Enhanced etoposide sensitivity following adenovirus-mediated human topoisomerase II α gene transfer is independent of topoisomerase II β

The roles that the α and β isoforms of topoisomerase II (topo II) play in anticancer drug action were determined using MDA-VP etoposide-resistant human breast cancer cells and a newly constructed adenoviral vector containing the topo IIα gene (Ad-topo IIα). MDA-VP cells were more resistant to etoposide than to amsacrine and had more resistance to etoposide than did MDA-parental cells. MDA-VP cells also expressed lower topo IIα RNA and protein levels than parental cells but had comparable topo IIβ levels. After infection with Ad-topo IIα, topo IIα, RNA and protein levels increased significantly, as did the cells' sensitivity to etoposide. In contrast, topo IIβ levels remained constant with little alteration in the cells' sensitivity to amsacrine. Band-depletion immunoblotting assays indicated that topo IIα was depleted in etoposide-treated, Ad-topo IIα-transduced MDA-VP cells but not in amsacrine-treated cells. Topo IIβ was depleted in amsacrine-treated, Ad-topo IIα-MDA-VP cells, with little change in the topo IIα levels. These results suggest that topo IIα gene transfer does not alter topo IIβ expression and that enhanced sensitivity to etoposide is therefore secondary to change in topo IIα levels. These studies support the theory that etoposide preferentially targets topo IIα, while amsacrine targets topo IIβ. © 2001 Cancer Research Campaign http://www.bjcancer.co

Impact of opioid rescue medication for breakthrough pain on the efficacy and tolerability of long-acting opioids in patients with chronic non-malignant pain

There is little evidence that short-acting opioids as rescue medication for breakthrough pain is an optimal long-term treatment strategy in chronic non-malignant pain. We compared clinical studies of long-acting opioids that allowed short-acting opioid rescue medication with those that did not, to determine the impact of opioid rescue medication use on the analgesic efficacy and tolerability of chronic opioid therapy in patients with chronic non-malignant pain. We searched MEDLINE (1950 to July 2006) and EMBASE (1974 to July 2006) using terms for chronic non-malignant pain and long-acting opioids. Independent review of the search results identified 48 studies that met the study selection criteria. The effect of opioid rescue medication on analgesic efficacy and the incidence of common opioid-related side-effects were analysed using meta-regression. After adjusting for potentially confounding variables (study design and type of opioid), the difference in analgesic efficacy between the 'rescue' and the 'no rescue' studies was not significant, with regression coefficients close to 0 and 95% confidence intervals that excluded an effect of more than 18 points on a 0-100 scale in each case. There was also no significant difference between the 'rescue' and the 'no rescue' studies for the incidence of nausea, constipation, or somnolence in both the unadjusted and the adjusted analyses. We found no evidence that rescue medication with short-acting opioids for breakthrough pain affects analgesic efficacy of long-acting opioids or the incidence of common opioid-related side-effects among chronic non-malignant pain patients

Bridging health technology assessment (HTA) with multicriteria decision analyses (MCDA): field testing of the EVIDEM framework for coverage decisions by a public payer in Canada

<p>Abstract</p> <p>Background</p> <p>Consistent healthcare decisionmaking requires systematic consideration of decision criteria and evidence available to inform them. This can be tackled by combining multicriteria decision analysis (MCDA) and Health Technology Assessment (HTA). The objective of this study was to field-test a decision support framework (EVIDEM), explore its utility to a drug advisory committee and test its reliability over time.</p> <p>Methods</p> <p>Tramadol for chronic non-cancer pain was selected by the health plan as a case study relevant to their context. Based on extensive literature review, a by-criterion HTA report was developed to provide synthesized evidence for each criterion of the framework (14 criteria for the MCDA Core Model and 6 qualitative criteria for the Contextual Tool). During workshop sessions, committee members tested the framework in three steps by assigning: 1) weights to each criterion of the MCDA Core Model representing individual perspective; 2) scores for tramadol for each criterion of the MCDA Core Model using synthesized data; and 3) qualitative impacts of criteria of the Contextual Tool on the appraisal. Utility and reliability of the approach were explored through discussion, survey and test-retest. Agreement between test and retest data was analyzed by calculating intra-rater correlation coefficients (ICCs) for weights, scores and MCDA value estimates.</p> <p>Results</p> <p>The framework was found useful by the drug advisory committee in supporting systematic consideration of a broad range of criteria to promote a consistent approach to appraising healthcare interventions. Directly integrated in the framework as a "by-criterion" HTA report, synthesized evidence for each criterion facilitated its consideration, although this was sometimes limited by lack of relevant data. Test-retest analysis showed fair to good consistency of weights, scores and MCDA value estimates at the individual level (ICC ranging from 0.676 to 0.698), thus lending some support for the reliability of the approach. Overall, committee members endorsed the inclusion of most framework criteria and revealed important areas of discussion, clarification and adaptation of the framework to the needs of the committee.</p> <p>Conclusions</p> <p>By promoting systematic consideration of all decision criteria and the underlying evidence, the framework allows a consistent approach to appraising healthcare interventions. Further testing and validation are needed to advance MCDA approaches in healthcare decisionmaking.</p

