Volume 47, No. 2/2009(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
A combination of cetirizine and pseudoephedrine has therapeutic benefits when compared to single drug treatment in allergic rhinitis
P. Badorrek, M. Dick, A. Schauerte, H. Hecker, R. Murdoch, B. Luettig, J.M. Hohlfeld and N. Krug
Abstract
P. Badorrek1, M. Dick1, A. Schauerte1, H. Hecker2, R. Murdoch3, B. Luettig1, J.M. Hohlfeld1 and N. Krug1
1Fraunhofer Institute of Toxicology and Experimental Medicine, 2Department of Biometrics, Hannover Medical School, Hannover, Germany, 3GlaxoSmithKline, Stevenage, UK
Antihistamines and nasal decongestants are well-established therapeutics in allergic rhinitis. However, no data are available which directly compare the effect size of the single substances with their combination in a single study including placebo (PLA) treatment. Objective: The aim of this study was to evaluate the effect of a combination of cetirizine (CET) and pseudoephedrine (PSE) and to compare it to treatment with CET or PSE alone and to PLA during grass pollen allergen challenge in an environmental challenge chamber (ECC). Material and methods: In a randomized, double-blind, placebo-controlled, four-way crossover study the effect of a combination of 10 mg CET with 120 mg PSE (CET + PSE) versus CET or PSE alone or PLA on symptoms, nasal flow, and nasal secretions was investigated in 49 patients with intermittent allergic rhinitis. Subjects underwent four 6-h pollen exposures in an ECC with administration of the drugs after 2 h. Results: The induction of nasal symptoms, nasal secretion and nasal obstruction (measured as nasal flow) during the first 2 h of pollen exposure was highly reproducible at the 4 consecutive exposures. The symptom of nasal obstruction was significantly reduced after treatment with CET + PSE compared to the treatment with CET or PSE alone or PLA (p < 0.0001). Furthermore, the combination treatment significantly reduced the total nasal symptom score (TNSS) and visual analogue scale score (VAS) compared to the single treatments or PLA. Nasal flow was significantly increased after treatment with CET + PSE and PSE and nasal secretions were significantly reduced by CET + PSE and CET without significant additional improvement of the combination therapy. Conclusion: The combination treatment with CET and PSE is more effective than treatment with single substances in subjects with allergic rhinitis.Correspondence to:
P. Badorrek, MD; Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Straße 1, 30625 Hannover, Germany
Email: philipp.badorrek@item.fraunhofer.de
Therapeutics
Inflammatory response to cardiopulmonary bypass with enoximone or steroids in patients undergoing myocardial revascularization: a preliminary report study
G. Santarpino, S. Caroleo, F. Onorati, G. Dimastromatteo, K. Abdalla, B. Amantea, E. Santangelo, E. Gulletta and A. Renzulli
Abstract
G. Santarpino1, S. Caroleo2, F. Onorati1, G. Dimastromatteo2, K. Abdalla2, B. Amantea2, E. Santangelo2, E. Gulletta2 and A. Renzulli3
1Cardiac Surgery Unit, 2Anesthesiology Unit, 3Clinical Pathology, Magna Graecia University of Catanzaro, Italy
Objective: Recent reports have showed an antiinflammatory effect of phosphodiesterase III inhibitors (PDEi) in patients undergoing cardiopulmonary bypass (CPB). We sought to evaluate the immunological and hemodynamic response to enoximone and methylprednisolone in patients undergoing CABG. Design: Prospective, randomized, controlled study. Setting: Cardiac surgery unit in a university hospital. Patients: 40 patients undergoing CPB-CABG. Interventions: Patients receive enoximone (20, Group A) or methylprednisolone (20, Group B). Measurements and main results: Hemodynamic response was evaluated by Swan-Ganz catheter serial measurements and