Volume 47, No. 5/2009(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacotherapy Guidlines for the Aged
Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors – Part D Basic conditions supporting drug treatment
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K.Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
Abstract
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K.Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
Physiological changes in old age: loss of muscle mass; reduction in bone mass; percentage of fat increased; lower amount of body water; lack of thirst; diminishing kidney function (caution: sufficient intake of fluids: 1.5 – 2 l and moderate intake of protein 8 g/kg body weight); reduced secretion of digestive enzymes, delayed emptying of stomach (which means premature feeling of repletion). Lack of fluids and nutrition is therefore likely. Daily intake of 1,500 kcal and 1.5 – 2 l fluids is necessary. An indicator for malnutrition is low body weight (defined for persons older than 65 years of age as BMI < 20) and a protein serum concentration < 35 g/l. Malnutrition carries an increased risk of infections, falling and fractures, bed sores, anemia, decompensation of chronic diseases. 10 – 20% of subjects over 80 years of age show signs of malnutrition, 40 – 60 % of subjects in care institutions or hospitals. There are regressive changes in the locomotor and the nervous system of the elderly which have an effect on physical fitness. These changes reduce strength, endurance, proprioceptive capacity (e.g. coordination, balance) and mobility. Exercise in the old and very old should increase skeletal muscle strength in particular and improve coordination and balance. Regular physical exercise and moderate training has a positive effect on mobility and thereby improves independence and reduces falls. Moreover, it has a positive effect on cardiac output, maximum heart rate, stroke volume and the risk of a cardiovascular event and mortality can be reduced. Moreover, moderate physical exercise is often more effective in treating chronic disease than drug therapy e.g. heart failure, coronary heart disease, asthma/COPD, stroke, diabetes mellitus Type 2, degenerative diseases of the joints, depression and others. Examine cardiovascular risks in persons over the age of 50 before beginning physical exercise. Avoid maximum stress levels.Correspondence to:
Dr. L. von Ferber, PD; Auf dem Ufer 7, 40593 Düsseldorf, Germany
Email: Liselotte.vonFerber@uni-duesseldorf.de
Case Report and Literature Review
Ciprofloxacin-associated seizures in a patient with underlying thyrotoxicosis: case report and literature review
K. Agbaht, B. Bitik, S. Piskinpasa, M. Bayraktar and A. Topeli
Abstract
K. Agbaht1, B. Bitik2, S. Piskinpasa2, M. Bayraktar3 and A. Topeli4
1Department of Internal Medicine, Endocrinology and Metabolism Unit, Ankara University Faculty of Medicine, 2Department of Internal Medicine, 3Department of Internal Medicine, Endocrinology and Metabolism Unit, and 4Department of Internal Medicine, Intensive Care Unit, Hacettepe University Faculty of Medicine, Sihhiye, Ankara, Turkey
Background: Ciprofloxacin-associated seizures (CAS) occur most commonly in patients with special risk factors that may cause accumulation of drug (high doses of the drug, old age, renal insufficiency, drug interactions) or that may decrease the threshold of epileptogenic activity (electrolyte abnormalities, history of seizures, electroconvulsive therapy). Objective: To report thyrotoxicosis as a risk factor previously not heralded for the development of CAS. Case summary: A 24-year-old woman was admitted to the hospital because of convulsions, severe myopathy, and acute renal failure after taking ciprofloxacin for sinusitis, and urinary tract infections. Prior to ciprofloxacin ingestion, she had no seizure history, was not receiving any other medication, and her routine laboratory results including creatinine and electrolytes were within normal ranges. Electroencephalogram suggested epileptiform waves. Cranial magnetic resonance imaging was normal. Further laboratory examinations documented thyrotoxicosis in association with postpartum thyroiditis. Discussion: In the reviewed literature, all cases of CAS occurred in the presence of at least one risk factor for CAS. Conclusions: CAS appear to be restricted to individuals with predisposing risk factors, therefore it is always necessary to search such fact. When a physician encounters the possibility of CAS, in addition to previously described risk factors, thyrotoxicosis should also be considered in the differential diagnosis. Further, in patients with untreated thyrotoxicosis, antibiotics other than ciprofloxacin might be preferable for therapy.Correspondence to:
K. Agbaht, MD; Ankara University Faculty of Medicine, Department of Endocrinology and Metabolism, Sihhiye, Ankara, 06100, Turkey
Email: kemala@hacettepe.edu.tr; dr_kemal@yahoo.com
Therapeutics
