Pharmacodynamics of glucose regulation by methylprednisolone. I. Adrenalectomized rats

Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50 mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3 mg/kg/h via subcutaneously implanted Alzet mini‐pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72 h after injection or 336 h after infusion. The pharmacokinetics of MPL was captured with a two‐compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6 h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic β‐cell secretion yielding a later insulin peak at around 10 h. In turn, insulin can stimulate glucose disposition. However, long‐term MPL treatment caused continuous hyperglycemia during and after infusion. Insulin was increased during infusion, and immediately returned to baseline after the infusion was terminated, despite the almost doubled glucose concentration. A disease progression model incorporating the reduced endogenous glucose disposition was included to capture glucose homeostasis under different treatments. The results exemplify the importance of the steroid dosing regimen in mediating pharmacological and adverse metabolic effects. This mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model quantitatively describes the induction of hyperglycemia and provides additional insights into metabolic disorders such as diabetes. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacodynamics of Methylprednisolone Phosphate After Single Intravenous Administration to Healthy Volunteers

The pharmacokinetics and pharmacodynamics of methylprednisolone were investigated after intravenous administration of methylprednisolone phosphate to healthy subjects at seven different doses (16 to 1000 mg). Forty different pharmacodynamic parameters were followed for 1 week. The pharmacodynamic data were analyzed as a function of time as well as cumulative effects in form of the areas under the effect–time curves. Statistically significant dose-dependent effects of methylprednisolone were observed for 15 pharmacodynamic parameters. Highly significant (P 0.0001) effects were increases in glucose levels, number of white blood cells, and segmented granulocytes as well as a decrease in the number of lymphocytes. For these pharmacodynamic effects an integrated pharmacokinetic/pharmacodynamic model was derived that translates the methylprednisolone plasma concentration–time profiles into effect– time profiles. This model allows prediction of pharmacodynamic effects for any single dose in the range studied at any time point.     

Facilitation of Pulmonary Insulin Absorption by H-MAP: Pharmacokinetics and Pharmacodynamics in Rats

Purpose. Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined. Methods. Aliquots (100 l) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined. Results. The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (C_max) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG_0t) was achieved for H-MAP/insulin combination (66 ± 5 %) compared to insulin alone (47 ± 10 %). Conclusion. H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.     

Receptor-mediated methylprednisolone pharmacodynamics in rats: Steroid-induced receptor down-regulation

Several approaches to receptor down-regulation were examined to extend previous receptor/ genemediated pharmacokinetic/dynamic models of corticosteroids. Down-regulation of the glucocorticoid receptor was considered as an instantaneous event or as a gradual steroid-receptor-mediated process. Concentrations of plasma methylprednisolone, free hepatic cytosolic receptors, and the activity of hepatic tyrosine aminotransferase (TAT) enzyme were measured for 16 hr following administration of 0, 10, and 50 mg/kg methylprednisolone sodium succinate to 93 adrenalectomized rats. Receptor down-regulation was best described by a fractional decrement in the rate of return of free cytosolic glucocorticoid receptor. Predicted values for free receptor, bound receptor, nuclear bound receptor, and transfer compartments were in accord with the expected rank order values based on the high and low steroid doses. Model parameter estimates were independent of dose and described the rapid depletion of free cytosolic receptor, latephase return of cytosolic receptor to a new baseline level that was 20–40% lower than control, and the TAT induction/dissipation pattern following steroid dosing. The microscopic association and dissociation constants describing the steroidreceptor interaction were 0.23 L/nmole per hr (k_on and 4.74 hr^–1 (k_off) for methylprednisolone compared to previously obtained values of 0.20 L/nmole per hr and 15.7 hr^–1 for the related steroid prednisolone. The time course of TAT induction was similar to that observed previously for prednisolone. Efficiency of TAT induction was more closely related to steroid receptor occupancy than plasma methylprednisolone concentrations due to receptor saturability and receptor recycling.Supported in part by Grant No. 24211 from the National Institutes of General Medical Sciences, NIH, and by a Fellowship from the American Foundation for Pharmaceutical Education for D.H.     

