Borderline Cases

To show a more complete picture on failed drugs, drugs that have been removed from the market and have been reintroduced later on with some restrictions as well as drugs that have been suspended from most drug markets but still remain on the market in only a few countries are listed in Table 1.2. As these drugs remain available on the Western market, they are not included in our statistics. 

Investigational Drugs That Failed in Clinical Phases from 1992 to 2002 

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Besides the five classical types there are borderline cases which, as in most classifications, are difficult to assign to one group rather than another. There are indeed a not inconsiderable number of isotherms which are difficult to fit into the classification at all. 

The N-Lim classification does not eliminate the possibility of borderline cases between these two categories, but it leads to the suggestion that no sharp distinction can be made between the possible intermediates in these mechanisms and that perhaps all solvolyses proceed via an intermediate. The mechanistic category of a particular solvolysis then depends upon the relative weights of the canonical structures 3, 4, and 5 to the transition state resonance hybrid. 

Grenzenlinie,/. boundary line, grenzenlos, a. unlimited, botmdless, infinite. Grenz-fall, m. limiting case borderline case, -fl che, /, boundary surface, surface of contact, interface. 

These ratios are useful in dealing with small towers, and serve as guides for the borderline cases of others. There are no guides to the smallest sized packing to place in a tower. However, /4-in. is about the smallest ceramic used with %-in. and 1-in. being the most popular. Operating and pressure drop factors will usually control this selection. 

To be effective, this method must be carried out on samples which have been blanched, and upon peas from which the skins have been removed. The heat applied in blanching drives off gases entrapped in the tissues, and removal of the skins is required to remove air that may be entrapped under them, although it materially slows up the operation and makes it very tedious. In order that there may be consistency in grading, the test must be conducted under closely standardized conditions of temperature and solution concentration. This becomes of considerable importance in borderline cases, and failure to take it into consideration no doubt accounts for some of the inconsistency in results experienced by the industry. The test is not a true measure of tenderness, in that it accounts for variation in skin texture only in so far as maturity affects skin texture. Skin texture is affected by factors other than maturity (4). Other methods for the estimation of maturity based upon density or specific gravity have been suggested by Jodidi (16) and by Lee (22). 

In reactions in which separated ion pairs are involved, e.g., R4N+, K or Na +, and as a borderline case, Li +, the cation does not contribute to the adjustment of the reaction partners in a dense, well-ordered transition state poor selcctivities arc usually the result of these carbanionic carbonyl additions. Further, the high basicity of such carbanionic species may cause decomposition or racemization of sensitive reactions partners. 

Szele and Zollinger (1978 b) have found that homolytic dediazoniation is favored by an increase in the nucleophilicity of the solvent and by an increase in the elec-trophilicity of the P-nitrogen atom of the arenediazonium ion. In Table 8-2 are listed the products of dediazoniation in various solvents that have been investigated in detail. Products obtained from heterolytic and homolytic intermediates are denoted by C (cationic) and R (radical) respectively for three typical substituted benzenediazonium salts and the unsubstituted salt. A borderline case is dediazoniation in DMSO, where the 4-nitrobenzenediazonium ion follows a homolytic mechanism, but the benzenediazonium ion decomposes heterolytically, as shown by product analyses by Kuokkanen (1989) the homolytic process has an activation volume AF = + (6.4 0.4) xlO-3 m-1, whereas for the heterolytic reaction AF = +(10.4 0.4) x 10 3 m-1. Both values are similar to the corresponding activation volumes found earlier in methanol (Kuokkanen, 1984) and in water (Ishida et al., 1970). 

Rigorous quantitative treatments lead to kinetic zone diagrams that distinguish between different extreme and borderline cases depending on which parameters controll the overall reaction (Fig. 2). A realistic picture is obtained from cross... 

Fig. 2a-c. Kinetic zone diagram for the catalysis at redox modified electrodes a. The kinetic zones are characterized by capital letters R control by rate of mediation reaction, S control by rate of subtrate diffusion, E control by electron diffusion rate, combinations are mixed and borderline cases b. The kinetic parameters on the axes are given in the form of characteristic currents i, current due to exchange reaction, ig current due to electron diffusion, iji current due to substrate diffusion c. The signpost on the left indicates how a position in the diagram will move on changing experimental parameters c% bulk concentration of substrate c, Cq catalyst concentration in the film Dj, Dg diffusion coefficients of substrate and electrons k, rate constant of exchange reaction k distribution coefficient of substrate between film and solution d> film thickness (from ref. 

Aluminum forms a complete series of AlYX compounds (Y = S, Se, Te X = Cl, Br, I). Furthermore, a number of compounds with Se(IV) and Te(IV) are known, such as TeClJ AlClj (197) and SeClJ AICI4 (364), which are not considered here. A borderline case consists in the reduced phases found in the systems (TeCl4-(-4AlCl3)-Te and (SeCl4 + 4A1C13)-Se (88), e.g., Te (AlCl4-)2 (89), Te + (Al Clf)2 (89), Te + (AlCli-) (88), Se5+ (AlClj) (88), and Se + (AlClj)2 (87), which contain cyclic pol3dellurium and polyselenium cations. For a detailed review of homopolyatomic ions of the posttransition elements, see (86). 

Hard Bases Soft Bases Borderline Cases... 

