The impact of isolated maternal hypothyroxinaemia on the incidence of large-for-gestational-age infants: the Ma'anshan Birth Cohort study.

OBJECTIVE: The purpose of this study was to investigate whether isolated maternal hypothyroxinaemia (IMH) is associated with risks of small/large-for-gestational-age (SGA/LGA) infants. DESIGN: Population-based prospective cohort study. SETTING: Ma'anshan Maternal and Child Health (MCH) clinics, China. POPULATION: Pregnant women with singleton births (n = 3178). METHODS: Descriptive statistics were calculated for the demographic characteristics of the mothers and their newborns. Linear regression was applied to estimate the association between thyroid hormone levels and birthweight. Logistic regression was performed to calculate the association between IMH and SGA/LGA. MAIN OUTCOME MEASURES: Outcomes included SGA/LGA. RESULTS: The prevalence of IMH, defined as a free thyroxine value (FT4) lower than the 2.5th percentile with normal thyroid stimulating hormone, was 2.5% (78/3080) and 2.5% (74/2999) in the first and second trimesters, respectively. Additionally, 306 (9.6%) and 524 (16.5%) infants were defined as SGA and LGA, respectively. No evidence supported the notion that IMH is associated with an increased risk for SGA in either the first [odds ratio (OR): 1.762, 95% confidence interval (CI): 0.759-4.089] or the second (OR: 0.763, 95% CI: 0.231-2.516) trimester. However, an increased risk of LGA was observed among IMH women in the second trimester (OR: 2.088, 95% CI: 1.193-3.654). Maternal TPO-Ab positivity in the second trimester increased the risk of SGA (OR: 2.094, 95% CI: 1.333-3.290). CONCLUSION: This study provides evidence that IMH is associated with LGA. FUNDING: This work was supported by the National Natural Science Foundation of China (No. 81330068). TWEETABLE ABSTRACT: Isolated maternal hypothyroxinaemia may increase the risk of large-for-gestational-age infants.

[Effect of breastfeeding on the behavioral development of infants and children: a birth cohort study in Ma'anshan].

Objective: To discuss the relationship between breastfeeding and the behavioral development of infants and children. Methods: Based on the Ma'anshan Birth Cohort Study, there were 3 474 pregnant women recruited from Ma'anshan Maternal and Child Care Center between May 2013 and September 2014, including 3 273 singleton live births. Follow up the infants to the age of 18 months old. Excluded the infants with incomplete information of breastfeeding and who did not finish the ASQ-3 evaluation in 6 months old and 18 months old, 2 404 valid subjects were included in the study. The information of demographic characteristics, deliver, infants and breastfeeding was collected. The behavioral development were evaluated by the third edition of Ages and Stages Questionnaire (ASQ-3) at 6 months old and 18 months old, and the effect of breastfeeding on behavioral development among infants and children were analyzed by multivariable logistic regression model. Results: The intensity of breastfeeding of infants within 6 months old was (26.56±10.56). The rate of breastfeeding as pure or major intake for infants between 0-5 months old were separately 54.2% (1 303), 54.0% (1 298). 54.0% (1 297), 50.5% (1 213), 34.4% (827) and 9.9% (237). After age, pre-pregnant BMI, intelligence, delivery mode, gender, gestational age, birth weight and family economic status adjusted, compared to never-breastfeeding, continuous breastfeeding for 1-3 months could protect children from severe developmental delay in fine motor domain aged 6 months old (RR=0.36, 95%CI: 0.17-0.79), communication domain aged 18 months old (RR=0.27, 95%CI: 0.08-0.88), and social domain aged 18 months old (RR=0.36, 95%CI: 0.21-0.63). Compared to never-breastfeeding, continuous breastfeeding for more than 4 months could protect children from severe developmental delay in fine motor domain aged 6 months old (RR=0.58, 95%CI: 0.34-0.97), communication domain (RR=0.57, 95%CI: 0.39-0.83) and mild developmental delay (RR=0.65, 95%CI: 0.48-0.87) aged 18 months old and fine motor domain (RR=0.57, 95%CI: 0.39-0.83) aged 18 months old and social domain aged 18 months old (RR=0.57, 95%CI: 0.39-0.83). With the breastfeeding intensity rising, there were less children evaluated as severe development delay in communication domain aged 6 months old, communication, fine motor and problem-solving domains aged 18 months old, with RR (95%CI) at 0.98 (0.96-1.00), 0.96 (0.93-0.99), 0.98 (0.97-1.00) and 0.98 (0.96-1.00); and less children evaluated as mild development delay in communication domain aged 18 months old with RR (95%CI) at 0.99 (0.98-1.00). Conclusion: Breastfeeding with longer duration and increased intensity could promote better development in children.

