Erythropoietin production in healthy volunteers subjected to controlled hypobaric hypoxia: further evidence against a role for adenosine

Aims Objective of this study was to investigate whether adenosine modulates renal erythropoietin production.
Methods In the present study erythropoietin production was stimulated by hypobaric hypoxia by subjecting healthy volunteers to a simulated altitude of 4000  m in a low pressure chamber for 5.5  h. During exposure to hypoxia the subjects received i.v. in a randomized, single-blind, cross-over fashion the non-specific adenosine antagonist theophylline, the adenosine reuptake inhibitor dipyridamole and placebo.
Results Contrary to the working hypothesis, theophylline did not decrease and dipyridamole did not further boost erythropoietin concentrations.
Conclusions The results are in agreement with our earlier study using haemorrhage as a controlled physiological stimulus of erythropoietin production, and would question a major role for adenosine as a mediator of renal erythropoietin production.     

Comparative effects of enoximone and theophylline on plasma catecholamines and haemodynamics in cardiosurgical patients

Summary The release of endogenous catecholamines in aorto-coronary bypass graft patients receiving either 0.5 mg/kg enoximone (n=10), 4.0 mg/kg theophylline (n=10) or saline solution (control,n=10) has been studied, as well as certain haemodynamic parameters. Adrenaline (A) and noradrenaline (NA) concentrations were not significantly changed by the administration of enoximone. Theophylline caused a small increase in NA (+ 40% in the 1st min) and a marked increase in A (approximately + 7000% in the 1st min), which still remained elevated at the end of the investigation period (+ 220% in the 30th min). The major haemodynamic effects of enoximone were a significant increase in cardiac index (CI; + 35%) and a decrease in pulmonary capillary wedge pressure (PCWP; −27%), pulmonary artery pressure (PAP; −21%), RVEDV and RVESV, while the heart rate (HR) remained almost unchanged. The dominant haemodynamic effects of theophylline were an increase in HR (+ 26%; arrhythmia in 3 patients), PAP (+ 22%), and RVEDV (+ 19%), while REVESV (+ 26%), MAP (−16%), CI (−14%), and RVEF (−15%) fell significantly. It is concluded that the haemodynamic actions of enoximone are not mediated by catecholamine release, whereas the adverse cardiovascular effects of theophylline might partly be explained by the significant increase in plasma adrenaline.     

紫外分光光度法测定甘氨酸茶碱钠中茶碱的含量

本文建立了用于甘氨酸茶碱钠中茶碱含量测定的紫外分光光度法。将样品溶于０．１ｍｏ１／Ｌ氢氧化钠溶液中，在２７４ｎｍ波长处测其吸收度，结果的相对标准偏差（ＲＳＤ）为０．２２％．与药典方法比较，Ｆ．ｔ检验均无显著性差异．本法简便，快速，结果可靠，准确．     

Chronic administration of theophylline to rats induces a post-insulin binding defect in adipocyte glucose transport

Summary To determine whether adenosine is involved in long-term regulation of glucose transport in adipose tissue, we have investigated effects of administration of an adenosine receptor antagonist (theophylline) on adipocyte glucose transport. Rats were injected with theophylline (30 mg/kg, dissolved in 0.9% NaCl) daily for 7 days. Controls were injected with saline. The rats were then killed, and epididymal adipocytes were isolated. Insulin-stimulated glucose transport rates were decreased by about 25%–30% in the cells from theophylline-treated rats at all insulin concentrations tested. The half-maximally effective concentration of insulin was not altered (6.5±0.5 and 6.7±0.5 mU/l in control and treated cells respectively), suggesting a post-insulin binding defect. This was confirmed by the finding that ¹²⁵I-insulin binding to the cells was not altered. Adenosine receptor number and affinity (measured on detergent-solubilized adipocyte extracts using ¹²⁵I-hydroxyphenylisopropyl adenosine) was also not changed by theophylline treatment. We conclude that theophylline administration causes decreased glucose transport rates in rat adipocytes at a post-insulin binding level. Thus, chronic adenosine receptor blockade impairs adipocyte glucose transport, suggesting that adenosine is involved in long-term regulation of glucose metabolism in adipose tissue.     

A theophylline dosage regimen which reduces round-the-clock variations in plasma concentrations resulting from diurnal pharmacokinetic variation

Summary Slower drug absorption at night can leave residual drug from an evening dose of a sustained-release product remaining to be absorbed at the time of the next morning's dose, thereby giving higher plasma concentrations of the drug during the day than the night.When a capsule product releasing theophylline over 12 h after a morning dose was given repetitively at 8 a.m. and 8 p.m. for 4 days, daytime plasma concentrations from 4 h to 8 h after the dose were about 40% greater than corresponding night-time concentrations, and the mean steady-state concentration during the night-time interval was only 81% of that during the daytime interval.Altering the regimen to one capsule at 12 noon and one at 10 p.m. eliminated all significant differences between a.m. and corresponding p.m. plasma concentrations of theophylline and between the mean steady-state concentrations for each of the interdose intervals within a day.     

