The effect of ferrous ions, calcium ions and citric acid on absorption of ciprofloxacin across caco-2 cells: practical and structural approach.

OBJECTIVE: To study the potential influence of selected metal ions on absorption (and hence oral bioavailability of ciprofloxacin (Cipro) in presence and absence of a competing ligand. SIGNIFICANCE: The presence of metal ions together with Cipro results in complexes exhibiting a decreased bioavailability. Attempts were made to better understand the mechanism of decreased Cipro bioavailability in the presence of metals such as calcium and ferrous ions, and a small-sized ligand citric acid (CitA). METHODS: Effect of complex size or other potential factors was studied using diffusion through synthetic membrane, permeation studies across Caco-2 cells and capillary electrophoresis. A molecular dynamics (MD) simulation study was conducted to find the arrangement and the nature of the interactions between Cipro molecules and ferrous ions. RESULTS: Cipro was shown to form complexes with metals and CitA. The presence of CitA improved permeation of Cipro through the synthetic membrane but this was not as obvious in case of Caco-2 cells. Capillary electrophoresis suggested the existence of large molecular aggregates of Cipro: metal complexes. MD simulations offered clear evidence of large size aggregates in line with the experimental findings. CitA alone significantly improved permeation of Cipro through Caco-2 cells. CONCLUSIONS: The size of the formed complexes, rather than the decrease in the solubility of formed complexes, plays a significant role in permeation (absorption) of Cipro. CitA might ameliorate the effect of co-administered metal ions on the bioavailability of Cipro.

Predictors of nonadherence in children and adolescents with epilepsy: A multimethod assessment approach.

BACKGROUND: There is a lack of a standardized tool for adherence measurement in patients with epilepsy. Studies in children with epilepsy have reported adherence in 50-96.5%. The primary objective of this study was to identify predictors of nonadherence to antiepileptic drugs (AEDs) using two different methods in Jordanian children and adolescents with epilepsy. METHODS: Participants included 63 children and adolescents with epilepsy and their primary caregivers. Adherence measures included a subjective approach (using parent and child self-reports via Medication Adherence Report Scale (MARS)) and an objective method (measuring plasma levels of AEDs coupled with the application of population pharmacokinetic models to predict AED concentrations in the children). The Beliefs about Medicines Questionnaire (BMQ) was used to examine the association beliefs about medicines with nonadherence in the participating patients. RESULTS: Measuring AEDs in plasma samples captured the highest percentage of nonadherence (36.2%). No significant agreement was found between the AED plasma level method and both the MARS (parent) and MARS (child). The overall nonadherence (combined methods) to AED therapy in children with epilepsy was 44.4%. Logistic regression analysis indicated that children with longer duration of disease were more likely (odds ratio [OR]: 1.54, 95% confidence interval [CI]: 1.16-2.04) to be classified as nonadherent as were children whose parents have lower AED Necessity scores (OR: 0.68, 95% CI: 0.53-0.87) and higher AED Concerns (OR: 1.6, 95% CI: 1.26-2.04) as measured by the BMQ. CONCLUSION: The use of a multimethod approach for assessing adherence increases sensitivity for detection of nonadherence to AEDs. Disease duration and parental necessity beliefs and concerns assessed by the BMQ-specific questionnaire were significant predictors of nonadherence to the AED therapy. The need for the development and implementation of interventions that can be employed to improve adherence within this pediatric population has been highlighted by the high levels of nonadherence identified.

Effect of Ramadan fasting on fatigue, mood, sleepiness, and health-related quality of life of healthy young men in summer time in Germany: A prospective controlled study.

