Prevalence and changes in analgesic medication utilisation 1 year prior to total joint replacement in an older cohort of patients.

OBJECTIVES: To evaluate the prevalence and change in analgesic medications use prior to joint replacement in older patients between 2001 and 2012. METHODS: A population based epidemiological study was conducted. Opioids, non-steroidal anti-inflammatories (NSAIDs), paracetamol, corticosteroid injections, medications for neuropathic pain, hypnotics, and muscle relaxants supplied 1 year prior to total knee replacement (TKR, n = 15,517) and hip replacement (THR, n = 10,018) were assessed. Patient characteristics and surgical indication adjusted prevalence ratios (PRs) and 95% confidence intervals (CI) are provided. RESULTS: From 2001 to 2012, in the TKR cohort (median age 78.9) the prevalence of opioid use prior to surgery increased from 37% to 49% (PR = 1.01, 95% CI 1.00-1.01, P = 0.01), while in the THR cohort (median age 81.1) it increased from 44% to 54% (PR = 1.01, 95% CI 1.01-1.02, P < 0.001). Paracetamol use increased from 52% to 61% (PR = 1.0, 95% CI 1.0-1.0, P = 0.913) in the TKR cohort and from 55% to 67% (PR = 1.01, 95% CI 1.00-1.01, P = 0.005) in the THR cohort. Neuropathic pain medication use increased from 5% to 11% in the TKR cohort (PR = 1.04, 95% CI 1.02-1.06, P < 0.0001) and from 6% to 12% in the THR cohort (PR = 1.06, 95% CI 1.04-1.09, P < 0.0001). NSAID use decreased from 76% to 50% in the TKR cohort (PR = 0.96, 95% CI 0.95-0.96, P < 0.0001), and from 81% to 47% in THR cohort (PR = 0.95, 95% CI 0.94-0.95, P < 0.0001). Corticosteroid injections prevalence also decreased (TKR: 21-18%, PR = 0.97, 95% CI 0.96-0.97, P < 0.001, THR: 18-17%, PR = 0.97, 95% CI 0.96-0.98, P < 0.001). CONCLUSION: Pain medication utilization prior to joint replacement surgery changed significantly in this national older cohort of patients during the 2000s.

MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2.

Recent studies suggest that physiological and tumorigenic proliferation of mammalian cells is controlled by multiple cyclin-dependent kinases (CDKs) largely in tissue-specific manners. We and others previously demonstrated that adult mice deficient for the Cyclin D partner CDK4 (Cdk4(-/-) mice) exhibit hypoplasia in the pituitary and pancreatic islet due to primary postnatal defects in proliferation. Intriguingly, those neuroendocrine tissues affected in Cdk4(-/-) mice are the primary targets of tumorigenesis in the syndrome of multiple endocrine neoplasia type-1 (MEN1). Mice with heterozygous disruption of the tumor suppressor Men1 gene (Men1(+/-)) develop tumors in the pituitary, pancreatic islets and other neuroendocrine tissues, which is analogous to humans with MEN1 mutations. To explore the genetic interactions between loss of Men1 and activation of CDKs, we examined the impact of Cdk4 or Cdk2 disruption on tumorigenesis in Men1(+/-) mice. A majority of Men1(+/-) mice with wild-type CDKs developed pituitary and islet tumors by 15 months of age. Strikingly, Men1(+/-); Cdk4(-/-) mice did not develop any tumors, and their islets and pituitaries remained hypoplastic with decreased proliferation. In contrast, Men1(+/-); Cdk2(-/-) mice showed pituitary and islet tumorigenesis comparable to those in Men1(+/-) mice. Pituitaries of Men1(+/-); Cdk4(-/-) mice showed no signs of loss of heterozygosity (LOH) in the Men1 locus, whereas tumors in Men1(+/-) mice and Men1(+/-); Cdk2(-/-) mice exhibited LOH. Consistently, CDK4 knockdown in INS-1 insulinoma cells inhibited glucose-stimulated cell cycle progression with a significant decrease in phosphorylation of retinoblastoma protein (RB) at specific sites including Ser780. CDK2 knockdown had minimum effects on RB phosphorylation and cell cycle progression. These data suggest that CDK4 is a critical downstream target of MEN1-dependent tumor suppression and is required for tumorigenic proliferation in the pituitary and pancreatic islet, whereas CDK2 is dispensable for tumorigenesis in these neuroendocrine cell types.

