Pharmaceutica acta Helvetiae最新文献

Much research has been done over the past two decades on the role of insulin-like growth factors I and II (IGF) in the maintenance of normal body homeostasis, especially in regard to various endocrine functions, growth and aging. For example, IGF-I is a well established promoter of tissue growth and has been used in the clinics for the treatment of growth related disorders, even being abused by athletes to enhance performance in competitions. In contrast, comparatively limited attention has been given to the potential significance of the IGFs in the central nervous system. Over the past few years, we have studied the trophic as well as neuromodulatory roles of the IGFs in the brain. IGF-I and IGF-II are potent modulators of acetylcholine release; IGF-I inhibiting release while IGF-II is a potent stimulant. Moreover, only the internalization of the IGF-I receptor complex was blocked by an inhibitor of phosphotyrosylation. This is in accordance with the differential nature of the IGF-I and IGF-II receptors, the former being a tyrosine kinase receptor while the later is a single transmembrane domain protein bearing binding sites for 6-mannose phosphate containing residues. The activation of IGF-I receptors protected neurons against cell death induced by amyloidogenic derivatives likely by an intracellular mechanism distinct from those involved in the regulation of acetylcholine release and neuronal growth. The stimulation of IGF-I receptors can activate intracellular pathways implicating a PI3/Akt kinase and CREB phosphorylation or modulate the production of free radicals. The effects, particularly those of IGF-I on key markers of the Alzheimer's (AD) brains namely cholinergic dysfunction, neuronal amyloid toxicity, tau phosphorylation and glucose metabolism suggest the potential usefulness of this growth factor in the treatment of neurodegenerative diseases. However, the poor bioavailability, enzymatic stability and brain penetration of IGF-I hamper progress in this regard. The recent development of a small, non-peptidyl mimetic of insulin able to directly activate the insulin receptor [Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M.T., Pelaez, F., Ruby, C., Kendall, R.L., Mao, X., Griffin, P., Calaycay, J., Zierath, J.R., Heck, J. V., Smith, R.G., Moller, D.E., 1999. Science, 284, 974–977] suggests that a similar strategy could be used for IGF-I and the IGF-I receptor leading to the characterization of IGF-I mimics of potential clinical usefulness.

Pelanserin, a weakly basic experimental drug with a short half-life, was taken as a model to study the influence of lactose on hydroxypropyl methylcellulose matrices to modulate a gradual release. Powder mixtures were wet-granulated with water and compressed in a hydraulic press at 55 MPa. Dissolution media were 900 ml HCl 0.1 N, the first 3 h and phosphate buffer pH 7.4, 3 to 8 h. Dissolution curves were described by M_t/M_inf=ktⁿ, applied separately for each dissolution medium. Dissolution mechanism involved diffusion/relaxation with a linear trend favoring the diffusion mechanism with increasing lactose concentrations. Increasing lactose concentrations produced higher kinetic constants, in a cubic relationship. A double HPMC proportion produced slower dissolution rates, with a more gradual lactose release but including certain degree of erosion. High lactose concentrations compensated for a decreased solubility of pelanserin at pH 7.4.

The purpose of this study is to evaluate and predict the apparent solubility of cefditoren pivoxil in different crystallinity in terms of the two dimensional solubility parameters. The crystallinity of cefditoren pivoxil gradually decreased through grinding process. The partial solubility parameters, δ_d and δ_s relating to dispersion force interaction and other specific interaction, respectively, were calculated for the ground samples of cefditoren pivoxil using the inverse gas chromatography. The values of δ_d were constant independently regardless of the crystallinity, while the values of δ_s became greater with a decrease in the crystallinity of cefditoren pivoxil, suggesting that the polarity on the surface of cefditoren pivoxil powders could become higher. Interaction radius was calculated from the partial solubility parameters of cefditoren pivoxil and water. The dissolution study in water demonstrated that the concentration of cefditoren pivoxil at 20 min increased with decreasing in crystallinity. From these results, the improvement of dissolution by grinding should result from the change of the surface energetics relating to the polarity of cefditoren pivoxil by grinding. Further, the interaction radius could be also applied to predict the apparent solubility of crystalline cefditoren pivoxil in various organic solvents.