新抗喘药物的研究——茶碱衍生物及卤代苯乙醇胺化合物的合成

本文根据β_2-受体兴奋剂和茶碱类药物的作用机制,结合两类药物的基本结构和构效关系,运用新药设计中的拼合原理及生物电子等排原理,设计扦合成了两类共十六个尚未见于文献报导的化合物。经初步药理实验证明均具有抗哮喘作用,其中I_(5-8)活性较高,且对心脏副作用轻微,可望成为治疗哮喘的新药。     

色甘酸钠混悬气雾剂与茶碱缓释胶囊治疗中度哮喘的比较

８４例中度哮喘病人分成２组。色甘酸钠组（男性２３例，女性２０例，年龄２６±ｓ８ａ）吸入色甘酸钠混悬气雾剂１０．５ｍｇ，ｔｉｄ。茶碱缓释胶囊组（男性２２例，女性１９例，年龄２７±８ａ）口服０．２５ｇ。ｂｉｄ。２组均连续观察３ｍｏ。结果：色甘酸钠在减轻病人慢性症状、改善肺功能和降低气道高反应性等方面优于茶碱缓释胶囊，（Ｐ＜０．０１）。而后药仅可缓解近期症状。     

Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl);weight was inferior to age and did not statistically improve the model (p>0.005when combined with age. Total Clincreased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Clvalues: for a given age, Clwas 34% higher for blacks than the reference population composed of the remaining patients, and Clfor males was 25% higher than that for females. The volume of distribution (Vdfor the population was estimated to be 0.62 L/kg. The interindividual variability in Cland Vdexpressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 g/ml. The STCs that represented some degree of outpatient dosing were 21 % lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.     

Glucagon-induced somatostatin release from perifused rat hypothalamus: calcium dependency and effect of cysteamine treatment

Somatostatin (SRIF) release from rat hypothalamus was investigated in vitro with a perifusion system. Glucagon (1 microM) and high potassium concentrations (56 mM) stimulated SRIF release in a calcium-dependent manner. Pretreatment of the rat with cysteamine (30 mg/100 g body weight, 7 h earlier) significantly reduced SRIF release from the hypothalamus in glucagon- and high potassium-stimulated states as well as in the basal state. SRIF release from rat hypothalamus was also stimulated by both dibutyryl cyclic AMP (1 mM) and theophylline (3 mM). These results suggest that glucagon, acting in a calcium-dependent manner and possibly through the adenylate cyclase-cyclic AMP system, stimulates SRIF release from rat hypothalamus and that cysteamine treatment reduces releasable SRIF in the hypothalamus.     

Correlation Between In Vivo Antipyrine Metabolite Formation and Theophylline Metabolism in Rats

Two model substrates for oxidative hepatic enzyme activity, viz. antipyrine (A) and theophylline (T), were given simultaneously to rats by iv administration. Blood concentrations of A and T were measured by a high-performance liquid chromatographic (HPLC) method. Urinary excretions of A, T, and the major metabolites arising from A—4-hydroxyantipyrine (OHA), norantipyrine (NORA), 3-hydroxymethylantipyrine (HMA), and 4,4-dihydroxyantipyrine (DOHA)—and from T—1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMU)—were also determined by HPLC. It was found that the pharmacokinetic parameters obtained after the simultaneous administration of A and T at relatively low dose levels (A, 5.0 mg; and T, 1.3 mg) were not different from those obtained after the separate administration of A or T at the same dose level. In order to investigate whether the metabolic pathways of A and T are mediated by the same or closely related forms of the cytochrome P-450 system, metabolic clearances of A (CL_A,M) and T (CL_T,M) and the clearances for production of their various metabolites, obtained in untreated rats and in rats pretreated with 3-methylcholanthrene (MC) or with MC followed by 9-hydroxyellipticine (E), were correlated. These two compounds are a selective cytochrome P-448 inducer and inhibitor, respectively. Strong correlations were found between CL_T,M and the clearances for production of OHA, NORA, and DOHA but not HMA. The best correlation, however, was observed between CL_T,M and CL_OHA, not only when all data points were taken into account (r = 0.99), but also in separate pretreatment groups (r ranging from 0.87 to 0.92). Moreover, the slopes of these correlation lines varied only slightly among groups, while the intercepts were not significantly different from zero. In the separate pretreatment groups, the correlation coefficients for the correlations between CL_T,M and the clearance for production of the other metabolites of A were considerably lower, while the slopes of the correlation lines varied substantially. Clearances for production of the metabolites of T were strongly correlated with each other (r = 0.99) and with CL_OHA (r = 0.95). It can be concluded that theophylline metabolism and formation of OHA are mediated by the same or very similar forms of cytochrome P-450, whereas formation of the other major metabolites of A is not or only partly. The study of the various pathways of metabolism after simultaneous administration of drugs is a powerful tool in the study of correlations in drug metabolism in vivo.