The progression of end-stage osteoarthritis: analysis of data from the Australian and Norwegian joint replacement registries using a multi-state model.

OBJECTIVE: The incidence of joint replacements is considered an indicator of symptomatic end-stage osteoarthritis (OA). We analysed data from two national joint replacement registries in order to investigate whether evidence of a pattern of progression of end-stage hip and knee OA could be found in data from large unselected populations. DESIGN: We obtained data on 78,634 hip and 122,096 knee arthroplasties from the Australian Orthopaedic Association National Joint Replacement Registry and 19,786 hip and 12,082 knee arthroplasties from the Norwegian Arthroplasty Register. A multi-state model was developed where individuals were followed from their first recorded hip or knee arthroplasty for OA to receiving subsequent hip and/or knee arthroplasties. We used this model to estimate relative hazard rates and probabilities for each registry separately. RESULTS: The hazard rates of receiving subsequent arthroplasties in non-cognate joints were higher on the contralateral side than on the ipsilateral side to the index arthroplasty, especially if the index was a hip arthroplasty. After 5 years, the estimated probabilities of having received a knee contralateral to the index hip were more than 1.7 times the probabilities of having received a knee ipsilateral to the index hip. CONCLUSION: The results indicate that there is an association between the side of the first hip arthroplasty and side of subsequent knee arthroplasties. Further studies are needed to investigate whether increased risk of receiving an arthroplasty in the contralateral knee is related to having a hip arthroplasty and/or preoperative factors such as pain and altered gait associated with hip OA.

Differential response of cancer cells to HDAC inhibitors trichostatin A and depsipeptide.

BACKGROUND: Over the last decade, several drugs that inhibit class I and/or class II histone deacetylases (HDACs) have been identified, including trichostatin A, the cyclic depsipeptide FR901228 and the antibiotic apicidin. These compounds have had immediate application in cancer research because of their ability to reactivate aberrantly silenced tumour suppressor genes and/or block tumour cell growth. Although a number of HDAC inhibitors are being evaluated in preclinical cancer models and in clinical trials, little is known about the differences in their specific mechanism of action and about the unique determinants of cancer cell sensitivity to each of these inhibitors. METHODS: Using a combination of cell viability assays, HDAC enzyme activity measurements, western blots for histone modifications, microarray gene expression analysis and qRT-PCR, we have characterised differences in trichostatin A vs depsipeptide-induced phenotypes in lung cancer, breast cancer and skin cancer cells and in normal cells and have then expanded these studies to other HDAC inhibitors. RESULTS: Cell viability profiles across panels of lung cancer, breast cancer and melanoma cell lines showed distinct sensitivities to the pan-inhibitor TSA compared with the class 1 selective inhibitor depsipeptide. In several instances, the cell lines most sensitive to one inhibitor were most resistant to the other inhibitor, demonstrating these drugs act on at least some non-overlapping cellular targets. These differences were not explained by the HDAC selectivity of these inhibitors alone since apicidin, which is a class 1 selective compound similar to depsipeptide, also showed a unique drug sensitivity profile of its own. TSA had greater specificity for cancer vs normal cells compared with other HDAC inhibitors. In addition, at concentrations that blocked cancer cell viability, TSA effectively inhibited purified recombinant HDACs 1, 2 and 5 and moderately inhibited HDAC8, while depsipeptide did not inhibit the activity of purified HDACs in vitro but did in cellular extracts, suggesting a potentially indirect action of this drug. Although both depsipeptide and TSA increased levels of histone acetylation in cancer cells, only depsipeptide decreased global levels of transcriptionally repressive histone methylation marks. Analysis of gene expression profiles of an isogenic cell line pair that showed discrepant sensitivity to depsipeptide, suggested that resistance to this inhibitor may be mediated by increased expression of multidrug resistance genes triggered by exposure to chemotherapy as was confirmed by verapamil studies. CONCLUSION: Although generally thought to have similar activities, the HDAC modulators trichostatin A and depsipeptide demonstrated distinct phenotypes in the inhibition of cancer cell viability and of HDAC activity, in their selectivity for cancer vs normal cells, and in their effects on histone modifications. These differences in mode of action may bear on the future therapeutic and research application of these inhibitors.

Improved n-3 fatty acid status does not modulate insulin resistance in fa/fa Zucker rats.

