Gabapentin Bioequivalence Study: Quantification By Liquid Chromatography Coupled To Mass Spectrometry

The study was performed to compare the bioavailability of two gabapentin 400 mg capsule formulation (Gabapentin from Arrow Farmacêutica S/A as test formulation and Neurontin ® from Pfizer, Brazil, as reference formulation) in 26 volunteers of both sexes. The study was conducted open with randomized two period crossover design and a one week wash out period. Plasma samples were obtained over a 48 hour interval. The gabapentin was analyzed by LC/MS/MS, in the presence of pracetamole as internal standard. With plasma concentration vs. time curves, data obtained from this metabolite, the following pharmacokinetics parameters were obtained: AUC 0-t, AUC 0-inf and C max. Geometric mean of gabapentin/Neurontin ® 400 mg individual percent ratio was 100.58% AUC 0-t, 101.35% for AUC 0-inf and 97.76% for C max. The 90% confidence intervals were 92.00 - 109.95%, 93.00 - 110.44%, 88.41 - 108.10%, respectively. Since the 90% confidence intervals for C max, AUC 0-t and AUC 0 -inf were within the 80 - 125% interval proposed by Food and Drug Administration, it was concluded that gabapentin 400 mg capsule was bioequivalent to Neurontin ® 400 mg capsule according to both the rate and extent of absorption. © 2011 Junior EA, et al.38187190Wattananat, T., Akarawut, W., Validated LC-MS-MS Method for the Determination of Gabapentin in Human Plasma: Application to a Bioequivalence Study (2009) J Chromatogr Sci, 47, pp. 868-871Stewart, B.H., Kagler, A.R., Thompson, P.R., Bockbrader, H.N., A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma (1993) Pharma Res, 10, pp. 276-281McLean, M.J., Gabapentin in the management of convulsive disorders (1999) Epilepsia, 40, pp. 39-50Goa, K.L., Sorkin, E.M., Gabapentin: A review of its pharmacological properties and clinical potential in epilepsy (1993) Drugs, 46, pp. 409-427Zhu, Z., Neirinck, L., High-performance liquid chromatographic method for the determination of gabapentin in human plasma (2002) J Chromatogr B Analyt Technol Biomed Life Sci, 779, pp. 307-312Sagirli, O., Cetin, S.M., Determination of gabapentin in human plasma and urine by high-performance liquid chromatography with UV-vis detection (2006) J Pharm Biomed Anal, 42, pp. 618-624Jalalizadeh, H., Souri, E., Tehrani, M.B., Jahangiri, A., Validated HPLC method for the determination of gabapentin in human plasma using precolumn derivatization with 1-fluoro-2,4-dinitrobenzene and its application to a pharmacokinetic study (2007) J Chromatogr B Analyt Technol Biomed Life Sci, 854, pp. 43-47Forrest, G., Sills, G.J., Leach, J.P., Brodie, M.J., Determination of gabapentin in plasma by high-performance liquid chromatography (1996) J Chromatogr B Analyt Technol Biomed Life Sci, 681, pp. 421-425Tang, P.H., Miles, M.V., Glauser, T.A., Degrauw, T., Automated microanalysis of gabapentin in human serum by high-performance liquid chromatography with fluorometric detection (1999) J Chromatogr B Analyt Technol Biomed Life Sci, 727, pp. 125-129Hassan, E.M., Belal, F., Al-Deeb, O.A., Khalil, N.Y., Spectrofluorimetric determination of vigabatrin and gabapentin in dosage forms and