Bioanalytical LC-QTOF/MS Method for a N-phenylpiperazine Derivate (LQFM05): An Anxiolytic- and Antidepressant-like Prototype Drug Applied to Pharmacokinetic and Biodistribution Studies.

The LQFM05 is a prototype drug designed for treatment of psychiatric disorders, such as schizophrenia, exhibiting anxiolytic- and antidepressant-like (12 or 24 µmol/kg) effects in classical behavioral tests. In order to evaluate its pharmacokinetic properties, a liquid chromatography method coupled to a quadrupole time of flight mass spectrometry system (LC-QTOF/MS) was developed and fully validated for LQFM05 analysis in rat plasma and tissue samples (brain, heart, liver, and kidneys). Liquid-liquid extraction, solid phase extraction and protein precipitation were assessed as clean-up procedures for biological samples and analyte enrichment. Plasma and tissue samples underwent protein precipitation as a preliminary step, using acetonitrile. Linearity was fully demonstrated for the dynamic range (10.0 to 900.0 ng/mL), with r2 values higher than 0.99 (RSDslope ≤ 2%, Fcal < Ftab, Ccal < Ctab). Biodistribution studies in rats revealed high brain tissue concentrations (12.4 µg/g), suggesting elevated drug affinity to the main therapeutic target tissue, showing a blood partition coefficient of 1.9. Kidneys also showed great exposure and tissue affinity, suggesting a potential extrahepatic clearance. Likewise, all examined tissues exhibited satisfactory LQFMF05 distribution. The mass fragmentation spectrum indicated the presence of its main metabolite, LQFM235, yielded by high hepatic hydroxylation route, an equally bioactive derivative. Lastly, the developed LC-QTOF/MS method was shown to be sensitive (LOQ = 10 ng/mL), precise and accurate for LQFM05 determination in tissue homogenates and plasma samples.

Improvement in Solubility-Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-ß-cyclodextrin.

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-ß-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-ß-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-ß-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-ß-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-ß-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.

Evaluation of the Impact of Different Doses of Curcuma longa L. on Antioxidant Capacity: A Randomized, Double-Blind, Crossover Pilot Trial.

Curcumin is a bioactive compound derived from Curcuma longa L. root, extensively studied due to its antioxidant and anti-inflammatory properties. This study evaluates the effects of different doses of powdered C. longa root on antioxidant capacity in healthy men. In a pilot randomized, double-blinded, crossover experiment, we acutely administered a low dose (1.5 g, LCG), moderate dose (3.0 g, MCG), and high dose (6.0 g, HCG) of C. longa to nine healthy men. There were no differences in plasma curcumin levels (p = 0.593) and antioxidant capacity (p = 0.473) for time × group interactions. Plasma curcumin levels increased in all groups after 20 and 90 min of C. longa intake (p < 0.05). HCG had a lower postprandial incremental area under the antioxidant capacity curve than LCG or MCG (p < 0.01). A low dose of C. longa increased the antioxidant capacity in healthy men. However, plasma curcumin levels were not dose dependently affected.

Liposomal Entrapment of 4-Nerolidylcatechol: Impact on Phospholipid Dynamics, Drug Stability and Bioactivity.

Liposomes containing 4-nerolidylcatechol (4-NC), the major metabolite isolated from Pothomorphe umbellata, were obtained and characterized. Influence of liposomal encapsulation on chemical stability of 4-NC and on cytotoxicity profile of this drug was evaluated. Soybean phosphatidylcholine liposomes were prepared by lipid film hydration followed by extrusion. Entrapment efficiency for 4-NC was approximately 92%. Mean diameter of liposomes was 100 nm with a polydispersity index below 0.13. Liposomal 4-NC (L4-NC) and free drug (F4-NC) were submitted to forced degradation assays, monitored by HPLC. Photodegradation assay followed ICH Guidelines, using a photostability chamber equipped with both UV and white light sources. Liposomal encapsulation was able to markedly reduce 4-NC degradation rates under all the conditions tested. L4-NC showed a half-live approximately 15% higher than F4-NC under light exposure. After 72 hours, acid and base hydrolysis of F4-NC lead to 13 and 16% of degradation, respectively. However, no degradation was observed in L4-NC. EPR spectra of liposomal membrane showed that greatest changes in membrane properties were obtained when 5-doxyl stearic acid was used as the spin label, indicating a marked decrease in the fluidity of the bilayer. Following incubation with K562 cells, 4-NC showed a concentration-dependent cytotoxicity profile, while L4-NC exhibited a time and concentration-dependent profile, consistent with a controlled drug release system. F4-NC induced extensive hemolysis under isotonic conditions; conversely liposomal encapsulation protected erythrocytes from 4-NC induced lysis. Liposomal 4-NC resulted in a hemocompatibility and stable formulation, representing a viable drug delivery system to further investigate in vivo performances of 4-NC in pre clinical studies.