The objective was to examine the effect of polyunsaturated fatty acid type (plant vs fish oil-derived n-3, compared to n-6 fatty acids in the presence of constant proportions of saturated, monounsaturated and polyunsaturated fatty acids) on obesity, insulin resistance and tissue fatty acid composition in genetically obese rats. Six-week-old fa/fa and lean Zucker rats were fed with a 10% (w/w) mixed fat diet containing predominantly flax-seed, menhaden or safflower oils for 9 weeks. There was no effect of dietary lipid on obesity, oral glucose tolerance (except t=60min insulin), pancreatic function or molecular markers related to insulin, glucose and lipid metabolism, despite increased n-3 fatty acids in muscle and adipose tissue. The menhaden oil diet reduced fasting serum free fatty acids in both fa/fa and lean rats. These data suggest that n-3 composition does not alter obesity and insulin resistance in the fa/fa Zucker rat model when dietary lipid classes are balanced.

Molecular analysis of the PDS gene in a nonconsanguineous Sicilian family with Pendred's syndrome.

OBJECTIVE: The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. In this study we performed clinical and molecular analyses in three siblings from a nonconsanguineous Sicilian family who presented with the clinical features of Pendred's syndrome. PATIENTS AND MOLECULAR ANALYSES: In two sisters and one brother, the clinical diagnosis of Pendred's syndrome was established based on the findings of sensorineural hearing loss and large goiters. Thyroid function tests, perchlorate discharge tests, thyroid ultrasound, and scintigraphy were performed in all affected individuals. Exons 2 to 21 of the PDS gene were amplified by polymerase chain reaction (PCR) and both strands were submitted to direct sequence analysis. RESULTS: The clinical diagnosis of Pendred's syndrome was supported by a positive perchlorate discharge test in the three afflicted siblings. Direct sequence analysis of the PDS gene revealed that all three harbored one allele with a novel mutation 890delC leading to a frameshift mutation and premature stop codon at position 302 (FS297 > 302X). On the other allele, two of the siblings had a previously described transition 1226G > A, which results in the substitution of arginine by histidine at position 409 (R409H). In the index patient, no mutation could be identified on the other allele. In functional studies, these mutants lose the ability of pendrin to mediate iodide efflux. CONCLUSIONS: All three patients included in this study presented with the classic Pendred syndrome triad. Two siblings were compound heterozygous for mutations in the coding region of the PDS gene. The third individual could have an unidentified mutation in a regulatory or intronic region of the PDS gene, or an identical phenotype caused by distinct pathogenic mechanisms.

Genetic regulation of thyroid development.

Normal thyroid function is essential for development, growth, and metabolic homeostasis. The prerequisites for an euthyroid metabolic state include a normally developed thyroid gland, a properly functioning system for thyroid hormone synthesis, and sufficient iodine intake. Defects in any of the essential steps in thyroid development or thyroid hormone synthesis may result in morphologic abnormalities and impaired hormonogenesis. These defects can be partial or complete, leading to varying degrees of hypothyroidism. Morphologic alterations associated with congenital hypothyroidism include the absence of detectable thyroid tissue, ectopic tissue, thyroid hypoplasia, or a goitrous thyroid. However, in some patients with hypothyroidism, the thyroid is of normal size. This article focuses on defects in thyroid development. Recent insights into the developmental regulation of the calcitonin-producing C cells will not be discussed, and defects in hormone synthesis are discussed in an accompanying article.

Genetic defects in thyroid hormone synthesis.

Thyroid hormone synthesis requires a normally developed thyroid gland, a properly functioning hypothalamic-pituitary-thyroid axis, and sufficient iodine intake. This article focuses on genetic defects in this axis. Defects that are primarily of developmental origin are discussed in our associated article in this issue. Defects in hormone synthesis usually are associated with the development of a goiter, provided that the bioactivity and action of thyrotropin (TSH) are not impaired. In contrast, hypoplasia of the gland may be caused by developmental defects, bioinactive TSH, or resistance to TSH at the level of the receptor or its signaling pathway. At the other end of the spectrum, hyperthyroidism may result from gain of function mutations in genes regulating growth and function.

Aggressive metastatic follicular thyroid carcinoma with anaplastic transformation arising from a long-standing goiter in a patient with Pendred's syndrome.