spiked plasma samples through derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (2001) J. AOAC Int., 84, pp. 1017-1024Gauthier, D., Gupta, R., Determination of gabapentin in plasma by liquid chromatography with fluorescence detection after solid-phase extraction with a C18 column (2002) Clin Chem, 48, pp. 2259-2261Chung, T.C., Tai, C.T., Wu, H.L., Simple and sensitive liquid chromatographic method with fluorimetric detection for the analysis of gabapentin in human plasma (2006) J Chromatogr A, 119, pp. 294-298Bahrami, G., Kiani, A., Sensitive high-performance liquid chromatographic quantitation of gabapentin in human serum using liquid-liquid extraction and pre-column derivatization with 9-fluorenylmethyl chloroformate (2006) J Chromatogr B Analyt Technol Biomed Life Sci, 835, pp. 123-126Krivanek, P., Koppatz, K., Turnheim, K., Simultaneous isocratic HPLC determination of vigabatrin and gabapentin in human plasma by dansyl derivatization (2003) Ther Drug Monit, 25, pp. 374-377Chang, S.Y., Wang, F.Y., Simple and sensitive liquid chromatographic method with fluorimetric detection for the analysis of gabapentin in human plasma (2004) J Chromatogr B Analyt Technol Biomed Life Sci, 799, pp. 265-270Wolf, C.E., Saady, J.J., Poklis, A., Determination of gabapentin in serum using solid phase extraction and gas-liquid chromatography (1996) J Anal Toxicol, 20, pp. 498-501Kushnir, M.M., Cossett, J., Brown, P.I., Urry, F.M., Analysis of gabapentin in serum and plasma by solid-phase extraction and gas chromatography-mass spectrometry for therapeutic drug monitoring (1999) J Anal Toxicol, 23, pp. 1-6Borrey, D.C., Godderis, K.O., Engelrelst, V.I., Bernard, D.R., Langlois, M.R., Quantitative determination of vigabatrin and gabapentin in human serum by gas chromatography-mass spectrometry (2005) Clin Chim Acta, 354, pp. 147-151Gambelunghe, C., Mariucci, G., Tantucci, M., Ambrosini, M.V., Gas chromatography-tandemmass spectrometry analysis of gabapentin in serum (2005) Biomed Chromatogr, 19, pp. 63-67Matar, K.M., Abdel-Hamid, M.E., Rapid tandem mass spectrometric method for determination of gabapentin in human plasma (2005) Chromatographia, 61, pp. 499-504Ramakrishna, N.V.S., Vishwottam, K.N., Koteshwara, M., Maroj, S., Santosh, M., Rapid quantification of gabapentin in human plasma by liquid chromatography/tandemmass spectrometry (2006) J Pharm Biomed Anal, 40, pp. 360-368Ifa, D.R., Falci, M., Moraes, M.E., Bezerra, F.A., Moraes, M.O., Gabapentin quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study (2001) J Mass Spectrom, 36, pp. 188-194Ji, H.Y., Jeong, D.W., Kim, Y.H., Kim, H.H., Yoon, Y.S., Determination of gabapentin in human plasma using hydrophilic interaction liquid chromatography with tandem mass spectrometry (2006) Rapid Commun Mass Spectrom, 20, pp. 2127-2132Carlsson, K.C., Reubsaet, J.L., Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry (2004) J Pharm Biomed Anal, 34, pp. 415-423Park, J.H., Jhee, O.H., Park, S.H., Lee, J.S., Lee, M.H., Validated LC-MS/ MS method for quantification of gabapentin in human plasma: Application to pharmacokinetic and bioequivalence studies in Korean volunteers (2007) Biomed Chromatogr, 21, pp. 829-83