Muslims around the world fast during the lunar month of Ramadan. The month consists of 29 or 30 days, which vary in length depending on geographic location and the time of year. During this month, Muslims abstain from food, drink, smoking, and sex from dawn until sunset. In 2015, Ramadan fell during the summer. As a result, Muslims in Germany fasted 19 h a day. Previous research has shown associations between fasting and mood enhancement. This study aimed to determine the effect of fasting on young, healthy males who fasted in Germany during Ramadan 2015. In particular, this study examined the impact of fasting on mood, fatigue, and health-related Quality of Life (QoL). This study had 2 groups: fasting group (FG; n = 25), and non-fasting group (NFG; n = 25). In FG, participants were assessed at four different points: one week before Ramadan (T1), mid Ramadan (T2), the last days of Ramadan (T3), and one week after Ramadan (T4). In NFG, participants were assessed only at T1 and T3. The results revealed that there were no significant differences between the participants in the FG and the NFG at T1 or T3 for any of the outcomes. However, participants in the FG demonstrated significant improvement from T2 to T4 in fatigue (visual analogue scale p < 0.01; fatigue severity scale:p < 0.01), mood (Beck's Depression Index-II; ANOVA; p < 0.05), and sleepiness during day time (Epworth Sleepiness Scale: ANOVA; p < 0.01). Participants in the FG also experienced significant loss of body weight (ANOVA; p < 0.001), body mass index (ANOVA; p < 0.001), skeletal muscle mass (ANOVA; p < 0.01) and fat free mass (ANOVA; p < 0.01). Findings demonstrate that Ramadan fasting did not significantly influence mood, fatigue and QoL, when compared to NFG. Even, it gives benefit to fasting group with regard to these parameters.

In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions.

Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug-protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.

Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation.

Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPßCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF-Na with HPßCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPßCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPßCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPßCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPßCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF2-Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPßCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPßCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPßCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPßCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal.

Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation.

Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPßCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF-Na with HPßCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPßCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPßCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPßCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPßCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF2-Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPßCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPßCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPßCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPßCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal.

In vitro evaluation of potential complexation between bovine insulin and bovine serum albumin.

The objective of this study was to examine the possible binding of bovine insulin (BI) with bovine serum albumin (BSA) to form a new potential diabetogenic irreversible complex protein. Several preparations of BSA and BI were prepared. Both capillary electrophoresis and spectrophotometric analysis were undertaken to test the possibility of complexation between BI and BSA. HPLC was used to test whether the potential complex of BI and BSA is reversible or irreversible. The optimum deviation between the real and calculated absorbances was observed at a BI/BSA ratio of 2. Moreover, the migration time of BI decreased substantially with increasing ratio of BI to BSA until it became almost constant at equal molar ratio of BI/BSA. While the majority of the 2:1 BI-BSA sample detached during the HPLC analysis, which confirms the reversible character of BI-BSA binding, the HPLC chromatogram also emphasizes the formation of an irreversible complexation between the two proteins. This study provides evidence of the formation of reversible and irreversible new BI-BSA complexes under physiological conditions. This highlights the importance of examining the possible diabetogenicity of BI-BSA complex in genetically susceptible people.

Alterations in anthropometric, inflammatory and mental health parameters during Ramadan intermittent fasting in a group of healthy people: a prospective cohort study.

Fasting has been practiced with different time span in different areas of the world and for various reasons. One of the types of fasting regimens is Ramadan intermittent fasting (RIF), which is described as intermittent dry fasting and known as the most commonly practiced form of religious fasting. Different studies have shown its effects on body composition parameters and mental health, fatigue and quality of life (QoL). Elucidating the relationship of RIF on biological parameters would also be of importance to show its mechanism. Therefore, we evaluated several biological mediators related to mental health, such as ß-nerve growth factor (ß-NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and insulin-like growth factor-1 (IGF-1), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and matrix-metalloproteinase-9 (MMP-9). This study consisted of fasting (FG; n = 25) and non-fasting group (NFG; n = 25). Four different time points were assessed for FG: one week before (T1), mid (T2), last days (T3), and one week after (T4) RIF. T1 and T3 were the assessment time points for NFG. Biological mediators were determined from serum samples by using Human Magnetic Luminex and enzyme-linked immunosorbent assay. Furthermore, we then performed correlation analyses between biological mediators and our previously published clinical parameters including body composition and mental health parameters at all time points. Significant alterations were shown in FG for ß-NGF (T2vsT3, p < 0.05; T2vsT4, p < 0.05), GDNF (T1vsT4, p < 0.05; T2vsT4, p < 0.05), IL-8 (T2vsT3, p < 0.05; T3vsT4, p < 0.05), TNF-α (T1vsT3, p < 0.05; T1vsT4, p < 0.001; T2vsT4, p < 0.001), and MMP-9 (T1vsT4, p < 0.01). There were no statistically significant differences between FG and NFG in all biological mediators at T1 and T3. Correlation analysis showed that MMP-9 levels had negative correlation with body mass index (BMI) at T3. At T3 BDNF levels had negative correlation with Epworth Sleepiness Scale (ESS) as one of measured QoL parameters. ß-NGF, GDNF, TNF-α, and MMP-9 had positive correlation with some of body composition and mental health parameters. Findings demonstrate that RIF altered different biological mediators could give benefit to health. Its benefit is mediated by the alteration of biological mediators.

