Current Pharmaceutical Design - Volume 20, Issue 34, 2014

The manuscripts of this special issue of Current Pharmaceutical Design cover a wide spectrum of relevant and fascinating topics in the area of developmental and reproductive toxicology. Experimental studies have consistently shown that commonly prescribed therapeutic agents can decrease embryonic cardiac output, leading to periods of embryonic hypoxia causing malformations or embryonic death. The article authored by Webster and co-workers [1] describes the available experimental data on the subject and discusses the potential consequences of drug-induced reduction in cardiac output in the human embryo. Alcohol is a well established human teratogen. It has been estimated that the incidence of Fetal Alcohol Syndrome (FAS), which is the most severe manifestation within the fetal alcohol spectrum disorders, is about 1 per 1000 in industrialized countries. In their review, Brennan and Giles [2] pay specific attention on the noxious effects of alcohol exposure on eye development. Insightful discussion on the mechanistic role played by sonic hedgehog pathway disruption is also provided. The potential of foreign compounds to induce ovarian damage, leading to ovarian reserve depletion or cancer, is a topic of increasing global concern. Iorio and co-workers [3] review the noxious effects induced by some widely diffused xenobiotics and by common anticancer therapies on ovary function. Research priorities for the development of preventive measures are also highlighted. Perobelli [4] focuses on male reproductive aspects in prepubertal toxicity assays. The human prepubertal phase has been regarded as a phase of reproductive tract quiescence and reduced vulnerability to toxicants, but emerging data suggest it may represent a susceptible window to endocrine disrupting chemicals. The paper presented by Kanungo et al. [5] summarizes current perspectives on the zebrafish model, which is emerging as a promising alternative animal model for developmental toxicity screening. The elevated potentiality for high-throughput screening is one of the remarkable features offered by this model system. Glucocorticoids play important roles in skeletogenesis. Cheng et al. [6] provide an update on the effects of the synthetic corticosteroid agent dexamethasone on embryo skeletogenesis. The potential impact of glucocorticoids on key regulators of embryo skeletogenesis, including BMPs, FGFs, Hedgehog and Wnt signaling pathways, is also discussed. Histone deacetylases (HDAC) are a family of enzymes playing an important role in the modulation of the transcriptional state of many regions of the genome. Inhibitors of HDAC are promising therapeutic agents in several conditions, including solid and hematological cancers. Updated research information on the teratogenic effects elicited by this class of agents is presented by Giavini and Menegola [7]. Nitric oxide (NO) is multifunctional gaseous molecule, playing crucial roles in the mediation of a wide spectrum of biological processes. The concept that optimal NO levels are essential for normal embryonic development is supported by an increasing number of experimental studies. This topic is reviewed by Tiboni and Ponzano [8].

During the organogenic period of development the cardiovascular system of the embryo fulfills several functions including delivery of oxygen and nutrients and a hemodynamic role necessary for cardiac morphogenesis, angiogenesis and hematopoiesis. It is expected that at each stage of embryonic development there is an ideal embryonic heart rate and contractility that maintains the optimal blood flow and pressure to fulfill these various functions. In vitro rat embryo culture studies have revealed that many therapeutic drugs (antiarrhythmics, antidepressants, antipsychotics and anticonvulsants), that may be taken during human pregnancy, cause a concentrationdependent slowing of the embryonic heart and irregular heart rate at higher concentrations. The concentrations causing bradycardia in vitro are often close to human therapeutic plasma concentrations and raise concern that these drugs can potentially cause embryonic death or malformations, and that current reproductive toxicity testing does not adequately examine possible effects of drugs on the embryo’s cardiac function.

