Modifications of the hydrophilicity of heterocyclic methacrylate copolymers for protein release

A series of copolymers comprising ethyl methacrylate (EM) and tetrahydrofurfuryl methacrylate (THFMA) gelled with either THFMA monomer or hydroxyethyl methacrylate (HEMA) monomer have been developed. In this paper, we examine the water uptake characteristics of the polymer systems and address the possibility of increasing the hydrophilicity of the systems by changing the ratios of the copolymers. We have investigated whether protein release from the polymers is related to the composition of the polymer systems. More protein was released from the polymers gelled with the more hydrophilic monomer (HEMA) than with THFMA. This was consistent with the calculated diffusion coefficients, which were 10 times greater for the polymers gelled with HEMA than those gelled with THFMA. Interestingly, the water uptake and protein release profiles were not dependent on the ratio of EM and THFMA in the copolymers. This is probably due to the conflicting roles of THFMA in the copolymer; it is both the more hydrophilic component as well as a cross-linking agent. In addition, it would appear that the structural and surface topography of these polymers had more significant effects on protein release than copolymer composition.     

Pharmacological modulation of endogenous dopamine and DOPAC outflow from nucleus accumbens

The release of endogenous DA and DOPAC from nucleus accumbens slices were studied measuring net outflow of DA and DOPAC in the superfusate of static chambers, to analyze the correlation between DA and DOPAC outflows and identify which DA stores may serve as possible sources for DOPAC formation. Under resting conditions, or following stimulation with low (< 15 mM) KCl concentration, DOPAC outflow was greater than DA. When DA release was stimulated by higher (> 25 mM) KCl concentrations, DA outflow increased, proportionally more than DOPAC. In the virtual absence of Ca²⁺ in the Krebs solution DA outflow, induced by 25 mM KCl, was reduced to about 10%, while DOPAC outflow was only reduced to 45%. When the synthesis of DA was inhibited with -MPT, DA and DOPAC outflow were unchanged during the first stimulation period. During a second stimulation period, however, their outflow were significantly reduced. Nomifensine, a DA uptake inhibitor, increased the basal DA outflow by about 100%, but only blocked DOPAC basal outflow by about 25%. The 25 mM KCl stimulated DA outflow was not affected by Nomifensine, while the stimulated DOPAC outflow was reduced by about 50%. These results demonstrate that there is a weak correlation between the outflows of DA and DOPAC, suggesting a complex relationship between the mobilization of the different DA pools and DOPAC outflow. The formation of DOPAC from some of these pools, appear to be dependent on the stimulation levels and on the pharmacological manipulation of the tissue.     

复方山绿茶缓释袋泡剂的研究

用网状多孔性纤维包念材料制备的复方山绿茶缓袋泡剂，具有速释和缓释作用，在１－８ｈ内按埝级方式释药。Ｔ０．５为１．３ｈ，Ｔｄ为３．２ｈ，１－８ｈ的平均释药速率７２．３５ｍｇ／ｈ。与传统的半生药型袋泡剂比较，具有栽药量高，使用方便，性质稳定，疗效确切的优点。     

Diadenosine polyphosphate (ApxA) as new neurotransmitters

The presence of diadenosine polyphosphates (Ap_xA), diadenosine tetraphosphate (Ap₄A), diadenosine pentaphosphate (Ap₆A), and diadenosine hexaphosphate (Ap₆A), has been described in secretory granules of chromaffin cells, Torpedo synaptic vesicles, and rat brain synaptosomes. The release of these compounds by the action of secretagogues and depolarizing agents, in the presence of calcium, increases their importance as active neurotransmitters. Two high affinity receptors have been described in the three neural models, with Kd values ranging from 0.08 to 0.40 nM for the first binding site and from 5.6 to 18nM for the second lower affinity binding site. Both binding sites exhibit a P_2y-like profile in chromaffin cells and Torpedo synaptic terminals and a different pattern in rat brain synaptosomes, suggesting the presence of a novel P₂-purinoceptor tentatively named P_2d. Studies about the second messenger linked to this receptor, in chromaffin cells, demonstrate the mobilization of calcium from internal stores. Ap_xA receptors at the extracellular milieu are responsible for the inhibition of catecholamine release stimulated by secretagogues. Finally, all diadenosine polyphosphates are destroyed by the action of an ecto-phosphodiesterase which, in chromaffin cells, shows Km values ranging from 1 to 4 μM. © 1993 Wiley-Liss, Inc.     

