Mechanisms of drug transfer across the human placenta.

In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flowdependent and membranelimited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.     

Effect of human serum albumin on transplacental transfer of glyburide

Glyburide is a second-generation sulfonylurea hypoglycemic drug used for the treatment of select women with pregestational and gestational diabetes mellitus (GDM). In vitro and in vivo investigations demonstrated its very low transplacental transfer to the fetal circulation. However, the factors influencing its low transfer across the human placenta remain unclear. Therefore, the goal of the current investigation was to determine the effect of human serum albumin (HSA) on the transfer and distribution of glyburide across the human placenta. To achieve this goal, the technique of dual perfusion of the placental lobule was utilized. The effect of HSA on the transfer of glyburide was determined at the range of glyburide to HSA molar ratios of 1:2-1:100. The transfer rate of free/unbound glyburide to the fetal circuit was 73+/-10% of the freely diffusible marker compound antipyrine (AP). Data obtained indicates the dependence of glyburide transfer and its retention by the placental tissue on the concentration of HSA.     

Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist

Tobacco addiction requires activation by nicotine of a variety of central nicotinic acetylcholine receptors (nAChRs). In animals, both nAChR antagonists and immunization against nicotine can reduce nAChR activation by nicotine and block a variety of addiction-relevant behaviors. However, clinical use of nAChR antagonists for smoking cessation is limited by dose-related side effects, and immunization does not reliably produce sufficient antibody levels in smokers to enhance smoking cessation rates. Combining these approaches may be one way of addressing the limitations of each while enhancing overall efficacy. This study examined the individual and combined effects of passive immunization with the monoclonal nicotine-specific antibody Nic311 and the nicotinic receptor antagonist mecamylamine (MEC) on nicotine's discriminative stimulus effects. Rats were trained to discriminate 0.4 mg/kg of nicotine from saline using a two-lever operant discrimination procedure. Antagonism of nicotine discrimination by Nic311 (160 mg/kg i.v.) and ascending doses of MEC (0.03, 0.1, 0.3, and 1.0 mg/kg s.c.) was assessed across four consecutive daily 2-min extinction test sessions using a 2 × 2 design. Nic311 alone produced a 24-48% reduction in % nicotine-lever responding (%NLR) across all four test sessions. MEC produced a dose-dependent decrease in %NLR, with no effect at the two lowest doses and 80-93% attenuation at the two highest doses. Nic311 combined with MEC significantly suppressed %NLR at every MEC dose (85-92% reduction across all four test sessions). Very low doses of MEC that were ineffective alone completely blocked nicotine discrimination when combined with Nic311. These data demonstrate that nicotine-specific antibodies and MEC can work synergistically to suppress the subjective effects of nicotine and suggest that low doses of MEC may significantly enhance the efficacy of immunotherapy.     

Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats

Rationale Immunization of rats against nicotine using a nicotine conjugate vaccine reduces the distribution of nicotine to brain in rats and attenuates some of nicotine's physiological and behavioral effects. It is not known whether such a vaccine can attenuate nicotine's reinforcing effects. Objective The present experiment was conducted to determine whether a nicotine conjugate vaccine could interfere with the acquisition and maintenance of nicotine self-administration (NSA) in rats given 23 h day⁻¹ access to nicotine. Methods To examine acquisition of NSA, rats were vaccinated with nicotine or control immunogen prior to being given access to a 0.01 mg kg⁻¹ infusion⁻¹ nicotine under a fixed-ratio(FR) 1 schedule for week 1, FR 2 for week 2, and FR 3 for week 3. Acquisition of cocaine self-administration (CSA) was similarly examined to determine the specificity of vaccination effects. To examine maintenance of NSA, rats were initially trained to self-administer nicotine under an FR 3 schedule, and then vaccinated with nicotine or control immunogen while NSA continued to be monitored. Results NSA was significantly lower in vaccinated rats compared to controls during the acquisition protocol, with a 38% decrease in the number of infusions during the last week of training. The percentage of rats meeting acquisition criteria in the vaccinated group was lower (36%) than that in the control group (70%), but this difference was not statistically significant. Vaccination did not affect acquisition of CSA, demonstrating its specificity for nicotine. Maintenance of NSA was significantly reduced in vaccinated rats as compared to controls after the final vaccine injection, with a mean reduction of 57%. There was no evidence in either protocol that vaccinated rats attempted to compensate for altered nicotine distribution by increasing nicotine intake. Conclusion These data suggest that vaccination against nicotine can reduce the reinforcing effects of nicotine in rats and may have therapeutic potential for the treatment of tobacco dependence.     

