الجملة المعترضة فى القرآن الكريم: دراسة بلاغية

This study aims to prove that the Parenthetical Sentences in the Quran are not a way to improve the beauty of literature, but if they appeared in a convenient location they became the requirements of the text. The main findings of this study include the parenthetical sentences in the Holy Quran characterized by specific semantics which is known by the context of Ayat and not only because of assertion, embellishment or clarification. These sentences would inspire the attention from the reciter of Quran to think of the underlying meaning. The parenthetical sentences in Quran cannot be nullified as this will divert the true meaning of Ayat e Kareemas.

Impact of Omeprazole, Rosuvastatin and Clopidogrel on the Pharmacokinetics of Cefixime in Healthy Adult Human Subjects

The aim of the present study is to evaluate the pharmacokinetics (PK) parameters of the cefixime in the local healthy human volunteers and to study the influence of its PK on the co-administration with omeprazole; rosuvastatin and clopidogrel on the pharmacokinetic of cefixime. The study was designed in three stages. In first stage of study, reverse phase high performance liquid chromatography (RP-HPLC-UV) method for the analysis of cefixime was developed and validated. In the second stage PK of cefixime was established in local healthy human volunteers while in the third stage potential drug-drug interaction of cefixime with concurrent administration of omeprazole, rosuvastatin and clopidogrel was investigated. A novel isocratic, simple, economic, precise, selective, and reproducible RP-HPLC-UV method of determination of cefixime and cefdinir (I.S) in human plasma was developed and validated. The cefixime was separated on a Supelco Discovery HS C 18 (150 x 4.6 mm, 5 μm) analytical column, fixed with Perkin Elmer C 18 (30 x 4.6 mm, 10 μm) guard cartridge. The methanol/acetonitrile (50/50 v/v):0.05% trifluoroacetic acid (19:81 v/v) was used as mobile phase. The flow rate was adjusted at 2.0 ml.min -1 . The temperature of the column was fixed at 50̊C and sample was injected using 20 μl loop and the eluents were monitored at a 285 nm. Sample preparation was based on a simple extraction procedure consisting of deproteination and extraction with 3 parts of 6% TCA solution (aqueous) followed by volume make up with the mobile phase. Separation of cefixime and cefdinir were achieved within 4 min. The present method demonstrated good values for specificity/selectivity, linearity (0.004-5.0 μg mL -1 ; r 2 >0.999 f), recovery I Abstract (>96% for cefixime), precision (%RSD <2.2 for cefixime), sensitivity (limit of detection: 1 ng mL -1 and lower limit of quantification: 4 ng mL -1 , stability of solutions, and robustness. The method was efficiently applied to a pharmacokinetic study in healthy adult volunteers. The PK study of cefixime in healthy human volunteers (n = 20) was conducted using single dose, open label study design. A strict inclusion and exclusion criterion was adopted. The physical, biochemical and hematological examination of every individual were conducted. Each individual volunteer was orally administered cefixime capsule (400 mg) with full glass of water (Ca ᴝ 250 ml) and blood samples were collected at preset time intervals and analyzed using HPLC. The plasma drug concentration was calculated and various PK parameters were calculated using PK summit ® a PK software. The mean ± SD of C max , T max AUC , AUC and AUMC of cefixime was 3.54 ± 0.55mg.ml -1 , 32.54 ± 5.81μg-hml -1 , 32.49 ± 5.99 μg-hml -1 and 246.67 ± 58.57 μg-h*h ml - 1 respectively. While the mean ± SD of Cl, Vd and MRT were 192.71 ± 31.46 ml/h/kg, 1200.13 ± 364.47 ml/kg and 7.23 ± 0.85h . The Pharmacokinetic analysis using non- compartment model for cefixime was also studied and the mean ± SD AUC , MRT, Cl and Vd were 33.492 ± 5.99 mg.ml -1 , 7.320 ± 0.853 h, 12270.252± 1958.550 ml/h/kg and 76485.611 ± 23318.799 ml, respectively. The present data reveal that most of the PK parameters of cefixime found in study are not significantly different from reported values in other nations and no need to adjust the dose under normal conditions. II Abstract The PK drug-drug interaction studies were carried out with same group of volunteers (n = 20) which participated in PK study with a wash out period of 3 weeks. Same protocol was adopted for inclusion and exclusion of volunteers. The single dose, two periods, two sequences, open labeled with wash out period of one week between the two interaction studies was designed. The plasma drug concentrations of cefixime following oral administration of cefixime (400 mg) alone and with simultaneous