Current Medicinal Chemistry - Volume 19, Issue 27, 2012

The use of antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), during pregnancy is rapidly increasing. To date, the effects of SSRI on pregnant women and fetuses are controversial and still a matter of debate. Although a number of studies have shown that these antidepressants are not teratogenic, some of them have reported an increase of congenital malformations after antenatal exposure to SSRIs. Moreover, fetal behavior is affected by these drugs, 30% of infants suffer from neonatal withdrawal symptoms and long term sequelae have not yet been excluded. Since there are no clear guidelines for SSRI treatment in pregnancy, potential risks must be balanced against the effects of untreated maternal depression. Treatment with SSRIs before and during pregnancy should only be considered in case of real necessity. Milder forms of depression should be treated with alternative methods. In this paper we have reviewed the literature on effects of SSRIs on embryonic, fetal and infant development.

Thromboembolism is an infrequent, yet serious cause of both maternal and fetal morbidity and death during pregnancy and the puerperium. Antithrombotic treatment and prophylaxis both before and during pregnancy are based on unfractionated heparin (UH), lowmolecularweight heparin (LMWH), Warfarin and Aspirin. The prevalence and severity of thromboembolism during pregnancy and puerperium warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. This paper assesses the safety and efficacy of antithrombotic therapy during pregnancy and the peripartum period. Its cardiovascular and obstetric indications, the evidence of association between thrombophilias and adverse pregnancy outcome, regimens and maternal and fetal side-effects are also discussed.f

The renin-angiotensin system is highly conserved through evolutionary history, and has multiple functions in addition to maintaining cardiovascular homeostasis: these include the regulation of renal cell survival and cell death, and development of the kidney. The importance of angiotensin (ANG) in normal kidney development was first recognized in infants with renal maldevelopment born to mothers treated with angiotensin converting enzyme (ACE) inhibitors or with ANG AT1 receptor blockers. The molecular role of ANG in renal development has been elucidated using gene targeting in mice, revealing major effects in branching morphogenesis, vasculogenesis, development of the papilla and renal concentrating mechanism. Although exposure of the fetus to ANG inhibitors is potentially harmful throughout pregnancy, effects are greater in late compared to early gestation. Significant differences between humans and rodents in placental transfer of ANG and timing of renal development contributed to initial delays in recognizing the teratogenic effects of ANG inhibitors. Although administration of ACE or AT1 receptor inhibitors can slow progression of renal disease in older children, ANG inhibition in the neonatal period can aggravate renal injury due to congenital urinary tract obstruction. Neonates are also far more sensitive than older children to the hypotensive actions these agents and doses must be markedly reduced to avoid precipitating oliguria. Understanding the complex interactions of the maturing renin-angiotensin system in the perinatal period is essential in the use of ANG or renin inhibitors in women during childbearing years or in neonates with cardiovascular or renal disease.

The liver represents the major site of drug metabolism in humans. The developmental changes that occur in the liver's metabolic activity during fetal life and in the perinatal period are at the basis of the varied sensitivity of human newborns to many drugs. The decreased capacity of the fetal and newborn liver to metabolize, detoxify, and excrete drugs - total cytochrome P450 content in the fetal liver being 30% to 60% of adult values - may explain the prolonged actions of many drugs in the newborn, as well as less their potential toxicity. On the other hand, the low levels of phase I (activation) enzymes, producing more polar reactive and often toxic metabolites, could explain the lower incidence of adverse effects of some drugs reported in newborns. Moreover, the greater capacity of newborns to synthesize glutathione is at the basis of their ability in inactivating many toxic metabolites. Here we review the acute and chronic liver toxicity due to the most widely used drugs in the neonate. We will discuss in detail the biochemical profile of the fetal and neonatal liver, and the toxic metabolites formed during the metabolism of the most widely used drugs in the neonate. The histological picture of liver disease related to the therapeutic use of drugs will be discussed, with particular emphasis on the mode of cell death involved in hepatitis induced by different drugs most frequently utilized in the neonatal intensive care units.

