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.     

Comparison of allergenicity and immunogenicity of an intact allergen vaccine and commercially available allergoid products for birch pollen immunotherapy

BACKGROUND: Specific immunotherapy with intact allergen vaccine is a well-documented treatment for allergic diseases. Different vaccine formulations are currently commercially available, the active ingredient either being intact allergens or chemically modified allergoids. The rationale behind allergoids is to decrease allergenicity while maintaining immunogenicity. However, data from the German health authorities based on reporting of adverse events over a 10-year period did not indicate increased safety of allergoids over intact allergens. OBJECTIVE: The objective of this study was to investigate the effect of chemical modification on allergenicity and immunogenicity comparing four commercial allergoid products for birch pollen immunotherapy with an intact allergen vaccine. METHODS: Solid-phase IgE inhibition and histamine release assays were selected as model systems for allergenicity, and a combination of human T cell proliferation and IgG titres following mouse immunizations were used to address the immunogenicity of the intact allergen vaccine and the four allergoids. In all assays, the products were normalized with respect to the manufacturer's recommended maintenance dose. RESULTS: IgE inhibition experiments showed a change in epitope composition comparing intact allergen vaccine with allergoid. One allergoid product induced enhanced histamine release compared to the intact allergens, while the other three allergoids showed reduced release. Standard T cell stimulation assays using lines from allergic patients showed a reduced response for all allergoids compared with the intact allergen vaccine regardless of the cell type used for antigen presentation. All allergoids showed reduced capacity to induce allergen-specific IgG responses in mice. CONCLUSION: While some allergoids were associated with reduced allergenicity, a clear reduction in immunogenicity was observed for all allergoid products compared with the intact allergen vaccine, and the commercial allergoids tested therefore do not fulfil the allergoid concept.     

盐酸维拉帕米自乳化缓释片的研制及释药行为的探讨

目的：探索固体自乳化释放药系统，研制自乳化缓释片，考察体外释药行为。方法：以盐酸维拉帕米（Verpamil Hydrochloride,VH)为模型药物，以吐温80（Tween80），豆磷脂（sbpc)为乳化剂，以羟丙甲纤维素（HPMC），卡波普（carbopol)为骨架材料，制备自乳化缓释片。结果：以含吐温80和豆磷脂10％，羟丙甲纤维素和卡波普30％的处方乳化效果好，体外释药符合要求。结论：通过调节乳化剂和骨架材料的比例，可以获得理想的自乳化固体缓释制剂。     

含服米索前列醇预防选择性剖宫产产后出血

目的：探讨舌下含服米索前列醇预防剖宫产产后出血的效果。方法：将妊娠晚期单胎选择性剖宫产者200例随机分为两组,研究组110例，在第二产程末胎头娩出后舌下含服米索400μg，对照组90例，在胎儿娩出后静脉注射催产素20IU，观察产后2h出血量和用米索前后血压及用药后出现的副作用，结果：产后2h内的出血量，研究组与对照组分别为174．43ml和219.73ml，二组比较有显著性差异（P＜0．01），用米索前后血压比较，二组无显著性差异（P＞0．05），结论：舌下含服前列醇促进子宫收缩作用强于催产素，能减少产后出血，也适用于某些与血管变化有关的高危孕产妇，预防产后出血。     

Release of newly synthesized h-dopamine in the striatum: An adaptation of the push-pull cannula method to awake restrained and anesthetized rats

The release of newly synthesized ³H-dopamine (³H-DA) was measured in the rat striatum superfused, through a push-pull cannula, with a physiological medium enriched in ³H-tyrosine. The level of spontaneous ³H-DA release was dependent on the topographical localisation of the cannula in the striatum (anterior parts displayed higher levels than posterior ones) and on the anesthetic state (halothane anesthetized rats demonstrated higher levels than awake ones). Inhibition of DA inactivation processes by local application of benztropine (a DA reuptake inhibitor, 10⁻⁶ M) or by IV administration of pargyline (a MAO inhibitor, 100 mg/kg) enhanced the detectable outflow of ³H-DA from the striatum in both halothane anesthetized and awake rats. Local application of D-amphetamine (10⁻⁵ M) or acetylcholine (5 × 10⁻⁵ M) in the presence of eserine (5 × 10⁻⁵ M) evoked respectively a fivefold and a 30% increase in spontaneous ³H-DA release in halothane anesthetized rats. Inhibition of the firing of dopaminergic neurons by IV injection of gamma-hydroxybutyrate (400 mg/kg) produced a 30% decrease in striatal ³H-DA release. The present results demonstrate that the push-pull cannula method is suitable for the study of DA release in both the anesthetized and the awake rat.     

