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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (157-161)

Oral tetracyclines may not be effective in treating acne: dominance of the placebo effect

Win L. Chiou

Chiou Consulting Inc., Burr Ridge, IL, USA
Oral tetracyclines (tetracycline, doxycycline, minocycline and lymecycline) have been commonly regarded as effective for treating both inflammatory and non-inflammatory acne. An excellent review of efficacy of 57 clinical trials by Simonart et al. in 2007 concluded that compared to the baseline before treatment, efficacies of all tetracyclines were similar (mean reduction in inflammatory lesions and non-inflammatory lesion being 54.3 ± 1.4% and 45 ± 2.6%, respectively) and were not affected by dosage amount (40 – 1,000 mg per day) and treatment period (4 – 24 weeks). These interesting findings may be pharmacodynamically rationalized by weak intrinsic anti-acne activity of tetracyclines and strong placebo effects. This hypothesis was supported by published data indicating that during weeks or months of daily administration, the placebo effect approached the effect of minocycline or doxycline in reducing acne lesions in three separate studies. The present work suggests the importance of considering placebo effects in the evaluation of anti-acne products. The treatability of acne was discussed in view of the slow and weak intrinsic anti-acne property of oral tetracyclines, and the reported fast (within days) elimination (curing) of severe acne by intralesional corticosteroids and antibiotics. The subantimicrobial or non-antimicrobial doses (e.g., only a small fraction) of various oral tetracyclines may be much lower than those commonly recognized.Correspondence to:
Win L. Chiou, PhD
Chiou Consulting Inc.
80 Burr Ridge Parkway
PO Box 187
Burr Ridge, IL 60527, USA
Email: win@chiouconsulting.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (162-184)

Electroencephalogram-based pharmacodynamic measures: a review

Michael Bewernitz and Hartmut Derendorf

Department of Pharmaceutics University of Florida, Gainesville, FL, USA
Pharmacokinetics and pharmacodynamics can provide a useful modeling framework for predicting drug activity and can serve as a basis for dose optimization. Determining a suitable biomarker or surrogate measure of drug effect for pharmacodynamic models can be challenging. The electroencephalograph is a widely-available and non-invasive tool for recording brainwave activity simultaneously from multiple brain regions. Certain drug classes (such as drugs that act on the central nervous system) also generate a reproducible electroencephalogram (EEG) effect. Characterization of such a drug-induced EEG effect can produce pharmacokinetic/pharmacodynamic models useful for titrating drug levels and expediting development of chemically-similar drug analogs. This paper reviews the relevant concepts involved in pharmacokinetic/pharmacodynamic modeling using EEG-based pharmacodynamic measures. In addition, examples of such models for various drugs are organized by drug activity as well as chemical structure and presented.Correspondence to:
Hartmut Derendorf, PhD, Distinguished Professor and Chairman
Department of Pharmaceutics
University of Florida 100494, College of Pharmacy
1600 SW Archer Road, P3-27
Gainesville, FL 32610, USA
Email: hartmut@ufl.edu

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (185-194)

Potentially inappropriate prescribing for elderly outpatients in Germany: a retrospective claims data analysis