IR microspectroscopic investigation of the interaction of some losartan salts with human stratum corneum protein and its effect on losartan transdermal permeation.

The interaction of pharmacologically active drugs with SC biochemical components is underestimated in pharmaceutical research. The aim of this research was to illustrate that some drugs intended for transdermal delivery could interact with the protein component of SC. Such interactions could be in favor of or opposition to their percutaneous absorption. IR microspectroscopy was used to delineate possible interaction of SC keratin with three losartan salts LOS-K, LOS-DEA and LOS-AML salts in addition to AML-BES salt. The results of PCA, combined with comparisons of average second derivative spectra of SC samples treated with these salts and the control SC, showed that LOS-DEA did not interact with SC, thus providing base line permeation of losartan. AML-BES, LOS-AML and LOS-K salts modified the conformational structure of keratin. The disorganization effect on the α-helical structure and induced formation of parallel ß-sheets and random coils were in the order of AML-BES˃LOS-AML˃LOS-K. The order of the impact of treatments which resulted in increased formation of ß-turns was AML-BES˃LOS-AML. The formation of antiparallel ß-sheets was manifested by LOS-AML. Thus, the overall effect of these salts on the SC protein was AML-BES˃LOS-AML˃LOS-K. The impact of LOS-K was associated with improved permeation whereas the impact of LOS-AML was associated with hindered permeation of both losartan and amlodipine. There is a possibility that losartan and amlodipine when present in combination inside SC, their binding to the protein is enhanced leading to being retained within SC.

Interaction of esomeprazole with insulin detemir and human albumin: A potential cause of hypoglycemia.

Insulin detemir (IDt) is long-acting insulin whose protraction mechanism is based on a covalently attached fatty acid to an insulin molecule. Utilizing the high affinity of fatty acids towards human serum albumin (HA), the modified detemir molecule binds with good affinity to HA, which functions as a reservoir that leads to a slow and prolonged release of insulin. However, questions were raised over potential interactions between other drugs and IDt through competitive binding on the binding site(s) of HA. In a previous study, concomitant use of esomeprazole (Esom) and erythromycin resulted in severe hypoglycemia, and thus: the drugs including Esom were suggested as enhancers of IDt action through displacing it from its binding site on HA. To further study this possibility, studies utilizing different techniques including, semipermeable membrane dialysis, capillary electrophoresis, UV,NMR spectroscopy, and molecular docking were carried out. Results from various techniques supported the simultaneous binding of Esom along with IDt to HA (i.e., binding in two different sites without signs of competition between the two). Moreover, capillary electrophoresis suggested an increase in the binding affinity of Esom to HA in the presence of IDt (1.9 × 103 Vs 2.7 × 104M-1). Perhaps most interesting was the observation that Esom could bind directly to IDt which was evidenced by all the employed techniques. Direct binding of Esom to IDt, might explain the enhancement in insulin action associated with the concomitant use of Esom. Therefore, Esom might represent a leading insulin-sensitizing compound that might lead to more effective insulin enhancing and less unwanted effects.

Evaluation of the acute antihyperglycemic effects of four selected indigenous plants from Jordan used in traditional medicine.

