Volume 41, No. 9/2003(September)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pain therapy
Relief of acute low back pain with diclofenac-K 12.5 mg tablets: a flexible
dose, ibuprofen 200 mg and placebo-controlled clinical trial
Abstract
R.L. Dreiser, M. Marty, E. Ionescu, M. Gold and J.H. Liu
1Paris, France, 2Clinica & Statistica, Issy les Moulineaux, France,
3Novartis Consumer Health SA, Nyon, Switzerland, and
4Novartis Consumer Health Inc., Parsippany, NJ, USA
Objective: To assess efficacy and safety of diclofenac-K 12.5 mg tablets in the treatment of acute low back pain (low back pain). Material/method: A multiple dose, double-blind, double-dummy, randomized, placebo-controlled, parallel group trial compared diclofenac-K (12.5 mg; n = 124) with ibuprofen (200 mg; n = 122) and placebo (n = 126) in patients with moderate-to-severe acute low back pain. The treatment consisted of an initial dose of 2 tablets followed by 1 or 2 tablets every 4 – 6 hours as needed (maximum 6 tablets/day) for 7 days. The primary efficacy outcome for the initial dose was TOTPAR-3, the summed total pain relief over the first 3 hours. Secondary initial dose outcomes included TOTPAR-6, summed pain intensity differences SPID-3 and SPID-6, time to rescue medication or remedicate, and the End of First Dose global efficacy assessment. The primary efficacy outcome for the flexible multiple dosing regimen was the End of Study global efficacy assessment. Secondary outcomes for multiple dosing included time to rescue medication over the entire study, the End of Day global efficacy assessments (daily over Days 1 – 7), pain intensity differences on the VAS measured at Visit 2 and 3, and change in Eifel algofunctional index. Safety/tolerability was assessed by recording adverse events. Results: Diclofenac-K 12.5 mg demonstrated superiority vs placebo on the primary efficacy parameter and almost all secondary initial dose outcomes. With respect to the initial dose, diclofenac-K 12.5 mg was also significantly superior to ibuprofen 200 mg on SPID-3. Ibuprofen 200 mg was superior to placebo only on the End of First Dose global efficacy assessment. The flexible multiple dosing regimens of diclofenac-K and ibuprofen were both significantly superior to placebo on the End of Study global efficacy assessment, time to rescue medication over the entire study period, the End of Day global efficacy assessment on Days 1 – 2, pain intensity difference on the VAS at Visit 3 and the Eifel algofunctional index at Visit 3 (also at Visit 2 in diclofenac-K 12.5 mg group). Both active treatments were as well tolerated as placebo. Conclusions: The flexible multiple dosing regimen of diclofenac-K 12.5 mg (initial dose of 2 tablets followed by 1 – 2 tablets every 4 – 6 hours, max. 75 mg/day) is an effective and safe treatment of acute low back pain.
Endothelial function
L-calcium channel blockade induced by diltiazem inhibits proliferation, migration and F-actin membrane rearrangements in human vascular smooth muscle cells stimulated with insulin and IGF-1
Abstract
A. Ruiz-Torres1, R. Lozano1, J. Melón2 and R. Carraro1,3
1University Research Institute of Aging and Metabolism,
2Department of Cardiovascular Surgery, and
3Department of Endocrinology, Hospital de la Princesa, Madrid, Spain
During the atheroma plaque formation, smooth muscle cells (SMC) have to change their differentiated phenotype in order to proliferate, migrate and synthesize collagen. These phenotypic changes are stimulated by insulin and IGF-1, and we have studied the effect of L-type calcium channel blockade produced by diltiazem on such changes. Mitotic activity was measured using bromodeoxyuridine DNA incorporation, the migration capability as chemotaxis index in a Boyden chamber, and cytoskeleton changes related to SMC movement in immunofluorescence studies. Diltiazem (10–7 – 10–6 M) reduced insulin-induced mitotic activity in cultured human vascular SMC more effectively than in IGF-1-induced mitotic activity, but at 10–5 M, the inhibitory effects were similar. Diltiazem also showed a clear inhibition of migration ability, both under basal conditions (p < 0.05) and after addition of insulin (p = 0.0001) and IGF-1 (p < 0.0001). Finally, diltiazem inhibited membrane ruffling induced both by insulin and IGF-1 in a similar manner, and similar results were obtained with SMC from rat aorta. We conclude that substances blocking the L-type calcium channels such as diltiazem, could inhibit those processes which in vivo lead SMC to form the atheroma plaque.
Pharmacokinetics
Impact of random and fixed (optimal) sampling approach on the Bayesian estimation of clearance
Abstract
I. Mahmood
Office of Therapeutic Research and Review, Division of Clinical Trial Design and Analysis, Clinical Pharmacology and Toxicology Branch, Center for Biologics Evaluation and Research, Food and Drug Administration, Woodmont Office Center I, Rockville, MD, US
Background and objective: The population pharmacokinetic approach is based on sparse sampling. In sparse sampling approaches, the selection of the time point(s) is very critical for the prediction of pharmacokinetic parameters. Several investigators have shown that the predictive performance of the Bayesian approach is influenced by the initial estimates of pharmacokinetic parameters as well as the time of blood sampling. The objective of this study is to evaluate the impact of random and fixed sparse sampling approach on the Bayesian estimation of clearance. Methods: Three drugs were selected for this study. Two sparse sampling methods (random or fixed) using Bayesian approach were used to assess clearance in healthy subjects following a single oral dose. The initial estimates of the model parameters and inter- and intra-subject variabilities were obtained from the previous pharmacokinetic studies conducted in healthy volunteers. The predicted clearance values using sparse sampling (1, 2 or 3 blood samples per subject) were compared with the clearance values obtained by extensive sampling. Results and conclusion: The results indicated that both random and fixed sampling approaches, irrespective of number of blood samples, can be used to estimate mean population as well as post hoc predicted individual clearance (Bayesian) with accuracy. However, the precision of the prediction of clearance was found to be better with fixed rather random blood sampling approach.
Pleiotropic effects of statins
Statins differ in their ability to block NF-kB activation in human blood monocytes
Abstract
A. Hilgendorff, H. Muth, B. Parviz, A. Staubitz, W. Haberbosch, H. Tillmanns and H. Hölschermann
Department of Internal Medicine, Justus Liebig University, Giessen, Germany
Objective: The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kB, a transcription factor involved in the activation of immediately early genes during inflammation. Methods: Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 mg/ml) in the presence and absence of statin (0.001 – 5 mM). NF-kB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkB-a (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed. Results: All statins inhibited LPS-induced NF-kB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kB inhibitor protein IkB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 ± 9% inhibition, p < 0.05) was 9-fold more effective in reducing NF-kB activation than Flu (5 ± 10% inhibition). The differences in the potency of statins (Cer > Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kB controlled tissue factor expression. Conclusions: The finding that statins differ in their potency in interfering with the activation of NF-kB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.
Drug development
Drug development Proceedings of the Fifth Scripps Clinic - BIO Conference on Drug Development
Abstract
La Jolla, California, February 11-13, 2003
Drug development
Erratum
Drug development
Announcement
