القوافل التجارية اإلفريقية خالل القرن التاسع عشر امليالدي: قوافل منطقة وادي نون منوذجا

ملخـص: اضطلعت قافلة منطقة وادي نون بدور مهم كوسيط وصـلة وصـل بـين اللـمال والجنـوب، فوقوع هذا المجال الصحراوي وسـط المغـرب، جعلـن منفـذا يجاريـا لل اـاري اإلفريقيـة اآلييـة مـن جنوب الصحراء، والمتجهة نحو شمال المغرب وأوروبا والعكس صحيح، إال أن ذلك ال يعني عـدم يعرض القوافل التجارية لملاكل يحول دون نجاح مهمتها، التـي يتطلـا الـتمكن مـن منهجيـة عمـل محكمة وما وطة، يحقق أرباح ونتارج إيجابية، سواء على المستوى االجتمـاعي أو االقتصـادي أو الثقافي. الكلمات المفتاحية: وادي نون، التجارة الصحراوية، القوافل التجارية.

Fixed Dose Combination: Antipsychotic Plus Mood Stabilizer In-Vitro and In-Vivo Investigation

Bipolar Affective Disorder (BAD) is one of the serious psychiatric illnesses characterized by unpredictable recurring course of ups (mania) and downs (depression) which make it difficult for patient to lead a stable and creative life.Treatment of BAD is always a challenge to psychiatrists because of the range of clinical symptoms during the course of the illness. Many antipsychotic drugs, alone or in combination with standard mood stabilizers and/ or antidepressants are used to treat such a complicated disorder. However, compliance is an issue in these patients and one potential reason is the need to take multiple medications. Keeping in mind the complexity of BAD and subsequent reluctance at patients’ end, it was suggested that practice of FDC should be reviewed in the field of psychiatry as many newer drugs have been introduced in the psychiatry and many fixed combination products are commonly developing in other fields of medicines. FDC formulations for the treatment of different clinical conditions offer many potential advantages in the form of convenience, cost, tolerability, efficacy and adherence thus, many clinicians encourage their use. Sodium valproate is an anticonvulsant and mood stabilizer used to treat mood disorders to manage severe and persistent mood swings. The concurrent use of sodium valproate and antipsychotics provides synergistic mood-stabilizing effect in bipolar patients. Aripiprazole is a new well tolerated atypical antipsychotic drug, effectively used to manage acute manic or mixed episodes both as monotherapy and in combination with mood stabilizers. Similarly, quetiapine is another novel atypical antipsychotic which is considered one of the first line agents in the treatment of mania and bipolar depression. Consequently, aripiprazole and/or quetiapine were suggested to be formulated with mood stabilizer in the form of FDC. FDC products of aripiprazole plus valproate (FDC1, aripiprazole 2.5 mg plus divalproex sodium 500 mg; FDC2, aripiprazole 5 mg plus divalproex sodium 500 mg) and quetiapine plus valproate (FDC3, quetiapine 100 mg plus divalproex sodium 500 mg; FDC4, quetiapine 200 mg plus divalproex sodium 500 mg) were formulated and manufactured. Besides, individual tablets of aripiprazole (A1, 2.5 mg and A2, 5 mg), quetiapine (Q1, 100 mg and Q2, 200 mg) and divalproex sodium tablets (D1, 500 mg) were also prepared as reference to compare with respective FDC tablets. In-vitro evaluation of these new formulations were carried out by conducting different official tests like weight variations, friability, drug contents uniformity, disintegration and dissolution. An accurate and simple isocratic HPLC-UV method for the simultaneous quantification of aripiprazole and valproic acid in the FDC tablets was also established and validated according to the International guidelines (ICH). These new formulations were then subjected to stability tests under accelerated conditions of temperature and humidity. After the successful in-vitro evaluation and stability studies of optimum formulations of aripiprazole plus valproate (FDC1 and FDC2), in-vivo evaluations of FDC1 and FDC2 were planned to be accomplished on animals and subsequently on human volunteers to establish pharmacokinetic and bioavailability profile in accordance with the guidelines established by ethical committee of University of Peshawar, Peshawar, Pakistan. Preclinical studies on animals were conducted using inbred rabbits whereas a team of experts and pharmacists invited the volunteers to participate in our research. Blood samples from both the animals and human subjects were collected after specified time intervals and plasma were separated. After the simple protein extraction process, plasma samples were analyzed using HPLC-UV to quantify the drugs. In preclinical studies on animals, drug contents each of ‘A’ tablets, ‘D’ tablets and FDC tablets (FDC1 & FDC2) in the plasma were measured and pharmacokinetic parameters were calculated using pharmacokinetic software PK solver 2.0. Valproate when co-administered with aripiprazole in FDC, increased the Cmax, Tmax and AUC of aripiprazole by 9.5%, 35.5%, 20.5% and 5.9%, respectively while t1/2, Vd and Cl of aripiprazole decreased by 12.8%, 16% and 6% respectively. Conversely, Cmax of valproate increased by 11% whereas Tmax, t1/2,AUC, Vd and Cl of valproate decreased by 9.8%, 4.3%, 1.8% and 0.7% respectively when used in combination with aripiprazole in the form of FDC. Statistically, increase in the Tmax, AUC and decrease in the Vd of aripiprazole were significant while increase or decrease in all the parameters for valproic acid were found insignificant. The differences in Tmax, AUC and Vd among FDC and reference individual tablets were statistically significant while in Cmax, t1/2 and Cl were found statistically insignificant. Similarly in clinical phase on human volunteers, valproate when co-administered with aripiprazole in FDC, increased the Cmax, Tmax and AUC of aripiprazole by 5.4%, 13.62% and 20% respectively while t1/2, Vd and Cl of aripiprazole decreased by 6.5%, 16% and 11% respectively. On the contrary, Cmax and AUC of valproate increased by 17% and 7.7% respectively whereas, Tmax, t1/2, Vd and Cl of valproate decreased by 12%, 5.4%, 6% and 0.23% respectively when used in combination with aripiprazole in the form of FDC. Statistically, increase in the AUC and decrease in the Vd of aripiprazole were found significant while increase or decrease in all the parameters for valproic acid were found insignificant. In clinical phase of study, combined aripiprazole and divalproex treatment to human volunteers showed the same tendency as observed in animal studies and did not produce any substantial changes as measured in animals. An enteric coated FDC product of aripiprazole and divalproex sodium with satisfactory physicochemical parameters is possible which has comparable bioavailability and absorption parameters to the two products administered separately. However, further studies are required to replicate our findings before the product can be considered for clinical use.