Pharmacokinetics of methylprednisolone after intravenous and intramuscular administration in rats

Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h(-1). The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h(-1) indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.     

Pharmacodynamics and pharmacogenomics of diverse receptor-mediated effects of methylprednisolone in rats using microarray analysis

Corticosteroids such as methylprednisolone (MPL) produce many of their anti-inflammatory, immunosuppressive, and exaggerated physiological effects by receptor and gene-mediated mechanisms. The temporal pattern of change in four genes in rat tissues was measured by quantitative Northern hybridization and rtPCR after a single dose of MPL. Two profiles were observed: two genes with enhanced expression showed a slow onset and moderate rate of decline within a 24 hr time frame while two genes with reduced expression exhibited a rapid onset and prolonged suppression over a 72 hr time span. These patterns are consistent with and rationalized by pharmacodynamic expectations based on earlier models. cDNA microarrays used to assess the expression levels of 5200 genes at one optimal time-point showed marked variation in baseline values. Of these, 20 genes showed statistically significant enhanced expression with increases ranging from 130 to 1690%, 31 genes exhibited reduced expression ranging from 31 to 72% of control. Many genes could be categorized as affecting acute phase/immune response, energy metabolism, microsomal metabolism, and hepatic function. These studies provide the first simultaneous assessment of the diversity in pharmacogenomic effects of corticosteroids. They also provide some insight into the advantages and limitations of microarray measurements in regard to the pharmacodynamics of drugs having complex, multi-faceted, and integrated mechanisms of action.     

Pharmacodynamics of Insulin Following Intravenous and Enteral Administrations of Porcine-Zinc Insulin to Rats

Previous work from this laboratory showed site-dependent variations in the apparent permeability of insulin as measured using the everted rat gut sac technique, with the greatest permeability in the distal jejunum and the lowest in the duodenum (5). To quantify better the rate and extent of insulin absorption from the small intestine, closed-loop in situ experiments were performed in nondiabetic rats. Results correlated with the everted gut sac technique in that the absolute bioavailability determined in situ was higher for insulin solution administered to the more distal region of the intestine (0.133%) than that absorbed from an earlier portion of the intestine (0.059%). While the difference in regional bioavailabilities was not significant (P = 0.08), the blood glucose response showed highly significant differences (P = 0.0015), with severe and prolonged hy-poglycemia resulting from insulin delivered to the distal jejunum/ proximal ileum. Insulin administered iv followed a two-compartment pharmacokinetic model. Whole-body elimination rate constants were similar for both iv and enteral insulin. Although therapeutic quantities of insulin were absorbed from the distal small intestine, absorption enhancers would be necessary to decrease the dose of insulin required.     

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes

Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group).In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration.In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response.In the subset with a fasting blood glucose concentration of less than 8 mmol·l^–1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.     

Fifth-generation model for corticosteroid pharmacodynamics: application to steady-state receptor down-regulation and enzyme induction patterns during seven-day continuous infusion of methylprednisolone in rats

A fifth-generation model for receptor/gene-mediated corticosteroid effects was proposed based on results from a 50 mg/kg IV bolus dose of methylprednisolone (MPL) in male adrenalectomized rats, and confirmed using data from other acute dosage regimens. Steady-state equations for receptor down-regulation and tyrosine aminotransferase (TAT) enzyme induction patterns were derived. Five groups of male Wistar rats (n=5/group) were subcutaneously implanted with Alzet mini-pumps primed to release saline or 0.05, 0.1, 0.2, and 0.3 mg/kg/hr of MPL for 7 days. Rats were sacrificed at the end of the infusion. Plasma MPL concentrations, blood lymphocyte counts, and hepatic cytosolic free receptor density, receptor mRNA, TAT mRNA, and TAT enzyme levels were quantitated. The pronounced steroid effects were evidenced by marked losses in body weights and changes in organ weights. All four treatments caused a dose-dependent reduction in hepatic receptor levels, which correlated with the induction of TAT mRNA and TAT enzyme levels. The 7 day receptor mRNA and free receptor density correlated well with the model predicted steady-state levels. However, the extent of enzyme induction was markedly higher than that predicted by the model suggesting that the usual receptor/gene-mediated effects observed upon single/intermittent dosing of MPL may be countered by alterations in other aspects of the system. A mean IC₅₀ of 6.1 ng/mL was estimated for the immunosuppressive effects of methylprednisolone on blood lymphocytes. The extent and duration of steroid exposure play a critical role in mediating steroid effects and advanced PK/PD models provide unique insights into controlling factors.     

