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Linagliptin: A Novel Methylxanthines Based Approved Dipeptidyl Peptidase-4 Inhibitor
Ritesh Agrawal, Pratima Jain and S. N. Dikshit
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00375]


The role of Cannabinoids in Inflammatory Modulation of Allergic Respiratory Disorders, inflammatory Pain and Ischemic Stroke
Alessandro Pini, Guido Mannaioni, Domenico Pellegrini-Giampietro, Maria Beatrice Passani, Rosanna Mastroianni, Daniele Bani and Emanuela Masini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00376]


Sodium Dependent Multivitamin Transporter (Smvt): A Potential Target For Drug Delivery
Aswani Dutt Vadlapudi, Ramya Krishna Vadlapatla and Ashim K Mitra
[Abstract] [Purchase Article] [BSP/CDT/E-Pub/00377]


Leukotriene C4 Synthase: Upcoming drug target for inflammation
Nisha. S. Devi and Mukesh Doble
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00378]


Editorial: Neurodegeneration with Brain Iron Accumulation
Hiroaki Miyajima
[BSP/CDT/E-Pub/00390]


Aceruloplasminemia
Satoshi Kono
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00391]


Pantothenate Kinase-Associated Neurodegeneration
Monika B. Hartig
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00392]


Neuroferritinopathy: Update On Clinical Features And Pathogenesis
Alisdair McNeill and Patrick F. Chinnery
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00393]


PLA2G6 mutations and other rare causes of Neurodegeneration with Brain Iron Accumulation
Alisdair McNeill
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00394]


Editorial: Drugs in Pediatric Intensive Care
Franco Cavaliere, Giorgio Conti and Domenico Pietrini
[BSP/CDT/E-Pub/00395]


Off-label Drug use in Paediatrics: a World-wide Problem
Christian Lenk
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00396]


Antibiotic use in children – off-label use
Walter Zingg and Klara M. Posfay-Barbe
[Abstract] [Purchase Article] [BSP/CDT/E-Pub/00397]


Plasma Substitutes Therapy in Pediatrics
D. Pietrini, D. De Luca, F. Tosi, F. Cavaliere, G. Conti and M. Piastra
[Abstract] [Purchase Article] [BSP/CDT/E-Pub/00398]


Inotropic and Vasoactive Drugs in Pediatric ICU
M. Piastra, E. Luca, S. Mensi, F. Visconti, D. De Luca and D. Pietrini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00399]


Pharmacological Therapies For Pediatric and Neonatal Ali/Ards: An Evidence-Based Review
Daniele De Luca, Marco Piastra, Federica Tosi, Silvia Pulitanò, Aldo Mancino, Orazio Genovese, Domenico Pietrini and Giorgio Conti
[Abstract] [Purchase Article] [BSP/CDT/E-Pub/00400]


Drugs in Pediatric Ischemic Stroke
Kimberly Statler Bennett and Denise Nielsen
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00401]


Neuroprotection and hypothermia in infants and children
D. Pietrini, M. Piastra, E. Luca, A. Mancino, G. Conti, F. Cavaliere and D. De Luca
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00402]


Sedation and Analgesia in Pediatric Intensive Care
Carmelo Minardi, Emre Sahillioğlu, Marinella Astuto, Marco Colombo and Pablo Mauricio Ingelmo
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00403]


General Anesthetics In Pediatric Anesthesia: Influences On The Developing Brain
Mary Ellen McCann and Sulpicio G. Soriano
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00404]


Local Anesthetis and Adjuvants In Pediatric Regional Anesthesia
Valeria Mossetti, Noemi Vicchio and Giorgio Ivani
[Abstract] [Purchase Article] [BSP/CDT/E-Pub/00405]


Ultrasound Guided Central Vascular Access In Neonates, Infants and Children
Mauro Pittiruti
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00406]



Abstracts

Linagliptin: A Novel Methylxanthines Based Approved Dipeptidyl Peptidase-4 Inhibitor
Ritesh Agrawal, Pratima Jain and S. N. Dikshit
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00375]

