Aims
Bioequivalence (BE) trials aim to demonstrate that the 90% confidence interval of the T/R‐ratio of the pharmacokinetic metrics between two formulations (test T and reference R) of a drug is ...fully included in the acceptance interval 0.80, 1.25. Traditionally, the sample size of BE trials is based on a power calculation based on the intrasubject variability coefficient of variation (CV) and the T/R‐ratio of the metrics. Since the exact value of the T/R‐ratio is not known prior to the trial, it is often assumed that the difference between the treatments does not exceed 5%. Hence, uncertainty about the T/R‐ratio is expressed by using a fixed value for the sample size calculation. We propose to characterise the uncertainty about the T/R‐ratio by a (normal) distribution for the log(T/R‐ratio), with an assumed mean of log θ = 0.00 (i.e. θ = 1.00) and a standard deviation σu, which quantifies the uncertainty. Evaluating this distribution leads to the statistical assurance of the BE trial.
Methods
The assurance of a clinical trial can be derived by integrating the power over the distribution of the input parameters, in this case, the assumed distribution of the log(T/R)‐ratio. Because it is an average power, the assurance can be interpreted as a measure of the probability of success that does not depend on a specific assumed value for the log(T/R)‐ratio. The relationship between power and assurance will be analysed by comparing the numerical outcomes.
Results
Using the assurance concept, values of the standard deviation for the distribution of potential log(T/R)‐ratios can be chosen to reflect the magnitude of uncertainty. For most practical cases (i.e. when 0.95 ≤ θ ≤ 1.05), the sample size is not, or only slightly, changed when σ = |log(θ)|.
Conclusion
The advantage of deriving the assurance for BE trials is that uncertainty is directly expressed as a parameter of variability.
In order to assess the pathogenesis of myopathological alterations induced by zidovudine, we studied muscle samples from 21 patients infected by human immunodeficiency virus with zidovudine myopathy. ...Cytochrome c oxidase histoenzymatic reaction was evaluated in skeletal muscle fibres and arterial smooth muscle cells. Other investigations included immunocytochemistry for membrane attack complex and endomysial capillary counts. All patients had partial cytochrome c oxidase deficiency. A perifascicular distribution of cytochrome c oxidase-deficient fibres was found in 14 of 21 patients. Cytochrome c oxidase-deficient fibres were significantly more frequent in perifascicular areas than in the complete muscle sections (28% vs 12%, P < 0.001). Cytochrome c oxidase-deficient arteries were found in 11 patients, of whom 10 also had a perifascicular deficiency. Mononuclear microvascular inflammation was observed in four patients and membrane attack complex deposition in capillary walls in two patients. The capillary counts were not significantly different in the patients and in the controls. These results suggest that, in addition to a direct action of zidovudine on mitochondrial DNA, chronic muscle ischaemia related to zidovudine-induced vascular dysfunction might be implicated at the inception of muscle damage in zidovudine myopathy.
Dans la maladie de Parkinson (MP), il est admis aujourd’hui que les signes moteurs sont associés et souvent précédés de manifestations non motrices dont la liste s’est beaucoup enrichie.
Rapporter la ...prévalence des symptômes non moteurs (SNM) au cours de la MP, afin d’optimiser leur prise en charge et améliorer ainsi la qualité de vie des patients.
Étude descriptive transversale étalée sur 01 mois chez des patients parkinsoniens suivis en consultation. Nous avons analysé les caractéristiques cliniques et épidémiologiques (l’âge, le sex-ratio, la durée d’évolution de la maladie, le score UPDRS III, le traitement en cours), ainsi que les SNM (psycho-cognitifs, dysautonomiques et sensitivo-douloureux), en délivrant un auto-questionnaire (NMSQuest) – en langues arabe ou française – rempli par le patient ou son aidant.
Au total, 54 patients ont été recensés, tous ont rempli le NMS Quest. Âge moyen : 61,17±9,82 (43–81) ans, sex-ratio H/F : 1,35, durée moyenne d’évolution de la maladie : 6±5,95 (1–35) ans, 94,44 % des patients sont sous dopathérapie (AD, IMAO-B, iCOMT, L-DOPA), la dose totale journalière moyenne est de 400mg/j. Tous les stades de Hoehn et Yahr (HY) ont été appréciés. La forme mixte est prédominante. La moyenne des SNM a été de 11,13 allant de 3–28, pour un maximum de 30.
