Janko Samardzic

Quantitative clinical pharmacology practice for optimal use of antibiotics during the neonatal period

ABSTRACT Introduction: For safe and effective neonatal antibiotic therapy, knowledge of the pharmacokinetic parameters of antibacterial agents in neonates is a prerequisite. Fast maturational changes during the neonatal period influence pharmacokinetic and pharmacodynamic parameters and their variability. Consequently, the need for applying quantitative clinical pharmacology and determining optimal drug dosing regimens in neonates has become increasingly recognized. Areas covered: Modern quantitative approaches, such as pharmacometrics, are increasingly utilized to characterize, understand and predict the pharmacokinetics of a drug and its effect, and to quantify the variability in the neonatal population. Individual factors, called covariates in modeling, are integrated in such approaches to explain inter-individual pharmacokinetic variability. Pharmacometrics has been shown to be a relevant tool to evaluate, optimize and individualize drug dosing regimens. Expert opinion: Challenges for optimal use of antibiotics in neonates can largely be overcome with quantitative clinical pharmacology practice. Clinicians should be aware that there is a next step to support the clinical decision-making based on clinical characteristics and therapeutic drug monitoring, through Bayesian-based modeling and simulation methods. Pharmacometric modeling and simulation approaches permit us to characterize population average, inter-subject and intra-subject variability of pharmacokinetic parameters such as clearance and volume of distribution, and to identify and quantify key factors that influence the pharmacokinetic behavior of antibiotics during the neonatal period.

Neonatal medicines research: challenges and opportunities

Introduction: The key feature of the newborn is its fast age-dependent maturation, resulting in extensive variability in pharmacokinetics and -dynamics, further aggravated by newly emerging covariates like treatment modalities, environmental issues or pharmacogenetics. This makes clinical research in neonates relevant and needed, but also challenging. Areas covered: To improve this knowledge, tailoring research tools as well as building research networks and clinical research skills for neonates are urgently needed. Tailoring of research tools is illustrated using the development of dried blood spot techniques and the introduction of micro-dosing and -tracer methodology in neonatal drug studies. Both techniques can be combined with sparse sampling techniques through population modeling. Building research networks and clinical research skills is illustrated by the initiatives of agencies to build and integrate knowledge on neonatal pharmacotherapy through dedicated working groups. Expert opinion: Challenges relating to neonatal medicine research can largely be overcome. Tailored tools and legal initiatives, combined with clever trial design will result in more robust information on neonatal pharmacotherapy. This necessitates collaborative efforts between clinical researchers, sponsors, regulatory authorities, and last but not least patient representatives and society.

Current use of mTOR inhibitors for the treatment of subependymal giant cell astrocytomas and epilepsy in patients with TSC.

The serine/threonine kinase mechanistic target of rapamycin (mTOR) is an important sensor of the cellular energy condition which, at the same time, represents a kind of master switch between anabolic and catabolic cellular processes. Tuberous sclerosis complex (TSC) is a genetic disease which is considered to be a prototype of a dysregulated mTOR signaling pathway. The dysregulated mTOR pathway in TSC leads to characteristic structural and physiologic abnormalities in multiple organs. In this review we focus on the pharmacological properties of mTOR inhibitors and clinical investigations of mTOR inhibitors for two important neurological TSC manifestations: subependymal giant cell astrocytomas (SEGAs) and epilepsy. Moreover, we present a safety profile of those agents and their current role in clinical practice.

Developmental pharmacology: a moving target

The main characteristic of pediatric and neonatal pharmacotherapy still is the insufficient availability of drugs with confirmed efficacy and safety data in children. Children differ from adults in the physiological, psychological and developmental terms and this subsequently results in differences in anticipated drug potency, efficacy and toxicity. This paper is focused on the most prominent issues of the contemporary developmental pharmacology. Childs age and development can significantly affect drug pharmacokinetics (PK) processes. The dosage of drugs for children must be based on the physiological characteristics, as well as PK parameters of the drug obtained from the clinical trials with children. While knowledge about the impact of developmental changes on drug PK is increasing, information regarding pharmacodynamics (PD) is still more limited. The examples from clinical and animal data on ontogeny of receptors resulted in strong evidence for changes in drug response during development, in addition to but independent from PK alterations. In order to improve the use of medicines in children, it is essentially to know the complex processes of growth and development into the pediatric drug development programs. This is because absence of PK/PD data leads to increased risk of over- or under-dosing, adverse reactions or inefficiency.

Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice

Background Neurosteroid dehydroepiandrosterone sulfate (DHEAS) has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration. Methods DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-D-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [3H]flunitrazepam binding to the mouse brain membranes. Results DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [3H]flunitrazepam binding of male and female mice. The results failed to demonstrate significant effects of single- and long-term DHEAS treatment on the convulsive susceptibility in both adult and aged mice of both sexes. However, small but significant changes regarding sex differences in the susceptibility to seizures were observed following DHEAS administration to mice. Conclusion Although our findings suggest that DHEAS treatment might be safe for various potential therapeutic applications in adult as well as in old age, they also support subtle interaction of DHEAS with male and female hormonal status, which may underline observed sex differences in the relationship between DHEAS and various health outcomes.

