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

Thesis Info

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Author

Zia Ahmed

Program

PhD

Institute

University of Peshawar

City

Peshawar

Province

KPK

Country

Pakistan

Thesis Completing Year

2018

Thesis Completion Status

Completed

Subject

Pharmacy

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/12809/1/Zia_Ahmed_Pharmacy_HSR_2018_UoP_Peshawar_25.09.2018.docx

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726211789

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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.
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درد تو سارے لکھ ڈالے ہیں

درد تو سارے لکھ ڈالے ہیں
کیوں نہیں تھمتے پھر نالے ہیں

دل کے بند اِن تہ خانوں میں
لگتے رہتے اب جالے ہیں

اُجلے اُجلے اِن چہروں کے
اندر کتنے ہی کالے ہیں

میں صدمات سے کیسے نکلوں
گرد مرے غم کے ہالے ہیں

لگتے ہیں جنت کے باسی
جو تیرے کوچے والے ہیں

چہرہ، آنکھیں، خوشبو، لہجہ
اُس کے وار کے سب آلے ہیں

وہ کیا عشق کی سرگم جانیں
بے سُر ہیں جو، بے تالے ہیں

Hak Anak Angkat Dalam Hukum Keluarga Islam di Indonesia

This research states that in Islamic law adopting a child is a good act, which helps adopted children get a proper education. The right to a proper education for adopted children is one of the main goals of adoption, this welfare is one of the rights that must be provided by adoptive parents. In general, implementing the above rights of children is an obligation and joint responsibility of the government and society. The phenomenon that occurs in Indonesia is that the educational rights of adopted children have shifted to utilization, due to several factors, one of which is economic. The aim of this research is to strengthen previous research, and examine further the shift in the educational rights of adopted children and look at the factors that result in non-fulfillment of adopted children's rights in Indonesia. This research uses an approachsociological normative  with the nature of the researchanalytical descriptive. The results of this research found several factors that resulted in a shift, even not being given the rights of adopted children, such as: f In fact, in Islam, adopting a child is a good act but over time it becomes exploitative.

Interleukin 28-B Polymorphism Associated With Hcv Treatment Induced Viral Clearance