Controlled Release of Substituted Benzole and Naphthoic Acids Using Carbopol ® Gels: Measurement of Drug Concentration Profiles and Correlation to Release Rate Kinetics

Purpose. The objective of this study is to correlate drug release mechanism with measured drug concentration profiles in gel layers of Carbopol^® matrices containing mesalamine or benzoic acid. Methods. Release rate experiments with Carbopol^® matrices were performed using a rotating disk apparatus. Matrices were frozen and the gel layer in the matrices was sliced using a microtome in a cryostat. Drug concentration profiles were determined by direct measurement of the concentration of the drug in the gel slices. The pH of the slices was measured using microelectrodes, and water content was measured by Karl Fisher titration. Results. The concentration gradient in mesalamine matrices decreased over time and correlated with square root of time release rate kinetics. The concentration profiles of benzoic acid were unchanged over time and correlated with zero order release rate kinetics. Carbopol gel layers were highly hydrated (93–95% water). Gel layers in matrices with mesalamine had a more alkaline microenvironmental pH. This higher pH resulted in increased growth of the thickness of the gel layer and a reduction drug diffusivity in comparison to benzoic acid matrices. Conclusions. The release rate kinetics of mesalamine and benzoic acid correlated to the measured concentration profiles. The shape of the concentration profiles is determined by the rate of growth of the Carbopol^® gel layer and drug diffusivity.     

Effects of cocaine and quinpirole on perceptual and motor functions in baboons

 The effects of cocaine and quinpirole were studied in baboons to determine whether quinpirole, a relatively selective D₂/D₃ dopamine agonist, produced effects similar to those of cocaine on perceptual and motor processes. To measure perceptual and motor function, three baboons were trained to discriminate differences between a standard vowel and four other synthetic vowels; response accuracy as well as response latencies, or ”reaction times”, were measured following drug administrations. Cocaine reduced reaction times in two baboons, and did not affect reaction times in a third; on the other hand, quinpirole lengthened reaction times in a dose-dependent manner in all baboons. Cocaine and quinpirole also differed in the time course to produce the maximal reaction time effect following drug administration. Cocaine and quinpirole did not differ consistently in their perceptual effects, as indicated by similar changes in d′, a signal-detection index of discriminability. These distinct profiles of effects for cocaine and quinpirole suggest differing neurochemical actions for these two drugs. Received: 10 August 1996 /Final version: 16 May 1997     

Neutrophil superoxide release and interleukin 8 in acute myocardial infarction: distinction between complicated and uncomplicated states

Superoxide release in neutrophils and sera levels of interleukin 8 (IL-8) were determined in 15 patients with complicated acute myocardial infarction (MI) and 15 patients with uncomplicated MI. All patients showed increased superoxide release in unstimulated and stimulated neutrophils compared with healthy control subjects, indicating priming of these cells. Superoxide release of unstimulated or stimulated neutrophils was found to be significantly higher in patients with complicated MI than in patients with uncomplicated MI. Thrombolytic therapy did not affect the rates of superoxide release. The neutrophil chemoattractant/activator IL-8 was detected in the sera of all patients, with significantly higher levels in those with complicated MI. The highest levels of IL-8 were detected at admission to the Coronary Care Unit and significantly decreased thereafter, suggesting its contribution to neutrophil-mediated tissue injury. The high levels of IL-8 may be one of the major contributors to the priming of neutrophils in these patients.     

Surface-related triggering of the neutrophil respiratory burst. Characterization of the response induced by IgG adsorbed to hydrophilic and hydrophobic glass surfaces

Hydrophilic and hydrophobic glass surfaces precoated with human albumin, fibrinogen, or IgG were investigated with respect to their ability to activate the neutrophil NADPH-oxidase. We found that IgG-coated surfaces induced a substantial and prolonged neutrophil production of reactive oxygen species (ROS). When a hydrophilic surface was used to support protein binding, a somewhat lower neutrophil response (around 35%) was obtained, compared with the response induced by IgG on a hydrophobic surface. The production of ROS was completely eliminated when cytochalasin B was added to the measuring system, suggesting the involvement of the cell cytoskeleton in the activation process. The relation between the intra- and extracellular generation of ROS was further assessed, and we found that most of the ROS produced were released from the cells, in agreement with a model in which the activating surfaces induce a ‘frustrated’ phagocytic response. Serum totally inhibited ‘frustrated’ phagocytosis provided that the IgG molecules were sticking to a hydrophilic surface.     

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

健康志愿者１０名，随机交叉口服硫酸吗啡控释片（ＣＲＭＳ）３０ｍｇ（３０ｍｇ×１）和硫酸吗啡普通片（ＩＲＭＳ）２０ｍｇ（１０ｍｇ×２），分别于服药前后各时点取静脉血，用ＧＣＭＳ测定血浆中吗啡含量。以药代软件程序处理，分别求得ＣＲＭＳ和ＩＲＭＳ的Ｃｍａｘ为１９．３８±３．８０和２１．２７±６．２１ｎｇ／ｍｌ；ｔｍａｘ为２．３６±０．３７ｈ和０．５５±０．１６ｈ；ｔ１／２β为３．５３±０．８７ｈ和３．０３±０．７４ｈ，曲线下面积ＡＵＣ为１４５．１５±１７．６５和９３．０８±１６．６５ｎｇ·ｈ／ｍｌ。癌症病人多次口服硫酸吗啡至稳态，ＣＲＭＳ和ＩＲＭＳ的峰浓度分别为２７．４３±０．３３ｎｇ／ｍｌ，２２．６８±０．１６ｎｇ／ｍｌ；谷浓度分别为１９．４５±１．４４ｎｇ／ｍｌ；１８．１４±０．４９ｎｇ／ｍｌ。     

A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.