Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 13, Issue 1, 2013

Oseltamivir is listed by the World Health Organization as an essential drug for the treatment and prophylaxis of both seasonal and pandemic influenza. Since influenza mortality is highest in neonates and infants, optimal dosing of oseltamivir in this high risk population is of utmost public health concern. To date, only two major clinical trials have been conducted investigating oselatmivir exposure and exposure/response in neonates and infants. The first study was a prospective, open label pharmacokinetic/pharmacodynamic and safety evaluation of oseltamivir in a total of 87 young children less than 2 years of age and was conducted by the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG). The second Roche sponsored study was also an open label, prospective, pharmacokinetic/ pharmacodynamic and safety evaluation of oseltamivir in the treatment of 65 children less than 12 months of age. A recent supplemental new drug application (sNDA) was submitted to the Food and Drug Administration (FDA) on the basis of these two studies which resulted in oseltamivir becoming the first and so far only neuraminidase inhibitor to gain FDA approval for treatment of influenza in neonates and infants less than 1 year of age. The two review articles in this volume discuss the complex pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate from different perspectives while attempting to contrast and critique different literature views of the optimal dose in neonates, infants and young children. The articles also offer suggestions to generate more robust pediatric PKPD data and mend current gaps in knowledge.

Pharmacokinetic-pharmacodynamic (PKPD) studies have the potential to yield useful information on whether and how a drug works, and what dose to use. This approach is often best suited to situations where dose-response relationships need to be elucidated and where randomisation is not feasible. Children make up around one third of cases during influenza outbreaks, and are more susceptible to certain complications such as otitis media. Despite this, high-quality randomised controlled trials (RCT) of antiviral therapies such as oseltamivir have not been performed, leaving open the question of whether and at what dose to use. This review therefore focusses on the available PKPD data in children. Oseltamivir has complex PK which requires modelling to properly understand the relationship between dose and concentration with time, and there is a lack of clarity on appropriate pharmacodynamic endpoints. Following a general overview of oseltamivir PKPD, this review seeks to summarise the available paediatric PKPD data, identify gaps in our knowledge and priorities for future research.

Influenza is a cause of significant morbidity and mortality in young children. It is associated with high annual attack rates as well as being responsible for frequent outpatient visits and hospitalisations. Children aged <2 years are at the highest risk for serious illness or death during the influenza season. The neuraminidase inhibitor oseltamivir has been proven to reduce the duration and severity of illness when treatment is commenced within 48 hours of symptom onset. The H1N1 pandemic of 2009 prompted temporary emergency authorisation of oseltamivir use in infants aged <1 year in the USA. In December 2012, Food and Drug Administration (FDA) reinstated approval of oseltamivir to treat children younger than 1 year old including neonates who have shown symptoms of influenza for less than 48 hours. Current data on the use of oseltamivir in neonates and infants are limited. In this review, we evaluated accumulated data on oseltamivir use in newborns, infants and young children with a special focus on pharmacokinetics, efficacy and safety.

Acute respiratory infections represent common diseases in childhood and a challenge to infection control, public heath, and the clinical management of patients and their families. Children are avid spreaders of respiratory viruses, and seasonal outbreaks of influenza create additional disease burden and healthcare cost. Infants under the age of two and children with chronic conditions are at high risk. The absence of pre-defined risk factors however, does not protect from serious disease. Immunisation rates remain low, and physical interventions are of limited value in young children. Children with influenza may be contagious prior to the onset of symptoms, and school closures have been shown to have a temporary effect at most. The timely detection of influenza in at-risk patients is important to prevent hospital-based transmission and influenza-associated morbidity and mortality. Guidelines issued by professional associations and public health agencies need to be translated into everyday clinical practice. Antiviral therapy should be initiated early and monitored closely, including virologic and clinical outcomes. The duration of treatment and the decision to readmit children to schools and kindergartens should be adjusted to the individual child patient using evidence-based clinical and virologic criteria. This article presents lessons learnt from a quality management program for infants and children with influenzalike illness at the Charite Department of Paediatrics in collaboration with the National Reference Centre for Influenza at the Robert Koch Institute, in Berlin, Germany. The Charite Influenza-Like Disease (ChILD) Cohort was established during the 2009 influenza pandemic and encompasses nearly 4000 disease episodes to date.