Lisa Goltz¹, Gerd A. Kullak-Ublick² and Wilhelm Kirch¹

¹Institute of Clinical Pharmacology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany and ²Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
Objective: To quantify the frequency of potentially inappropriate medication (PIM) prescribing for outpatients aged 65 years and older using claims data of a German statutory health insurance. Methods: Based on the 2002 Beers criteria for PIM use, a retrospective evaluation of drug prescription data in outpatient care was conducted for the years 2003 and 2004 using data from a German statutory health insurance (AOK) in the area of Saxony. The study was limited to those drugs classified as being potentially inappropriate according to the criteria independent of existing medical conditions and without any restrictions concerning dosage or duration of use, because this information was not available from the data. Results: In 2003, 3.3% (408,375) of all 12,513,584 drug prescriptions for patients 65 years and older which were analyzed included a PIM from the Beers list. In 2004, it was 2.9% (297,524) of 10,126,809 (p < 0.001). The most frequently prescribed PIMs were short-acting nifedipine (13.4%), indomethacin (12.3%) and diazepam (11.8%) in 2003, and diazepam (14.6%) followed by indomethacin (13.7%) and doxazosin (10.9%) in 2004. 21.7% (119,482) and 18.2% (98,465) of patients 65 years or older received at least one prescription of a PIM in 2003 and 2004, respectively (p < 0.001). In a multivariate logistic regression model female gender and a higher number of prescribed drugs were significantly associated with an increased frequency of receiving a PIM in both years. Conclusions: In our study, approximately every 5^th older patient was prescribed at least one PIM. For the future an ongoing update of the Beers criteria to further include newer agents and an adaptation to the different situation in European countries is desirable.Correspondence to:
Prof. Dr. med. Dr. med. dent. Wilhelm Kirch
Institute of Clinical Pharmacology
Faculty of Medicine, Technische Universität Dresden
Fiedlerstr. 27
01307 Dresden, Germany
Email: Wilhelm.Kirch@ mailbox.tu-dresden.de

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (195-201)

Antihypertensive treatment and risk of dementia: a retrospective database study

Gabriele Wagner², Andrea Icks¹, Heinz-Harald Abholz², Detlef Schröder-Bernhardi³, Wolfgang Rathmann¹ and Karel Kostev³

¹German Diabetes Center, Institute of Biometrics and Epidemiology, ²Department of General Practice, University Clinic, Heinrich Heine University, Düsseldorf, and ³IMS Health, Frankfurt/Main, Germany
Objective: Vascular risk factors play an important role in the pathogenesis of vascular dementia, as well as in Alzheimer disease. The effect of antihypertensive medication on risk of dementia is unclear. The aim was to investigate the association between antihypertensive prescriptions and incident dementia, using a primary care database. Methods: The analysis was based on 575 general and internal practices in Germany (10/2003 – 09/2008) (Disease analyzer database). Antihypertensive medication (ATC codes) during 3 years before newly diagnosed dementia (ICD codes or specific medication) in 1,297 patients was compared to 1,297 controls without dementia after matching for age (mean age: 80.6 ± 8.6 y), sex (females: 62%) and date of diagnosis. Conditional logistic regression was used to calculate crude and adjusted odds ratios (95% confidence intervals). Results: Betablocker prescriptions (≥ 1 per year over 3 y) showed a significant inverse association with newly diagnosed dementia (Odds ratio, OR: 0.79 95% CI 0.61 – 0.99) after adjusting for demographic covariates, health care use, and cardiovascular and neurological comorbidity. In the fully adjusted model, ACE inhibitors also tended to be inversely associated with incident dementia, but failed statistical significance (OR 0.84 95% CI 0.65 – 1.08). Calcium channel blockers were positively related to cognitive impairment only in the crude analysis. The other drug groups were not significantly related to dementia (diuretics OR: 0.89; 0.67 – 1.19; angiotensin- 1-inhibitors OR: 1.04; 0.66 – 1.64). Conclusions: This practice-based case-control study indicated a possible protective effect of some antihypertensive agents (betablockers, ACE-inhibitors) on the development of dementia. Randomized controlled trials are required to confirm this finding.Correspondence to:
Dr. med. Wolfgang Rathmann, MSPH (USA)
German Diabetes Center, Institute of Biometrics and Epidemiology
Auf´m Hennekamp 65, 40225 Düsseldorf, Germany
Email: rathmann@ddz. uni-duesseldorf.de

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (202-217)

Once daily nifedipine: the formulation dictates the pharmacokinetic characteristics and the therapeutic responses

