Current Pharmaceutical Biotechnology - Volume 12, Issue 5, 2011

This special international issue of ‘Current Pharmaceutical Biotechnology’, entitled “Drugs and pregnancy”, contains review articles on subjects concerning various molecular and pharmacological aspects of current obstetrics. In utero the fetus is exposed to a wide variety of foreign chemicals, which can enter via the transplacental transport. This exposure is commonly due to maternal medications, lifestyle factors, and environmental sources. As Holcberg and his co-writers note, it has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. The authors focus on the main placental transporters, i.e. P-glycoprotein, breast cancer resistance protein, multidrug resistance associated protein transporters, organic anion transporters, organic anion transporting polypeptides, monoamine transporters, and organic cation transporters. Detailed understanding of the molecular mechanisms employed in the transplacental transfer of the drug and of the various polymorphisms of drug transporters across the placental barrier is essential for the optimization of pharmacotherapy during pregnancy, and for controlling fetal drug exposure. Stejskalova and Pavek summarize the recent findings related to the function of the cytochrome P450 1A1 enzyme (CYP1A1) and aryl hydrocarbon receptor (AhR) in the human placenta during pregnancy. CYP1A1, an enzyme of the cytochrome P450 superfamily, is the most important xenobiotic-metabolizing enzyme of the placenta, the expression of which is transcriptionally up-regulated through the ligand-activated AhR. CYP1A1 metabolizes several drugs and compounds widely used in pharmacotherapy or which are present in diets. At the same time, this enzyme plays a key role in the bioactivation of procarcinogens and proteratogens, such as arylamines and polycyclic aromatic hydrocarbons, which bind to placental and fetal DNA as DNA-adducts. The authors stress the fact that elevated CYP1A1 activity through activated AhR in the placentas of women smokers has been associated with pregnancy complications, such as premature birth, intrauterine growth retardation, structural abnormalities, fetal death or placenta abruption. During the past decade there has been an explosion in the number of nanoparticulate drugs or drug delivery systems being explored, developed and marketed for the treatment and prevention of human diseases. Nanoparticulate delivery systems offer a potential avenue for delivering therapeutics to maternal tissues with minimal risk of incidental fetal exposure, depending on the ability of the nanoparticle in question to cross the placenta. The limited studies on this topic show considerable uncertainty regarding the transplacental passage of nanoparticles, and the understanding of the criteria that determine transferability is poor. Keelan and his research group examine the evidence relating to the potential toxicity of nanoparticles in pregnancy, the ability of the placenta to take up and transfer nanoparticles to the fetus, and the theoretical benefits and risks of the administration of nanoparticle-based therapeutics in pregnancy. Poniedzialek-Czajkowska et al. present the theoretical background and significance of nitric oxide (NO) in normal and preeclamptic pregnancy, as well as considering how NO donors could be useful in clinical practice. Many studies have been devoted to establishing the role of this key molecule in perinatal medicine, and the different findings have promoted the clinical use of NO donors as new pharmacological tools. It has been shown to participate in the extravillous trophoblast invasion of the decidua and myometrium, in the regulation of the vascular reactivity of utero-placental and fetal-placental circulations, in the prevention of platelet and neutrophil aggregation and adhesion in the intervillous space, and in trophoblast apoptosis. Due to a variety of common medical conditions in women of reproductive age (i.e. allergy, asthma, collagen vascular diseases, inflammatory bowel disease) glucocorticoids (GSs) are used. Furthermore, approximately 7% 322x22x of pregnant women in Europe and North America are treated with synthetic GSs to promote lung maturation in fetuses at risk of preterm delivery. The metabolism of GSs during pregnancy, and their changes in the placenta which affect fetal development, are analyzed by Marciniak et al. The theme of prevention and the management of allergic asthma and anaphylactic reactions during pregnancy is considered by Markert and his international research group. The pharmacokinetic characteristics and the US Food and Drug Administration (FDA) classification of conventional anti-allergic drugs, and the immunological implications of immunotherapy, are summarized. The authors conclude that anti-inflammatory and pro-resolving mediators, including lipoxins, resolvins and protectins, as well as nutritional factors, such as omega-3 long-chain polyunsaturated fatty acid, may have the potential to prevent allergies in newborns....