Chemically, methylxanthine nucleus based Linagliptin (BI-1356, BI-1356-BS) is a dipeptidyl peptidase-IV inhibitor, which has been developed by Boehringer Ingelheim in association with Lilly for the treatment of Type-II Diabetes. Linagliptin was marketed by Lilly under the trade name Tradjenta and Trajenta. Linagliptin was approved as the once-daily dose by USFDA on 2 May 2011, for the treatment of Type-II Diabetes. Linagliptin 5mg once daily dose was approved based on a clinical trial program, which was conducted on approximately 4,000 adults with Type-II Diabetes. Linagliptin demonstrated statistically significant mean difference in HbA1c from placebo of up to 0.72 percent, when it was used monotherapically.  In patients, who were not adequately controlled on metformin or metformin plus sulphonylurea, the addition of Linagliptin resulted in a statistically significant mean difference in HbA1c from placebo of -0.6 percent. Linagliptin was observed to produce significant reduction in fasting plasma glucose (FPG) compared to placebo, when used as a monotherapy in combination with metformin, sulfonylurea and/or pioglitazone. Linagliptin demonstrated significant reduction post-prandial glucose (PPG) levels in two hours as compared with placebo in monotherapy as well as in combination with metformin.  In vitro assays also anticipated that Linagliptin is a potent DPP-IV inhibitor as well as it exhibits good selectivity for DPP-IV as compared with other DPPs. The in-vivo studies also demonstrated same anticipation with respect to Linagliptin. Consequently, increasing the GLP-1 levels so far improved glucose tolerance in both healthy animals. X-ray crystallography anticipates that Linagliptin  complexes with human DPP-IV enzyme, e.g. butynyl substituent occupies the S1 hydrophobic pocket of the enzyme; the aminopiperidine substituent in the xanthine scaffold occupies the S2 subsite and its primary amine interacts with the key amino acid residues, which involves in the recognition of peptide substrates. In the present review, we have tried to cover comparative study of DPP-IV inhibitors, chemistry, physical properties, commercial synthesis, patent portfolio, crystalline polymorphic forms of Linagliptin and its receptor interaction, Pharmacophore rational, mechanism, clinical studies, preclinical, adverse effect, available formulations, dose regimen, co-therapy of Linagliptin, giving emphasis on the medicinal chemistry aspects.
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The role of Cannabinoids in Inflammatory Modulation of Allergic Respiratory Disorders, inflammatory Pain and Ischemic Stroke
Alessandro Pini, Guido Mannaioni, Domenico Pellegrini-Giampietro, Maria Beatrice Passani, Rosanna Mastroianni, Daniele Bani and Emanuela Masini
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00376]

This review is intended to offer updated information on the involvement of cannabinoids in the process of inflammation, focusing on immune/allergic reactions, inflammatory pain and neuroinflammation and discussing the interactions among endocannabinoid metabolism, prostanoids and nitric oxide. Two types of cannabinoid receptors, CB₁ and CB₂, which belong to the G protein-coupled receptor family, have been identified and are targeted by numerous exogenous and endogenous ligands. The activation of CB₂ receptors on mast cells has direct antiinflammatory effects, causing decreased release of pro-inflammatory mediators by these cells.  The activation of CB₁ receptors on bronchial nerve endings has bronchodilator effects by acting on the airway smooth muscle and may be beneficial in airway hyperreactivity and asthma. Moreover, pharmacologic interference with endocannabinoid metabolism has been demonstrated to result in anti-nociceptive activity, mediated by CB₁ and CB₂ receptors, in animal models of inflammatory pain. The presence of endocannabinoid machinery in the central nervous system, together with high levels of CB₁ expression, suggests that the endocannabinoid system is an important modulator of neuroinflammation and a possible drug target. In selected conditions, the activation of CB₁ receptors in cerebral blood vessels can have beneficial anti-ischemic effects. However, as endocannabinoids can also bind to vanilloid receptors, they may also mediate neurotoxic effects.
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Sodium Dependent Multivitamin Transporter (Smvt): A Potential Target For Drug Delivery
Aswani Dutt Vadlapudi, Ramya Krishna Vadlapatla and Ashim K Mitra
[Purchase Article] [BSP/CDT/E-Pub/00377]

Sodium dependent multivitamin transporter (SMVT; product of the Slc5a6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge, etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems.
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Leukotriene C4 Synthase: Upcoming drug target for inflammation
Nisha. S. Devi and Mukesh Doble
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00378]