Fetal Alcohol Syndrome (FAS), the most severe manifestation of Fetal Alcohol Spectrum Disorder (FASD) is considered the leading non-hereditary cause of mental retardation and neurological deficit in the Western world. There lie a huge associated human cost to both FASD victims and their families and a considerable financial burden. This problem is being tackled on many fronts including community awareness programs, biomarker development for fetal alcohol exposure, research into preventative treatments and the development of more robust diagnostic systems for the early detection of FASD. Although ethanol can affect many of the major systems of the body, the eye is a primary target. Ocular aberrations including optic nerve hypoplasia, tortuosity of retinal vessels, coloboma and microphthalmia are frequently observed in children diagnosed with FAS. In this regard, ocular involvement in FAS has gained importance, particularly in relation to early diagnosis and identification of FAS. Furthermore, our considerable knowledge of the molecular mechanisms underlying eye development has provided a powerful tool for the investigation of the teratogenic actions of ethanol. In this review, we initially provide an overview of FASD in terms of historical background, epidemiology and current status. Next, we explore the role of ocular involvement in FASD and the use of eye measurements in the diagnosis of FAS. Lastly, we review how current knowledge of early eye development can be used to gain new insights into the molecular mechanisms of ethanol teratogenicity with particular reference to the sonic hedgehog pathway.

Unlike men, who have continuous spermatogenesis throughout most of their lifetime, women are born with a fixed supply of follicles, and this number progressively declines with age until the menopause. Beside age, the speed of follicle depletion can be regulated by genetic, hormonal and environmental influences. In the course of their lives, women are exposed to multiple chemicals and radiation sources that can increase the chance of developing permanent infertility and premature ovarian failure (POF). A wealth of experimental data indicate that iatrogenic (chemotherapy, radiotherapy) and xenobiotic agents (e.g., chemicals, pharmaceuticals) are potent ovotoxicants capable of accelerating ovarian reserve depletion. In the present review we reported the negative effects exerted on mammalian ovary by some widely diffused environmental chemicals, as polycyclic aromatic hydrocarbons (PAHs) and dithiocarbamate mancozeb, and by 1-3 butadiene and 4-vinylcycloexene, two occupational chemicals known to be capable of inducing ovarian cancer and infertility. Furthermore, attention has been devoted to the consequences of chemo- and radiotherapy on the ovary, both known to affect reproductive lifespan. Our increasing understanding of metabolic alterations induced by these agents is fundamental to individuate new therapeutic strategies aimed to prevent ovarian dysfunction in fertile women.

The normal development of the male reproductive system can be divided into five phases: fetal, neonatal, childhood, puberty and adulthood. Childhood/peripuberty has yet been relatively little studied. Chemical insults during the peripubertal phase may result in adverse consequences that may be already visible during puberty as well as during later adult life. This occurs because endocrine disruptors often interfere in the developmental programming. The most important is to note that children are not just little adults and should be particularly investigated. The aim of this review is to discuss the recent literature (2000-2013) on male reproductive aspects in prepubertal toxicity assays, focusing on experimental in vivo studies, establishing a comparative analysis between the design, endpoints, results and consequent conclusion. The studies discussed in the present review were selected based on the period of exposure. Only studies with post-lactational exposures were included. 33 papers were included using rats, mice, rabbits or pigs as experimental model. There is a relative scarcity of studies investigating animals in development and thus an urgent need for further studies in order to evaluate the possible persistent effects on fertility and other reproductive parameters at adulthood. Another point is the lack of studies with chemical mixtures, an imminent problem in modern society. It is vital to consider the refinement of alternative methods and the experimental designs and endpoints to improve the scientific knowledge in this area.

Over the past decade, zebrafish are being increasingly used in assessing the effects of chemical compounds. Especially, the embryos and larvae, due to their microscopically small size and optical transparency, are compatible with multi-well microtiter plates for high throughput screening. Being transparent, they allow for non-invasive visualization of internal organs during early development. The organization of the genome, the genetic pathways controlling signal transduction and the developmental pattern appear to be significantly conserved between zebrafish and humans. Major organ systems including the nervous, cardiovascular, digestive and visual systems of zebrafish are also similar to their mammalian counterparts at the anatomical, physiological and molecular levels. Therefore, zebrafish assays are ideal for evaluating multiple organ toxicities simultaneously that contrast in vitro assays performed on cultured cells or tissue explants and organ slices. Although research on zebrafish as a model system began a few decades ago, later studies on zebrafish developmental biology and developmental genetics resulted in the characterization of a large number of genes involved in vertebrate development and biological pathways thus establishing zebrafish as a relevant human disease model for research. Recently, zebrafish have become an attractive vertebrate model for pharmaceutical and toxicological studies. We have outlined in this review some of the toxicological screens and tools that used zebrafish early life stages, and the efforts made to validate zebrafish assays against mammalian drug screens.