奎硫平对大鼠血糖的影响及其机制研究

目的探讨奎硫平对血糖影响的可能机制。方法正常SD大鼠20只,随机分为对照组和奎硫平组,分别于给药前、给药1、2、3、4周后测体重及空腹血糖;给药4周后放免法测血胰岛素、C肽及RT-qPCR法分析胰腺组织GLUT2mR-NA的表达。结果 (1)给药2、3、4周后,奎硫平组大鼠体重均大于对照组(P<0.05);每周体重增加量奎硫平组均大于对照组,但只有第1周差异有显著性(P<0.01)。(2)奎硫平组空腹血糖呈增长趋势,给药2、3、4周后均高于给药前(P<0.05)。(3)奎硫平组大鼠血胰岛素、C肽水平高于对照组,差异无显著性(P>0.05)。(4)奎硫平组大鼠GLUT2mRNA表达水平低于对照组(P<0.01)。结论奎硫平可以降低GLUT2mRNA的表达,这可能是长期应用奎硫平后引起血糖异常的发生机制之一。     

A comparative population pharmacokinetic analysis for methylprednisolone following multiple dosing of two prodrugs in patients with acute asthma

Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) in patients hospitalized with acute asthma.
Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40  mg (MP equivalents) i.v. 6 hourly for 48  h. The bio-conversion and disposition of a 40  mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono-exponential elimination phase.
Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0  h⁻¹ vs 5.5  h⁻¹ respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half-life (2.7  h vs 3.0  h), steady-state AUC (2007.0  ng  ml⁻¹  h vs 2321.0  ng  ml⁻¹  h) and steady-state C _max (698.4  ng  ml⁻¹ vs 647.8  ng  ml⁻¹ ) for MP suleptanate and MP succinate respectively.
Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.     

Estimation of the initial distribution volume of glucose by an incremental plasma glucose level at 3 min after i.v. glucose in humans

AIMS: The initial distribution volume of glucose (IDVG) could be a clinically useful indicator of the central extracellular fluid (ECF) space volume, namely the interstitial fluid volume status of highly perfused organs. In this study, we determined the formula of IDVG using incremental plasma glucose levels after i.v. glucose. METHODS: One hundred and fifty patients admitted to the general intensive care unit of the University of Hirosaki hospital were entered into this prospective study which was conducted in two stages. In the first stage 300 data points from 100 patients were used to measure the IDVG (3 determinations for each patients). This utilized a one compartment model to describe the incremental plasma glucose decay curve following an intravenous bolus injection of glucose which, in turn, was used to derive the parameters of an equation for IDVG prediction following a single plasma sample. The second stage was a validation of the equation using a separate data set (150 points) from a further 50 patients. RESULTS: A one phase exponential decay model was well-fitted for the IDVG-postadministration glucose level curve, and indicated that the incremental glucose level at 3 min after i.v. glucose was best-correlated to the IDVG compared with those at 1, 2, 4, 5 and 7 min postadministration. The formula of the IDVG was obtained from the curve: IDVG=24.44xe-0.0298xDeltaGL+2.70, where DeltaGL=incremental glucose level at 3 min after i.v. glucose. Another 150 samples showed that the measured-IDVG from a one compartment model and predicted-IDVG from the formula were 7.24+/-1. 63 and 7.27+/-1.52 l, respectively, and that there was a significant correlation between the two IDVGs (r=0.966, P<0.0001). CONCLUSIONS: Using an incremental glucose level at 3 min after i.v. glucose, we have established the reliable formula for determination of the IDVG which could be a clinically useful indicator of the central ECF volume.     