It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. In recent years, research on human placental transporters has been developing due to the increase of knowledge technology in pharmacology. In this review we will focus on the main placental transporters which are known today. The P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP/ABCG2) and Multidrug resistance associated protein 2 (MDR2) transporters are expressed at the apical surface of the syncytiotrophoblast, and have a protective effect. Transporters for 5-HT (SERT) and NE (NET) are also expressed at the apical surface and regulate extracellular concentrations of monoamines. The physiologic function of Multidrug resistance associated protein (MRP) transporters (which is expressed at the basal surface of the syncytiotrophoblast) may be the removal of metabolic end products from the fetus. Some of the members of the organic anion transporters are also expressed at the basolateral surface of the syncytiotrophoblast.

CYP1A1, an enzyme of the cytochrome P450 superfamily, is the most important xenobiotic-metabolizing enzyme of the placenta for which relevant inducible activity has been demonstrated throughout pregnancy. CYP1A1 metabolizes several drugs and compounds widely used in pharmacotherapy or present in diets. At the same time, this enzyme plays a key role in the bioactivation of procarcinogens and proteratogens, such as arylamines and polycyclic aromatic hydrocarbons (PAHs), which bind to placental and foetal DNA as DNA-adducts. The expression of CYP1A1 is transcriptionally up-regulated through the ligand-activated aryl hydrocarbon receptor (AhR). AhR plays an important role as mediator of an adaptive response to xenobiotics, as well as in normal physiology and embryonic development. Several exogenous AhR ligands, such as PAHs, polychlorinated biphenyls and halogenated dioxins, can be found in the constituents of numerous commercial products, including insulators and flame retardants, or as products of combustion processes, including chimney soot, charbroiled foods and cigarette smoke, or as the product of waste incineration. Exposure to these compounds subsequently affects cellular growth and differentiation, homeostasis, level of growth factors, reproduction function and hormonal regulation. Importantly, elevated CYP1A1 activity through activated AhR in placentas of women smokers has been associated with pregnancy complications, such as premature birth, intrauterine growth retardation (IUGR), structural abnormalities, foetal death or placental abruption, risk of low birth weight, low birth length and low head circumference. We summarize the recent findings related to toxicological consequences of AhR activation and CYP1A1 induction in the human placenta during pregnancy.

During the past decade there has been an explosion in the number of nanoparticulate drugs or drug delivery systems being explored, developed and marketed for the treatment and prevention of human diseases. While the potential dangers of drug administration in pregnancy are well known, there are circumstances where the benefits of maternal drug administration are perceived to outweigh the risks to the fetus. Hence, the administration of potentially harmful drugs in pregnancy is surprisingly common. Nanoparticulate delivery systems offer a potential avenue for delivering therapeutics to maternal tissues with minimal risk of incidental fetal exposure, depending on the ability of the nanoparticle in question to cross the placenta. As the conduit to the fetus, the placenta is both a drug target and a drug barrier, as well as a potential target of any toxicity. Limited studies on this topic show considerable uncertainty regarding the transplacental passage of nanoparticles, and our understanding of the criteria that determine transferability is poor. Despite the fact that the toxicity caused by environmental and man-made nanoparticulates has been widely studied in various organ systems, data on the effects of maternal nanoparticle exposure on human fetal tissues are lacking, although studies in rodents indicate that caution is justified. In this review, we examine the evidence relating to the potential toxicity of nanoparticles in pregnancy, the ability of the placenta to take up and transfer nanoparticles to the fetus, and the theoretical benefits and risks of administration of nanoparticle-based therapeutics in pregnancy.

Nitric oxide (NO) is a key molecule involved in a variety of biological functions throughout the whole body. Many studies have been devoted to establish the role of NO in perinatal medicine and the different findings have promoted the clinical use of NO donors as new pharmacological tools. NO regulates the vascular tone and blood flow by activating soluble guanylate cyclase in the vascular smooth muscles. NO is essential for leukocyte adhesion and platelet aggregation, and it controls mitochondrial oxygen consumption. Abnormalities in vascular NO production and transport result in endothelial dysfunction with various cardiovascular disorders such as hypertension, atherosclerosis and angiogenesis- associated disorders. The NO system has important roles in mammalian reproductive physiology, especially in the utero-placental system. It has been shown to participate in the extravillous trophoblast invasion of decidua and myometrium, in regulation of vascular reactivity of utero-placental and fetal-placental circulations, in prevention of platelet and neutrophil aggregation and adhesion in the intervillous space, and in trophoblast apoptosis. The aim of this review is to present the theoretical background and significance of NO in normal and preeclamptic pregnancy as well as to consider how NO donors could be useful in clinical practice.