Corey B. Toal¹, Peter A. Meredith² and Henry L. Elliott³

¹Department of Pharmacology, University of Toronto, Toronto, Canada, ²University of Glasgow and ³University of Strathclyde, Glasgow, UK
Nifedipine as a pharmacologic agent for treating hypertension and angina pectoris has been available worldwide since the early 1980’s. However, the formulation of nifedipine has undergone a number of modifications over time to improve the pharmacokinetic profile and administration regimen from 3 times daily to once daily. Nifedipine Gastrointestinal Therapeutic System (GITS) is the most widely studied of the once daily formulations from both a pharmacokinetic and clinical perspective. Nifedipine GITS was registered in most major countries worldwide based on both clinical pharmacology and clinical trial data in adequately powered studies. Moreover, outcome trials in both hypertension (INSIGHT) and angina pectoris (ACTION) have been completed and published. Other once daily modified release nifedipine formulations are available in a number of countries but limited published data is available on these formulations. A Pubmed (Medline) search using the terms “nifedipine pharmacokinetics” yielded 162 articles of which 7 provided detailed pharmacokinetic values in head to head comparisons of nifedipine GITS and another once a day formulation. These published pharmacokinetic studies have failed to show that any of the other formulations is consistently bioequivalent to the reference formulation, nifedipine GITS. In addition, other Pubmed searches yielded limited data from comparative clinical studies, which show significant differences in favor of the nifedipine GITS formulation in terms of blood pressure control and activation of the sympathetic nervous system. With limited data comparing once daily formulations of nifedipine to nifedipine GITS and no data comparing between other once a day formulations, for both pharmacokinetic and therapeutic reasons, the evidence indicates that patients should not be switched between once daily formulations of nifedipine.Correspondence to:
Dr. Corey B. Toal
Department of Pharmacology
University of Toronto
1 Kings College Circle
Toronto, Ontario, Canada
Email: SLIDES@bell.net

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (218-223)

Tocilizumab has no clinically relevant effects on methotrexate pharmacokinetics in patients with rheumatoid arthritis

Christophe Schmitt¹, Barbara Kuhn¹, Xiaoping Zhang², Alan Kivitz³ and Susan Grange¹

¹F. Hoffmann-La Roche AG, Basel, Switzerland, ²Hoffmann-La Roche Inc., Nutley, NJ, and ³Altoona Center for Clinical Research, Duncansville, PA, USA
Objective: To assess the effects of tocilizumab on methotrexate and 7-hydroxymethotrexate pharmacokinetics in patients with rheumatoid arthritis and to explore the pharmacodynamic effect of tocilizumab on C-reactive protein (CRP), a marker of inflammation. Methods: Methotrexate (10 – 25 mg) was administered orally on Days 1, 8, 15, 22, 29, 36, and 43. On Day 8 patients received 10 mg/kg tocilizumab intravenously. Blood samples for pharmacokinetic analyses were collected on Days 1, 15, and 43 and for pharmacodynamics (CRP) throughout the study. Results: 90% CIs for mean effect ratios (Day 15/Day 1 and Day 43/Day 1) of methotrexate and 7-hydroxymethotrexate (AUC_last and C_max) were close to or within the bioequivalence boundaries (80 – 125%). CRP normalized within 1 week after tocilizumab injection and remained within normal limits for 3 weeks. Conclusion: Tocilizumab and methotrexate can be administered concurrently without dosage adjustments.Correspondence to:
Christophe Schmitt, PharmD
Department of Clinical Pharmacology
F. Hoffmann-La Roche AG
Hochstrasse 16
Basel, 4070, Switzerland
Email: christophe.schmitt@roche.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (224-232)

A positron emission tomography microdosing study with sertraline in healthy volunteers

Kwang-Hee Shin¹, Kyu-pyo Kim¹, Kyoung Soo Lim¹, Ji Who Kim², Yun-Sang Lee², Bo Yeun Yang², Jae Sung Lee², Jae-Min Jung², Seo-Hyun Yoon¹, In-Jin Jang¹ and Kyung-Sang Yu¹