Leukotrienes are important mediators of pain and inflammation and they are produced in the arachidonic acid pathway via 5-lipoxygenase. They have been shown to have important roles in pyresis following antigen attack and in aspirin-intolerant asthma. They promote inflammation processes including eosinophil migration, increase in vascular permeability and bronchoconstriction. Hence, targeting the enzymes involved in the synthesis of these mediators can lead to the development of novel anti-inflammatory drugs. However, no drugs have yet been developed targeting leukotriene C4 synthase, a key enzyme leading to the synthesis of cysteinyl leukotrienes. The recent elucidation of its crystal structure now opens up the possibility of drugs against it. The inhibitors developed for this enzyme until now and the structural features responsible for their activity are discussed in this review. This understanding could lead to the design of new chemical entities.
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Editorial: Neurodegeneration with Brain Iron Accumulation
Hiroaki Miyajima
[BSP/CDT/E-Pub/00390]

Iron is the most abundant heavy metal in the human body. It is an essential element for a functional component of hemoglobin, cytochromes, and other iron enzymes. On the other hand, it is well known that an excess amount of iron in vivo is toxic through the production of reactive oxygen species. In the normal brain, iron is predominantly present in a nonhemin 6-oxygen and 4-iron coordination form, which is characteristic of the ferritin core. The nonhemin iron in the human brain increases in the first two to three decades of the life, and is unequally distributed in various regions. Brain iron is required for critical, diverse processes including neurotransmitter biosynthesis, myelin formation, and nitric oxide signaling, as well as oxidative phosphorylation essential for sustaining brain energy requirements. Despite this critical role of iron in brain function, the molecular and cellular details of iron metabolism within the human central nervous system remain poorly understood.

Iron deficiency in the developing human has been clearly established as a causative factor in long-term development and cognitive impairment. In contrast while several prominent neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease have been reported to be associated with excessive iron accumulation in specific brain regions the relationship of this accumulation to the disease pathogenesis is far from clear. The recent molecular investigations of inherited neurodegenerative disorders have revealed the existence of genetic disorders termed “neurodegeneration with brain iron accumulation” (NBIA) due to genetic defects associated with iron metabolism. Pantothenate kinase-associated neurodegeneration (PKAN) is the most frequent form of NBIA. Autosomal recessive mutations in PANK2 cause PCAN which comprises about 50 % of NBIA. PANK2 has linked the disorder to coenzyme A (CoA) metabolism [1]. Aceruloplasminemia and neuroferritinopathy has provided new insights into the pathways of brain iron metabolism and the mechanisms underlying the unique susceptibility of the brain region including the basal ganglia to iron-mediated neurodegeneration [2, 3]. Up to now, five further genes (PLA2G6, FA2H, ATP13A2, C2orf37, C19orf12) have been linked to NBIA. PLA2G6 and C19orf12 encode mitochondrial proteins that play a role in lipid homeostasis [4]. Fatty acid hydroxylase (FA2H) produces 2-hydroxylated fatty acids for incorporation into ceramide species. Careful analysis of human genetic disorders of brain iron metabolism may provide answers and permit new insights into the neurobiology, pathogenesis and treatment of neurodegenerative diseases.
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Aceruloplasminemia
Satoshi Kono
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00391]

Ceruloplasmin contains 95% of the copper in human serum and plays an important role in iron efflux from mammalian cells, including brain cells, due to the activity of ferroxidase, which oxidizes ferrous iron following its transfer to the cell surface via the iron transporter, ferroportin, and delivers ferric iron to extracellular transferrin. In the central nervous system, a glycosylphosphatidylinositol (GPI)-anchored ceruloplasmin bound to the cell membranes of astrocytes was found to be the major isoform of this protein. Inherited loss of the protein causes aceruloplasminemia, which is an autosomal recessive disorder characterized by progressive neurodegeneration of the retina and basal ganglia associated with specific inherited mutations in the ceruloplasmin gene. Aceruloplasminemia is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA) due to genetic defects associated with iron metabolism. Clinical and pathologic studies in patients with aceruloplasminemia and ceruloplasmin knockout mice revealed increased lipid peroxidation due to iron-mediated cellular radical injury which is caused by a marked accumulation of iron in the affected parenchymal tissues such as the retina, liver, pancreas and brain. In the following review of aceruloplasminemia, the ceruloplasmin gene expression, structure and function will be presented, and the role of ceruloplasmin in iron metabolism will be discussed. The pathogenesis of aceruloplasminemia provides valuable insights into the mechanisms regulating iron homeostasis and also identified models that can be used to further dissect the role of this metal in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, in which iron is accumulated.
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Pantothenate Kinase-Associated Neurodegeneration
Monika B. Hartig
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00392]

Abstract: Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic “eye of the tiger” sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological examinations.  The discovery of the disease causing mutations in PANK2 has linked the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis.

