Home > Development and Comparative Evaluation of Controlled Release Tablets Vs. Conventional Tablets of Olanzapine and Prochlorperazine for Clinical Safety and Therapeutic Efficacy
Development and Comparative Evaluation of Controlled Release Tablets Vs. Conventional Tablets of Olanzapine and Prochlorperazine for Clinical Safety and Therapeutic Efficacy
Schizophrenia is a persistent and relapsing mental disorder that affects 1% of world wide population belonging to all races, social classes, countries and both genders. Major symptoms of it included positive, negative and cognitive dysfuntioning. Besides psychotherapy, pharmacotherapy of this disease is quite complicated and long lasting that can be mostly done by an appropriate selection of either typical or atypical antipsychotics or both, accompanied with other supportive therapy. Among these, olanzapine (atypical antipsychotic) has broader spectrum of activity against all three mentioned symptoms, while prochlorperazine (typical antipsychotic) can predominantly eradicate positive symptoms only. Unlikely, main adverse effects of these drugs include somnolence, excessive weight gain, hyperprolactinaemia, akathisia, tardive dyskinesia, extrapyramidal symptoms and insomnia. Considering such untoward effects, poor acceptability and tolerability, non-stop long lasting multiple drugs regimen and higher dosing frequency, reported rates of non-adherence (noncompliance) by patients range from 20%–89%, with an average rate of about 50%. This non-compliance usually leads to psychotic reversion, re-hospitalization, and more recurrent and frequent clinic and emergency room visits, which contribute significantly to schizophrenia’s estimated annual cost of $33–$65 billions (on average) in the developed countries. In this study, controlled release tablets of olanzapine and prochlorperazine were developed mainly aiming to minimize dosing frequency and to evaluate and validate the improvement in their safety and adherence profiles by reducing the severity of associated adverse reactions of respective antipsychotic. This was predominantly based on the formulation and subsequent in-vivo release evaluation in animal model adopted by our research group in previous study. After formulating both mentioned active pharmaceutical ingredients into controlled release (CR) tablets, comprehensive evaluation were performed via in-vitro characterization, comparative pharmacokinetic behavior and clinical safety and effectiveness assessments against their respective conventional/reference tablet dosage forms considering the internationally approved and recognized procedures. In first phase, the previous CR tablet formulations of olanzapine and prochlorperazine were modified for required improvement in release pattern and minimizing manufacturing complications, followed by their in-vitro characterization considering official parametric requirements of United States Pharmacopoeia USPXXXI. Based on that, results obtained for in-vitro assessment of powder mixtures regarding angle of repose and compressibility index indicated an adequate flowability and compressibility for tablet dosage form. On the basis of variable proportionality, binary mixture of Methocel® K100 Premium LV-CR and Ethocel® standard 7 Premium as commonly used polymers were able to provide three distinct formulations of F-A, F-B and F-C. However, only selected formulation F-C, in which the amount of ethocel was subsequently increased to 60% was able to give release of respective drug up to 24 hours duration. The same formulation of both drugs also meet up the dosage uniformity requirements of USPXXXI for physical dimensions (7.9 – 8.2 x 3.3 – 3.5 mm, L x W), percent weight variation (3.8 – 5 %), percent friability (0.48 – 0.64 %), and percent drug contents (98 – 102 %). In-vitro dissolution testing of the selected formulation exhibited pH independent zero-order release kinetics. In second phase, comparative pharmacokinetic behavior of CR