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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (633-642)

Medical treatment of Parkinson’s disease: today and the future

G. Gárdián and L. Vécsei

Department of Neurology, Faculty of Medicine, University of Szeged, Szeged, Hungary
Idiopathic Parkinson’s disease (PD) is the only neurodegenerative disorder for which highly effective symptomatic therapy is available. Although levodopa continues to be the gold standard of symptomatic efficacy for treatment of the cardinal motor features, its chronic use is associated with potentially disabling motor complications. This review provides a survey of the medication that can currently be utilized for pharmacological management of the motor and non-motor symptoms of Parkinson’s disease. Focus is placed on recent and evolving studies evaluating symptomatic and neuroprotective effects of such medication, and on how such studies may impact the future management of Parkinson’s disease.Correspondence to:
Prof. L. Vécsei, MD, PhD, DSc
Department of Neurology
University of Szeged
6725 Szeged, Semmelweis u. 6., Hungary
Email: vecsei@nepsy.szote.u-szeged.hu

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (643-651)

Single-dose ticagrelor does not prolong the QT interval in healthy subjects

K. Butler, C. Wei and R. Teng

AstraZeneca LP, Wilmington, DE, USA
Ticagrelor (AZD6140), the first reversibly binding oral platelet P2Y12 receptor inhibitor, is currently under development for reduction of thrombotic events in patients with acute coronary syndrome (ACS). Objective: This study was designed to assess the potential effects of a single oral dose of ticagrelor on QT interval. Methods: In this randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study, 36 healthy males received single doses of ticagrelor 900 mg, moxifloxacin (positive control) 400 mg, or placebo in three treatment periods. This ticagrelor dose is substantially higher than the proposed therapeutic dose (90 mg twice daily after a 180 mg loading dose). QT intervals were assessed from 12-lead digital electrocardiogram (ECG) recordings over 24 h. Plasma levels of ticagrelor and its major metabolite AR-C124910XX were measured. Exploratory analyses of exposure-QTc interval relationships were conducted. Safety assessments were made throughout the study. Results: Mean QTcX, QTcF, and QTcB intervals were similar between ticagrelor and placebo. All point estimates for comparisons between ticagrelor and placebo in QTcX over 24 h post dosing were < 5 milliseconds and all upper confidence limits (UCL) from two-sided 95% confidence intervals were < 10 milliseconds (maximum time-matched mean effect 2.27 milliseconds with UCL 6.05 milliseconds at 12 h). With moxifloxacin, all point estimates and UCLs (except at 24 h post dose) were > 5 milliseconds and > 10 milliseconds, respectively, versus placebo; indicating the study had sufficient sensitivity to detect clinically meaningful changes in QT interval. There was no apparent relationship between ticagrelor or AR-C124910XX levels and QT intervals. Ticagrelor was well tolerated at the tested dose. Conclusions: A single oral dose of 900 mg ticagrelor did not prolong the QT interval in healthy volunteers compared with placebo. Thus, it is expected that ticagrelor will not affect cardiac repolarization in ACS patients.Correspondence to:
Dr. R. Teng
Clinical Pharmacology
AstraZeneca LP, OW3-117
1800 Concord Pike
P.O. Box 15437
Wilmington, DE 19850-5437, USA
Email: renli.teng@astrazeneca.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (652-661)

Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers

E.U. Graefe-Mody¹, A. Jungnik¹, A. Ring¹, H.J. Woerle¹ and K.A. Dugi²

¹Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach/Riss, and ²Boehringer Ingelheim GmbH, Ingelheim, Germany
Objective: Co-administration of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) with pioglitazone may improve glycemic control in patients with Type 2 diabetes due to their complementary mechanisms of action. This study aimed to investigate any potential pharmacokinetic interaction between linagliptin and pioglitazone, a CYP 2C8 substrate. Methods: 20 (10 male and 10 female) healthy subjects, between 22 and 65 years of age with a BMI range of >= 18.5 and <= 29.9 kg/m², took part in this single center open-label, randomized, two-way cross-over study. The subjects were administered linagliptin 10 mg/day and/or pioglitazone 45 mg/day until steady state was reached. Results: Co-administration of pioglitazone did not significantly affect linagliptin C_max,ss (geometric mean ratio (GMR) 107.3; 90% confidence interval (CI); 92.3 – 124.8) or AUC_Tau,ss (GMR 113.4; 90% CI 103.0 – 124.9). Co-administration of linagliptin did not significantly affect pioglitazone AUC_Tau,ss (GMR 94.4; 90% CI 87.1 – 102.2), but reduced C_max,ss by 14% (GMR 85.6; 90% CI 78.1 – 93.8). As expected, linagliptin and pioglitazone were well tolerated, whether administered alone or concomitantly. There were no reported serious adverse events. The investigator defined 5 adverse events as drug-related with linagliptin, and 4 with pioglitazone. Conclusions: Linagliptin and pioglitazone have no clinically relevant pharmacokinetic interaction and may be co-administered without dose adjustment. These data further confirm that linagliptin is not an inhibitor of CYP 2C8 in vivo. As the pharmacokinetic profiles of linagliptin and pioglitazone are similar in Type 2 diabetes patients and healthy subjects, it is reasonable to assume that they may be administered together to Type 2 diabetes patients without dose adjustment.Correspondence to:
Dr. U. Graefe-Mody
Therapeutic Area Metabolism
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Str. 65, 88397 Biberach, Germany
Email: Ulrike.Graefe-Mody@boehringer-ingelheim.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (662-669)

Population pharmacokinetics study of azithromycin oral formulations using NONMEM

X.-Y. Zhang¹,², Y.-R. Wang³, Q. Zhang³,⁴ and W. Lu³,⁴

¹College of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, ²Center for Drug Evaluation, State Food and Drug Administration, ³School of Pharmaceutical Science, and ⁴State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Objective: A population pharmacokinetic study of orally dosed azithromycin was conducted in order to determine if the antibiotic usage in clinical practice is reasonable and individualized. Method: A nonlinear mixed effect model with various oral azithromycin formulations was constructed using the NONMEM program. Based on a dataset of 160 healthy volunteers, the pharmacokinetic parameters and the relationship between the inter-individual effects and fixed effects were estimated. Result: A two compartment model with first-order absorption and elimination was established. The values for Cl₁/F, Cl₂/F, V₁/F, V₂/F and Ka were 121 ml/h, 282 ml/h, 1,939 ml, 5,650 ml and 1.05 h^–1, respectively. The results provided evidence that the body weight affects the Cl₁/F and Cl₂/F and age affects the V₁/F. Conclusion: A nonlinear mixed effect model for oral azithromycin formulations was developed for a Chinese healthy population.Correspondence to:
Prof. W. Lu, PhD
School of Pharmaceutical Science
Peking University, Beijing, 100083, China
Email: luweippk@gmail.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (670-677)

Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis

D. Díaz-Carballo¹*, K. Ueberla²*, V. Kleff³, S. Ergun³, S. Malak⁴, M. Freistuehler⁵, S. Somogyi⁶, C. Kücherer⁶, W. Bardenheuer¹ and D. Strumberg¹

¹Institute for Molecular Oncology and Experimental Therapeutics, Marienhospital Herne, Ruhr University of Bochum, Herne, ²Department of Molecular and Medical Virology, Ruhr University of Bochum, Bochum, ³Institute of Anatomy, ⁴West German Cancer Center, ⁵Department of Ophthalmology, University of Duisburg-Essen, School of Medicine, Essen and ⁶Project HIV Variability and Molecular Epidemiology/P¹¹, Robert Koch Institute, Berlin, Germany

*The two first authors contributed equally to this work.
Objectives: Polyisoprenylated acylphloroglucinols have recently emerged as antitumoral agents. This study aims at elucidating the antiretroviral activity of two such compounds which were isolated from Caribbean propolis: 7-epi-nemorosone and plukenetione A, the structure of which is based on an adamantane moiety. Plukenetione A is for the first time shown to have antiretroviral activity. Material and methods: The isolation of both small molecules was carried out using RP-HPLC. Their antiretroviral activity was studied based on lentiviral particles produced in HEK293T cells from the SIV-based vector VLDBH; their cytotoxicity was monitored by MTT proliferation assay. The antiviral activity of 7-epi-nemorosone was studied in CEMx174-SEAP infected with the HIV-1-strain pNL4.3wt. Reverse transcriptase inhibition was determined by a standard two-step RT-PCR using MMLV RT. Results: 7-epi-nemorosone and plukenetione A were found to be potent antilentiviral agents in the employed system, inhibiting viral infection at concentrations below 1 µM/2 µM, respectively. Whereas 7-epi-nemorosone was not able to inhibit the reverse transcriptase in vitro (IC₅₀ > 25 µM), plukenetione A effectively inhibited its enzymatic activity at an IC₅₀ of 1.75 µM. Conclusions: Despite 7-epi-nemorosone and plukenetione A sharing some structural core elements, the mechanism of action involved in their antiretroviral activity seems to be different. We propose that 7-epi-nemorosone inhibits the viral replication by interrupting the Akt/PKB signaling cascade, as was demonstrated previously in various cell lines. Since plukenetione A effectively inhibits the enzymatic activity of MMLV reverse transcriptase at concentrations that show antilentiviral activity, we suggest that this small molecule acts by interfering with the enzyme’s catalytic site.Correspondence to:
Dr. D. Diaz-Carballo
Institut für Molekulare Onkologie und Substanzentwicklung
Marienhospital Herne
Katholische Stiftung
Ruhr-Universität Bochum
Düngelstraße 33, 44625 Herne, Germany
Email: david.diaz-carballo@marienhospital-herne.de

