Primary Mode of Action

Primary mode of action is inhibition of amino acid synthesis. 

The primary mode of action of the sulfonamides is, however, the interference with the uptake of PABA for the formation of foHc acid [59-30-3]. 

The primary mode of action of this class of antimycotics is interference with uptake and accumulation of products required for cell membrane synthesis. In higher concentrations it causes a disturbance of the cellular permeability. Some investigations show an interaction with Fe(M)- ions the compounds acting as chelators. Very high concentrations interfere with the function of fungal mitochondria. 

Once you have established a medical purpose, a careful examination of its primary mode of action will allow you to decide whether the product is a drug or device. 

Dantrolene is the mainstay of MH treatment. It has long been available for the treatment of muscle spasm in cerebral palsy and similar diseases. It is a hydantoin derivative that was first synthesized in 1967, and reported to be effective in the treatment of porcine MH in 1975. Also in 1975, dantrolene was shown to be more effective than procainamide in the treatment of human MH, which until that time was the drug of choice. However, the intravenous preparation was not made available until November 1979. It significantly lowered mortality. The half-life of dantrolene is estimated to be 6-8 hr. Dantrolene s primary mode of action is the reduction in calcium release by the sarcoplasmic reticulum. Dantrolene also exerts a primary antiarrhythmic effect by increasing atrial and ventricular refractory periods. Side effects of dentrolene include hepatotoxicity, muscle weakness, ataxia, blurred vision, slurred speech, nausea, and vomiting. Dantrolene is not contraindicated in pregnancy, but it does cross into breast milk and its effect on the neonate is unknown. 

A liquid, powder, or other similar formulation intended only to serve as a component, part, or accessory to a device with a primary mode of action that is physical in nature will be regulated as a device by CDRH. 

Our objective was to study in detail these systems by identifying the allelochemicals involved, their primary modes of action as mediated by soils, and as appropriate the microflora, microclimate, soil moisture and other factors that may influence allelopathy. 

Although all tetracyclines have a similar mechanism of action, they have different chemical structures and are produced by different species of Streptomyces. In addition, structural analogues of these compounds have been synthesized to improve pharmacokinetic properties and antimicrobial activity. While several biological processes in the bacterial cells are modified by the tetracyclines, their primary mode of action is inhibition of protein synthesis. Tetracyclines bind to the SOS ribosome and thereby prevent the binding of aminoacyl transfer RNA (tRNA) to the A site (acceptor site) on the 50S ri-bosomal unit. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacteria, because they readily penetrate microbial membranes and accumulate in the cytoplasm through an energy-dependent tetracycline transport system that is absent from mammalian cells. 

Several compounds may interfere with nucleic acid metabolism but commonly their effects are secondary to their primary mode of action, for example, the benzimidazoles. Compounds that inhibit nucleic acid biosynthesis directly are either phenylamides, pyrimidines or hydroxy-pyrimidines. Recently, the phenoxyquinolines were identified as exhibiting a novel mode of action in purine biosynthesis and are potentially useful fungicides. 

Auxins produce many changes in cells, including increased wall plasticity, enhanced respiratory rate and alterations in nucleic acid metabolism. Although the primary mode of action of auxins is not fully understood the development of the chemistry has progressed rapidly. Early discoveries identified and exploited the herbicide potential of super-optimal concentrations of auxin (Chapter 2, Herbicides) but their... 

This primary mode of action of tomatine, that involves the formation of complexes with membrane sterols is similar to that described for polyene antibiotics [2, 4], and results in pore formation and loss of membrane integrity. This mode of action is supported by the reduced activity of tomatine on sterol-free bacteria and Oomycete fungi such as Pythium and Phytophthora [15, 28], and the strongly reduced toxicity of hydrolysis products of the glycoalkaloid which fail to bind sterols [57]. 

Endocrine Influences. A number of hormones are known to influence carbohydrate metabolism in the mammal. Insulin seems to increase oxidation of glucose, lipogenesis. and glycogenesis. Its primary mode of action may be io facilitate the entry of glucose into the cell. 

Tier-4 methods, referred to as highly specific methods in Chapter 10, address nonuniform mixtures from the perspective of using not only the assumed primary mode of action but also the assumed characteristics of the receptor species. Tier 4 methods can be applied when the assessment problem is defined specifically (regarding site, species, and compounds), and where an accurate result is preferred over a conservative one. 

Two protocols are presented, the first for baseline toxicity, and the second for groups of compounds with the same assumed primary mode of action. The protocols are more broadly explained in De Zwart and Posthuma (2005). Example spreadsheet calculations can be found in Box 5.2. 

Two phytoene desaturase herbicides have been introduced since 2000 picolina-fen (Pico ) [182], introduced in 2001 by BASF, and beflubutamid [183], introduced in 2003 by Ube Industries. The primary mode of action of picolinafen and beflutamid is interference of carotenoid biosynthesis at the phytoene desaturation level, causing bleaching of the plant affected. As in previously developed phytoene desaturase herbicides, a meta-substituted trifluoromethylphenyl group is key for activity in this class of herbicides, pointing to the need for a lipophilic and electron-withdrawing group at this position of the molecule. 

Jet Mill. Jet mills are an alternative to hammer or pin milling, where the primary mode of action is the mechanical impact with the particle. With jet milling, microni-zation is accomplished through the action of fluid energy, resulting in particle-particle collisions and the subsequent reduction in size. Spiral jet mills, loop jet mills and fluidized bed jet mills are examples of fluid energy mills. 

Although the primary mode of action of ACTH is via cyclic AMP and cyclic AMP-dependent protein kinase (A-kinase), calcium probably plays a secondary role in enhancing and modulating the action of ACTH via the A-kinase pathway. This is discussed later in the consideration of the interaction of the A-kinase pathway of activation by ACTH and other second messenger systems involving calcium and protein kinase C. 

Once a Sponsor determines that their product fits one of the definitions of a combination product, the sponsor then must determine the lead Center within the FDA that will assume regulatory responsibility for the product. This determination is made by considering the primary mode of action (PMOA) [4] of the product. In simple terms, if the main function of the product is a device function, then it is likely that the Center for Devices and Radiological Health (CDRH) will have primary responsibility for the product. On the other hand, either the Center for Biologies Evaluation (CBER) or the Center for Drug Evaluation and Research (CDER) will be assigned primary review responsibility based on whether the PMOA of the product is dependent on... 

Definition of Primary Mode of Action of a Combination Product, http //www.fda. gov/OHRMS/DOCKETS/98fr/05-16527.htm... 

For example, the scaffold or biomaterial component of a neo-organ would normally fall under CDRH jurisdiction, while biological components (i.e., cells) would normally fall under CBER s authority if these components were being used alone. Similarly a biologically active pharmaceutical product would normally be reviewed by CDER. However, review of a combination product can require expertise from multiple centers and the lead center is assigned based on the component that the FDA decides is delivering the primary mode of action. 

The RFD document presents the sponsor s recommendation and rationale for how the combination product should be regulated. The FDA s decision about regulatory pathway rests on its evaluation of the primary mode of action, a judgment that focuses on the primary therapeutic process whereby the neo-organ activates the therapeutic outcome—usually a choice between scaffold and cellular or constitutive components. If a product is sufficiently related to a product already regulated by a particular center or one that has... 

Name of product Composition of product Primary mode of action Method of manufacture... 

Final neo-organ products that are cell based or neo-organs in which the primary mode of action is mediated through cellular constituents of a scaffoldcell combination product require an assortment of studies. Scaffold and cellular components are evaluated through appropriate endpoint selection. Endpoints selected should have direct translation to the clinical testing phase,... 

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