Experimental acute anti-inflammatory activity of preparations with complexed cannabidiol in carriers

Abstract Cannabidiol (CBD) is a bioactive compound with promising anti-inflammatory results but has low aqueous solubility. Complexation of drugs with this characteristic in carriers is an alternative to improve their efficiency. This study aimed to prepare and characterize CBD complexes in different carriers, and to evaluate the anti-inflammatory effect of such preparations using an experimental model of edema induction in rat paws. The results were compared to a reference drug, ibuprofen (IBU). The carriers evaluated were beta cyclodextrin (bCD) and activated charcoal (AC). Quantification of the drugs in the complexes was determined, and different qualitative analyses were also performed. Oral treatments in single doses with CBD showed inhibitory effects similar to that of IBU, potentiating its bioactivity without significant adverse effects. CBD*bCD doses at 4.375, 8.75, 17.5, and 35 mg/kg significantly reduced the intensity of edema compared to equivalent doses of pure bioactive. In contrast, CBD*AC did not generate benefits. There was no significant inhibitory effect on myeloperoxidase activity, requiring more specific analyses to assess this parameter. The results suggest that the CBD*bCD complexation is perfectly feasible, increasing its anti-edematogenic efficacy in the experimental model used.

Antibacterial and Cytotoxic Effects of Cyclodextrin-Triazole-Titanium Based Nanocomposite

Abstract In this paper, the antibacterial activity of triazole functionalized cyclodextrin (CD.Click) and cyclodextrin-triazole-titanium based nanocomposite (CD.COM) was evaluated. The results indicated that CD.Click and CD.COM perform a wide range of antibacterial activity against both gram positive (Staphylococcus aureus and Bacillus subtilis) and gram negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. The cytotoxic effect of CD.COM was investigated in vitro on cancerous cell lines (cervical cancer, breast carcinoma and sarcoma osteogenic) and fibroblast cells by MTT assay. The cell viability evaluation confirmed that the growth of cancerous cells is inhibited in a dose and time dependent way without any significant effect on the normal fibroblast cells.

Avaliação do impacto causado pela disponibilidade de 17β-estradiol livre ou complexado à β -ciclodextrina no ambiente aquático sobre Oreochromis niloticus (tilápia) / Impact evaluation caused by disponibility of free and complexed 17β -estradiol into cyclodextrin in the aquatic environment in tilapia (Oreochromis niloticus)

Foram avaliados os efeitos tóxicos do hormônio 17β-estradiol (E2) livre e complexado à β-ciclodextrina (CD) sobre o comportamento e a fisiologia de tilápia (Oreochromis niloticus). Os peixes foram observados por 30 dias, em dois estágios do desenvolvimento (alevino e juvenil), pelo método ad libitum, para a confecção de um etograma. Posteriormente, juvenis foram divididos em três grupos: controle e expostos ao E2 (10ng/L) livre e complexado à β-ciclodextrina (β-CD:E2) por 90 dias. Foram avaliados o comportamento pelo método de varredura instantânea, o consumo de ração, o ganho de peso e a mortalidade em diferentes intervalos. Os alevinos e os juvenis apresentaram frequências de exibição comportamentais diferentes (P<0,05) nos eventos: Afastar (4,7±1,3 e 3,6±0,6%) e Ondulação de repulsão (2,3±0,9 e 1,3±1,0%). Os juvenis expostos ao complexo β-CD:E2 apresentaram aumento (P<0,05) na exibição dos comportamentos agressivos, como Afastar, Ataque caudal, Confronto prolongado, Perseguição, Fuga, e menor mortalidade, quando comparados ao grupo exposto ao E2 livre e controle. Pode-se concluir que a complexação do E2 com a β-CD alterou a toxicidade do E2, pois promoveu um aumento na frequência de exibição dos comportamentos agressivos e interferiu na mortalidade dos animais.(AU)

Toxic effects of free and complexed 17β-estradiol (E2) hormone into β-cyclodextrin (CD) on the behavior and physiology of tilapia (Oreochromis niloticus) were evaluated. The fish were observed for 30 days in two stages of development (fingerling and juvenile) by the ad libitum method to make an ethogram. After this, juveniles were divided into three groups: control and exposed to free E2 (10ng/L) and complexed into β-cyclodextrin (β-CD:E2) for 90 days. The behavior was evaluated through scan sampling method, feed intake, body mass and mortality at different intervals. The fingerlings and juveniles showed behavioral patterns with different display frequencies (P<0.05) for events: Move Away (4.7±1.3 and 3.6±0.6%) and Waving Repulsion (2.3±0.9 and 1.3±1.0%). The juveniles exposed to β-CD:E2 complex showed a significant increase (P<0.05) in the frequency of display of aggressive behaviors as Move Away, Caudal Attack, Clash Extended, Chase, Escape and decrease of mortality when compared to group exposed to free E2 and control. In conclusion, complexation of E2 into β-CD modified E2 toxicity, because it promoted an increase in the frequency of display of aggressive behaviors and it affected the mortality of animals.(AU)