In this article we describe detailed pathological and molecular genetics studies in a consanguineous kindred with Pendred's syndrome. The index patient was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendred's syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformation. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 microU/mL (0.2-3.2), a serum total thyroxine (T4) of 90 nmol/L (54-142), and a serum total triiodothyronine (T3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed, and the mass in the right lobe was found to have invaded adjacent tissues. The histopathological findings were consistent with a follicular carcinoma with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi 131iodine (3,700 MBq) and received suppressive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels remained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudden severe episode of hemoptysis. Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendred's syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. We concluded that prolonged TSH stimulation because of iodine deficiency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroid carcinomas that undergo transformation into anaplastic cancers. It is likely that these pathogenetic mechanisms have been involved in the development of aggressive metastatic thyroid cancer in this unusual patient with Pendred's syndrome.

Defining, identifying, and measuring error in emergency medicine.

The findings of a consensus committee created to address the definition, measurement, and identification of error in emergency medicine (EM) are presented. The literature of error measurement in medicine is also reviewed and analyzed. The consensus committee recommended adopting a standard set of terms found in the medical error literature. Issues surrounding error identification are discussed. The pros and cons of mandatory reporting, voluntary reporting, and surveillance systems are addressed, as is error reporting at the clinician, hospital, and oversight group levels. Committee recommendations are made regarding the initial steps EM should take to address error. The establishment of patient safety boards at each institution is also recommended.

Transplacental pharmacokinetics and fetal distribution of 2', 3'-didehydro-3'-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques.

BACKGROUND: The overall goal of human immunodeficiency virus (HIV) therapy during pregnancy is to maintain maternal health and reduce the probability of vertical transmission during gestation and delivery, while keeping toxicity risks low. Azidothymidine (AZT) is currently recommended for pregnant women infected with HIV; however, many pregnant women are unable to tolerate AZT because of toxicity. In the present study, the placental transfer and fetal accumulation of the anti-HIV compound 2',3'-didehydro-3'-deoxythymidine (d4T) and its active (triphosphorylated) and inactive (thymine and beta-aminoisobutyric acid) metabolites were examined at steady state in late-term rhesus macaques. METHODS: On the day of the hysterotomy, the mother was administered an intravenous loading dose of d4T, followed by a 3-hr steady-state intravenous infusion that also included [(3)H]d4T as a tracer. After 3 hr of infusion, the fetus was delivered by cesarean section under halothane/N(2)O anesthesia. Plasma, amniotic fluid, and tissues were analyzed for d4T and its inactive metabolites by HPLC; tissue samples were analyzed for d4T and active (phosphorylated) metabolites by strong anion-exchange HPLC. RESULTS: Maternal steady-state plasma concentrations of d4T were 1-2 microg/ml, with a fetal-to-maternal plasma ratio of 0.85 +/- 0.09. The fetal tissue distribution of radioactivity was highest in the kidney and lowest in the brain. D4T, thymine, and beta-aminoisobutyric acid were detected in all fetal tissues examined. CONCLUSIONS: Our data indicate that d4T readily crosses the placenta and is present in the fetus as parent compound or its inactive metabolites after maternal infusion. Although fetal plasma concentrations of d4T were similar to clinical d4T concentrations, no phosphorylated metabolites were detected. Teratology 62:93-99, 2000. Published 2000 Wiley-Liss, Inc.

Computers and connectivity in Illinois emergency departments.

UNLABELLED: Although the Internet has been described as "ubiquitous," little is known about the extent to which physicians have access to the Internet while providing clinical care. OBJECTIVE: To assess the extent of Internet connectivity within the clinical area of every ED within the state of Illinois. METHODS: This was a prospective observational study. Each Illinois ED listed in a published directory was called by telephone, and a responsible party was identified to provide information regarding the type and size of the ED, patient demographics, the types of personal computers (PCs) available in the ED (if any), the types of operating systems used, the availability of access to the World Wide Web (Web), and the highest speed at which an Internet connection could be established. Responses regarding the presence and types of PCs and the types of operating systems used were assessed using one-factor chi-square. Univariate and multivariate predictors of the type of PC used, the presence or absence of Web access, and the highest speed of Internet access were evaluated using optimal discriminant analysis and nonlinear classification tree analysis, respectively. RESULTS: One hundred ninety-eight of the 199 EDs in the state of Illinois (99.5%) completed the survey. Of the responding EDs, 50.5% had PCs, but only 17.6% had Web access. When Web access was available, it was most often available through a high-speed Internet connection that was faster than a dial-up modem. Most departments (68.1%) with PCs used the Windows 95 or Windows 98 operating systems. A majority (62.5%) used the Netscape browser exclusively. Larger EDs (more than six ED beds) in rural or suburban areas were more likely to have a PC compared with smaller EDs (six or fewer beds). Large EDs (more than 12 ED beds) in private tertiary care or academic hospitals were most likely to have Web access. CONCLUSIONS: Although half of Illinois EDs have PCs, only one in six has access to the Internet; thus, most emergency physicians do not have ready access to the Web from the site where they deliver clinical care.

