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PubMed2002

Improvement of "hit-to-lead" optimization by integration of in vitro HTS experimental models for early determination of pharmacokinetic properties.

Development of predictive in vitro surrogate methods for traditional approaches assessing bioavailability and pharmacokinetics of lead compounds must be made to both keep pace with high-throughput (HT) lead identification and to mitigate the high costs associated with progression of compounds with poor chances of developmental success. Indeed opportunities for improvement still exist in the lead optimization phase versus the lead identification phase, where HT methodologies have been nearly optimized. Review of examples, limitations, and development of high-throughput microtiterplate-based assays for evaluating metabolic liabilities, such as in vitro radiometric and fluorometric assays for inhibition of cytochrome p450 (CYP) activity, determination of stability of a compound in liver microsomes, or cloned CYPs coupled to reconstituting systems are described. Parallel approaches to improve speed, resolution, sample preparation, as well as data analysis using LC/MS and LC/MS/MS approaches and technologies to assess compound integrity and biotransformation by automation and multiplexing are also discussed. Realization of the benefits in automation of cell-based models for determining drug permeability to predict drug absorption are still hampered by bottlenecks in analytical analysis of compounds. The implementation and limitations of surrogate physiochemical methods for passive adsorption such as immobilized artificial membranes (IAM) and parallel artificial membrane permeation assays (PAMPA), and compound solubility by laser nephelometry are reviewed as well. Additionally, data from a high-throughput 96-well equilibrium dialysis device, showing good correlation to classical methods, is presented. Finally, the impact of improvements in these downstream bottlenecks in lead optimization and preclinical drug discovery are discussed in this review.

Animals↗
PubMed1995

Chemical oscillations arise solely from kinetic nonlinearity and hence can occur near equilibrium.

A minimal kinetic scheme for a system displaying sustained chemical oscillations is presented. The system is isothermal, and all steps in the scheme are kinetically reversible. The oscillations are analyzed and the crucial points elucidated. Both positive and negative feedback, if properly introduced, support oscillations, provided the state responsible for feedback is optimally buffered. It is shown that the requisite nonlinearity is introduced at the kinetic level because of feedback regulation and not, as is usually assumed, by large affinities that introduce nonlinearity at the thermodynamic level. Hence, sustained oscillations may occur near equilibrium.

Biophysical Phenomena↗
PubMed1994

Acid-base regulation in peritoneal dialysis.

To prevent increased protein degradation and renal bone disease, optimal correction of acidosis should therefore be a priority in the management of CAPD patients. Initial results suggest that bicarbonate solutions may be more biocompatible than lactate, and one would expect increasing use over the next decade. Manufacturers could help to improve acid-base regulation in CAPD by providing a range of solutions with varying lactate and bicarbonate concentration, so that correction of acidosis could be optimized individually.

Acid-Base Equilibrium↗
PubMed2000

Sexual selection and the evolution of costly female preferences: spatial effects.

Models of Fisher's runaway process show that if there is a cost to female preference, no preference or male trait exaggeration will evolve. Surprisingly, this is true no matter how small the cost, which reveals that these models of Fisher's process are structurally unstable (Bulmer 1989). Here a model of Fisher's runaway process is presented to demonstrate that costly female preference evolves very easily when space is explicitly included in the model. The only requirement is that the optimal male phenotype changes across the species' range. The model shows that the spatial average of the female preference and male trait reach an evolutionary equilibrium that is identical to those of nonspatial models, but that the preference and male trait can deviate greatly from these averages at any point in space. For example, if random mating results in the lowest cost to females, then at equilibrium the spatial average preference will be zero. Nevertheless, there will be some locations at which females prefer males with larger ornaments and others where they prefer males with smaller ornaments. Results also show that the structural instability of nonspatial models of Fisher's process is less of a problem in spatial models. In particular, many of the main qualitative features of cost-free spatial models of Fisher's process remain valid even when there are small costs of female preference. Finally, the model shows that abrupt changes in the optimal male phenotype across space can result in an amplification of this pattern when preference has a small cost, but it can also result in a pattern similar to reproductive character displacement. Which of these occurs depends on the magnitude of the cost of female preference. This suggests that some patterns of reproductive character displacement in nature might be explained simply by sexual selection rather than by hybrid dysgenesis and reinforcement.

