The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous,intramuscular, and subcutaneous injection

Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 g lisuride hydrogen maleate as an aqueous solution.After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min^–1·kg^–1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration.The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.     

Yohimbine pharmacokinetics and interaction with the sympathetic nervous system in normal volunteers

Summary The pharmacokinetics of yohimbine and its effects on sympathoadrenal function were studied in 13 young, healthy, male volunteers after an IV bolus dose of 0.25 or 0.5 mg · kg^–1.Pharmacokinetic analysis showed that distribution was rapid, with a half life between 0.4 and IS min, and the elimination half life ranged between 0.25 and 2.5 h. The volume of distribution (V_ss) was 741, (range 26 to 1271). Only 0.5 to 1 % of unchanged yohimbine was found in the urine, indicating that the major part of the drug was eliminated by hepatic clearance. Total plasma clearance was 1171. h^–1, which exceeds the hepatic plasma flow. This means that yohimbine is a high extraction drug with considerable extra-hepatic metabolism. Fractional urine sampling revealed that 0.5-1 % of unchanged yohimbine was excreted in urine in a biphasic manner. The data also suggested the existence of a slower elimination phase, with a half life of 13 h. The venous plasma concentration of noradrenaline (NA) increased 3-fold within 15 min after the yohimbine injection while plasma adrenaline (A) and neuropeptide Y-like immunoreactivity (NPY LI) remained unchanged. The plasma concentration-effect relationship of the changes in circulating NA followed counter-clockwise hysteresis. The results show that the hyperadrenergic state elicited by therapeutic doses of the ₂-adrenergic autoreceptor antagonist, yohimbine, is due to an interaction with NA but not to release of A or NPY in man.     

Dysregulation of the Hypothalamus-Pituitary-Adrenal Axis in Male and Female, Genetically Obese (ob/ob) Mice

The autosomal, recessive obesity of ob/ob mice is associated with hypercorticosteronemia and amelioration of most symptoms of obesity following adrenalectomy. Increased adrenocorticotropic hormone (ACTH) secretion has been hypothesized on the basis of several reports of higher pituitary ACTH content in ob/ob mice compared to lean littermates. However, the only measurement of ACTH blood concentration found lower levels in ob/ob mice than in leans suggesting that hypercorticosteronemia might result solely from an enhanced adrenal response to ACTH and also suggesting that the ob/ob's elevated pituitary ACTH content might be due to decreased ACTH secretion rather than increased ACTH synthesis. In our study, basal serum ACTH levels were higher in ob/ob males and females compared to sex-matched lean littermates. Anterior pituitary ACTH synthesis was also elevated as indicated by increased content of ACTH and proopiomelanocortin mRNA in obese mice of both sexes; however hypothalamic corticotropin-releasing factor content was not different in lean and obese mice. Basal serum ACTH and corticosterone (CS) levels showed normal circadian rhythm in both phenotypes and sexes, but the circadian increase in CS level was much greater in obese mice than in leans despite equal serum ACTH increases in the two phenotypes. Ether stress at both peak and trough of the circadian rhythm also stimulated much larger serum CS increases in obese mice even though ACTH increases were again equal in the two phenotypes. Taken together, these results strongly indicate that ob/ob mice have increased synthesis and secretion of pituitary ACTH despite the presence of chronically elevated serum CS. This hyperactivity of the hypothalamo-pituitary-adrenal axis appears to be most pronounced in ob/ob females since pituitary ACTH content was equal in obese males and females despite much higher circulating CS levels in the females. Furthermore, the results also indicate an enhanced response to ACTH by the adrenal cortex of the obese mouse. Thus, ob/ob mice exhibit abnormal hypothalamo-pituitary-adrenal axis function with hyperactivity occurring at the level of pituitary ACTH synthesis/secretion as well as at the level of adrenocortical response to ACTH.     

The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide

Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects, the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (), these are the only parameters which can be reported without qualification as to the concentration. The mean ± SD total body clearance of unbound drug in the eight subjects was 5.40± 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of , while the renal clearance of total disopyramide is dependent upon .     