The effects of resveratrol on rat behaviour in the forced swim test

INTRODUCTION The trans-isomer of resveratrol is the active ingredient of Poligonum cuspidatum, known for its medicinal properties and traditionally used in the treatment of neuropsychiatric disorders. It is also found abundantly in the skin of red grapes and red wine. Previous studies have suggested that trans-resveratrol demonstrates a variety of pharmacological activities including antioxidant, anti-inflammatory, as well as neuroprotective properties and procognitive effects. OBJECTIVE The goal of the present study was to examine the influence of trans-resveratrol on behavior in rats and its antidepressant properties. METHODS Male Wistar rats were treated intraperitoneally (i.p.) with the increasing doses of trans-resveratrol (5, 10 and 20 mg/kg) or vehicle (dimethyl sulfoxide--DMSO), 30 minutes before testing of the spontaneous locomotor activity or forced swimming. For the experiments, the behavior of the animals was recorded by a digital camera, and the data were analyzed by one-way ANOVA, followed by Tukey post-hoc test. RESULTS Testing of spontaneous locomotor activity, after the application of vehicle or increasing doses of trans-resveratrol, showed no statistically significant difference between groups (p > 0.05). In the forced swim test, one-way ANOVA indicated statistically significant effects of trans-resveratrol (p < 0.001).Tukey post-hoc test showed that resveratrol significantly decreased immobility time at the doses of 10 mg/kg and 20 mg/kg, manifesting the acute antidepressant-like effects. There were no statistically significant differences between the resveratrol treatment of 5 mg/kg and vehicle (p > 0.05). CONCLUSION The results from our study suggest that transresveratrol produces significant effects in the central nervous system. After single application, it has acute antidepressant effects, but without influence on locomotor activity.

Neurosteroid dehydroepiandrosterone improves active avoidance retrieval and induces antidepressant-like behavior in rats

Various studies reported beneficial effects of dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), the neurosteroids involved in various brain functions, on synaptic plasticity, neuronal survival, memory, learning and behavior. This study aimed to investigate the behavioral profile of acute DHEA treatment by using active avoidance (AA) task, primarily predictive of the effects on the retrieval-based learning, and by applying forced swim test (FST), for assessment of antidepressant-like potential. Adult male Wistar rats received intraperitoneal injections of either DHEA (2, 10, 20mg/kg) or solvent, 30min prior to testing. DHEA, in a manner resembling an inverted U shape, influenced the retrieval imposed to rats in AA paradigm. The significant improvement of the performance in the retention session was observed following 10mg/kg DHEA treatment and it was not due to the changes in the motor activity, as indicated by unaltered locomotor parameters (inter-trial crossing). Moreover, 10mg/kg of DHEA significantly decreased the duration of immobility in FST, demonstrating antidepressant-like effects. The capability of bicuculline (2mg/kg) to antagonize the effects of DHEA has been evaluated simultaneously. The retrieval-facilitating as well as antidepressant-like effects of 10mg/kg DHEA were counteracted by bicuculline, a competitive antagonist of GABAA receptors, suggesting involvement of GABAergic system. These results support administration of DHEA as potential therapeutic strategy for treating depression and related cognitive impairments, but emphasized the importance of adequate dosing, as DHEA levels that are too high or too low may not be beneficial.

Evidence-based decision making in healthcare in Central Eastern Europe

Alessandra Ferrario*, Dragana Baltezarević, Tanja Novakovic, Mark Parker and Janko Samardzic London School of Economics and Political Science, LSE Health, Houghton Street, London, UK Pricing and reimbursement Department, National Health Insurance Fund (RFZO), Belgrade, Serbia Pharmacoeconomics Section, Pharmaceutical Association of Serbia, Belgrade, Serbia Health Economics Unit, Liverpool of University Management School, Liverpool, UK Medical Faculty, University of Belgrade, Belgrade, Serbia *Author for correspondence: a.ferrario@lse.ac.uk The Fourth International Conference: Evidence Based Decision-Making in Central Eastern Europe Health Care Belgrade, Serbia, 15–16 May 2014

In vivo methodology in behavioural pharmacology: Where are we now?

*Institute of Pharmacology, Clinical Pharmacology and Toxicology, Clinic of Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia; Psychiatric Clinic, Clinical Center Kragujevac, Kragujevac, Serbia; Clinic for Psychiatric Disorders “Dr Laza Lazarević”, Belgrade, Serbia

Leber's Heriditary Optic Neuropathy: The Shift from an Opthalmologic Disease to a Multi-Systemic Paradigm.

BACKGROUND & OBJECTIVE Lebers hereditary optic neuropathy is an inherited form of optic neuropathy, genetically and pathophysiologically based on mitochondrial insufficiency causing bilateral loss of central vision mostly amongst young adults. Despite being one of the most common mitochondrial diseases, the explanation for its pathophysiological background and effective clinical solutions remain elusive. Widening the scope in the search for pathological findings beyond the optic system has yielded several non-ophthalmologic findings, which might imply that Lebers hereditary optic neuropathy is in fact a multi-systemic disease. CONCLUSION The aim of this review is to provide an overview of literature regarding the epidemiology, etiology, pathogenesis, clinical features, diagnostics and possible treatment options and drug targets, as well as presenting challenges related to the disease and proposing a diagnostic algorithm based on current clinical experience.