For a long time, nephrotoxicity has been definitively defined as renal injury or dysfunction that arises as a direct or indirect result of exposure to drugs and industrial or environmental chemicals. There are a number of inherent difficulties in diagnostic procedures for toxic nephropathy, which include the absence of standard diagnostic criteria and the inability to relate exposure to a given agent and the observed effect. Critically ill newborns represent a high risk population for developing toxic nephropathy because of incomplete maturation of the kidney; furthermore, they are often treated with a combination of various therapeutic agents, each of them potentially inducing renal tissue injury. Antibiotics, antifungals, and non-steroidal antiiflammatory drugs (NSAIDs) can induce nephrotoxic damage by several, concomitant mechanisms of action on different segments of the nephron. The most common clinical feature following a nephrotoxic effect is acute kidney injury (AKI) which, in turn, comprises a spectrum of severe tissue damages along the nephron, leading to an abrupt decline in renal function. Because early stages of toxic nephropathy are characterized by very few specific clinical signs and symptoms, there is the urgent need to investigate new biomarkers for predicting nephrotoxicity and localizing the injury to a specific nephron site, in order to reduce the risk of acute renal injury and/or acute tubular necrosis. The most promising biomarker for the early assessment of kidney injury and damage is neutrophil gelatinase-associated lipocalin (NGAL). NGAL can be easily measured in urine by an automated analytical method, allowing its clinical use in emergency likewise creatinine. Considerable expectations in terms of improvement of the management of newborns developing drug-induced nephropaties derive from the clinical application of metabolomics.

Temperature control, airway management and support of circulation remain the gold-standards for the majority of neonates requiring resuscitation at birth. For the minority of neonates in which the basic steps of resuscitation fail to reverse an adverse situation, drug administration is justifiable. The 2010 International Liaison Committee on Resuscitation (ILCOR) guidelines for newborn resuscitation state: “Drugs are rarely indicated in resuscitation of the newly born infant. Bradycardia in the newborn infant is usually caused by inadequate lung inflation or profound hypoxia, and establishing adequate ventilation is the most important step to correct it. However, if the HR remains less than 60 min-1 despite adequate ventilation and chest compressions, it is reasonable to consider the use of drugs. These are best given via an umbilical venous catheter”. Even though drugs have been used in neonatal resuscitation for long, their doses, order and route of administration have been issues of debate among neonatologists, mainly due to the lack of data in human studies. This review will examine existing evidence behind the medications currently used in neonatal resuscitation.

Invasive candidiasis (IC) in the premature infant population is a common infection that results in substantial morbidity and mortality. For these patients, fluconazole is among the first line therapies to treat and prevent IC, and yet few prospective studies investigating its pharmacokinetics (PK) and safety have been performed in this vulnerable population. We review five phase I studies examining the PK of fluconazole in premature infants, which demonstrate markedly differing kinetics compared to adults. Based on these data, a treatment dose of 12mg/kg/day, with the potential need of a loading dose of 25mg/kg to achieve rapid steady state concentrations, achieves surrogate pharmacodynamic targets. Additionally, fluconazole appears to be safe to use in this population, with only minimal reversible hepatobiliary effects.

The prevention and treatment of pediatric fungal infections are limited by the fact that not all antifungal drugs are approved for the pediatric age and appropriate dosages have not been established for each age group. The management of neonates and infants with invasive fungal infection is becoming more complex with an increasing number of antifungal agents available. Dosing information, is not available for newer antifungals and is limited with older antifungal agents. Insufficient neonatal studies have been performed with newer agents and there are numerous differences between neonates, children and adults with invasive fungal infection. Kinetic parameters such as the half-life [t1/2], clearance [CL], and volume of distribution [Vd] change with development, therefore the kinetics of antifungals need to be studied in order to optimize therapy with these drugs. A reasonable aim of pediatric dosing is to ensure levels of drug exposure which are comparable to those achievable in adults and which approximate those for which antifungal efficacy has been established. Therefore it will be of clinical relevance to ascertain the dosages of antifungals which produce an equivalent magnitude of exposure to that observed in adults. Drug therapy, studies on prescription and dosing should consider differences between neonates, infants and toddlers, children and adolescents in terms of drug disposition: absorption, metabolism and elimination/excretion. Determining the safety and pharmacokinetics of antifungals in neonates addresses an unfulfilled medical need given that data are sparse in neonates; at present, reports of antifungal pharmacokinetics in the treatment of neonatal fungal infections are limited to case series. The aim of this article is to review the pharmacokinetics of old and new antifungal drugs in neonates and young infants in a single article in order to provide a critical analysis of the literature. It will be important to evaluate all newly developed antifungals in neonates and infants to assure their maximum efficacy and safety. More pharmacokinetic data are required to ensure that the dose recommended for the treatment of fungal infections in the neonate achieves evidence based medicine.