tablets of olanzapine and prochlorperazine were assessed in healthy human volunteers against their respective conventional tablets. Utilizing validated high performance liquid chromatography (HPLC) methods coupled with electrochemical detector (for olanzapine) and ultraviolet visible detector (for prochlorperazine) for quantification of respective active ingredient in serum samples of healthy human volunteers, various pharmacokinetic parameters included maximum concentration (Cmax), time to reach maximum concentration (Tmax), are under the curve (AUC0–t), mean residence time (MRT) and half life (t1/2) using the statistical package, PK Solutions 2.0 were determined for required comparison. For test tablets of olanzapine, comparative study showed statistically significant optimization regarding Cmax (7.98 vs 12.59 ng/mL, P < 0.0001), Tmax (10.67 vs. 6.67 hours, P < 0.05), MRT (66.90 vs. 39.40 hours, P < 0.05), and t1/2 values (44.19 vs. 30.70 hours, P < 0.05). Similarly, controlled release tablets of prochlorperazine showed significantly higher values of Tmax (8.93 vs. 4.27 hours, P < 0.001), Cmax (4.517 vs. 3.467 ng/mL, P < 0.05), MRT0–28 h (30.51 vs. 8.340 hours, P < 0.0001), and t 1/2 (11.21 vs. 5.33 hours, P < 0.0001). These findings revealed extended release pattern with least fluctuation of their serum concentrations. In third phase, CR tablets of olanzapine and prochlorperazine were evaluated for clinical safety and therapeutic efficacy against their conventional tablet dosage forms regarding psychiatric, biochemical and neurochemical parameters in schizophrenic patients. This study was conducted at Khyber Teaching Hospital, Peshawar and Syed’s Clinic for Psychiatric Illness, Peshawar, in collaboration with and assistance of qualified and professionally competent and renowned clinician(s)/psychiatrists and psychologists. Psychiatric study included, assessment of included schizophrenics at baseline and after 30 days medication by conventional vs. CR tablets of their respective drug for alteration in rating score of Positive and Negative Syndrome Scale, PANSS (as therapeutic efficacy measure) and Abnormal Involuntary Movements Scale, AIMS (as clinical safety measure). Both test as well as reference treated groups of either antipsychotic showed statistically significant reduction in PANSS score from baseline to endpoint (28 – 33 by olanzapine and 11.9 – 12.2 by prochlorperazine), but no significant difference was observed between test vs. reference treated patients (P > 0.05). Similarly, no significant difference between CR tablets vs. conventional tablets treated group was seen regarding increase in the rating score of AIMS (P > 0.05). Based on the internationally recognized adult treatment panel-III (ATP-III) criteria, comparative biochemical evaluation of schizophrenic patients treated with CR tablets of olanzapine or prochlorperazine vs. their respective conventional counter-parts revealed that there was statistically insignificant difference regarding induction of metabolic syndrome. However in contrast to test tablets, it was observed that reference tablets treated patients showed significant difference (as increase) in blood cholesterol (23.13 vs. 45.43 mg/dL) and triglycerides level (8.79 vs. 10.83 mg/dL, in case of prochlorperazine). Besides this, in-spite of higher magnitude of mean body weight gain by reference treated group (3.37 vs. 4.25 Kg, especially in case of olanzapine), no statistical difference was seen by patients treated by CR tablets vs. conventional tablets of respective antipsychotic. In the last phase of the study, blood samples of test vs. reference treated schizophrenics were analyzed for quantification and modulation of neurotransmitters included dopamine and serotonin as well as their metabolites. The validated HPLC coupled with electrochemical detector method (developed by our lab) was employed for determination of mentioned neurotransmitters. Results from this study indicated that