How similar is "similar," or what is the best measure of soil spectral and physiochemical similarity?

Spectral similarity indices were used to select similar soil samples from a spectral library and improve the predictive accuracy of target samples. There are many similarity indices available, and precisely how to select the optimum index has become a critical question. Five similarity indices were evaluated: Spectral angle mapper (SAM), Euclidean distance (ED), Mahalanobis distance (MD), SAM_pca and ED_pca in the space of principal components applied to a global soil spectral library. The accordance between spectral and compositional similarity was used to select the optimum index. Then the optimum index was evaluated if it can maintain the greatest predictive accuracy when selecting similar samples from a spectral library for the prediction of a target sample using a partial least squares regression (PLSR) model. The evaluated physiochemical properties were: soil organic carbon, pH, cation exchange capacity (CEC), clay, silt, and sand content. SAM and SAM_pca selected samples were closer in composition compared to the target samples. Based on similar samples selected using these two indices, PLSR models achieved the highest predictive accuracy for all soil properties, save for CEC. This validates the hypothesis that the accordance information between spectral and compositional similarity can help select the appropriate similarity index when selecting similar samples from a spectral library for prediction.

[Pre-pregnancy BMI, gestational diabetes and different indicators of childhood obesity at the age of four: a prospective cohort study].

Objective: To examine the relationship between pre-pregnancy BMI, gestational diabetes (GDM) and different indicators of childhood obesity at the age of 4. Methods: Based on Ma'anshan Birth Cohort Study, singleton children who were born in Ma'anshan of Anhui province from October 2013 to April 2015, were followed for 4 years, consecutively. During the first questionnaire survey, data including pre-pregnancy weight, height and socio-demography were collected. During 24-28 week of gestation, 75 g oral glucose tolerance test was conducted for them. Childhood height, weight, waist circumference and body composition were measured at the age of 4. Comparisons between groups were performed using chi-square test, analysis of variance or t-test. The relationship between pre-pregnancy overweight/obesity, GDM and childhood obesity-related characteristics were analyzed by logistic regression model and generalized linear model analysis. Results: The prevalence rates of overweight and obesity in children at the age of 4 were 13.08% and 6.03%, respectively. After adjustment for characteristics related to mothers and their children, significantly increased risk of obesity (OR=3.27, 95%CI: 2.15-4.98), larger waist circumference (OR=2.32, 95%CI: 1.72-3.14) and higher waist-to-weight ratio (OR=2.29, 95%CI: 1.73-3.02) were seen in the offspring of women with pre-pregnancy overweight/obesity. Body composition (skeletal muscle, body fat, body fat percentage) of the offspring were strongly correlated with pre-pregnancy overweight/obesity of the mothers (P<0.05). Maternal GDM was associated with higher risk of childhood obesity (OR=1.78, 95%CI: 1.14-2.79), on mothers without GDM during pregnancy. However, neither larger waist circumference, or higher waist-to-weight ratio seemed to increase the risk. Moreover, maternal GDM was not associated with body composition measures (skeletal muscle, body fat, body fat percentage). Conclusion: Pre-pregnancy BMI and maternal GDM were independent risk factors for obesity in 4-year-old children, and pre-pregnancy BMI was correlated with various indicators of body composition in children.

[Excision of thyroglossal cyst in children by transverse submentum incision].