perioperative Lactate and Troponin I leakage, immunological response was analyzed by IL-2, IL-4, IL-6, TNF-alpah, IFN-gamma, IL-10 before anesthetic induction (T0), at aortic-declamping (T1), at the end of surgery (T2), ITU admission (T3), 24 hs (T4) postoperatively. Morbidity and mortality were comparable between the two groups. Group A demonstrated higher cardiac index at T2 (2.93 l/min m2 vs 2.06, p < 0.001), at T3 (3.01 vs 2.18, p < 0.001), lower indexed systemic vascular resistance at T2 (2,044 dyne s cm–5 m–2 vs 3,132, p < 0.001). Except for higher TNF-alpha in Group B at T2 (15.89 vs 22.68, p = 0.005) proinflammatory cytokines were comparable. IL-10 was higher in Group B at any postoperative time (IL-10: T1 80.74 vs 143.3, p < 0.001, T2 165.7 vs 377.4, p < 0.001, T3 203.4 vs 443.5, p < 0,001, T4 251.8 vs 437.1, p < 0.001), whereas IL-4 and IFN-gamma proved higher in Group A at all time-points (IL-4: T1 45.9 vs 31.2, p = 0.008, T2 67.2 vs 39.7, p < 0.001, T3 77.9 vs 39.2, p < 0.001, T4 102.9 vs 42.2, p < 0.001. IFN-gamma: T1 25.8 vs 15.8, p < 0.001, T2 52.2 vs 30.3, p < 0.001, T3 78.4 vs 40.8, p < 0.001, T4 159.9 vs 67.4, p < 0.001). Conclusions: Despite comparable major clinical endpoints enoximone showed a different antiinflammatory pattern compared to methylprednisolone, however, the better hemodynamic response in enoximone compared to methylprednisolone suggests enoximone as a potential antiinflammatory tool to improve the outcome in cardiac surgery.Correspondence to:
F. Onorati, MD; Viale dei Pini 28, 80131 Napoli, Italy
Email: frankono@libero.it
Therapeutics
Comparison of the efficacy and safety of a novel meloxicam ophthalmic formulation with a reference diclofenac solution in cataract surgery
L.M. Baiza-Duran, J. Quintana-Hau, R. Tornero-Montaño, M.I. Ortiz, G. Castañeda-Hernández, L. Alanis-Villarreal, G. Avalos-Urzua, R. Bustos-Zermeño, J.L. Domene-Hinojosa, P. Gómez-Bastar, M.A. Ibañez-Her
Abstract
L.M. Baiza-Duran1, J. Quintana-Hau1, R. Tornero-Montaño1, M.I. Ortiz2, G. Castañeda-Hernández3, L. Alanis-Villarreal4, G. Avalos-Urzua4, R. Bustos-Zermeño4, J.L. Domene-Hinojosa4, P. Gómez-Bastar4, M.A. Ibañez-Her
1Clinical Research Department, Laboratorios Sophia S.A. de C.V. Guadalajara, Jalisco, 2Area Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, Hidalgo, 3Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados de Instituto Politécnico Nacional, México, 4Meloxicam in Cataract Surgery Study Group Mexico
A novel topical ophthalmic formulation of the preferential COX-2 inhibitor meloxicam has recently been developed. The purpose of the present study was to evaluate the efficacy and safety of this novel 0.03% meloxicam solution with regard to a reference 0.1% diclofenac formulation in a prospective, parallel, randomized, multicenter, double-blind study. Two groups of patients submitted to phacoemulsification with intraocular lens implantation were formed. Patients in one group were treated with meloxicam and those in the other group with diclofenac. Dosing was 1 drop t.i.d. for 30 days, beginning the first day after surgery, for both treatments. Inflammation was assessed by the presence of cells in the anterior chamber, anterior chamber flare, ciliary flush, photophobia and pain. Both treatments significantly reduced these indicators. Topical meloxicam and diclofenac produced a similar degree of burning sensation and conjunctival hyperemia. There was no significant difference between treatments in any of the measured parameters. It is concluded that the novel meloxicam solution is effective and safe. Meloxicam, however, did not offer any significant benefit over the diclofenac formulation in patients submitted to cataract surgery.Correspondence to:
L.M. Baiza-Duran, MD; Hidalgo 737, Guadalajara, Jalisco, Mexico