both formulations of olanzapine were able to significantly reduce blood serum upsurge of dopamine (P = 0.0399 by test and P = 0.016 by conventional tablets)and serotonin (P = 0.007 by test and P = 0.0003 by conventional tablets) along with their respective metabolites. Similarly, both formulations of prochlorperazine significantly reduced dopamine (P = 0.006 by test and P = 0.0008 by reference tablets) and its metabolites but no significant decrease was noticed in case of serotonin (P = 0.246 by test and P = 0.681 by reference tablets) as well as its metabolite. However, we could not find any significant dissimilarity regarding the neurochemical alteration between the test and reference formulations of either antipsychotic under investigation (P > 0.05). In conclusion, in comparison to reference tablets, newly developed controlled release tablets of olanzapine and prochlorperazine revealed optimized pharmacokinetic behavior that facilitated the superior clinical safety and comparable therapeutic efficacy in schizophrenic patients. Importantly, for more validation, the study needs further extension for some broader range of parameters over numerically considerable population investigated for repeatedly follow-up visits." xml:lang="en_US
میں اور دکتور محمود قاہرہ یونیورسٹی سے کبری الجامعہ کی طرف گامزن تھے کہ سڑک کے کنارے ایک ادھیڑ عمر کا آدمی دیکھا جس کا چہرہ غربت اور معاشی بد حالی کا منہ بولتا ثبوت تھا ۔ موصوف سڑک پر جھاڑو لگا رہا تھا اور بہت سارا کچرا اس کے ناتواں ہاتھوں سے زیادہ کمزور تیلی دار جھاڑو سے اس طرح واپس نکل رہا تھا جس طرح ارنسٹ ہمینگوے کے ناول ’’اولڈ مین اینڈ سی ‘‘ کے مرکزی کردار مچھیرے کے سمندر میں پھینکے ہوئے جال سے نکلتا ہوا پانی ۔میں نے دکتور محمود کو کہا تمھاری حکومت اس آدمی کو جتنی تنخواہ دے رہی ہے اس میں ایسے ہی کام کی گنجائش نکلتی ہے ۔ مصر کی معاشی حالت اور یہاں کے مزدور کی اوقات کی تلخی کو مدِ نظر رکھ کر میں نے پوچھا کہ تمھارے حکمران بھی تو ساٹھ عشرے میں اشتراکی تھے ، جواب دیا جی بالکل ۔اس نے کہا روس سے مراسم ہی کی وجہ سے یہا ں پر پین عرب ازم اور مصری تہذیب کو زیادہ اجاگر کیا جاتا رہا ہے ۔میں نے کہا شاید اس لیے یہاں کے چوراہوں پر ابوالہول براجمان ہے اور پوری مصری قوم اس آس پر بیٹھی ہے کہ پنجوں پر کھڑا ابوالہول ایک نہ ایک دن اٹھے گا اور مصر ترقی کی شاہرہ پر گامزن ہو گا اور صرف یہ نہیں بلکہ مصریوں کے بیٹوں کو قتل کر نے والے رعمسیس کے نام پر ایک بڑی شاہرہ اور چوک کے نام بھی قاہرہ شہر میں رکھے گئے ۔ دکتور محمود مصر کے سیاسی حالات سے گفتگو کو موڑتے ہوئے مجھ سے پوچھتے ہیں کہ اشتراکیوں کی زندگی کیسے گزرتی ہے ۔میں نے کہا آئیڈیل کی تلاش میں گھٹ گھٹ کر ۔میں نے بات پھر مصر کی طرف...
Islām is a religion of peace and it gives great importance to peace. Islamic teachings and laws are meant to create and maintain peace in the human society. But, unfortunately, Islām has been targeted as a source of terrorism, today. In this article, the author tries to defend Islām and differentiate between Jihād and terrorism. The word terrorism needs to be seen in its historical perspective. Different definitions of terrorism have been presented, but still it is an ambiguous term. In this paper, the author tries to define terrorism in the Islamic perspective. This paper discusses the points given below: m The concept of terrorism, its manifestations and types. M Encountering and prevention of terrorism from Islamic perspective. M Islām and the global brotherhood. M The punishment of terrorism. M The religious viewpoint against a cruel government. M The peaceful struggle against cruelty and injustice. Also, the difference between terrorism and jihad has been clarified. The rules and regulations of Jihād make it clear that it has nothing to do with terrorism, which is an unruly activity. A Muslim is supposed to be a peaceful citizen, who can never indulge in any act of terrorism. The rebellion against the rulers has also been discussed to draw the conclusion that it is not allowed except against the blatant kufr. The objectives of the Islamic punishments indicate the Islamic approach to minimize terrorism in the human society.