Comparative Bioavailability Of Two Quetiapine Formulations In Healthy Volunteers After A Single Dose Administration

The study was performed to compare the bioavailability of two quetiapine 25 mg tablet formulations: the test formulation was quetiapine fumarate (kitapen®) manufactured by Cobalt Pharmaceuticals, Canada/ Arrow Farmacêutica Ltda* (Erowlabs). Seroquel® (quetiapine) from Astrazeneca Brazil was used as reference formulation. The study was conducted open with randomized two period crossover design and one week wash out period in 64 volunteers of both sexes. Plasma samples were obtained over a 48 hour interval. Quetiapine was analyzed by LC-MS-MS in the presence of quetiapine-D8 as internal standard. Plasma samples were obtained over a 48 hour interval. Quetiapine was analyzed by LC-MS-MS in the presence of quetiapine-D8 as internal standard. The mean ratio of parameters Cmax and AUC 0-t and 90% confidence intervals of correspondents were calculated to determine the bioequivalence. The means AUC 0-t for test and reference formulation were 432.41 ng.h/mL and 412.20 ng.h/mL, for AUC 0-∞ were 440.06 ng.h/mL and 418.90 ng.h/mL and, for Cmax 126.94 ng/mL and 108.71 ng/mL, respectively. Geometric mean of quetiapine (kitapen®)/Seroquel® 25 mg individual percent ratio was 97.68% AUC 0-t, 97.47% for AUC 0-∞ and 90.68% for C max. The 90% confidence intervals were 92.67 - 102.96%, 92.53 - 102.67%, 83.37 - 98.64%, respectively. Since the 90% confidence intervals for C max, AUC 0-t and AUC 0-∞ were within the 80 - 125% interval proposed by Food and Drug Administration, it was concluded that quetiapine (kitapen®) 25 mg tablet was bioequivalent to Seroquel® 25 mg tablet according to both the rate and extent of absorption. © 2011 Junior EA, et al.38178181Barrett, B., Capek, H.M., Huclova, J., Borek-Dohalsky, V., Fejt, P., Validated HPLC-MS/MS method for determination of quetiapine in human plasma (2007) Journal of Pharmaceutical and Biomedical Analysis, 44, pp. 498-505DeVane, C.L., Nemeroff, C.B., Clinical Pharmacokinetics of quetiapine: An Atypical Antipsychotic (2001) Clinical Pharmacokinet, 40, pp. 509-522Kasper, S., Müller-Spahn, F., Review of quetiapine and its clinical applications in schizophrenia (2000) Expert Opin Pharmacother, 1, pp. 783-801Tilden, D., Aristides, M., Meddis, D., Burns, T., An economic assessment of quetiapine and haloperidol in patients with schizophrenia only partially responsive to conventional antipsychotics (2002) Clin Ther., 24, pp. 1648-1667Mario, A., Michael, E., The Role of Quetiapine Extended Release in the Treatment of Bipolar Depression (2010) Adv Ther, 27, pp. 1-11Keck, P., McIntyre, R., Shelton, R., Bipolar depression: Best practices for the outpatient (2007) CNS Spectr., 12, pp. 1-16Judd, L., Akishal, H., Schettler, P., The long-term natural history of the weekly symptomatic status of bipolar I disorder (2002) Arch Gen Psychiatry., 59, pp. 530-537Goldstein, J.M., Atypical antipsychotic drugs: Beyond acute psychosis, new directions (1999) Emerging Drugs, 4, pp. 127-151Abi-Dargham, A., Laruelle, M., Aghajanian, G.K., Charney, D., Krystal, J., The role of serotonin in the pathophysiology and treatment of schizophrenia (1997) J Neuropsychiatry Clin Neurosci, 9, pp. 1-17Kapur, S., Remington, G., Serotonin-dopamine interaction and its relevance to schizophrenia (1996) Am J Psychiatry, 153, pp. 466-476Calabrese, J.R., Keck Jr., P.E., McFadden, W., Minkwitz, M., Ketter, T.A., Weisler, R.H., Cutler, A.J., Mullen, J., A randomized, doubleblind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression (2005) Am J Psychiatry, 162, pp. 1351-1360Copolov, D.L., Kowalcyk, B., A multicentre, double-blind, randomized comparison of quetiapine and haloperidol in schizophrenia (2000) Psychol Med, 30, pp. 95-105Figueroa, C., Brecher, M., Hamer-Maansson, J., Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release (2009) Prog Neuropsychopharmacol Biol Psychiatry, 33, pp. 199-204Goldstein, J.M., Litwin, L.C., Sutton, E.B., Malick, J.B., Seroquel: Electrophysiological profile of a potential atypical antipsychotic (1993) Psychopharmacology, 112, pp. 293-298Kasper, S., Tauscher, J., Küfferle, B., Barnas, C., Pezawas, L., Dopamine and serotonin-receptors in schizophrenia: Results of imaging-studies and implications for pharmacology in schizophrenia (1999) Eur. Arch. Psychiatry Clin. Neurosci., 249, pp. 83-89Peuskens, J., A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia (1997) Acta Psychiatr Scand, 96, pp. 265-273Saller, F., Salama, A.I., Seroquel: Biochemical profile of a potential atypical antipsychotic (1993) Psychopharmacology, 112, pp. 285-292Thase, M.E., McFadden, W., Weisler, R., Efficacy of quetiapine monotherapy in bipolar I and II depression: A double-blind, placebo-controlled study (2006) J Clin Psychopharmacol, 26, pp. 600-609Vieta, E., Mullen, J., Brecher, M., Paulsson, B., Jones, M., Quetiapine monotherapy for mania associated with bipolar disorder: Combined analysis of two international, double-blind, randomised, placebo-controlled studies (2005) Curr Med Res Opin, 21, pp. 923-93

