Current Medicinal Chemistry (v.21, #27)

In adult patients, cardiovascular drugs are widely administered in the treatment of numerous diseases. The indications anddoses are strictly codified by international Guidelines, which are periodically updated by the American and European Societiesof Cardiology. In paediatric patients, however, the situation is substantially different. The lack of large interventional studies onthe use of these compounds has led to a greater uncertainty, with a less extensive administration and more limited indications.Furthermore, some important differences in therapeutic approach for the same diseases are present between the U.S. andEurope. The purpose of this Special Issue is to review the pharmacological treatment of certain heart diseases, such as heartfailure, and arterial blood pressure, which can result in both adult and pediatric patients [1, 2]. Differences and similarities havebeen highlighted. Regarding the differences in medical treatment for the same disease in the U.S. and Europe, it has been emphasizedthat the regulation of drugs is largely determined not only by scientific considerations, but also by other concerns -legal, cultural - which vary in different parts of the world. Such discrepancies are found even in the informational documentsprovided by pharmaceutical companies (different in USA and Europe for the same drug) and drug agencies (different betweenFDA and equivalent agencies in Europe).In this issue of Current Medicinal Chemistry, a specific paper is dedicated to the pharmacological treatment of the patencyof ductus arteriosus in neonates, which is still a controversial issue. In fact, notwithstanding ibuprofen appears to be lesser dangerousfor newborns than indomethacin, with a similar efficacy in closing the ductus; in a number of countries the latter is stilladministered to all preterm subjects as a prophylactic tool [3].An unusual case report is the interesting starting point to perform an extensive literature review about the new indications ofbeta blockers [4]. In this respect, beta blockers, most specifically propranolol, have serendipitously been shown to induce involutionof infantile hemangiomas. Mechanisms of action, target doses, formulation, contraindications and cardiovascular monitoringfor beta blockers have been analyzed as well.It has recently been demonstrated that preterm birth is negatively associated with an early onset of cardiovascular diseases.Cardiovascular mortality is higher among former preterm adults than those born at term. This condition is referred to as cardiovascularperinatal programming.Metabolomics, a new and promising technique which allows the systematic study of the complete set of metabolites in abiological sample, has been recently applied to the identification of a possible future cardiovascular system involvement in subjectsborn preterm.Based on these premises, the purpose of the last review was to analyse the relationship between impaired growth during intrauterinelife and adult cardiovascular disease risk and death [5].

Heart Failure Pharmacotherapy: Differences Between Adult and Paediatric Patients by M. Bajcetic, T. Vidonja Uzelac, I. Jovanovic (3108-3120).
During the last decades, the introduction of new, more efficient drugs, has significantly improved the heart failure(HF) therapy of adults. Therapeutic focus has shifted from simple hemodynamic manipulation to include neurohumoralmodulation as a consequence of the better understanding of mechanisms of HF formation, in particular at the cellularlevel. The aetiologies of HF in children are remarkably different and more varied than in the adult population. Cardiacfailure is usually caused by congenital heart disease and cardiomyopathy in children, whereas in adults, coronary arterydisease, hypertension and myocardial infarction are the most common causes. Despite this fact, pharmacotherapy of childrenis based on the same drugs, usually extrapolated from adult HF regimens. A recently published study in childrentreated with the drugs known to be efficient in adult HF therapy, provides encouragement that the outcomes might besimilarly beneficial. On the other hand, some reports outline that children with HF, especially patients with systemic rightventricles or single ventricle physiology, require specific drug guidelines. A general characteristic of HF pharmacotherapyin children is the lack of paediatrically designed drugs. Drugs currently used in the treatment of HF in paediatric patientsare designed for adults, and their efficacy, safety and quality have generally not been confirmed by clinical studies ofchildren. Aside from this, availability of commercial paediatric drug formulations labelled for treatment of HF in childrensignificantly influences the quality and efficacy of therapy.

Antihypertensive Therapy in Children: Differences in Medical Approach Between the United States and Europe by P.P. Bassareo, V. Bassareo, N. Iacovidou, G. Mercuro (3121-3131).
Similarly to a series of chronic diseases, essential arterial hypertension (HTN) may be manifested during childhoodas a blood pressure (BP) reading which repeatedly rises above the 95th percentile of population-specific standards.Since BP tends to track along the same percentiles throughout life, children with higher BPs are more likely to becomehypertensive adults. When healthy measures aimed at reducing BP (i.e. body weight reduction, aerobic physical exercise,low sodium intake) have failed, pharmacological treatment is usually required. This paper aims to undertake a review ofantihypertensive pharmacological therapy in children, examining the drugs used in chronic treatment as well as those administeredto treat hypertensive crisis (i.e. a BP major than 99th percentile of paediatric normograms). Moreover, severalimportant differences registered in the therapeutic approach to paediatric HTN between US and European Guidelines willbe underlined.