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (678-687)

A thorough QT/QTc study of multiple doses of tapentadol immediate release in healthy subjects

C. Oh¹, J. Rengelshausen², B. Mangold¹, M. Etropolski¹, C. Rauschkolb¹, S.S. Wang¹, D. Upmalis¹ and T. Häufel³

¹Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA, ²Global Clinical Development, Grünenthal GmbH, Aachen, and ³Global Drug Safety, Grünenthal GmbH, Aachen, Germany
Objective: This randomized, double-blind, placebo- and positive-controlled 4-way crossover study evaluated the effects of tapentadol immediate release (IR) on the QT/QTc interval. Materials and methods: Healthy subjects received tapentadol IR 100 mg or 150 mg, or placebo, every 6 h on Days 1 and 2, with a >= 7-day washout between treatments. Moxifloxacin 400 mg was the positive control. Serial triplicate 12-lead electrocardiograms (ECGs) were performed; the Fridericia correction (QTcF) was the primary correction method. Serial blood sampling was performed for pharmacokinetic analyses. Results: Of the 75 subjects who were randomized, 68 received at least 1 dose of study medication, and 59 completed the study. Upper limits of the 90% confidence intervals (CIs) for the difference in mean DeltaQTcF between tapentadol IR 100 or 150 mg and placebo were < 10 ms (non-inferiority criterion) for all time points. The lower limit of the 90% CI for mean DeltaQTcF between moxifloxacin and placebo exceeded 5 ms from 1 to 6 h after dosing, establishing assay sensitivity. No subject had a postdose QTc interval > 480 ms, change from baseline > 60 ms, or clinically relevant change in heart rate or other ECG variables. Steady-state concentrations were reached within 18 to 24 h. Common adverse events were vertigo (central nervous system (CNS) origin), headache, somnolence, nausea, vomiting, and feeling drunk. Conclusion: Therapeutic and supratherapeutic doses of tapentadol do not affect the QT/QTc interval.Correspondence to:
C. Oh, MD
430 Route 22 East
Bridgewater, NJ 08807, USA
Email: coh2@its.jnj.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 10/2010 (688-694)

N-Acetyltransferase-2 (NAT2) genotype frequency among Jordanian volunteers

Y.B. Jarrar¹*, S. Ismail² and Y.M. Irshaid¹

Departments of ¹Pharmacology and ²Biochemistry and Physiology, Faculty of Medicine, University of Jordan, Amman, Jordan

*Y.B. Jarrar is a Master degree graduate from the Department of
Pharmacology.
Objective: To determine the frequency of major NAT2 alleles and genotypes among the Jordanian population. Methods: DNA samples from 150 healthy Jordanian volunteers were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism assays (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6 and NAT2*7. Results: The frequency (95% confidence interval) of NAT2*4, NAT2*5, NAT2*6 and NAT2*7 alleles was 0.247 (0.198 – 0.296), 0.373 (0.318 – 0.428), 0.347. 0.293 – 0.401) and 0.033 (0.013 – 0.053), respectively. The most prevalent genotypes are those which encode slow acetylation phenotype. Around 58.7%, 33.3% and 8% of volunteers carried the slow, the intermediate and the fast-encoding genotypes, respectively. Conclusion: NAT2 genotype profile among Jordanians is similar to Caucasians. However, NAT2*6 allele is slightly high in comparison with Arab Middle Eastern populations.Correspondence to:
Y.M. Irshaid
Department of Pharmacology
Faculty of Medicine
University of Jordan
Amman 11942, Jordan
Email: y.irshaid@ju.edu.jo

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Volume 48, No. 10/2010(October)