The transition metals are also good conductors as they have a similar sp band as the free-electron metals, plus a partially filled d band. The Group IB metals, copper, silver and gold, represent borderline cases, as the d band is filled and located a few eV below the Fermi level. Their sp band, however, ensures that these metals are good conductors. 

Looking at the trends in dissociation probability across the transition metal series, dissociation is favored towards the left, and associative chemisorption towards the right. This is nicely illustrated for CO on the 4d transition metals in Fig. 6.36, which shows how, for Pd and Ag, molecular adsorption of CO is more stable than adsorption of the dissociation products. Rhodium is a borderline case and to the left of rhodium dissociation is favored. Note that the heat of adsorption of the C and O atoms changes much more steeply across the periodic table than that for the CO molecule. A similar situation occurs with NO, which, however, is more reactive than CO, and hence barriers for dissociation are considerably lower for NO. 

Whitmont, Edward C. Alchemy, homeopathy and the treatment of borderline cases. J Anal Psychol 41, no. 3 (Jul 1996) 369-386. 

J. In borderline cases, high value requires high hazard classification. 

From the most general point of view, the theory of fractals (Mandelbrot [1977]), one-, two-, three-, m-dimensional figures are only borderline cases. Only a straight line is strictly one-dimensional, an even area strictly two-dimensional, and so on. Curves such as in Fig. 3.11 may have a fractal dimension of about 1.1 to 1.3 according to the principles of fractals areas such as in Fig. 3.12b may have a fractal dimension of about 2.2 to 2.4 and the figure given in Fig. 3.14 drawn by one line may have a dimension of about 1.9 (Mandelbrot [1977]). Fractal dimensions in analytical chemistry may be of importance in materials characterization and problems of sample homogeneity (Danzer and Kuchler [1977]). 

The same family of compounds shows another interesting feature, namely, the existence of borderline cases exhibiting an intermediate behavior between the concerted and stepwise mechanisms. More precisely, the width of the cyclic voltammetric peak and the variation of its location with scan rate change from a concerted to a stepwise behavior as the scan rate is raised (Fig. 4 and Scheme 6). 

Thus, in the present approach, the major focus is on the question of how we can influence the external parameters like solvent and counterion and the intrinsic structural parameters within the systems A-l-A to force the electron-hopping process into the timescale of the experiment, or at least to establish clearly the borderline cases. That we are still looking at an electron-hopping process in the case of effective charge delocalization over the entire molecule and not at a pure resonance phenomenon may be reassured by VIS/NIR spectroscopy of the neutral and charged species the absorption of a single chromophore should be detected unless a very fast process > 1012 Hz is taking place. 

For PR3/P(OR)3-stabilized nickel complexes, there are two borderline cases known from the experimental investigation of Heimbach et al. 1 which, unlike the usual behavior, redirect the cyclo-oligomerization reaction into the Ci2-cyclo-oligomer production channel. Catalysts bearing either strong a-donor ligands that must also introduce severe steric pressure (e.g., PBu Pr2) or sterically compact n-acceptors (like P(OMe)3) are known to yield CDT as the predominant product. From a statistical analysis it was concluded,8a,8c that the C8 Ci2-cyclo-oligomer product ratio is mainly determined by steric factors (75%) with electronic factors are less important. 

To decide whether to reject or accept these batches, we would need to know how the reference value was set (e.g. was it set taking into account the possible uncertainty ) and the criticality of the measurement. It is important to discuss such borderline cases with the end-user of the data, and agree how they are to be handled, before the measurements are made. 

The unresolved borderline cases have the solvent as one of the reagents and the order of the reaction with respect to the solvent is indeterminate. Their behavior resembles that of typical first order displacements in some ways and typical second order displacements in others. 

Jellium is a good model for sp metals. This group of metals comprises, amongst others, the elements Hg, Cd, Zn, Tl, In, Ga and Pb, all of which are important as electrode materials in aqueous solutions. They possess wide conduction bands with delocalized electrons, which form a quasi-free-electron gas. The jellium model cannot be applied to transition metals, which have narrow d bands with a localized character. The sd metals Cu, Ag and Au are borderline cases. Cu and Ag have been successfully treated by a modified version of jellium [3], because their d orbitals are sufficiently low in energy. This is not possible for gold, whose characteristic color is caused by a d band near the Fermi level. 

Thomas model is usually appropriate somewhere between these two. These criteria are guidelines only and must be carefully applied. All three models should be tested for borderline cases. In practice, the models are valid only if no mass flows to or from the vessels, negligible reactants are consumed, and heat is generated only by reactions. 

Protein structures are so diverse that it is sometimes difficult to assign them unambiguously to particular structural classes. Such borderline cases are, in fact, useful in that they mandate precise definition of the structural classes. In the present context, several proteins have been called //-helical although, in a strict sense, they do not fit the definitions of //-helices or //-solenoids. For example, Perutz et al. (2002) proposed a water-filled nanotube model for amyloid fibrils formed as polymers of the Asp2Glni5Lys2 peptide. This model has been called //-helical (Kishimoto et al., 2004 Merlino et al., 2006), but it differs from known //-helices in that (i) it has circular coils formed by uniform deformation of the peptide //-conformation with no turns or linear //-strands, as are usually observed in //-solenoids and (ii) it envisages a tubular structure with a water-filled axial lumen instead of the water-excluding core with tightly packed side chains that is characteristic of //-solenoids. 

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