Impact of insulin sensitivity treatment with pioglitazone on endothelial function in non-diabetic patients with arterial hypertension
F. Schneider, S. Vossler, S. Franke, F. Bär and T. Konrad
Abstract
F. Schneider, S. Vossler, S. Franke, F. Bär and T. Konrad
Institute for Metabolic Research, Frankfurt am Main, Germany
Objective: The thiazolidindione (TDZ) pioglitazone reduces insulin resistance and blood pressure in non-diabetic patients with arterial hypertension as previously reported [Füllert et al. 2002]. The question is still not answered whether it is a direct effect on the endothelial wall or it is related with improvement of insulin sensitivity. The present investigation is the first placebo controlled study which examines the effect of TDZ induced changes of insulin sensitivity (SI) on endothelial function and blood pressure in in non-diabetic patients with high blood pressure. Material and methods: Insulin sensitivity indices (SI indices) were obtained by analyzing fasting glucose and insulin concentration with homeostasis model assessment (HOMA), the glucose and insulin profiles after 75 g dextrose oral glucose tolerance tests (OGTT, Matsuda-Index) and euglycemic hyperinsulinemic clamp (m-value) in a double-blind placebo-controlled study in 60 patients with arterial hypertension before and after 4 months treatment with Pioglitazone 45 mg (PIO45). Flow-mediated dilatation of brachial artery (FMD) after reperfusion was used to determine endothelial function. Blood pressure in the morning of every visit (casual blood pressure, RRc) and 24-h ambulatory blood pressure (24RR) were measured. Results: Antihypertensive treatments were equally distributed in the placebo and PIO45 group. All SI indices were closely related to with alanine-aminotransferase activities (ALAT): HOMA r = 0.1041, p < 0.05, Matsuda-Index r = 0.4242, p < 0.01, M value r = 0.1944, p < 0.01. There were no relationships of SI indices with FMD, RRc and 24RR in the study population with treated arterial hypertension. FMD was closely related to the nocturnal systolic and diastolic 24hRR (systolic r = 0.0943, p < 0.05, diastolic r = 0.0947, p < 0.05). SI indices improved after 4-month therapy with PIO45 when compared with controls: HOMA 65% (p < 0.01), Matsuda-Index 60% (p < 0.01) and M value 17.7% (p = 0.008). FMD did not change after PIO45. Casual diastolic blood pressure (p = 0.016) and systolic blood pressure were lower (p = 0.053) under PIO45. No significant changes of 24-h blood pressure were found after treatment with TDZ. Conclusion: 4-month treatment with PIO45 improves SI, liver function and lowers casual blood pressure (RRc. No effects on 24-h ambulatory blood pressure and on endothelial function after PIO45 therapy were observed. The higher insulin sensitivity was not related to lower blood pressure. Thus, PIO45 appears to have a direct effect on the arterial system which cannot be explained by changes of endothelial function or improved SI in non-diabetic patients with treated high blood pressure.Correspondence to:
Ass. Prof. Dr. T. Konrad, MD; Institute for Metabolic Research, Academic Institute of the Medical Faculty of Johann Wolfgang Goethe University, Heidelbergstr. 13, 60327 Frankfurt am Main, Germany
Email: t.konrad@em.uni-frankfurt.de
Pharmacodynamics
Deferasirox does not induce QT/QTc-prolongation in healthy subjects
R. Sechaud, T. Dumortier and S. Balez
Abstract
R. Sechaud1, T. Dumortier1 and S. Balez2
1Novartis Institutes for BioMedical Research – Translational Sciences Basel, Switzerland, and 2Novartis Pharma SAS, Rueil-Malmaison, France
The International Conference on Harmonization (ICH) E14 guidance recommends that almost all drugs should undergo careful clinical testing in a thorough QT/QTc study. Deferasirox (Exjade®, ICL670) is a once-daily oral iron chelator, developed for the treatment of blood transfusion-related iron overload. Objective: This study was designed to investigate the effect of deferasirox on the QT/QTc interval. Methods: A randomized, single-dose, placebo- and positive-controlled, parallel-group study was conducted in a total of 182 healthy subjects. Study participants were randomized to four treatments arms: deferasirox 20 mg/kg (n = 46), deferasirox 40 mg/kg (n = 46), placebo (n = 46) or moxifloxacin 400 mg (n = 44). Moxifloxacin tablets were taken in an open-label fashion, while the subjects and investigator staff remained blinded for the other treatments. Electrocardiograms, obtained at various time points during a 24-h period, were evaluated centrally in a blinded fashion. The primary endpoint was the average change from baseline in QT/QTc over the 24-h period following intake of study medication. It was prospectively defined that deferasirox will be considered devoid of inducing QT/QTc-prolongation if the upper bound of the 95% 2-sided confidence interval (CI) for the difference to placebo is below 8 milliseconds (i.e., being noninferior to placebo). Results: Deferasirox 20 and 40 mg/kg were noninferior to placebo with respect to the average change from baseline in QT/QTc, as indicated