Farmaco (Societa chimica italiana : 1989)最新文献

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 α₁- and α₂-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 2.7 mg kg^–1, and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected α₁-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.

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. Our primary data suggest noncompetitive and reversible character of caspase-3 inhibition.

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 β-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the β-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the β₃-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express β₁-, β₂- and β₃-adrenoceptors, respectively. When compared with the reference, non-specific, β-adrenoceptor agonist isoprenaline, the products tested did not show any consistent β-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 μmol/l), ICI 118,551 (1 μmol/l) or bupranolol (1–10 μmol/l), thus excluding that the spasmolytic effect involves any β-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting β-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with β-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at β₃-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at β₁- (cardiac) adrenoceptors. At the maximum concentrations tested (1–100 μmol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca²⁺-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes.

A new, simple, rapid and accurate spectrophotometric method is proposed for determination of sodium diclofenac (SD) in pharmaceutical preparations based on its reaction with concentrated nitric acid (63% w/v). The reaction product is a yellowish compound with maximum absorbance at 380 nm. The corresponding calibration curve is linear over the range of 1–30 mg l⁻¹, while the limit of detection is 0.46 mg l⁻¹.

A method based on micellar electrokinetic capillary chromatography (MEKC) was developed for determination of minoxidil in Rogaine and competing products. The original intent of the work was to offer an orthogonal means to HPLC for testing illicit imitations of Rogaine. However, because the patent has since expired, we offer the procedure as a confirmatory measure to HPLC for assay of generic minoxidil products. The MEKC procedure complements an earlier method based on free solution capillary electrophoresis (FSCE), designed to the same end. Validation was carried out on both a Dionex CES-1, which utilizes gravity injection, and a PE-ABI 270HT, which employs vacuum injection. The procedure was validated for both active pharmaceutical ingredient and for minoxidil solutions. The run buffer is pH 7.0, 20 mM sodium phosphate, 20 mM sodium dodecyl sulfate, with 10% isopropanol; the internal standard is dl-tryptophan. The method bears the attributes of simplicity, ease of use, and short analysis time (12 min). It is selective with respect to known process and degradation impurities. High efficiency was achieved on the CES-1, with a plate count exceeding 200,000 for minoxidil at an elution time of 9 min. Although slight differences in performance were noted across the two instruments, results on both were in conformance with modern day validation expectations. Comparison of MEKC with HPLC resulted in slightly higher values for the former, but all results met registration specifications and internal targets.

This study describes an orthogonal experimental design to optimize the formulation of 5-fluorouracil (5-FU) loaded poly d,l (lactide-co-glycolide) (PLGA) nanoparticles (5FU-NP) by a nanoprecipitation-solvent displacement technique. The type of surfactant, amount of acetone and molecular weight of the polymer with three levels of each factor were selected and arranged in an L₁₈(3⁵) orthogonal experimental table. From the statistical analysis of the data polynominal equations were generated. Optimized formulations have the particle size ranging from 160 to 250 nm. Smallest nanoparticles (161 ± 1.22 nm) were obtained using Resomer PLGA 755 and pluronic F-68 with 10 ml acetone amount. Under these conditions the 5-FU entrapment percentage was maximum 78.30%, suggesting 5-FU might be entrapped and adsorbed on the nanoparticle surface. In vitro release of three formulations with maximum drug entrapment efficiency and minimum particle size, were also investigated by release kinetics. According to the determined coefficients, release data fit to Higuchi's diffusion kinetics. The in vitro release of 5FU-NP in phosphate buffered saline (PBS, pH 7.4) is suggested to be controlled by a combination of diffusion with slow and gradual erosion of the particles. Also, the antimicrobial activity was observed even on the end of seventh day with all formulations.

A differential pulse voltammetric method was described for the determination of domperidone. The method was based on the anodic oxidation of domperidone on a glassy carbon electrode at +0.64 V vs. SCE in Britton–Robinson buffer solution of pH 2.3. The reversibility of the oxidation was tested by cyclic voltammetry; the electrode process is irreversible and diffusion–adsorption controlled. Calibrations are linear over the range 1.0 × 10^–6–2.0 × 10^–5 M of domperidone with a detection limit of 4.0 × 10^–7 M. The method was applied, without any interference from the excipients, to the determination of the drug in a tablet dosage form.

The chiral separation of racemic tamsulosin hydrochloride (TH) was carried out using cyclodextrin (CD)-mediated capillary electrophoresis (CE) with DAD at 200 nm. The best separation of enantiomers of the studied compound was achieved at 20 kV with 30 cm × 50 μm I.D. polyacrylamide (PAA)-coated fused-silica capillary (effective length 20 cm) and running buffer with sulfated-β-CD (S-β-CD) as chiral selector. Other selected native or derivatized CDs were also tested: β-CD (5, 15 mmol l⁻¹), carboxymethyl-β-CD (5, 30 mmol l⁻¹), dimethyl-β-CD (15 mmol l⁻¹) and hydroxypropyl-β-CD (5, 30 mmol l⁻¹). Several parameters such as capillary pretreatment, buffer type and concentration, pH of background electrolyte, methanol content, separation temperature and voltage, were optimized. The excellent baseline separation of chiral TH was successfully achieved within 12 min using 100 mmol l⁻¹ phosphate buffer with pH 2.5 containing 1.7 mmol l⁻¹ S-β-CD. Rectilinear calibration range was 50.0–500.0 μmol l⁻¹ of each enantiomer (r = 0.9993–0.9996).

The method was applied to the assay of R-TH in Omnic, capsules (nominal content 0.4 mg per capsule) with R.S.D. 2.75% (n = 6), recovery 99.3–101.7% and it was suitable for the chiral purity control of the active enantiomer in the pharmaceutical.

QSAR modeling was performed on 58 (S) N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxy benzamides as dopamine (DA) D₂ receptor antagonists to identify the structural requirements for DA D₂ receptor binding affinity. The study pointed out that the presence of hydrophobic substituents at R₃ position and electron-donating groups at R₅ position increased the biological activity. Substitutions at phenyl ring favored the binding affinity of these benzamides. Ethyl group and iodine at R₃ position were advantageous to the activity whereas nitro group at phenyl ring hindered the antagonistic activity.