Objective:To explore the application of transverse submentum incision in thyroglossal duct cyst surgery. Method:Submentum transverse incision for thyroglossal duct cyst removal in 14 children with thyroglossal duct cyst from January 2014 to December 2017. All cases were performed submentum dermatoglyphic incision, skin incision, subcutaneous tissue, platysma muscle incision, down lifting flap, along the white line incision and separation of banded muscle on both sides, see the mass along the wall of the capsule separated to the attachment of the hyoid bone, ablation of the mucosa of the capsule wall of the hyoid bone attachment, electrotome to break the hyoid bone. The cavity is indeed stopped after bleeding, and the skin is sutured continuously for continuous intradermal suture. The operation time, bleeding volume, severe complications, wound healing time and severe surgical scars were recorded. Close follow-up was performed to observe whether there was infection or recurrence of incisional wound. Parents were informed by telephone to go back to the outpatient clinic. RUTTER Children's Behavior Questionnaire was used to assess the children's psychological status. Vancouver Scar Rating Scale was used to evaluate the children's surgical scars, and to investigate whether parents satisfactory surgical methods. Result:Fourteen cases of thyroglossal duct cyst underwent transverse incision thyroglossal duct cyst excision successfully. The average operative time was 55 minutes, and the standard deviation was 10.5 min, bleeding was less than 10 ml, postoperative hoarseness and weakness of voice, silence became low, wound healing time averaged one week, no serious surgical scars, no wound infection and recurrence. Among the normal children of the same age group, 14 parents were satisfied with the operation. Conclusion:Excision of thyroglossal duct cyst under transverse incision is safe, reliable and satisfactory in appearance.

[Association between pregnancy-related anxiety of pregnant women and autism-like behavior in their offspring at 18 months of age].

Objective: To investigate the relationship of pregnancy-related anxiety of pregnant women in second/third trimesters and autism-like behaviors in their offspring at 18 months of age. Methods: Based on a prospective cohort study design, we evaluated the situation of pregnancy-related anxiety of women during second and third trimesters through a Pregnancy-Related Anxiety Questionnaire. Subjects under study were classified into three groups, 1) those with pregnancy- related anxiety during both trimesters, 2) those with pregnancy-related anxiety at one trimester and 3) those without pregnancy-related anxiety in either trimester. When their children were 18 months, autism-like behaviors (ALB) were evaluated, using the part A of Checklist for Autism in Toddlers-23, and then classified into three groups as non-ALB group, minor ALB group and major ALB group. Multi-nominal logistic Regression was used to analyze the relationship of pregnancy-related anxiety with autism-like behaviors. Results: Compared with non-ALB group, children whose mother with pregnancy-related anxiety during both trimesters presented significant higher risk on ALB than children whose mother without pregnancy-related anxiety in these two periods (relative risk, RR=2.43, 95% CI: 1.21-4.86, P=0.012), major factors as pregnant women's IQ and gestational diabetes mellitus, premature delivery and education levels of fosterers on these pregnant women were under control. Our results from the stratified analysis showed: when in the subgroup that mother was the main fosterer of the child, there was an significant increase of risk in children whose mothers with pregnancy-related anxiety during both trimesters (RR=4.22, 95%CI: 1.73-10.32, P=0.002). Conclusion: The association between pregnancy-related anxiety and autism-like behavior was not strong but influenced by the fosterer of the child.

Replication of an rRNA gene origin plasmid in the Tetrahymena thermophila macronucleus is prevented by transcription through the origin from an RNA polymerase I promoter.

In the somatic macronucleus of the ciliate Tetrahymena thermophila, the palindromic rRNA gene (rDNA) minichromosome is replicated from an origin near the center of the molecule in the 5' nontranscribed spacer. The replication of this rDNA minichromosome is under both cell cycle and copy number control. We addressed the effect on origin function of transcription through this origin region. A construct containing a pair of 1.9-kb tandem direct repeats of the rDNA origin region, containing the origin plus a mutated (+G), but not a wild type, rRNA promoter, is initially maintained in macronuclei as an episome. Late, linear and circular replicons with long arrays of tandem repeats accumulate (W.-J. Pan and E. H. Blackburn, Nucleic Acids Res, in press). We present direct evidence that the +G mutation inactivates this rRNA promoter. It lacks the footprint seen on the wild-type promoter and produces no detectable in vivo transcript. Independent evidence that the failure to maintain wild-type 1.9-kb repeats was caused by transcription through the origin came from placing a short DNA segment containing the rRNA gene transcriptional termination region immediately downstream of the wild-type rRNA promoter. Insertion of this terminator sequence in the correct, but not the inverted, orientation restored plasmid maintenance. Hence, origin function was restored by inactivating the rRNA promoter through the +G mutation or causing termination before transcripts from a wild-type promoter reached the origin region. We propose that transcription by RNA polymerase I through the rDNA origin inhibits replication by preventing replication factors from assembling at the origin.