The fetus may be exposed to increased endogenous or synthetic glucocorticoid (GS) exposure in late gestation. Approximately 7% of pregnant women in Europe and North America are treated with synthetic GSs to promote lung maturation in fetuses at risk of preterm delivery. Maternal steroid treatment before preterm delivery is one of the best documented and most cost effective life saving treatments in prenatal medicine but, in certain circumstances, the price of accelerated lung maturity may be loss of brain cells, increased neurodevelopmental disability, intra-uterine growth restriction (IUGR), and an increased risk of preterm delivery, of programming of post-natal hypertension, and of increased postnatal activity in the hypothalamo-pituitary-adrenal (HPA) axis. Placental 11β-hydroxysteroid dehydrogenase type 2 (11β- HSD2) is the key enzyme which protects the fetus from overexposure to GSs by their oxidation into inactive derivates. We review the evidence for the metabolism of GSs during pregnancy and how endogenous and synthetic GSs cause other changes in the placenta which affect fetal development.

Different conventional anti-asthmatic and anti-allergic drugs are commonly used in pregnancy, including inhaled corticosteroids, long- and short-acting β-agonists, leukotriene modifiers, cromolyn, and theophylline. Alternatively, immunotherapy with allergens before and during pregnancy is accepted as a causal treatment of allergies, but the allergy specifity and severity in combination with a variety of application protocols and procedures cause wide heterogenity of this treatment principle. Furthermore, the pharmacokinetic characteristics and the US Food and Drug Administration (FDA) classification of conventional anti-allergic drugs and immunological implications of immunotherapy are summarized in this review, and insights on fetal programming of allergies are introduced. We propose a potential perspective of treatment with anti-inflammatory and pro-resolving mediators, such as lipoxins, resolvins and protectins; these are lipid mediators physiologically generated during the immune response from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. This proposal fits with the recently appreciated approaches to allergy prevention for the newborn child by a balanced maternal nutrition and omega-3 long-chain polyunsaturated fatty acid consumption.

The aim of the present article was to review the role of the placenta function in the transfer of immunosuppressants and monoclonal antibodies used for the treatment of inflammatory bowel disease, as well as the available data regarding the safety of these therapies during pregnancy. Methotrexate can cause congenital abnormalities and is contraindicated during pregnancy. Available data suggest that thiopurines are safe and well tolerated during pregnancy. Treatment with cyclosporine for steroid refratory ulcerative colitis during pregnancy can be considered effective and safe. Biological therapies appear to be safe during pregnancy, as no increased risk of malformations has been demonstrated. Transplacental exchanges are known to involve passive transfer, active transport and facilitated diffusion. Thiopurines are transported by passive transfer. The transport across the placenta of corticosteroids, methotrexate and cyclosporine is modulated by protein “pumps”. Infliximab and adalimumab bind the FcRn-receptor as other IgG proteins do. The mechanisms of the diffusion of certolizumab across the placenta barrier remain unknown.

Thyroid disorders are quite a common health problem in pregnant women, thus adequate treatment in this period is very important in order to decrease maternal and fetal morbidity. The prevalence of hyperthyroidism is estimated to be present in approximately 0.2-0.4% of all pregnancies and the most common is Graves disease. Untreated hyperthyroidism is connected with disturbed fertilisation, recurrent miscarriages, preeclampsia development, hypotrophy of the fetus, and haemorrhage in the postpartum period. Hypothyroidism is found in pregnant women in 0.3-0.7% of all cases. Uncontrolled hypothyroidism in pregnancy can lead to preterm birth, low birth weight and mental retardation. The goal of the treatment of both hypo- and hyperthyroidism is to reach a stable euthyroid state by applying thyroid hormones or antithyroid drugs, respectively. It seems that well-controlled management of thyroid diseases does not pose any problem for pregnancy. However, the most important is to avoid any neurological abnormalities in the fetus in hyperthyroid women resulting from antithyroid drugs exposure. Moreover, it is also crucial to abstain from subclinical hypothyroidism and hypothyroxinaemia in the mother and its effect on the fetus's development which merits exact screening and intense monitoring. In this paper we described the complex pharmacology of the drugs that are used in pregnant women suffering from thyroid disorders, considering the clinical application, practical recommendation, and side effects in pregnancy and lactation. This systematic analysis could contribute some pharmacological knowledge which will be helpful in the clinical management of thyroid disorders during pregnancy.

