A Stochastic Compartmental Model with Long Lasting Infusion

Most of the compartmental models in current use to model pharmacokinetic systems are deterministic. Stochastic formulations of pharmacokinetic compartmental models introduce stochasticity through either a probabilistic transfer mechanism or the randomization of the transfer rate constants. In this paper we consider a linear stochastic differential equation (LSDE) which represents a stochastic version of a one‐compartment linear model when input function undergoes random fluctuations. The solution of the LSDE, its mean value and covariance structure are derived. An explicit likelihood function is obtained either when the process is observed continuously over a period of time or when sampled data are available, as it is generally feasible. We discuss some asymptotic properties of the maximum likelihood estimators for the model parameters. Furthermore we develop expressions for two random variables of interest in pharmacokinetics: the area under the time‐concentration curve, M₀(T), and the plateau concentration, x_ss. Finally the estimation procedure is illustrated by an application to real data.     

瑞芬太尼复合异丙酚靶控输注对脊柱结核手术患者麻醉效果、血流动力学及应激反应的影响

摘要 目的：探讨瑞芬太尼复合异丙酚靶控输注对脊柱结核手术患者麻醉效果、血流动力学及应激反应的影响。方法：选取2018年3月15日~2019年12月24日期间我院收治的100例行脊柱结核手术患者,根据随机数字表法将患者分为对照组（n=50）和研究组（n=50）,对照组患者给予瑞芬太尼+异丙酚静吸复合麻醉,研究组给予瑞芬太尼+异丙酚靶控输注,比较两组患者麻醉效果、血流动力学、应激反应及不良反应情况。结果：研究组术后2 h 视觉模拟评分（VAS）低于对照组（P<0.05）,睁眼时间、睫毛反射时间、术后自主呼吸恢复时间、指令动作恢复时间、拔管时间均短于对照组（P<0.05）。研究组术毕时、拔管时、拔管后5 min平均动脉压（MAP）、心率（HR）高于对照组（P<0.05）。研究组术后1 d、术后3 d血管紧张素 Ⅱ（AngⅡ）、去甲肾上腺素（NE）、醛固酮（ALD）低于对照组（P<0.05）。两组不良反应发生率比较无统计学差异（P>0.05）。结论：脊柱结核手术患者采用瑞芬太尼复合异丙酚靶控输注,麻醉效果确切,可有效减轻血流波动及应激反应,且安全性较好。     

双囊气压输液袋在失血性休克病人中的应用

目的:评价应用双囊气压输液袋抢救失血性休克病人的疗效.方法:根据纳入/排除标准选择2009年1月至2012年6月收入我科的创伤失血性休克病人40例做为研究对象,分别采用双囊气压输液袋(实验组)或传统注射器配合三通管快速输液(对照组)恢复患者血压,观察和比较两种方法处理的患者输完250 mL液体所需的时间,恢复正常收缩压和正常动脉血氧饱和度的时间,以及连续扩容1000mL后的收缩压值、心率、体温和患者存活率.结果:实验组输注250mL液体所需的时间明显少于对照组(P＜0.01),实验组恢复正常收缩压和正常动脉血氧饱和度的时间少于对照组(P＜0.05),而两组患者在扩容1000 mL后收缩压、心率、体温的平均值的差异无统计学意义(P＞0.05),两组患者的存活率的差异无统计学意义(P＞0.05).结论:应用双囊气压输液袋补液抢救失血性休克病人能更迅速、有效恢复患者的收缩压.     

Evolution of infection in mice inoculated by the oral route with different developmental forms of Trypanosoma cruzi I and II