Email: drbvista@sophia.com.mx
Therapeutics
A PK/PD approach on the effects of clarithromycin against oral and nasal microbiota of healthy volunteers
A.P. Del Bortolo Ruenis, G.C. Nobre Franco, S. Baglie, R.H. Lopes Motta, R.P. Simões, P.L. Rosalen, L.M. Franco, R.A. Moreno, E. Abib Jr. and F.C. Groppo
Abstract
A.P. Del Bortolo Ruenis1, G.C. Nobre Franco2, S. Baglie6, R.H. Lopes Motta3, R.P. Simões1, P.L. Rosalen1, L.M. Franco4, R.A. Moreno5, E. Abib Jr.5 and F.C. Groppo1
1Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, 2University of Taubaté (UNITAU), Taubaté, 3Department of Physiological Sciences, São Leopoldo Dentistry School, Campinas, 4Faculty of Health Sciences, Methodist University of Piracicaba, Piracicaba, 5Synchrophar Assessoria e Desenvolvimento de Projetos Clínicos, Campinas, SP, 6Department of Pharmaceutical Sciences, Ponta Grossa State University, Ponta Grossa, PR, Brazil
Objective: To assess the pharmacokinetics of clarithromycin (CLR) and its effects on oral and nasal microbiota in healthy volunteers in an open, randomized, two-period crossover design. Methods: A single 500 mg oral dose of CLR (Group 1: Merck; Group 2: Klaricid) was administered observing a 1-week interval between doses. Blood samples were collected from pre-dose to 24 h. Plasmatic concentrations of CLR were quantified by the LC-MS-MS method. Saliva and nasal mucosa swabs were obtained previously and after 1.33, 2, 6 and 12 h of drug administration. Pharmacokinetics and PK/PD (t > MIC, %t > MIC and AUC0-24/MIC ratio) parameters were estimated. The microorganism counts were obtained on different culture media. Results: No statistically significant differences were observed between the two formulations (p > 0.05) regarding the pharmacokinetic parameters. Total microorganisms, staphylococci and streptococci counts did not show statistical differences (p > 0.05) between the two groups during each sampling time. Considering the microorganisms of each group, no statistically significant differences were found after drug administration, but all differed from pre-dose counts (p < 0.05). The observed t > MIC ranged from 14.45 h (± 1.69) to 1.19 h (± 2.17) considering MICs of 0.25 µg/ml and 2.0 µg/ml, respectively. There was no correlation between any t > MIC, %t > MIC or AUC0-24 and bacterial reduction (between 0- and 12-h periods). However, the profile of reduction of microorganisms in both saliva and nasal samples were compatible with high values of t > MIC verified for both clarithromycin formulations. Conclusion: Both formulations of clarithromycin had similar pharmacokinetics and efficacy.Correspondence to:
Prof. Dr. F.C. Groppo; Piracicaba Dental School, State University of Campinas (UNICAMP), Av. Limeira 901, ZIP 13414-903, Piracicaba, SP, Brazil
Email: fcgroppo@fop.unicamp.br
Drug Utilization
Appropriateness and surveillance of medication in a cohort of diabetic patients on polypharmacy
S. Harder, K. Saal, E. Blauth, M. Beyer and F.M. Gerlach
Abstract
S. Harder1, K. Saal2, E. Blauth2, M. Beyer2 and F.M. Gerlach2
1Institute for Clinical Pharmacology, 2Institute for General Practice, University Hospital Frankfurt am Main, Germany
Context: It is assumed that with increasing polypharmacy, medication surveillance by the General Practitioner (GP) and adherence to the therapy regimen by the patient will both decline. Aim of the study: We evaluated clinical and medication records taken from GP documentations in a cohort of 102 diabetic patients (48 f, 54 m, median age 70, range 39 – 81) with 3 or more chronic prescriptions. Patients were asked about their current medication and its tolerability by means of a structured telephone interview. Results: 45% of the patients received up to 6 medications, 36% 7 – 9 and 19% > 10. The main comorbidity was hypertension (93%) and symptomatic CAD (39%). The use of established medications (beta-blockers and ACE inhibitors) for these comorbidities was appropriate. Although 76% were eligible for a statin therapy, only 51% actually took a statin, and 28% had a dose lower than the defined daily dose. 68% of the patients had no prescriptions other than those recorded in the GP documentation, but 8% of the total number of medicines taken by the patients were not recorded in the GP’s database. 