Actividad antioxidante del complejo de inclusión del extracto de semilla de Bixa orellana en ß-ciclodextrina obtenido por CO2 supercrítico / Antioxidant activity of the inclusion complex of Bixa orellana seeds extract in ß-cyclodextrin obtained by supercritical CO2

Antecedentes: los extractos de Bixa orellana son utilizados como colorante de alimentos, y presentan una actividad antioxidante de importancia farmacéutica. Su uso puede limitarse por su inestabilidad, donde el proceso de inclusión en ß-ciclodextrina (ß-CD) por fluido supercrítico con CO2 (FSC-CO2) es una alternativa para mediar esta desventaja. Objetivos: comparar diferentes condiciones de temperatura y presión de extracción por FSC-CO2, para determinar cuál de estas permite obtener un extracto de Bixa orellana con mayor actividad antioxidante, y evaluar el efecto de la inclusión en ß-CD, en dicha capacidad antioxidante. Métodos: se obtuvieron extractos por FSC-CO2 variando condiciones de presión y temperatura: (I) 3583 psi, 35°C, (II) 1413 psi, 35°C, (III) 2184 psi, 45°C, (IV) 5076 psi, 45°C, y (V) 2300 psi, 40°C. Se evaluó la actividad antioxidante de los extractos obtenidos mediante el método DPPH, determinando su IC50. Se realizó el complejo de inclusión en ß-CD del extracto que presentó la mayor actividad antioxidante, por el método FSC-CO2, y fue caracterizado por IR, DSC y RMN. Mediante análisis comparativo de los espectros de la ß-CD, extracto libre y el complejo extracto/ß-CD, se verificó el acomplejamiento, y se evaluó la capacidad antioxidante del complejo de inclusión. Resultados: el extracto con mayor actividad antioxidante se obtuvo bajo la condición de extracción IV, con un IC50 de 23,55 µg/ mL, seguido del extracto II (28,76 µg/mL), del extracto III (37,23 µg/mL), del extracto V (81,09 µg/mL) y del extracto I (193,82 µg/mL), los cuales presentaron diferencias significativas (P<0,01). Los espectros obtenidos por IR, DSC y RMN presentaron desplazamientos propios del proceso de encapsulamiento. El valor IC50 del complejo extracto/ß-CD fue de 104,84 µg/mL, siendo significativamente mayor al valor obtenido para el extracto puro (23,55 µg/mL). Conclusión: el extracto de Bixa orellana con una actividad antioxidante mayor se obtuvo por fluido supercrítico a 5076 psi de presión y 45°C de temperatura. Las variaciones de los espectros IR, DSC y RMN demuestran la inclusión del extracto en la ß-CD, y los valores de IC50 indican el efecto protector de la ß-CD ante la reacción con el radical DPPH.

Background: Bixa orellana extracts are used to food coloring and it is important in pharmaceutical industry as a potential source of antioxidant activity. The application may be limited because it is unstable, but the process of inclusion in ß-cyclodextrin (ß-CD) by supercritical fluid CO2 (FSC-CO2) is an alternative to mediate this disadvantage. Objectives: we compared different conditions of temperature and pressure of FSC-CO2 extraction, to obtain a Bixa orellana extract with excellent antioxidant activity, and we evaluated the effect of inclusion in ß-CD in the antioxidant capacity. Methods: extracts were obtained by FSC-CO2 with different conditions of pressure and temperature: (I) 3583 psi, 35°C, (II) 1413 psi, 35°C, (III) 2184 psi, 45°C, (IV) 5076 psi, 45°C, and (V) 2300 psi, 40°C. The antioxidant activity by DPPH assay was determined and the IC50 was evaluated. We performed the inclusion complex in ß-CD with the highest antioxidant activity extract. The extract/ß-CD complex was characterized by IR, DSC and NMR. This complexation was verified by comparative analysis of the spectra of the ß-CD, free extract and ß-CD/extract complex. The antioxidant capacity of this inclusion complex was evaluated. Results: the extract with highest antioxidant activity was obtained under the extraction condition IV, with an IC50 of 23.55 µg/mL, followed extract II (28.76 µg/mL), extract III (37.23 µg/mL), extract V (81.09 µg/mL) and extract I (193.82 µg/mL). Analysis showed significant differences (P<0.01) between these extracts. The spectra obtained by IR, DSC and NMR evidence the encapsulation process. The IC50 value of the extract/ß-CD complex (104.84 µg/mL) was significantly higher than the value obtained for the pure extract (23.55 µg/mL). Conclusions: the highest antioxidant activity of Bixa orellana extracts was obtained by supercritical fluid pressure at 5076 psi and temperature of 45°C. Variations in IR, DSC and NMR spectra showed the inclusion of the ß-CD/extract, and the IC50 values indicated the protective effect of ß-CD to the reaction with DPPH radical.