Pharmacokinetic evaluation of a new oral sustained release dosage form of tramadol

Aims: To compare the pharmacokinetic profile of a new modified release formulation of tramadol (Tramadol LP 200 mg, SMB Technology, Marche-en-Famenne, Belgium) with that of an immediate release capsule (Topalgic® 50 mg, Grünenthal, Aachen, Germany) after single and multiple dosing and to assess the potential effect of food on its relative bioavailability. Methods: The first study had an open, single-dose, three-treatment, three-period, six-sequence, randomised, crossover design with at least a five-day wash-out. The second study had an open, steady-state, two-treatment, two-period, two-sequence, randomised crossover design with at least a seven-day wash-out. Both studies contained 30 healthy subjects. Both enantiomers of tramadol and O-demethyl-tramadol (the only active metabolite of tramadol) were assayed in the plasma using an LC-MS/MS method. AUC∞, AUCt, Cmax, Tmax, and T1/2 were estimated. Statistical analysis was performed using univariate ANOVA, the Wilcoxon nonparametric method or Friedman's nonparametric ANOVA where appropriate. Results: Tramadol had a significantly lower Cmax and longer Tmax than the conventional formulation. Thus, the mean (± sd) Cmax, of tramadol were 646 ± 192 and 300 ± 94 ng ml-1 for Topalgic® 4 x 50mg and Tramadol LP 200 mg, respectively (95% confidence interval on the difference expressed as a percentage 42-51). AUC of tramadol from both formulations was comparable (similar AUC∞ and AUCt). Thus, the mean AUC∞ of (+/-)tramadol obtained after multiple dosing were 4611 ± 1944 and 5105 ± 2101 ngh ml-1 after Topalgic® 4 x 50mg and Tramadol LP 200 mg, respectively (95%Cl 102-123%). We also demonstrate that the pharmacokinetics of the drug are not influenced by the intake of food. Thus, the mean AUC∞ of (+/-) tramadol were 5444 ± 1637 and 5169 ± 1580 ngh ml-1 after Tramadol LP 200 mg given in the fasting and fed states, respectively (95%Cl = 88-103%). Conclusions: The new sustained release form of tramadol exhibits adequate properties for once a day administration. Furthermore, its pharmacokinetic profile is not affected by the intake of food.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Use of hydrophilic natural gums in formulation of sustained-release matrix tablets of tramadol hydrochloride

The objective of this work was to develop matrix sustained-release tablets of highly water-soluble tramadol HCl using natural gums (xanthan [X gum] and guar [G gum]) as cost-effective, nontoxic, easily available, and suitable hydrophilic matrix systems compared with the extensively investigated hydrophilic matrices (ie, hydroxypropyl methylcellulose [HPMC]/carboxymethyl cellulose [CMC] with respect to in vitro drug release rate) and hydration rate of the polymers. Matrix tablets of tramadol (dose 100 mg) were produced by direct compression method. Different ratios, of 100∶0, 80∶20, 60∶40, 20∶80, 0∶100 of G gum (or X):HPMC, X gum:G gum, and triple mixture of these polymers (G gum, X gum, HPMC) were applied. After evaluation of physical characteristics of tablets, the dissolution test was, performed in the phosphate buffer media (pH 7.4) up to 8 hours. Tablets with only X had the highest mean dissolution time (MDT), the least dissolution efficiency (DE8%), and released the drug following a zero-order model via swelling, diffusion, and erosion mechanisms. Guar gum alone could not efficiently control the drug release, while X and all combinations of natural gums with HPMC could retard tramadol HCl release. However, according to the similarity factor (f2), pure HPMC and H8G2 were the most similar formulations to Topalgic-LP as the reference standard