62% of patients took all the medication prescribed by the GP, while 7% of all medicines recorded in the GP’s database were not taken by the patients. In 10% of cases, an incompatible medication (defined in accordance with a consented list) was taken by the patient. 81% of patients regularly (twice per year) had their HbA1c checked, but only 62% had their potassium levels checked, despite the use of ACI and diuretics. Most patients knew the reason for taking at least one medication, but 18% knew this for less than half of their (multiple) medications. 70% of the patients said they had been informed about the possible risks of their medication by the GP, and 7% knew the risks for only one medication. Conclusion: In this cohort of patients on polypharmacy and with a high risk profile for adverse drug reactions, we found a mismatch between GPs’ documentation of prescriptions and the medication taken by the patient. Patients had no detailed knowledge about indications and almost no knowledge about risks. Although the overall performance of therapy (appropriateness) was deemed sufficient, there would appear to be room for improvement in order to fill information gaps and strive for stricter surveillance.Correspondence to:
Prof. Dr. med. S. Harder; Institute for Clinical Pharmacology, Pharmazentrum Frankfurt, University Hospital Frankfurt/Main, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
Email: harder@em.uni-frankfurt.de
Drug Utilization
Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe
J.D. Ma, N.M. Lawendy, T. Fullerton, P.J. Snyder,, A.N. Nafziger and J.S. Bertino Jr.
Abstract
J.D. Ma1, N.M. Lawendy2, T. Fullerton2, P.J. Snyder3,4,5, A.N. Nafziger1 and J.S. Bertino Jr.1
1Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, NY, 2Pfizer Global Research and Development (PGRD), New London, CT, 3Department of Psychology, University of Connecticut, Storrs, CT, 4Department of Neurology, University of Connecticut School of Medicine, Farmington, CT, 5Child Study Center, Yale University School of Medicine, New Haven, CT, USA
Phenotyping intestinal and hepatic cytochrome P450 (CYP) 3A activity with oral midazolam can be limited by midazolam-induced central nervous system (CNS) side effects. Determining methods to minimize CNS side effects optimizes use of midazolam as a CYP3A probe. Objective: The objective of this study was to determine the effect of intravenous (i.v.) flumazenil on midazolam apparent oral clearance (a surrogate marker of CYP3A activity). Midazolam pharmacodynamics were also evaluated. Methods: This was a randomized, double-blind, placebo-controlled, single-dose, two-way crossover study. 16 healthy volunteers (8 women) were concomitantly administered i.v. flumazenil 0.005 mg/kg or i.v. placebo and oral midazolam 0.075 mg/kg. Blood samples were obtained to determine midazolam and flumazenil plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMR) and 90% confidence intervals (90% CI). Baseline and post dose digit symbol substitution tests (DSST), Groton maze learning tests (GMLT), and Stanford sleepiness scales (SSS) were conducted. Results: Apparent oral clearance was 2,030 ± 651 and 1,939 ± 658 ml/min for the midazolam plus flumazenil and midazolam plus placebo groups. Equivalence in midazolam apparent oral clearance was observed (%GMR flumazenil/placebo, 90% CI 104.8, 94 – 116.6%). Flumazenil partially attenuated oral midazolam pharmacodynamics. Exploratory post hoc analyses revealed that midazolam exposure was 1.9-fold higher in men compared to women. Conclusion: i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.Correspondence to:
J.D. Ma, PhD; University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, 3855 Health Sciences Drive MC #0698, La Jolla, CA 92093-0698, USA
Email: joema@ucsd.edu
Adverse Drug Reactions – Case Report
Status epilepticus in a patient treated with olanzapine and mirtazapine
S. Spyridi, S. Sokolaki, J. Nimatoudis, A. Iacovides and G. Kaprinis
Abstract
S. Spyridi, S. Sokolaki, J. Nimatoudis, A. Iacovides and G. Kaprinis
C’Department of Psychiatry, Faculty of Medicine, Aristotle University of Thessaloniki, Greece
Objective: Few cases of seizures associated with olanzapine therapy and even fewer with mirtazapine have been published, most of them in patients with confounding risk factors. Our objective was to report a case of Status epilepticus in a patient receiving olanzapine and mirtazapine, with no previous history of seizure and no confirmed underlying cause for seizure. Case summary: A 48-year-old white, psychotic woman developed generalized tonic-clonic seizures that progressed to Status epilepticus during hospitalization. 4 days before the incident, mirtazapine (30 mg) was added to the treatment, while 2 days before the incident, the treatment switched from quetiapine to olanzapine, and mirtazapine was increased to 60 mg. No other toxic, metabolic, electrolyte or anatomic abnormality was identified. After discontinuation of olanzapine, the patient remained seizure-free. Conclusion: To our knowledge, this is the second reported case of Status epilepticus that has been associated with the use of olanzapine, while only one report of seizures, but none of Status epilepticus connected to mirtazapine is found in the literature. Although olanzapine has infrequently been associated with epileptogenic risk, it should be used cautiously especially when concomitant medication or other predisposing factors exist.Correspondence to:
S. Spyridi, MD; C’Department of Psychiatry, AHEPA University Hospital, St. Kyriakidi 1, 54636, Thessaloniki, Greece
Email: spyridesstella@yahoo.com
Bioavailability Section
Bioequivalence evaluation of two strengths of risperidone tablet formulations in healthy volunteers
M. Cánovas, J. Delgadillo, F. Torres, N. Riba, J. Cebrecos, P. Pelagio and F. Cabré
Abstract
M. Cánovas1, J. Delgadillo2, F. Torres3, N. Riba4, J. Cebrecos5, P. Pelagio6 and F. Cabré1
1R&D area, Laboratorios Lesvi, S.L., Invent Farma Group, 2Vita-Invest, S.A., 3Laboratori de Bioestadistica i Epidemiologia, Universitat Autónoma de Barcelona, Servei de Farmacologia Clínica, IDIBAPS, Hospital Clinic, Barcelona, 4Servei de Farmacologia Clínica UASP, Hospital Clinic, Barcelona, 5Phase I Unit of Laboratorio Dr. F. Echevarne Análisis, S.A., 6Bioanalysis-Pharmacokinetic Unit of Laboratorio Dr. F. Echevarne Análisis S.A., Barcelona, Spain
Objective: The objective of the study was to evaluate bioequivalence of two strengths (1 and 2 mg) of oral risperidone tablet formulations (test product manufactured by Vita-Invest, S.A., Barcelona, Spain, reference product manufactured by Janssen-Cilag Ltd., UK). Subjects and methods: In each of the 2 studies, 30 healthy volunteers were administered 1 or 2 mg, respectively, of test or reference formulation under fasting conditions in an open, two-way crossover, controlled, randomized and single-site fashion. Blood withdrawal was performed prior to dosing as well as 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 24 h, 48 h, 72 h, and 96 h after drug administration. Plasma concentrations