Role of P-glycoprotein in transplacental transfer of methadone

Methadone is the therapeutic agent of choice for treatment of the pregnant opiate addict. However, little is known on the factors affecting its concentration in the fetal circulation during pregnancy and how it might relate to neonatal outcome. Therefore, a better understanding of the function of placental metabolic enzymes and transporters should add to the knowledge of the role of the tissue in the disposition of methadone and its relation to neonatal outcome. We hypothesized that the expression and activity of the placental efflux transporter P-glycoprotein (P-gp) would affect the transfer of methadone to the fetal circulation. Data obtained utilizing dual perfusion of placental lobule and monolayers of Be-Wo cell line indicated that methadone is extruded by P-gp. Transfer of methadone to the fetal circuit was increased by 30% in the presence of the P-gp inhibitor GF120918 while the transfer of paclitaxel, a typical substrate of the glycoprotein, was increased by 50%. In the Be-Wo cell line, methadone and paclitaxel uptake was also increased in the presence of the P-gp inhibitor cyclosporin A. Moreover, the expression of P-gp in placental brush-border membranes varied between term placentas. Taken together, these data strongly suggest that the concentration of methadone in the fetal circulation is affected by the expression and activity of P-gp. It is reasonable to speculate that placental disposition of methadone affects its concentration in the fetal circulation. If true, this may also be directly related to the incidence and intensity of neonatal abstinence syndrome (NAS).     

Effects of smoking different doses of nicotine on human aggressive behavior

A new methodology was employed to study the effects of drugs on human aggressive behavior in a laboratory situation. The effects of not smoking, smoking a low nicotine dose (0.42 mg/cigarette), and smoking a high nicotine dose (2.19 mg/cigarette) on human nonaggressive and aggressive responding was determined. A nonaggressive response, which resulted in the accumulation of money, was continuously available to the subject. Two different aggressive responses were also available: the ostensible subtraction of money from, and the ostensible presentation of a 1-s blast of white noise to a (fictitious) person. Aggressive responding was elicited by subtracting money from the research subjects, which was attributed to a fictitious person paired with the research subject randomly each day. Nicotine, administered with experimental cigarettes, produced dose-dependent decreases in both types of aggressive responding elicited by low or high frequency subtractions of money attributed to another person. Generally, the more aggressive response option, i.e., subtraction of money from another person, decreased more following nicotine administration. Smoking the same doses of nicotine increased nonaggressive monetary reinforced responding. This indicates that the suppressant effect of nicotine on aggressive responding was not due to a nonspecific depressant action.Portions of these data have been previously reported at a regional meeting of the International Society for Research on Aggression held in Boston, MA, in August, 1981.     

Effects of pregnancy on nicotine self-administration and nicotine pharmacokinetics in rats

Rationale Because of the adverse effects of smoking during pregnancy, understanding the factors that influence maternal smoking may help in developing better treatments to help women quit smoking during pregnancy. Animal models could be useful for this purpose. Objective The purpose of the present study was to begin the development of an animal model of smoking during pregnancy by initially characterizing nicotine self-administration (NSA) in pregnant rats. Another purpose was to begin to explore the effects of pregnancy on nicotine pharmacokinetics in rats. Materials and methods In experiment 1, female rats self-administering nicotine during 23-h sessions were examined throughout gestation and lactation. In experiment 2, locomotor activity was measured during pregnancy to assess further potential motor effects of pregnancy. Experiments 3 and 4 compared the single-dose pharmacokinetics of nicotine in male, nonpregnant female, and pregnant females in the first and third trimester of pregnancy and the first week of lactation. Results NSA decreased over the course of pregnancy with NSA significantly lower in the third trimester compared to nonpregnant controls. NSA remained suppressed for up to 10 days into lactation. Locomotor behavior was also significantly suppressed during the second and third trimesters and throughout lactation. Nicotine elimination was slower in pregnant females compared to nonpregnant females only in the third trimester. Conclusions NSA, locomotor behavior, and nicotine elimination in rats are decreased during late pregnancy. The present study is the first to characterize NSA during pregnancy in animals, providing a potential model of maternal smoking in humans.     

