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When betamethasone phosphate equivalent to 8 mg betamethasone was administered intramuscularly in solution (Celestone Injection) to pregnant women, a large proportion of this ester was absorbed unchanged. Bioavailability of betamethasone from the phosphate ester was as high as after intravenous injection. When pregnant patients received the equivalent of either 6 or 12 mg betamethasone in a formulation containing 3.1 mg/ml betamethasone acetate suspended in a solution of 4 mg/ml betamethasone phosphate (Celestone Chronodose), much of the phosphate ester was absorbed intact but betamethasone acetate was not detected in plasma. Availability of betamethasone from Celestone Chronodose was much lower than from Celestone Injection. After administration of either formulation, maternal plasma cortisol concentrations fell towards a basal level but were rising again within 2 to 3 days of the last dose. We conclude that Celestone Chronodose does not provide prolonged release of betamethasone and offers no advantage over Celestone Injection. [ABSTRACT FROM AUTHOR]

Although thalidomide (alpha-phthalimidoglutarimide) is a potent teratogen, in recent years it has become widely used in the treatment of a variety of diseases. Despite many studies, the mechanism of its teratogenic action is still not clear. Recently we reported that only the glutarimide moiety bound to rat embryonic DNA. This result could explain our earlier observation, that thalidomide induced alteration in the secondary structure of rat embryonic DNA. In this study it was shown that [glutarimide-2-14C]-thalidomide also interacts with the DNA of rabbit embryos. This interaction is a possible explanation for the diverse types of malformations caused by thalidomide and may also account for its immunosuppressant action which makes it useful in the treatment of graft-versus-host disease.

We have investigated the possibility of [phthalimide carbonyl-14C]thalidomide and [glutarimide-2-14C]thalidomide interaction with DNA. In each experiment, groups of pregnant Wistar rats were treated with a labeled compound on day 12 of gestation. The embryos were harvested 24 h later, and dimethlformamide-treated control groups and groups treated with the same labeled compound and with the same radioactive doses were pooled respectively and analyzed. The DNA from each group was purified and monitored for 14C radioactivity. Low but statistically significant radioactivity was detected in only the DNA samples prepared from the [glutarimide-2-14C]thalidomide-treated embryos. This result demonstrates the binding of the glutarimide moiety, or its reactive intermediates, with rat embryonic DNA in vivo.

Teratogenicity of thalidomide was demonstrated in Wistar rats following a single maternal intravenous injection during the embryonic organogenetic period. When compared to day 13 embryonic DNA isolated from untreated control mothers, differences were observed in the mean wet weights of day 13 embryos from rats treated with thalidomide during days 10 or 11 of gestation, and significantly less amounts of embryonic DNA were recovered from mothers similarly treated on days 10 or 12 of their respective gestation periods. Rat embryonic DNA may be separated into two fractions by stepwise elution from benzoylated DEAE-cellulose (BD-cellulose) columns with 1.0 M NaCl (SE-DNA) and 1.8% (w/v) caffeine (CE-DNA) solutions, respectively. Other studies using bacterial, yeast, and rat liver DNA suggested that the first fraction contains native DNA, whereas the second may exhibit some degree of single-stranded character. Similar reproducible chromatographic profiles were obtained using a novel "batch method" developed for general application. Rat embryonic DNA was monitored by labelling in vivo with an i.p. injection of [methyl-3H]-thymidine (3H-TdR) during days 5, 6, and 7 of the gestation period. All samples were analysed on day 13 of gestation. A simple increase in percentage of caffeine-eluted DNA was not detected in thalidomide treated samples; however, diversity of percent (%) CE-DNA within litter was noted. Briefly, the percent CE-DNA values for embryos in one litter were ranked and arbitrarily grouped in classes with limits of mean +/- 1 SD, mean +/- 2 SD, and so on to generate a characteristic profile of percent CE-DNA distribution. The number of embryos within the range of each SD unit was expressed as a percentage of each litter. A plot of the ranges of percent CE-DNA versus percentage of each litter was used to illustrate the distribution profile of the particular litter and to be used for comparison between samples from untreated control and thalidomide and/or dimethylformamide (DMF) treated DNA. Treatment of day 12 mothers with thalidomide produced a majority of embryos having percent CE-DNA values similar to those of untreated controls with the exception of the inclusion of a second population of embryos with much higher percent CE-DNA values than those of the untreated controls. Similar treatment of day 11 animals produced a majority of embryos still having percent CE-DNA values similar to those of untreated controls and also having a second group of embryos with a lower percent CE-DNA values than those of untreated controls.(ABSTRACT TRUNCATED AT 400 WORDS)

