Vancomycin toxicity in neonates: a review of the evidence.

PURPOSE OF REVIEW: Vancomycin is a first-line agent in the treatment of serious Gram-positive infections in the neonatal population. The published evidence on vancomycin toxicity in neonates is limited. This review summarizes preclinical studies and clinical trials describing vancomycin toxicity. We discuss proposed pathophysiology and summarize evidence supporting dose-response relationships, genetic and environmental determinants, and consider future research required to further define vancomycin toxicity. RECENT FINDINGS: Current dosing regimens for vancomycin result in subtherapeutic levels in a large proportion of patients. Higher daily doses have been proposed, which have led to concerns regarding increased toxicity. Nephrotoxicity occurs in 1-9% of neonates receiving currently recommended doses. The incidence is highest in those receiving concomitant nephrotoxic drugs. Vancomycin-associated ototoxicity is rare in patients of all ages. Exposure-toxicity relationships in relation to nephrotoxicity and ototoxicity have not been clearly defined in neonates receiving vancomycin. SUMMARY: Current evidence supports the favourable safety profile of vancomycin in neonates. Further studies that address safety concerns relating to high-dose intermittent dosing regimens are needed. Such studies must include robust and standardized definitions of renal and hearing impairment, and include follow-up of sufficient length to establish the long-term implications of experimental findings

Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis.

Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2-weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAmB) is unknown. The pharmacodynamics of LAmB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAmB in plasma and brain of mice were measured using HPLC. Histopathological changes were determined. The penetration of LAmB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brain of mice with near-maximal efficacy achieved with LAmB 10-20 mg/kg/day. The terminal elimination half-life in brain was 133 hours. The pharmacodynamics of a single dose of 20 mg/kg was the same as 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAmB 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative AUC 2500 mg.h/L). Amphotericin B was visible in the intra- and perivascular spaces, leptomeninges and choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggest abbreviated induction regimens of LAmB are possible for cryptococcal meningoencephalitis

Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children

BACKGROUND Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited PK data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. OBJECTIVES To describe the pharmacokinetics of LAmB in children aged 1-17 years with suspected or documented IFD. METHODS Thirty-five children were treated with LAmB at dosages of 2.5-10 mg kg(-1) daily. Samples were taken at baseline and at 0.5-2.0 hourly intervals for twenty-four hours after receipt of the first dose (n=35 patients) and on the final day of therapy (n=25 patients). LAmB was measured using high performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. RESULTS An evolution in PK was observed during the course of therapy resulting in a proportion of patients (n=13) having significantly higher maximum serum concentration (Cmax) and area under the concentration time curve (AUC0-24) later in the course of therapy, without evidence of drug accumulation (Cmin accumulation ratio, AR < 1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24 and probability of nephrotoxicity (OR 2.37; 95% CI 1.84-3.22, p=0.004). CONCLUSIONS LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation or observed clinical factors

Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease

Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans. Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans, with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log10CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis

Fildelning och upphovsrätten i Finland

Detta lärdomsprov är gjort för att ge en bild av hur fildelningen och upphovsrätten ser ut i Finland idag. I teoridelen går jag in på hur EU påverkar Finland med nya direktiv och metoder för att kämpa mot piratism. Jag beskriver även upphovsrättens historia och utveckling samt tar upp olika tekniker och programvaror som används inom fildelning. Orsaken till att jag valde detta ämne som lärdomsprov är för att ämnet fått så stor uppmärksamhet i medier under de senaste tio åren. Nuförtiden har de flesta tillgång till snabba nätverk och många sysslar med illegal fildelning för att det är så enkelt, snabbt och riskfritt, men också för att dagens ungdom kräver att nytt material genast skall finnas till hands. Till sist går jag igenom hur upphovsrätten ser ut idag och hur musik och filmbranschen påverkas av långsamma lagförändringar. Lärdomsprovet innehåller en undersökning i form av enkät som 28 personer svarade på. Resultatet gav samma svar som de flesta andra liknande undersökningar på nätet gav. Slutledningen av undersökningen var att illegal fildelning är vanligt ännu idag men att lagliga alternativ har lyckats vända på spelet och fått människor att välja lagliga alternativ på grund av lättillgänglighet av material.This thesis is done to provide a picture of what file sharing and copyright laws looks like in Finland today. In the theoretical part I go into how the EU affects Finland, with new directives and the methods in the fight against piracy. I will go a bit into the history of copyright and the development of it. I will also discuss various techniques and software used in file sharing. The reason for choosing to study this topic is that the substance has received so much attention in the media over the 10 last years. Nowadays, most people have access to fast networks and many are engaged in illegal file sharing because it is so simple, quick and safe. But also because the youth today requires that new material are immediately to be available. Finally, I go through how copyright law is today, and how the music and film industry is affected by the slow legislative changes. The thesis includes a study in form of a questionnaire that 28 people responded to. The result gave the same answer as most other similar studies online have given. The conclusion of the study was that illegal file sharing is common even today but the legal options have managed to turn the tables and led people to choose the legal option because of the easy availability of materials