Gel de doxiciclina encapsulada em ß-ciclodextrina como agente tópico adjuvante para o tratamento não cirúrgico da periodontite crônica: um ensaio clínico randomizado / Efeito de gel de doxiciclina encapsulada em ß-ciclodextrina como agente tópico adjuvante para periodontite crônica: um ensaio clínico / Doxycycline gel encapsulated in ß-cyclodextrin as adjunctive topical agent for the treatment non surgical of chronic periodontitis: a randomized clinical trial

Objetivo: comparar a eficácia clínica de um gel de doxiciclina 10% encapsulada em ß-ciclodextrina (DOX) / ßCD), com o gel de 10% DOX - pura, como adjuvantes da Raspagem e Alisamento Radicular (RAR) em um ensaio clínico. Materiais e Métodos: trinta e três indivíduos com diagnóstico de periodontite crônica (PC) foram randomizados para: grupo I (GI) (10% de gel DOX + RAR), grupo II (GII) (10% de gel de DOX / ß-CD + RAR) que receberam aplicação dos géis em T0 e T1 e grupo III (GIII), apenas RAR. Os parâmetros clínicos de Profundidade à Sondagem Periodontal (PSP), Nível de Inserção Clínica (NIC), Sangramento à sondagem (SS) e Índice de Placa Visível (IPV) foram avaliados em: tempo inicial (T0), 30 dias (T1) e 60 dias (T2). Resultados: Dentro dos grupos, GII apresentou a redução mais significativa nas médias de PSP e SS e o maior ganho médio em NIC (p <0,05). Ao comparar os três grupos, GII apresentou maior redução em PSP (2,62 mm) (p <0,003) e atingiu o maior número de indivíduos com ganho de inserção clínica (2,54 mm) em T2 (p <0,003). O SS e IPV apresentaram uma forte redução em todos os grupos, comparando T2 com T0 (p <0,05). IPV e SS diminuiram ≥ 5 vezes e duas vezes, respectivamente em T0 até T1, mas diminuíram de forma semelhante em todos os grupos, sem diferença significativa. Na avaliação comparativa das densidades ósseas obtidas nos exames radiográficos de GI e GII realizados nos momentos T0 (RX inicial), T2 (RX 60 dias após T0) e T Final (RX 18 meses após T0), observou-se aumento da densidade óssea ao longo do tempo em todos os grupos. Houve um aumento maior na densidade óssea até 60 dias (TI). No entanto, o GII mostrou maior aumento na densidade óssea, mas não teve diferença significativa em relação ao tipo de gel aplicado. Conclusão: O presente estudo mostrou que a aplicação do gel de DOX a 10% incluída em ß-CD associada à RAR apresentou melhora significativa nos parâmetros clínicos periodontais (PSP, NIC e SS) e do IPV, em todos os protocolos analisados, proporcionando benefícios adicionais à RAR sozinha. Nos indivíduos tratados, as bolsas periodontais ficaram mais rasas ao final da investigação. Houve aumento da densidade óssea ao longo do tempo em todos os grupos. No entanto, GII mostrou um aumento estatisticamente significativo na densidade óssea entre os tempos T0 e T2, sem diferença significativa em relação à GI. O gel contendo somente DOX a 10% também apresentou benefícios significativos à RAR, porém menores se comparado ao gel com o composto de inclusão (DOX/ ß-CD). Estes resultados traduzem-se em um ganho real na saúde periodontal. Portanto, a inclusão da doxiciclina em ß-CD, liberada localmente, pode ser um adjuvante quimioterapêutico importante no tratamento da periodontite crônica.(AU)

Aim: to compare the clinical efficacy of 10% doxycycline encapsulated in ß- cyclodextrin (DOX)/ßCD) in gel with 10% DOX- pure gel along adjuvants with scaling and root planning (SRP) in a clinical trial. Materials and Methods: Thirty-three subjects with diagnosis of chronic periodontitis (CP) were randomized into: group I (GI) (10% DOX gel + SRP), group II (GII) (10% DOX / ß-CD gel + SRP) that received application of the gels at T0 and T1, and group III (GIII), only SRP. The clinical parameters of Periodontal Probing Depth (PPD), Clinical Attachment Level (CAL), Bleeding on Probing (BOP) and Visible Plaque Index (VPI) were evaluated at baseline (T0), 30 days (T1) and 60 days (T2). Results: Within the groups, GII presented the most significant reduction in the mean of PPD and BOP and the highest mean gain in CAL (p <0.05). When comparing the three groups, the GII presented a greater reduction in PPD (2.62 mm) (p <0.003) and reached the greatest number of individuals with a gain of clinical attachment (2.54 mm) at T2 (p <0.003). The BOP and VPI had a strong reduction in all groups, comparing T2 with T0 (p <0.05). The VPI and BOP decreased ≥ 5 times and twice, respectively at T0 up to T1 in a similar way for all groups, without significant difference. In the comparative evaluation of the bone density obtained in the radiographic examinations of GI and GII performed at moments T0 (initial RX), T2 (RX 60 days after T0) and T Final (RX 18 months after T0), it was observed increase in bone density over time in all groups. There was a greater increase in bone density up to 60 days (TI). However, GII showed greater increase in bone density, but didn't have a significant difference in relation to the type of gel applied. Conclusion: the present study showed that the application of the 10% DOX gel included in ß-CD associated with SRP showed a significant improvement in periodontal clinical parameters (PPD, CAL and BOP) and VPI, in all analyzed protocols, providing additional benefits to the SRP alone. In the treated individuals, the periodontal pockets were shallower at the end of the investigation. There was an increase in bone density over time in all groups. However, GII showed a statistically significant increase in bone density between T0 and T2 times, without significant difference in relation to GI. The gel containing only 10% DOX also presented significant benefits to RAR, but smaller when compared to gel with inclusion compound (DOX / ß-CD). These results translate to a real gain in periodontal health. Therefore, the inclusion of locally released doxycycline into ß-CD may be an important chemotherapeutic adjuvant in the treatment of chronic periodontitis.(AU)