[Relations between hypertensive disorders in pregnancy and subsequent risk of early-term birth: a birth cohort study].

Objective: To evaluate the relations between hypertensive disorders (HDP) in pregnancy and early-term birth. Methods: A total of 3 474 pregnant women were consecutively recruited. Demographic information was collected in early pregnancy. HDP was diagnosed in the first, second and third trimesters, respectively. On the basis of precise evaluation on gestation age, early-term birth was defined as gestational age of 37-38 weeks+6 days. Logistic regression models were conducted to examine the associations between HDP and early-term birth. Results: The current study included 3 260 pregnant women, with the rates of HDP, pregnancy-induced hypertension syndrome and pre-eclampsia as 6.0% (n=194), 4.2% (n=137) and 1.8% (n=57), respectively. After controlling for potential confounders, no significant differences between pregnancy-induced hypertension syndrome and earlyterm birth (OR=1.49, 95%CI: 0.94-2.36) were found. Pre-eclampsia appeared to have increased the risk of early-term birth (OR=4.46, 95%CI: 2.09-9.54). Conclusion: Pre-eclampsia could significantly increase the risk of early-term birth. This finding suggested that early detection and intervention programs were helpful in reducing the risk of early-term birth.

[Previous medical or surgical abortions and subsequent risk of preterm birth: a birth cohort study].

Objective: To understand the association between medical abortion (MA) or surgical abortion (SA) and the risk of preterm birth (PTB) in subsequent pregnancy. Methods: The prospective cohort study was conducted in Ma'anshan, Anhui province. The information about demographic characteristics and previous MA or SA of 3 474 pregnant women were collected before 14 gestational weeks. Logistic regression analysis was conducted to compare the rates of preterm birth based on the history of previous MA or SA, and 3 256 live births were included in the analysis. Results: The PTB rate and spontaneous preterm birth (sPTB) rate were 4.12% (n=134) and 2.49% (n=81) respectively. Previous MA was associated with an increased risk of total PTB (RR=2.00, 95%CI: 1.04-3.85 for one MA and RR=3.58, 95%CI: 1.04-12.30 for two or more MAs) and sPTB (RR=2.51, 95% CI: 1.23-5.15). The risk of PTB in women with one SA (RR=0.67, 95%CI: 0.42-1.01) or more SA (RR=0.97, 95%CI: 0.51-1.85) did not differ significantly compared with the women with no history of SA. Conclusion: This study suggests that medical abortion could increase the risk of PTB or sPTB.

[Intrahepatic cholestasis of pregnancy and fetal outcomes: a prospective birth cohort study].

OBJECTIVE: To evaluate the relations between the second and third trimesters intrahepatic cholestasis of pregnancy (ICP) and the fetal outcomes, in order to provide medical advice for early detection and intervention on ICP. METHODS: A prospective cohort study was conducted in Ma' anshan, Anhui, China (Ma'anshan Birth Cohort, MABC). Pregnant women within 14 weeks of gestation were consecutively recruited when standards were met. Anthropometrics were collected in early pregnancy. Maternal serum total bile acid level (TBA) was collected in the second and third trimesters, and women were viewed as cases if the results were accorded with clinical diagnosis. Logistic regressions were conducted to examine the associations of the second and third trimester ICP, and fetal outcomes. RESULTS: A total of 2 978 pregnant women were included in this study. The rate of ICP was 6.5% (n=196), and the rates of the second and third trimesters were 1.4% (n=43) and 5.1% (n=153) respectively. After controlling for potential confounders, we found that ICP from both the second and third trimesters could increase the risks of preterm birth, low birth weight (LBW), fetal distress and meconium-stained amniotic fluid.OR values (95% CI) were 6.42 (2.59-15.93) and 3.73 (2.07-6.72) for preterm birth while 6.52 (2.19-19.45) and 4.90 (2.43-9.90) for LBW, 2.91 (1.27-6.67) and 1.88 (1.11-3.19) for fetal distress and 2.34 (1.19-4.61) and 1.66 (1.11-2.48) for meconium-stained amniotic fluids, respectively. The risk of adverse fetal outcomes caused by the second trimester ICP appeared significantly higher than the third trimester ICP. CONCLUSION: ICP from the second and third trimesters significantly increased the risk of adverse fetal outcomes, suggesting that clinicians should put more attention to the second trimester ICP. Both early detection and intervention were of great importance in reducing the adverse fetal outcomes.