Animals↗
PubMed1991

Mathematical modelling of competitive labelled-ligand assay systems. Theoretical re-evaluation of optimum assay conditions and precision data for some experimentally established radioimmunoassay systems.

A mathematical theory of competitive labelled-ligand assays was developed with the intention of theoretically re-evaluating the optimal assay conditions and precision data of assay systems established by experiment. Our theory is based upon the assumptions of a simple bimolecular reaction mechanism, homogeneous reactants, as well as kinetically indistinguishable labelled and non-labelled ligands. The general case of two-step (non-equilibrium) assay was considered including the one-step (equilibrium) assay as a special case. The solution of the system of corresponding kinetic differential equations was used to mathematically construct standard curves. Furthermore, intraassay precision profiles and indices as well as detection limits were calculated considering solely the pipetting error, epsilon, as a source of experimental error. A procedure was outlined to mathematically determine the optimal incubation conditions for any assay system targeted to a given analyte concentration, P, at which the standard deviation of assay results is to be minimized. Estimates of both the content of binding sites and the equilibrium constant, K, of the specific binding agent are necessary, and these can be derived from Scatchard plots. For six RIA systems, of which three were one-step and three were two-step assays, experimental assay conditions and precision data were compared with theoretical predictions. Experimentally determined antibody binding site concentrations agreed fairly well with those independently evaluated by mathematical optimization. Mean precision indices, defined as constituting an average over the complete precision profile, were found to be within the theoretically predicted range, i.e. two- to threefold the pipetting error.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites, Antibody↗
PubMed1986

Comparison of acute hemodynamic response to dobutamine and intravenous MDL 17,043 (enoximone) in severe congestive heart failure secondary to ischemic cardiomyopathy or idiopathic dilated cardiomyopathy.

The acute hemodynamic response to intravenous dobutamine administration was compared with intravenous MDL 17,043 administration in 8 patients with severe, chronic congestive heart failure. Simultaneous radionuclide angiography was performed with gated equilibrium blood pool imaging to derive left ventricular volumes and ejection fraction during serial hemodynamic measurements. Six patients had an optimal dobutamine dose of 10 micrograms/kg/min; 2 others were compared at a dose of 7.5 micrograms/kg/min; comparisons with MDL 17,043 were after a 1.5-mg/kg bolus dose in all 8 patients. Dobutamine and MDL 17,043 caused significant and similar increases in cardiac index and stroke volume index. Dobutamine significantly increased heart rate and MDL 17,043 did not. MDL 17,043 significantly decreased pulmonary artery wedge, mean pulmonary artery and right atrial pressures; dobutamine did not. Dobutamine increased end-diastolic volume in 4 patients, with little concomitant decrease in wedge pressure; MDL 17,043 caused no change or a decrease in left ventricular end-diastolic volume in 5 patients, but consistently decreased wedge pressure in all. Thus, the left ventricular pressure-volume curve was displaced downward to a more favorable position after MDL 17,043 but not after dobutamine. In patients with chronic congestive heart failure, acute myocardial performance was more optimally influenced by MDL 17,043 than dobutamine administration.

Adult↗
PubMed1988

Epstein-Barr virus nuclear antigen type 1 binding: electron microscopy.

Epstein-Barr virus (EBV) nuclear antigen type-1 (EBNA-1) was extracted and purified from Raji cells by chromatography on DNA-Sepharose and Blue-dextran Sepharose. Its complexes with plasmid pM765-10 derived from EBV (strain M-ABA) DNA were visualized by electron microscopy. The criteria of specificity were as follows: (1) preferential binding of EBNA-1 to the ori-P region of pM765-10; (2) specific enlargement of EBV DNA/EBNA-1 complexes with anti-EBNA-1 (IR-3) IgG antibody; and (3) resistance of the resulting EBV DNA/EBNA-1/anti-EBNA-1 antibody complexes to treatment with 1.5 M NaCl. The optimal conditions for the formation of EBV DNA/EBNA-1 complexes were 50 to 150 mM NaCl and pH 6.0. A balanced equilibrium of EBNA-1 and pM765-10 was necessary to achieve both a high yield and specificity of EBV DNA/EBNA-1 complexes.

