Volume 47, No. 7/2009(July)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
“One-size-fits-all” in bioavailability and bioequivalence testing?
H.H. Blume
Original Reserach
Oral immunoglobulin induces mononuclear cell apoptosis in patients suffering from idiopathic chronic pain syndrome: Results from a pilot study
A.M. Waaga-Gasser, M. Gasser, M. Stock, M. Grimm and G. Sprotte
Abstract
A.M. Waaga-Gasser1, M. Gasser2, M. Stock3, M. Grimm1 and G. Sprotte3
1Department of Surgery I, Molecular Oncology and Immunology, 2Department of Surgery I and 3Pain Relief Center, Department of Anaesthesia and Critical Care, University of Wuerzburg, Germany
Objective: The objective of this clinical pilot study was to examine the induction of apoptosis in mononuclear cells on treatment of patients with chronic pain syndrome with oral immunoglobulin produced from bovine colostrum (BCC). Design: The 4 patients suffering from chronic idiopathic pain (idiopathic facial pain, CRPS or fibromyalgia) who were enrolled in the study had previously successfully been treated with BCC (varying individual doses). Mononuclear cells from peripheral blood were analyzed for representative cytokines in the serum as well as by TUNEL-assay to detect apoptotic cellular events 14 days after the last treatment with BCC and 14 days after restarting the treatment protocol with BCC. The clinical response (pain and quality of life parameters using a visual analogue scale (VAS)) were determined regularly in each patient. Results: The findings showed a disturbed apoptosis homeostasis in 3 of the 4 patients. These results were accompanied by a relief of the pain symptoms. The 4th patient was found not to need any further analgetic treatment since she demonstrated only nonsignificant changes in her laboratory screening and immunological parameters and by the end of the study she was also completely free of pain (long-term treatment with BCC). Conclusions: In spite of the low patient number, the results were obtained with a sufficiently high degree of control because of the study design. The agreement of the clinical data with our laboratory measurements suggests that the induction of apoptotic events in mononuclear cells is the result of the dominant immunological effects of BCC treatment.Correspondence to:
Prof. Dr. G. Sprotte
Pain Relief Centre
Department of Anaesthesia and Critical Care
University of Wuerzburg
Josef-Schneider-Straße 6
97080 Wuerzburg, Germany
Email: Sprotte_G@klinik.uni-wuerzburg.de
Original Research
Target blood pressure attainment in diabetic hypertensive patients: need for more diuretics?
W.M. Sweileh
Abstract
W.M. Sweileh
College of Pharmacy, An-Najah National University, Palestine
Objective: To determine target blood pressure attainment and to evaluate blood pressure control relative to type of therapy among diabetic hypertensive patients. Methodology: An observational retrospective study of all diabetic hypertensive patients visiting Al-Watani governmental medical center from August 01, 2006 until August 01, 2007. The blood pressure (BP) measurement made during the patient’s recent visit and documented in the medical files was used in the study. Controlled BP values for hypertensive patients with diabetes mellitus were defined per JNC 7 guidelines: 130/80 mmHg or lower. Proportions of use of 5 different antihypertensive drug classes were compared between patients with controlled and uncontrolled BP. Results: Of the 311 patients, 79 (25.4%) had their BP controlled. No significant differences in age, gender, body weight, duration of hypertension or diabetes, renal function, average number of anti-hypertensive medications and doses of most commonly reported antihypertensive medications were found between controlled and uncontrolled BP groups. ACE-I/ARB was the most commonly used drug class in both groups. Overall, the use of ACE-I/ARB, beta-blockers, calcium channel blockers, alpha-blockers and multi drug regimens were also not significantly different between the controlled and uncontrolled groups. However, overall use of diuretics was significantly higher in controlled group than uncontrolled group (59.5% versus 45.7%, p < 0.001). Conclusion: Despite the common use of ACE-I/ ARB as recommended per JNC 7th report, the majority of the patients had uncontrolled BP. Diuretics is an important drug class in attaining target BP. Use of diuretics in combination with ACE-I as well as drug compliance needs to be emphasized and encouraged.Correspondence to:
W.M. Sweileh, PhD, Associate Professor
Clinical Pharmacology, College of Pharmacy
An-Najah National University, Palestine
Email: waleedsweileh@yahoo.com
Original Research
Once daily monotherapy with prolonged-release valproate minitablets given in the evening – a chronopharmacological study
W. Graf, B. Fraunberger, T. Yang, F. Kerling, E. Pauli and H. Stefan
Abstract
W. Graf1, B. Fraunberger1, T. Yang2, F. Kerling1, E. Pauli1 and H. Stefan1
1Department of Neurology – Epilepsy Center, University Erlangen-Nürnberg, Erlangen, Germany, and 2Department of Neurology – West China Hospital, Sichuan-University, PR China
Background: Chronopharmacological investigations concerning efficacy, side effects and circadian serum concentration are lacking for many antiepileptic drugs. Patients and methods: In this study 27 patients with focal or generalized epilepsy receiving a single dosage of prolonged-release valproate given in the evening were included. The valproate serum concentration over a course of 24 hours and their correlation with the value measured at 9:00 am was examined. In approximately 60% of the patients the serum level measured at 9:00 am corresponded to the peak value. In an additional 33% of the patients the peak value was reached at either 12:00 midnight or at 3:00 am. Results: During the course of the day all patients showed on average an additional decline in these values compared to the 9:00 am serum level of 41%. In only a third of the patients did the 24-hour profile exhibit an average increase that exceeded the 9:00 am value by as much as 4%. In the case of the 24-hour serum profile, when the daily dosage was weight-correlated no values for the normal dosage range (18 – 24 mg/kg body weight) gave values that exceeded or fell below the so-called therapeutic serum level range (50 – 100 mg/l). Neither seizures nor new adverse reactions occurred in this group. Conclusion: Therefore, in the case of adults and young adults, therapy with valproate prolonged-release at a dose rate of 24 mg/kg preparation given as a single dosage in the evening will be sufficient for seizure control in most patients. The low-dosage group (10 – 17 mg/kg body weight) exhibited values that fell below this range in the afternoon and early evening. The results are discussed with regards to the treatment in young adults and the elderly.Correspondence to:
Prof. Dr. H. Stefan
Epilepsy Center
University Erlangen
Schwabachanlage 6
91054 Erlangen, Germany
Email: hermann.stefan@neuro.imed.uni-erlangen.de
Original Research
The effect on proteinuria and urinary NAG of treatment with meloxicam in chronic glomerular disease patients – a preliminary study
G. Gluhovschi, S. Velciov, A. Kaycsa, V. Trandafirescu, L. Petrica, G. Bozdog, C. Gluhovschi, F. Bob and C. Vernic
Abstract
G. Gluhovschi1, S. Velciov1, A. Kaycsa2, V. Trandafirescu1, L. Petrica1, G. Bozdog1, C. Gluhovschi1, F. Bob1 and C. Vernic3
1Deparment of Nephrology, 2Dept. of Biochemistry and 3Dept. of Statistics, University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) that primarily has an antiproteinuric effect and is used for the treatment of chronic glomerular diseases. In chronic glomerular disease (CGD), proteinuria is involved in the production of tubulo-interstitial lesions and has an important role in their progression. CGD improves with steroid therapy and immunosuppression. In the case of a favorable outcome, a reduction in proteinuria is also attained. In some situations, this therapy is prohibited, requiring alternative medication. NSAIDs are one class of these alternative drugs; in addition to having anti-inflammatory actions, they also have antiproteinuric effects. The aim of the study has been to assess the effect of the anti-inflammatory