of risperidone and its metabolite 9-hydroxy-risperidone were analyzed using LC/MS/MS. Descriptive data of AUC0-t, AUC0-¥, Cmax, and Cmax/AUC0-¥ were log-transformed to evaluate bioequivalence based on the ratios of the geometric means of test and reference formulations. tmax was analyzed using nonparametric methods. Results: The results show that in both studies, 1 and 2 mg formulations, the 90% confidence intervals for the geometric means ratios of the test and reference products for both the parent compound risperidone and its metabolite 9-hydroxy-risperidone were all within the bioequivalence acceptance criteria of 0.80 – 1.25 of the European CPMP and the US FDA guidelines, with the exception of tmax for risperidone parent compound in the 2 mg formulation, which was slightly suprabioequivalent for test formulation. Conclusion: This study demonstrated the bioequivalence between the test and the reference product of risperidone of both 1 and 2 mg formulations. Both formulations of each strength may, therefore, be prescribed interchangeably.Correspondence to:
M. Cánovas, PhD; Biological Development Manager of Laboratorios Lesvi, S.L., Avda.,
Barcelona 69, 08970 Sant Joan Despí, Barcelona, Spain
Email: mcanovas@lesvi.com
Bioavailability Section
A simple high-performance liquid chromatographic method for the determination of diclofenac in human plasma: application to a comparative bioavailability study
H.M. Rigato, R.A. Moreno, E.Z. Orpinelli, B.C. Borges, C.E. Sverdloff, J. Pedrazzoli Jr. and N.C. Borges,
Abstract
H.M. Rigato1, R.A. Moreno2,3, E.Z. Orpinelli3, B.C. Borges4, C.E. Sverdloff2, J. Pedrazzoli Jr.5 and N.C. Borges1,3
1Department of Medical Clinic, 2Department of Pharmacology, State University of Campinas, 3Synchrophar Assessoria e Desenvolvimento de Projetos Clínicos, Campinas, SP, 4College of Medicine, Pontificia Universidade Católica, Sorocaba, SP, 5Integrated Unit of Pharmacology and Gastroenterology, Sao Francisco University Medical School, Bragança Paulista/SP, Brazil
A rapid, sensitive and specific method to quantify diclofenac in human plasma using indomethacin as the internal standard (IS) is described. Samples were extracted using protein precipitation protocol and analyzed by high performance liquid chromatography coupled to ultraviolet detection at 276 nm. Chromatography was performed isocratically with a run time of 8.0 min and the retention time observed for diclofenac and IS was 6.0 and 7.0 min, respectively. The calibration curve was linear over the range 50 – 4,000 ng/ml (r2 > 0.9995). The mean recovery of diclofenac ranged from 88.76 to 99.14% and the limit of quantification was 50 ng/ml. Intrabatch precision and accuracy (%CV) of the method ranged from 0.86 to 7.60%, and 99.34 to 103.8%, respectively. Interbatch precision (%CV) and accuracy ranged from 0.26 to 11.4%, and 92.00 to 105.34%, respectively. This HPLC method was used to determine the relative pharmacokinetics of two diclofenac-cholestyramine 140 mg capsule formulations. The study was conducted using an open, randomized and crossover design with a 1-week washout interval. A single 140 mg dose (equivalent to 70 mg of diclofenac) of each formulation was administered to 26 healthy volunteers (13 males and 13 females) and blood samples were obtained over 12-h interval. The geometric mean of diclofenac-cholestyramine/Flotac® ratio was 90.53% for AUC0-12 and 100.22% for Cmax. Since the 90% CI for Cmax and AUCs ratios were all inside the 80 – 125% interval, it was concluded that the diclofenac-cholestyramine test formulation is bioequivalent to Flotac® regarding both the rate and the extent of absorption.Correspondence to:
N. Carter Borges, MD, MSc, PhD; 24 Cesar Bierrenbach Street, Campinas, SP 13015-025, Brazil
Email: medney@synchrophar.com