The plasma level: time profile for dexamethasone after dexamethasone phosphate 8 mg by intravenous bolus (n = 6) or intramuscular injection (n = 6) to pregnant women near term who were to undergo cesarean section was determined by high-performance liquid chromatography. Although pregnancy did not affect the terminal half-life (mean, 142 min; n = 10), the estimate of total plasma clearance was greater in pregnant (559 ml/min) than in nonpregnant women (243 ml/min). The umbilical/maternal venous plasma level ratios of dexamethasone rose with time from last dose to delivery, toward a plateau value of about 0.45. Plasma binding was not different between blood from pregnant (66.6% bound, n = 11) and nonpregnant women (68.1% bound, n = 6) but was lower in umbilical vein blood (60.8% bound, n = 11). Blood/plasma level ratio was higher in maternal (0.92, n = 7) and umbilical vein blood (1.04, n = 7) than in blood from nonpregnant subjects (0.81, n = 12). We conclude that the fetus is a slowly equilibrating compartment for dexamethasone and that the transplacental dexamethasone concentration gradient as well as the increased total clearance in the mother near parturition are most likely attributable to metabolic clearance by the placenta.

A study of 400 Sydney children of preschool age has found a range of blood lead levels from 0.1 mumol/L to 1.4 mumol/L (2 micrograms/100 mL to 29 micrograms/100 mL), with no children having readings above the currently accepted "level of concern". Within the Sydney metropolitan area, a significant inverse relationship was found between blood lead level and distance of the home from the city centre. Within the range of blood lead levels, no relationship appeared between blood lead levels and performance in verbal intelligence test, three of the tests of motor ability, and a parent rating. In one of the tests of fine motor coordination, there was a tendency for the children with lower lead levels to perform better than those with moderate blood lead levels. In one of the tests of gross motor skill, the results for the two age groups were conflicting. Further studies of a prospective nature covering the period of maximum vulnerability (0 to three years) are essential before any conclusion can be drawn about the effects of subclinical blood levels of lead.

Thalidomide administered to the marmoset (Callithrix jacchus) will produce a pattern of deformities similar to those found in man. In the cervical and lumbar regions of the thalidomide malformed marmoset fetus, the spinal cord and dorsal root ganglia are smaller than those of the control. The reduction in size of the D.R.G.'s is due to a marked reduction in the number of neurons. Drugs which influence the function of cholinergic nerves in the chick and rabbit embryo interfere with development. Thalidomide produced peripheral neuropathy in adults by interference with the function of the cholinergic nerves. Thus it appears that thalidomide malformations are due in part, to an interference with numbers of, and probably the functions of, the cholinergic nerves in the embryo. It would appear that cholinergic nerves have a possible morphogenetic and trophic influence in embryogenesis.

A controlled retrospective study of some short-term and long-term effects of elective induction of labour was conducted. There did not appear to be any increase in the incidence of maternal complications during labour, or of neonatal problems in the induced-labour group compared with the remainder of the mothers in the hospital. In the follow-up phase of the study, two treatment groups of children who were delivered after amniotomy and amniotomy plus the administration of oxytocin were compared with each other, and with a control group of children born after spontaneous labour. The children were assessed at the age of five years on verbal and non-verbal subtests of a standardized intelligence scale, tests of gross motor and fine motor coordination, and auditory and visual tests. A full physical examination was also performed. No statistically significant differences nor trends of clinical interest were found between the groups on any measure.