Hepatitis C virus (HCV) infection is one of the leading causes of chronic liver disease and has emerged as a global concern of public health, affecting about 3% of the world’s population. Pakistan is the sixth most populated country in the world and has a HCV prevalence rate of 5.9%. While there are different subtypes of HCV, genotype 3a is the most common form in patients from Pakistan. The clinical outcome of HVC infection is determined by the interplay between viral, environmental and host related factors. The host’s immune system is the most important factor in viral persistence and innate immunity is the first line of defense, intervening with interferons and natural killer cells. On the basis of the available information regarding the HCV patient’s treatment with pegylated interferon-α and ribavirin, it has been observed that less than 50 % patients show the sustained virologic response six months after treatment cessation. Genome wide association studies have been linked to the responses against the treatment. Therefore this study was designed to identify the variations in the IL 28-B in the HCV patients which does not show the sustained virologic response against the pegylated interferon- α and ribavirin therapy. The IL28 B haplotypes associated with treatment response are also associated with spontaneous HCV clearance. IL28 B and racial differences in HCV control is because of SNPs in IL28B gene, 3’ un-translated region and promoter region and these have varied distributions among ethnic groups. It is fascinating to consider whether the differences at this locus account for the association between different ethnic groups and increased spontaneous and treatment induced clearance. In this study we selected HCV positive patients including male and female with different age groups. The viral loads were quantified on real-time PCR at base line and after 24 weeks of treatment of patients with pegylated interferon- α and ribavirin therapy. Hepatitis C virus genotyping was performed to classify the virus in different genotypes. The role of the genetic polymorphisms present in interferon-λ genes was investigated by scanning an area of 624 Kb on chromosome 19q13.13 (nucleotide positions, 39719200 – 39781600) encoding IL 29 (IFNL1), IL28A (IFNL 2), IL28B (IFNL3) and IFNL 4. Out of fifty SNPs, twenty five were designed in the IL28B gene coding region, which is considered to be the main factor for inducing the expression of Interferon stimulated genes (ISGs) using the iPLEX assay on a SEQUENOM MassARRAY® platform. Twenty three SNPs covered the 3’ and 5’ UTR’s of all four IFN-λ genes. The remaining two SNPs were designed in the newly discovered IFNL-4 gene. Our findings support that younger HCV patient’s shows better response to interferon and ribavirin combination therapy than older ones. Females aged ≤ 30years is a favorable marker. HCV genotypes showed different geographic distribution in regions of Punjab province. Over all distribution of HCV genotype in Punjab were given as 3a= 81%, 1a= 11%, 4a= 4%, 3a+1a=3%, and 1a+4a =1 %. It is further evident from the findings of the present study that in Pakistan more than one genotype exists. HCV genotypes 1 and 4 have been detected with genotype 3a being most frequent, which predict short duration with better biochemical and virologic response. Therefore, it is beneficial to include the predictive variables such as genotype in the cost-benefit analysis of HCV treatment to plan policies to increase the effectuality. These results can be used to counsel patients on the likelihood of response and may influence the patient’s decision on treatment. The allelic association data revealed that a region of ~ 39 Kb (Chr. 19, nucleotide positions, 39729450-39768250; build GRCh37.p10) containing 13 polymorphic SNPs in Pakistani population is strongly associated (Fisher’s P value = 0.0003-0.0130) with spontaneous clearance and for all of these SNPs, spontaneous HCV clearance was more common with the major alleles. The most significant results were obtained with RS8109886 (Odds ratio of presenting HCV clearance [OR] for C vs. A = 3.6 [95% CI: 1.9-6.5] Fisher’s P = 0.0001), RS8113007 (A vs. T OR = 3.6 [1.9-6.5]; Fisher’s P = 0.0001) and RS12979860 (C vs. T OR = 3.1 [1.7-5.3]; Fisher’s P = 0.0002). The linkage disequilibrium data performed between 23 polymorphic IFN-λ region SNPs, revealed three haplotypic blocks: haplotype block I, of eight Kb, included eight SNPs (RS35790907, RS12972991, RS12980275, RS12982533, RS8105790, RS688187, RS4803217 and RS12979860) in strong linkage disequilibrium (r2 ≥ 0.85) among themselves and haplotype, haplotype block II, of 4Kb included seven SNPs (RS4803221, RS1549928, RS10853727, RS109886, RS8113007, RS8099917, RS7248668) in strong linkage disequilibrium (r2 ≥ 0.95) among themselves and haplotype and block III contained just two SNPs (RS1671087 and RS11665818) lying approximately 6 kb apart from each other and in strong linkage disequilibrium (r2 ≥ 0.85%). In total 6 haplotypes were investigated comprising of 15 IFN-λ region SNPs, haplotype one (AAATTGCCCATCATG) comprising of major alleles of 15 SNPs (RS35790907, RS12972991, RS12980275, RS12982533, RS8105790, RS688187, RS4803217, RS12979860, RS4803221, RS1549928, RS10853727, RS8109886, RS8113007, RS8099917 and RS7248668) had most significant association (OR = 2.37, 95% CI = 1.34-4.20, P = 2.8x10-3) with therapy response in comparison with other detected haplotypes. HCV clearance is a complex process that is dependent on the type of HCV infection and the host’s immunity-related genetic factors. Some SNPs that are associated with HCV clearance in Pakistani patients are the same as those that have been associated in other cohorts and suggest a common genetic background across multiple populations for HCV clearance. However, a number of alleles identified in this study were unique to the patient cohort and could suggest Pakistani-specific factors for HCV clearance, particularly for genotype 3a. These data, however, do support findings that have been widely reported from other groups where host genotype has been a proven factor in HCV clearance and treatment response. Tailoring treatments to target potential responders, as opposed to generalized, universal treatment strategies, will be of economic benefit but more importantly will have substantial patient benefits as patients would recover quicker and be less likely to require multiple ‘trial-and-error’ treatments. Our data supports the associations of SNPs present in the IFN-λ genes with HCV clearance after interferon and ribavirin combined therapy in Pakistani individuals infected with genotype 3a and provides preliminary evidence to suggest patients should be genotyped for the relevant SNPs in order to predict drug response before starting therapy.