Efecto citotóxico de los compuestos de inclusión de paladio (II) en la beta-ciclodextrina / Cytotoxic effect of palladium (II) inclusion compounds in beta-cyclodextrin

Resumen Introducción. Las tiosemicarbazonas y sus complejos de paladio (II) poseen actividad antineoplásica con pocos efectos secundarios, por lo cual se las considera como una nueva alternativa terapéutica. Sin embargo, existen diferencias en los rangos de la concentración inhibitoria media (CI50) asociada a la divergencia estructural y la solubilidad de los complejos, así como a la sensibilidad de los blancos celulares. La inclusión de fármacos en la beta-ciclodextrina con fines terapéuticos ha mejorado su solubilidad y estabilidad, pero los efectos de su combinación con los complejos de paladio (II) y las tiosemicarbazonas no se han comprobado aún. Objetivo. Estudiar el efecto citotóxico de los complejos de paladio en la beta-ciclodextrina. Materiales y métodos. La actividad citotóxica de los complejos de paladio en la beta-ciclodextrina se evaluó en la línea celular de cáncer de mama (MCF-7), empleando el método de la sulforodamina B. Resultados. Los ligandos MePhPzTSC y Ph2PzTSC, sus complejos de paladio (II) libres e incluidos en la beta-ciclodextrina y el cisplatino mostraron actividad citotóxica en la línea celular MCF-7; sin embargo, la citotoxicidad fue mayor con la inclusión en la beta-ciclodextrina ([Pd(MePhPzTSC)2]•ß-CD y [Pd(Ph2PzTSC)2]•ß-CD). La concentración inhibitoria media (CI50) para estos complejos se obtuvo en concentraciones de 0,14 y 0,49 μM, y con dosis hasta cinco veces inferiores comparadas con las concentraciones de los ligandos libres (1,4 y 2,9 μM), de los complejos de paladio (II) libres (0,57 y 1,24 μM) y del cisplatino (6,87 μM). Conclusiones. El uso de la beta-ciclodextrina mejoró significativamente la actividad citotóxica de las tiosemicarbazonas y sus complejos de paladio (II), lo cual probablemente está asociado al incremento de la solubilidad y biodisponibilidad del compuesto, estrategia que se puede sugerir para el diseño de futuros fármacos antineoplásicos.

Abstract Introduction: Thiosemicarbazones and palladium (II) complexes have antineoplastic activities with mild side effects, for which they are considered new alternative antineoplastic drugs. However, the IC50 ranges of these complexes vary due to differences in their structure and solubility and their sensitivities for various cellular targets. Beta-cyclodextrin is an additive used to improve the solubility and stability of various drugs for therapeutic use, but the combination of beta-cyclodextrin with palladium (II) complexes and thiosemicarbazones has not been tested yet. Objective: To study the cytotoxic effect of palladium (II) inclusion complexes in beta-cyclodextrin. Materials and methods: We tested the cytotoxic activity of palladium complexes combined with betacyclodextrin in the breast cancer cell line MCF-7 using a sulforhodamine B assay. Results: We tested the antiproliferative activity of palladium (II) complexes with and without the ligands MePhPzTSC and Ph2PzTSC and with and without beta-cyclodextrin in MCF-7 cells and compared them to that of cisplatin. All combinations showed antiproliferative activity; however, the activity was greater for the combinations that included beta-cyclodextrin: ([Pd (MePhPzTSC) 2] • ß-CD and [Pd (Ph2PzTSC) 2] • ß-CD), at concentrations of 0.14 and 0.49 μM, respectively. The IC50 for this complex was 5-fold lower than that of the ligand-free combinations (1.4 and 2.9 μM, respectively). The IC50 for free palladium (II) complex was 0.571.24 μM and that for cisplatin was 6.87 μM. Conclusions: Beta-cyclodextrin significantly enhanced the cytotoxic activities of palladium (II) complexes and thiosemicarbazones probably by improving their solubility and bioavailability. The addition of betacyclodextrin is a possible strategy for designing new anticancer drugs.