The pharmacokinetics of betamethasone and its phosphate ester are described in 8 healthy adults after i.v. bolus injection of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultraviolet detection using sample handling methods which prevented hydrolysis of the ester in vitro. Betamethasone phosphate disappeared rapidly from plasma (mean half-life = 4.7 min) as betamethasone levels rose. Betamethasone plasma levels reached a peak 10-36 min after administration of the phosphate before declining in a biexponential manner. The terminal slow disposition phase had a mean half-life of 6.5 h. Only about 5% of the dose was recovered from urine as betamethasone, indicating extensive extrarenal clearance of betamethasone. Protein binding and blood/plasma concentration ratio were also determined. In comparison with its stereoisomer, dexamethasone, betamethasone is also cleared mainly by metabolism but has a lower plasma clearance, is less plasma bound, has a higher blood/plasma concentration ratio, and a higher volume of distribution. Endogenous cortisol levels were measured in the subjects who received betamethasone phosphate and in a matched control group of 4 subjects who did not. Betamethasone abolished the normal episodic secretion of cortisol and rapidly reduced its plasma concentration to a basal level. Cortisol plasma levels were not restored at 24 h but had returned to normal by 48 h after dosing.

Thalidomide was administered to pregnant rabbits in dosages of 150-250 mg/kg/day on days 8-12 of gestation. These females produced 40 offspring, 21 of which were deformed. Four control females produced 34 offspring, none of which was deformed. The C6 and C7 ganglia of day-13, -15, -17, and -21 control and experimental embryos and fetuses were examined electron microscopically. Degenerative changes were found in the neurons and axons of dorsal root ganglia in day-13 experimental embryos, i.e., at least 16h before the earliest signs of thalidomide dysmelia have been reported in rabbits (Vickers, '67). Since the dorsal root ganglia form in rabbits on days 11 and 12 the changes evident at day 13 indicate that degeneration of neurons and axons may be a pathogenetic factor in thalidomide-induced peripheral deformities.

To demonstrate a causal relationship between neuronal damage and peripheral mesodermal anomalies, an operation was performed through oblique incisions in the dorsum of 247 chick embryos at stages 12-15 of development. In the region of the 24-30th presumptive somites, a three to four somite length of the right half of the neural tube was cut with fine glass sytlettes and removed with a 40μm glass pipette. Immediately after the operation and at intervals during continued incubation (37±, 75% R.H.), embryos were processed for histology. Fifty one embryos survived until day 14 when they were examined for malformations. Excision frequently resulted in a variety of reduction deformities: some embryos appeared normal; 31 displayed unilateral hemimelia or amelia. Examination of serially sectioned embryos fixed immediately and at varying intervals after the operation, demonstrated that this range of malformations was consistent with variation in the amount of neural tissue excised. Disruption of the mesoderm and regeneration of nervous tissue was minimal. It is concluded that the nervous system per se or some factor produced by the nervous system is essential for the development of the limb.

A controlled follow-up study examined the impact of delivery method on developmental outcome of the child. The modes of delivery investigated were low forceps delivery (188 infants), midcavity forceps delivery (51 infants), forceps rotation with forceps delivery (57 infants), manual rotation with forceps delivery (67 infants), elective caesarean section (101 infants) and spontaneous delivery (control, 207 infants). Breech presentation (100 infants) was separately compared with the vertex presentation groups. Sample selection controlled for complications during pregnancy and low birthweight and was restricted to married English-speaking mothers. The children were assessed at the age of five years on verbal and non-verbal subtests of a standardized intelligence scale, tests of gross motor coordination, and auditory and visual tests. A full paediatric examination was also performed. Breech presentation children performed less well on tests of balance and fine motor coordination and on visual acuity and stereopsis testing than children who presented in the vertex position. No deleterious effect of delivery method was found. In the absence of other complicating events (like a poor antenatal history, prematurity, and a disorganized home environment) delivery complication constitutes an early risk factor which the growing child is able to overcome.

There has been much debate concerning the teratogenic potential of the organophosphate pesticides, including malathion, although few experimental studies have been performed on mammals. This study was designed to expand the range of animal species used in the testing of malathion and to further evaluate malathion's teratogenic potential. A 100-mg/kg dose regimen from d 7 to d 12 of gestation was administered to New Zealand white rabbits. This produced no detectable differences in the number of resorptions, fetal size, and external or visceral anomalies between the treated and control groups. This suggests, as has been previously reported, that malathion has little or no teratogenic potential in the mammal.

