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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (497-503)

Non-concurrent dosing attenuates the pharmacokinetic interaction between amlodipine and simvastatin

C.G. Park¹, H. Lee²*, J.W. Choi³, S.J. Lee⁴, S.H. Kim¹ and H.E. Lim¹

¹Cardiovascular Center, Guro Hospital, Korea University, Seoul, South Korea, ²UC Washington Center for Drug Development Science, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, Washington, DC, USA, ³R&D Center, Hanall Pharmaceutical Co., Ltd., Gyeonggi-do and ⁴R&D Center, Hanall Pharmaceutical Co., Ltd., Daejeon, South Korea
Objectives: To explore if non-concurrent amlodipine dosing results in less drug interaction, the pharmacokinetic profiles, safety and efficacy endpoints were assessed following repeated doses of simvastatin, co-administered concurrently or non-concurrently with amlodipine in patients with coexisting hypertension and hyperlipidemia. Methods: Seventeen patients randomly received daily doses of 20 mg simvastatin and 5 mg amlodipine for 6 weeks, either with both drugs at 7:00 PM (concurrent) or with simvastatin at 7:00 PM followed by amlodipine at 11:00 PM (non-concurrent). The maximum plasma concentration (C_max) and the area under the concentration-time curve up to the last quantifiable concentration (AUC_last) were estimated at steady state. Lipid profiles and blood pressure values were also compared between the concurrent and non-concurrent groups. Results: The C_max and AUC_last and of simvastatin acid in the non-concurrent amlodipine dosing group were 63.2% and 66.0%, respectively, of the values obtained in the concurrent group (1.2 ± 1.0 vs. 1.9 ± 0.9 ng/ml and 10.3 ± 8.3 vs. 15.6 ± 7.5 h ng/ml, respectively, mean ± standard deviation). Changes from baseline in lipid profile and blood pressure were comparable between the groups. Conclusions: Non-concurrent dosing may be a useful and safe therapeutic option for patients who require two or more drugs administered concomitantly, but who are likely to develop unwanted drug interactions.Correspondence to:
H. Lee, MD, PhD
Associate Adjunct Professor
Director Center for Drug Development Science
Department of Biopharmaceutical
Sciences
School of Pharmacy
University of California
San Francisco, UC Washington Center
1608 Rhode Island Avenue, NW
Washington, DC 20036, USA
Email: Howard.Lee@ucsf.edu

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (504-508)

Screening for G71R mutation of the UDP-glucuronosyltransferase 1 (UGT1A1) gene in neonates with pathologic and prolonged hyperbilirubinemia in Turkey

I. Kilic¹, A. Koseler², I. Cakaloz¹ and E. Atalay²

¹Department of Pediatrics and ²Department of Biophysics, Pamukkale University, Faculty of Medicine, Denizli, Turkey
Objective: Whether the G71R mutation contributes to the high incidence of neonatal indirect hyperbilirubinemia in Turkey remains unknown. In this study we screened for G71R mutation of the UGT1A1 gene in prolonged and pathological hyperbilirubinemia with unexplained etiology in newborns in Turkey. Method: In this study, we screened the G71R mutation of the UGT1A1 gene in 70 Turkish newborn infants: 23 infants with pathologic hyperbilirubinemia, 24 infants with prolonged hyperbilirubinemia and 23 infants without pathologic and prolonged hyperbilirubinemia. Mutations were detected by non-radioactive dye terminator cycle sequencing. Results: In these seventy infants enrolled in this study, there were 62 with G/G (88.5 %), 8 with G/R (11.5%), and none with R/R. Two (8.7%) infants in the pathologic jaundice group and 5 (20.8 %) infants in the prolonged indirect hyperbilirubinemia, one (4.3%) infant in the control group had G/R genotype. Although G/R mutation is higher in the prolonged indirect hyperbilirubinemia group, genotypic distributions among the three groups were not statistically significant. The allele frequency of the G71R mutation was found 4.3%, 10.4%, and 2.2% in the pathologic jaundice group, in the prolonged indirect hyperbilirubinemia group, and in the control group respectively. When we compared the peak serum total bilirubin concentrations of neonates according to their genotypes, the peak bilirubin concentration was higher in G/R genotype than G/G genotype. Conclusions: G71R mutation of UGT1A1 gene is also present in Turkish population and the presence of this mutation is associated with otherwise unexplained pathological or prolonged neonatal hyperbilirubinemia in a Turkish population.Correspondence to:
I. Kilic
Professor in Pediatrics
Division of Neonatology
Pamukkale University
Faculty of Medicine
Denizli, Turkey
Email: ikilic@pau.edu.tr

