Efficacy data level

The EU will accept applications without supporting pre-clinical and clinical data, if it can be demonstrated that the active substances have been in well-established medical use in the Community for at least 10 years, with recognised efficacy and an acceptable level of safety. This route would be appropriate for many common over-the-counter (OTC) products. Safety and efficacy is supported by providing copies of published scientific literature as part of the submission that is, the submission relies on safety and efficacy data available in the public domain, as opposed to confidential data from authorised applications that is the cornerstone of generic applications. 

Recently, a Japanese research group published preclinical safety and efficacy data of an oral antiestrogen (TZE-5323) (Saito et al. 2003). This drug has been shown to have a strong affinity for human ERa and ER/i and a dose-dependent capacity to inhibit estradiol-stimulated transcriptional activation (Saito et al. 2003). In the experimental endometriosis model in rats, TZE-5323 dose-dependently reduced the volume of the endometrial implant with an effectiveness similar to that of danazol and leuprorelin acetate without causing significant changes in bone mineral density and in serum estradiol levels (Saito et al. 2003). 

Phase I clinical evaluation of BMS 599626 is ongoing [79,80] however, no efficacy data have been reported to date. Dose escalation has proceeded to 660 mg/day and is ongoing since a MTD has not been reached. The pharmacokinetic profile in both healthy volunteers and cancer patients supports once-daily dosing with a half-life of ca. 20 h. An area under the curve of ca. 2.4 xgh/ml with a maximum concentration of ca. 0.18 xg/ml was achieved at steady state after 100-mg dosing in patients. In mice at a dose that resulted in modest antitumor activity (ca. 50% TGI), significantly higher plasma levels were achieved (AUC ca. 14.5 xgh/ml and Cmax ca. 5.0 xg/ml) [76]. 

A summary of the plasma concentration-efficacy data with these four TCAs supports the use of TDM, at least once, as a routine aspect of therapy for major depressive disorder. The data are consistent across three of these agents that optimal plasma levels are associated with a greater likelihood of full remission after 4 weeks. Translated into clinical terms. Perry et al. (326) find a 1.7- to 3-fold increase in clinical response to TCAs if the depressed patient obtains an optimal TCA plasma level. 

It also exhibited significant reduction in fat mass and triglyceride levels. The synthesis, in-vitro binding data along with SAR and in-vivo efficacy data of the lead molecule will be presented. 

Serious hepatotoxicity of tacrine has been documented. More recent data suggest, however, that this toxicity can be reduced by carehiUy monitoring semm alanine aminotransferase levels (125). The side effects of tacrine also include gastrointestinal disturbances and emesis, and alternative AChE therapies are being advanced. Velnacrine (20), a metaboUte of tacrine, was expected to have reduced hepatotoxicity. However, its limited efficacy and side-effect profile, which includes dmg-related hematological changes, caused it to be dropped from further development. 

The optimization of empirical correlations developed from the ASPEN-PLUS model yielded operating conditions which reduced the steam-to-slurry ratio by 33%, increased throughput by 20% while maintaining the solvent residual at the desired level. While very successful in this industrial application the approach is not without shortcomings. The main disadvantage is the inherent assumption that the data are normally distributed, which may or may not be valid. However, previous experience had shown the efficacy of the assumption in other similar situations. 

In view of these potentials for major reductions in preservative efficacy, considerable effort has gone into attempts to devise equations in which one might substitute variously derived system parameters such as partition coefficients, surfactant and polymer binding constants and oil water ratios in order to obtain estimates of residual preservative levels in aqueous phases. Although some modestly successful predictions have been obtained for very simple laboratory systems, they have proved of limited practical value as data for many of the required parameters are unavailable for technical grade ingredients or for the more complex commercial systems. 

Reliable analytical methods are available for determination of many volatile nitrosamines at concentrations of 0.1 to 10 ppb in a variety of environmental and biological samples. Most methods employ distillation, extraction, an optional cleanup step, concentration, and final separation by gas chromatography (GC). Use of the highly specific Thermal Energy Analyzer (TEA) as a GC detector affords simplification of sample handling and cleanup without sacrifice of selectivity or sensitivity. Mass spectrometry (MS) is usually employed to confirm the identity of nitrosamines. Utilization of the mass spectrometer s capability to provide quantitative data affords additional confirmatory evidence and quantitative confirmation should be a required criterion of environmental sample analysis. Artifactual formation of nitrosamines continues to be a problem, especially at low levels (0.1 to 1 ppb), and precautions must be taken, such as addition of sulfamic acid or other nitrosation inhibitors. The efficacy of measures for prevention of artifactual nitrosamine formation should be evaluated in each type of sample examined. 

It is not often that researchers find their work leading to such widespread changes of behaviour. Still, the 44 per cent figure reveals a split opinion. Most physicians did not intend to alter their prescribing practices. Our analysis has provoked a vociferous and continuing debate on the effectiveness of antidepressants and the circumstances under which they should be prescribed. In this chapter I consider and respond to the various criticisms that have been levelled at our data-based conclusions about the efficacy of antidepressants. 

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

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