Myocardial ischemic preconditioning upregulated protein 1(Mipu1):zinc finger protein 667 - a multifunctional KRAB/C2H2 zinc finger protein.

Myocardial ischemic preconditioning upregulated protein 1 (Mipu1) is a newly discovered upregulated gene produced in rats during the myocardial ischemic preconditioning process. Mipu1 cDNA contains a 1824-base pair open reading frame and encodes a 608 amino acid protein with an N-terminal Krüppel-associated box (KRAB) domain and classical zinc finger C2H2 motifs in the C-terminus. Mipu1 protein is located in the cell nucleus. Recent studies found that Mipu1 has a protective effect on the ischemia-reperfusion injury of heart, brain, and other organs. As a nuclear factor, Mipu1 may perform its protective function through directly transcribing and repressing the expression of proapoptotic genes to repress cell apoptosis. In addition, Mipu1 also plays an important role in regulating the gene expression of downstream inflammatory mediators by inhibiting the activation of activator protein-1 and serum response element.

Preclinical development of AMG 139, a human antibody specifically targeting IL-23.

BACKGROUND AND PURPOSE: AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. EXPERIMENTAL APPROACH: The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys. KEY RESULTS: AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4-13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg(-1) and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg(-1) s.c. or i.v.). CONCLUSIONS AND IMPLICATIONS: The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.

beta-adrenergic antagonism alters the behavioral and neurochemical responses to cocaine.

The effects of the beta-adrenergic antagonist propranolol on the locomotor stimulating, neurochemical, and reinforcing effects of cocaine were examined in rats. In Experiment 1, propranolol (1, 3 and 10 mg/kg, IP) produced a dose-dependent increase in the motor stimulant effects of cocaine without affecting basal motor activity. Atenolol, a peripherally restricted beta 1 antagonist, and (+) propranolol, the inactive isomer of propranolol, did not alter cocaine-induced locomotion. In Experiment 2, propranolol was shown to augment significantly the increase in extracellular dopamine content in the nucleus accumbens that accompanies a cocaine challenge. Experiment 3 demonstrated that propranolol produced a dose-dependent decrease in cocaine self-administration. Atenolol (10 mg/kg, IP) reduced cocaine self-administration but to a much lesser extent than propranolol. Experiment 4 demonstrated that coadministration of propranolol and cocaine did not alter the levels of cocaine in the brain and plasma achieved by cocaine administration alone. These data suggest that the blockade of beta-adrenergic receptors potentiates cocaine-induced elevation of dopamine transmission in the nucleus accumbens, which is associated with an increase in cocaine-induced motor activity and a decrease in cocaine self-administration.

Lack of a pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline.

AIM: To study the potential pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline at steady state. METHODS: Theophylline 200 mg extended-release formulation was administered twice daily on days 1-11 to 30 healthy, non-smoking males. On days 5-11, 15 subjects received concomitant lansoprazole 30 mg once daily (o.d.) and 15 subjects received concomitant pantoprazole 40 mg o.d. RESULTS: No significant changes in the steady-state theophylline maximum plasma concentration (Cmax), time to Cmax (Tmax), minimum plasma concentration (Cmin), area under the plasma concentration-time curve over the 12-h dosing interval (AUC0-12), or apparent total oral clearance (CL/F) were observed within the two treatment groups when theophylline was administered alone or in combination with lansoprazole or pantoprazole. In addition, no significant differences in the changes of steady-state theophylline pharmacokinetics from day 4 to day 11 were noted between the two treatment groups. Treatment with theophylline in combination with either lansoprazole or pantoprazole was well tolerated. All adverse events were transient and rated mild to moderate in severity. CONCLUSION: Co-administration of either lansoprazole or pantoprazole in healthy subjects does not significantly affect the steady-state pharmacokinetics of theophylline at the therapeutic doses tested.

A comparison of simplified lansoprazole suspension administered nasogastrically and pantoprazole administered intravenously: effects on 24-h intragastric pH.