Nonionic surfactant vesicles were prepared using Span 60, cholesterol and dicetyl phosphate. The prepared multilamellar vesicles (MLVs) were coated by interfacial polymerization technique using p-phthaloyl dichloride and l-lysine. The formation of the polymeric coat was confirmed by optical microscopic and transmission electron microscopic studies. The prepared, plain and polymer-coated MLVs were studied for their size, shape, encapsulation efficiency, in vitro release profile and effect of osmotic shock on vesicle. The results observed showed that the polymer-coated MLVs were stable under various osmotic conditions. In vivo studies were carried out on albino rats. The half-life and area under curve were found to be high in the case of polymer-coated MLVs as compared to plain MLVs and plain drug solution. In vivo studies using inflammed rat model also indicated that the polymer-coated MLVs were more stable and could release the drug in a controlled fashion as compared to plain MLVs.

l-asparaginase from Escherichia coli is an important enzyme widely used in leukemia treatment under the trade name Elspar®. Up to now, however, the aspects of its stability and storage has not been studied in detail. The aim of this work is to analyze the factors that could interfere in the enzyme's stability. The enzymatic activity was found to be stable in wide pH range (4.5–11.5), showing a slight increase in activity and stability in alkaline pHs, which indicates a more stable conformation of the molecule. The enzyme proved to have a high activity restoration capacity when submitted to temperatures of 65°C, in pH 8.6 buffer and, surprisingly, in physiologic solution. This suggests a positive effect of sodium ions on such restoration capacity. Stability was high in different diluents used as parenteral solutions and in recipients used in medical practice without significant loss of activity for at least 7 days. These results lead us to conclude that the enzyme has a high stability after the lyophilized form has been reconstituted (at least 7 days), since the necessary precautions are taken in terms of sterile manipulation and if it is stored in a suitable parenteral vehicle under low temperature (about 8°C).

In an ongoing research program aiming at the synthesis and pharmacological evaluation of new possible prototype candidates exploring the molecular hybridation and bioisosterism principles for molecular designing, we describe in this paper the design and synthesis of a series of new functionalized oxime O-benzylethers (4a–b) and (14a–b) as antiplatelet agents based on the inhibition of arachidonic acid (AA) cascade enzymes. For the synthesis of these new bioactive derivatives we used safrole (5), a Brazilian abundant natural product, as starting material. The platelet anti-aggregating evaluation of these oxime O-benzylether compounds (4a–b) and (14a–b) in model induced by ADP, collagen and AA, has permitted to evidence an antithrombotic profile to these new derivatives, being the most active the derivative methyl [[3,4-methylenedioxyphenyl]methylene]amino]oxy]-4-methylenephenylacetic acid (14a).

In this study, controlled release dosage forms of dimenhydrinate were prepared with different polymers as MC, HEC, Carbopol 934, Eudragit RLPM and Eudragit NE 30 D at different concentrations (2.5–10%). Direct compression (DC) and wet granulation (WG) techniques were used to prepare the tablets. Magnesium stearate was the lubricant while starch gel was the binder. For the quality control of tablets prepared according to 11 different formulations, weight deviation, hardness, friability, diameter–height ratio, content uniformity of the active substance and in vitro dissolution techniques were performed. Dissolution rate of these tablets was controlled by USP XXII dissolution method and the profile of each tablet was plotted and only for F 5 was evaluated kinetically.

The first synthesis of 1-(1,2-dihydro-2-acenaphthylenyl)piperazine 5 — a new arylpiperazine is described. Preliminary binding studies on this new arylpiperazine reveal affinity for the 5-HT_1A and 5-HT_2A receptor subtypes. Incorporation of a dopamine pharmacophore onto this arylpiperazine provided compound 7 a potential antipsychotic with an atypical profile.