Global Initiative for Children’s Surgery (GICS) Pediatric Trauma Care Initiative: A Call for a Comprehensive Approach to a Global Problem

Introduction: Trauma is a major problem which has a significant health, social, and economic impact. Particularly, pediatric trauma carries substantial mortality and morbidity. This is a great concern for subspecialized general and pediatric surgeons. Therefore, a global initiative for pediatric trauma care is warranted and should be initiated. Aim: The international association “Global Initiative for Children’s Surgery” (GICS) would like to propose and organize a children’s trauma care (CTC) initiative. This initiative should comprehensively address pediatric trauma management globally, especially in low- and middle-income countries (LMICs). The initiative seeks to achieve a structured cooperation and collaboration with respective sister organizations and local stakeholders. Methods: The initiative will address these relevant aspects: 1. first aid; 2. prehospital primary trauma care; 3. hospital primary trauma care; 4. advanced care (ATLS); 5. diagnostic facilities; 6. operation room (OR) equipment; 7. specialized surgical services; 8. rehabilitation; 9. registry, research, and auditing; 10. specialization in pediatric trauma; 11. capacity and confidence building in pediatric trauma; 12. prevention. The GICS CTC provided activities have been recorded and evaluated in a structured manner. This statement paper is based on data of a narrative review as well as expert opinions. Results: The Trauma Working Group of GICS provided specialized trauma prevention leaflets available for translation to different languages. A one-day children’s primary trauma course has been designed to be delivered at the physical GICS meetings. Exercising advocacy, the group addressed several meetings on prevention of pediatric trauma, which included the 75th United Nations General Assembly (UNGA) (2020), GICS IVth meeting in Johannesburg (2020), Norwich (UK) Joint SPRINT Symposium on Pediatric Surgery for Pediatricians (2021), the second online Pan African Pediatric Surgical Association (PAPSA) meeting (2021), the seventh World Congress of the World Federation of Associations of Pediatric Surgeons (WOFAPS) in Prague (2022), and GICS pediatric trauma webinar (2023). Additionally, the working group participated in the preparations of a pediatric trauma module for the World Health Organization (WHO) and published several related studies. The contents of the selected articles added relevant information to the categories stated above. Conclusions: The CTC initiative of GICS is proposed as a mean to address pediatric trauma comprehensively through a process of collaboration and advocacy with existing organizations to achieve awareness, health education, prevention, health, and training. Further, it will support the provision of suitable facilities to health institutions. The establishment of a specialization in pediatric trauma is encouraged. GICS CTC initiative aims to improve pediatric trauma care in LMICs by developing injury prevention strategies; optimizing the use of locally available resources; obtaining commitment by LMICs governments; improvement in all fields of hospital care; improvements in infrastructure, education and training, and attention to data registry and research

A saúde como tema do componente curricular Educação Física no Referencial Curricular “Lições do Rio Grande”

