Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs

Tick-borne encephalitis (TBE) virus is an important human pathogenic flavivirus that is endemic in Europe and Asia. The disease can be effectively prevented by inactivated vaccines and vaccination breakthroughs (VBTs) are rare. We investigated the characteristics of antibody responses in such VBTs in comparison to those in unvaccinated TBE patients. In contrast to the unvaccinated controls, most of the VBTs displayed a delayed IgM antibody response and had high avidity and strongly neutralizing antibodies already in the first sample taken upon hospitalization. The antibody profile of these patients therefore had the characteristics of an anamnestic immune response. In the VBTs analyzed, immunological priming and memory were apparently not sufficient or fast enough to prevent the disease.     

IL-4与IL-10联合诱导异种骨移植免疫耐受的体外研究

目的　探讨 IL - 4和 IL - 10在诱导异种骨移植免疫耐受中的作用。方法　反应细胞为 BAL B/c小鼠脾淋巴细胞 ,刺激细胞为新西兰白兔血淋巴细胞 ,刺激抗原为兔骨上清液。采用经典的混合淋巴细胞培养法及骨上清液与淋巴细胞混合培养法作为异种骨移植的体外实验模型。在各培养液中分别加入 IL - 4、IL - 10及两者联合应用 ,通过测定其 3H- Td R掺入率 ,观察不同细胞因子对刺激淋巴细胞增殖的影响。结果　无论在细胞刺激组还是骨上清液刺激组 ,IL- 4对淋巴细胞增殖均有显著抑制作用 (P<0 .0 0 1和 P<0 .0 5 ) ,IL- 10未表现出抑制作用 (P>0 .0 5 )。在两组 IL- 4和 IL - 10联合应用均产生比 IL - 4单独应用更为明显的细胞增殖抑制作用 (P<0 .0 0 1和 P<0 .0 5 )。结论　 IL - 4对由细胞或骨上清液刺激产生的淋巴细胞增殖均有很好的抑制作用 ,IL- 10没有表现出抑制作用 ;IL- 4与 IL- 10联合应用有协同抑制作用。     

Response rates,duration of response,and dose response effects in phase I studies of antineoplastics

Summary Over a period of 14 years, 7,960 patients were treated in 228 phase I trials. In these patients, there were 75 complete and 432 partial responses for an overall objective response rate of 6%. Complete responses lasted a median of six months (range 1–18), while partial responses lasted a median of three months (range 1–17). Of note is that no drug has made it to the market which has not had a response in phase I trials. Responses were noted in very diverse histologic types of tumors. Although there were responses at doses which were as low as 3–5% of the recommended dose for phase II trials, the majority of responses did occur at 80–120% of the dose recommended for phase II trials. Although the response rate in phase I trials is indeed low, responses do occur. This response rate information should help the clinician provide facts for the patient considering a phase I trial with new anticancer agents. These findings also emphasize that although phase I trials are characteristically dose-finding studies, if no responses are noted in phase I studies, it is unlikely the drug will be used routinely in the clinic.     

A simulation study of three sequential methods for the comparison of two treatment groups when the response criterion is censored

Three recent sequential methods, group sequential analysis (GSA), the sequential probability ratio test (SPRT) and the triangular test (TT) are well suited to randomized clinical trials with a censored response criterion, as they do not require matched pairs of patients. We undertook a simulation study to investigate their statistical properties and to compare these three methods with the fixed-sample design. Our results suggest that the three methods have the expected statistical properties for size and power; they allow an important reduction of the average number of events before stopping, except with GSA when there is no treatment difference; the triangular test (closed design) appears the optimal design, as the variance of the number of events is smaller than with the sequential probability ratio test (open design) and analysis after every twenty new events does not alter the statistical properties of these sequential methods and enhances their usefulness.     

The interactive role of mucosal T lymphocytes in intestinal growth, development and enteropathy

Abstract Over the past 15–20 years, research has progressively focused on the mucosal T cell as the central factor in the initiation of physiological or pathological changes, first in the growth and maturation of the early (postnatal) intestine, and second in adult-type enteropathies resulting from sensitivity to either food or pathogen-derived antigens. T cell-mediated events may be measured, for example, in terms of specific immunopathologic patterns of change and injury, such as type 1 (lymphocyte infiltration), type 2 (crypt hyperplasia) and type 3 (flat-destructive), which can be recognized and quantitated microscopically; by determination of lymphocyte reactivity through secretion of interleukin-2 receptors (IL-2R) into plasma or expression by mucosal lymphocytes; by quantitation of lymphocyte subsets emigrating into inflamed tissues by immunoperoxidase-labelled monoclonal antibodies; or by the determination of T cell receptor polymorphisms. Alterations in intestinal growth, structure and function at weaning are likely to be T cell-mediated as they are analogous to the same type 1/2 lesions that reflect modulation of adult mucosal architecture in food and parasite-induced hypersensitivity reactions. Enteropathies associated with HIV infection and T cell deficiency display a milder degree of villous flattening and impaired crypt hyperplasia than that typical of gluten-sensitivity, suggesting a reversion to lesser degrees of mucosal pathology (type 1/2). Clearly more information will accrue; meanwhile the remarks in this brief survey should provide a firm basis whereby clinician and scientist can meet, and together recognize and further dissect the modulatory effect of T lymphocytes on mucosal structure and function.     

