was similar among all groups (overall mean 34.6 +/- 2.5 l/day), although a slight but non-significant fall was apparent at day 16. When account was taken of changes in maternal weight, the MCR decreased progressively from 139 +/- 10 1/day per kg before pregnancy to reach a minimum of 88 +/- 7 1/day per kg on day 16. Transuterine extraction of corticosterone on day 22 of pregnancy was 19.2 +/- 3.1% and so, based on this and estimates of uterine blood flow, the uterus must account for around 15% of corticosterone clearance at this time. Because this uterine contribution is effectively additional clearance, it is likely that without it the MCR of corticosterone would have fallen during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Modelling of the passage of drugs into milk.

Pharmacokinetic modelling of plasma to milk transfer of drugs has assisted our understanding of the milk to plasma ratio (M/P) and pitfalls associated with it. The most useful way of measuring M/P ratios is, however, by model independent analysis. Physiological models have been proposed to enable the prediction of M/P ratios. The most accurate in prospective performance is the log-transformed phase distribution model. This model, developed by stepwise multiple linear regression analysis, also assists in the understanding of the relative contribution of the various physiological factors involved in the distribution of drugs into milk.

Prospective evaluation of a model for the prediction of milk:plasma drug concentrations from physicochemical characteristics.

1. Milk:plasma (M/P) drug concentration ratios predicted by a model utilizing pKa, plasma protein binding and octanol:water partition coefficients have been compared with actual M/P values for 10 basic drugs. 2. There was a close relationship between predicted and observed M/P ratios with a coefficient of determination r2 of 0.97. However, there was a proportional error. 3. The data were transformed by taking logs of predicted and observed (M/P + 1) values. Regression analysis resulted in an r2 of 0.95, an intercept on the Y-axis not significantly different from zero and a slope not significantly different from one. 4. The 95% confidence interval around a single prediction revealed an error between 150% for the lowest and 23% for the highest M/P ratios. The error is therefore lowest for the drugs likely to have the greatest transfer into milk. 5. There was no significant bias in the predictions. 6. The model was refined by multiple linear regression analysis utilising the observed M/P ratios for the 10 basic drugs in addition to those of the original drugs. The revised equation resulted in an improvement in the explained variance. 7. Protein binding was the most important single predictor. 8. The results confirm that M/P ratios for basic drugs can be predicted accurately from their physicochemical characteristics.

Serum aminoglycoside clearance is predicted as poorly by renal aminoglycoside clearance as by creatinine clearance in critically ill patients.

OBJECTIVE: To determine the relationships among serum aminoglycoside clearance, renal aminoglycoside clearance, measured creatinine clearance, and estimated creatinine clearance derived from a standard formula in critically ill patients. SETTING: A ten-bed general ICU in a university hospital. PATIENTS: Eighteen critically ill patients who were being treated with gentamicin or tobramycin for severe infections, and were hemodynamically stable. INTERVENTIONS: The various clearances were measured simultaneously after the administration of a dose of aminoglycoside by assaying serial blood samples for aminoglycoside and creatinine concentration, and by measuring the content of these substances in urine collected over the same time period. OUTCOME MEASURES: The slopes, intercepts and coefficients of determination (r2) of the various regressions were determined, along with the 95% confidence intervals for the prediction of serum aminoglycoside clearance from each other variable. RESULTS: Renal aminoglycoside clearance, creatinine clearance, and estimated creatinine clearance accounted for only 58%, 59%, and 62%, respectively, of the variance in serum aminoglycoside clearance. Only 64% of the variance in renal aminoglycoside clearance was explained by creatinine clearance. Substantial and variable nonrenal aminoglycoside clearance was evident. CONCLUSIONS: The 95% confidence intervals for the prediction of serum aminoglycoside clearance from each index of renal function indicated that none of these indices provided acceptable accuracy for the prediction of serum aminoglycoside clearance and dosage requirements in critically ill patients. Renal aminoglycoside clearance was not better than creatinine clearance in this respect, and thus no other index of renal function is likely to be more accurate. This finding implies that the only accurate method of determining the dose requirements to achieve target serum concentrations in such patients will be individualized pharmacokinetic dosing.

Prediction of drug loss from PVC infusion bags.

PVC:water partition coefficients for a series of 13 drugs have been calculated from literature data and a high degree of correlation with octanol:water partition coefficients demonstrated. The resulting model, log PPVC = -0.35 + 0.69 log P. (r2 = 0.88) has been prospectively tested with 10 drugs. All the test drugs were within the 95% confidence intervals associated with predicted log PPVC values consistent with a valid model. In practice, predicted log PPVC values may be used to estimate drug loss from the aqueous phase of PVC bags at equilibrium. Equations are described which enable calculation of likely drug loss from 100, 500 and 1000 mL PVC bags. It is recommended that this approach is used to identify drugs which are unlikely to be significantly absorbed into PVC.

Partitioning of drugs into human milk.

Breast fed infants ingest drugs present in the milk. All drugs pass from plasma into milk to some extent. The milk to plasma concentration ratio (M/P) is the most commonly quoted index of drug distribution into milk. This ratio is determined by many factors such as maternal plasma protein binding, the protein binding in the milk, solubility of drug in lipid and physicochemical factors affecting diffusion of drug through biological barriers. Most drugs have M/P ratios less than 1. The M/P ratio is used to calculate the likely infant dose from the likely maternal plasma concentration. The infant dose can then be compared with maternal doses, or with doses used therapeutically in infants. The plasma clearance of the drug by the infant compared with that of the mother will determine the mean concentrations finally achieved in the infant's plasma. Assessment of these factors enables decisions to be made regarding the safety of breast feeding during maternal ingestion of drugs.

Interaction of bovine estrogen receptor with immobilized zinc.

The metal-binding properties of partially purified untransformed or salt-dissociated bovine estrogen receptors were studied using zinc-chelated iminodiacetic acid gels. Only the salt-dissociated 5S receptor is retained by the metal-chelated resin, and this interaction is dependent on the presence of dithiothreitol. The untransformed 9S receptor is not retained, indicating that the zinc-interacting amino acid residues may be masked by receptor-associated proteins such as 90K heat-shock protein or because of an unfavorable receptor conformation.

Comparative effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of theophylline.

Nine healthy male volunteers were studied to assess the interaction between theophylline and ciprofloxacin and to assess whether a similar interaction occurred with lomefloxacin, using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without lomefloxacin 400 mg 12 hourly or ciprofloxacin 500 mg 12 hourly for 7 days. Ciprofloxacin treatment lowered total theophylline clearance by 27%, owing to a decreased clearance via 1-, 3-demethylation and 8-hydroxylation. Lomefloxacin treatment did not alter theophylline clearance. Ciprofloxacin, at usual clinical doses, could cause a clinically significant interaction when co-administered with theophylline.