¹Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, and ²Department of Nuclear Medicine, Seoul National University College of Medicine and Hospital, Seoul, Korea
Objective: This study explored microdosing methods for evaluating the distribution and pharmacokinetics (PK) of a central nervous system (CNS) drug candidate. Methods: We used sertraline as a model drug. In this open-label, one-arm, three-period, multiple-dosing study, 10 healthy male volunteers received 6-day administrations of sertraline at doses of 5, 25 or 50 mg/d in three different periods. Before the first dose of Period 1, and 24 h after the last dose of each period, an intravenous bolus of [¹¹C]sertraline was injected for positron emission tomography (PET) scanning. After the sixth dose in each period, serial blood samples were collected at scheduled intervals over 48 h; then serum sertraline concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Sertraline was distributed in the brain within 20 min, and it was highly distributed in the putamen, cingulate, and thalamus. Linearity in steady-state C_max and AUC_last were observed in the 5 – 50 mg dose range. The results suggested that microdosing with PET was a useful method for exploring the bloodbrain- barrier penetration and distribution of a candidate CNS drug. Conclusions: This study described a microdosing method that combined PET with LC-MS/MS for determining the brain distribution and PK characteristics of a CNS drug candidate.Correspondence to:
Kyung-Sang Yu, MD, PhD
Assistant Professor of Clinical Pharmacology
College of Medicine
Seoul National University Clinical Trials
Center Seoul National University Hospital
101 Daehangno, Jongno-gu,
Seoul, 110-744 Korea
Email: happyi69@snu.ac.kr

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (233-236)

In vitro activity of green tea extract against Leishmania major promastigotes

Amir Feily¹, Jasem Saki², Sharif Maraghi², Zahra Moosavi¹, Sharam Khademvatan³ and Amir Siahpoosh⁴

¹Infectious Diseases and Tropical Research Center and Department of Dermatology, ²Department of Medical Parasitology, School of Medicine and Infectious Diseases and Tropical Research Center, ³Department of Medical Parasitology, School of Medicine and Cellular and Molecular Research Center and ⁴Medicinal Plant and Natural Product Research Center, Department of Pharmacognosy, School of Pharmacy, School of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran
Background: Systemic and topical treatment options against Leishmaniasis are limited to a few drugs with inconsistent efficacy and unacceptable side effects and none of them is suitable for all forms of the disease. Objective: The aim of this study was to search the in vitro activity of green tea extract against L. major promastigotes and compare it with glucantime. Methods: Extract was prepared by percolation method. The extract was dried and dissolved in DMSO 1% solvent. Leishmania major promastigotes treated with 6 concentrations (3, 6, 12, 24, 48, 96 mg/ml) of the extract. As control positive group glucantime 85 mg/ml and additional untreated control group were included in this study. All cultures were performed in triplicate. The promastigotes were also counted and their flagellate’s motilities were assessed microscopically. Results: Ethanolic extract of green tea showed significant leishmanicidal activity against L. major promastigotes in different concentrations. Notably there was a concordance in anti-leishmanial effect of the ethanol extract with the increasing of the dosage (3, 6, 12, 24, 48, 96 mg/ml). In comparison with glucantime the mean alive promastigotes in 12 mg/ml concentration of green tea was almost as same as 85 mg/ml glucantime and higher green tea extract concentrations were higher effective than glucantime. Conclusion: Our study revealed a novel pharmacological activity against promastigotes of L. major and suggests that green tea extract has the potential of being used in leishmaniasis but more studies are needed to find out its activity against amastigote and appropriate route of application.Correspondence to:
J. Saki, PhD, Assistant Professor of Parasitology
Department of Medical Parasitology
Jundishapur University of Medical Sciences
Ahvaz, Iran
Email: jasem.saki@gmail.com

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Volume 50, No. 3/2012(March)