AIM: To compare the 24-h intragastric pH effects of simplified lansoprazole suspension, 30 mg, administered nasogastrically, with pantoprazole, 40 mg, administered intravenously. METHODS: Thirty-six healthy adults were enrolled and given simplified lansoprazole suspension, 30 mg (nasogastrically), or pantoprazole, 40 mg (intravenously), once daily for five consecutive days in a cross-over fashion. Intragastric pH was monitored at baseline and on Days 1 and 5 of each treatment period. The pharmacokinetic parameters of lansoprazole and pantoprazole were also determined on Days 1 and 5. RESULTS: No statistically significant changes in pharmacokinetic parameters occurred between Days 1 and 5 with either regimen, except for pantoprazole Cmax. On Days 1 and 5, significantly higher mean 24-h intragastric pH values were observed with 30 mg simplified lansoprazole suspension compared with 40 mg intravenous pantoprazole (Day 1, 3.13 vs. 2.67; Day 5, 3.95 vs. 3.61, respectively; P < 0.05). Additionally, 30 mg simplified lansoprazole suspension produced significantly (P < 0.05) higher percentages of time intragastric pH was above 3, 4, 5 or 6 as compared with 40 mg intravenous pantoprazole throughout Days 1 and 5. CONCLUSIONS: A 30 mg dose of simplified lansoprazole suspension administered nasogastrically was consistently more effective at controlling intragastric pH than pantoprazole, 40 mg, administered intravenously.

Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers.

This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single-dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three-period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3 alpha-hydroxy-isopravastatin (3 alpha-iso-PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0-infinity and Cmax of 3 alpha-iso-PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.

An animal model for simultaneous pharmacokinetic/pharmacodynamic investigations: application to cocaine.

An animal model suitable for pharmacokinetic/pharmacodynamic investigations is described. This model allows drug administration via different routes, serial blood sampling, serial brain ECF sampling, and monitoring the cardiovascular functions without touching the animal. This rat model was utilized to study the relationship between cocaine pharmacokinetics and the neurochemical and cardiovascular responses to cocaine administration via different routes. The pharmacokinetic results showed that the average cocaine bioavailability after i.p. administration was 71% and after oral administration was only 19.2%. Cocaine was rapidly distributed into the brain, and the brain ECF/plasma distribution ratio measured as the ratio of the brain ECF AUC to the plasma AUC was 2.02 +/- 0.59. The relationship between cocaine brain ECF concentration and the change in dopamine brain ECF concentration was described by the sigmoid Emax pharmacodynamic model. When the relationship between cocaine plasma concentration and the change in the cardiovascular functions was examined, hysteresis loops were observed. These hysteresis loops may suggest the existence of an effect compartment for the cardiovascular effects of cocaine or that cocaine metabolites are contributing to cocaine cardiovascular effects. These results indicate that the described animal model is useful in simultaneous pharmacokinetic/pharmacodynamic investigations specifically for studies that involve centrally acting drugs.

Cocaine and alcohol interactions in the rat: effect on cocaine pharmacokinetics and pharmacodynamics.

The effect of alcohol coadministration on cocaine pharmacokinetics and pharmacodynamics was investigated in awake, freely moving rats. Cocaine plasma and brain extracellular fluid (ECF) concentration-time profiles were characterized after intraperitoneal (ip) administration of 30 mg/kg cocaine to rats that were pretreated with either normal saline or alcohol at 5 g/kg in a balanced crossover experimental design. The neurochemical response to cocaine administration, measured as the change in dopamine concentration in the nucleus accumbens (N ACC) and the change in the mean arterial blood pressure were monitored simultaneously. Intragastric alcohol administration significantly increased cocaine systemic bioavailability after ip administration from 0.550 +/- 0.044 to 0. 754 +/- 0.071. Also, the absorption rate constant increased from 0. 199 +/- 0.045 to 0.276 +/- 0.059 min-1 due to alcohol coadministration; however, this increase was not significant. Alcohol inhibition of cocaine metabolism caused an increase in cocaine elimination half-life from 26.3 +/- 3.6 to 40.0 +/- 8.1 min. Also, cocaine tissue distribution was enhanced by alcohol, resulting in a significant increase in cocaine volume of distribution. Analysis of the brain cocaine concentration-neurochemical effect relationship by the sigmoid-Emax pharmacodynamic model showed that Emax increased from 850 +/- 200 to 1550 +/- 640% of baseline due to alcohol coadministration, whereas EC50 decreased from 3400 +/- 580 to 2000 +/- 650 ng/mL, indicating higher cocaine potency in the presence of alcohol. The estimates of the indirect inhibitory pharmacodynamic model used to examine the plasma cocaine concentration-change in blood pressure relationship were not significantly different after the two treatments. These results indicate that alcohol significantly alters cocaine absorption, distribution, and elimination, resulting in higher and prolonged cocaine plasma concentration. Alcohol coadministration also potentiates the neurochemical response to cocaine administration.

