Current Drug Targets (v.13, #7)
Editorial [Hot Topic: Drugs in Pediatric Intensive Care (Guest Editors: Franco Cavaliere, Giorgio Conti & Domenico Pietrini)] by Franco Cavaliere (877-877).
Off-Label Drug Use in Paediatrics: A World-Wide Problem by Christian Lenk (878-884).
Since more than 35 years, the international medical scientific community tries to solve the problem of the offlabel 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.
Antibiotic Use in Children - Off-Label Use by Walter Zingg (885-892).
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.
Plasma Substitutes Therapy in Pediatrics by Domenico Pietrini (893-899).
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 represents a common intervention after hemorrhagic shock occurring during surgical procedures or in patients with trauma. Notwithstanding, there is uncertainty whether the type of fluid may significantly influence the outcome, especially in pediatrics. Both human albumin and crystalloids are usually administered: the advantages of crystalloids 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 surgical wounds and peripheral edema. Moreover, intravascular volume expansion obtained by crystalloids is known to be significantly shorter and less efficacious than colloids. Among synthetic colloids, gelatins have been used for many years in children, also in early infancy, to treat intravascular fluid deficits. Hydroxyethylstarch (HES) preparations have been introduced 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.
Inotropic and Vasoactive Drugs in Pediatric ICU by Marco Piastra (900-905).
Circulatory failure recognition and treatment represents an important issue in critically ill infants and children. Early diagnosis and prompt institution of adequate treatment may be life-saving for pediatric patients with cardiocirculatory instability in the setting of intensive care. However, the hemodynamic status of the critically ill child is poorly reflected by baseline vital parameters or laboratory blood tests. A reliable tool for diagnosis and monitoring of evolution of both heart performance and vascular status is strictly needed. 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 also been recently appreciated in pediatric critical care. In the last decade, the number of vasoactive drugs has increased, together with a better understanding of clinical application of both different monitoring devices and treatment strategies.
Pharmacological Therapies for Pediatric and Neonatal ALI/ARDS: An Evidence-Based Review by Daniele De Luca (906-916).
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.
Drugs in Pediatric Ischemic Stroke by Kimberly Statler Bennett (917-924).
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.
Neuroprotection and Hypothermia in Infants and Children by Domenico Pietrini (925-935).
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 superrefractory 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.
Sedation and Analgesia in Pediatric Intensive Care by Carmelo Minardi (936-943).
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.
General Anesthetics in Pediatric Anesthesia: Influences on the Developing Brain by Mary Ellen McCann (944-951).
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.
Local Anesthetis and Adjuvants in Pediatric Regional Anesthesia by Valeria Mossetti (952-960).
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 has shown 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, 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. Therefore, the use of enantiomers, in association with adjuvants as clonidine or ketamine, using the multimodal approach of integrated anesthesia, makes the clinical practice effective and safe in the pediatric operating rooms. This review focuses on the overview of local anesthetics and adjuvants used today in locoregional pediatric anesthesia, with an emphasis on the advantages and disadvantages of each drug.
Ultrasound Guided Central Vascular Access in Neonates, Infants and Children by Mauro Pittiruti (961-969).
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 or pleuro-pulmonary damages, during and after the procedure. Ultrasound guided central venous cannulation has 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, the best 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.
Linagliptin: A Novel Methylxanthin Based Approved Dipeptidyl Peptidase-4 Inhibitor by Ritesh Agrawal (970-983).
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 DPPIV 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 DPPIV 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 DPPIV 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.
The Role of Cannabinoids in Inflammatory Modulation of Allergic Respiratory Disorders, Inflammatory Pain and Ischemic Stroke by Alessandro Pini (984-993).
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 antiischemic effects. However, as endocannabinoids can also bind to vanilloid receptors, they may also mediate neurotoxic effects.
Sodium Dependent Multivitamin Transporter (SMVT): A Potential Target for Drug Delivery by Aswani Dutt Vadlapudi (994-1003).
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.