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (509-513)

Comparison of the therapeutic effects of leflunomide and mycophenolate mofetil in the treatment of immunoglobulin A nephropathy manifesting with nephrotic syndrome

X.W. Liu¹*, D.M. Li²*, G.S. Xu¹ and S.R. Sun¹

¹Department of Nephrology, and ²Information Section, Xijing Hospital, The Fourth Military Medical University, Xi’an, China

*The first two authors contributed equally to this work.
Objective: To evaluate the therapeutic effects and safety of a combination therapy of leflunomide (LEF) and prednisone for the treatment of immunoglobulin A (IgA) nephropathy manifesting with nephrotic syndrome. Methods: 40 patients with IgA nephropathy manifesting with nephrotic syndrome were randomly divided into two groups. The treatment group was administered with a combination therapy of prednisone and LEF, and the control group with a combination therapy of prednisone and MMF. For the following comparison 24-h urinary protein excretion and the serum levels of albumin, cholesterol, and creatinine before and after the therapy were assessed. Results: In the treatment group, the medication was markedly effective in 5 cases and effective in 7 cases; the total efficacy rate was 60.0%. In the control group, the treatment was markedly effective in 5 cases and effective in 8 cases; the total efficacy rate was 65.0%. The IgA levels in both groups decreased after therapy. There were no significant differences between the results for the two groups (p > 0.05). The treatments were well tolerated in both groups. Conclusion: LEF is a safe and effective drug for the treatment of IgA nephropathy manifesting with nephrotic syndrome.Correspondence to:
X.W. Liu and S.R. Sun
Department of Nephrology
Xijing Hospital
The Fourth Military Medical University
Xi’an 710032, China
Email: liuxiaow@fmmu.edu.cn

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (514-516)

Irreversible sensorineural hearing loss: an unusual side effect of non-steroidal anti-inflammatory drugs

S. Ahmad, A. Bhanji, S. Pal and M. Karim

Department of Renal Medicine, Norfolk and Norwich University Hospital, Norwich, UK
Objective: Non-steroidal anti-inflammatory drugs are known to have a number of potential side effects. Here we report a case demonstrating an uncommon complication, irreversible sensorineural deafness. Case history: A 41-year-old man with pre-existing cardiac and renal dysfunction (for which his regular medications included furosemide) presumed secondary to a viral myocarditis developed acute sensorineural hearing loss 5 days after commencing treatment with indomethacin 25 mg tds for acute gout. His hearing loss was preceded by the development of tinnitus and failed to recover. Conclusion: Permanent deafness is a rare but serious side effect of NSAIDs. Tinnitus developing in patients on these agents should be regarded as a potential warning sign of impending irreversible ototoxicity.Correspondence to:
M. Karim
Department of Renal Medicine
Norfolk and Norwich University Hospital
Colney Lane, Norwich NR4 7UY, UK
Email: mkarim@doctors.org.uk

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (517-524)

Prevalence of iatrogenic admissions to the Departments of Medicine/Cardiology/ Pulmonology in a 1,250 bed general hospital