CONTEXT: Eryngium creticum Lam. (Umbelliferae), Geranium graveolens L.Her.exn Ait (Geraniaceae), Paronychia argentea Lam. (Caryophyllaceae), and Varthemia iphionoides Boiss (Compositae) have traditionally been used as antidiabetic phytomedicines. However, their alleged benefits and mechanisms remain elusive. OBJECTIVES: To evaluate the effect of these plants on in vitro and in vivo enzymatic starch digestion. MATERIALS AND METHODS: In vitro enzymatic starch digestion with acarbose or (1-50 or 100 mg/ml) plants aqueous extracts was assayed using α-amylase and α-amyloglucosidase. Oral starch tolerance tests and oral glucose tolerance tests were determined for the plant extracts at concentrations 125, 250, and 500 mg/kg body weight. Blood glucose levels in rats treated with plant extracts or drugs (acarbose or metformin and glipizide) were measured at -30, 0, 45, 90, and 135 min. RESULTS AND DISCUSSION: In vitro, acarbose, and water extracts of G. graveolens and V. iphionoides exerted significant dose-dependent dual inhibition of α-amylase and α-glucosidase, with respective IC50s of 1.2 µg/ml, 84.7, and 65.2 mg/ml. Comparable in vivo acute postprandial antihyperglycemic efficacies were obtained for G. graveolens and V. iphionoides in starch-fed rats. E. creticum exhibited substantial acute antihyperglycemic activities in starch-treated rats, despite lacking any favorable in vitro effectiveness. However, P. argentea lacked any inhibitory efficacy. None of the plant extracts qualified for improving the glucose tolerance in fasted rats on glucose loading. CONCLUSION: G. graveolens and V. iphionoides can be considered as potential candidates for therapeutic modulation of impaired fasting glycemia, impaired glucose tolerance, and type 2 diabetes.

Preparation, characterization and antimicrobial assessment of selected ciprofloxacin salts.

The formation of salts is considered a simple strategy to modify the physicochemical properties of active pharmaceutical ingredients. In this study, seven novel binary and ternary organic salts of ciprofloxacin (CP) were prepared with benzoic acid (BA), acetylsalicylic acid (ASA), p-coumaric acid (PCMA) and p-aminosalicylic acid (PASA). They were characterized by spectroscopic techniques and differential scanning calorimetry. Solubility and partition coefficients values were also measured. Evaluation of the antimicrobial activity of the organic salts against Staphylococcus aureus and Staphylococcus epidermidis revealed that most of the new salts had higher antimicrobial activity than CPHCl against both strains. The most active compounds against S. epidermidis and S. aureus were CP-PASA and CPPCMA, resp., which were up to fourteen times more potent than parent CP-HCl. Our findings indicated a strong correlation between the lipophilicity of the formed salts and their antimicrobial activity and showed that an optimum value of lipophilicity (log P = 0.75) seemed to be necessary to maximize the antimicrobial activity. These findings highlighted the improved physical, thermal and antimicrobial properties of the new salts of CP that can aid in providing higher bioavailability than CP-HCl.

HPLC method development/validation and skin diffusion study of caffeine, methyl paraben and butyl paraben as skin-diffusing model drugs.

The focus of this research was to develop and validate a suitable HPLC method, which allows simultaneous determination of three proposed skin model penetrants to investigate the percutaneous diffusion behavior of their combination: caffeine, methyl paraben and butyl paraben. These penetrants were selected because they represent a wide range of lipophilicities. This model highlights the effect of combining penetrants of different molecular properties on their diffusion behavior through skin. The proposed method employed a gradient system that was systematically optimized for separation and quantification of the penetrants. The effect of the stationary phase (C18, C4 and cyano (CN)) was assessed with CN proven to be superior in terms of peak shape, retentivity and dynamic linear range. Significant differences in retention time, peak broadening, and quantifiability between different stationary phases could be demonstrated. The method was validated as per ICH guidelines Q2 (R1) with a satisfactory outcome. The method was successfully applied for real diffusion experiments, and revealed notable differences between the individual penetrants and their ternary mixture on transdermal permeation. The method could potentially be extended to determine these analytes in other related skin permeation investigations.

Development of a capillary electrophoresis method for the determination of orphenadrine citrate in tablets in the presence of paracetamol.