Pharmacoimmunodynamics of methylprednisolone: Trafficking of helper T lymphocytes

A two-compartment dosed model was used to characterize the cell trafficking behavior of helper T cells in response to various single doses of methylprednisolone. Steroids are assumed to inhibit the circadian-determined cell return from extravascular sites to blood in a classic inhibitory pattern reflected by an IC₅₀.The rate of cell efflux from tissues is modeled with a cosine function having a period of 24 hr and a maximum at about 1 am. Nonlinear leastsquares regression employing differential equations was used to analyze helper T-cell data from three human studies from our laboratory. The IC₅₀ value of methylprednisolone of 12–19 ng/ml approximates receptor K_D values. Simulations were performed to demonstrate the log-linear role of steroid dose or AUCon the integral of effect of helper T cells over a wide range of methylprednisolone doses. This pharmacodynamic model allows flexibility for characterizing any type of steroid dosing regimen and is relevent in describing complex response data for corticosteroid immunosuppressive effects in man.Supported in part by grant GM 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

高甘油三酯并糖调节异常及正常者的胰岛素抵抗及胰岛素分泌的研究

目的:了解高甘油三酯并糖调节异常(IGR)[包括空腹血糖受损(IFG)或/和糖耐量减低(IGT)者]及正常(NGT)者的胰岛素抵抗及胰岛素分泌。方法:在体检人群中筛选出高甘油三酯并IGR及NGT者62人及健康者14人为研究对象,测血压、身高、体重、腰围、臀围,计算体重指数(BMI)及腰臀比(腰/臀)。经口服葡萄糖耐量试验(OGTT)测血糖(PG),同时检测甘油三酯(TG)及真胰岛素(TINS)、胰岛素原(PINS),根据血糖和TG结果将研究对象分为四组。①组(健康对照组):为NGT和TG正常者14人,②组(NGT+HTG):为NGT而高TG者即20人,③组(IFG/IGT+HTG):IFG或IGT伴高TG者23人,④组(IFG+IGT+HTG):IFG并IGT伴高TG者19人,四组均排除高血压病、肥胖及其它疾病。根据稳态模型公式计算各组的胰岛素抵抗指数(HOMA-IR),HOMA胰岛β细胞功能指数(HOMA-β),胰岛素快速反应指数(AIR)。结果:四组的BMI、腰/臀,真胰岛素,胰岛素原水平呈现①②③④组依次递增的趋势,③④组的HOMA-IR有别于①②组,四组的HOMA-β依次递减,差异均有显著性,P<0.05~0.000。结论:高甘油三酯并IGR及NGT者已出现胰岛素抵抗、胰岛素分泌及胰岛β细胞功能变化。     

Pharmacodynamics and pharmacokinetics of three different doses of urapidil infused in hypertensive patients

Summary The study was designed to follow the haemodynamic effects and pharmacokinetics under steady-state conditions of three different doses of urapidil infused continuously. Nine male hypertensive patients received three randomly assigned intravenous infusions of 32.5, 65 and 130 mg urapidil, over 14 h during 6 consecutive days, in a change-over fashion. Blood pressure and heart rate were measured over a period of 28 h after the infusion began and were compared with a reference profile obtained prior to the treatment periods. Urapidil and its main metabolite, parahydroxylated urapidil, were also determined for 28 h after the infusion began using HPLC. The 32.5 mg dose of urapidil caused a maximum decrease in systolic blood pressure of 33±8 mmHg, the 65 mg dose a maximum decrease of 39±12 mmHg and the 130 mg dose a maximum decrease of 50±12 mmHg. The 32.5 and 65 mg doses resulted in similar serum urapidil concentrations, with maximum levels in the 100 to 200 ng/ml range, and the 130 mg dose caused a maximum level approximately four times that achieved with the 32.5 mg dose. The serum concentration of parahydroxy urapidil was proportional to the corresponding dose of urapidil. Four patients reported mild headache, fatigue, weakness, pressure in the head, perspiration and orthostatic dysregulation. The side-effects were probably drug related but required no specific therapy. In summary, the 32.5 mg dose of urapidil resulted in a pronounced decrease in blood pressure. The average pressure reduction over the 14-h infusion period showed further dose-dependent increases after the 65 and 130 mg doses. In severe hypertension, the 130 mg dose can be employed, since it does result in a further, significantly larger decrease in blood pressure.     

