RESUMEN
Neumann et al. [1] developed a widely used model for the analysis of hepatitis C virus (HCV) dynamics after the initiation of interferon therapy that assumes the effectiveness of therapy in blocking virion production, epsilon, is constant. However, with pegylated interferon alpha-2b (PEG-IFN) given weekly, there are significant changes in drug concentration between doses, leading to changes in drug effectiveness and viral rebounds. To investigate the appropriateness of the constant effectiveness (CE) model [1] for studies involving PEG-IFN, we simulated PEG-IFN treatment, using 294 sets of pharmacokinetic/pharmacodynamic (PK/PD) parameters that span observed ranges and fit the simulated data to the CE model. For most combinations of PK/PD parameters, the fits resulted in an infected cell loss rate, delta, that underestimates the true value used in the simulations and yielded over-estimates of the average effectiveness of PEG-IFN. In the setting of PEG-IFN therapy, the use of the CE model of HCV kinetics has to be reevaluated and the validity of its use depends on the amount of HCV RNA rebound observed between doses.
Asunto(s)
Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Interferón-alfa/farmacología , Interferón-alfa/farmacocinética , Carga Viral , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/uso terapéutico , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Modelos Biológicos , Modelos Teóricos , Polietilenglicoles , ARN Viral/sangre , Proteínas RecombinantesRESUMEN
Viral kinetic models for hepatitis C virus (HCV) have generally assumed that the effectiveness of therapy in blocking virion production, epsilon, is constant. However, with pegylated interferon alpha-2b (PEG-IFN) given weekly, there are significant changes in drug concentration between doses that may lead to changes in drug effectiveness and viral rebounds towards the end of the dosing interval. Here we investigate the effects of using a model that assumes a constant effectiveness for studies involving PEG-IFN. We simulated PEG-IFN treatment in a population of 294 computer simulated 'patients', each characterized by a different set of pharmacokinetic and pharmacodynamic parameters. We then sampled the simulated treatment data over 4 weeks with a schedule similar to that used in viral kinetic studies, and fitted a viral kinetic model assuming constant drug effectiveness, the CE model, to that data. Although the CE model was able to fit to the data well in most cases, the parameter estimates obtained scattered widely both above and below the true values. Thus, this model is less useful to analyse HCV RNA data during therapy with PEG-IFN than with standard IFN given daily. With PEG-IFN accurate estimation of viral dynamic parameters necessitates concomitant measurements of serum viral load and drug concentration.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Interferón-alfa/uso terapéutico , Carga Viral , Antivirales/farmacocinética , Antivirales/farmacología , Simulación por Computador , Humanos , Interferón alfa-2 , Interferón-alfa/farmacocinética , Interferón-alfa/farmacología , Modelos Biológicos , Polietilenglicoles , ARN Viral/sangre , Proteínas RecombinantesRESUMEN
Defense against pathogen, parasites and herbivores is often enhanced after their invasion into the host's body. Sometimes different options are adopted depending on the identity and the quantity of the pathogen, exemplified by the switch between Th1 and Th2 systems in mammalian immunity. In this paper, we study the optimal defense of the host when two alternative responses are available, which differ in the effectiveness of suppressing the growth of pathogen (parasite, or herbivore), the damage to the host caused by the defense response, and the magnitude of time delay before the defense response becomes fully effective. The optimal defense is the one that minimizes the sum of the damages caused by the pathogen and the cost due to defense activities. The damage by pathogens increases in proportion to the time integral of the pathogen abundance, and the cost is proportional to the defense activity. We can prove that a single globally optimal combination of defense options always exists and there is no other local optimum. Depending on the parameters, the optimal is to adopt only the early response, only the late response, or both responses. The defense response with a shorter time delay is more heavily used when the pathogen grows fast, the initial pathogen abundance is large, and the difference in time delay is long. We also study the host's optimal choice between constitutive and inducible defenses. In the constitutive defense, the response to pathogen attack works without delay, but it causes the cost even when the pathogen attack does not occur. We discuss mammalian immunity and the plant chemical defense from the model's viewpoint.
Asunto(s)
Infecciones Bacterianas/inmunología , Mamíferos/inmunología , Modelos Inmunológicos , Enfermedades Parasitarias/inmunología , Animales , Enfermedades de las Plantas , Plantas , Factores de TiempoRESUMEN
Polymerase chain reaction was applied to the diagnosis of mycobacterial infections. This reaction could detect bacteria in clinical specimens within a few hours. Sensitivities of the five primer systems reported in 1990 were compared. It was proved that the primer system reported by Eisenach et al. was as sensitive as culture on Ogawa's medium for the detection of Mycobacterium tuberculosis in sputa. Other systems were found to be less sensitive than this system, and the nested PCR should be applied to make these systems highly sensitive. For the practical application of PCR method, we should improve the detection system to fit for the practice in clinical laboratory. High cost of PCR system could be another barrier for the practical application.