Volume 44, No. 6/2006(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Plant stanol and sterol esters in prevention of cardiovascular diseases: a review
Abstract
T.A. Miettinen and H. Gylling
1Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, and 2Department of Clinical Nutrition, University of Kuopio, and Kuopio University Hospital, Kuopio, Finland
Plant sterol and stanol esters have been introduced as an additional dietary means to lower serum total and LDL cholesterol concentration. In short-term studies they lower LDL cholesterol by 10%, and according to a meta-analysis by Malcolm Law the incidence of coronary heart disease is considered to be reduced by over 20% in long-term use of these products. Plant stanol and sterol esters are not identical sterols; they have different metabolic effects and their long-term efficacy seems to be different. The present review deals with the differences of the sterols and discusses what is known of their role in preventing the cardiovascular diseases.Correspondence to:
T.A. Miettinen, MD
Biomedicum Helsinki, Room C422
P.O. Box 700
00029 Hus, Finland
Email: tatu.a.miettinen@helsinki.fi
Adverse Drug Reactions
Effect of long-term atorvastatin treatment on the electrophysiological and mechanical functions of muscle
Abstract
S. Delliaux, J.G. Steinberg, N. Lesavre, F. Paganelli, C. Oliver and Y. Jammes
1Aix-Marseille 2 University, EA 2201, Institute Jean Roche, Faculty of Medicine, and Assistance Public Hospitals Marseille, Department of Functional Respiratory Research, North Hospital, Marseille, 2Clinical Investigations Center (CIC), and 3Department of Cardiology, Public Hospitals Marseille, North Hospital Marseille, France
Objective: To study alterations in muscle function combining physiological, electrophysiological and metabolic measurements in patients receiving a statin at various dosages during long-term therapy. Material: A 3-month (D0, D30 and D90) longitudinal physiological and electrophysiological muscle study was performed in 26 patients receiving 10, 40 or 80 mg/day atorvastatin. Method: All subjects performed maximal (MVC) and submaximal (60% MVC) isometric thumb adduction, handgrip and knee extension exercises during the recording of surface electromyograms (EMG) of the adductor pollicis (AP), flexor digitorum (FD) and vastus lateralis (VL). The compound muscle potential (M-wave) evoked by direct muscle stimulation was measured at rest and after 60% MVCs and the EMG power spectrum was analyzed during sustained effort. Blood was sampled from an antecubital vein for measurements of pH, lactate and potassium levels after thumb adduction and handgrip exercises. The measurements were repeated on Day 0 (D0), D30 and D90. Results: Atorvastatin did not affect the MVC and endurance time to fatigue. Post-exercise M-wave alterations in the AP began at D30 with the 80 mg/day treatment and there was a reduced or suppressed leftward shift in the EMG power spectrum in the AP and VL with all 3 dosages. In the AP, the EMG changes appeared earlier (D30) with 80 mg/day whereas they only occurred at D90 on the lower dosages. Atorvastatin had no effect on the maximal post-exercise variations in pHv and lactate but it significantly reduced the maximal increase in plasma potassium concentration after thumb adduction and handgrip exercise, the effects being only present at D90 on 10 mg/day but occurring as early as D30 with higher dosages. Conclusion: A 3-month atorvastatin treatment did not affect the maximal performance of skeletal muscle during voluntary efforts but EMG analysis revealed a reduced muscle excitability and an attenuated adaptation to fatigue. These effects prevailed in muscles containing the largest proportion of slow-oxidative fibers and were associated with a reduced outward flow of potassium. Correspondence to:
Prof. Y. Jammes
Jean Roche Institute
Faculty of Medicine
Bd. Pierre Dramard
13916 Marseille cedex 20, France
Email: jammes.y@jean-roche.univ-mrs.fr
Therapeutics
Do intensive care patients need an individualized dosing regimen for levofloxacin?
Abstract
Z.R. Tayab1, G. Hochhaus1, S. Kaufmann2, D. Jäger2 and J. Barth2
1Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA, and 2Clinics of the Berufsgenossenschaft Bergmannstrost, Halle, Germany
Objective: In general, the pharmacokinetics (PK) of antibiotics in intensive care unit (ICU) patients are known to differ from healthy subjects. These differences can pose challenges in developing appropriate dosing guidelines. The primary objective of this report was to characterize the disposition of levofloxacin in critically ill patients and to assess any relationships between patient covariates and the PK parameters. Methods: 20 patients in the ICU were given levofloxacin, 500 mg, as an i.v. infusion for a half hour. Plasma samples were taken until 24 hours and assayed using HPLC. The concentration-time data were analyzed using population analysis with NONMEM. Results: The data were described using a 2-compartment model. Creatinine clearance was determined to be a statistically significant predictor of variability in total levofloxacin clearance. For patients with higher levofloxacin clearance, the resulting efficacy for different strains of bacteria (expressed as free AUC/MIC ratios) suggested that for less sensitive pathogens, a dosage adjustment may be needed. Conclusion: A model describing the pharmacokinetics of levofloxacin in critically ill patients was developed. It was determined that creatinine clearance has a significant role in the disposition of levofloxacin. This may have significant implications in the clinical setting for identifying optimal dosage regimens for ICU patients.Correspondence to:
G. Hochhaus, PhD
P.O. Box 100494
Department of Pharmaceutics
College of Pharmacy, JHMHC
University of Florida
Gainesville, FL 32610, USA
Email: hochhaus@cop.ufl.edu
Pharmacokinetics
The diffusion of nimesulide gel into synovial fluid: a comparison between administration routes
Abstract
F. Erdogan2, H. Ergün1, N.S. Gökay2, S.E. Gulmez1, B. Bolay3 and F.C. Tulunay1
