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      Therapeutics and Clinical Risk Management (submit here)

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      In vitro and in vivo postmarketing surveillance of valsartan, alone or in combination with amlodipine or hydrochlorothiazide, among Palestinian hypertensive patients


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          The objectives of this study were to evaluate the general quality of the most prescribed products of valsartan (VL; alone or in combination) and to evaluate their efficacy and safety among Palestinian population through in vivo postmarketing surveillance.

          Patients and methods

          The first part was pharmacopeial quality control assay, including dissolution, disintegration, friability, and weight uniformity for VL. The second part was a 3-month cardiology clinics, observational, postmarketing surveillance pilot study that included 103 hypertensive patients who were prescribed 80 mg or 160 mg of VL as monotherapy or combination therapy. The end points were reduction in blood pressure (BP) and the rate of incidence of adverse effects (AEs) at weeks 4 and 8.


          According to our quality control tests, all VL products showed high-quality standards according to the international guidelines. A reduction in BP was observed at weeks 4 and 8, and no significant difference was observed between the strengths of 80 mg and 160 mg. Higher BP reduction was observed after the use of combination therapy. Moreover, VL was well tolerated; most of the AEs were of mild-to-moderate intensity. In general, the most frequently reported AEs included headache (17.5%), dizziness (11.75%), and weakness (11.7%). No serious AEs or death cases were reported during the study period.


          High quality of VL tablet products was used; hence, the observed efficacy and safety results should be related to patient’s factors and not due to any product defects or substandard quality. Moreover, VL is an effective treatment for essential hypertension.

          Most cited references24

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          Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension.

          The relative effectiveness of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) for lowering blood pressure is unknown. To compare the benefits and harms of ACE inhibitors versus ARBs for treating essential hypertension in adults. MEDLINE (1966 to May 2006), the Cochrane Central Register of Controlled Trials (Issue 2, 2006), and selected reference lists were searched for relevant English-language trials. The MEDLINE search was updated to August 2007 to identify head-to-head trials that reported blood pressure outcomes and major cardiovascular events. 61 clinical studies that directly compared ACE inhibitors versus ARBs in adult patients with essential hypertension, reported an outcome of interest, lasted at least 12 weeks, and included at least 20 patients. A standardized protocol with predefined criteria was used to extract data on study design, interventions, population characteristics, and outcomes; evaluate study quality and applicability; and assess the strength of the body of evidence for key outcomes. ACE inhibitors and ARBs had similar long-term effects on blood pressure (50 studies; strength of evidence, high). No consistent differential effects were observed for other outcomes (few studies reported long-term outcomes), including death, cardiovascular events, quality of life, rate of single antihypertensive agent use, lipid levels, progression to diabetes, left ventricular mass or function, and kidney disease. Consistent fair- to good-quality evidence showed that ACE inhibitors were associated with a greater risk for cough. There were fewer withdrawals due to adverse events and greater persistence with therapy for ARBs than for ACE inhibitors, although this evidence was not definitive. Patient subgroups for whom ACE inhibitors or ARBs were more effective, associated with fewer adverse events, or better tolerated were not identified. Few studies involved a representative sample treated in a typical clinical setting over a long duration, treatment protocols had marked heterogeneity, and substantive amounts of data about important outcomes and patient subgroups were missing. Available evidence shows that ACE inhibitors and ARBs have similar effects on blood pressure control, and that ACE inhibitors have higher rates of cough than ARBs. Data regarding other outcomes are limited.
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            In vitro - in vivo correlation: from theory to applications.

            A key goal in pharmaceutical development of dosage forms is a good understanding of the in vitro and in vivo performance of the dosage forms. One of the challenges of biopharmaceutics research is correlating in vitro drug release information of various drug formulations to the in vivo drug profiles (IVIVC). Thus the need for a tool to reliably correlate in vitro and in vivo drug release data has exceedingly increased. Such a tool shortens the drug development period, economizes the resources and leads to improved product quality. Increased activity in developing IVIVCs indicates the value of IVIVCs to the pharmaceutical industry. IVIVC can be used in the development of new pharmaceuticals to reduce the number of human studies during the formulation development as the main objective of an IVIVC is to serve as a surrogate for in vivo bioavailability and to support biowaivers. It supports and/or validates the use of dissolution methods and specification settings. This is because the IVIVC includes in vivo relevance to in vitro dissolution specifications. It can also assist in quality control for certain scale-up and post-approval changes (SUPAC). With the proliferation of modified-release products, it becomes necessary to examine the concept of IVIVC in greater depth. Investigations of IVIVC are increasingly becoming an integral part of extended release drug development. There must be some in vitro means of assuring that each batch of the same product will perform identically in vivo. This review article represents the FDA guidance, development, evaluation, and validation of an IVIVC to grant biowaivers, and to set dissolution specifications for oral dosage forms, biopharmaceutics classification systems (BCS), BCS biowaivers, application of BCS in IVIVC development and concept of mapping. The importance of dissolution media and methodology and pharmacokinetic studies in the context of IVIVC has been highlighted. The review also covers the literature examples of IVIVCs regarding internal and external validation, compendial dissolution assessment, formulation dependency of IVIVCs, and IVIVCs of pure enantiomers versus racemate drugs. The same principles of IVIVC used for oral extended release products may be applied for non-oral products such as parenteral depot formulations and novel drug delivery systems as well.
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              Influence of blood pressure reduction on composite cardiovascular endpoints in clinical trials.

              The use of a composite cardiovascular endpoint (CCEP) is frequent in clinical trials. However, the relation between the reduction in blood pressure (BP) and the risk of CCEP is poorly known. We conducted a meta-analysis of trials, which compared different BP-lowering agents with placebo or active treatments in patients with hypertension or composite features of high cardiovascular risk. The outcome measure was a triple (myocardial infarction, stroke and cardiovascular death) or quadruple (those mentioned above and congestive heart failure) CCEP. Thirty trials fulfilled the inclusion criteria, for a total of 221 024 patients. Experimental treatments reduced the risk of CCEP by 9% (P < 0.0001). In a multivariable meta-regression analysis, for each 5-mmHg reduction in SBP, there was a 13% less risk of CCEP (95% confidence interval 8-19, P = 0.001) and, for each 2-mmHg reduction in DBP, there was a 12% less risk of CCEP (95% confidence interval 7-16, P = 0.001). Use of triple or quadruple CCEP (P = 0.150), its definition as primary or nonprimary endpoint (P = 0.305) and use of placebo or active control as comparators (P = 0.552) did not influence the estimates. A different BP reduction of at least 4.6 mmHg in SBP or at least 2.2 mmHg in DBP was required to achieve a 95% prediction interval entirely lying below the unity. BP reduction is important to reduce the risk of CCEP in clinical trials. A significant difference between two treatment groups in the risk of CCEP may be anticipated for a SBP/DBP reduction differing by 4.6/2.2 mmHg or more.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                19 September 2016
                : 12
                : 1425-1432
                [1 ]Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus
                [2 ]Pharmacare Ltd, Ramallah, Palestine
                Author notes
                Correspondence: Abdel Naser Zaid, Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, PO Box 7, Nablus, Palestine, Tel +970 9 72 9234 5113, Fax +970 9 72 9234 5982, Email anzaid@ 123456najah.edu
                © 2016 Zaid et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                valsartan,quality control,postmarketing,surveillance,palestine
                valsartan, quality control, postmarketing, surveillance, palestine


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