An evaluation of numerical integration algorithms for the estimation of the area under the curve (AUC) in pharmacokinetic studies

Six numerical integration algorithms based on linear and log trapezoidal methods as well as four cubic-spline methods were proposed for estimation of area under the curve (AUC). These six different algorithms were implemented using IMSL/IDL^TM command language and evaluated using data simulated under five different dosing conditions and two different sampling conditions. Comparisons between AUC estimations using these six different algorithms and the theoretical results were made in terms of both overall AUC values and the superimposability of the concentration-time profiles. In well designed studies with ample data points, the algorithm based on IMSL/IDL^TM function CSSHAPE with concavity preservation gave the best performance. In contrast, when the frequency of blood collection was limited, the algorithm based on the log trapezoidal rule proved to be stable with reasonable accuracy, and is recommended as the practical method for numerical interpolation and integration in pharmacokinetic studies. Algorithms based on the combination of the log trapezoidal rule and cubic-spline methods using IMSL/IDL^TM function CSSHAPE can be developed to enhance overall performance.     

Disposition of a silicon-containing amide, an inhibitor of acyl-CoA: cholesterol acyltransferase, in dog and rat

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide (DMPP), an inhibitor of acyl-CoA:cholesterol acyltransferase, have been studied in the dog and the rat using 14C and 3H dual-labelled drug. In both species, gastrointestinal absorption of DMPP was slow and incomplete, amounting to approximately 20 per cent of the oral dose given in corn oil. In the rat, use of PEG-400, Tween 80, ethanol, and aqueous CMC as vehicles resulted in similar or lower absorption than corn oil. Absorbed DMPP was rapidly and extensively distributed to body tissues. Data from the rat showed highest concentrations of radioactivity in the liver and spleen, while concentrations in the adrenals and lung also markedly exceeded circulating radioactivity levels. In both dog and rat. DMPP was completely metabolized prior to excretion. The routes of biotransformation involved hydrolysis of the amide bond, oxidation of the phenyl ring, and degradation of the decyldimethylsilyl propanoyl moiety. The metabolites of DMPP were excreted slowly, predominantly in the faeces. The elimination half-life of 14C was 105 h in the dog and 83 h in the rat, while that of 3H was approximately 32 h in both species.     

Recombinant tissue-plasminogen activator (rt-PA) in acute myocardial infarction in the Chinese in Hong Kong.

Eighty-nine consecutive Chinese patients (69 males, 20 females) with acute myocardial infarction treated by 100 mg recombinant tissue-plasminogen activator (rt-PA) (7 intracoronarily, 82 intravenously) at 3.7 +/- 1.0 hours after onset, and intravenous heparin or dipyridamole therapy started at 3 hours, were studied prospectively. Their mean age was 59.6 +/- 10.6 years. Forty-six patients (51.7%) had anterior and 39 patients (43.8%) had inferior infarcts. Clinical evidence of reperfusion was seen in 63 patients (72.8%), while new complications included hypotension (5.6%), heart failure (6.7%), cardiac arrhythmias (76.4%), hematoma around vascular access sites (23.6%), melena (2.2%) and cerebral infarction (2.2%). Maximal changes in coagulation profiles were seen at 3 hours, including a decrease in fibrinogen (by 64.2%), an increase in FDP by 11.7 times and D-dimers by 4.4 times. Nine patients (10.1%) had recurrence of angina and 6 patients (6.9%) died due to pump failure (5) and reinfarction (1). Angiogram at 14 days confirmed TIMI (2 or 3) patency of infarct related arteries in 62/81 (76.5%) patients, with a mean global ejection fraction of 52.5 +/- 12.4%. Nearly all survivors could maintain class I-II functional status after discharge. The safety and promises of rt-PA for acute myocardial infarction in the Chinese were confirmed.