The present article aims to analyze how the health theme is approached in Rio Grande do Sul Curriculum Reference – Lessons from Rio Grande, specifically in the Physical Education curricular component. From the analysis of the texts that refer to Physical Education in the referential and the books of teacher and student, some considerations could be made: the displacement of the health theme from a dimension of know-how to know-about; an expanded conception of health in terms of its different dimensions; health as a content in different structuring themes of the proposed curriculum for Physical Education.El presente artículo tiene como objetivo analizar de qué manera el tema salud se aborda en el marco curricular de Rio Grande do Sul - Lecciones del Río Grande, más específicamente en el componente curricular Educación Física. A partir del análisis de los textos que versan sobre Educación Física en el marco curricular y de los cuadernos del profesor y del alumno, algunas consideraciones pudieron ser hechas: el cambio del tema salud de una dimensión del saber-hacer para el saber-sobre; una concepción ampliada sobre salud, con respecto a sus diferentes dimensiones; la salud como contenido en diferentes temas estructurantes del plan de estudios propuesto para Educación Física.O presente artigo tem como objetivo analisar de que maneira o tema saúde é abordado no Referencial Curricular do Rio Grande do Sul – Lições do Rio Grande, mais especificamente no componente curricular Educação Física. A partir da análise dos textos que versam sobre Educação Física no referencial e dos cadernos do professor e do aluno, algumas considerações puderam ser feitas: o deslocamento do tema saúde de uma dimensão do saber-fazer para o saber-sobre; uma concepção ampliada sobre saúde, no tocante às suas diferentes dimensões; a saúde enquanto um conteúdo em diferentes temas estruturantes do currículo proposto para a Educação Física

O CORPO NA SOCIEDADE DE CONSUMIDORES: INTERPRETAÇÕES A PARTIR DE ESTUDANTES DO COLÉGIO PEDRO II

El objetivo de la investigación fue analizar las representaciones corporales de un grupo de estudiantes de secundaria del Colégio Pedro II. La investigación se llevó a cabo con 77 estudiantes de secundaria regular e integrada del Colégio Pedro II – Campus São Cristóvão III. Los instrumentos para la recolección de información fueron un cuestionario de encuesta en línea y un grupo focal, con análisis basado en el Método de Interpretación de los Sentidos, privilegiando el diálogo con el enfoque sociológico de Zygmunt Bauman. Los análisis desarrollados demostraron, en línea con el argumento baumaniano sobre los procesos de privatización y consumo, que los estudiantes tienen identidades corporales ambivalentes y sus entendimientos sobre el cuerpo son fluidos en función de las estrategias de responsabilidad individual en torno a decisiones sobre el cuerpo, los cuales fueron influenciados, en el ámbito de esta investigación, por acciones educativas presentes en la institución en foco y por influencias mediáticas.The purpose of the research was to analyze the body representations of a group of high school students at Colégio Pedro II. The study was carried out with 77 students from regular and integrated high school at Colégio Pedro II – Campus São Cristóvão III. The tools used for data collection were an online survey questionnaire and focus group, with analysis based on the Meaning Interpretation Method, privileging the dialog with the sociological approach of Zygmunt Bauman. The developed analysis showed, in line with the baumanian argument surrounding privatization and consumption processes, that students have ambivalent bodily identities, in other words, their understandings about the body are fluid, due to individual accountability strategies around decisions about the body, which were influenced, in the scope of this research, by educational actions present in the institution in focus and by media influences.O objetivo da pesquisa foi analisar as representações corporais de um grupo de estudantes do Ensino Médio do Colégio Pedro II. A pesquisa se desenvolveu com 77 estudantes do Ensino Médio regular e integrado do Colégio Pedro II – Campus São Cristóvão III. Os instrumentos para coleta de informações foram um questionário survey on-line e grupo focal, com análise baseada no Método de Interpretação dos Sentidos, privilegiando o diálogo com a abordagem sociológica de Zygmunt Bauman. As análises desenvolvidas demonstraram, em consonância com o argumento baumaniano em torno dos processos de privatização e consumo, que os estudantes possuem identidades corporais ambivalentes, ou seja, seus entendimentos sobre o corpo são fluidos em função das estratégias de responsabilização individual em torno das decisões sobre o corpo, que foram influenciadas, no escopo dessa pesquisa, por ações educativas presentes na instituição em foco e por influências midiáticas

Efeito da elevação sobre a estrutura horizontal e riqueza da vegetação em planos de manejo na Amazônia.

