Proof-of-mechanism

Bhat, B. G., Hosea, N., Fanjul, A., Herrera, J., Chapman, J., Thalacker, F., Stewart, P. M., Rejto, P. A. (2008) Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4,-cyanobiphenyl-4-sulfonic acid(6-amino-pyridin-2-yl)amide (PF-915275), an... 

X. POLYMERIZATION OF ACETYLENES BY OLEFIN METATHESIS CATALYSTS A. Proof of Mechanism... 

During the past few years the number of photochemical reactions known not to occur via free radical intermediates has grown a very great deal until one might almost feel that they are the rule rather than the exception for many complex molecules and even for some simple ones. The detailed proof of mechanism often proves to be extremely difficult. 

The first example will demonstrate how RNA or DNA aptamers are used to provide proof of mechanism for the inhibition of a neurotransmitter receptor. 

Within the framework of type verifications for and testing of electrical apparatus in general, technical tests shall furnish proof of mechanical, thermal or electrical properties as specified in the relevant standards. Some examples for type tests are given in the following ... 

More importantly, proof-of-mechanism with proteasome inhibition levels in packed whole blood (inhibition of CT-L activity increasing with time and dose up to 100% Figure 12.4) reaching and exceeding those reported with therapeutic doses of bortezomib was attained at lower doses, suggesting potential for a significantly improved therapeutic ratio. Of particular interest, the profile of adverse events associated with NPI-0052 was quite different from those generally reported with bortezomib. 

There are at least two approaches for defining the order of the activities. The first is the "plan for success" approach in which as many activities as possible are conducted in parallel to provide the shortest time path to the Go/No-Go decisions (proof of mechanism/ proof of concept/ etc.) and to the project completion. The second approach is used when there are very scarce resources or when there is a low probability of project success. This second approach defers expensive activities until a proof of concept (POC) has been achieved for the project. Once the POC has been achieved/ then a plan-for-success-style development plan for the project will be developed and implemented. One can also stage the development of lower prioritized projects in a portfolio/ if resources are limited/ or if the risk is still high and the project needs to be managed more conservatively by the organization. 

Phase II consists of small trials in individuals with the illness to be treated (usually trials of 24 to 300 persons). The goals of Phase II trials are to provide either a proof of mechanism or a proof of the hypothesized therapeutic concept, identify the patient population(s) in which the new drug appears to work, and determine an appropriate dose regimen for subsequent large-scale trials. Dose regimen includes the loading dose, maintenance dose, dose frequency, dose duration, and dose adjustments for special populations and for coadministration with other drugs. 

Have Clinical Proof of Mechanism and Proof of Concept Been Obtained ... 

I Clinical pharmacology studies Single-ascending-dose safety, PK, and PD Multiple-ascending-dose safety, PK, and PD Proof of mechanism study... 

The simplest example of a productive cross-metathesis reaction between acyclic olefins is that between ethene and but-2-ene reaction (1). In this case only one product is possible, apart from cis/trans isomerization of the but-2-ene the equilibrium mixture thus consists of four compounds. At the other extreme, the reaction of two unsymmetrical olefins, R CH=CHR and R CH=CHR , with R, R, R, R all different, can produce cis/trans isomers of four different unsymmetrical olefins by cross-metathesis as well as four symmetrical olefins by self-metathesis. Counting the cis/trans isomers of the reactants as well, this means that the equilibrium mixture will contain 20 different compounds. Side reactions, such as double-bond shift reactions, will complicate the situation still further. The main value of cross-metathesis reactions, apart from their use in the proof of mechanism, lies in their application to the synthesis of olefins that are otherwise expensive or difficult to prepare. A number of higher olefins, useful as insect sex attractants, have been made in this way. 

Perhaps the criteria which lead most directly to a conclusion are those which were applied in the first unambiguous demonstration of this kind of mechanism for reactions between metal ion complexes. When Co(NH3)5CP" reacts with Cr " (aq) in acidic solution, the products are Co " (aq), NH4+ and Cr(H20)5CF", the latter being formed virtually quantitatively. In the absence of further information, the identification of products would by no means provide proof of mechanism. The additional information which is pertinent to the issue follows (a) the oxidizing agent, Co(NH3)5CP", undergoes aquation much less rapidly than it does reduction by Cr (aq) ... 

Sealing motor parts Tamper proofing of mechanical fasteners Cotume jewelry... 

But the latter do not assume any adsorption equilibrium. This ambiguity is frequentiy expressed by a warning that mere kinetics can contribute no proof of mechanism. In this case mechanism means the proper sequence of steps. This warning must always be kept in mind Chemical kinetics is a necessary but insufficient tool in the study of chemical change. 

Wittram C, Yoo AJ (2007) Transient interruption of contrast on CT pulmonary angiography proof of mechanism. J Thorac Imaging 22 125-129... 

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