Oral infection has become the most important transmission mechanism of Chagas disease in Brazil. For this study, the development of Trypanosoma cruzi infection in mice, induced by the oral and intraperitoneal (IP) routes, was compared. Four groups of Swiss mice were used to evaluate the influence of parasite genetics, number of parasites, inoculation volume and developmental stages on the development of the orally induced infection: 1 – blood trypomastigotes (BT) via oral; 2 – BT via IP; 3 – culture metacyclic trypomastigotes (MT) via oral; and 4 – culture MT via IP. Animals inoculated orally showed levels of parasitemia, as well as infectivity and mortality rates, lower than animals inoculated via IP, regardless of DTU (discrete typing unit) and inoculum. Animals infected with TcII showed higher levels of these parameters than did animals infected with TcI. The larger volume of inoculum showed a greater capacity to cause an infection when administered via the oral route. BT infection was more virulent than culture MT infection for both routes (oral and IP). However, mice inoculated orally with BT showed lower levels than via IP, while mice inoculated orally with culture MT showed similar levels of infection to those inoculated via IP. Mice inoculated with culture MT showed more histopathological changes than those inoculated with BT, regardless of the inoculation route. These results indicate that this alternative experimental model is useful for evaluating infection by T. cruzi isolates with subpatent parasitemia and low virulence, such as those belonging to the TcI and TcIV DTUs, which are prevalent in outbreaks of orally transmitted Chagas disease.     

Day-Night and Individual Differences in Response to Constant-Rate Ranitidine Infusion

Twelve ulcer patients with inactive disease received constant-rate infusions of ranitidine, in doses of 6.25 and 10.0 mg/hr, during separate 24-h spans. Gastric pH and serum ranitidine concentrations were monitored. Serum ranitidine concentrations did not vary significantly after attainment of steady-state. For the group, gastric acidity was controlled above pH 4 during the day; however, at night, when gastric acid secretion was greatest under placebo conditions, ranitidine less effectively controlled gastric pH. There was individual variation in response to ranitidine. Patients (8/12) evidencing control of gastric acidity (pH ± 4) for at least 16 h when infused with ranitidine (6.25 mg/h) were considered re-sponders. Those (4/12) not so well controlled were designated poor responders. With parenteral infusion of 6.25, as well as 10.0 mg/h ranitidine, responders evidenced a relatively high 24-h mean pH and only minor day-night variation in gastric acidity. In contrast, poor responders were characterized by a low 24-h mean pH and high-amplitude circadian variation in gastric acidity. Poor responders evidenced statistically significant (p < 0.05) lower gastric pH responses to parenteral infusions than did responders. A similar, significant difference between the two groups was observed when the percentage of time that gastric pH was maintained below 4 was considered. Differences between responders and poor responders to ranitidine infusion are unknown. Since Zollinger-Ellison syndrome patients were not included in the study, observed differences in drug response cannot be ascribed to hypersecretion of gastric acid.     

Short-term parenteral application of α-tocopherol leads to increased concentration in plasma and tissues of the rat

Numerous studies suggest that supplemental vitamin E prior to or during vast surgeries might diminish or even prevent ischemia/reperfusion-induced injuries. In the present placebo-controlled study male Sprague-Dawley rats were supplemented parenterally or orally with α-tocopherol for three consecutive days. The applied amount of α-tocopherol was 2.3 μmol per day for oral and 1.2 μmol per day for parenteral supplementation. The enrichment of vitamin E concentrations in plasma and tissue samples (aortic endothelium, liver, and lung) was determined by HPLC. The vitamin E level was elevated following intravenous supplementation in plasma (21.4±1.9 μmol/L vs. 10.2±1.7 μmol/L in parenteral control group), in aortic endothelium (1.1±0.2 pmol/mm² vs. 0.5±0.1 pmol/mm²) and in liver and lung (41.3±7.5 pmol/mg vs. 22.9±6.5 pmol/mg and 75.6±13.6 pmol/mg vs. 51.7±5.9 pmol/mg, respectively). Oral supplementation for three days also led to an increased level in liver (38.2±7.7 pmol/mg vs. 22.9±6.6 pmol/mg in oral control group) and in lung (67.8±5.7 pmol/mg vs. 51.7±9.3 pmol/mg) but not in aortic endothelium or plasma (0.8±0.3 pmol/mm² vs. 0.6±0.3 pmol/mm² and 12.0±2.2 μmol/L vs. 10.7±2.6 μol/L.)     