administration of omeprazole (40 mg) were investigated. The concentration of cefixime in plasma samples following simultaneous administration of cefixime (400 mg) and omeprazole (40 mg) capsule were calculated. The different PK parameters were determined to investigate interaction between cefixime and omeprazole. The C max of cefixime was significantly decreased from 3.545 ± 0.552 μg.ml -1 to 2.648 ± 0.356 mg.ml -1 whereas t max was non-significantly increase to 3.964 ± 0.118 to 4.00 ± 00 h. The decrease in AUC AUC ∞ and were also observed from 37.67 ± 3.77 μg-h ml -1 to 27.25 ± 5.94 μg-h ml - 1, 34.03 ± 5.496 μg-h ml -1 to 22.629 ± 5.99 μg-h ml - 1 and 435.415 ± 48.37, to 234.32 ± 52.43 μg-h*h/ml, respectively. The mean ± SD of Cl and Vd were reduced and MRT was increased from 192.71 ± 31.46 ml/h/kg to 188.70 ± 36.62, 1200.13 ± 364.47 to 1756.439 ± 900.81 ml/kg and 7.46 ± 4.55 h to 11.444 ± 5.42. The Pharmacokinetic analysis using non-compartment model for cefixime with simultaneous administration of omeprazole was also studied that also showed similar alteration in PK of cefixime following simultaneous administration of cefixime and III Abstract omeprazole. The alteration in drug plasma profile by changes in bound and un-bound fraction mainly affects the changes in the Cl and Vd. The change in the Cl and Vd will also alter the Vss and AUC. Similar protocol was adopted to study the PK drug drug interaction between the cefixime and rosuvastatin. Single oral dose of cefixime capsule (400 mg) alone and in combination with rosuvastatin (40 mg) were administered in healthy human volunteers (n = 20) using two periods, two sequence, open labeled, cross over design with washout period of 7 days between two treatments. Concurrent administration of cefixime with rosuvastatin significantly decreased C max , AUC and AUC ∞ of cefixime from 3.79 ± 0.69 mg.ml -1 to 2.88 ± 0.33 mg.ml -1 , 33.79 ± 6.22 μg.h ml -1 to 27.89 ± 3.80 μg.h ml -1 and from 29.06 ± 4.99 μg.h ml -1 to 25.01 ± 6.15 μg.h ml -1 , respectively. Similarly the Cl, MRT, and Vd also decreased significantly from 194.67 ± 54.23 to ± 42.48 ml/h/kg, 9.80 ± 5.22 to 8.65 ± 4.59 h and from 1435.24 ± 398.26 to 1246.21 ± 500.38 ml/h/kg, respectively. The non-compartment model analysis of the data for cefixime with co-administration with rosuvastatin showed significant decrease in AUC , and Cl from 33.49 ± 5.99 to 31.37 ± 3.89 mg.ml -1 , 12653.44 ± 7246.82 to 11893.69 ± 2761.52 ml/h/kg, respectively. while the MRT and Vd were also significantly decreased from 9.21 ± 1.21 to 8.49 ± 2.36 h and 97221.61 ± 33215.21 to 82341.41 ± 29368.67 ml. The decrease in the parameters may be due to the use of same class of transporter (SLC) both cefixime and rosuvastatin may either compete for same transporter or rosuvastatin may inhibit the transporter responsible for the transport of the cefixime across the G.I.T. membrane. IV Abstract The PK drug-drug interaction study of cefixime (400 mg) with clopidogrel (150 mg) was carried out with in healthy human volunteers (n= 20) using two period, two sequence, open labeled, cross over design with one week washout time between treatment periods. Various PK parameters like C max , T max , AUC, AUMC, MRT, t 1⁄2 β, Cl, Vd and t 1/2 β etc were calculated for cefixime single oral dose of cefixime following single oral dose of cefixime (400 mg capsule) alone and concurrent administration with clopidogrel (150 mg tablet). The data showed the decrease in the C max of cefixime from 3.35 ± 0.538 mg.ml -1 to 3.13 ± 1.13 mg.ml -1 . Whereas AUC , AUC and MRT of cefixime were also decreased from 37.67 ± 21.97 μg-h ml -1 to 32.97 ± 6.44 μg-h ml -1 , 34.04 ± 22.65 to 30.974 ± 3.664 and from 7.462 ± 5.22 h to 7.213 ± 3.198h, respectively. Moreover, non- compartment PK model was applied for cefixime with co-administration with clopidogrel was studied and the mean ± SD AUC , and Cl were decreased 41.27 ± 23.67 to 35.42 ± 6.90 mg.ml -1 , 12653.44 ± 7246.46 to 11627.21 ± 1930.77 ml/h/kg, respectively. While the MRT and Vd was decreased from 7.33 ± 0.86 to 6.96 ± 1.49 h and 76485.61± 23318.79 to 97295.95 ± 21281.29 ml, respectively. The t 1/2 β of cefixime changed from 3.64 ± 1.88 h to 6.96 ± 1.49 h with simultaneous administration of clopidogrel. The reason of alteration may be due to that; clopidogrel may competitively displace cefixime from protein and re-distribution of cefixime that may result in changes of PK parameters. The oral concurrent administration of the clopidogrel and cefixime is considered to be safe. The drug-drug interaction between the cefixime and clopidogrel may be classified as moderate type of drug-drug interaction." xml:lang="en_US