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The salts, 2-methyl-5,5-disubstituted 4,5-dihydroisoxazolium methylsulfates comprising various substituents at the C-3 carbon atom were subjected to transformations. The structure of applied compounds permitted to monitor the effect of this factor on the transformation course of the 2-isoxazoline ring. The nucleophilic addition of cyanide anion to the selected salts enabled the obtaining of a next heterocyclic system of changed physicochemical and biological properties in comparison to the starting 2-isoxazolines...

In this study, heparin-loaded microspheres having smooth surface and small particle size were designed in order to provide the absorption of heparin through nasal mucosa. For this purpose, microspheres at different polymer/drug ratios (1:10, 1:2.5 and 1:1) and at different concentrations of polyvinyl alcohol, emulsifying agent (1.5% and 2.5% w/v) were prepared by solvent evaporation method with poly(lactic acid). The microspheres were for evaluated shape and surface properties, particle size, production yield, encapsulation efficiency and in vitro drug release...

The synthesis and structure determination of 8-aryl /alkyl aryl 1, 3-dimethyl-3, 7-dihydropurin-2, 6-dione derivatives (1-13), was carried out in this study. Bronchodilator activity is investigated using isolated guinea-pig tracheal strips, pre-contracted by acetylcholine and histamine. Spasmolytic activity of the compounds was compared to theophylline. Synthesized compounds (1-13) did not inhibit the acetylcholine-induced pre-contractions except compound (8) at 10(-5) M concentration. In contrast, some of the compounds, especially (7), (11), (12) at 10(-5) M and (3), (4), (9) and (11) in 10(-4) M displayed inhibitory activity on the tracheal strips pre-contracted by histamine...

The present investigation attempts to increase intestinal permeability and hence absorption of biopharmaceutic classification system (BCS) Class III (cefotaxime sodium (CX)) and Class IV (cyclosporin A (CSA)) drugs by employing certain absorption enhancers. Drugs were co-perfused with sodium caprate (SC, 0.25% w/v), piperine (P, 0.004% w/v) and sodium deoxycholate (SD, 1.0% w/v) separately in rat in situ single pass intestinal perfusion model. These additives increased intestinal permeability (P(app)) and absorption rate constant (K(a)) up to two and fourfold, respectively...

A simple, convenient and straightforward synthesis of 3-aryl-1,2,4-oxadiazoles 4a-f from arylamidoximes 1a-f and palmitic acid 2 is described. Compounds 4a-f are non-lethal in mice at four times the therapeutic dose (i.p., LD50>1 g kg(-1) of the animals' body weight). These heterocycles have been found to possess antiinflammatory property similar to aspirin and ibuprofen. Three compounds, viz., 4a, d, e have also been evaluated for antitumor activity, where 4d exhibited an excellent activity comparable to lapachol...

A series of dithiines were synthesized by cyclization of 4-(alkylamino)-4-oxobutanoic acids under the action of SOCl2. Their in vitro antibacterial and antifungal activities have been evaluated against reference strains and versus reference compounds. The so-called 'isoimides' 2a, 2b were totally inactive whereas some imides had low MICs for few bacteria and for few fungal microorganisms.

New, simple and cost effective UV-spectrophotometric methods were developed for the estimation of gatifloxacin in bulk and pharmaceutical formulations. Gatifloxacin was estimated at 286 nm in 100 mM phosphate buffer (pH 7.4) and 292 nm in 100 mM hydrochloric acid (pH 1.2). Linearity range was found to be 1-18 mug ml(-1) (regression equation: absorbance=0.0684 x Concentration in microg ml(-1) + 0.0050; r2 = 0.9998) in the phosphate buffer (pH 7.4) and 1-14 microg ml(-1) (regression equation: absorbance = 0.0864 x Concentration in microg ml(-1) + 0...

The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model...

Formulation excipients can frequently affect the drug analysis in pharmaceuticals yielding background interference by ultraviolet spectrophotometry. Sample separation procedures to diminish such interferences are usually recommended as sample pre-treatment, however it can be difficult to eliminate them and they can still persist. In addition, these procedures can be time consuming and laborious to perform. Excipients, like dyeing agents can also be present in a formulation and yield color to drug solution. This work reports the successful development of a derivative ultraviolet spectrophotometry for dexchlorpheniramine maleate (DPM) determination in solid dosage forms, in spite of the color imparted to tablets solution...