Effects of nicotine and amphetamine on latent inhibition in human subjects

Latent inhibition (LI) is a phenomenon in which repeated non-reinforced exposure to a stimulus retards subsequent conditioning to that stimulus; it reflects a process whereby irrelevant stimuli become ignored, and has been the subject of study concerning attentional abnormalities in schizophrenia. Low doses of the indirect dopamine (DA) agonists, amphetamine and nicotine, disrupt LI in the rat. These drugs are believed to disrupt LI via DA release in the nucleus accumbens; LI in amphetamine- and nicotine-treated rats is reinstated by administration of the DA antagonist haloperidol. In human subjects, low doses of amphetamine abolish LI, and more recently haloperidol has been shown to potentiate LI. The present study investigated the effects of nicotine on LI in human subjects, and also attempted to replicate the abolition of LI by amphetamine. Nicotine failed to affect LI when administered either subcutaneously or by cigarette smoking. LI was, however, abolished in a group of subjects given 5 mg amphetamine 90 min before testing. Supplementary analyses of the data pooled from all three experiments showed that, in contrast to an earlier report, LI was no weaker in smokers than in non-smokers.     

Transplacental transfer of amitriptyline and nortriptyline in isolated perfused human placenta

RATIONALE: Although tricyclic antidepressants (TCAs) have gained wide acceptance for use in the treatment of depression in pregnant women, their pharmacokinetics during pregnancy have been poorly characterized. The aim of the present study was to investigate the transplacental transfer of amitriptyline (AMI) and its main active metabolite nortriptyline (NOR) in isolated perfused human placenta. METHODS: Nine term human placentae were obtained immediately after delivery with maternal consent and a 2-h non-recirculating perfusion of a single placental cotyledon was performed. AMI (200 ng/ml) and NOR (150 ng/ml), with antipyrine as a reference compound, were added to the maternal reservoir and their appearance to the fetal circulation was followed for 2 h. AMI and NOR concentrations were measured by high performance liquid chromatography (HPLC) and antipyrine concentrations spectrophotometrically. RESULTS: The mean (SD) transplacental transfers (TPT(SS)%) for AMI and NOR were 8.2 (2.3)% and 6.5 (1.8)%, respectively, calculated as the ratio between the steady-state concentrations in fetal venous and maternal arterial sides. The TPTs of AMI and NOR were 81% and 62% of the freely diffusable antipyrine. The absolute fraction of the dose that crossed the placenta (TPT(A)) was moderately, but significantly higher for AMI (7.7%) than for NOR (5.7%) (P=0.037). In all perfusions, steady state at the fetal side was reached by 30 min for AMI and by 50 min for NOR in the fetal side. The viability of the placentae was retained during the 2-h perfusion, as evidenced by unchanged pH of the perfusate and by stable perfusion pressures in fetal artery and stable antipyrine transfer. CONCLUSIONS: Both AMI and NOR cross the human placenta. However, the fetal exposure with NOR may be somewhat smaller compared with AMI, probably due to the higher lipophilicity of AMI.     

Maternal–fetal transfer of indocyanine green across the perfused human placenta

Indocyanine green (ICG) is an FDA-approved near-infrared imaging probe, given also to pregnant women. We aimed to characterize ICG's transplacental transfer using the ex-vivo perfusion model. Placentas were obtained from caesarean deliveries. Cotyledons were cannulated and dually perfused. ICG, 9.6 μg/mL and antipyrine (50 μg/mL) were added to the maternal circulation in the absence (n = 4) or the presence of the organic anion transporting polypeptide (OATPs) inhibitor rifampin (10 μg/mL; n = 5) or the P-glycoprotein inhibitor valspodar (2 μg/mL; n = 3). ICG's maternal-to-fetal transfer was evaluated over 180 min. The cumulative percent of ICG in the fetal reservoir was minor. When ICG transfer was normalized to that of antipyrine, it was lower in the presence of rifampin (a 41% decrease; p < 0.05). Valspodar did not appear to modify the kinetics of ICG. ICG's transplacental transfer is minimal and is probably OATP-mediated. The placenta is an effective protective barrier to ICG's distribution into the fetus.     

Bidirectional placental transfer of Bisphenol A and its main metabolite,Bisphenol A-Glucuronide,in the isolated perfused human placenta

The widespread human exposure to Bisphenol A (BPA), an endocrine disruptor interfering with developmental processes, raises the question of the risk for human health of BPA fetal exposure. In humans, highly variable BPA concentrations have been reported in the feto-placental compartment. However the human fetal exposure to BPA still remains unclear. The aim of the study was to characterize placental exchanges of BPA and its main metabolite, Bisphenol A-Glucuronide (BPA-G) using the non-recirculating dual human placental perfusion. This high placental bidirectional permeability to the lipid soluble BPA strongly suggests a transport by passive diffusion in both materno-to-fetal and feto-to-maternal direction, leading to a calculated ratio between fetal and maternal free BPA concentrations of about 1. In contrast, BPA-G has limited placental permeability, particularly in the materno-to-fetal direction. Thus the fetal exposure to BPA conjugates could be explained mainly by its limited capacity to extrude BPA-G.     