The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest polyexponential equation that is consistent with the data. The terminal phase half-life t1/2 beta was significantly greater (P less than 0.05) in males (mean 201.5 min) than in females (mean 142.3 min). They prolonged t1/2 beta in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 24.5 ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation between t1/2 beta and Vdss among the 12 adults (r = 0.92, p less than 0.001). There were also significant correlation between Vdss and body weight (r = 0.67, p less than 0.05) and t1/2 beta and body weight (r = 0.80, p less than 0.01). The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t1/2 beta. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.

The plasma binding of diazepam was determined serially in 24 women undergoing either elective induction of labour (vaginal or emergency caesarean delivery) or elective caesarean section at term and in 5 nonpregnant women requiring abdominal surgery. In the majority of pregnant patients, a marked increase in diazepam percentage free was observed during labour or prior to caesarean section, reaching a maximum, 1.6 to 3.2 fold increase at delivery or within 4 h postpartum; by the fifth day postpartum, diazepam percentage free was lower than on admission to hospital. In contrast, little change in diazepam percentage free was observed during the perisurgical period in nonpregnant patients. In parturient and surgical patients, the time courses of diazepam percentage free and plasma nonesterified fatty acid (NEFA) concentration were parallel. Bivariate regression analyses of pooled data demonstrated a strong correlation (r = 0.642, p = less than 0.010 between diazepam percentage free and corresponding NEFA concentration and a weaker correlation between diazepam percentage free and both albumin (r = 0.319, p less than 0.02) or total protein (r = 0.438, p less than 0.01). From multiple linear regression it was demonstrated that 54% of the variability in diazepam percentage free could be attributed to plasma NEFA and albumin concentrations. NEFA displacement of plasma bound diazepam was substantiated using crystalline human serum albumin. An approximate 65% increase in plasma alpha 1 acid glycoprotein levels was observed posttrauma in both parturient and surgical patients but was unrelated to diazepam binding events. A relationship between diazepam plasma binding changes and concurrently altered disposition of diazepam during parturition is postulated.

It has been hypothesized that acetylcholine, choline acetylase and acetylcholinesterase may have an ontogenic and trophic influence in the embryo, and that therefore certain drugs may produce malformations via their effect on the acetylcholine and choline levels in the fetus. Thalidomide and the anticholinergics, scopolamine hydrobromide and orphenadrine hydrochloride, and doxylamine succinate, an antihistamine with secondary anticholinergic action, were administered to pregnant New Zealand White rabbit does from day 8 to day 15 of gestation. Cesarean sections were performed on gestational day 16, the fetuses removed and the acetylcholine and choline contents of the fetuses and placentas were estimated by organic extraction and derivation for injection into a GCMS. These acetylcholine and choline levels were compared with those of the fetuses and placentas of the control animals mated with the same buck on the same day as the treated animals. Thalidomide (50 mg/kg) did not affect acetylcholine or choline levels in the fetuses or the placentas obtained from the treated animal. Scopolamine (approximately 100 micrograms/kg) reduced the choline level in the placenta and fetus but not the acetylcholine levels. Orphenadrine (approximately 24 mg/kg) reduced acetylcholine and choline levels in the fetus and choline levels in the placenta. Doxylamine succinate (10 mg/kg) reduced the acetylcholine levels in the fetus and the choline levels in the placenta. The placenta is a fetal organ and the significance of acetylcholine production by the placenta is as yet unknown. The reduction in acetylcholine levels in the fetus exposed to drugs with an anticholinergic action may be of significance in the production of malformations.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison was made between the performance at eight years of age of 63 children who were born after elective induction of labour, and 29 spontaneously born children. The children had been tested previously at five years of age. Tests of reading and arithmetic achievement, visuomotor coordination, aural-visual coordination, auditory discrimination, and behavioural rating scales were administered. On two of the 12 measures (reading comprehension and euroticism) the induced children performed better than the spontaneously born. On all other measures there were no significant differences. There appeared to be no evidence of specific learning disabilities or behavioural problems among the induced children.