R. Atiqi¹, E. van Bommel¹, T.J. Cleophas²,³ and A.H. Zwinderman²,⁴

¹Department of Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands, ²European Interuniversity College of Pharmaceutical Medicine, Lyon, France, ³Department of Statistics, Circulation, Boston, MA, USA and ⁴Department of Biostatistics, Academic Medical Center, Amsterdam, Netherlands
A recent meta-analysis in this journal showed incidences between 3.4 and 33.9%. Studies performed by pharmacists and epidemiologists produced lower incidences than internists’ studies. We reassessed the prevalence of iatrogenic admissions in a study of internists. Iatrogenic disease was defined as adverse drug reactions according to the World Health Organization Definition and complications induced by non-drug medical interventions. Subsequent admissions at the Departments of Medicine/Cardiology/Pulmonology in a 1,250 bed general hospital in the Netherlands from May 2007 to August 2007 were studied. 2,000 consecutive admissions were studied: 576 (29%, 26 – 32%) were classified as possibly iatrogenic; out of these 380 (19%, 17 – 22%) as definitely iatrogenic, out of whom 229 (12%, 10 – 14%) had already been classified as iatrogenic by the admitting physicians. Patients with cardiac disease, hypertension, gastrointestinal conditions, anticoagulant treatment and use of NSAIDs were, particularly, at risk of iatrogenic admission with percentages of 22 (16 – 24), 13 (11 – 18), 12 (9 – 15), and 7 (5 – 11) %. An independent predictor of iatrogenic admissions was age with an odds ratio of 1.27 per 10 years (p = 0.0001). 1. At least 19% of admissions to the Departments of Internal Medicine/Cardiology/Pulmonology, and, maybe, even percentages up to 29% were due to adverse drug effects. 2. A large difference between the numbers of iatrogenic admission according to the physicians in charge of admission and the investigators, 229 versus 380 patients, was observed. 3. Most often iatrogenic admissions were observed with cardiac disease, hypertension, gastrointestinal conditions, anticoagulant treatment, and use of NSAIDs.Correspondence to:
Prof. Dr. T.J. Cleophas
Department of Statistics
Circulation, Boston, MA, USA
c/o Department Medicine, Box 444
3300 AK Dordrecht, The Netherlands
Email: ajm.cleophas@wxs.nl

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (525-533)

Population pharmacokinetics of vancomycin in adult and geriatric patients: comparison of eleven approaches

J.L. Sánchez¹, A.R. Dominguez², J.R. Lane², P.O. Anderson², E.V. Capparelli² and J.M. Cornejo-Bravo¹

¹Universidad Autónoma de Baja California, Facultad de Ciencias Químicas e Ingeniería,Tijuana, Mexico, and ²University of California, San Diego, Department of Pharmacy, San Diego, CA, USA
Purpose: A vancomycin population pharmacokinetic prediction model for adult and elderly patients was developed using NONMEM. The predictability of the model was studied and compared with ten other models. Methods: Data were collected from routine care of 141 subjects. NONMEM was used to derive a population model. After internal evaluation using the bootstrap technique, external validation was studied using an independent dataset that consisted of 95 subjects; a statistical comparison of precision and bias was conducted. Results: A two-compartment open model was derived with body weight, age, and CL_cr as covariates. The bootstrap process showed stability of the model. A comparison of subjects older and younger than 65 years found that the older group had a mean clearance of 2.24 (± 1.2) l/h compared to 4.03 (± 1.7) l/h, and a peripheral volume of 43.7 (± 5.1) l compared to 28.4 (± 5.3) l compared to younger patients. These values were modeled using CL_cr in the clearance equation and V_d as a function of age. The eleven models studied showed a bias in predicting serum concentrations from the test database that ranged from 0.35 mg/l to –5.93 mg/l. Precision ranged from 4.53 mg/l to 8.05 mg/l. Our method ranked in fourth place overall and when compared statistically its bias was different from the method that ranked in second place by –1.45 (95% CI –2.46, –0.42; p = 0.005), and different from all the methods that ranked worse. The only difference in precision was with the method that ranked in eleventh place with a relative precision of 0.49 (95% CI 0.27, 0.70; p < 0.001). Conclusions: A two-compartment open model fitted the data with weight, age, and CL_cr as covariates. The derived method ranked in fourth place overall. The two-compartment nature of two of the equations studied did not provide an advantage. A future study with more data in the distribution phase could provide a model with better predictability.Correspondence to:
A.R. Dominguez, PharmD, M.A.S.
University of California
San Diego Department of Pharmacy
20 W Arbor Drive
San Diego, CA 92103-8765, USA
Email: adominguez@ucsd.edu

