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

Evaluation Of The Pharmacokinetic Interaction Between Candesartan Cilexetil And Felodipine

The study was performed to evaluate the pharmacokinetic interaction of test formulation of candesartan 16 mg tablet and felodipine extended release 5 mg tablet together in a combination package, comparing with the fasting period intake of commercial formulations of both Atacand® 16 mg tablet and Splendil® extended release 5 mg tablet (Test formulation and reference formulation from AstraZeneca, Brazil) in 36 volunteers of both sexes. The study was conducted open with randomized three period crossover design and a one week wash out period. The candesartan and felodipine were analyzed by LC-MS-MS. The mean ratio of parameters Cmax and AUC0-t and 90% confidence intervals of correspondents were calculated to determine the pharmacokinetic interaction. Geometric mean of candesartan exposure together in a combination package felodipine individual percent ratio was 102.51% AUC0-t and 110.40% for Cmax. The 90% confidence intervals were 90.00 - 116.77% and 93.94 - 129.74%, respectively. Geometric mean of felodipine exposure together in a combination package candesartan individual percent ratio was 102.69% AUC0-t and 96.17% for Cmax. The 90% confidence intervals were 89.46 - 117.88% and 82.07 - 112.69%, respectively. The major variable in this respect, AUC, was not signicantly affected by felodipine and candesartan with concomitant administration. The Cmax of candesartan was not signicantly affected by co-administration of felodipine. Based on these data and in presence in the market of isolated candersatana and felodipino formularizations used in combination in medical practice, it is concluded that there are no risk with concomitant administration between felodipine and candesartan.© 2011 Abib Jr E, et al.31510Blyckert, E., Wingstrand, K., Edgar, B., Lidman, K., Plasma concentration profiles® and antihypertensive effect of conventional and extended release felodipine tablets (1990) Br J Clin Pharmacol, 29, pp. 39-45Blychert, E., Edgar, B., Elmfeldt, D., Hedner, T., A population study of the pharmacokinetics of felodipine (1991) Blood Press, 31, pp. 15-24Blychert, E., Felodipine pharmacokinetics and plasma concentration vs effect relationships (1992) Blood Press, 2, pp. 1-30Dahlöf, B., Andersson, O.K., A felodipine-metoprolol extended-release tablet: Its properties and clinical development (1995) J Hum Hypertens, 9, pp. 43-47Dunselman, P.H., Edgar, B., Felodipine clinical pharmacokinetics (1991) Clin Pharmacokinet, 21, pp. 418-430Edgar, B., Regardh, C., Lundborg, G., Romare, P.S., Nyberg, G., Pharmacokinetics and pharmacodynamic studies of felodipine in healthy subjects after various single, oral and intravenous doses (1987) Biopharm. Drug Dispos, 8, pp. 235-248Eriksson, M., Nyberg, G., Lidman, K., Aiming for steady 24-hour plasma concentrations: A comparison of two calcium antagonist and beta-blocker combinations (1993) Blood Press Suppl, 1, pp. 16-21Gleiter, C.H., Morike, K.E., Clinical pharmacokinetics of candesartan (2002) Clin Pharmacokinet, 41, pp. 07-17Gradman, A.H., Lewin, A., Bowling, B.T., For the candesartan versus losartan efficacy comparison (CANDLE) study group. Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension (1999) Heart Dis, 1, pp. 52-57Hallin, L., Andren, L., Hansson, L., Controlled trial of nifedipine and bendroflumethiazide in hypertension (1983) J Cardiovasc Pharmacol, 5, pp. 1083-1085Hansson, L., Zanchetti, A., Carruthers, S.G., Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomized trial (1998) Lancet, 351, pp. 1755-1762Hedner, T., Sjogren, E., Elmfeldt, D., Antihypertensive effects and pharmacokinetics of felodipine combined with a,-blocker and, a diuretic (1987) J Cardiovasc Pharmac, 10, pp. 177-184Ikechi, G.O., Brian, L.R., Update on the role of candesartan in the optimal management of hypertension and cardiovascular risk reduction (2010) Integrated Blood Pressure Control, 3, pp. 45-55Kloner, R.A., Weinberger, M., Pool, J.L., For the comparison of candesartan and amlodipine for safety, tolerability and efficacy (CASTLE) study investigators. Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension (2001) Am J Cardiol, 87, pp. 727-731Little, W.C., Cheng, C.P., Elvelin, L., Vascular selective calcium entry blockers in the treatment of cardiovascuolar disorders: Focus on felodipine. Cardiovasc (1995) Drugs Ther, 9, pp. 657-663Maccarthy, E.P., Dihydropyridines and beta-adrenoceptor antagonists as combination treatment in hypertension (1987) J Hypertens, 5, pp. 133-137Macconnachie, A.M., Maclean, D., Low dose combination antihypertensive therapy: Additional efficacy without additional adverse effects (1995) Drug Saf, 12, pp. 85-90Mann, S.J., Gerber, L.M., Low-dose alpha/beta blockade in the treatment of essential hypertension (2001) Am J Hypertens, 14, pp. 553-558Matheson, A.J., Cheer, S.M., Goa, K.L., Perindopril/indapamide 2/0.625 mg/ day: A review of its place in the management of hypertension (2001) Drugs, 61, pp. 1211-1229McFayden, R.J., Reid, J.L., Angiotensin receptor antagonists as a treatment for hypertension (1994) J Hypertens, 12, pp. 1333-1338Melian, E.B., Jarvis, B., Candesartan cilexetil plus hydrochlorothiazide combination: A review of its use in hypertension (2002) Drugs, 62, pp. 787-816Messerli, F.H., Combination therapy in hypertension (1992) J HumHypertens, 6, pp. 19-21Messerli, F.H., Chander, K., Cardiac effects of combination therapy in hypertension (2000) J Cardiovasc Pharmacol, 35, pp. 17-22Michalewicz, L., Messerli, F.H., Cardiac effects of calcium antagonists in systemic hypertension (1997) Am J Cardiol, 79, pp. 39-46Morgan, T., Anderson, A.A., Comparison of candesartan, felodipine, and their combination in the treatment of elderly patients with systolic hypertension (2002) Am J Hypertens, 15, pp. 544-549Morimoto, S., Ogibara, T., TCV-116: A new angiotensin n type-1 receptor antagonist (1994) Cardiovasc Drug Rev, 12, pp. 153-164Muller, J.E., Circadian variation in cardiovascular events (1999) AM J Hypertens, 12, pp. 35-42Nalbantgil, I., Önder, R., Kiliccioglu, B., Turkoglu, C., Combination therapy with verapamil and nitrendipine in patients with hypertension (1993) J Hum Hypertens, 7, pp. 305-308Nalbantgil, I., Önder, R., Nalbantgil, S., Sustained-release verapamil and trandolapril, alone and in combination, in the treatment of obese hypertensive patients: A double-blind pilot study (1996) Curr Ther Res Clin Exp, 57, pp. 990-997Nalbantgil, S., Nalbantgil, I., Önder, R., Clinically additive effect between doxazosin and amlodipine in the treatment of essential hypertension (2000) Am J Hypertens, 13, pp. 921-926Neutel, J.M., Low-dose antihypertensive combination therapy: Its rationale and role in cardiovascular risk management (1999) Am J Hypertens, 12, pp. 73-79Nishikawa, K., Naka, T., Chatani, F., Yoshimura, Y., Candesartan cilexetil: A review of its preclinical pharmacology (1997) J Human Hypertens, 11, pp. 9-17O'Brien, E.T., Mackinnon, J., Propranolol and polythiazide in the treatment of hypertension (1972) Br Heart J, 34, pp. 1042-1044Oparil, S., Levine, J.H., Zuschke, C.A., For the candesartan cilexetil study investigators. 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II Ciclo de Conferências : Conselho Técnico-Científico: temas atuais em investigação