Understanding ecological variations in tropical forests is essential for defining conservation and management strategies. Changes in the composition and structure of forests, in relation to altitude, have been investigated on many tropical slopes. Although the degradation of its natural habitat continues, the Amazon biome represents 30% of the world's tropical forests and houses at least 10% of the known biodiversity. Considering the magnitude of Amazon diversity, this study evaluated the influence of terrain elevation on abundance, dominance and floristic richness of the primary vegetation in four neighboring farms (Caçula, Guarujá, Anhumas and Jaraguá) located in State of Acre, Brazil, by means of Shuttle Radar Topography Mission (SRTM) image. Data from each area were obtained from Acre Institute of the Environment's (IMAC) census inventory. Segmented linear regression models were used to observe the effect of the terrain elevation on the variables studied. The selection of models was made considering the Akaike?s Information Criterion (AIC). For Guarujá and Jaraguá farms, the models indicated a relationship between altitude and ecological variation. On the other hand, in Caçula and Anhumas, it was not possible to observe the influence of terrain elevation on any variable. It is important to take into consideration the impact of break-points, applicable in Guarujá and Jaraguá farms, when creating altitude stratified limits to manage the landscape

Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c) (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product) and Levaquin(c) (Janssen-Cilag Farmacêutica Ltda, Brazil, test product) was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c) and Levaquin(c) are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies

Implementation strategies for knowledge products in primary healthcare: A systematic review of systematic reviews

BACKGROUND: The underuse or overuse of knowledge products leads to waste in healthcare, and primary care is no exception. OBJECTIVE: We aimed to characterize which knowledge products are frequently implemented, the implementation strategies used in primary care, and the implementation outcomes that are measured. METHODS: We performed a systematic review of systematic reviews (SR) using the Cochrane systematic approach to include eligible SR. The inclusion criteria were: any primary care contexts; healthcare professionals and patients; any EPOC implementation strategies of specified knowledge products; any comparator; and any implementation outcomes based on the Proctor framework. We searched the Medline, EMBASE, CINAHL, Ovid PsycINFO, Web of Science, and Cochrane Library databases from their inception to October 2019, without any restriction. We searched the references of the included SR. Pairs of reviewers independently performed selection, data extraction and methodological quality assessment with AMSTAR 2. Data extraction was informed by EPOC taxonomy for implementation strategies and the Proctor framework for implementation outcomes. We performed a descriptive analysis and summarized the results using a narrative synthesis. RESULTS: Of the 11,101 records identified, 81 SR were included. Forty-seven SR involved healthcare professionals alone. Fifteen SR were of high or moderate methodological quality. Most of them addressed one type of knowledge product (56/81), common clinical practice guidelines (26/56) or management, and behavioural or pharmacological health interventions (24/56). Mixed strategies were used for implementation (67/81), predominantly educational-based (meetings in 60/81, materials distribution in 59/81, and academic detailing in 45/81), reminder (53/81) and audit and feedback (40/81) strategies. Education meetings (P=.13) and academic detailing (P=.11) seem to be more used when the population is composed of Healthcare professionals alone. The improvement of the adoption of knowledge products was the most commonly measured outcome (72/81). The evidence level was reported in 10/81 SR on 62 outcomes (including 48 improvement of adoption), of which 16 outcomes were of moderate or high level. CONCLUSIONS: Clinical practice guidelines and management, behavioural or pharmacological health interventions are the most commonly implemented knowledge products through the mixed use of educational, reminders and audit and feedback strategies. There is need for a strong methodology for the SR of RCTs to explore their effectiveness and the whole cascade of implementation outcomes. CLINICALTRIAL: Not applicable