Epilepsy represents the most common maternal neurological disorder requiring continuous treatment during pregnancy. Maintaining optimum seizure control is an important objective in pregnancy, and the majority of women with epilepsy will need to continue antiepileptic drugs (AEDs). AEDs are frequently used to treat several other conditions, such as headaches and mood disorders. They have been associated with an increased risk of congenital malformations, minor anomalies, congenital syndrome and development disorders. This risk seems to be higher among women using polypharmacy and valproic acid. Neural tube defects are associated with valproic acid and carbamazepine exposure. New AEDs seem to have a less teratogenic effect, but human experience is still limited. The purpose of this review is to provide an update on AED exposure in pregnancy, focusing on pharmacokinetics and transplacental transport.

The recent H1N1 influenza pandemic has highlighted the potential for viral infections to cause severe disease in mothers disproportionate to the general population and have deleterious effects on the fetus. Vaccines have been used in pregnant women for over 200 years. Current guidelines recommend vaccination with only inactivated virus due to potential risk to mother and fetus with live vaccine. The exception is during times of pandemic or biological weapons attack, when the risk of life-threatening disease outweighs the risk of vaccination. A paucity of data is available regarding actual risk and mechanisms of live viral vaccine transfer from mother to fetus. Pregnancy-induced changes to the maternal immune system, effects of maternal infection on neonatal immunity, and the role of the placenta in transmission of infection and passive immunity to the fetus are incompletely understood. The aim of this paper is to review available data pertaining to newer vaccines such as the pandemic H1N1 and HPV vaccines in pregnancy, the role of Fc receptors in active transport of immunoglobulin across the placenta, and cytokine activity during maternal infection and after vaccination. We will also discuss potential areas for future research.

Over the past decade therapeutic interventions during pregnancy, including the use of drugs, has increased; for example, the prescription use of opioids and nonopioid analgesics for pain management during pregnancy has increased by about 40%. Additionally, women also self-medicate during pregnancy with opioids, and are treated with methadone and buprenorphine which are used as substitution therapy for substance dependence during pregnancy. A nationally representative survey noted that ∼74% of women of reproductive age reported substance use during the previous year, decreasing to ∼ 63% amongst those who were pregnant. Substance dependence was reported by ∼ 20% of women who were not pregnant, and ∼ 15% of those who were pregnant. Understanding the consequences of opioid treatment or dependence during pregnancy requires an investigation of the placental disposition (metabolism and transfer), as well as of the impact of the drugs on the placental function. This review summarizes the research on the placental disposition of opioids and their impact on the placental function.

Assessing drug transport across the human placental barrier is of vital importance in order to guarantee drug safety during pregnancy. However, due to ethical reasons, in vivo fetal development risk assessment studies related to maternal drugs and chemicals exposure remain extremely limited. To overcome any ethical issues, several in vitro models applying primary trophoblastic cells, immortal cell lines and tissue explants of placental origin have recently been advanced. Alternatively, ex vivo human placental perfusion seems to be a more representative and highly informative method, which offers better insights into the different drug transporters, xenobiotic metabolism and tissue binding. Recently, in silico techniques have further been advanced as complementary tools to validate experimental placental transfer data, offering an attractive alternative for high throughput screening of potential fetotoxicity at the early stages of drug design. The present review scrutinizes, from a critical point of view, the current trends and perspectives in the emerging topic of drug transport across the human placental barrier. The special characteristics of the recently developed biopharmaceuticals on the transplacental transfer process are also discussed.

