الاحتلال الفرنسي لتونس وتوقيع معاهدة باردو عام 1881 والموقف العثماني منه عام 1881م

تعود الأطماع الفرنسية في تونس الى عهد بعيد ففي عام 1270م قام الملك لويس التاسع حملة عسكرية على تونس كان مصيرها الفشل، وبعدها تمكنت فرنسا من فرض معاهدة عام 1685م على تونس تخولها أحقية الامتيازات على بقية الدول الأخرى لكن بعد الاحتلال الفرنسي للجزائر عام 1830 أولت فرنسا اهتماماً خاصاً لتونس التي عدتها امتداداً للجزائر من الجبهة الشرقية واخذت فرنسا تخلق الذرائع لاحتلال الأيالة التونسية. وكثرة المشاكل على الحدود الجزائرية التونسية التي أعطت الذريعة لفرنسا في حشد قواتها العسكرية للدخول الى أرض الأيالة وطلب الباي الحكومة الفرنسية لحل المشاكل ودياً, ومعاقبة المشاكسين من قبله, لكن الحكومة الفرنسية رفضت ذلك وأرسل حاكم تونس برقية الى حكومة اسطنبول طالباً منها التدخل لاحتواء المشكلة حيث كانت الايالة التونسية تابعة اسمياً للدولة العثمانية.

Cost of Iiiness of Schizophrenia from Societal Perspective. a Case Study of Khyber Pakhtunkhwa Pakistan