Post-surgical pain relief with zero-order intravenous infusions of meptazinol and morphine: a double-blind placebo-controlled evaluation of their effects on ventilation

Summary A double-blind, placebo-controlled study has been made of the analgesic and respiratory effects of constant rate infusions of meptazinol and morphine in 30 patients after abdominal surgery. Group I received meptazinol, loading dose 50 mg followed by i.v. infusion 0.5 mg · kg⁻¹ · h⁻¹, Group II received morphine, loading dose 5 mg and then an infusion of 0.05 mg · kg⁻¹ · h⁻¹, and Group III received saline. After recovery from inhalation anaesthesia (without opiates or a local anaesthetic) pain relief and chemoreceptor carbon dioxide tolerance were assessed before and at various times after starting the analgesic infusion. A similar degree of pain relief was found after 10 min in Groups I and II, which lasted until the end of observation period (20 h). Heart rate and systolic and diastolic blood pressures were lower in Group II than in Groups I and III, and respiratory rate fell in Groups I and II. After 6 h arterial carbon dioxide tensions (P_aCO₂) became significantly higher in Group II than Group III. The maximum percentage fall in mean tidal volume (V_T) and expired minute volume (0V_E) from the preinjection values was significant in Groups I and II. End-tidal carbon-dioxide (P_ETCO₂) and P_aCO₂ were significantly higher after 20 h of infusion in Group II compared to Group I. The slope of 0V_E/P_ETCO₂ (<S>) was increased in Group I and it was significantly reduced in Group II. Analysis of derived variables, such as the CO₂ intercept (CO₂I) and minute ventilation at 7 kPa (0V_E7), indicated a shift to the right of the slopes in Groups I and II, initially more so in Group I. It is concluded that constant rate infusions of meptazinol and morphine were effective in providing postoperative pain relief. However, their effects on the central regulation of respiration were different, as meptazinol did not impair CO₂ sensitivity whereas morphine did.     

Effect of ceruletide on microvibration in schizophrenics

Ceruletide, a potent analogue of cholecystokinin, was administered by injection to eight schizophrenics treated with neuroleptics. We examined the dose–response effect on microvibration (MV) recorded from the chin of these patients. After 15 min of bed rest, MV was recorded for 5 min as a control recording. Subsequently, saline or ceruletide, at a dose of either 0.4 m?g/kg or at 0.8 m?g/kg, was injected according to a Latin square design with an interval of 4 weeks for washing out the drug effect and MV was recorded for 30 min. MV data obtained were subjected to the fast Fourier transform and an average power spectrum was computed. A three-way analysis of variance for these data was performed upon dose-effect, time-effect after treatment, and band-effect of the average power spectrum. The present results were similar to previous findings which had revealed effects of ceruletide on tardive dyskinesia symptoms, namely, the effects of ceruletide on MV were different according to the subjects (three cases: facilitation followed by inhibition, three cases: inhibition, two cases: no effects). The dose-response curve of ceruletide appears to be linear in some cases and an inverted U-shape in other cases. Present findings showed small doses of systemically administered ceruletide would modify muscle tonus of schizophrenics under chronic treatment of neuroleptics, and provided further reason for the therapeutic drug of tardive dyskinesia.     

Disorders in early embryonal cellular proliferative properties distort the postnatal formation of nervous, immune, and endocrine regulation systems in a newborn

Disorders in the postnatal nervous, immune, and endocrine regulation systems were revealed in the progeny of rats irradiated during the preimplantation period of embryogenesis. These disorders persist till adult age. The direction of disorders confirms the hypothesis about memorization of changed proliferative properties of embryonal cells during the development of the (pro)endocrine system of a new organism. Memorization results in distortion of postnatal nervous immunoendocrine regulation: hypertrophy of the endocrine component and coadaptive underdevelopment of the nervous and immune components. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 8, pp. 164–166, August, 1998     

红细胞不同温度长期冻存后形态和免疫功能的变化及其临床意义

目的 探讨一种简便、有效的红细胞长期保存的方法。方法 红细胞在－40℃、80℃及－196℃（液氮）不同温度下长期保存18个月后，分别测定冻存前后红细胞平均体积（MCV）、红细胞渗透脆性（RFT）及红细胞免疫功能（RBC－C3bRR、ERPN）。结果 红细胞－40℃长期冻存后，MCV和RFT较冻存前显著提高（P＜0.05)，RBC－C3bRRt ERPN较冻存前显著降低（P＜0.05)。红细胞－80℃、－196℃长期冻存后，MCV、RFT、RBC－C3bRR及ERPN较冻存前无明显改变（P＞0.05)。结论 红细胞经－80℃、－196℃长期冻存后，其形态、结构和免疫功能保存良好。－80℃低温冻存是一种简便、有效的红细胞长期保存的方法。