Exercise responses of healthy subjects in the evaluation of cardioselectivity ofβ-blockers

Summary The effects of intravenous propranolol, metoprolol, acebutolol and placebo on exercise-induced changes in heart rate and peak flow rate (PFR) have been studied in a group of healthy subjects. The three -blockers produced significant and comparable reductions in exercise-induced tachycardia and the magnitude of the reduction was related to the log plasma concentration of each drug. Significant cardiac -blockade was detectable for three hours after giving propranolol and for four hours after metoprolol and acebutolol. The exercise-induced changes in PFR were small and variable and were not significantly affected by any of the drugs. We conclude that, contrary to published reports, exercise-induced changes in heart rate and PFR in healthy subjects do not provide a satisfactory test system for assessing the selectivity of -blockers.     

Pharmacokinetics of methyldopa in healthy man

Summary The pharmacokinetics of 2-¹⁴C-L--methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined -methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of -methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.     

正常儿童、青少年血清胰岛素样生长因子结合蛋白-3水平的变化

目的测定正常儿童、青少年血清胰岛素样生长因子结合蛋白-3(IGFBP-3)水平。方法对北京市东城区190名(男102名,女88名)健康的4.0~18.9岁儿童、青少年,应用放射免疫分析法(RIA)测定空腹血清IGFBP-3水平。结果随着年龄的增加,血清IGFBP-3水平逐渐升高,到青春期达到峰值。女性血清IGFBP-3水平达峰值时间较男性早1~2年,男、女性达峰时间分别为13.0~14.9及11.0~14.9岁,峰值分别为(4.58±0.64)、(4.67±0.93)mg/L。达峰值后血清IGFBP-3水平逐渐下降至各自9.0~10.9岁水平。血清IGFBP-3水平分别与身高和血清胰岛素样生长因-子1(IGF-1)水平呈显著正相关。结论血清IGFBP-3水平与年龄、青春发育期、身高及血清IGF-1水平明显相关。同年龄血清IGFBP-3水平无性别差异。     

普通高校大学生亚健康状态原因分析

目的：了解大学生亚健康状态形成原因及影响因素.方法：采用自行设计问卷对五所高校1 600名学生进行问卷调查.结果：大学生普遍存在不同程度的亚健康状态,56项亚健康状态有7项表现的学生占34.38%以上.其中影响健康的主要因素是学习学业、心理精神、就业形势、生活等.结论：普通高校更应加强大学生健康教育,多渠道、广泛开展多种形式的健康讲座、活动以及干预性的研究工作,促进和确保高校学生身心健康,为更好就业、适应社会及挑战未来提供保障.     

Impact of corneal parameters on intraocular pressure measurements in different tonometry methods

AIM: To evaluate the impact of central corneal thickness (CCT) and corneal curvature on intraocular pressure (IOP) measurements performed by three different tonometers. METHODS: IOP in 132 healthy eyes of 66 participants was measured using three different tonometry techniques: Goldmann applanation tonometer (GAT), Pascal dynamic contour tonometer (DCT), and ICare rebound tonometer (RT). CCT and corneal curvature were assessed. RESULTS: In healthy eyes, DCT presents significantly higher values of IOP than GAT (17.34±3.69 and 15.27±4.06 mm Hg, P<0.0001). RT measurements are significantly lower than GAT (13.56±4.33 mm Hg, P<0.0001). Compared with GAT, DCT presented on average 2.51 mm Hg higher values in eyes with CCT<600 μm and 0.99 mm Hg higher results in eyes with CCT≥600 μm. The RT results were lower on average by 1.61 and 1.95 mm Hg than those obtained by GAT, respectively. Positive correlations between CCT in eyes with CCT<600 μm were detected for all IOP measurement techniques, whereas a similar relationship was not observed in eyes with thicker corneas. A correlation between IOP values and keratometry in the group with CCT<600 μm was not detected with any of the tonometry methods. In thicker corneas, a positive correlation was found for GAT and mean keratometry values (R=0.369, P=0.005). CONCLUSION: The same method should always be chosen for routine IOP control, and measurements obtained by different methods cannot be compared. All analysed tonometry methods are dependent on CCT; thus, CCT should be taken into consideration for both diagnostics and monitoring.