With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of dystonia. Recently, studies in the PANK drosophila model “fumble” revealed improvement by the compound pantethine which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately powered randomized clinical trial will start in 2012.
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Neuroferritinopathy: Update On Clinical Features And Pathogenesis
Alisdair McNeill and Patrick F. Chinnery
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00393]

Neuroferritinopathy is an autosomal dominant extra – pyramidal movement disorder caused by mutations in the ferritin light chain gene (FTL).  The most frequent presentation is with chorea (50%), followed by dystonia (42.5 %) and parkinsonism (7.5%).   Seven different mutations are known; 6 insertions in exon 4 and a missense mutation in exon 3 with the 460insA mutation in exon 4 being the most common. Brain magnetic resonance imaging demonstrates iron deposition in the basal ganglia and cavitation. Neuropathological studies have shown neuronal loss in the cerebral cortex, cerebellum and basal ganglia.  Ferritin inclusion bodies were demonstrated within neurons and glia.  Studies of patient derived fibroblasts and HeLa cells expressing mutant ferritin demonstrate increased iron levels and oxidative stress.  These abnormalities have been recapitulated in mouse models of neuroferritinopathy.  There is no disease modifying treatement for neuroferritinopathy but benzodiazepines and botulinum toxin may palliate dystonia and tetrabenazine may relieve chorea and facial tics.  There is no role for iron chelation.
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PLA2G6 mutations and other rare causes of Neurodegeneration with Brain Iron Accumulation
Alisdair McNeill
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00394]

There is a wide variety of genetic and sporadic causes for neurodegenerative disorders with apparent brain iron accumulation on magnetic resonance imaging.  Rare recessive causes include PLA2G6 mutations (infantile neuroaxonal dystrophy), and mutations of ATP13A2 (Kufor Rakeb syndrome) and FA2H.  A variety of sporadic neurological disorders can present brain iron accumulation on imaging, including multiple sclerosis and neurological manifestations of HIV infection.  The relevant clinical and imaging features will be discussed.
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Editorial: Drugs in Pediatric Intensive Care
Franco Cavaliere, Giorgio Conti and Domenico Pietrini
[BSP/CDT/E-Pub/00395]

This issue of Current Drug Targets is focused on pediatric intensive care. Drug therapy is particularly delicate in critically-ill patients because powerful agents are employed and pharmacokinetics is often impaired. Pediatric critically-ill patients are even more difficult to treat because of many peculiarities, which are not only related to patient body size. The issue includes some traditional subjects, such as sedation and analgesia, fluid infusion, and the use of inotropes and vasoactive drugs, and some hot topics. Among these is the off-label use of drugs in critically-ill pediatric patients. As a matter of fact, many drugs largely utilized in children have only been registered for adults, and pediatric use is consequently off-label; two reviews, one in general and the other centered on antibiotics, analyze this topic. Another article deals with the pharmacological treatment of acute pulmonary damage, which proved to be effective in children, unlike adults.  Treatment and prevention of neurological damage have also been treated under several points of view. They include drug therapy in ischemic stroke and the prevention of cerebral damage caused by global hypoxia by means of hypothermia, as well as the intriguing topic of the potential damages caused to the developing brain by general anesthetics. Drugs utilized for regional anesthesia in pediatric patients have been also treated, as well as the techniques of echo-guided central catheterization in neonates, infants, and children that often represent the necessary premise to the administration of many drugs in critically-ill patients.