treatment with meloxicam upon proteinuria as well as upon tubular lesions by determining urinary NAG in its dynamics. The study was performed on 12 patients with CGD, 6 of them with nephrotic syndrome. On all patients we administered treatment with meloxicam 15 mg/day, 30 days. On all patients we performed proteinuria and urinary N-acetyl b D glucosaminidase (NAG) at the beginning, after 7 days and after 30 days of treatment. A 24-hour urine collection was taken from all patients. The urinary protein concentration was determined with the use of the Dimension (Dade Behring, Inc., Newark, DE, USA) clinical chemistry system UCFP method. We found a decrease of proteinuria under treatment from 2.85 ± 1.69 g/24h to 1.53 ± 0.83 g/24h, which was significantly lower, compared to the initial measurement (p = 0.01878). After 30 days of treatment with meloxicam, urinary NAG decreased from 10.6 ± 12.56 U/g creatinine to 6.44 ± 7 U/g, a decrease that was statistically non-significant. We observed a strong correlation between initial urinary NAG and initial proteinuria ri = 0.924, p < 0.001 and between final urinary NAG and final proteinuria rf = 0.856, p < 0.001. Our study revealed the favorable effect of meloxicam on patients with CGD on a 30-day treatment phase reflected on the evolution of proteinuria. Only in one case we did reveal a possible deleterious effect of this treatment. The assessment of the effect on tubulo-interstitial lesions in this short treatment period through urinary NAG assessment indicated only a modest and statistically non-significant response. We consider that meloxicam can be a useful drug in the treatment of proteinuric glomerular diseases.Correspondence to:
Prof. Dr. G. Gluhovschi
Calea Aradului 8 Ap. 16
300088 Timisoara, Romania
Email: ggluhovschi@yahoo.com
Original Research
The influence of beta-blockade on the hemodynamic effects of levosimendan in elderly (>= 70 years) patients with acutely decompensated systolic heart failure
T.T. Kirlidis, J. Skoularigis, K.T. Tsaknakis, G. Karayiannis, T.K. Tsaknakis and F. Triposkiadis
Abstract
T.T. Kirlidis1, J. Skoularigis1, K.T. Tsaknakis2, G. Karayiannis1, T.K. Tsaknakis2 and F. Triposkiadis1
1Department of Cardiology, Larissa University Hospital, Larissa, and 2Department of Cardiology, General Hospital of Volos, Volos, Greece
The purpose of this study was to evaluate the influence of chronic beta-blockade on the hemodynamic parameters in elderly (>= 70 years) patients with acutely decompensated systolic heart failure treated with levosimendan. Eighteen patients with acutely decompensated systolic heart failure (8 on chronic beta-blockade) were included in this study. Inclusion criteria were symptoms and signs of acute heart failure in the presence of: a) left ventricular ejection fraction < 0.35; b) cardiac index < 2.5 l/min/m2, c) pulmonary capillary wedge pressure > 15 mmHg; and d) systolic blood pressure between 90 and 110 mmHg. After completion of baseline hemodynamic measurements, a levosimendan intravenous infusion was started (initial loading dose given as an infusion of 24 µg/kg over 10 minutes, followed by a continuous infusion of 0.1 µg/kg/min for 24 hours). At the end of levosimendan infusion hemodynamic measurements were repeated. Demographic characteristics as well as baseline systolic and diastolic blood pressure were not significantly different between patients not receiving beta-blockers (Group A) and those under beta-blockade (Group B), whereas heart rate was significantly lower in the latter. Treatment with levosimendan was associated with an increase in the cardiac index and a decrease in wedge pressure in both groups (Group A: 43.8% and 33%; p < 0.001 vs. baseline; Group B: 17.72% and 17.5%, p < 0.001 vs. baseline, respectively). Peripheral and pulmonary resistance significantly decreased in both groups (31% vs. 15%, p < 0.001 and 44.5% vs. 25%, p < 0.001, respectively). Thus, the beneficial hemodynamic effects of levosimendan are maintained in elderly patients with acute decompensated systolic heart failure treated with beta-blockers.Correspondence to:
F. Triposkiadis, MD, FESC, FACC
Professor of Cardiology, Director
Department of Cardiology
University of Thessaly, Medical School
Larissa University Hospital
P.O. Box 1425
411 10 Larissa, Greece
Email: ftriposkiadis@yahoo.com
Original Research
Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects
J.M. Jansat, R. Lamarca, E. Garcia Gil and P. Ferrer
Abstract
J.M. Jansat1, R. Lamarca1, E. Garcia Gil1 and P. Ferrer2
1Laboratorios Almirall, SA, Barcelona, Spain, and 2Centre Hospitalier de la Polynésie française, Tahiti, French Polynesia
Objective: Aclidinium bromide is a novel antimuscarinic being developed for the treatment of chronic obstructive pulmonary disease. The objective of this Phase I study was to determine the maximum tolerated dose (MTD) as well as the tolerability, safety and pharmacokinetics of aclidinium in healthy subjects. Materials and methods: 16 healthy subjects were randomized to receive 5 single ascending doses of aclidinium 600 – 6,000 µg or placebo inhaled via dry powder inhaler, with 7 day washouts. Safety measurements included adverse events (AEs), physical examination, vital signs, pupillometry examination, clinical laboratory tests, and 12-lead electrocardiogram. Pharmacokinetic parameters of aclidinium and its metabolites were assessed. Results: The incidence of AEs was comparable between aclidinium and placebo at all doses. Most AEs were mild to moderate with no dose-related or anticholinergic/cardiac AEs. At doses >= 2,400 µg, only 13 AEs were considered treatment related. Aclidinium (600 – 6,000 µg) did not produce function-limiting or severe AEs in >= 50% of subjects; hence, the prospectively-defined MTD was not established. Aclidinium was rapidly converted in plasma into alcohol and carboxylic acid metabolites, and was no longer detectable after 3 hours post-dose for all doses. At lower doses, aclidinium was quantifiable only up to 1 hour post-dose in the majority of subjects. Maximum plasma concentrations for aclidinium were reached within 5 – 7 minutes (all doses) and declined rapidly. Mean elimination half-lives of aclidinium > 2,400 µg were approximately 1 hour. AUC and Cmax increased proportionately up to 4,800 µg. Conclusions: Aclidinium appears to be safe and well tolerated in single doses of 600 – 6,000 µg.Correspondence to:
J.M. Jansat, PhD
Head of Bioanalysis and Pharmacokinetics
Laboratorios Almirall, SA
Research Centre
Laurea Miro 408-410
08980 Saint Feliu de Llobregat, Barcelona, Spain
Email: josep.maria.jansat@almirall.es
Original Reserach
Consumption of statins in Croatia in the 2002 – 2006 period – a retrospective study
D. Grgurevic, J. Grgurevic, T. Strizrep, V. Bacic Vrca and L. Grgurevic
Abstract
D. Grgurevic1, J. Grgurevic2, T. Strizrep3, V. Bacic Vrca1 and L. Grgurevic4
1Faculty of Pharmacy and Biochemistry, University of Zagreb, 2Zagreb Dental Clinic, 3Croatian Institute for Health Insurance and 4Faculty of Dental Medicine, University of Zagreb, Croatia
Objective: The objective of this research is to quantify the trends in the consumption of statins in the Republic of Croatia on the national level in the 5-year period between 2002 and 2006. Methods: Data on the consumption of different statins have been obtained from the database of the Croatian Institute of Health Insurance. Statistical Annals have provided data on the population in the Republic of Croatia for the period observed. Consumption of statins expressed in Defined daily doses (DDD) per 1,000 inhabitants per day (DID) was computed and statistically processed. Results: Of the total number of insured persons statins were used in the treatment of 2.57% patients in 2002 and grew to 6.48% in 2006. The total consumption of statins was increased from 12.39 DID in 2002 to 44.77 DID in 2006. In the period observed, simvastatin had the greatest individual share in the consumption of statins. Thus in 2002 it accounted for 73.12% of the total consumption of statins, while in 2006 it was 48.87%. The share of other statins in the total consumption did not change substantially, except for atorvastatin, whose share increased from 15.3% in 2002 to 42.38% in 2006. Mostly women (57%) and patients above 55 years of age were treated with statins. Conclusions: In the 2002 – 2006 period the total consumption of statins increased by 261%, while the number of patients treated with statins increased by 252%. Simvastatin had the greatest share in the total consumption, while atorvastatin consumption recorded the greatest individual increase.Correspondence to:
D. Grgurevic
BPharm
Bolnicka 95
10090 Zagreb, Croatia
Email: dijana.grgurevic@gmail.com
Original Research
A fully validated HPLC method for the simultaneous determination of acitretin and etretinate in plasma and its application to a pharmacokinetic study in healthy Korean subjects
H.-D. Park, H.-K. Kim, M.-R. Chun, J.-W. Kim, D.-W. Kim, J.-H. Lee, W.S. Huh, J.-I. Youn, H.-G. Kim, Y.G. Kim, M.-H. Kim and S.-Y. Lee
Abstract
H.-D. Park1, H.-K. Kim1, M.-R. Chun1, J.-W. Kim1, D.-W. Kim1, J.-H. Lee2, W.S. Huh3,4, J.-I. Youn5, H.-G. Kim6, Y.G. Kim6, M.-H. Kim7 and S.-Y. Lee1
1Department of Laboratory Medicine and Genetics, 2Department of Dermatology, 3Department of Internal Medicine, 4Clinical Trial Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 5Department of Dermatology, 6Department of Pharmacology and 7Department of Dermatology, College of Medicine, Dankook University, Chonan, Korea
Objective: Acitretin is used for the treatment of psoriasis. The purpose of this study was to validate an HPLC method for the determination of acitretin and etretinate and to investigate the pharmacokinetic characteristics of acitretin in healthy Korean subjects. Materials and methods: Plasma samples or calibrators were mixed with acetonitrile and retinyl acetate (internal standard). Butanol: acetonitrile (1:1 v/v) and K2HPO4 were added later. After vortexing, 30 µl of the supernatant was injected directly into the analytical column of an HPLC system. The samples were separated by C18 reversed phase HPLC and UV detection was performed at 350 nm. Various assay performances were evaluated. Results: The linearity of acitretin and etretinate was adequate up to 500 ng/ml (R2 = 0.9937 for acitretin and R2 = 0.9923 for etretinate). The accuracy was 89.5 – 113.5% and the precision was satisfactory (within-run CV, 4.4 – 15.8%; between-run CV, 3.3 – 17.4%). The LLOQ was 2 ng/ml and the stability and specificity were satisfactory. However, after storage at room temperature for 24 h under light exposure, the concentrations of acitretin and etretinate decreased by 26.0 – 66.5%. Extraction recovery was 75.1 – 91.5%. Nine healthy Korean subjects were evaluated to study the pharmacokinetics of acitretin. A single oral dose of 30 mg acitretin (Neotigason, Roche Pharmaceuticals) was given to all volunteers. The mean ± SD pharmacokinetics of acitretin in Koreans were as follows: Cmax 148.7 ± 93.0 ng/ml, tmax 3.2 ± 1.3 h, t1/2 81.2 ± 26.5 h, and AUClast 2641.9 ± 1274.8 ng*h/ml. Conclusion: A simple HPLC method for the simultaneous determination of acitretin and etretinate was validated, and the pharmacokinetic characteristics of acitretin in the Korean population were investigated.Correspondence to:
S.-Y. Lee MD, PhD
Samsung Medical Center
50 Ilwon-dong, Gangnam-gu
Seoul, 135-710, Korea
Email: suddenbz@skku.edu
Original Research
Randomized, crossover, single-blind, placebo-controlled, human pharmacology clinical trial with desoxypeganine, a new cholinesterase and selective MAO-A inhibitor: Multiple-dose pharmacokinetics
J. Algorta, M.A. Pena, A. Álvarez, C. Maraschiello, D. Maruhn, M. Windisch and H.A.M. Mucke
Abstract
J. Algorta1,2, M.A. Pena1, A. Álvarez3, C. Maraschiello4, D. Maruhn5, M. Windisch6 and H.A.M. Mucke7
1Clinical Trials Unit, Hospital Txagorritxu, Vitoria-Gasteiz, 2University of Basque Country-EHU, 3Department of Neuropharmacology, EuroEspes, A Coruña, 4Center for Research and Applied Development (RCC CIDA, S.A.), Santa Perpètua de la Mogoda, Barcelona, Spain, 5HF Arzneimittelforschung GmbH, Werne, Germany, 6JSW-Research Forschungslabor GmbH, Graz, and 7HM Pharma Consultancy, Wien, Austria
