الفهرس 
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Abstract
English summary
Recently, the co-administration of tramadol (TMD) with sildenafil (SDF) to manage premature ejaculation is illegally increased and thus drug-drug interaction study of these substances is of great importance.
Herein, an HPLC method with photometric detection was developed for the determination of a binary mixture of TMD and SDF in rabbit plasma.
We use a different technique to investigate the drug-drug interaction between SDF and TMD like HPLC-UV and HPLC-MS/MS
This thesis consists of three chapters as the following:
Chapter 1 : introduction
a. Rational of this study discussing the reasons that inspired this study
b. Pulmonary hypertension : Definition- classification- causes- treatment
c. Sexual dysfuction : definition – prevalence-recommendations of management
d. Analgesic : definition- mechanism of action- classification
e. Tramadol : properties-mechanism of action -pharmacokinetics and pharmacodynamics -doses
f. Sildenafil:properties-mechanism of action -pharmacokinetics and pharmacodynamics -doses
Chapter 2 : HPLC Analysis of Sildenafil and Tramadol
an HPLC method with photometric detection was developed for the determination of a binary mixture of TMD and SDF in rabbit plasma. Reversed-phase chromatography was performed at room temperature on a C18 column with the mobile phase consisting of a 10 mM Na2HPO4 solution (pH 7.5): acetonitrile (45:55, v/v) at a flow rate of 0.8 mL min-1 using caffeine (CAF) as an internal standard. The detector was set at 220 nm. The total analysis time was 9 min. Calibration graphs were linear in the concentration ranges of 0.1–10 and 0.05–10 µg mL-1 with a detection limit of 0.05 and 0.02 µg mL-1 for TMD and SDF, respectively. The method was validated in terms of accuracy, precision, limit of detection and quantitation, recovery, and stability as per US-FDA bioanalytical guidelines. The proposed method was specific for determination of the mixture in rabbit plasma after solid phase extraction on an Oasis HLB cartridge. The simultaneous administration of TMD with SDF affected both peak plasma concentration (Cmax), Tmax, and area under the concentration-time curve (AUC), elimination rate constant (Kel) of SDF. The present study introduced for the first time a potential DDI of SDF and TMD, which deserves a further attention and more studies.
Chapter 3 : Enhanced LC -MS/MS spectrometry method for determination of Sildenafil and Tramadol drug drug interaction in plasma of rabbit
Optimization of chromatographic conditions
In the present work, different RP columns were tested such
as C18, C8, CN. The greater retention of analytes and IS was achieved on
Agilent Eclipse Plus C18 (4.6 x 100 mm, 3.5 μm), which utilized in previous
studies to separate drugs including, TMD and SDF showing a
promising resolution and symmetric peak shape. On another hand, the mobile
phase composition played a critical role in the chromatographic separation.
ACN was selected because itgave acceptable analytes response and peak shape. Mobile phase pH played avital role in the separation;
Initially, 100 ng/ml solutions of the target analytes were directly
infused to catch the protonated precursor ion and the most stable and intense
the protonated precursor ion and the most stable and intense product ion in a mass range of 50-200 amu for Tramadol and 100-500 amu for sildenafil and caffeine using ESI sources in positive ion modes.TMD,SDF and CAF using ESI sources in positive ion modes.
respectively. Most prominent and stable product ions for quantification of Sildenafil, Tramadol and caffeine were found at m/z 100.3, 58, 138, respectively. The fragment ions at m/z 100.3, 58, and 138 for sildenafil tramadol and caffeine
qualifying peaks were also monitored for unambiguous identification of the analytes at m/z 58.0 and 249 for sildenafil and Tramadol, respectively, which attributed to 1,2-dihydro−1,3-diazet−1-ium and O-demethyl tramadol.