The plasma concentrations of betamethasone in a maternal peripheral vein (mv) and in the umbilical vein (uv) were measured at delivery in eleven patients after the administration of betamethasone phosphate equivalent to 8 mg betamethasone. Betamethasone concentrations were measured in plasma using a specific and sensitive HPLC assay. The time interval between the last dose and delivery ranged from 56 min to 800 min and over this time period the mean plasma concentration ratio Cuv/Cmv was 0.28 +/- 0.04 (SD) and exhibited no time dependence.

A high-performance liquid chromatographic (HPLC) assay to quantitate methylparaben in urine was developed. Standard curves were linear and recovery of the paraben from urine averaged 82.6%. The urinary excretion of methylparaben in six preterm infants (less than or equal to 31 weeks gestational age), who were receiving intramuscular injections of a paraben-containing gentamicin formulation, ranged from 13.2 to 88.1%. Small quantities of the metabolite, p-hydroxybenzoic acid, were detected by GC-MS.

Modified rodent embryo culture techniques were used to maintain 10 1/2 day rabbit embryos in vitro for up to 24 hr. In homologous, immediately centrifuged, heat inactivated serum containing 2 μCi/ml 3 H-thymidine, observed status was consistently high at 12 hr but fell thereafter. Liquid scintillation counting and autoradiography revealed rapid uptake of radioactivity during the first 12 hr. The splanchnopleure of the inverted yolk-sac is only partially vascularised in the rabbit and is thus inadequate as a medium of metabolic exchange in extended culture. Nevertheless, this technique will enable a study of the morphology and biochemistry of teratology in vitro in a sensitive species.

A sensitive and specific method for the quantitation of dexamethasone in plasma and urine is described. The specificity of the method is obtained using adsoprtion chromatography on a high-performance liquid chromatograph. The dexamethasone is detected with a variable-wavelength UV detector. An internal standard technique is used for quantitation of dexamethasone with a minimum sensitivity of 15 ng. Preliminary results of the application of the method to pharmacokinetic studies of dexamethasone in humans are reported.

The pharmacokinetics of betamethasone and its phosphate ester are described in nine women in late pregnancy who each received a bolus intravenous dose of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultra-violet detection using sample handling methods which prevent in vitro hydrolysis of the ester. The plasma clearance of betamethasone phosphate (mean = 980 ml/min) and its apparent distribution volume (mean = 5.61) were both higher than previously found for nonpregnant subjects, but its half-life (mean = 4.6 min) was unchanged. Plasma concentrations of betamethasone reached a peak 5-37 min after dosing with betamethasone phosphate, then declined biexponentially with a mean terminal half-life of 262 min. Plasma clearance in pregnant patients (mean = 287 ml/min) was higher than previously reported for nonpregnant subjects. Evidence from urinary excretion and plasma binding measurements and the previously reported transplacental plasma concentration gradient indicated that the increase in clearance was due to increased metabolism possibly by the placental/fetal unit. Plasma binding of beta-methasone was higher in maternal than fetal plasma; binding to alpha 1-acid glycoprotein was more important than binding to albumin as a determinant of this difference. In pregnant patients the decline of endogenous cortisol concentrations in maternal venous plasma was less marked and slower than in nonpregnant subjects. The data now available allows comparison of pharmacokinetic properties between betamethasone and its stereoisomer dexamethasone with respect to their use in preventing neonatal respiratory distress syndrome.

To determine whether thalidomide dysmorphogenesis was preceded by a changed pattern of cell division, embryos from thalidomide treated rabbits were cultured for four hours in a medium containing 3 H-thymidine. Automated image analysis of serial autoradiographs of the embryos revealed no focus of increased or decreased cell division in the neural tube or limb bud. Thalidomide pretreatment caused a general decrease in cell division at 10 days post coitum. A similar effect was observed only in those 10 3/4 day embryos whose status in culture was low. It was concluded that unlike methotrexate, the dysmorphogenic effect of thalidomide could not be attributed to a generally suppressed mitotic rate; rather, this teratogen preprogrammes dysmorphogenesis before the onset of the limb bud outgrowth (10 days) with the result that teratogenesis is manifest only during limb development after 11 days.