Nos données diffèrent des données de la littérature classant les troubles sexuels en 1er lieu, sous évalués chez nous (tabou : 20 % patients n’ont pas répondu aux questions 18 et 19 du NMSQuest). Corrélation significative entre la sévérité de la maladie jugée par le score de Hoehn et Yahr et le score NMSQuest.
La plupart des SNM sont traitables. La validation du NMSQuest en arabe et en français serait intéressante car c’est un outil d’évaluation simple et performant.
We studied mitochondrial function in inflammatory myopathies, using cytochrome c oxidase (COX) reaction on muscle biopsy samples from 30 patients (15 with dermatomyositis, 12 with polymyositis, and 3 ...with inclusion body myositis) and 30 age-matched controls. We also performed immunocytochemistry for COX II and COX IV subunits in 7 of these patients who had COX deficiency. COX-deficient fibers were a constant finding in patients or controls older than 65 years and the percentage of COX-deficient fibers correlated with age in both patients and controls. Focal COX deficiency was found in 24 patients (13 of 15 with dermatomyositis, 8 of 12 with polymyositis, and 3 of 3 with inclusion body myositis) and 18 controls. The percentages of COX-deficient fibers were higher in patients with inflammatory myopathies (range: 0-4.7%; mean: 1.2%) than in age-matched controls (range: 0-1.9%; mean: 0.4%) (P < 0.01). In the subgroup of patients under age 65, COX-deficient fibers were more frequent in dermatomyositis than in polymyositis (mean: 0.8% vs 0.2%, P = 0.02). In patients with dermatomyositis, capillary loss correlated positively with COX deficiency (P < 0.02). Immunocytochemistry for COX II and IV showed that 82% of COX-negative fibers were COX II-negative and 26% were COX IV-negative, suggesting that proteins encoded by mitochondrial DNA are predominantly, but not exclusively, involved in COX deficiency. We conclude that mitochondrial dysfunction and COX deficiency can occur in inflammatory myopathies. Such a mitochondrial dysfunction is not solely related to the aging process. We suggest that muscle ischemia contributes to mitochondrial dysfunction in dermatomyositis.
The phospholipase (PL)A2 inhibitor p-bromophenacyl bromide (p-BPB), the antagonists of the platelet activating factor (PAF) 3-(4-(2-chlorophenyl)-9-methyl-6H-thieno(3,2-f)-(1,2,4)triazolo(4, ...3-a)(1,4)diazepine-2-yl)-1-(4-morpholinyl)-1-propanone (a thieno-triazolo-diazepine, WEB 2086) and terpene-ginkgolide B and the antihistamine with PAF antagonistic qualities 4,9-dihydro-4-(1-methyl-4-piperidinylidene)-10H-benzo2,5cyclo hep ta1,2-bthiophen-10-one (ketotifen) inhibit in the order p-BPB greater than terpene-ginkgolide B greater than ketotifen greater than WEB 2086 with decreasing activity the protamine sulphate activated histamine release from peritoneal rat mast cells (pRMC) in vitro. All compounds also inhibit the PAF induced aggregation of human platelets. The order of inhibition of the histamine release by these compounds does not agree with the order of their inhibitory activity on PAF induced aggregation of human platelets, indicating that the inhibition of the mast cell degranulation caused by PAF antagonists does not occur via PAF receptors. A generally membrane stabilizing quality of terpene-ginkgolide B and WEB 2086 may be ruled out as the cause of degranulation inhibition because none of the compounds suppresses the cytotoxic, triton X-100 induced release of histamine from pRMC. The mechanism of mast cell degranulation inhibition by PAF antagonists is unclear. An inhibition of PLA2 and/or inhibition of the Ca(2+)-activation are suggested.
The crystal and molecular structure of the potential cardiotonic agent AWD 122-60 have been determined by X-ray structure analysis. Based on the molecular structure charge distribution and molecular ...electrostatic potential were evaluated. The results are discussed in comparison with those of other cardiotonic 3,4'-bipyridines.
Using Hansch formalism, the suthors studied quantitatively the relationship between the structure and the inhibitory action of 3- and 4-substituted amidinophenyl derivatives on thrombin, plasmin and ...trypsin. It was found that the inhibitory action on all three enzymes depends in the same way from the hydrophobic and electronic properties of the substituents and from an additional term in case of substituents with X-CO-Y structure. The predictive value of the equations is satisfactory.
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