Finally, we would like to thank all the Authors that contributed to this issue for their help and cooperation.
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Off-label Drug use in Paediatrics: a World-wide Problem
Christian Lenk
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00396]

Since more than 35 years, the international medical scientific community tries to solve the problem of the off-label use of paediatric drugs. The aim is simple, but ambitious: to supply children and adolescents with effective drugs, as safe as possible, with known and well-documented side effects, and with accurate and up-to-date information on dosage and administration form. However, despite the significant efforts of paediatricians, researchers and international health politics, a number of severe obstacles for the optimal supply of children and adolescents with safe drugs remain. The detailed analysis of the problem shows not only a still remaining lack of medical knowledge, but also persistent weaknesses in the ethical, legal, medical, pharmacological, and political practices that surround the phenomenon of off-label use in paediatrics. The article gives an overview about the remaining difficulties in the field of paediatric off-label medication with special consideration to ethical and regulatory questions.
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Antibiotic use in children – off-label use
Walter Zingg and Klara M. Posfay-Barbe
[Purchase Article] [BSP/CDT/E-Pub/00397]

Systemic antibiotics are the group of drugs most commonly used in children. Off-label antibiotic use in children is still common in the community and in hospitals, mostly because of young age, dosage, or frequency of drug application. There is an important incentive gap that hinders paediatric drug development resulting from a series of factors, such as small market size, a predominance of off-patent use, no incentives for generic drug manufacturers, and a greater complexity of drug development. The latter is due to varying capacities of drug absorption and metabolism during growth and maturation and the need for oral formulations in neonates and infants. High ethical barriers, combined with concerns of parents about drug safety, further complicate the conduct of clinical studies in children. While many off-patent antibiotics today are labelled for use in children, newer substances such as fluoroquinolones, azithromycin, linezolid, or daptomycin are not. This is of concern in the light of emerging multidrug-resistant pathogens.
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Plasma Substitutes Therapy in Pediatrics
D. Pietrini, D. De Luca, F. Tosi, F. Cavaliere, G. Conti and M. Piastra
[Purchase Article] [BSP/CDT/E-Pub/00398]

Hypovolemia is the most common cause of circulatory failure in children and may lead to critical tissue perfusion and eventually multiple-organ failure. Administration of fluids to maintain or restore intravascular volume is a common intervention after hemorrhagic shock occurring during surgical procedures or in patients with trauma. Notwithstanding, there is uncertainty whether the type of fluid chosen might significantly influence the outcome, especially in pediatrics.

Human albumin  and crystalloids are normally administered: their advantages include low cost, lack of effect on coagulation, no risk of anaphylactic reaction or transmission of  infectious agents. However, large amount of crystalloid infusion has been correlated with pulmonary oedema, bilateral pleural effusions, intestinal intussusception, excessive bowel edema, impairing closure of an incision and peripheral edema. Moreover, intravascular volume expansion obtained by crystalloids is known to be significantly shorter and less efficacious  than that of the colloids. Among synthetic colloids,   gelatins have been used for many years in children, but also in early infancy to treat intravascular fluid deficits. Hydroxyethylstarch (HES) preparations are  more recently  becoming very popular for vascular loading both in adults and children. However, the number of pediatric studies aimed at evaluating HES efficacy and tolerance is limited.

Given the ongoing controversies on the use of colloids in childhood,  this review will focus on the pharmacodynamics of synthetic and non synthetic colloids for the treatment of critical blood loss in pediatrics.
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Inotropic and Vasoactive Drugs in Pediatric ICU
M. Piastra, E. Luca, S. Mensi, F. Visconti, D. De Luca and D. Pietrini
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00399]

Circulatory failure recognition and treatment is an important issue in critically ill infants and children. Early diagnosis and prompt institution of adequate treatment may be life-saving for pediatric patients requiring intensive care. However, the hemodynamic status of the critically ill child is poorly reflected by baseline vital parameters or laboratory blood tests. Advanced hemodynamic monitoring consists – among others - of measuring cardiac output, predicting fluid responsiveness and calculating systemic oxygen delivery. Identification and quantifying of pulmonary edema has been recently appreciated in critical care.  In the last decade, the number of vasoactive drugs has increased, together with a better understanding of clinical application of both monitoring devices and treatment strategies.
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Pharmacological Therapies For Pediatric and Neonatal Ali/Ards: An Evidence-Based Review
Daniele De Luca, Marco Piastra, Federica Tosi, Silvia Pulitanò, Aldo Mancino, Orazio Genovese, Domenico Pietrini and Giorgio Conti
[Purchase Article] [BSP/CDT/E-Pub/00400]

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threating conditions still lacking a definite therapy and carrying a high mortality and morbidity, especially in children and infants. Albeit  respiratory assistance and supportive therapies are crucial for ALI/ARDS, many drugs have been proposed to treat such syndromes  through various mechanisms of action.