A series of new 4-arylpiperazine derivatives of isothiazolopyridine of Mannich base type and their non-4-arylpiperazine analogues (3 and 4) were synthesized and assayed as potential analgesic agents. Pharmacological assay demonstrated that all the compounds prepared, without exception, displayed significant activity in the mouse writhing assay. The analgesic action, expressed as ED50, was found to be 2-10 times more potent than that of acetylsalicylic acid and 1.5-10 times weaker than that of morphine, these being used as standards...

The affinities of the enantiomers of 1,3,4,14b-tetrahydro-2,10-dimethyl-2H,10H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzotriazepine (10-methyl-10-azaaptazepine, 5) and 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 10,10-dioxide (tiaaptazepine, 6) were evaluated in receptor binding assays. Compound (+)-(S)-5, the most significant tested enantiomer, showed good affinities for 5-HT1A, 5-HT2A 5-HT2C and alpha2NA receptors, moderate affinities for DA1, DA3r and 5-HT3 receptors and it was devoid of affinity for DA2, alpha(1NA) and muscarinic receptors...

Thermal treatment of acrylic matrices was recently introduced as a tool for prolonging the release of drug. Thermal treatment at temperatures above the T(g) of the polymer can decrease drug release rate. In this research we studied the mechanism of the effect of thermal treatment on Eudragit RS matrices. Indomethacin was used as model drug. The results showed that polymer chain movement and redistribution of the polymer in the tablet matrix structure after thermal-treating is the possible mechanism of drug release prolongation...

Absorption enhancers (AEs) have been shown to be specific in permeation enhancement capabilities because of which they increase absorption of some drug molecules more than others. Present study was designed to investigate the relationship between lipophilicity of drug molecules and the absorption enhancement potential of AEs. Four drug molecules of different lipophilicity were selected as model compounds, namely, cefotaxime sodium, ceftazidime pentahydrate, lovastatin and cyclosporin A. Their apparent permeability coefficients in the absence and presence of three classes of AEs (fatty acids, cyclodextrins, and bile salts) were determined using in vitro everted rat intestinal sac absorption model...

Extended-release theophylline (TP) matrix tablets were prepared by direct compression of drug and different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent (Eudragit RLPO and RSPO) polymer combinations. The influence of varying the polymer/polymer (w/w) ratio and the drug incorporation method (simple blend or solid dispersion) was also evaluated. Drug release, monitored using the Through Flow Cell system, markedly depended on both the kind of Eudragit polymer combinations used and their relative content in the matrix...

In the current investigation, paclitaxel (PCL) delivery into the different layers of skin, vehicle optimization and relationship between vehicle composition and the relative contribution of solubility, partition and diffusion towards drug transport has been outlined. Saturation solubility of PCL was determined in ethanol (EtOH), isopropyl myristate (IPM) and their binary combinations, and partition studies performed to study the probability of skin depot formation. Epidermal and dermal partitioning was carried from PCL saturated vehicles...

The Bcl-2 family of antiapoptotic proteins is commonly over expressed in many types of human cancer and remains one of the few validated targets. Antiapoptotic family proteins such as Bcl-2 and Bcl-XL function, at least in part, by binding proapoptotic members such as Bax and Bak and thereby prevent release of the apoptotic cascade of events. "BH3-only" members of the family disrupt this interaction by binding, via their BH3 domain, to a hydrophobic pocket on the surface of the antiapoptotic members. Disruption of heterodimerization could be used to modulate cell death reinstating apoptosis in cancer cells...

A series of thiazolyl-N-phenyl piperazines has been synthesised and tested for anti-inflammatory activity. Their R(M) values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and logPsk also performed. The effect of the synthesised compounds on inflammation, using the carrageenin induced mouse paw oedema model was studied. In general, the studied compounds were found to be potent anti-inflammatory agents (44-74.1%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesised compounds...

A convenient synthesis of novel 8-sulfonyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines is described. As key steps to assemble the target molecular scaffold, our method features (a) Pfitzinger reaction of isatin-5-sulfonate 1 with methyl 3-oxo-3-phenylpropanoate, (b) formation of 1-(1H-pyrazol-4-yl)-1H-pyrrole-2,5-dione intermediate 5, and (c) reaction of sulfinic acid 9 with acrylate or methylacrylate leading to the corresponding sulfonyl propionates. Two compounds, ester 11 and morpholide 13, have been identified as potent inhibitors of caspase-3 with IC50 = 6 nM...

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2...

The synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1-7) or 7- (compounds 8-14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at beta-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the beta-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the beta3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express beta1-, beta2- and beta3-adrenoceptors, respectively...