Neuraminidase inhibitors (NAIs), such as oseltamivir and zanamivir, are the medicines of choice against influenza A or B. Oseltamivir resistance can be conferred by a single point missense mutation from histidine to tyrosine at position 275 (H275Y) of the neuraminidase gene. Oseltamivir resistance in seasonal influenza A/H1N1 strains rose markedly during the 2007-2008 season. Furthermore, oseltamivir resistant (OsR) strains of pandemic influenza A/H1N1 2009 (influenza A(H1N1)pdm09) have been increasingly isolated, although the majority remain sensitive. These OsR strains retain virulence, replicative fitness and transmissibility from person to person, with outbreaks reported. Treatment options in those at risk of severe or complicated disease are limited to zanamivir which is only licenced in those over the age of 5 years; of further concern, strains demonstrating low level resistance to both oseltamivir and zanamivir have been reported. Strategies to reduce emergence of resistant strains, such as higher dose oseltamivir regimens, need further examination.

Influenza remains an important cause of morbidity and mortality, and incurs substantial economic costs (mainly due to hospitalisation) especially for the elderly aged 65 years or more, and among those with high-risk medical conditions. Influenza vaccination is the most effective control measure for both healthy populations and the chronically ill in whom complications of influenza cluster. Unfortunately, vaccination is less effective in the elderly and immunocompromised persons. Additional benefit may accrue from other health care interventions including antiviral therapy. Oseltamivir, a neuraminidase inhibitor, has become a drug of public health importance since it was included in influenza pandemic management plans. Many systematic reviews and meta-analyses of oseltamivir treatment and prophylaxis trials have been published. We provide a summary of the conclusions and review the various findings of economic analyses. Future randomised controlled trials should focus upon costly outcomes such as hospital admissions and should be conducted in populations at high risk of complications from influenza. Future economic analyses need to address variation in (1) willing-to-pay value, (2) annual attack rate of influenza, and (3) influenza vaccination effectiveness and uptake rates.

Recent research suggests that inflammation and immunity may have a role in the etiology of psychotic disorders. There is evidence of proinflammatory activation of the innate immune system and an activation of the T-cells of the adaptive immune system in both schizophrenia and bipolar disorder. Studies of antipsychotic-naive patients with firstepisode psychosis have found that inflammation is present already at this stage. Some of these abnormalities resolve after the initiation of treatment, suggesting that they are state markers of acute psychosis, but other abnormalities persist. There is also evidence for prenatal infections being involved in the etiology of schizophrenia. Several hypotheses link inflammation and immunity with psychotic disorders. In this review, we focus on hypotheses related to prenatal development, disturbed regulation of neurogenesis, microglial activation, autoimmunity and microbial environment, and consider the potential confounding effects related to stress, childhood adversities, lifestyle and medical comorbidity as well as some methodological limitations. We also review the current evidence for the effectiveness of anti-inflammatory medication in the treatment of psychotic disorders.

Acquired Immune Deficiency Syndrome is one of the world's serious health problems. Immune-based therapy is a new approach in the treatment of HIV infected patients. IMODTM with the ability to correct immune deficiencies has been introduced for the management of HIV infection. In the phase IV trial study the main objectives were to assess the possible side effects, evaluate its effect on CD4+ T Lymphocyte count and patients’ and physicians’ satisfactions for 600 HIV infected patients in 13 centers during 2007. The observed adverse events in patients included: headache and vertigo (1.2%), nausea (1.2%), gastritis (1.2%), phlebitis (1%) and mild rash (1%); serious adverse events were not observed in any of IMODTM recipients. Therefore it was not needed to terminate the treatment in any of patient. The results of this study demonstrated that daily prescription of IMODTM significantly increases T Lymphocyte CD4+ and Total Lymphocyte Count in HIV-positive patients. In addition, nearly 90% of the patients and 70% physicians are satisfied by IMODTM treatment.

Periodontal diseases are comprised of a group of inflammatory conditions that result in the destruction of the supporting structures of the dentition. Emphasis has traditionally been placed on the deleterious actions of lipid mediators, such as prostanoids and leukotrienes, in propagating the inflammatory response and enhancing tissue destruction. Recently, the emerging understanding of the molecular basis of inflammation has elucidated that return of tissue homeostasis, triggered as part of a normal inflammatory response i.e. resolution of inflammation is an active, agonist-mediated, well-orchestrated phenomenon. The naturally-occurring pro-resolution lipid mediators, lipoxins, resolvins, protectins, maresins etc. have been identified as a novel genus of potent and stereoselective players that counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. In this Review, we provide an update and overview of newly identified mediators that play pivotal roles in resolution and focus on the emerging appreciation of the endogenous pathways and mediators that control timely resolution which can be exploited as novel drug targets to extend the pharamaceutical armamentarium to combat chronic inflammation, thus controlling periodontal inflammation and the associated systemic inflammatory effects on the body, in general.