A validated method using capillary electrophoresis was developed, for the determination of orphenadrine citrate in its tablet formulations, in the presence of paracetamol. The method employs a running buffer of 30 mM pentane sulfonate sodium, dissolved in 20 mM MOPS buffer pH 7.7. Samples were injected using hydrodynamic sample injection mode (25 mbar, for 25 s), using positive polarity of 25 kV, at a constant temperature of 30 °C. Samples of orphenadrine citrate alone or in mixture solutions with paracetamol were exposed to various degradation conditions, and were electrophoresed using the recommended condition. The method was found to be specific, linear (r (2) = 0.994), precise, accurate, and robust, with an LOQ of 0.02 mg/mL. The proposed method was successfully applied for measurement of the percentage per label of orphenadrine citrate in commercially available tablets.

Capillary electrophoresis as a screening tool for alpha amylase inhibitors in plant extracts.

Capillary electrophoresis (CE) method was developed for screening plant extract for potential alpha amylase (AA) inhibitory activity. The method was validated against a well established UV method. Overall, the proposed method was shown able to detect plants with significant alpha amylase inhibitory activity but not those with rather clinically insignificant activities. Fifty plant species were screened using both the proposed CE method and the UV method and seven plant species were found to possess significant AA inhibitory activities. Two plant species were proved to have alpha amylase inhibitory activity for the first time.

A prospective controlled study on Ramadan fasting in the healthy young males in summer in Germany: effect on cytokines.

SHORT COMMUNICATION: During the Ramadan fasting (RF) month, participants restrict some activities during day time, particularly consumption of food and beverages. In Germany, Muslims fast about 18-19 h a day when Ramadan falls in the summer. This longer period of restriction could lead to the changes of the body physiology, anthropometric parameters and biological mediators. OBJECTIVES: This study aimed to determine the effect of Ramadan fasting on cytokines (Interleukin (IL)-1ß. IL-6, IL-8, IL-10, IL-12, tumor necrosis factor (TNF)-α) during RF in Germany. Correlations of cytokines with anthropometric parameters were also determined. METHODS: Fifty healthy adult males were recruited and divided into two equal groups: fasting group (FG) and non-fasting group (NFG). FG was evaluated at T1: one week before, T2: mid-, T3: last days of, and T4: one week after Ramadan. The NFG were evaluated only at T1 and T3. RESULTS: In FG significant alterations of IL-1ß was observed. Insignificant differences were found between the FG and NFG at T1 and T3 concerning the measured cytokines. Circulating IL-1ß increased significantly from T2 to T4 and from T3 to T4. At T3, TNF-α was correlated significantly with anthropometric parameters such as the body weight, the skeletal muscle mass and the fat free mass, whilst IL-12 was correlated significantly with the skeletal muscle mass, the fat free mass and the body water mass at T4. CONCLUSIONS: Significant Alterations of IL-1ß during RF in FG were observed. Anthropometric parameters correlate with TNF-α and IL-12 levels during at T3 and T4, respectively.

Studies on potential interaction between cinacalcet hydrochloride and diclofenac sodium.

Cinacalcet (CT) is an important drug for the treatment hyperparathyroidism. Only few studies havereported thepotential interaction between CT and other potentially coadministered drugs. In this study, the potential of invitro interaction between CT and DF sodium (DF-Na) was investigated. An ion pair salt of CT with DF was obtained by mixing the two compounds in solution; the product was fully characterized by HPLC analysis, UV, FTIR, NMR spectroscopy in addition to DSC. The solubility and partition coefficients were found to significantly decrease and increase, respectively, for the obtained ion pair salt in comparison to the parent compounds. Dissolution studies in phosphate buffer pH 6.8 revealed a significant decrease in the dissolution of an already poorly water soluble drug (decrease to ~20% of the original). Permeation studies, through Caco-2 cells monolayer, revealed a significant decrease in permeation of CT when coexisted with DF (almost to half). Apparent permeability coefficient (Papp) decreased from 3.6 × 10-6 to 1.8 × 10-6 cm/s. Interestingly, a structure for the formed CT-DF salt that could explain the above findings (increase in lipophilicity), could be proposed based on structural modelling, molecular dynamic simulations and NMR proton chemical shifts analysis.