This dissertation consists of two parts; “Part A” and “Part B”. The “Part A” consists of phytochemical studies on three indigenous medicinal plants; Berberis brevissima Jafri, Berberis parkeriana Schneid and Berberis royleana Ahrendt. The selected species of Berberis have been investigated for the first time for their phytochemical constituents. Three new (tirahamine (65), 13-nitrotirahamine (67) and peshawarine (68)) and eighteen known compounds (berberine (69), dehydrocheilanthifoline (70), jatrorrhizine (71), berberrubine (72), 8-oxoberberine (73), columbamine (74), palmatine (75), glutamic acid (76), glutamic acid, methyl ester (77), di-glutamic acid (78), di-glutamic acid, methyl ester (79), di-glutamic acid, di-methyl ester (80), docosanoic acid (81), 23a- homostigmast-5-en-3ß-ol (82), β-sitosterol-3-O-β-D-glucopyranoside (83), nonacosane- 10-ol (84), palmitic acid (85) and linoleic acid (86)) have been isolated for the first time from these selected species. The three new bisbenzylisoquinoline alkaloids (tirahamine, 13-nitrotirahamine and peshawarine) have been isolated from B. brevissima. The spectral studies of the two of the compounds tirahamine and 13-nitrotirahamine were performed at different temperature using different solvents. Acetylation and nitration of tirahamine (65) have also been performed. In this part (Part A) we have described the isolation and structural elucidation of the three new and eighteen reported compounds. The structural characterization of the compounds have been achieved by using UV-Vis, IR, EI-MS, ESI-MS, 1 H NMR, 13 C NMR, DEPTq, DEPT-90, DEPT-135, HMBC, HSQC, COSY, NOESY and NOE techniques. xiIn the “Part B” of the dissertation anticancer, antidiabetic, antimicrobial, antitrypanosomal and nematicidal activities of the fractions and the compounds isolated from B. brevissima, B. parkeriana and B. royleana have been discussed. The anticancer activities were performed against six cancer cell lines i.e. L1210 (Murine lyphocytic leukemia), Colon 38 (Murine colon adrenocarcinoma), CFU-GM (Murine granulocyte macrophage colony forming unit), H-116 (Human colon adrenocarcinoma), H-125 (Human lung adrenocarcinoma) and CEM (Humane leukemic lymphoid). Berberine (69) and jatrorrhizine (71) showed significant activity and selectivity against L1210 and Colon 38 cell lines while palmatine (75) was inactive. The antidiabetic activities were performed against Protein Tyrosine Phosphatase 1B (PTP 1B) which is a negative insulin regulator. Amongst the tested compounds, 8-oxob- berberine (73) was significantly active and showed 29 % of the control. The other isolated compounds i.e berberine (69) (35 %), dehydrocheilanthifoline (70) (38 %), columbamine (74) (33 %) and jatrorrhizine (71) (36 %) also showed good activity while glutamic acid (76) (78 %) was inactive. Antimicrobial activities were carried out against four microbial strains i.e Mycobacterium marinum, sporadic methicillin resistant Staphylococcus aureus (SMRSA), endemic methicillin resistant Staphylococcus aureus (EMRSA) and Escherichia coli while antitrypanosomal against Trypanosoma brucei which is a protozoa belonging to the genus Trypanosoma, causing sleeping sickness. Tsetse fly is responsible for the transferring of this parasitic protozoa from infected human and animals. The Berberis brevissima roots xiifraction C (BBR-C) showed good activity against M. marinum (2.4 % of DMSO (D) control), high activity against SMRSA (0.2 % of D control) and EMRSA (0.2 of % D control) while against E. coli it was inactive. Berberine (69) showed good selectivity and activity against SMRSA and EMRSA (1.1 and 0.5 % of D control). Some of the fractions and compounds have also been tested for % mortality of stage two juvenile of root knot nematodes i.e Meloidogyne javanica. Amongst the various fractions, the Berberis brevissima roots fraction A (BBR-A) exhibited the highest mortality (62.22 %) followed by Berberis parkeriana roots fraction C (BPR-C) 57.22 % and BBR-C (54.00 %). Berberine (69) showed the highest nematicidal potential at 97.3 % of the standard (carbofuran) at the highest conc. (300 μg ml -1 ). Jatrorrhizine (71) ranked second and exhibited 59.50 % mortality followed by berberrubine (72) (49.17 %). Dehydrocheilnthifoline (70) was the least effective, nevertheless, showed good mortality at the highest conc.