Freedom of the Press: The War on Words (1977-1978)

Journalism in Pakistan has passed through successive phases of trials and tribulations. The crises journalism had to undergo since independence had their origin both in the state policies as well as the authoritarianism embedded in the society. The book under review does not claim to divulge into the societal challenges which have emerged more visibly in the last three or four decades, especially, in the context of the spread of religious extremism and ethnic and other types of militancy in the society. Studies need to be done on these aspects as well as the external factors that have had impact on the growth and the content of media. The latter has come in the garb of globalization that has greatly affected the local environment and has come to strongly affect, if not directly dictate, what the media should encompass and present. Leaving the societal and global aspects aside, the role of the state and the successive governments has a lot to offer to be written about by way of what the media has endured in the last seventy plus years. It doesn’t need too much of pondering to conclude that the major pressures over media have come from the governments who, by and large, had been quite at unease with independent flow of information, and criticism of their policies. And, unfortunately, this process had begun right after Independence when newspapers’ and periodicals’ independent voice was tried to be silenced, and they were pressurized to toe the official line with respect to domestic and foreign policies. Pakistan’s independent journey, unfortunately, began with the imposition of black laws which prohibited dissent and curtailed freedom of expression in the strongest possible manner.

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