A obra é constituída pelos resumos das comunicações apresentadas pelos docentes da Escola Superior Agrária do Instituto Politécnico de Castelo Branco e são referentes aos projetos de investigação nos quais estão envolvidos.O atual Conselho Técnico-Científico (CTC) da Escola Superior Agrária de Castelo Branco (ESACB) tomou posse em fevereiro de 2012, tendo decidido dar continuidade ao ciclo de conferências iniciado pelo CTC anterior. Os trabalhos de Investigação, Inovação e Experimentação que foram apresentados demonstram não só o dinamismo e a ligação com a comunidade, como também a preocupação na identificação e resolução de problemas, que acrescentem valor aos produtos e processos que se situam no âmbito das competências desta Escola. Sendo este um objetivo prioritário da missão do IPCB/ESA, a divulgação destas conferências permite chegar a um público mais alargado e abrir caminhos para a concretização de novos projetos, que contribuam de forma efetiva para o desenvolvimento e aumento da competitividade da região e do país

Cross-national variations in reported discrimination among people treated for major depression worldwide: The ASPEN/INDIGO international study

Background: No study has so far explored differences in discrimination reported by people with major depressive disorder (MDD) across countries and cultures. Aims: To (a) compare reported discrimination across different countries, and (b) explore the relative weight of individual and contextual factors in explaining levels of reported discrimination in people with MDD. Method: Cross-sectional multisite international survey (34 countries worldwide) of 1082 people with MDD. Experienced and anticipated discrimination were assessed by the Discrimination and Stigma Scale (DISC). Countries were classified according to their rating on the Human Development Index (HDI). Multilevel negative binomial and Poisson models were used. Results: People living in 'very high HDI' countries reported higher discrimination than those in 'medium/low HDI' countries. Variation in reported discrimination across countries was only partially explained by individual-level variables. The contribution of country-level variables was significant for anticipated discrimination only. Conclusions: Contextual factors play an important role in anticipated discrimination. Country-specific interventions should be implemented to prevent discrimination towards people with MDD