Objective: The purpose of this study was to characterize the human term placental villous tissue explant culture model as a tool to study the formation and efflux of 1-chloro-2,4-dinitrobenzene (CDNB) conjugate 2,4-dinitrophenyl-Sglutathione (DNP-SG) as a model system for phase II metabolism and ATP-binding cassette (ABC) transporter-mediated cellular efflux. Methods: Placental tissue samples were obtained after cesarean section following normal pregnancies (n=9). Cultured villous tissue was monitored up to 48 h to study the effect of time in culture on biochemical parameters, formation and efflux of DNP-SG in the absence or presence of ATPase inhibitor sodium orthovanadate and the protein expression of ABC transporters - multidrug resistance associated protein 2 (MRP2), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and enzyme glutathione-S-transferase isoform P1-1 (GSTP1-1). Results: Villous tissue structure, tissue viability and expression of BCRP, GSTP1-1 remained unchanged, while expression of MRP2, P-gp and total tissue glutathione decreased with time in culture. Tissue integrity was unchanged up to 24 h but declined at 48 h. However, DNP-SG formation, DNP-SG efflux, and the extent of inhibition of DNP-SG efflux by sodium orthovanadate showed only minor changes through 48 h. Sodium orthovanadate decreased DNP-SG efflux, consistent with inhibition of apical ABC transporters. Conclusion: The results support the use of the cultured human term placental villous tissue explants model to study the coordinated function of GSTP1-1 and apical ABC transporters in the formation and efflux of the model substrate DNP-SG.

We present a new approach to distinguish between non-ergodic and ergodic behavior. Performing ensemble averaging in a subpopulation of individual molecules leads to a mean value that can be similar to the mean value obtained in an ergodic system. The averaging is carried out by minimizing the variation between the sum of the temporal averaged mean square deviation of the simulated data with respect to the logarithmic scaling behavior of the subpopulation. For this reason, we first introduce a kind of Continuous Time Random Walks (CTRW), which we call Limited Continuous Time Random Walks (LCTRW) on fractal support. The random waiting time distributions are sampled at points which fulfill the condition N < 1, where N is the Poisson probability of finding a single molecule in the femtoliter-sized observation volume ΔV at the single-molecule level. Given a subpopulation of different single molecules of the same kind, the ratio T/ Tm between the measurement time T and the meaningful time Tm, which is the time for observing just one and the same single molecule, is the experimentally accessible quantity that allows to compare different molecule numbers in the subpopulation. In addition, the mean square displacement traveled by the molecule during the time t is determined by an upper limit of the geometric dimension of the living cell or its nucleus.

MMP-9 enzyme recognizes a peptide sequence Lys-Gly-Pro-Arg-Ser-Leu-Ser-Gly-Lys and cleaves the peptide into two parts. We synthesized a dual fluorophore beacon consisting of 5-FAM and Cy5 dyes. The fluorescence emission of the fluorescein moiety is dramatically quenched by Cy5 molecule due to Förster Resonance Energy Transfer (FRET) and the fluorescence of Cy5 is strongly enhanced. Upon addition of MMP-9 enzyme, the fluorescence of 5-FAM intensifies and Cy5 decreases. The control MMP-2 enzyme does not cause any changes in either 5-FAM or Cy5 fluorescence. We believe that our observation will help in early detection of elevated MMP-9 levels under disease conditions.

Three blending methods were introduced to combine a biodegradable cationic- polyurethane (PUg3) and polyethylenimine (PEI) together with DNA by different mixing sequences. Results of gel electrophoresis assays and particle size measurements show that complexes prepared by method 1 and 3 bear an ability to condense DNA into small nanoparticles. On the contrary, the use of method 2 in making complexes produces significantly large particles because of the weaker interaction with DNA and lack of DNA condensation. Moreover, cell proliferation assays show that no cytotoxicity of the DNA/blended-polymers complexes (exhibited by method 1) was found and due to a result of the outer coating of PUg3, reducing cytotoxic PEI exposure outside the complexes. With a new technique in pharmaceutics, the complexes prepared for DNA delivery by mixing of PEI and PUg3 with DNA in a sequence (method 1) could achieve an even better transfection efficiency (reaching 40% higher) than using PEI alone as well as reduce the cytotoxicity substantially. In conclusion, a new class of complexes (non-viral combo-system) made by a skillful blending sequence (method 1) has been designed and demonstrated to obtain the beneficial properties from two useful and individual polymers for gene delivery. This method can be used in greatly improving the transfection efficiency of polymer-based gene vectors. The blended polymers with DNA also have a better biocompatibility and no cytotoxicity, which are the requirements and critical points for great success in performing gene therapy in vivo.

Due to the high affinity of metallothioneins (MTs) toward various transition metal ions, MTs play an important role in regulation of essential metals, detoxification of heavy metals, and scavenging of free radicals. In this review, we focus on the recent development on the metal release from and sequestration by MTs characterized by electrochemistry and surface plasmon resonance (SPR). The investigation of metal release and coordination processes is of great significance in illustrating the intriguing role of MTs in environmental toxicology.