La sertralina incluida en la ß-ciclodextrina no induce un perfil tolerogénico en células dendríticas derivadas de monocitos / Title: Sertraline Included in ß-ciclodextrin does not Induce a Tolero- genic Profile in Monocyted-Derived Dendritic Cells

Objetivo: Evaluar el efecto inmunomodulador de la sertralina (SRT) y la sertralinaincluida en la ß-ciclodextrina (LF) en células dendríticas humanas (CD) generadas invitro a partir de monocitos sobre marcadores de fenotipo y la producción de citocinas.Materiales y métodos: Se aislaron monocitos CD14+ de células mononucleares desangre periférica y se diferenciaron a CD; posteriormente, se pretrataron con SRT oLF durante una hora. Finalmente, las CD se maduraron con lipopolisacárido (LPS)durante 24 horas y se analizó el fenotipo de las CD y las concentraciones de citocinasen los sobrenadantes de cultivo. Resultados: No se observaron cambios al compararel fenotipo de las CD maduradas con LPS en ausencia o presencia de la SRT. Asímismo, no hubo variación en cuanto a la producción de citocinas. Conclusión: LaSRT incluida o no en la ß-ciclodextrina no afecta el fenotipo y la secreción de las CDtratadas con LPS.

To evaluate the immunomodulatory effect of sertraline (SRT) and sertraline inclu - ded in ß-cyclodextrin (LF) in human dendritic cells (DCs) generated in vitro from monocytes on phenotype markers and cytokine produc - tion. Materials and Methods: CD14 + mono - cytes from peripheral blood mononuclear cells were isolated and differentiated to DCs. DCs were subsequently pretreated with LF or SRT for one hour. Finally DCs were matured with lipopolysaccharide (LPS) for 24 hours and the CDs phenotype and the levels of cytokines in the culture supernatants were analyzed. Results: No change on the phenotype of the DCs matured with LPS in the absence or presence of the SRT was observed. Likewise, there was no variation in cytokine production. Conclusion : SRT or not including ß-cyclodextrin does not affect the phenotype and secretion of LPS-treated DCs.

A randomized, open-label study to evaluate the effectiveness and safety of betahistine dihydrochloride in beta-cyclodextrin versus betahistine dihydrochloride in the treatment of vertigo

OBJECTIVE: To compare the effectiveness and safety of Betahistine dihydrochloride (in beta cyclodextrin) with Betahistine dihydrochloride in treating patients with vertigo.DESIGN/METHODS: This was a randomized, open label study enrolling 68 patients, ages 18 to 65 years old, diagnosed clinically with vertigo.RESULTS: Sixty two patients completed the study. EEV scores of both groups continuously decreased to similar levels. EEV scores significantly deceased from baseline to week 4. In group A patients, EEV scores decreased from 9.81+/- 3.73 at baseline to 2.39 +/- 3.46, pGroup A patients reported 2.6 +\- 2.9 side effects while Group B patients reported 2.7 +/- 2.5 side effects (p=0.92). There were more patients who experienced vomiting, abdominal pain, nausea, vomiting and/ or diarrhea in Group B patients (8/32 in Group A vs 16/30 in Group B, p=0.022).CONCLUSION: Betahistine dihydrochloride with beta cyclodextrin and Betahistine dihydrochloride alone are both effective in reducing the symptoms of dizziness from vertiginous syndromes. Betahistine dihydrochloride with beta cyclodextrin appears to have less gastrointestinal side effects than Betahistine dihydrochloride alone.

A preliminary study of pharmacokinetics of evodiamine hydroxypropyl-β-cyclodextrin inclusion complex / 南方医科大学学报

<p><b>OBJECTIVE</b>To compare the pharmacokinetic parameters of evodiamine hydroxypropyl-β-cyclodextrin inclusion complex and free evodiamine suspension in rats, and investigate the pharmacokinetic characteristics of evodiamine inclusion complex.</p><p><b>METHODS</b>Both water solubility and cumulative release percentage of EHD were tested with evodiamine as the control. Blood samples were collected from the venous plexus of SD rats after intravenous administration with evodiamine inclusion complex and free evodiamine at 100 mg/kg (equivalent evodiamine dose). Plasma concentrations of evodiamine were determined by high-performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated using DAS 2.1.1.</p><p><b>RESULTS</b>The evodiamine inclusion complex showed a better water solubility (18.46±0.36 µg/mL) and a higher cumulative release percentage [(76.8±4.9)%] than free evodiamine. The pharmacokinetic parameters of evodiamine inclusion complex and free evodiamine in rats were as follows: Cmax, 252.5±12.43 vs 161.3±3.45 µg/L; T(max), 4.00±0 vs 4.07±0 h; MRT(0-∞), 8.46±0.91 vs 4.43±0.74 h; AUC(0-t), 2266.40±28.64 vs 911.92±8.53 µg·L(-1)·h(-1); AUC(0-∞), 2359.76±31.58 vs 919.16±9.73 µg·L(-1)·h(-1). The relative bioavailability of evodiamine inclusion complex was 256.73%.</p><p><b>CONCLUSION</b>Compared with free evodiamine, evodiamine inclusion complex has a higher bioavailability.</p>

Effect of β-cyclodextrin inclusion complex on transport of major components of Xiangfu Siwu decoction essential oil in Caco-2 cell monolayer model / 中国中药杂志