On the whole the pharmacological therapy might play an important role in such a complex clinical situation but few evidence based data are available in pediatric and neonatal critical care.  

This review will focus on drugs directly available on the bedside, that is, medicines already administered in the practice or investigated in at least one clinical study. We will value the differences due to patient’s age and the various causes of the syndrome, that may affect the response to the pharmacological therapy. A special attention will be given to the drugs directly deliverable into the lungs, as this strategy allows a total availability to the lung tissue. The experimental background behind each drug will be discussed and then clinical data in neonates and infants will be presented, if available. Data coming from adult critical care and thought to be somehow pertinent for the pediatric setting will otherwise be reviewed.

Quality and evidence for or against each therapy will be evaluated according to the Scottish Intercollegiate Guidelines Network statement and  practical reminders for clinicians will accordingly be provided.
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Drugs in Pediatric Ischemic Stroke
Kimberly Statler Bennett and Denise Nielsen
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00401]

Traditionally, drug therapy for pediatric ischemic stroke has been extrapolated from adult guidelines and studies.  This approach is not optimal due to important differences between adult and pediatric stroke (e.g. etiologies, maturation changes in hemostasis).  Research in pediatric stroke is increasing, and pediatric specific management guidelines have recently become available. This manuscript summarizes available drug therapy recommendations for pediatric ischemic stroke.  Both acute management and secondary stroke prevention are discussed, including antiplatelet, anticoagulant, and thrombolytic drugs. When relevant, recommendations from adult ischemic stroke guidelines and data from pediatric stroke studies are incorporated.
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Neuroprotection and hypothermia in infants and children
D. Pietrini, M. Piastra, E. Luca, A. Mancino, G. Conti, F. Cavaliere and D. De Luca
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00402]

Brain injury is the leading cause of death in pediatric ICU. Current evidence supports the use of therapeutic hypothermia (TH) in unconscious patients after out-of-hospital cardiac arrest when the initial heart rhythm was ventricular fibrillation. TH has been proved to be also beneficial in term neonates  after hypoxic–ischemic encephalopathy (HIE) and   in children with  traumatic brain injury (TBI). Recent reports have also investigated TH for the treatment of super-refractory status epilepticus. The clinical application of TH is based on the possibility to inhibit or lessen a myriad of destructive processes (including excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood– brain barrier disruption, blood vessel leakage) that take place in the injured tissue following ischemia–reperfusion. TH may also represent a useful tool when conventional therapy fails to achieve an effective control of elevated intracranial pressure.  This review is aimed to provide an update of the available literature concerning this intriguing topic.
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Sedation and Analgesia in Pediatric Intensive Care
Carmelo Minardi, Emre Sahillioğlu, Marinella Astuto, Marco Colombo and Pablo Mauricio Ingelmo
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00403]

Almost all children in the pediatric intensive care (PICU) need analgesia and/or sedation. Analgesics drugs are used to control pain from surgical incisions, drainages, vascular access or endotracheal suctioning. Sedatives are used to facilitate the delivery of nursing care, to facilitate mechanical ventilation, prevent self-extubation and to minimize patient discomfort. A therapeutic plan for analgesia and sedation should be established for each patient and regularly reviewed. The most often used sedation agents in PICU patients are Morphine or Fentanyl alone or in combination with Midazolam. Several other drugs should be helpful to manage PICU patients therefore techniques like regional anesthesia and patient controlled analgesia to decrease the use of intravenous analgesia and sedation and to reduce the incidence of withdrawal syndrome. The therapeutic plan for analgesia and sedation should be established for each patient and regularly reviewed. Doses of sedative agents should be titrated to produce the desired level of sedation.