Transplacental pharmacokinetics of cocaine and benzoylecgonine in plasma and hair of rhesus monkeys.

There is large variability in the rate and extent of fetal damage from cocaine in humans; however, the sources of such variability are not presently known. In order to study the relationship between maternal cocaine pharmacokinetics at the end of pregnancy and maternal or infant cocaine and benzoylecgonine hair concentrations at birth, ten rhesus monkeys were administered cocaine intramuscularly throughout pregnancy. Cocaine and benzoylecgonine hair concentrations were determined at birth and correlated with maternal pharmacokinetics during pregnancy. There were no correlations between either maternal cocaine Cmax or AUC0-infinity and maternal and infant hair cocaine or benzoylecgonine concentrations. There were no significant correlations between maternal hair benzoylecgonine concentrations and either maternal benzoylecgonine AUC0-120 (r = 0.60; P = 0.07) or benzoylecgonine Cmax (r = 0.60; P = 0.07). No correlations existed between infant hair benzoylecgonine concentrations and either maternal benzoylecgonine AUC0-120 (r = 0.30; P = 0.40) or benzoylecgonine Cmax (r = 0.30; P = 0.40). Also, no correlation was found between maternal cocaine dose and maternal or infant cocaine and benzoylecgonine hair concentrations. In comparison to toxicants such as nicotine and carbon monoxide for which there is a good correlation between maternal systemic exposure and neonatal concentrations, the lack of a similar relationship for cocaine is consistent with the role of the placenta in contributing to the variability in the amounts of cocaine reaching the fetus and hence, potentially to the risk of adverse fetal outcome.

The effects of cocaine on nonhuman primate brain function are age dependent.

The effects of acute intravenous (i.v.) cocaine (COC) on several complex brain functions were studied in rhesus monkeys at 1.5, 3 and 10-11 years of age. Subjects performed several operant tasks (for food) that were used to model learning, short-term memory, color and position discrimination, and motivation, and disruption of performance of these tasks was used to quantitate drug effect. Drug effects were age dependent: The youngest subjects were 3 to 10 times less sensitive than the oldest. Presuming the observed behavioral effects of cocaine were caused primarily via its interaction with dopamine (DA) systems, changes in sensitivity to its effects with age are likely a reflection of the functional status of the DA system. These data, along with preliminary data on levels of DA transporters, suggest that the age-related differences in sensitivity to cocaine lie in, 'downstream' from, the dopamine receptor.

Acute effects of dexfenfluramine (d-FEN) and methylenedioxymethamphetamine (MDMA) before and after short-course, high-dose treatment.

The acute behavioral effects of methylenedioxymethamphetamine (MDMA) and dexfenfluramine (d-FEN) were assessed in six rhesus monkeys using performance in the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB); three additional animals served as controls for neurochemical endpoints. The OTB consists of five food-reinforced tasks designed to model aspects of learning, short-term memory and attention, time estimation, motivation, and color and position discrimination. Shortly after the acute effects of each drug were determined, three of the monkeys received a short-course, high-dose exposure (2x /day x 4 days, intramuscular (i.m.) injections) of MDMA (10 mg/kg), while three monkeys were exposed to an identical regimen of d-FEN (5 mg/kg). Approximately one month later, the acute effects of each drug were again determined. In monkeys exposed to high-dose d-FEN, the sensitivities of the OTB tasks to acute disruption by either MDMA or d-FEN were essentially unchanged. Conversely, monkeys treated with high-dose MDMA were less sensitive to the acute behavioral effects of both drugs, although such an effect was seen more frequently for d-FEN and was OTB task specific. Thus a residual behavioral tolerance to the acute behavioral effects of MDMA and d-FEN was noted after high-dose MDMA exposure, but not after high-dose d-FEN exposure. These findings are surprising, as similar neurochemical effects (i.e., significant decreases of ca. 50% in serotonin in frontal cortex and hippocampus) were observed in all monkeys approximately six months after short-course, high-dose MDMA or d-FEN treatment.