Sufficient organ blood flow of healthy newborn babies is maintained by relatively low systemic blood pressure. Premature infants are at an increased risk of systemic hypotension, often but not obviously, resulting in hypoperfusion of the cerebral, renal and intestinal vascular beds. Maintaining a stable blood pressure in preterm babies is of high importance in order to prevent complications such as intraventricular hemorrhage, periventricular leucomalatia, necrotizing enterocolitis or renal failure. The regulation of systemic and local hemodynamics in newborns differs substantially from that of the adults. Developmental changes in catecholamine sensitivity, higher local vasodilator factor activity and structural differences of the immature myocardium should be taken into account when applying vasoactive agents in neonates. The effects of widely used catecholamines such as dopamine, epinephrine or dobutamine can not be directly adapted from adult therapeutics to neonatal care. Their administration should be supported by data on their effects on systemic and cerebral blood flow in addition to blood pressure changes. At the bedside, neonatologists should use new diagnostic tools to differentiate between neonatal hypotension and hypoperfusion, vasoconstriction and myocardial dysfunction in order to choose the appropriate medication. Newer vasoactive agents already used in adult or pediatric cardiovascular therapy such as milrinone, levosimendan or terlipressin need to be carefully evaluated before introducing them to the treatment of neonatal hypotensive states. Welldesigned preclinical and human newborn studies also evaluating their local effects are warranted.

Despite recent advances, Persistent Pulmonary Hypertension of the Newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of selective pulmonary vasodilators as inhaled Nitric Oxide (iNO). However, not all the neonates with PPHN are responsive to this clinical approach. Recent studies have proposed the use of alternative therapies to iNO, when it is not available, or there is no or only a transitory response. Sildenafil, a phosphodiesterase 5 inhibitor, appears as a frequent used therapy in refractory forms of PPHN. The aim of this review is to analyze the current therapeutic strategies in PPHN with special emphasis on iNO.

The purpose of this review is to describe the state of the art of the pharmacological applications in perinatal medicine and highlight how a new emerging discipline, metabolomics, may have a significant impact on understanding complex biological processes associated with the drugs actions. Currently, there is great demand for new information regarding the use of drugs, especially during the perinatal period in order to minimize the occurrence of adverse drug reactions and to maximize the desired therapeutic effect. Metabolomics is a functional genomic tool concerned with the high-throughput identification, quantification and characterization of small molecule metabolites. This new technique has been shown to have a great impact on classifying phenotypes, investigation of physiological status, diagnosing disease, measuring the response to treatment, discovering biomarkers, and identifying perturbed pathways due to disease or treatment. Metabolic profiles appear to be a key factor in predicting the outcome of a pathological condition and the individual's response to a pharmacological treatment. This new systems biology tool may have important potential implication for pharmacological science, in particular drug discovery, development, and prediction of the drug’s effects on the body by explaining the mechanisms by which drug response causes adverse effects.

Blood platelets play a fundamental role in primary haemostasis and wound repair, but are also involved in several thrombotic and bleeding disorders for which the underlying mechanisms are still largely unknown. Elucidating platelet biology would help in finding novel disease biomarkers and drug targets in complex and/or genetically unknown platelet-related disorders. Proteomics, which allows studying thousands of gene products at once, represents an efficient tool to quali-quantitatively analyze and compare the platelet protein patterns of different samples (i.e. control/patient, treated/untreated, drug sensitive/resistant), to investigate post-translation modifications, protein-protein interactions and the underlying molecular pathways. This review gives an overview of the applications of proteomic strategies to study platelet biology and function, as well as to unravel differences in protein expression according to specific platelet conditions (i.e. basic versus activated), compartments (i.e. membrane or granules) and fractions (i.e. phosphoproteins and glycoproteins). The use of innovative powerful proteomic technologies can lead to the identification of proteins whose expression is altered in pathological conditions, allowing the identification of candidate biomarkers for: i) understanding the molecular defects underlying platelet disorders, ii) obtaining novel insights in more complex diseases that involve platelets, iii) unraveling the drug mode of action or identifying the mechanisms of drug resistance and iv) detecting novel therapeutic antiplatelet targets based on fundamental platelet research studies. Several studies on how proteomics proved to be useful in our understanding of platelet function and its diseases are discussed. Eventually, this could result in the discovery of novel drug targets for antiplatelet therapy.