Although the essential oil of Xiangfu Siwu decoction (XFSWD) has strong pharmacological activity, its special physical and chemical properties restrict the clinical application and curative effect. In this paper, Xiangfu Siwu decoction essential oil (XFS-WO) was prepared by forming inclusion complex with β-cyclodextrin (β-CD). The present study is to investigate the effect of β-CD inclusion complex on the transport of major components of XFSWO using Caco-2 cell monolayer model, thus to research the effect of this formation on the absorption of drugs with low solubility and high permeability, which belong to class 2 in biopharmaceutics classification system. A sensitive and rapid UPLC-MS/MS method was developed for simultaneous quantification of senkyunolide A, 3-n-butylphthalide, Z-ligustilide, dehydrocostus lactone and α-cyperone, which are active compounds in XFSWO. The transport parameters were analyzed and compared in free oil and its β-CD inclusion complex. The result revealed that the formation of XFSWO/β-CD inclusion complex has significantly increased the transportation and absorption of major active ingredients than free oil. Accordingly, it can be speculated that cyclodextrin inclusion complex can improve bioavailability of poorly water-soluble drugs. Above all these mentioned researches, it provided foundation and basis for physiological disposition and pharmaceutical study of XFSWD.

Determination of the interaction kinetics between meloxicam and β-cyclodextrin using the quantitative high-performance affinity chromatography coupled with mass spectrometry / 药学学报

The association rate constant and dissociation rate constant are important parameters of the drug-cyclodextrin supermolecule systems, which determine the dissociation of drugs from the complex and the further in vivo absorption of drugs. However, the current studies of drug-cyclodextrin interactions mostly focus on the thermodynamic parameter of equilibrium constants (K). In this paper, a method based on quantitative high performance affinity chromatography coupled with mass spectrometry was developed to determine the apparent dissociation rate constant (k(off,app)) of drug-cyclodextrin supermolecule systems. This method was employed to measure the k(off,app) of meloxicam and acetaminophen. Firstly, chromatographic peaks of drugs and non-retained solute (uracil) on β-cyclodextrin column at different flow rates were acquired, and the retention time and variance values were obtained via the fitting the peaks. Then, the plate heights of drugs (H(R)) and uracil (H(M,C)) were calculated. The plate height of theoretical non-retained solute (H(M,T)) was calculated based on the differences of diffusion coefficient and the stagnant mobile phase mass transfer between drugs and uracil. Finally, the k(off,app) was calculated from the slope of the regression equation between (H(R)-H(M,T)) and uk/(1+k)2, (0.13 ± 0.00) s(-1) and (4.83 ± 0.10) s(-1) for meloxicam and acetaminophen (control drug), respectively. In addition, the apparent association rate constant (k(on,app)) was also calculated through the product of K (12.53 L x mol(-1)) and k(off,app). In summary, it has been proved that the method established in our study was simple, efficiently fast and reproducible for investigation on the kinetics of drug-cyclodextrin interactions.

Caveolin-1 and glucose transporter 4 involved in the regulation of glucose-deprivation stress in PC12 cells / 生理学报

Recent evidence suggests that caveolin-1 (Cav-1), the major protein constituent of caveolae, plays a prominent role in neuronal nutritional availability with cellular fate regulation besides in several cellular processes such as cholesterol homeostasis, regulation of signal transduction, integrin signaling and cell growth. Here, we aimed to investigate the function of Cav-1 and glucose transporter 4 (GLUT4) upon glucose deprivation (GD) in PC12 cells. The results demonstrated firstly that both Cav-1 and GLUT4 were up-regulated by glucose withdrawal in PC12 cells by using Western blot and laser confocal technology. Also, we found that the cell death rate, mitochondrial membrane potential (MMP) and intracellular free Ca(2+) concentration ([Ca(2+)]i) were also respectively changed followed the GD stress tested by CCK8 and flow cytometry. After knocking down of Cav-1 in the cells by siRNA, the level of [Ca(2+)]i was increased, and MMP was reduced further in GD-treated PC12 cells. Knockdown of Cav-1 or methylated-β-Cyclodextrin (M-β-CD) treatment inhibited the expression of GLUT4 protein upon GD. Additionally, we found that GLUT4 could translocate from cytoplasm to cell membrane upon GD. These findings might suggest a neuroprotective role for Cav-1, through coordination of GLUT4 in GD.

Calendario de inicio sexual en México: Comparación entre encuestas nacionales y tendencias en el tiempo / Sexual debut in Mexico: a comparison of household national surveys

Objetivo. Estimar el calendario de inicio sexual en México y sus tendencias a partir de encuestas poblacionales. Material y métodos. Se analizaron cinco cohortes de nacimiento con cuatro encuestas nacionales (Encuesta Nacional de Salud 2000, Encuesta Nacional de la Dinámica Demográfica 2009, Encuesta Nacional de Juventud 2010 y Encuesta Nacional de Salud y Nutrición 2012) y se identificaron las proporciones de individuos que iniciaron actividad sexual antes de los 16 y antes de los 20 años. Resultados. Las distintas encuestas son, en general, consistentes, pero difieren entre ellas en algunas cohortes. En las cohortes más jóvenes, se identificó una proporción algo mayor de individuos que iniciaron antes de los 20 años; no se advierten cambios en el inicio sexual antes de los 16 años. Conclusiones. La falta de grandes cambios en la edad de inicio de vida sexual con tendencia al adelanto del calendario en México llama a fortalecer la educación sexual integral y la oferta de servicios de salud sexual y reproductiva accesibles a los adolescentes.