紫河车对骨质疏松症的治疗效果

目的 探讨紫河车对骨质疏松症的治疗效果.方法 将200例骨质疏松症患者分成对照组和治疗组,每组各100例,对照组患者每日口服碳酸钙D3片,治疗组患者每日口服紫河车胶囊,比较两组的治疗效果.结果 对照组治疗前后的新骨形成三项生化指标值差异无统计学意义（P＞0.05）;治疗组治疗前后的新骨形成三项生化指标值差异有统计学意义（P＜0.05）.结论 紫河车能明显改善新骨形成三项生化指标值,对骨质疏松症有明显的治疗作用.     

Effects of nicotine,nicotine monomethiodide,lobeline, chlordiazepoxide., meprobamate and caffeine on a discrimination task in laboratory rats

Hungry rats were trained on a discrimination task in order to obtain food rewards. During each experimental session, discrete stimuli of 1 min duration were delivered through a small speaker in the experimental chamber at random intervals on the average of once every 2 min. Lever responses in the presence of a light and tone were correct and produced food rewards. Lever responses in the presence of the light stimulus were incorrect and were punished by total inactivation of the experimental chamber. Rats were selected for this experiment based on their inability to acquire the discrimination task even after six months of training. Administration of nicotine, lobeline, chlordiazepoxide and meprobamate produced an improvement in discrimination performance through a reduction of responses to incorrect stimuli. Caffeine and nicotine monomethiodide, the quaternary salt of nicotine, were without effect on the discrimination.     

Transfer of nitrazepam across the human placenta

Summary Six women from 14 to 17 weeks pregnant, and 12 woman from 36 to 40 weeks pregnant, were given nitrazepam 5 mg orally about 12 h before legal abortion by hysterotomy in the former group and elective caesarean section in the latter group. The concentration of nitrazepam was determined by gas-liquid chromatography. Binding to plasma proteins was evaluated by separation of the protein-free fraction by ultracentrifugation. In the first group (early pregnancy) the level of nitrazepam was found to be lower in the fetal than in the maternal circulation. The concentration in amniotic fluid was still lower. In the latter group (late pregnancy) the concentration both of unbound and total nitrazepam in maternal and fetal plasma were in equilibrium, which indicated an increase in transplacental transfer in late pregnancy. The percentage of unbound nitrazepam in both cases was 12%.     

Assessing the senok,sory role of nicotine in cigarette smoking

Thirty-two subjects were tested in five double-blind sessions (16 subjects in the morning following overnight smoking abstention, and 16 in the afternoon following ad-lib smoking). In each session, subjects smoked one of five experimental (EX) cigarettes having the following FTC nicotine/‘tar’ yields in mg: 0.08/8.5, 0.17/9.1, 0.37/9.8, 0.48/9.8, and 0.74/10.4. In a sixth session, subjects smoked a 0.71/8.6 commercial ‘light’ (CL) cigarette that was their usual brand. Before and after smoking, subjects subjectively rated their desire to smoke a cigarette of their usual brand and had blood smaples drawn. Following smoking subjects rated the cigarette on a variety of sensory dimensions; they also rated smoking satisfaction. Analysis of variance indicated that nicotine played an important sensory role for a variety of dimensions related to cigarette taste and sensory impact but not perceived draw. Principal-components analyses indicated that sensory factors were at least as important as nicotine pharmacology (indirectly indexed by the preto post-smoking rise in blood nicotine concentration) when considering smoking’s overall effects on satisfaction, product acceptance, and reduction in desire to smoke. A preliminary version of these data was presented at the International Symposium on Nicotine. The Effects of Nicotine on Biological Systems II, Montreal, July 21–24, 1994. The authors thank Drs. Brad Ingebrethsen, Deborah Pritchard, and two anonymous reviewers for comments on earlier drafts.     

Effects of continuous nicotine infusion on nicotine self-administration in rats: relationship between continuously infused and self-administered nicotine doses and serum concentrations