控制性肺膨胀在食管癌术后应用的临床对比研究

目的　观察在食管癌术后应用控制性肺膨胀防止急性呼吸衰竭的疗效。方法　随机设立应用控制性肺膨胀组 4 3例和对照组 33例 ,年龄和手术时间等无显著差异。观察撤离呼吸机时间。撤机后 1 2、2 4h的呼吸频率、心率、血氧饱和度和氧分压。结果　 (1 )应用控制性肺膨胀后 ,撤机时间由 (1 0 4± 1 5 )min缩短到 (87± 1 3)min。 (2 )撤机后 1 2h ,控制性肺膨胀组血氧饱和度和氧分压异常的患者率分别由 30 .30 %下降到 6 .98% ,2 4 .2 4 %下降到 6 .98%。 (3)撤机后 2 4h ,血氧饱和度异常的患者率由1 8.1 8%下降到 2 .33%。结论　食管癌术后应用控制性肺膨胀能有效防止急性呼吸衰竭的发生。     

Differential Stimulation of Noradrenaline Release by Reversal of the Na+/Ca2+ Exchanger and Depolarization in Chromaffin Cells

We compared the effectiveness of Ca²⁺ entering by Na⁺/Ca²⁺ exchange with that of Ca²⁺ entering by channels produced by membrane depolarization with K⁺ in inducing catecholamine release from bovine adrenal chromaffin cells. The Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger was promoted by reversing the normal inward gradient of Na⁺ by preincubating the cells with ouabain to increase the intracellular Na⁺ and then removing Na⁺ from the external medium. In this way we were able to increase the cytosolic free Ca²⁺ concentration ([Ca²⁺]_c) by Na⁺/Ca²⁺ exchange to 325 ± 14 nM, which was similar to the rise in [Ca²⁺]_c observed upon depolarization with 35 mM K⁺ of cells not treated with ouabain. After incubating the cells with ouabain, K⁺ depolarization raised the [Ca²⁺]_c to 398 ± 31 nM, and the recovery of [Ca²⁺]_c to resting levels was significantly slower. Reversal of the Na⁺ gradient caused an −6-fold increase in the release of noradrenaline or adrenaline, whereas K⁺ depolarization induced a 12-fold increase in noradrenaline release but only a 9-fold increase in adrenaline release. The ratio of noradrenaline to adrenaline release was 1.24 ± 0.23 upon reversal of the Na⁺/Ca²⁺ exchange, whereas it was 1.83 ± 0.19 for K⁺ depolarization. Reversal of the Na⁺/Ca²⁺ exchange appeared to be as efficient as membrane depolarization in inducing adrenaline release, in that the relation of [Ca²⁺]_c to adrenaline release was the same in both cases. In contrast, we found that for the same average [Ca²⁺]_c, the Ca²⁺ influx through voltage-gated channels was much more efficient than the Ca²⁺ entering through the Na⁺/Ca²⁺ exchanger in inducing noradrenaline release from chromaffin ceils. This greater effectiveness of membrane depolarization in stimulating noradrenaline release suggests that there is a pool of noradrenaline vesicles which is more accessible to Ca²⁺ entering through voltage-gated Ca²⁺ channels than to Ca²⁺ entering through the Na⁺/Ca²⁺ exchanger, whereas the adrenaline vesicles do not distinguish between the source of Ca²⁺.     