Acute effects of LSD on rhesus monkey operant test battery performance.

The acute effects of LSD were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation, short-term memory and attention, motivation, learning, and color and position discrimination. The end points monitored included percent task completed, response rate, and accuracy. LSD (0.0003-0.03 mg/kg intravenously) significantly decreased percent task completed and accuracy in the time estimation task at doses < or = 0.003 mg/kg, but did not significantly affect response rate in this task at any dose tested. Accuracy in the short-term memory task was significantly decreased at the highest dose tested (0.03 mg/kg), but no other end points were affected in this task. Response rate was decreased in both the motivation and learning tasks at doses (0.01 and 0.003 mg/kg, respectively) lower than those affecting other end points. In the color and position discrimination task, only response rate was affected (0.01 and 0.03 mg/kg). These data demonstrate that in rhesus monkeys, performance of tasks believed to depend on aspects of time estimation and motivation are more sensitive to the acute disruptive effects of LSD than are tasks thought to model learning, short-term memory, and color and position discrimination.

Transplacental pharmacokinetics and fetal distribution of azidothymidine, its glucuronide, and phosphorylated metabolites in late-term rhesus macaques after maternal infusion.

3'-Azido-3'-deoxythymidine (AZT) is currently prescribed to pregnant women infected with human immunodeficiency virus to reduce the risk of vertical transmission of the virus to the fetus. Consequently, more information is needed concerning the placental transfer and tissue distribution of AZT and its metabolites. In the present study, the placental transfer and fetal accumulation of AZT, its glucuronide metabolite [3'-azido-3'-deoxythymidine-beta-D-glucuronide (AZTG)], and phosphorylated metabolites were examined at steady-state in near-term rhesus macaques. One to 2 weeks before a chronic infusion, an intravenous bolus of 8 mg/kg AZT was administered to pregnant animals to determine the dose of AZT needed to reach steady-state plasma concentrations. On the day of hysterotomy, the mother was administered an intravenous loading dose of AZT, followed by a 3-hr steady-state intravenous infusion that also included a trace of [3H]AZT. After 3 hr of infusion, the mother was anesthetized, and the fetus was delivered. Plasma and amniotic fluid were analyzed for AZT and AZTG by HPLC, and tissue samples were analyzed for AZT, AZTG, and phosphorylated metabolites by strong anion exchange HPLC. Maternal steady-state plasma concentrations were 1.3-2.2 micrograms/ml for AZT and 2.3-8.0 micrograms/ml for AZTG. Fetal AZT and AZTG plasma concentrations were both lower (0.98-2.3 micrograms/ml and 1.3-5.4 micrograms/ml, respectively) than maternal concentrations, with fetal-to-maternal plasma ratios of 0.63-1.0 for AZT. Fetal tissue distribution of tritium was highest in the kidney and lowest in the brain. Although the active triphosphorylated metabolite was not detected in the fetus, the AZT-monophosphate was detected in almost all fetal tissues examined. Our data indicate that AZT is rapidly converted to the glucuronide and monophosphate metabolites in the fetus after maternal infusion.

The effect of chronic cocaine exposure throughout pregnancy on maternal and infant outcomes in the rhesus monkey.

To explore the effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were either treated (N = 10) with escalating doses of cocaine up to 7.5 mg/kg (IM), three times per day, 5 consecutive days per week, prior to conception and throughout gestation, or were not treated (N = 10) with cocaine at all. Substantial levels of both cocaine and its major metabolite, benzoylecgonine, were observed in samples of hair taken at birth from mothers and infants of the cocaine-treated group. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to maternal outcome, as measured by body weight again during pregnancy and length of pregnancy. On the other hand, the experimental groups did differ significantly with respect to infant outcome, as measured at birth by body weight, overall length, and crown circumference, all of which were decreased in the cocaine-treated group. A variety of reflexes tested at birth were normal in the cocaine-treated group. It was concluded that, in a rhesus monkey model, chronic cocaine exposure throughout pregnancy had no significant effect on maternal outcome, but did significantly affect infant outcome as assessed in this investigation.