Rationale The efficacy of nicotine replacement therapy (NRT) for smoking cessation is limited. One reason for this limited efficacy may be that typical serum nicotine concentrations provided by NRT do not match the peak arterial nicotine concentrations achieved from smoking.Objective The purpose of the present study was to determine whether continuous nicotine infusion at a rate producing serum nicotine concentrations that match the estimated peak arterial nicotine concentrations associated with nicotine self-administration (NSA) in rats produces greater suppression of NSA than lower infusion rates.Methods The effects of continuous nicotine infusion were studied by intravenously administering nicotine at various rates (1.0, 3.0, and 8.0 mg/kg per day) to rats concurrently self-administering nicotine (0.03 mg/kg per infusion) during 23-h sessions or cocaine (0.17 mg/kg per infusion) during 2-h sessions.Results Continuous nicotine infusion suppressed NSA in a rate-related fashion. NSA was suppressed by 17, 50, and 73% at infusion rates of 1.0, 3.0 and 8.0 mg/kg per day, respectively. The 8.0-mg/kg per day infusion rate, which provided venous serum nicotine concentrations equaling the peak arterial concentrations associated with NSA, suppressed NSA to a greater extent than lower infusion rates. The 8.0-mg/kg per day nicotine infusion rate had no effect on cocaine-maintained responding, demonstrating that its effects were specific for suppression of NSA. This infusion rate provided a mean percentage replacement of nicotine from NSA of more than 700%. Reacquisition of NSA after suppression by the two highest infusion rates was delayed compared with reacquisition after saline extinction.Conclusions Continuous nicotine infusion produced an infusion rate-related suppression of NSA that was greatest when the infusion provided nicotine doses and venous serum concentrations substantially higher than those typically associated with NRT in humans.     

Effects of post-trial administration of nicotine on human memory: evaluating the conditions for improving memory

In the studies reported here, we investigated the effects of nicotine on memory for unrelated word lists. Nicotine was delivered through cigarette smoking, and memory performance was assessed using both intentional and incidental recall tasks, and employing an additional, indirect measure of memory. We report the results of four experiments in which we manipulated 1) the intake of nicotine using nicotine-containing and nicotine-free cigarettes, 2) the associative aspects of the word-sets, by unrelated words and category words and by instructing subjects to use an associative mnemonic strategy, 3) the opportunity for rehearsal between the presentation and recall, and 4) the time of nicotine administration, post- or pre-trial. We found a positive effect of post-trial nicotine on memory in the incidental recall task, as indicated by enhanced repetition priming, but no effect of nicotine on either immediate recall or pronunciation times (experiments 1 and 2). In experiment 3 we examined the effects of post-trial nicotine using associative and unrelated word-lists, when volunteers were instructed to use an associative mnemonic strategy. We found no main effect of nicotine, but when volunteers were distracted from rehearsal, related words were recalled better than unrelated words. Experiment 4 was a positive control for the timing of nicotine administration within our experimental design, and this showed that pre-trial nicotine not only improved free recall but differentially enhanced the recall of category words over unrelated words. We conclude that nicotine does modulate memory, that associative aspects of verbal memory in particular are sensitive to modulation by nicotine, and that the effects are more reliably observed with pre-trial than with post-trial administration. The conditions under which post-trial effects can be observed remain unclear.     

凶险型前置胎盘对孕产妇妊娠结局的影响研究

目的 探讨凶险型前置胎盘对孕产妇妊娠结局的影响。方法 选取2010年1月～2013年12月于本院施行手术治疗的192例前置胎盘患者,根据疾病情况,将32例凶险型前置胎盘患者设为凶险组．将160例普通型前置胎盘患者设为普通组。比较两组患者胎盘植入的差异,评价患者产后出血率、输血率及手术方面的情况。结果 凶险组胎盘植入发生率为53．1％,显著高于普通组的7．5％,差异有统计学意义（P〈0．05）;凶险组产后出血发生率为93．8％,显著高于普通组的36．9％,差异有统计学意义（P〈0．05）;凶险组输血发生率为71．9％,明显高于普通组的21.3％,差异有统计学意义（P〈0．05）。凶险组手术时间长于普通组,产后2、24h出血量多于普通组,差异有统计学意义（P〈0．05）。结论 凶险型前置胎盘具有较高的胎盘植入发生率,患者产后出血率、输血率、产后出血量较高。临床应提高凶险型前置胎盘的认识,产前做好预防保健工作,严格掌握剖宫产手术的适应证及禁忌证。     

Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Transfer of free and conjugated oxazepam across the human placenta

Summary Six women, 13 to 16 weeks pregnant, and 12 women at 38 to 40 weeks gestation, received oral oxazepam about 12 h before legal abortion, by hysterotomy in the former and before elective caesarean section in the latter group. The concentrations of free and conjugated oxazepam in maternal and fetal plasma were determined by gas-liquid chromatography. In early pregnancy the mean ratio between the plasma concentration of total (free + conjugated) drug in the umbilical cord and a maternal vein was 0.6, whereas in late pregnancy the ratio vein was 1.1. Both in early and late pregnancy, the free and glucuronide conjugate of oxazepam were found in the fetus at concentrations which indicated transplacental passage of the parent drug and its metabolite. There was great interindividual variation in the plasma levels both of free and conjugated oxazepam.