1Faculty of Medicine, Department of Pharmacology and Clinical Pharmacology, Ankara University, Ankara, 2Department of Orthopedics and Traumatology, and 3Physical Medicine and Rehabilitation, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey
Background: Nimesulide is available in gel formulation and applied mainly for topical pain management. However, its passage to the synovial fluid is not yet clear. The aim of this study was to evaluate if topical administered nimesulide passes into the synovial fluid and to compare its concentration with the oral nimesulide administration regimen. Methods: Synovia and plasma nimesulide concentrations were investigated in patients after topical (Sulidin gel® 1%) and oral (Mesulid® tablet) drug administration. 34 adult outpatients who were scheduled to have an arthroscopic knee examination for mainly meniscal tears repair and who had knee pain during this period were enrolled in the first part of the study. One group received topical nimesulide gel to the skin of the knee whereas the second group received oral 2 × 100 mg nimesulide tablets, 4 – 7 days before the planned arthroscopy. Synovial fluid and plasma samples were taken simultaneously during the arthroscopy and analyzed using HPLC. In addition, an open-label pilot study was performed to investigate the efficacy and safety of 1-week administration of nimesulide gel. 63 knee osteoarthritis patients were asked to complete the WOMAC Osteoarthritis Index questionnaire before and 1 week after use of Sulidin gel® applied 3 times daily. Results: Synovia and plasma nimesulide concentrations were 19.7 ± 8.6, 11.8 ± 3.0 and 1,958.8 ± 397.5, 3,631.9 ± 799.3 ng/ ml for topical and oral administration groups, respectively. There was a significant (paired Student’s t-test) improvement after 1 week nimesulide treatment in all WOMAC Osteoarthritis Index parameters measured. Conclusion: Nimesulide passes into the synovial fluid after topical administration and may have potential benefits in knee osteoarthritis treatment. The actual efficacy and safety of topical nimesulide gel administration should be investigated in a long-term, randomized, placebo-controlled clinical trial. Correspondence to:
Doç. Dr. H. Ergün
Ankara University
Faculty of Medicine
Department of Pharmacology and Clinical Pharmacology Ab.D.
06100, Sihhiye, Ankara, Turkey
Email: hergun@medicine.ankara.edu.tr
Biavailability Section
Nevirapine/lamivudine/stavudine as a combined-formulation tablet: bioequivalence study compared with each component administered concurrently under fasting condition
Abstract
T. Monif1, S.K. Tippabhotla1, M. Garg2, A.K. Singla2 and T. Vijan2
1Department of Clinical Pharmacology and Pharmacokinetics, and 2Department of Product Development and Research, Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India
Objective: The objective of the study was to compare the bioequivalence of a fixed-dose combination of a nevirapine 200 mg, lamivudine 150 mg and stavudine 30 mg combination tablet with application of the 3 medications, at the same dosage, concurrently as separate formulations, in healthy, adult subjects under fasting conditions. Material and methods: An open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover bioavailability study was conducted in 40 subjects with 21-day washout period between each treatment. Blood samples were collected for 168 hours. Plasma concentrations of nevirapine, lamivudine and stavudine were determined using a validated LC-MS-MS method. Non-compartmental pharmacokinetics and statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC, USA) software (SAS System under Windows, Version 8.02). Results: The ratios of least-square means and the 90% confidence intervals of the log-transformed data were calculated for AUC0-t, AUC0-inf, and Cmax. The 90% confidence interval for least-square mean ratio between test and reference formulation for log-transformed parameters Cmax, AUC0-t and AUC0-inf were within the requirements of the 80 – 125% range. Conclusion: The test formulation (Ranbaxy Laboratories Ltd., Gurgaon, India) is bioequivalent to the reference formulations both in terms of rate and extent of absorption after single-dose administration under fasting condition.Correspondence to:
T. Monif, PhD
Director, Department of Clinical Pharmacology and Pharmacokinetics
Ranbaxy Laboratories Ltd.
Plot No. 20, Sector-18
Udyog Vihar Industrial Area
Gurgaon – 122 001, Haryana, India
Email: tausif.monif@ranbaxy.com
Biavailability Section
Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions
Abstract
J.F. Marier1, M. Borges1, G. Plante1, M. DiMarco1, G. Morelli1, S.K. Tippabhotla2, T. Vijan2, A.K. Singla2, M. Garg2 and T. Monif2
1MDS Pharma Services, St.-Laurent, Montreal, Quebec, Canada, 2Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India
Objective: Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. Material and methods: A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n = 40) and fed (n = 40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. Results: Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC0-t), area under the curve extrapolated to infinity (AUC0-¥) and maximum plasma concentrations (Cmax) of abacavir for the generic (5,565 ng × h/ml, 5,668 ng × h/ml and 2,526 ng/ml, respectively) and innovator (5,675 ng × h/ml, 5,770 ng × h/ml and 2,528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC0-t, AUC0-¥ and Cmax for the generic (4,487 ng × h/ml, 4,571 ng × h/ml and 1,841 ng/ml, respectively) and innovator (4,574 ng × h/ml, 4,654 ng × h/ml and 1,781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 – 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. Conclusions: Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.
Correspondence to:
T. Monif, PhD
Director, Department of Clinical Pharmacology and Pharmacokinetics
Ranbaxy Laboratories Ltd.
Plot No. 20, Sector-18
Udyog Vihar Industrial Area
Gurgaon – 122 001, Haryana, India
Email: tausif.monif@ranbaxy.com
Letters to the Editor
Pharmacokinetic simulations and AUC: Center specificity in the limited sampling model
Letters to the Editor
Reply to J. Proost
Letters to the Editor
Commercial Announcement