尼莫地平控释片释放度试验研究

本文研究了尼莫地平控释片的释放度试验方法——转篮法，释放介质为含有２２％异丙醇的０．１ｍｏｌ·Ｌ－１盐酸液；磷酸盐缓冲液（ｐＨ５．８）和ｐＨ７．２的溶液。含量测定方法：紫外分光光度法，在三种介质中尼莫地平分别在１～３０μｇ·ｍｌ－１，１０～５０μｇ·ｍｌ－１和１０～５０μｇ·ｍｌ－１的范围内，浓度与吸收度有较好的线性关系。回归方程分别为Ａ＝０．６１５Ｃ＋０．０２３（ｒ＝０．９９９９）；Ａ＝０．０６１４Ｃ＋０．０１２（ｒ＝０．９９９５）；Ａ＝０．０６１２Ｃ＋０．００８８（ｒ＝０．９９９９）。平均回收率分别为９９．６３％，９９．９８％及１００．７７％，ＲＳＤ（％）分别为１．３４％，１．５９％及１．４１％。本方法的体外释放百分率与体内吸收分数有较好的相关性（ｒ＝０．９９１）。     

头孢氨苄缓释片在健康人体内的生物利用度和药物动力学

目的:比较头孢氨苄缓释片和普通胶囊的生物利用度和药物动力学。方法：10例健康志愿者分别单剂量口服500mg头孢氨苄缓释片和普通胶囊，血药浓度测定方法为HPLC法。结果：两种剂型体内过程均符合一室开放模型，缓释片的达峰时间（Tmax）为（2．58±0．59）h，峰浓度（Cmax）为（10．08±1．68）μg／ml．吸收速率常数（Ka）为（0．90±0．53）／h，消除速率常数（Ke）为（0.26±0.02）／g，半衰期（T1／2）为（2.67±0.23）h，清除率（Cl）为（6.93±1.71）L／h，分布容积（Vd）为（26.66±6.72）L，药一时曲线下面积（AUC）为（48.31±9.32）μg·h／ml。两种剂型T一C一Ka、Ke、T1／2和Cl均存在显著性差异（P＜0．01），Vd、AUC无显著性差异（P＞0．05）；缓释片的相对生物利用度为（104．90±8．35）％。结论：缓释片的吸收减慢，Tmax推迟，T1／2延长，可减少服药次数，提高药物治疗的顺应性。     

Preparation and evaluation of temperature sensitive liposomes containing adriamycin and cytarabine

Temperature sensitive liposomes (TSL) containing adriamycin (ADM) and cytarabine (Ara-C) were prepared. ADM and Ara-C were selected as model compounds of amphiphilic and hydrophilic drug, respectively. Encapsulation efficiency of ADM entrapped into TSL was about twice greater than that of Ara-C. It might be due to different polarity of the drugs. Lipid compositions of TSL had no effect on the encapsulation efficiency of drugs. Thermal behavior of TSL using a differential scanning calorimetry (DSC) was also investigated. Phase transition temperature (T_c) of TSL was dependent on the lipid compositions of TSL.ADM broadened thermogram of TSL but Ara-C did not. However, T_c of TSL was not changed by any drug. Release rate of drugs was highly dependent on temperature. The release profile of ADM was similar to that of Ara-C. The maximum release rate of drugs from TSL was occurred at the near T_c and observed at 39–41°C for DPPC (Dipalmitoylphosphatidylcholine) only, 52–54°C for DSPC (Distearoylphosphatidylcholine) only, 41–43°C for DPPC and DSPC (3∶1), and 43–45°C for DPPC and DSPC (1∶1), respectively. Effect of human serum albumin (HSA) on the release rate of ADM was investigated. HSA had no significant effect on the release of ADM below T_c. However, ADM release from TSL was increased at the near and above T_c. The HSA-induced leakage of drug may result from the interaction of liposomal constituents with HSA structure at the near T_c. From the fact that the release profiles of ADM from freshly prepared TSL and stored TSL for 1 week at 4°C was not changed, the TSL was considered to be stable for at least 1 week at 4°C. Based on these findings, TSL may be useful to deliver drugs to preheated target sites due to its thermal behaviors.