摘要:

Within the past decade, gene therapy strategies have come to the forefront of novel therapeutics. Tremendous advances in vector technology along with deeper understandings of vector biology and the molecular mechanisms of disease have significantly advanced the field of human gene therapy. This manuscript will discuss the viral-based subset of current gene transfer vectors. In particular, the most established viral vectors to date, including parvovirus, adenovirus, retrovirus, lentivirus, and herpesvirus-based vectors, are described, as well as the current innovative improvements being made to each. From past experience, it has become evident that in addition to optimising the vectors in terms of transgene expression, minimising vector-related immunology, and vector production, methods of vector delivery resulting in optimum vector transduction of target cells need to be established. This review will also illustrate several current improved physical delivery systems for optimal vector administration.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity.In EMs, ~80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately $US5000 for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease andH. pyloriinfection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs.Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal.Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Dramatic developmental changes in the physiological and biochemical processes that govern drug pharmacokinetics and pharmacodynamics occur during the first year of life. These changes may have significant consequences for the way infants respond to and deal with drugs. The ontogenesis of systemic clearance mechanisms is probably the most critical determinant of a pharmacological response in the developing infant. In recent years, advances in molecular techniques and an increased availability of fetal and infant tissues have afforded enhanced insight into the ontogeny of clearance mechanisms. Information from these studies is reviewed to highlight the dynamic and complex nature of developmental changes in clearance mechanisms in infants during the first year of life.Hepatic and renal elimination mechanisms constitute the two principal clearance pathways of the developing infant. Drug metabolising enzyme activity is primarily responsible for the hepatic clearance of many drugs. In general, when compared with adult activity levels normalised to amount of hepatic microsomal protein, hepatic cytochrome P450-mediated metabolism and the phase II reactions of glucuronidation, glutathione conjugation and acetylation are deficient in the neonate, but sulfate conjugation is an efficient pathway at birth. Parturition triggers the dramatic development of drug metabolising enzymes, and each enzyme demonstrates an independent rate and pattern of maturation. Marked interindividual variability is associated with their developmental expression, making the ontogenesis of hepatic metabolism a highly variable process. By the first year of life, most enzymes have matured to adult activity levels.When compared with adult values, renal clearance mechanisms are compromised at birth. Dramatic increases in renal function occur in the ensuing postpartum period, and by 6 months of age glomerular filtration rate normalised to bodyweight has approached adult values. Maturation of renal tubular functions exhibits a more protracted time course of development, resulting in a glomerulotubular imbalance. This imbalance exists until adult renal tubule function values are approached by 1 year of age. The ontogeny of hepatic biliary and renal tubular transport processes and their impact on the elimination of drugs remain largely unknown.The summary of the current understanding of the ontogeny of individual pathways of hepatic and renal elimination presented in this review should serve as a basis for the continued accruement of age-specific information concerning the ontogeny of clearance mechanisms in infants. Such information can only help to improve the pharmacotherapeutic management of paediatric patients.The dearth of pharmacological data specific for the infant population poses a significant obstacle to the successful pharmacotherapeutic management of such patients. Until recently, moral, ethical and legal issues had seriously impeded rigorous scientific investigation into paediatric drug pharmacokinetics, such that most marketed drugs merely contain disclaimers for their use in these populations.[1] In the absence of age-specific pharmacological data, infant dosage regimens become based upon information available only in adult patient populations. Despite their prudence and conservatism, empirical approaches to pharmacotherapy still produce suboptimal, serious and even lethal consequences of drug exposure in infants. Such adverse outcomes exist because physiological and biochemical maturation of pharmacokinetic and pharmacodynamic characteristics alter the pharmacology and potential toxicity of drugs in infants as compared with adult patients.Systemic clearance constitutes a critical pharmacokinetic parameter in the determination of a pharmacological response. Yet the exact impact of clearance pathway ontogenesis on an infant's capacity to eliminate drugs remains largely unknown. With recent improvements in molecular technology, more precise information on the development of individual clearance pathways has become available. Part I of this review provides a comprehensive and descriptive account of the ontogenesis of hepatic and renal elimination mechanisms, principally based upon recently available molecular andin vitroenzyme activity data for hepatic metabolic clearance mechanisms andin vivoprobe substrate data for renal clearance due to glomerular filtration. Such descriptions highlight the dynamic nature of these developmental processes during early postnatal life and how these processes may affect drug elimination and pharmacological response in infants. In general, hepatic and renal clearance mechanisms are underdeveloped and inefficient in the neonate, a condition further exacerbated in the premature infant. These mechanisms undergo dramatic developmental changes following birth and demonstrate different rates and patterns of maturation to adult values. Discussion herein of the ontogeny of such hepatic and renal clearance mechanisms is based upon hepatic microsomal activity data normalised to the amount (mg) of microsomal protein content and renal glomerular filtration rate (GFR) normalised to bodyweight (kg) for both infant and adult data. Such background information should allow the reader to draw his/her own conclusions concerning the risk of adverse drug exposure.Based upon thein vitroenzyme kinetic data andin vivoprobe substrate data, part II of the review[2] proposes a tentative mathematical model to serve as a foundation for the development of a more comprehensive model that may predict infant clearance in the first 6 months of life.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo examine the pharmacokinetics of omeprazole during intravenous infusion in patients with varying degrees of liver dysfunction (Child-Pugh categories A to C).DesignNonblinded single-period study.PatientsThirteen patients, five males and eight females with a mean age of 59 years and proven hepatic cirrhosis, classified according to Child-Pugh criteria as A (n = 5), B (n = 4) or C (n = 4).MethodsEach patient received an 80mg bolus of omeprazole over 30 minutes followed by a continuous infusion of 8 mg/h for 47.5 hours. Blood samples were taken frequently throughout the infusion and during the subsequent 24-hour washout period for determination of omeprazole and its metabolites. Laboratory screening was also performed at the start of the study, after 72 hours and at the 14 day follow-up visit.ResultsData were evaluable for 12 patients. For omeprazole, the mean total area under the plasma concentration-time curve (AUC) was 286.5 μmol • h/L, peak plasma concentration was 14.9 μmol/L and terminal elimination half-life was 4.1 hours; these values were higher than those observed historically in control patient populations. Concentrations of the metabolite omeprazole sulphone were also increased, but there was a decrease in concentrations of hydroxy-omeprazole. Deviations from normal values increased with increasing disease severity for all parameters. For example, in patients with liver dysfunction of Child-Pugh categories A, B and C, AUC48was 240.8, 280.4 and 323.3 μmol • h/L compared with 151.3 μmol • h/L in the historical control population. Despite its altered pharmacokinetics, omeprazole was not associated with any serious or untoward effects.ConclusionExposure to omeprazole following intravenous administration was higher in patients with liver dysfunction than in the normal population. However, even in patients with severely impaired liver function, the omeprazole plasma concentration did not change by more than 100% and the drug was well tolerated.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS