Effects of Green Tea Extract on Atorvastatin Pharmacokinetics in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Green tea catechins were recently reported to inhibit drug transporters such as organic anion-transporting polypeptides (OATPs) and metabolic enzymes, affecting the bioavailability of many drugs. This study aimed to evaluate the clinical significance of the effects of different doses of green tea extract on the pharmacokinetic parameters of atorvastatin and to rationalize the associated interaction mechanism. METHODS: A randomized, double-blind, three-phase crossover study involving 12 healthy volunteers was performed. Participants received a single dose of atorvastatin 40 mg alone (control group), atorvastatin 40 mg plus a capsule containing 300 mg of dry green tea extract, or atorvastatin 40 mg plus a capsule containing 600 mg of dry green tea extract. Plasma samples taken from the volunteers were analyzed for atorvastatin using liquid chromatography-tandom mass spectrometry (LC/MS/MS). RESULTS: Compared to atorvastatin alone, the administration of 300 mg or 600 mg of the green tea extract along with atorvastatin decreased the peak plasma concentration (Cmax) of atorvastatin by 25% and 24%, respectively (P < 0.05), and the area under the plasma concentration-time curve (AUC0-∞) of atorvastatin by 24% and 22%, respectively (P < 0.05). Additionally, administration of 300 mg or 600 mg of the green tea extract increased the apparent oral clearance (CL/F) of atorvastatin by 31% and 29%, respectively. The time to Cmax (Tmax) and the elimination half-life (t1/2) of atorvastatin did not differ among the three phases. The effects of 600 mg of the green tea extract on the pharmacokinetic parameters of atorvastatin were not significantly different from the effects of 300 mg of the green tea extract. CONCLUSION: Green tea extract decreases the absorption but not the elimination of atorvastatin, possibly by inhibiting OATP, albeit not in a dose-dependent manner. Coadministration of green tea extract with atorvastatin may necessitate the monitoring of the plasma concentration of atorvastatin in clinical practice.

Miconazole-Urea in a Buccal Film as a New Trend for Treatment of Resistant Mouth Fungal White Patches.

A growing concern about Candida albicans is the emergence of high incidence of resistance against antifungal agents, which requires searching for new medications or improving the response to the existing members. The objective of this work was to evaluate the effectiveness of the miconazole in the absence and presence of urea, as a penetration enhancer, against C. albicans. In addition to, formulating both of them in a polymer film to be used topically for treatment of mouth fungal white patches caused by C. albicans. A synergistic effect was recorded between this imidazole and urea against the test strain. Miconazole MIC (32 mg/L) was dramatically reduced to 0.0625 mg/L following combination with urea. Transmission electron microscopy explained the mechanisms of action mediated by the test agents. Minimal fungicidal dose of miconazole combined with urea showed early apoptotic cells with condensed chromatin and small blebs. Cytoplasmic leakage and necrosis in some cells was observed at high fungicidal dose. Buccal bioadhesive films were prepared using increasing values of the drug MIC and urea. The physicochemical characters of the prepared films including; film weight, thickness, swelling index, drug content, folding endurance, surface pH, bioadhesion force and time and drug release kinetics, were studied. Microbiological evaluation of all prepared films showed an increase in the inhibition zone diameters for films containing increasing concentrations of both miconazole and urea in a concentration-dependent manner (30-40 mm) compared to miconazole alone (18 mm). Based on our results, the prepared films are promising for buccal administration of miconazole/urea showing synergistic effect for treatment of C. albicans infection.

Controlled precipitation for enhanced dissolution rate of flurbiprofen: development of rapidly disintegrating tablets.

OBJECTIVE: The aim of this work was to investigate the potential of controlled precipitation of flurbiprofen on solid surface, in the presence or absence of hydrophilic polymers, as a tool for enhanced dissolution rate of the drug. The work was extended to develop rapidly disintegrated tablets. SIGNIFICANCE: This strategy provides simple technique for dissolution enhancement of slowly dissolving drugs with high scaling up potential. METHODS: Aerosil was dispersed in ethanolic solution of flurbiprofen in the presence and absence of hydrophilic polymers. Acidified water was added as antisolvent to produce controlled precipitation. The resultant particles were centrifuged and dried at ambient temperature before monitoring the dissolution pattern. The particles were also subjected to FTIR spectroscopic, X-ray diffraction and thermal analyses. RESULTS: The FTIR spectroscopy excluded any interaction between flurbiprofen and excipients. The thermal analysis reflected possible change in the crystalline structure and or crystal size of the drug after controlled precipitation in the presence of hydrophilic polymers. This was further confirmed by X-ray diffraction. The modulation in the crystalline structure and size was associated with a significant enhancement in the dissolution rate of flurbiprofen. Optimum formulations were successfully formulated as rapidly disintegrating tablet with subsequent fast dissolution. CONCLUSIONS: Precipitation on a large solid surface area is a promising strategy for enhanced dissolution rate with the presence of hydrophilic polymers during precipitation process improving the efficiency.

Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects.

BACKGROUND: The package leaflet for dapoxetine, an effective treatment for premature ejaculation, includes a strict warning against coadministration with drugs or herbal remedies that strongly induce or inhibit the activity of Cytochrome P450 (CYP) 3A4 enzyme. OBJECTIVE: To assess the effects of multiple daily consumption of grapefruit juice (GFJ) and pomegranate juice (PJ) on the pharmacokinetics of dapoxetine, we conducted an open-label, three-way crossover study in 12 healthy subjects using midazolam as a probe substrate for CYP3A4. METHODS: Participants received a single oral dose of dapoxetine (60 mg) and midazolam (7.5 mg) after pretreatment with 250 ml of either water, undiluted GFJ, or PJ for three consecutive days. All subjects were monitored for adverse effects during the study period. RESULTS: Compared to pretreatment with water, GFJ increased the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) and peak plasma concentration (C max) of dapoxetine by 60 and 80 %, respectively, and prolonged its elimination half-life (t 1/2) by 43 %. Similar effects of GFJ on the pharmacokinetics of midazolam were observed with a significant increase in AUC0-∞ (75 %), C max (40 %), and t 1/2 (92 %). Slight but not statistically significant changes were observed in the pharmacokinetics of dapoxetine and midazolam after pretreatment with PJ. Time to reach C max (T max) did not differ among the three phases. CONCLUSION: These results suggest that GFJ increases the extent of absorption and reduces clearance of dapoxetine possibly by inhibition of both intestinal and hepatic CYP3A4, whereas PJ has little effect on dapoxetine pharmacokinetics. Although the impact of GFJ on the pharmacokinetics of dapoxetine was mild, a great caution should be considered when they are concomitantly administered.

Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects.

PURPOSE: Several severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose. METHODS: We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration. RESULTS: Compared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30-60) and 18 % (90 % CI 108-129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63-75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study. CONCLUSIONS: Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.

Fast kinetic and efficient removal of As(V) from aqueous solution using anion exchange resins.

Glycidyl methacrylate/methelenebisacrylamide resin with immobilized tetraethylenepentamine ligand was prepared. This pentamine containing resin was transformed to two anion exchange resins through treatment by glycidyl trimethylammonium chloride to give (RI) or hydrochloric acid giving (RII). The resins were used to adsorb As(V) at different experimental conditions using batch and column methods. Kinetics and thermodynamic properties as well as the mechanism of interaction between As(V) and resin active sites were discussed. The maximum adsorption capacities of As(V) on RI and RII were found to be 1.83 and 1.12 mmol/g, respectively. The regeneration and the durability of the loaded resin towards the successive reuse were also investigated.

Effect of structural properties of acid dyes on their adsorption behaviour from aqueous solutions by amine modified silica.

Monoamine modified silica particles (MAMS) were prepared and characterized by infrared (FT-IR) and thermogravimetric analysis (TGA). The modified silica particles were used for removal of acid orange 10 (AO-10) and acid orange 12 (AO-12) from their aqueous solutions. The adsorption behaviour of the two dyes was studied at different experimental conditions of pH, contact time, concentration of dye, temperature and salt solution. The adsorption of AO-10 followed pseudo-first order kinetics whereas AO-12 followed pseudo-second order. The two dyes showed different modes of interaction with silica surface. Desorption of the loaded dyes was carried out at pH 10 and found to be 10.4 and 91.6% for AO-12 and AO-10, respectively.

Synthesis of magnetic chelating resins functionalized with tetraethylenepentamine for adsorption of molybdate anions from aqueous solutions.

Magnetic resins were synthesized through polymerization of glycidyl methacrylate (GMA) in the presence of divinylbenzene (DVB) or N,N'-methylenebisacrylamide (MBA) as hydrophobic or hydrophilic crosslinker, respectively and in presence of suspended magnetite particles. The resins containing (DVB or MBA) as crosslinker were immobilized with tetraethylenepentamine (TEP) to give the amino resins, GMA/DVB/TEP (R1-en) and GMA/MBA/TEP (R2-en), respectively. The uptake behavior of the two resins was studied towards molybdate anions and uptake capacities of 4.24 and 6.18 mmol/g [as (Mo(VI)] were obtained using (R1-en) and (R2-en). Kinetic studies showed that the adsorption followed the pseudo-second-order model pointing the influence of the textural properties of the resin on the rate of adsorption. Thermodynamic data indicated an endothermic adsorption process. The uptake of Mo(VI) and regeneration of the resins were also studied using the column method. Regeneration efficiency up to 90-96% was reached using ammonia buffer.

Selective separation of mercury(II) using magnetic chitosan resin modified with Schiff's base derived from thiourea and glutaraldehyde.

Magnetic chitosan resin was chemically modified by a Schiff's base cross-linker. The interaction of the resin obtained with Hg(II) was studied and uptake value of 2.8 mmol/g was reported. The kinetic and thermodynamic parameters of the adsorption process were estimated. These data indicated that the adsorption process is exothermic and follow the pseudo-second-order kinetics. The selectivity of Hg(II) from other different metal ions in solutions using the studied resin was also reported. Breakthrough curves for the recovery of Hg(II) were studied. The critical bed height was found to be 2.05 cm. The adsorbed Hg(II) was eluted from the resin effectively using 0.1 M potassium iodide.

Influence of a niosomal formulation on the oral bioavailability of acyclovir in rabbits.

The purpose of this research was to prepare acyclovir niosomes in a trial to improve its poor and variable oral bioavailability. The nonionic surfactant vesicles were prepared by the conventional thin film hydration method. The lipid mixture consisted of cholesterol, span 60, and dicetyl phosphate in the molar ratio of 65:60:5, respectively. The percentage entrapment was approximately 11% of acyclovir used in the hydration process. The vesicles have an average size of 0.95 microm, a most probable size of 0.8 microm, and a size range of 0.4 to 2.2 microm. Most of the niosomes have unilamellar spherical shape. In vitro drug release profile was found to follow Higuchi's equation for free and niosomal drug. The niosomal formulation exhibited significantly retarded release compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of acyclovir in rabbits after a single oral dose of 40 mg kg(-1). The average relative bioavailability of the drug from the niosomal dispersion in relation to the free solution was 2.55 indicating more than 2-fold increase in drug bioavailability. The niosomal dispersion showed significant increase in the mean residence time (MRT) of acyclovir reflecting sustained release characteristics. In conclusion, the niosomal formulation could be a promising delivery system for acyclovir with improved oral bioavailability and prolonged drug release profiles.