by 95% CIs for the mean treatment difference (deferasirox 20 or 40 mg/kg minus placebo), which were entirely below 8 milliseconds. The lower limit of the 95% 2-sided CI for the difference between moxifloxacin and placebo was greater than 0 milliseconds, demonstrating the sensitivity of the study. Deferasirox Cmax and AUC following intake of deferasirox 40 mg/kg was higher by factor 1.6 and 2.3, respectively, than observed at a steady state in beta-thalassemia patients treated for 6 months with deferasirox 30 mg/kg, the recommended maximum dose. Conclusions: This study demonstrates that deferasirox does not prolong the QT/QTc interval at both therapeutic and supratherapeutic plasma concentrations. It is, therefore, not expected that deferasirox has a negative effect on cardiac repolarization in patients under treatment with this medication.Correspondence to:
Dr. R. Sechaud; Novartis Institutes for BioMedical Research – Translational Sciences, WSJ-210.4.20, 4002 Basel, Switzerland
Email: romain.sechaud@novartis.com
Pharmacogenetics
Whole genome analysis of the action of interferon-beta
M.A. Kauffman, P. Yankilevich, P. Barrero, R. Bello, L. Marangunich, A. Vidal, M. Criscuolo, R.A. Diez and A. Sterin Prync
Abstract
M.A. Kauffman1, P. Yankilevich1, P. Barrero2, R. Bello1, L. Marangunich1, A. Vidal1, M. Criscuolo1, R.A. Diez1 and A. Sterin Prync1
1Bio Sidus SA, Buenos Aires, Argentina, and 2Laboratorio de Virología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
Objectives: To characterize the IFNbeta1a-regulated gene expression on leukocytes of Multiple Sclerosis (MS) patients using microarrays with whole human genome representation. Methods: Genes differentially expressed by interferon-beta were identified by a microarray in vitro study performed in leukocytes obtained from 5 MS relapsing-remitting patients. Results: Following the culture of peripheral blood mononuclear cells from MS relapsing-remitting patients for 24 hs with IFNbeta1a, the expression of 868 genes was modified: 545 increased (including CXCL11, CCL8, INDO, IFI27, CFB, CXCL10 and IFIT1) and 323 diminished (including RBP7, SEPT5, RNF8, ADORA2B and FOS). Conclusions: Since many of them were previously recognized as involved in MS pathogenesis, the IFNbeta1a mechanism of action could imply a compensatory regulation of systems deregulated in MS.Correspondence to:
M.A. Kauffman, MSc; Constitución 4234 (1254)
Buenos Aires, Argentina
Email: m.kauffman@biosidus.com.ar
Bioavailability Section
Bioequivalence study of a film-coated tablet of deferiprone in healthy Thai volunteers
N.P. Morales, L.M.G. Limenta*, P. Yamanont, T. Jirasomprasert, P. Wilairat, U. Chantharaksri, S. Chuncharunee and S. Fucharoen
Abstract
N.P. Morales1, L.M.G. Limenta1*, P. Yamanont1, T. Jirasomprasert1, P. Wilairat2, U. Chantharaksri1, S. Chuncharunee3 and S. Fucharoen4
1Department of Pharmacology,2Department of Chemistry, Faculty of Science, Mahidol University, 3Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok,and 4Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya Campus, Nakornpathom, Thailand
Objective: To evaluate the bioequivalence of a single dose of deferiprone tablet manufactured locally (GPO-L-ONE®, GPO, Thailand) with a reference formulation (Ferriprox®, ApoPharma, Canada). Volunteers and methods: A randomized, single dose, two-treatment, two-period, two- sequence crossover study was conducted in 24 healthy volunteers. Each subject received a single dose of 3 tablets of 500 mg deferiprone of both formulations with a two-week washout period. Blood samples were collected at 12 points for 480 min. Serum deferiprone levels were analyzed using high performance liquid chromatography (HPLC) method. Pharmacokinetic parameters were calculated from serum concentration-time curve and applying the non-compartment model. Statistical comparisons of Cmax, AUC0-t, AUC0-inf values were evaluated after logarithmic transformation. Other pharmacokinetic parameters were tested non-parametrically. Results: The Cmax value (mean ± SD) for reference and test product was 32.4 ± 13.2 and 27.8 ± 12.8 µg/ml, respectively. Mean ratio (test/reference) of Cmax was 0.852 with 90% CI of 0.772 – 0.934. Mean ratio (test/reference) of AUC0-t was 0.962 with 90% CI of 0.914 to 1.012, and of AUC0-inf was 0.966 with 90% CI of 0.918-1.016. Both formulations were well tolerated and no adverse effects were observed. Conclusion: The 90% CI of mean ratio of AUC0-t and AUC0-inf fell within the acceptable range (0.80 – 1.25) for bioequivalent eligibility. Regarding the efficacy of deferiprone, which depends on AUC rather than Cmax, 90% CI of mean ratio of Cmax was within the acceptable range of WHO criteria for bioequivalence study (0.75 – 1.33). Therefore the two film-coated formulations of deferiprone tablet were proven bioequivalent in healthy Thai volunteers.Correspondence to:
N. P. Morales, PD; Department of Pharmacology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajatevee, Bangkok 10400, Thailand
Email: scnpm@mahidol.ac.th