Glucocorticoids are important regulators of cell differentiation and mesenchymal cell lineage commitment during skeletogenesis. In clinical practice, it has been difficult to study the effects of glucocorticoids on target tissues because patients taking glucocorticoids often suffer from adverse skeletal effects. Dexamethasone (Dex) is a long-acting synthetic corticosteroid hormone that ranks amongst the most widely used prescribed drugs, and it is a powerful medication that is increasingly employed during the perinatal and neonatal periods. However, Dex is a potential teratogen. In particular, it has been claimed that Dex exposure during pregnancy can affect osteogenesis in the developing embryo, although this claim remains highly controversial. In this review, we summarize the published data from numerous clinical follow-up, animal-based and in vitro studies on the effects of Dex exposure on embryonic skeletogenesis. These studies indicate that Dex may adversely affect skeletal progenitor cells during development. In addition, Dex can exert a number of effects on bone growth at different developmental stages. We also discuss how glucocorticoids influence the BMP, FGF, Hedgehog and Wnt signaling pathways, which are key regulators of skeletogenesis in the embryo. A fuller understanding of the negative, and perhaps teratogenic, effects of Dex on skeletogenesis will have important implications for the routine use of Dex in clinical practice.

Modification of the terminal tails of histones is considered one of the documented mechanisms for epigenetic control of gene expression. Histone deacetylase inhibitors (HDACi) lead to a state of hyperacetylation of histone, a condition that can affect normal gene transcription. Furthermore, HDACi have many other protein targets involved in regulation of gene expression, cell proliferation and cell death. For these properties some HDACi are nowadays used as anticancer drugs with promising results. Several molecules with HDACi properties (valproic acid, trichostatin A, apicidin, MS-275, sodium butyrate, boric acid, salicylic acid) have been found to induce congenital malformations associated with hyperacetylation of histones in the target organs. Cell death is the major event in the target organs a few hours after embryonic exposure to HDACi. Gene deregulation, oxidative stress, DNA demethylation, and/or retinoic acid imbalance are the modes of action postulated for HDACi-induced teratogenesis.

Nitric oxide (NO), generated by NO synthase (NOS) enzymes, is an important bioactive molecule involved in the regulation of several biological phenomena that are crucial for organogenesis, including gene expression, cell growth, matrix remolding, proliferation, differentiation and apoptosis. The expression of NOS isoforms in embryonic tissues is temporally and spatially regulated, and disruption of endogenous NO can lead to developmental defects. Maternal treatment with pan NOS inhibitors during early organogenesis caused severe malformations of the axial skeleton. In utero exposure during the fetal period induced limb reduction defects of vascular origin. Knock-out mice have been used to define the role of the various NOS isoforms on the origin of the abnormal development. Cardiovascular malformations, limb reduction defects, reduced growth and reduced survival have been observed in knock-out mice with targeted disruption of endothelial NOS (eNOS). Limited morphological changes were observed in mice lacking inducible NOS (iNOS) or neuronal NOS n(NOS). Results obtained with in vitro studies suggest that optimal levels of NO are required for neural tube closure. Disregulation of NO production was also recently proposed as a contributing mechanism in the origin of malformations associated with exposure to known environmental teratogens, such as valproic acid, thalidomide, copper deficiency, and diabetes.