Desoxypeganine, a naturally occurring alkaloid, is being developed for its potential utility in the pharmacological treatment of alcohol abuse to reduce craving and depression in alcohol abusers, and might also be useful as a smoking cessation aid. During the preclinical development it was characterized as a cholinesterase inhibitor, acting preferentially on butyrylcholinesterase, and as a selective inhibitor of monoamine oxidase A but not monoamine oxidase B. Objective: The aim of the present human pharmacology clinical trial was to assess the oral bioavailability, pharmacokinetic profile and tolerability of desoxypeganine, administered in a multiple-dose regimen to healthy volunteers. Subjects and methods: Eighteen healthy adult volunteers of both sexes received placebo, 50 mg and 100 mg desoxypeganine (b.i.d. for 3 days) in a single-blind, crossover, randomized manner. Main pharmacokinetic parameters after single and multiple doses were estimated. Clinical tolerability and clinical laboratory safety, including effect on QTc interval, were assessed. Results: Non-compartmental estimations of Cmax, AUC, tmax, t1/2 and MRT at 12-h intervals are given. No significant dose effect was observed in tmax, t1/2 and MRT. Cmax and AUC are approximately double with the dose of 100 mg comparing with the dose of 50 mg. A significant increase (p < 0.05) on Cmax and AUC was also obtained with the highest dose administered in comparison with the lowest one, revealing a slight but clinically insignificant accumulation. Steady state of drug concentration was reached in both genders during the study period. Plasma protein binding of desoxypeganine amounted to approximately 18%. No severe adverse events were recorded and none of the subjects suffered from any adverse event that led to withdrawal from the study. Most frequently recorded adverse event was dizziness. No significant effects of desoxypeganine on vital signs, laboratory parameters or QTc interval were observed. Conclusions: The present clinical trial describes the pharmacokinetic profile of two doses of desoxypeganine, administered orally in multiple dose to healthy volunteers. The drug was well tolerated without any severe clinical, clinical laboratory, or ECG adverse events being recorded.Correspondence to:
J. Algorta, MD, PhD
Clinical Trials Unit (Fundacion Leia)
Hospital Txagorritxu
C/José Achótegui s/n
01009 Vitoria-Gasteiz, Spain
Email: jaime.algorta@ehu.es
Bioavailability Section
Pharmacokinetic study and comparative bioavailability of two nelfinavir tablet formulations in Iranian healthy volunteers after a low-dose administration
K. Derakhshandeh and A. Sohrabi
Abstract
K. Derakhshandeh and A. Sohrabi
Department of Pharmaceutics, Faculty of Pharmacy, Kermanshah University of Medical Scinences, Kermanshah, Iran
The objective of this study is to evaluate pharmacokinetic parameters, bioavailability of a potent HIV protease inhibitor, nelfinavir mesylate (NFV), following a single oral administration of 2 tablet formulations. A randomized, 2-way, crossover, bioequivalence study was conducted in 24 healthy male volunteers to compare 2 brands of nelfinavir 250 mg tablets, Nelfabiovir (Bakhtar Bioshimi, Iran) as test and Viracept (Roche, Germany) as reference product. Blood samples were collected at selected times during 12 h and plasma concentrations were determined with a sensitive and validated HPLC method involving a simple protein precipitation step. Individual pharmacokinetic parameters, t1/2, t1/2(abs), K, Ka, tmax, Cmax, Vd/F, Cl/F, AUC0-12 and AUC0-¥ were determined from plasma concentration-time profiles for both formulations and were compared statistically. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. In vitro parameters of mean dissolution time (MDT) and time for 70% dissolution (T70) were also determined. There was no significant difference between these parameters for two dosage forms (p > 0.05). It was concluded that the two nelfinavir products are bioequivalent with respect to the rate and extent of absorption.Correspondence to:
K. Derakhshandeh
Department of Pharmaceutics
Faculty of Pharmacy
Kermanshah University of Medical Sciences
67145-1673, Kermanshah, Iran
Email: kderakhshandeh@kums.ac.ir