Cocaine and alcohol interactions in the rat: contribution of cocaine metabolites to the pharmacological effects.

The pharmacokinetics and pharmacodynamics of cocaine and its three metabolites, benzoylecgonine, norcocaine, and cocaethylene, were investigated in awake, freely moving rats. This work was performed to examine the effect of alcohol coadministration on the metabolic profile of cocaine and to determine the contribution of cocaine metabolites to the pharmacological responses observed after cocaine administration. The plasma and brain extracellular fluid concentration-time profiles were characterized after intravenous (iv) administration of cocaine and the three metabolites in a crossover experimental design. The neurochemical response, measured as the change in dopamine concentration in the nucleus accumbens, and the cardiovascular responses, measured as the change in the mean arterial blood pressure, heart rate, and QRS interval, were monitored simultaneously. Cocaethylene had the highest brain-to-plasma distribution ratio, followed by cocaine, norcocaine, and benzoylecgonine. The estimated total body clearances for cocaine, benzoylecgonine, norcocaine, and cocaethylene were 140 +/- 19, 14.7 +/- 1.2, 130 +/- 19, and 111 +/- 16 mL/min/kg, respectively. Alcohol coadministration increased the formation of norcocaine, decreased the formation of benzoylecgonine, and resulted in the formation of the pharmacologically active metabolite cocaethylene. When cocaine was administered with alcohol, 12.9 +/- 3.1% to 15.3 +/- 2.9% of the cocaine dose was converted to cocaethylene. Benzoylecgonine did not have any central nervous system or cardiovascular activities after iv administration. Compared with cocaine, norcocaine and cocaethylene had more potent and prolonged effects on the neurochemical, heart rate, and QRS interval responses, and were equipotent in increasing the mean arterial blood pressure. These results indicate that changes in the cocaine metabolic profile and the formation of the pharmacologically active metabolite cocaethylene are, at least partially, responsible for the more intense and longer lasting effects reported after using this drug in combination with alcohol.

Cocaine and alcohol interactions in the rat: effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics.

This experiment was designed to investigate the effect of pretreatment with cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups of rats (n = 8 per group) received one of the following pretreatments for two weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg/kg/day ip), and alcohol+cocaine (10% v/v in drinking water + 15 mg/kg/day ip). On the day of the experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or in combination with alcohol (5 g/kg, po), in a balanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC-UV. The percent change in brain dopamine concentration, mean arterial blood pressure, and heart rate were determined simultaneously. A sigmoid-E(max) model was used to describe the brain cocaine concentration-neurochemical effect (dopamine) relationship, and an indirect pharmacodynamic response model was used to describe the plasma cocaine concentration-cardiovascular effect relationships. Alcohol pretreatment led to significant increase in cocaine AUC(p), alpha(t1/2), and beta(t1/2). Cocaine pretreatment significantly increased cocaine bioavailability, absorption rate constant, TBC, and the formation clearance of cocaethylene. Acute alcohol coadministration with cocaine increased cocaine AUC(p) and bioavailability, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the pharmacokinetics of cocaine, either administered alone or in combination with alcohol, is significantly altered due to prior cocaine and/or alcohol use. Both cocaine and alcohol pretreatments increased the E(max) for dopamine, with no effect on the EC(50). Acute alcohol coadministration with cocaine significantly increased the E(max) for dopamine and reduced the EC(50). Cocaine pretreatment significantly decreased the I(max) for blood pressure, IC(50), and R(max). For the heart rate response, both alcohol and cocaine pretreatments significantly increased the IC(50), with no effect on I(max). These results indicate that both cocaine and alcohol pretreatments as well as acute alcohol coadministration lead to significant alterations in cocaine pharmacodynamics that are due, at least in part, to the changes in cocaine pharmacokinetics. If similar effects occur in humans, chronic cocaine and alcohol abusers may respond differently to cocaine administration compared to naïve users and may be at higher risks of cocaine central nervous system toxicity.