The possibility of achieving organ protection by the perioperative administration of different drugs opens up a new field of research in preoperative medicine, anesthesia, and critical care surgery. In this study we review the current situation in perioperative management of various diseases and assess the benefits of different drugs for organ preservation, in order to evaluate the current evidence on the organ protection offered by different pharmacological groups [1]. The intraoperative administration of halogenated anesthetic drugs is a controversial issue. Previous studies have not conclusively demonstrated the clinical benefit of these agents on the target organ. Here we assess their effect in a variety of situations, including systemic inflammatory response syndrome, which is particularly frequent in the postoperative period [1,2]. Ketamine has been constantly reviewed because through its activity on NMDA-receptors, might be related to a neuroprotective effect on the brain areas. where neurological damage usually happens. We explore the experience with this drug in order to determine the current state of the art and to assess the indication of different hypnotic drugs in these situations [3]. In certain specialties such as cardiac surgery, preoperative optimization of patients is becoming increasingly important. For this purpose, a variety of drugs are administered. The preoperative use of calcium channel sensitizers to provide cardiac protection is a particularly novel development. Several studies are currently underway to assess its value, and their results may lead to changes in clinical practice in our patients [4].Since kidney acute failure represents a cause of high morbidity and mortality during cardiac surgery, the possibility of their protection in this context has been also an objective of this review through a detailed study of the current evidence of perioperative therapeutic measures applied in this situation [1,5]. The cardiac protective properties of halogenated agents (desflurane, isoflurane and sevoflurane) when they are compared with intravenous hypnotic drugs; have not been confirmed in non-cardiac surgery and mixed results exist for patients admitted in postoperative intensive care units; Dr. Landoni, explains the evidence in this issue [6]. Finally, we review the intraoperative use of opioids and the evidence of their superiority over other techniques for reducing nociception, and our results shed new light on the current situation. The electrophysiologic effects of opioids should be taken in consideration for the choice of anesthetic agents [7].

Tissue injury secondary to surgical lesion produces profound changes in endocrine-metabolic function and defence mechanisms in the patient (inflammatory, immunological), leading to an increase in catabolism, immunosuppression and postoperative morbidity. The best anaesthetic and surgical technique should be capable of modulating this response, especially in major surgery, where it can be most harmful and increase patient morbidity. Many of the changes that maintain homeostasis are controlled by the hypothalamicpituitary- adrenal axis. The autonomic-adrenal response is usually immediate, compared to the hypothalamus-pituitary gland, which is slower and longer lasting. Cytokine synthesis and release are the earliest stages in the response to tissue lesion. The most frequently studied cytokines in surgical stress response are IL-6 and TNF-α. Inflammatory mediator concentrations are direct indicators of perioperative stress, while haemodynamic changes are considered the indirect indicators of this response. Multiple anaesthetic techniques have been described to modify the stress response in patients undergoing elective surgery. The aim of this review is to present clinical evidence on perioperative stress modulation with different anesthetics. We also describe a different point of view in immunomodulation with the intraoperative management of haemodynamic responses with inhalational bolus of sevoflurane or with remifentanil intravenous bolus. The effects of sevoflurane used as an inhalational bolus to counteract patients’ intraoperative haemodynamic responses modulates the immune response the same than opioid remifentanil.

Perioperative cerebral damage can result in various clinical sequela ranging from minor neurocognitive deficits to catastrophic neurological morbidity with permanent impairment and death. The goal of neuroprotective treatments is to reduce the clinical effects of cerebral damage through two major mechanisms: increased tolerance of neurological tissue to ischemia and changes in intra-cellular responses to energy supply deprivation. In this review, we present the clinical evidence of intravenous anesthetics on perioperative neuroprotection, and we also provide a critical perspective for future studies. The neuroprotective efficacy of the intravenous anesthetics thiopental, propofol and etomidate is unproven. Lidocaine may be neuroprotective in non-diabetic patients who have undergoing cardiac surgery with cardiopulmonary bypass (CBP) or with a 48-hour infusion, but conclusive data are lacking. There are several limitations of clinical studies that evaluate postoperative cognitive dysfunction (POCD), including difficulties in identifying patients at high-risk and a lack of consensus for defining the “gold-standard” neuropsychological testing. Although a battery of neurocognitive tests remains the primary method for diagnosing POCD, recent evidence suggests a role for novel biomarkers and neuroimaging to preemptively identify patients more susceptible to cognitive decline in the perioperative period. Current evidence, while inconclusive, suggest that intravenous anesthetics may be both neuroprotective and neurotoxic in the perioperative period. A critical analysis on data recorded from randomized control trials (RCTs) is essential in identifying patients who may benefit or be harmed by a particular anesthetic. RCTs will also contribute to defining methodologies for future studies on the neuroprotective effects of intravenous anesthetics.