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (534-541)

Clinical factors affecting the efficacy of vancomycin in methicillin-resistant Staphylococcus aureus pneumonia

N. Shimazaki¹, H. Hayashi², K. Umeda¹, T. Aoyama², H. Iida³ and Y. Matsumoto²

¹Department of Pharmacy, International Goodwill Hospital, Yokohama, Kanagawa, ²Department of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, and ³Department of Neurosurgery and Infection Control Committee, International Goodwill Hospital, Yokohama, Kanagawa, Japan
Objective: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Patients with risk factors such as long hospital admission and compromised hosts are prone to MRSA infection, particularly MRSA pneumonia that is not resolved effectively and causes significant mortality. To identify the factors affecting the efficacy of vancomycin (VCM) therapy on MRSA pneumonia, a retrospective investigation was carried out. Methods: Severity rating of pneumonia, pharmacokinetic parameters of VCM, clinical improvement following VCM therapy, clinical data and patient’s background were investigated in 40 patients from January 2003 to March 2008. The outcome was evaluated 30 days after the initiation of VCM therapy, and multivariate logistic regression analysis was performed. Results: The 30 day mortality rate was 15.0% (6 patients). As a result of multivariate logistic regression analysis, underlying malignancy and parenteral nutrition as the route of feeding during VCM therapy (odds ratio (OR) = 22.3, 95% confidence interval (CI) = 1.55 – 322; OR = 12.6, 95% CI = 1.15 – 139, respectively) were found to be significant factors affecting the survival. No pharmacokinetic parameters of VCM and severity of pneumonia were significant. Conclusion: Underlying malignancy and parenteral nutrition, which were associated with nutrition and the immune system, were found to affect the survival after 30 days of VCM therapy.Correspondence to:
N. Shimazaki, MSc
Department of Pharmacy
International Goodwill Hospital
1-28-1, Nishigaoka, Izumi-ku
Yokohama, Kanagawa 245-0006, Japan
Email: shimazaki-nobuo@shinzen.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (542-548)

Remifentanil in combination with ketamine versus remifentanil in spinal fusion surgery – a double blind study

B.A. Hadi¹, R. Al Ramadani¹, R. Daas², I. Naylor³ and R. Zelkó⁴

¹Faculty of Pharmacy, Philadelphia University, ²Arab Medical Center, Amman, Jordan, ³School of Pharmacy, Bradford University, Bradford, UK, and ⁴University Pharmacy, Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary
Aim: This study is aimed at conducting a program for two different anesthetic methods used during a spinal fusion surgery to ensure better intra-operative hemodynamic stability and post-operative pain control. Methods: A prospective, randomized, double blind study in patients scheduled for spinal fusion surgery, who were randomly allocated to two groups, G1 and G2, (n = 15 per group), class I – II ASA, was carried out. Both groups received pre-operatively midazolam, followed intra-operatively by propofol, sevoflurane, atracurium, and either remifentanil infusion 0.2 µg/kg/min (G1), or the same dose of remifentanil infusion and low doses of ketamine infusion 1 µg/ kg/min (G2) anesthetics, antidote medication and post-operative morphine doses. HR, MAP, vital signs, surgical bleeding, urine output, duration of surgery and duration of anesthesia were recorded. In a 24-h recovery period in a post-anesthesia care unit (PACU) the recovery time, the first pain score and analgesic requirements were measured. Results: Intra-operative HR and arterial BP were significantly less (p < 0.05) in G1 as compared to G2. In the PACU the first pain scores were significantly less (p < 0.05) in G2 than in G1. The time for the first patient analgesia demand dose was greater in G2, as also morphine consumption which was greater in G1 than G2 (p < 0.05). Other results were the same. None of the patients had any adverse drug reaction. Conclusions: Adding low doses of ketamine hydrochloride could be a routine therapy to improve the hemodynamic stability and reduce the post-operative morphine consumption during spinal fusion surgery.Correspondence to:
B.A. Hadi, Clinical Pharmacist
Faculty of Pharmacy
Philadelphia University
P.O. Box 1, Postal Code 19392, Amman, Jordan
Email: Bushra_abdul@yahoo.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (549-551)