Objective. To estimate calendar of sexual debut in Mexico and its trends using national representative household surveys. Materials and methods. Analysis of five birth cohorts extracted from four national population based household surveys in Mexico (National Health Survey 2000, National Survey on Demographic Dynamics 2009, National Youth Survey 2010, and National Health & Nutrition Survey 2012), using as outcome the proportion of individuals that reported sexual debut before the age of 16 and before the age of 20. Results. Overall, the four analyzed surveys produce consistent results, although some differences were found. While a larger proportion among younger cohorts reported sexual debut before the age of 20, that was not the case for sexual debut before 16 years. Conclusions. While data seems to reflect a relative stable age of sexual debut in Mexico, there is a recent trend to prepone sexual initiation that highlights the need to strengthen comprehensive sexual education and the supply of sexual & reproductive health services that are accessible and friendly to adolescents thus responding to the growing demand from this age group.

Determination of kaempferol and quercetin in xindakang tablet by beta-cyclodextrin modified micellar electrokinetic capillary chromatography

A method was proposed to determine kaempferol and quercetin in Hippophae rhamnoides L medicinal preparation xindakang tablet by beta-cyclodextrin modified micellar electrokinetic capillary chromatography. Under the optimized conditions: buffer solution of 20 mmol/L Na[2]B[4]O[7]-KH[2]PO[4] [pH 9.0]-20mmol/L SDS-6mmol/L beta-CD-5%[v/v] MeCN, applied voltage of 16 kV and injection time of 8s, the two analytes were separated well within 10 minutes. The calibration was linear in the 0.02-0.80 and 0.02-0.70 mg/mL range for kaempferol and quercetin, respectively. The reproducibility based on migration time and peak height were 0.47% and1.87% for kaempferol, 0.55% and 2.02% for quercetin. The detection limits based on three times noise were 0.010 mg/mL and 0.008 mg/mL for kaempferol and quercetin, respectively. The developed method was utilized to analyze real samples and running recovery experiments with satisfactory results.

Synergetic taste masking of lipid coating and beta-cyclodextrin inclusion / 药学学报

Paracetamol was used as a model drug in this study to investigate the synergetic effects of lipid coating and beta-cyclodextrin (beta-CD) inclusion for masking the bitter taste of poorly soluble drugs. To control the concentration as low as possible of the free drug which produced a bitter taste, a kinetic model was established to calculate the drug distribution theoretically among the free drug in medium, lipid coated particles and molecular inclusion on the basis of the preparation and characterization of the lipid microspheres, so as to select the proper amount of beta-CD. Finally, the synergetic drug delivery systems were prepared and characterized by 1H nuclear magnetic resonance (1H NMR), molecular simulation and the electronic tongue. As a result, the drug release rate constant (k) of the lipid microspheres coated with octadecanol was determined as 0.001 270 s(-1). Then, the synergetic drug delivery systems were prepared with the ratio of 6.74 : 1 (w/w) for beta-CD and paracetamol. The chemical shift values for the fingerprint peaks of paracetamol all increased and hydrogen bonds were formed between the oxygen on the phenolic hydroxyl group, the nitrogen on the imino in paracetamol and the hydrogens on the hydroxyl groups in beta-CD. The results tested by the electronic tongue indicated that the paracetamol, lipid microspheres, beta-CD inclusion and their mixture showed different taste characteristics, with the bitterness order of the synergetic drug delivery systems approximately lipid microspheres < beta-CD inclusion < paracetamol, which confirmed the synergetic taste masking effects of lipid coating and beta-CD molecular inclusion. In summary, the synergetic taste masking was jointly achieved through the retard of the drug release by the lipid coating and the inclusion of the free paracetamol by beta-CD through hydrogen bonds.

Investigation of properties of the resveratrol-beta-cyclodextrin inclusion complex by drug-protein interaction spectra and molecular modeling / 药学学报

The supramolecular inclusion properties of beta-cyclodextrin (beta-CD) and resveratrol (Res) were investigated using drug-protein interaction spectroscopy method. The differences between the results of interaction spectroscopy method and the results of classical method were compared. The total energy of the stable inclusion of cyclodextrin-resveratrol was calculated by Gaussian theory calculation. The stable inclusions in the process of interaction between resveratrol/inclusion complex and bovine lactgoferrin (BLF) were studied by molecular modeling. The results showed that the interaction spectroscopy method could explain the property of the inclusion in a more sensitive manner, it also interpreted the conveying mechanism of BLF binding with inclusion complex. The molecular modeling result showed consistent results with Gaussian theory calculation; both of the two methods obtained the stable configuration of beta-CD-Res inclusion. The relevant result provided an experimental consequence for the pharmacology research of beta-cyclodextrin-resveratrol inclusion complex as well as offering a new reference to the future research of supramolecular inclusion compound.