The assessment of percutaneous absorption of molecules is a very important step in the evaluation of any dermal or transdermal drug delivery system. In order to perform percutaneous drug absorption studies, it is essential that the methods are standardized and that the integrity of the skin is monitored and maintained to ensure that the data obtained are valid and relevant. Reproducible data on percutaneous absorption in humans are as well required to predict the systemic risk from dermal exposure to chemicals, such as hazardous substances at the workplace, agrochemicals and cosmetic ingredients. In vitro and animal models provide important tools for screening a series of drug formulations, evaluation of skin permeation enhancing properties and mechanism of action of the carrier systems and estimation of rank of skin transport for a series of drug molecules. In this review, we have summarized in vitro testing of skin absorption using static Franz-type diffusion cells.

Prostate cancer is the second most common cancer worldwide and the sixth cause of cancer-related death in men. When hormone therapy fails to control tumour growth, castration-resistant prostate cancer (CRPC) occurs and chemotherapy drugs must be administered. Since 2004, docetaxel administration is the standard of care in metastatic CRPC, although it presents severe limitations such as acquired resistance and poor prognosis. An analogue (cabazitaxel) was approved by the FDA in 2010 as a second-line chemotherapeutic agent. Novel immuno- and hormonal therapy agents, as well as tumour vaccines, have been recently developed, but new strategies are still needed for effectively handling this type of neoplasia. Platinum compounds, in particular, have been the object of a growing interest, despite the former belief that they should have modest activity against prostate cancer. Compounds such as carboplatin, oxaliplatin or satraplatin, either alone or in combination, have lately shown promising results. In order to overcome the deleterious side-effects usually associated to these metal-based agents, several approaches have been followed with a view to optimise drug delivery and targeting, some of which showed considerable success in CRPC. Platinum drugs may therefore have an important role in the chemotherapeutic management of human metastatic castration-resistant prostate cancer, mostly in second-line strategies. The present review addresses the most relevant studies on platinum-based antineoplastic agents towards CRPC in the last decade – from first- and second-generation complexes to newly developed compounds.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with an increased risk of stroke and systemic embolism. Oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin, has historically been the mainstay of long-term thromboprophylaxis in AF patients. However, although highly effective, VKAs have a number of limitations that make their use difficult and cumbersome in clinical practice. They have a slow onset and offset of action, narrow therapeutic window, marked dose-response variability, and multiple food and drug interactions, and require frequent coagulation monitoring and dose adjustments. To overcome VKA drawbacks, several new oral anticoagulants have been recently developed for use in AF, and three of them, the direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban, have completed phase III trials. New agents have proven to be noninferior or superior to warfarin for AF-related stroke prevention, with similar or better safety profiles. These new drugs, with their predictable anticoagulant effect that allows for fixed dosing with no need for coagulation monitoring, have the potential to greatly simplify anticoagulation therapy for AF. Dabigatran etexilate and rivaroxaban are already approved in the United States and Europe for stroke prevention in nonvalvular AF, and dabigatran etexilate has entered current AF guidelines as an alternative to warfarin. However, some issues with new compounds are still unresolved, such as the lack of antidotes and standardized tests to measure drug activity. Active postmarketing monitoring surveillance of effectiveness and safety is required in the implementation of new anticoagulant therapies.

The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the µ- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was κ/μ= 269 and δ/μ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).

Dendrimers are artificial polymeric macromolecules which are widely considered to be a promising tool for future gene therapy applications. They have been used as efficient delivery vehicles for antisense oligonucleotides targeting the interior of cells. We demonstrate that dendriplexes formed from anti-HIV oligodeoxynucleotides ANTI-TAR, GEM91, and SREV in complex with generation 4 maltose (PPI-Mal G4) and maltotriose (PPI-Mal-III G4) modified poly(propylene imine) dendrimers are able to self-assemble into highly organized 1D and 3D nanostructures. The resulting nanostructures were characterized by fluorescence methods, laser Doppler electrophoresis, dynamic light scattering (DLS), atomic force microscopy (AFM) and molecular modeling. The results show that ANTI-TAR and GEM 91 dendriplexes self-assemble into fibrils with length scales up to several hundreds of nm. SREV, on the contrary, forms quadrilateral- like 3D nanostructures. A good correlation between the various experimental methods and molecular modeling indicates the formation of those nanostructures in solution. Space symmetry of the oligonucleotides and the resulting dendriplex monomeric units are probably the most important factors which influence the way of self-assembling.