Preoperative use of levosimendan in cardiac surgery patients is one of the most attractive therapeutic alternatives in subjects with left or right ventricular dysfunction. Our review explores the pharmacological bases and clinical evidence for the use of levosimendan, with the intention of making a series of recommendations regarding its use in preoperative optimization prior to cardiac surgery. We carried out a survey of 102 Spanish anesthesiologists in order to shed light on the grey areas regarding the use of this drug prior to surgery. Our findings suggest that levosimendan is recommended for patients with severe left or right ventricular dysfunction, moderate left ventricular dysfunction in which Intra-aortic Balloon Counterpulsation (IABC) is necessary and severe pulmonary hypertension. Administration of levosimendan prior to surgical cardiac intervention without an initial bolus reduces the likelihood of complications.

Context: Post cardiac surgery acute kidney injury (AKI) is common, poorly understood and associated with a significant increase in morbidity and mortality. Objectives: An overview of systematic reviews that have evaluated pharmacological agents for the prevention of AKI post cardiac surgery. Data Sources: We searched electronic databases (PubMed and the Cochrane Database of Systematic Reviews) from inception to January 2014. Study Selection: Systematic reviews of randomized controlled trials that have evaluated pharmacological agents for the prevention of AKI in adult patients undergoing cardiac surgery. Data Analysis: Numbers needed to treat (NNT) or harm (NNH) were calculated from pooled events given in each meta-analysis. Primary outcome measures were defined as (i) mortality, (ii) need for renal replacement therapy (RRT), and (iii) acute kidney injury. Results: Data from 7 systematic reviews evaluating 6 different pharmacological renoprotective agents were included. Dopamine, fenoldopam and N-acetylcysteine did not demonstrate any benefit in terms of mortality, need for RRT or incidence of AKI. Atrial natriuretic peptide reduced the need for RRT (NNT = 22 (95% CI: 13 to 73) and brain natriuretic peptide reduced the incidence of AKI (NNT = 11 (95% CI: 6 to 32), although both agents did not demonstrate any effect on mortality. Loop diuretics demonstrated increased incidence of AKI (NNH = 8 (95% CI: 5 to 15). Conclusion: There is a paucity of effective renoprotective agents that can be used in adult cardiac surgical patients. There is an urgent need to develop novel renoprotective strategies.

Remifentanil is a selective mu-opioid receptor agonist characterized by a rapid onset and ultrashort predictable duration of action providing intense analgesia without prolonged respiratory depression. Remifentanil has been implicated in the causation of intraoperative bradyarrhythmias and asystole both in adults and in pediatric patients. Electrophysiological studies in humans and animals show that remifentanil provokes a dose-dependent depressor effect on sinus and AV node function, manifested by a significant prolongation of sinus node recovery time, sino-atrial conduction time and Wenckebach cycle length. These electrophysiologic effects of remifentanil suggest that it should be used with attention in vulnerable patients with predisposition to bradiarritmias during anesthesia.

There is initial evidence, at least in cardiac surgery, that total intra-venous anesthesia (usually a propofol-based total intravenous anesthesia) is associated with an increased mortality when compared to an anesthetic plan including a halogenated anesthetics. The cardiac protective properties of halogenated agents (desflurane, isoflurane and sevoflurane) have not been confirmed in non-cardiac surgery and mixed results exist for patients admitted in postoperative intensive care units. This article summarizes the papers with the most impressive findings in favor of halogenated anesthetics, but it recognizes that, at the same time, there is no evidence based medicine against the use of propofol, highlighting the need for large randomized trials that should focus on survival.