     

Plasma Histamine After Methacholine, Allergen, and Aspirin Challenges

Plasma histamine levels were measured by radio-enzymatic technique in seven patients following 10 challenges: five methacholine challenge tests, four antigen inhalation challenge tests, and one oral aspirin challenge test. Baseline plasma histamine was the same in all patients except in the aspirin-challenged patient, who had a higher baseline histamine level. There was no statistical change in the level of histamine throughout the test in either the methacholine-challenged or the antigen-challenged patients, whereas there was a marked increase in histamine levels in the aspirin challenged patient. A possible explanation is that methacholine and antigen are inhaled and therefore have primarily local effects on the lung, whereas oral aspirin has a systemic effect with consequently systemic changes in histamine which are detectable as changes in plasma level.     

Inhibition of human endothelial cell proliferation in vitro in response to n-butyrate and propionate

The study aimed to investigate the effects of n-butyrate and propionate on the proliferation and viability of human endothelial cells in culture. Proliferation was assessed by a 24-hour bromodeoxyuridine pulse labelling and immunoperoxidase method and viability was assessed by a colorimetric viability (MTT) assay. Endothelial cells were isolated from human umbilical vein by collagenase digestion. Experiments were performed on 96-well plates and cultures were exposed to different concentrations of n-butyrate and propionate for 2 days. n-butyrate and propionate caused significant reductions in the proliferation of endothelial cells at concentrations of 1.25 mM and 10 mM respectively (p less than 0.05); the reduction in proliferation was dose-dependent for both agents. n-butyrate was a more potent inhibitor of proliferation than propionate. However, there were no significant effects on the viability of the cells with both agents up to the highest concentrations tested (25 mM). The data indicate that n-butyrate and propionate inhibit endothelial cell proliferation which may contribute to the pathogenic effects of dental plaque in periodontal disease.     

一些保肝药物对原代培养大鼠肝细胞糖原合成功能的影响

本文参照PO Seglen的方法并加以修改,建立了原代培养大鼠肝细胞糖原合成功能的测定体系。观察到联苯双酯既能使正常肝细胞合成糖原增加88%,又能保护肝细胞完全拮抗四氯化碳对其功能的损伤;银耳多糖能使四氯化碳对肝细胞糖原合成功能的损伤减轻57%;去甲斑蝥素10μg/ml能增加肝细胞糖原合成,浓度增加到100μg/ml时,此作用减弱,1000μg/ml则明显抑制糖原的合成,而且在10～100μg/ml浓度时,即能加强四氯化碳的损伤作用;100μg/ml CL₁₅₀₀和熊果酸二钠单独应用可增加肝细胞糖原合成,但与四氯化碳同时应用,反而加重对糖原合成的抑制作用。     

Stress-activated protein kinases mediate cell migration in human airway epithelial cells

Airway epithelial cell (AEC) repair immediately after injury requires coordinated cell spreading and migration at the site of injury. Stress-activated protein kinases such as p38 MAPK and c-Jun N-terminal Protein Kinase (JNK) modulate several responses to cell stress and injury, but their role in AEC migration is not clear. We examined migration in confluent 16HBE14o(-) human AEC lines and in primary AEC grown on collagen-IV. Wounds were created by mechanical abrasion and followed to closure using digital microscopy. Inhibitors of either p38 extracellular signal-regulated kinase (ERK)1/2 (PD98059), mitogen-activated protein kinase (MAPK) (SB203580), or JNK (SP600125) could block cell migration substantially. Inhibiting JNK but not p38 MAPK or ERK1/2 blocked extension of cells into the wound region from the original line of injury. Initial migration was associated with phosphorylation of ERK, p38 MAPK, and JNK within 5-15 min. The downstream effector of p38, heat shock protein 27, also was phosphorylated rapidly after injury; phosphorylation could be blocked by prior treatment with SB203580 but not SP600125. The downstream effector of JNK, c-Jun, likewise was phosphorylated rapidly after injury and could be blocked by inhibiting JNK. Our data demonstrate that p38 MAPK, JNK, and ERK1/2 participate in the early stages of AEC migration.