The level of sedation should be regularly assessed and documented using few validated sedation assessment tool. However, behavioral evaluation tools based on patient responsiveness, cannot be used during the administration of neuromuscular blocking agents. Under this conditions it could be difficult to interpret the degree of sedation. EEG derived Monitoring devices may represents an useful tools of assessing the level of sedation, but there is insufficient evidence to support the routine use of the BIS monitor in PICU.
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General Anesthetics In Pediatric Anesthesia: Influences On The Developing Brain
Mary Ellen McCann and Sulpicio G. Soriano
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00404]

Millions of newborn and infants receive anesthetic, sedative and analgesic drugs for surgery and painful procedures on a daily basis. However, recent laboratory reports clearly demonstrate that anesthetic and sedative drugs induced both neuroapoptosis and neurocognitive deficits in laboratory models. This issue is of paramount interest to pediatric anesthesiologists and intensivists because it questions the safety of anesthetics used for fetal and neonatal anesthesia. Most clinically utilized anesthetic drugs have been found to induce neuronal cell death in the developing brain and to potentially cause long-term neurological impairment. Conversely, painful stimuli without analgesia and anesthesia have been implicated in triggering neuro-apoptosis in juvenile mammalian models.  Published retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long-term neurodevelopmental impairment after neonatal surgery and anesthesia. This paper examines the evidence for the effects of commonly used anesthetics on neuronal structure and neurocognitive function in laboratory models and reviews the relevant clinical human epidemiologic data.
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Local Anesthetis and Adjuvants In Pediatric Regional Anesthesia
Valeria Mossetti, Noemi Vicchio and Giorgio Ivani
[Purchase Article] [BSP/CDT/E-Pub/00405]

The pediatric loco-regional techniques are considered very safe and effective, first of all because they target the therapy directly to the site of surgery, decreasing the risks of intravenous analgesia. The quality of local anesthesia is influenced by structural and biophysical characteristics of local anesthetics drug, dose, site of injection, mixture of local anesthetics and possible addition of a vasoconstrictor or an adjuvant to prolong the analgesic effect. In children, unlike adults, small nerve diameters and short distance between Ranvier nodes permit to use large volumes and low concentrations of local anesthetics. The clinical practice have showed that in pediatric population effective analgesia is obtained by 1% mepivacaine, 1% lidocaine and 0.25% bupivacaine or better 0.2% ropivacaine, 0.2–0.25% levobupivacaine. In addition emerges that levobupivacaine and ropivacaine have  a better profile in terms of safety in comparison to bupivacaine and are the local anesthetics of choice for the daily clinical practice also in children as in adults. Among the adjuvant, clonidine and ketamine showed the best pharmacokinetic and pharmacodynamic profiles of effective and safety, improving and prolonging the action of associated local anesthetics. So the use of enantiomers, in association with adjuvants as clonidine or ketamine, using the multimodal approach of integrated anesthesia, makes effective and safe the clinical practice in the pediatric operating rooms. This review focuses on the overview of local anesthetics and adjuvants used for today in locoregional pediatric anesthesia, with an emphasis on the advantages and disadvantages of each drugs.
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Ultrasound Guided Central Vascular Access In Neonates, Infants and Children
Mauro Pittiruti
[FULL-TEXT INQUIRY] [BSP/CDT/E-Pub/00406]

Ultrasound guided central venous cannulation is rapidly becoming the standard technique for achieving a central line in neonates, infants and children. Older techniques such as surgical cutdown and ‘blind’ percutaneous venipuncture have many disadvantages: they are time consuming, vein consuming and/or associated with dangerous immediate or late complications. On the other hand, ultrasound has only advantages, giving the operator the possibility of (a) choosing the most appropriate and safest venous access on the basis of ultrasound assessment, (b) performing a 100% safe insertion, (c) ruling out malpositions orpleuro-pulmonary damages, during and after the procedure. Ultrasound guided central venous cannulationhas been described in many clinical studies of the last decade, each one showing the higher efficacy and safety of ultrasound guidance in children when compared to the traditional landmark method. Ultrasound can be used for puncturing many different deep veins of the arm, neck, groin and thorax. The vein can be visualized either in short axis or in long axis, while the puncture can be performed ‘in-plane’ (when the needle trajectory is included in the plane of the ultrasound probe) or ‘out-of-plane’ (when the needle trajectory is not in that plane). Though, thebest clinical results of ultrasound guidance can be achieved - particularly in neonates and infants - only if the operator has been properly trained in this technique through an appropriate curriculum that should include theory lessons, simulation practice and a tutored learning curve.
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