Effects of Hemodialysis,Dialyser Type and Iron Infusion on Oxidative Stress in Uremic Patients

Uremic patients undergoing hemodialysis (HD) are considered to face an elevated risk for atherosclerosis and cancer. This has been attributed in part to an increased oxidative stress. In this pilot study, oxidative cell damage in blood of HD-patients was compared to those of controls: total DNA damage (basic and specific oxidative DNA damage), modulation of glutathione levels (total and oxidized glutathione) and of lipid peroxidation were monitored via the Comet assay (with and without FPG), a kinetic photometric assay and HPLC quantification of plasma malondialdehyde (MDA), respectively. In some samples, leukocytes were analysed for malondialdehyde–deoxyguanosine-adducts (M₁dG) with an immunoslot blot technique.

HD-patients (n=21) showed a significant increase of total DNA damage (p<10^-12), compared to controls (n=12). In a subset of patients and controls, GSSG levels and M₁dG, however, only increased slightly, while tGSH and MDA levels did not differ. The influence of different low flux HD-membranes was tested in a pilot study with nine patients consecutively dialysed on three membrane types for four weeks each. In addition to the individual disposition of the patient, the dialyser membrane had a significant impact on oxidative stress. Total DNA damage was found to be almost identical for polysulfone and vitamin E coated cellulosic membranes, whereas a slight, but significant increase was observed with cellulose-diacetate (p<0.001). In patients receiving iron infusion during HD, MDA-formation (n=11) and total DNA damage (n=10) were additionally increased (p<0.005).

Our results show an increased oxidative damage in HD-patients, compared to healthy volunteers. Significant influences were found for the dialyser membrane type and iron infusion.     

Optimizing the concentration and bolus of a drug delivered by continuous infusion

We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intraarterially as rapid treatment for acute ischemic stroke.     

American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus

ObjectiveTo provide evidence-based recommendations regarding the use of advanced technology in the management of persons with diabetes mellitus to clinicians, diabetes-care teams, health care professionals, and other stakeholders.MethodsThe American Association of Clinical Endocrinology (AACE) conducted literature searches for relevant articles published from 2012 to 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established AACE protocol for guideline development.Main Outcome MeasuresPrimary outcomes of interest included hemoglobin A1C, rates and severity of hypoglycemia, time in range, time above range, and time below range.ResultsThis guideline includes 37 evidence-based clinical practice recommendations for advanced diabetes technology and contains 357 citations that inform the evidence base.RecommendationsEvidence-based recommendations were developed regarding the efficacy and safety of devices for the management of persons with diabetes mellitus, metrics used to aide with the assessment of advanced diabetes technology, and standards for the implementation of this technology.ConclusionsAdvanced diabetes technology can assist persons with diabetes to safely and effectively achieve glycemic targets, improve quality of life, add greater convenience, potentially reduce burden of care, and offer a personalized approach to self-management. Furthermore, diabetes technology can improve the efficiency and effectiveness of clinical decision-making. Successful integration of these technologies into care requires knowledge about the functionality of devices in this rapidly changing field. This information will allow health care professionals to provide necessary education and training to persons accessing these treatments and have the required expertise to interpret data and make appropriate treatment adjustments.     

门冬胰岛素与人普通胰岛素及胰岛素泵在2型糖尿病患者围手术期的疗效比较

目的：探讨速效胰岛素类似物（门冬胰岛素,诺和锐）与人普通胰岛素（诺和灵R）及胰岛素泵在2型糖尿病（T2DM）围手术期治疗中的有效性和安全性。方法：158例围手术期T2DM患者随机分为胰岛素泵输注门冬胰岛素治疗CSII组52例,门冬胰岛素多次皮下注射治疗MSII（A）组56例,人普通胰岛素多次皮下注射治疗MSII（B）组50例。观察各组患者治疗前后空腹和餐后2h血糖变化、血糖迭标时间、胰岛素用量、低血糖发生率及术后并发症发生率。结果：3组治疗后血糖均明显低于抬疗前,CSII组治疗后血糖低于MSII（A）组（P〈o．05）,MSII（A）组治疗后血糖低于MSII（B）组（P〈0．05）;术后并发症CSII组低于MSII（A）组（P〈0．05）,MSII㈧组低于MSII（B）组（P〈0．05）。结论：门冬胰岛素对T2DM围手术期血糖控制有较好的有效性、安全性和顺应性,胰岛素泵是2型糖尿病患者围手术期胰岛素输注的最佳模式。