Preparation process of rutacarpine-hydroxypropyl-beta-cyclodextrin inclusion complex / 中国中药杂志

Rutaecarpine (Rut) is a type of indole quinazoline alkaloid exracted from Ruticarpum. Studies showed that Rut has a wide range of pharmacological effects, such as anti-hypertension, anticancer, anti-inflammation, anti-thrombus formation. Currently, many scholars are committed to developing it into a new antihypertensive and anti-inflammatory drug with all new mechanisms. But studies found that Rut is a highly fat-soluble drug with low water and oil solubility. Its high insolubility is the main obstacle in its oral absorption and application, which greatly reduced its bioavailability. Therefore, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was used as the inclusion material to prepare Rut-HP-beta-CD inclusion complex in this experiment, in order to increase its water solubility and bioavailability. In this experiment, the inclusion complex was prepared by the stirring-freeze-dry method. The preparation process was optimized by the orthogonal test, with the inclusion rate as the index, and molar ratio between host and guest molecules, inclusion temperature, time and stirring speed as the impacting factors. Moreover, the inclusion complex was verified by detecting the apparent solubility, thin layer chromatography, microscopic identification, melting point detection and dissolution study. The results showed that under the conditions of the molar ratio between Rut and HP-beta-CD of 1: 1, temperature at 60 degrees C, inclusion time of 4h and stirring speed at 600 r x min(-1), the inclusion rate of Rut-HP-beta-CD reached 91.04%. Therefore, the preparation process of Rut-HP-beta-CD inclusion under the optimum conditions is simple and feasible, with a highest inclusion rate and reproducibility, and could significantly improve Rut's solubility and bioavailability, and provide a reliable experimental basis for its clinical application.

Impact of drug molecules on HP-β-CD compound inclusion / 中国中药杂志

To study the interaction of drugs of different properties, namely puerarin, borneol and catalpol in the process of in- clusion, in order to explore the inclusion regularity of multi-component and multi-property traditional Chinese medicine compound in- clusions. With HP-β-CD as the inclusion material, the freeze-drying method was used to prepare the inclusion. The inclusion between puerarin, borneol and catalpol was tested by measuring the inclusion concentration, DSC and X-ray diffraction. According to the find- ings, when insoluble drugs puerarin and borneol were included simultaneously, and puerarin was overdosed, puerarin included was almost equal to puerarin included, and borneol was not included. When puerarin was under-dosed, and HP-β-CD was overdosed, borne- ol was included, and the simultaneous inclusion was lower than the separate inclusion of borneol. When water-soluble drug catalpol was jointly included with puerarin or borneol, the simultaneous inclusion was almost the same with their separate inclusion, without charac- teristic peak of catalpol in DSC and X-ray diffraction patterns. There is a competition in the simultaneous inclusion between water-solu- ble drugs puerarin and borneol and a stronger competition in puerarin. The water-soluble drug catalpol could be included with HP-β-CD with no impact on the inclusion of puerarin or borneol.

Research on flavonoids contents in Fructus sophorae with capillary zone electrophoresis

Genistin, genistein, kaempferol, quercetin and rutin, five kinds of flavonoids in Fructus sophorae, have been analyzed by capillary zone electrophoresis with internal standard calibration. Buffer pH and concentration, applied voltage, Beta -cyclodextrin and ethanol concentration were optimized and the optimum conditions are: 20 mmol/L borax [pH 9.5] with 8 mmol/L Beta -cyclodextrin and 5% [v/v] ethanol and at a voltage of 25 kV. The contents of five flavonoids in Fructus Sophorae grown in different area of Dezhou, Shandong Province of China were determined by the developed method and with satisfactory results. The distributions of the studied flavonoids were also investigated

Preparation of colon target pellets of Pulsatilla total saponins-hydroxypropyl-beta-cyclodextrin inclusion / 中国中药杂志

<p><b>OBJECTIVE</b>To prepare colon target pellets of Pulsatilla total saponins.</p><p><b>METHOD</b>Pulsatilla total saponins-hydroxypropyl-beta-cyclodextrin inclusion was prepared by the water solution-mixing method. Then plain pills of inclusion were prepared by the granulation-spheronization method, and coated by Glatt fluid bed.</p><p><b>RESULT</b>The dissolution of plain pills of Pulsatilla total saponins at 2 h was 16.0%, while that of plain pills of inclusion at 0.5 h was 91.9%. With Eudragit S100 as the coating material, TEC as the plasticizer and talcum power as the anti-adherent, when the coating weight was 12%, the coating efficiency was high, with almost no bonding and drug release of coated pellets in artificial gastric juice for 2 h. The accumulated drug release in artificial intestinal fluid for 4 h was less than 15%, and that in artificial colon fluid for 4 h was more than 90%.</p><p><b>CONCLUSION</b>Coated pellets of Pulsatilla total saponins-hydroxypropyl-beta-cyclodextrin inclusion showed a good colon targeted drug release in vitro, thus could be further developed to be oral colon targeted preparations.</p>