Toxic epidermal necrolysis associated with carvedilol treatment

V. Vlahovic-Palcevski¹, S. Milic², G. Hauser², A. Protic³, Ž. Župan⁴, M. Reljic³ and D. Štimac²

¹Unit of Clinical Pharmacology, ²Department of Internal Medicine, University Hospital Rijeka, University of Rijeka Medical Faculty, ³Department of Anesthesiology and Intensive Care Unit, University Hospital Rijeka and ⁴Department of Anesthesiology and Intensive Care Unit, University Hospital Rijeka, University of Rijeka Medical Faculty, Rijeka, Croatia
Objective: To report a case of fatal toxic epidermal necrolysis associated with carvedilol treatment. Case summary: Two days after the initiation of carvedilol treatment, a 70-year old woman presented with skin eruptions in the form of maculous rash with blisters that rapidly progressed to epidermal necrolysis. Although the suspected drug was withdrawn, the reaction was extremely rapid in its development with fatal outcome. Discussion: Carvedilol is not a drug commonly associated with TEN. To our knowledge there are no cases of carvedilol related TEN reported in the literature. Conclusion: Because of the close temporal relationship between the initiation of carvedilol treatment and the appearance of skin eruptions, and because carvedilol was the only new medication the patient had taken, the etiology of TEN was most likely a reaction to this drug. Physicians should be aware of this extremely rare but serious ADR.Correspondence to:
V. Vlahovic-Palcevski, MD, PhD
Unit of Clinical Pharmacology
University Hospital Rijeka
Krešimirova 42
51000 Rijeka, Croatia
Email: vvlahovic@inet.hr

Abstract

The potential anti-atherosclerotic effect of itraconazole – a medical hypothesis

A. Feily

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 8/2010 (554-562)

Comparative bioavailability of two escitalopram formulations in healthy human volunteers

G.D. Mendes¹,²,³, T. Babadopulos³, F.R. Bau¹, L.S. Chen³ and G. De Nucci¹,⁴

¹Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, ²Faculty of Odontology, University Camilo Castelo Branco (UNICASTELO), São Paulo, ³Galeno Research Unit, Latino Coelho St., Campinas, Brazil, and ⁴College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
Objective: To assess the bioequivalence of two escitalopram formulations (Test formulation: escitalopram (10 mg tablet) manufactured by Apsen Farmacêutica S.A.) Reference formulation: escitalopram (Lexapro^®; 10 mg tablet) from Lundbeck Brasil Ltda) in healthy volunteers of both sexes. Methods: The study was conducted using an open, randomized, two-period crossover design with at least a 21-day washout interval. Plasma samples were obtained over a 168 h period. Plasma escitalopram concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). The following pharmacokinetic parameters were obtained from the escitalopram plasma concentration vs. time curves: AUC_last, AUC_inf and C_max. Results: The limit of quantification for escitalopram was 0.2 ng.ml^-1. The geometric mean with corresponding 90% confidence interval (CI) for Test/Reference percent ratios were 97.35% (90% CI = 90.28 – 104.96%) for C_max, 99.60% (90% CI = 92.93 – 106.74%) for AUC_last and 99.92% (90% CI = 93.34 – 106.97%) for AUC_inf. Conclusion: Since the 90% CI for AUC_last, AUC_inf and C_max ratios were within the 80 – 125% interval proposed by the US FDA, it was concluded that escitalopram formulation manufactured by Apsen Farmacêutica S.A. is bioequivalent to the Lexapro^® formulation in regard to both the rate and the extent of absorption.Correspondence to:
G.D. Mendes, DDS, PhD
415 Jesuino Marcondes Machado Ave
Campinas, SP 13092-320, Brazil
Email: gugamendes@terra.com.br

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Volume 48, No. 8/2010(August)