The primary objective of this review is to verify if there are differences in the diagnostic and therapeutic strategiesin cases of PDA employed in different NICUs that might help explain the different percentages of duct closure, surgicalligation and outcome in these vulnerable patients. The secondary objective is to document if the selection of a specificNSAID and/or the way of administration are based on factors such as costs and local availability of drugs, as well as influencedby clinical and haemodynamic parameters, potential risks, local experience and the existing literature. DataSources were MEDLINE, EMBASE, Cochrane Library and analysis of the most important papers were performed. Weexamined a total of 89 trials including 15,657 neonates (with gestational ages between 22 and 35 weeks and study weightsbetween 380 and 2500 g), due to the lack of homogeneity of case studies it was not possible to standardize for gestationalage and weight. To simplify, the studies we considered were subdivided into 5 groups corresponding to 5 tables: 1-INDO-prophylaxis (15 trials); 2- IBU-prophylaxis (11 trials); 3- INDO-therapy (18 trials); 4- IBU-therapy (16 trials); 5-IBU vs INDO therapy (29 trials). Each table reports the journal, the reference, the type of study, the number of neonatesenrolled, the drugs used, management after failure of the first cycle, percentage of duct closure and adverse effects.Treatment with indomethacin is prescribed prevalently in the United States and Canada. According to the data collected,prolonged treatment and administration of high doses would appear to be more effective. The early administration of indometacinhas been associated with gastrointestinal bleeding, renal insufficiency, altered cerebral self-regulation and, especiallywhen administered together with postnatal steroids, it has been correlated with isolated intestinal perforation.Ibuprofen treatment is preferred in Europe but it may be associated with nephrotoxicity and an increase in BDP and ROP,although less frequently compared to indometacin. Indometacin is associated with major nephrotoxicity, as well as with ahigher incidence of NEC, intestinal perforations and a reduced cerebral blood flow. Despite this, the administration ofibuprofen does not appear to be without short- and long-term renal adverse effects.

A PHACES Syndrome Unmasked by Propranolol Interruption in a Tetralogy of Fallot Patient: Case Report and Extensive Review on New Indications of Beta Blockers by G. Bronzetti, A. Patrizi, F. Giacomini, F. Savoia, B. Raone, M. Brighenti, M. Bonvicini, I. Neri, G.D. Gargiulo (3153-3164).
Infantile hemangiomas (IHs) are the most common benign tumors of infancy and usually they don't requirespecific therapy. In 10-20% of cases IHs are able to generate complication and medical/surgical intervention is needed.For many decades standard treatment consisted in oral or intralesional corticosteroids until Leaute-Labreze and colleaguespublished the first report on the efficacy of propranolol for cutaneous infantile hemangiomas in 2008. IHs can be sometimespart of complex syndrome. Here we report the case of a patient with tetralogy of Fallot operated at 5 month of agewho stopped propranolol treatment for hypoxic spells and unusually developed facial and subglottic IHs configuring thediagnosis of PHACES syndrome (posterior fossa brain malformations, hemangioma, arterial anomalies, cardiac defectsand/or aortic coarctation, ocular anomalies and sternal defects). To our knowledge this is the first report in the internationalliterature of a delayed appearance of an infantile hemangioma involving the skin and the airways (PHACES syndrome).The pathophysiological explanation relies on the mechanism of action of propranolol which seems to act initiallywith vasoconstriction, down-regulating proangiogenetic factors and inducing endothelial cell apoptosis. Many decadessince their introduction β -blockers are useful in a growing group of diseases. The pleiotropic effect of β -adrenoceptors antagonistsis not yet deeply understood, residing in neurohormonal regulation systems and angiogenesis and proving to bean effective treatment from cardiovascular to oncological illnesses.

Perinatal Heart Programming: Long-term Consequences by A. Faa, R. Ambu, G. Faa, V. Fanos (3165-3172).
Objective: evaluate the relationship between impaired growth during intrauterine life and adult risk of cardiovasculardisease and death. Materials: review of the most important contributions to the relationship between intrauterinefetal life and heart disease insurgence in childhood and adulthood, starting with a schematic representation of the principalsteps in human heart development, discussion of the new theory on the relevance of the number of cardiomyocytes thatevery heart shows at birth. Results: intrauterine environment defines the epigenetic profile of newborns, with implicationsfor the risk of developing diseases later in adult life. This means that the programming of cardiovascular risk and other pathologies,such as obesity, in adulthood takes place starting from intrauterine life. Conclusions: it can be hypothesized thatby preventing and eventually treating cardiovascular diseases in the pediatric age, if these are already present in their earlyand/or in light forms, the long-term management of complications could be approached differently and more effectivelythan by postponing the treatment to adulthood. The future challenge in this fascinating field of clinical research is the discoveryof the molecular mechanisms underlying the association between intrauterine growth restriction and fetal onset ofadult cardiac disease, so as to make a dream come true by applying primary prevention of adult heart disease in the womb.

Multiple myeloma is the second most hematological malignancy, accounting for more than 10% of all bloodcancers and 2% of annual cancer-related deaths due to lack of curable drugs. Novel and molecularly targeted anti-MMdrugs are in urgent need. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a critical regulatory rolein multiple myeloma pathophysiology, including survival, proliferation, migration, angiogenesis, as well as drug resistance,and has emerged as a key therapeutic target. Many potent inhibitors targeting this pathway have been developedand some have been moved for clinical evaluations for multiple myeloma. In this review, we highlighted the role of thePI3K/AKT pathway in the pathogenesis of multiple myeloma, and current advances in drug discovery for this class of inhibitors.Discovery strategies toward the PI3K/AKT inhibitors were also discussed.

Herein, we present an overview of the historic development of drugs for the treatment of Parkinson's disease aswell as prospective novel treatment forms based on targeting the dopamine and adenosine receptors. The review includesthe development of levodopa, a precursor of the neurotransmitter dopamine, which to date is the most commonlyprescribed and most effective drug for controlling the motor symptoms of Parkinson's disease, to more recent studies ofthe adenosine receptor; a promising target for the treatment of Parkinson's disease due to its intrinsic neuroprotectivenature. Ongoing and future drug-based research on the dopamine and adenosine receptors has the advantage of beingguided by the improved understanding of receptor topography as well as their functional roles. Breakthroughs such as thefirst ligand-bound X-ray structure of a selective adenosine A2A receptor antagonist in complex with the adenosine A2Areceptor, the discovery of the existence of dopamine D2 homodimers, dopamine D2- adenosine A2A heterodimers andhigher order oligomers in addition to technological progress have changed the direction of research in academia andindustry and form the pillars for novel and exciting discoveries in this field.