Pancreatic lipase inhibitory activity of selected pharmaceutical agents.

Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the relationship comprising structural attributes of the compounds could be established to correlate with the observed inhibitory activity. Compounds that exerted inhibitory action through surface activity were of different profile from the rest of compounds. When co-incubated with orlistat (OsT), important synergistic effects for some compounds (orphenadrine, gliclazide, cefuroxime and sulfacetamide) were revealed, while antagonistic effects were demonstrated for others (camphor sulfonic acid and dinitro salicylic acid). Docking studies for the most active molecules were performed and molecular interaction forces with the PL active site were identified. The results suggested co-binding of OsT along with the other inhibitor in the binding site in cases of synergistic effect but not in the case of antagonistic effect. These results were additionally supported by affinity capillary electrophoresis. In conclusion, synergistic lipase inhibitory activity between OsT and some other pharmaceutical compounds was demonstrated for the first time, which might help improve the pharmacological effect of OsT.

Interaction of pseudoephedrine and azithromycin with losartan: Spectroscopic, dissolution and permeation studies.

This study aims at investigating the potential effect of selected cationic drugs (azithromycin (AZN) and pseudoephedrine sulfate (PSD) on the dissolution profile and intestinal permeation of losartan potassium (LOS) that might occur due to ion pair salt formation. DSC, FT-IR and 1H NMR indicated the formation of ion pair salts between LOS and each of AZN and PSD. Based on NMR chemical shifts calculations, utilizing specialized software, the most likely structures of the salt were proposed and revealed interesting structural features. The obtained ion pair products were shown to have lower aqueous solubilities (water and phosphate buffer pH 6.8) and higher apparent partition coefficient values compared to the parent compound. Neither of the cations affected the dissolution of LOS tablet (Cozaar® 100 mg) in the studied media (HCl pH 1.2 and phosphate buffer pH 6.8). Interestingly, AZN significantly increased the dissolution of LOS in phosphate buffer pH 4.5 (f2 = 33), and an explanation based on distinguished association pattern between AZN and LOS (CH/π) was offered. Employing permeation test across Caco-2 cells monolayer, the apparent permeability coefficient (Papp) of LOS increased significantly (from 0.9 × 10-5 cm/s to 1.8 × 10-5 cm/s) in the presence of the selected cations. Therefore, while the employed cationic drugs were not shown to form ion pair salts under the in-vitro dissolution conditions, they may still participate in significant in-vivo interaction with LOS.

Effects of dietary broccoli on human in vivo caffeine metabolism: a pilot study on a group of Jordanian volunteers.

OBJECTIVES: Induction or inhibition of cytochrome P450 (CYP) enzyme activities, enzymes that activate or detoxify xenobiotics, is one mechanism by which vegetables may alter cancer risk. As the effect of food on CYP enzyme activities have not been studied in the Jordanian population, we examined the effect of supplementing the diet with broccoli on CYP1A2 and CYP2A6 activities. METHODS: Five men and five women, non-smokers, consumed a standard diet of broccoli (500 g) for 6 days. Enzyme activities were determined by measuring urinary metabolite ratios after a 100 mg caffeine tablet on the seventh day. RESULTS: The mean CYP1A2 activity for men (21.1+/-3.2) was significantly lower than that for women (27.6+/-1.6) before the consumption of broccoli (P<0.05). These activities were significantly induced in both men (52.5+/-6.6) and women (36.6+/-8.4) after a standard diet of broccoli (P<0.005). Similarly, the mean value of CYP2A6 activity for men was 0.061+/-0.040 and for women, 0.144+/-0.039 before consumption of broccoli, which were significantly different (P<0.05). The activity of CYP2A6 was induced in both groups significantly after broccoli consumption (P<0.05). The mean value for men was 0.193+/-0.02 and for women, 0.214+/-0.064. CONCLUSION: Our study on a group of Jordanians confirmed the well-established observation that broccoli induces CYP1A2 activity. This study also demonstrates the effect of gender and broccoli consumption on CYP2A6 activity in Jordanians.