Population Pharmacokinetics and Pharmacodynamics of Sotalol in Pediatric Patients with Supraventricular or Ventricular Tachyarrhythmia

Aims: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT).Methods: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m² sotalol, extensive blood samples (n=10) were taken. The PK–PD study used a dose escalation design with doses of 10, 30, and 70 mg/m², each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology.Results: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E₀ were 86.7 and 14.4%, respectively.Conclusions: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc–C relation, while the RR–C relation shows age or BSA dependency.     

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*

Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple-dose regimens.
Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100  mg three times daily and 12.5, 50, 200  mg three times daily, respectively. Plasma levels of levodopa, 3- O -methyldopa (3-OMD) and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250  mg  levodopa.
Results Endogenous concentrations of levodopa and 3-OMD increased dose-dependently (from 8 up to 52  μg  l⁻¹ and from 0.02 up to 0.50  mg  l⁻¹, respectively, at doses of 200  mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration-time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9  mg  l⁻¹  h at benserazide doses of 100–200  mg three times daily. Benserazide caused a dose-dependent increase in the AUC of 3-OMD from 7.4 to 106  mg  l⁻¹   h at doses of 200  mg. Formation of DOPAC was dose-dependently suppressed, with benserazide 5  mg three times daily already halving its AUC.
Conclusions The benserazide-dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.     

去胸腺对大鼠糖代谢的影响及地黄寡糖对其的调节作用

目的　观察去胸腺 (Tx)大鼠血糖、血浆胰岛素水平及肝糖原的变化及地黄寡糖 (ROS)对去胸腺大鼠糖代谢的调节作用。方法　① 4wk龄Wistar大鼠手术摘除胸腺 ,测定大鼠去胸腺 3、4、8、15mon后血浆葡萄糖、肝糖原含量、血浆胰岛素水平 ;②观察ROS(2 5 0mg·kg-1,po,× 6 0d)给予去胸腺术 7月后对大鼠脾淋巴细胞增殖、血糖、肝糖原、血浆胰岛素及皮质酮水平的影响。结果　①大鼠去胸腺术后 3～ 15mon血糖无明显变化 ,但从 8mon起肝糖原含量及胰岛素水平均升高 ;②ROS可基本逆转去胸腺大鼠糖代谢变化 ,使之向正常发展 :使肝糖原由高向正常转化 ;血浆胰岛素水平在Tx大鼠有升高趋势 ,ROS可使之恢复正常 ;血浆皮质酮水平在Tx大鼠有下降 ,ROS可使之恢复上升 ;ROS可逆转因去胸腺引起之脾淋巴细胞增殖下降。结论　大鼠去胸腺可引起糖代谢的某些变化 ,ROS可以大部分逆转这种变化     

Liraglutide-loaded multivesicular liposome as a sustained-delivery reduces blood glucose in SD rats with diabetes

Subcutaneous liraglutide-loaded multivesicular liposomes (Lrg-MVLs) were developed as a sustained drug-delivery system for treating diabetes and their properties were characterized. The Lrg-MVLs prepared using a two-step water-in-oil-in-water double emulsification process had a spherical appearance with a mean diameter of 6.69?μm and an encapsulation efficiency of 82.23?±?4.78% without any initial burst release. Their pharmacodynamics (PD) and pharmacokinetics (PK) were also studied after a single subcutaneous administration to Sprague-Dawley (SD) rats with diabetes. The PD results demonstrated that Lrg-MVLs presented sustained glucose-lowering effects for nearly a week, while the pharmacokinetic parameters showed that the plasma liraglutide concentration of the designed preparation produced C_max of 81.979?±?12.140?pg/ml and an MRT_0–t of 88.224?±?3.893?h. Furthermore, retention of Lrg-MVLs at the injection site was studied semiquantitatively by an in vivo imaging system, which can be used to evaluate the drug release from MVLs in vivo. In conclusion, MVLs are a promising carrier for liraglutide and Lrg-MVLs deserve further study for the treatment of diabetes.