Determination of captopril in human plasma, using solid phase extraction and high-performance liquid chromatography, coupled to mass spectrometry: application to bioequivalence study.

A specific high performance liquid chromatography-mass spectrometric (LC-MS/MS) assay was developed for the determination of captopryl in plasma. The retention time was 1.45 and 1.37 min for captopril and enalapril, respectively. The overall mean recovery, using SPE extraction with OASIS HLB cartridges, was found to be 107.2+/-9.5 and 100.04+/-2%, respectively. Calibration curves were linear in the concentration range of 10.00-2000.00 ng/ml, and the lower limit of quantification (LLOQ) was 10.00 ng/ml. The LLOQ was sensitive enough for detecting terminal phase concentrations of the drug. Inter-batch precision of the method ranged from 0.88 to 1.95%. Intra-batch accuracy ranged from 97.15 to 105.77%, while intra-batch precision ranged from 2.49 to 5.66% at concentrations of 30.00, 760.00 and 1500.00 ng/ml. The developed method was applied to study bioequivalence of captopril in a group of 25 human subjects at a single oral dose of a 50mg tablet.

Antioxidant activity of aryltetralone lignans and derivatives from Virola sebifera (Aubl.).

Aryltetralone lignans bearing methylenedioxy groups (1a-b; 2a-b) were isolated from seeds of Virola sebifera. Their antioxidant activities were evaluated by inhibition of lipid peroxidation as indicated by TBARS and chemiluminescence emission (CL) assays. The lignan 1c, 'having a 2'-hydroxy-4',5'-methylenedioxyphenyl group, was the most active compound with TBARS/CL Q 1/2 values of 0.89 and 0.10 microg/mL, respectively. The catechol derivatives 3 and 4, obtained by demethylenation of lignans 1a and 2a, were of similar activity to 1c, and all were much more effective as antioxidants than alpha-tocopherol.

Dibenzylbutane and aryltetralone lignans from seeds of Virola sebifera.

Two lignans rel-(8R, 8'R)-3,4:3',4'-bis-(methylenedioxy)-7.7'-dioxo-lignan and (7'R,8'S,8S)-2'-hydroxy-3,4:4',5'-bis-(methylenedioxy)-7-oxo-2,7'-cyclolignan were isolated from seeds of Virola sebifera. The cyclolignan showed two atropisomers as determined by 1H NMR spectroscopy at low temperature.

Estudo comparativo da cinética de dissolução de ibuprofeno em comprimidos de liberação imediata comercializados no Brasil / Comparative study of the dissolution kinetics of ibuprofen in immediate-release tablets of the Brazilian market

Avaliaram-se as características físicas e físico-químicas de diferentes lotes de quatro especialidades farmacêuticas contendo ibuprofeno (produtos A, B, C e D), sob a forma de comprimidos de liberação imediata, disponíveis no mercado nacional e comercializados como similares intercambiáveis, enfatizando-se o estudo comparativo da cinética de dissolução do fármaco. Utilizou-se equipamento para dissolução de formas sólidas de acordo com a USP 23, empregando-se tampão fosfato pH 7,2 como meio de dissolução a 37,0 ñ 0,5 ºC e aparato 1 na velocidade de 150 rpm. Os produtos A e B e os produtos C e D, respectivamente, poderiam, teoricamente, ser considerados equivalentes farmacêuticos, segundo a definição da Food and Drug Administration (FDA-USA)...