In the present study, pharmacokinetics of piroxicam in healthy human volunteers were studied and then potential pharmacokinetic herb-drug interaction of piroxicam with commonly used herbal medicines i.e. ginkgo biloba and milk thistle were investigated. The study was composed of five phases. The first phase of present study comprised of development and validation of method i.e., reverse phase high pressure/performance liquid chromatography connected with ultravoilet visible detector (RP-HPLC/UV), for the assessment of piroxicam and 5-hydroxypiroxicam in human plasma, the major metabolite of piroxicam. In the second phase, pharmacokinetics of piroxicam was quantified in healthy human volunteers. In the third phase herbal products were characterized against their reference standards. In phase four, single oral dose pharmacokinetic herb- drug interactions of piroxicam with single dose of ginkgo biloba (120 mg/day) and milk thistle (180 mg/day), was investigated in human volunteers. In phase five the impact of multiple doses (single dose for 7 days) of ginkgo biloba and milk thistle over the pharmacokinetics of piroxicam single oral dose (20 mg) were evaluated in healthy human volunteers. A precise, accurate, simple and cost-effective method was developed, optimized and then validated according to standard protocols for analysis of piroxicam and 5-hydroxypiroxicam by “RP- HPLC/ UV” method. The plasma samples of volunteers were first processed and then quantified after injecting 20 µL of sample into the high performance liquid chromatography system via CNW C18 (250 mm × 4.6 mm, 5 μm) as a stationary phase, which was pre- protected through Perkin Elmer guard column i.e., 30 mm × 4.6 mm, 10 µm. The mobile system used in the proposed method was composed of HPLC grade acetonitrile and trifluro acetic acid (TFA) aqueous solution which was in ratio 62:38 % (v/v), respectively, the mobile phase was pumped at flow rate of 1 mL/ min at 25oC, the piroxicam, 5- hydroxypiroxicam and meloxicam (I.S) were studied at 353 nm. Piroxicam and metabolite were extracted from human plasma using diethyl ether. The present RP-HPLC/UV method showed linearity in the range of 20 – 2,500 and 22 – 2,500 ng/mL for piroxicam and 5-hydroxypiroxicam, respectively. The lower limits of detection for piroxicam and 5-hydroxypiroxicam were 6 and 7 ng/mL, whereas lower limits of quantification were 20 and 22 ng/mL, respectively. The suggested method was productively used for assessment of processed plasma samples of healthy humans to study the piroxicam pharmacokinetics in Pakistani population. The pharmacokinetics study of piroxicam was carried out in healthy males (group A + B; n = 30) aged between 19 to 24 years, they were examined for various biochemical and physical tests and inclusion- exclusion criterion was followed strictly. Piroxicam (20 mg capsule) was taken orally by all participants of the study with one glass of water (250 mL) and plasma samples were then collected from volunteers at prior selected time points and analyzed using the developed RP-HPLC/UV method. Pharmacokinetic parameters like area under plasma concentration (AUC), area under first moment plasma concentration (AUMC), volume of distribution (Vd), clearance (Cl),elimination half life of piroxicam (t1/2), Mean residence time (MRT) and drug elimination rate from central compartment (K10) of piroxicam were determined using software like “PK- Summit®” and Microsoft office Excel®, while some parameters, like maximum plasma drug concentration and time required to reach maximum plasma drug concentration were directly assessed from the chromatogram. pharmacokinetic parameters (Average ± S.D) of piroxicam, maximum plasma drug concentration (Cmax), time required to reach maximum plasma drug concentration (tmax), area under curves from time zero to 96 hrs 〖(AUC)〗_0^t, area under curves from time zero to infinity 〖(AUC)〗_0^∞,area under first moment plasma drug concentration (AUMC), volume of distribution (Vd) and total clearance (Cl) in the present study were 1965.604 ± 301.945 ng/mL, 1.95 ± 0.442 hr, 73714.094 ± 15715.759 ng.hr/mL, 104074.203 ± 21782.849 ng.hr/mL, 7924414.158 ± 1623018.810 ng.hr.hr/mL, 8.858 ±1.549 L and 2.362 ± 0.532mL/min, respectively. Herbal products in the current study were characterized for major constituents against their reference standards using RP- HPLC/UV system. The total content of flavonoids and terpenoids in the ginkgo biloba extract capsules used in this study were in the range of 22- 24 % and 4- 6 %, respectively. Similarly, total content of sylimarin in the milk thistle extract capsule used in the present study was in the range 65- 80 %. The concomitant administration of piroxicam and ginkgo biloba single dose in healthy human volunteers (group A; n= 15) showed an increase in Cmax of piroxicam from 1914.816 ± 358.140 ng/mL to 2063.998 ± 364.860 ng/mL and Tmax from 2.0 ± 0.50 hr to 2.30 ± 0.368 hr. The 〖[AUC]〗_0^t and 〖[AUC]〗_0^∞ were increased from 72943.843 ± 10350.840 ng.hr/mL to 80576.925 ± 11116.597 ng.hr/mL and 106388.785 ± 14361.506 ng.hr/mL to 111977.651 ± 14443.069 ng.hr/mL, respectively. The Vd and Cl decreased from 8.75014 ± 1.673 L to 8.137533 ± 1.488 L and from2.433 ± 0.591 mL/min to 2.107 ± 0.554 mL/min mL/min, respectively, whereas elimination half-life was increased from 55.140 ± 7.369 hr to59.692 ± 8.990 hr. While in case of multiple dose study ginkgo biloba capsule were administered to a group “A” volunteers for seven successive days and on day 8 piroxicam was administered along with ginkgo biloba capsule. In multiple dose study Cmax, Tmax and elimination half-life of piroxicam was increased from 1914.816 ± 35.140 ng/mL to 2408.890 ± 402.823 ng/mL, 2.00 ± 0.50 hr to 2.933 ± 0.372 hr and 55.140 ± 7.369 hr to 74.15504 ± 11.695 hr, respectively. The 〖[AUC]〗_0^t and 〖[AUC]〗_0^∞ increase from 72943.843 ±10350.840 ng.hr/mL to 91833.976 ±15336.392 ng.hr/mL and 106388.785 ± 14361.506 ng.hr/mL to 131322.031 ± 21590.224 ng.hr/mL, respectively, while Vd and Cl decreased from8.750 ± 1.673 to 7.824 ± 1.548 L and from 2.433 ± 0.591 mL/min to 1.788 ± 0.546 mL/min, respectively. The PK-HDI study followed by concomitant administration oforal single dose of piroxicam and ginkgo biloba standardized capsule did not affect significantly on the pharmacokinetics of piroxicam, therefore, can be used without dose adjustment. However, due to significant changes in pharmacokinetics of piroxicam after concomitant administration with ginkgo biloba multiple doses, dosage adjustment of piroxicam may be required for maintenance of steady state concentration. The PK-HDI study between single oral dose of piroxicam and milk thistle showed insignificant increase in the pharmacokinetic parameters like Cmax, tmax, 〖[AUC]〗_0^t and 〖[AUC]〗_0^∞ from 2016.392 ± 234.654 ng/mL to 2146.720 ± 234.935 ng/mL, 1.9 ± 0.387 hr to 2.066 ± 0.372 hr, 74484.345 ± 20079.860 ng.hr/mL to 84692.477 ± 17957.531 ng.hr/mL and 101759.621 ± 27661.242 ng.hr/mL to 114706.691 ± 27505.697 ng.hr/mL, respectively. The elimination half life was insignificantly increased from 54.371 ± 11.118 hr to59.787 ± 11.689 hr, where Vd and Cl were decreased from 8.967 ± 1.467 L to 8.760± 1.390 L and 2.291 ± 0.475 mL/min to 2.020 ± 0.403 mL/min, respectively. However, in case of multiple dose study milk thistle capsule were administered to group B volunteers for seven successive days and on day 8th piroxicam was administered along with milk thistle capsule. In multiple dose study the Cmax, Tmax, 〖[AUC]〗_0^t, 〖[AUC]〗_0^∞and elimination half- life of piroxicam were significantly increased from 2016.392 ± 234.654 ng/mL to 2560.901 ± 258.430 ng/mL, 1.9 ± 0.387 hr to 2.767 ± 0.371hr, 74484.345 9 ± 20079.860 ng.hr/mL to 97832.563 ± 19288.928 ng.hr/mL, 101759.621 ±27661.242 ng.hr/mL to 137476.148 ± 31765.452 ng.hr/mL and 54.371 ± 11.118 hr to 74.527 ± 14.606 hr, respectively, while Vd and Cl were decreased insignificantly and significantly from 8.967 ± 1.467 to 8.187 ± 1.223 L and2.291 ± 0.475 mL/min to 1.672 ± 0.337 mL/min, respectively. The PK-HDI study followed by concomitant administration oforal single dose of piroxicam and milk thistle standardized capsule did not affect significantly the pharmacokinetics of piroxicam and can be used without dose modification. However, due to significant changes in pharmacokinetics profile of piroxicam after co- administration with milk thistle multiple doses, dosage adjustment of piroxicam may be required for maintenance ofsteady state concentration. The present studies evaluated the PK-HDI between the piroxicam and ginkgo biloba & milk thistle (single or multiple doses administration), these findings are helpful for the patients using the piroxicam over the period for the treatment of different ailments." xml:lang="en_US