Antigens, Viral↗
PubMed1993

International migration, economic policy and human capital accumulation: a simulation study.

"This paper examines the economic policy implications of international migration and human capital accumulation within a dynamic general equilibrium model. Each country produces by means of physical and human capital of two types (skilled and unskilled labour). Along optimal growth paths in a world of diverging population growth rates immigration can only be beneficial when the free rider effect (i.e., not paying for training costs) exceeds the capital dilution effect of an increase in population growth. Under quite general conditions the optimal immigration rate is zero."

Demography↗
PubMed1994

Use of ionic detergents for enterovirus recovery from waste water.

Virus recovery from poliovirus-seeded waste water was attempted after treatment of the samples with ionic detergents in the presence of acoustic energy. Viral titers strongly fluctuated depending upon concentration and chemical structure of the detergent as well as upon the dissolved organic content of the aqueous samples. Supplementation of the cellular monolayers with an additional amount of cell culture medium or with a nonionic detergent in a subcytotoxic concentration 48 h after inoculation partly induced cytopathic effects in silent dilution steps. Since, in the presence of the same detergent, viral recovery rates varied with the type of waste water, titer-conditioning activity of detergents was suggested to depend upon their effective critical micellization concentration. Especially for virus recovery from concentrated waste water, treatment with strongly disruptive detergents such as sodium dodecylsulfate revealed to be much more efficient than with the less hydrophilic sodium N-laurylsarcosine, sodium glycodeoxycholate or lauryldimethylamine-oxide, whereas the opposite seemed to be the case if virus recovery from filtrate samples were to be optimized. The mechanisms by which viral particles become infectious for the cell appear to be triggered by general principles of equilibrium thermodynamics, which means that interactions between viral surface proteins and cellular receptor molecules seem to reflect the tendency of these reagents to assume the energetically most favored orientation.

Animals↗
PubMed1997

On the degree of solute mixing in liver models of drug elimination.

One of the fundamental differences between various liver models regards the underlying assumptions on the intrahepatic mixing process. A model-independent method for the evaluation of the departure from the perfectly mixed system is proposed which is based on an application of the relative entropy concept to hepatic transit time distributions of intravascular markers. This approach provides a measure of the distance between two probability distributions. Available data measured in isolated perfused livers indicate that sinusoidal solute mixing is nearly optimal. The suggestion of maximum mixedness in the liver may explain the discrepancy between the apparent validity of the venous equilibrium model and the physiological irrelevance of the underlying well-stirred assumption. In terms of the dispersion model the results are in accordance with the model equation obtained for mixed boundary conditions.

Entropy↗
PubMed1953

Mitochondria in the flight muscles of insects. II. Effects of the medium on the size form, and organization of isolated sarcosomes.

1. The sarcosomes of Drosophila and the blowfly, Phormia, are dense, spherical, homogeneous bodies when isolated from flight muscle and promptly examined under the phase contrast, oil immersion objective. 2. Their average diameter in newly emerged flies is about 1 micro. This value increases rapidly during the 1st week of adult life and then becomes constant at approximately 2.5 micro. At each age the variation in sarcosome diameter conforms approximately to a normal distribution. 3. The degree to which isolated sarcosomes retain their initial size and organization is remarkably conditioned by the composition and the hydrogen ion concentration of the medium in which they are teased and suspended. In suboptimal media three major categories of change were encountered: (1) swelling, with or without compaction of the contents (as in distilled water and salt solutions); (2) shrinkage to rod-like, pleomorphic forms (as in blood serum); and (3) fuzzy degeneration (as in sugar solutions). 4. The membrane that surrounds each sarcosome becomes plainly visible in swollen sarcosomes. A continuation of swelling is accompanied by the escape of the sarcosomal contents, the vacated membrane persisting as a spherical, optically empty ghost. 5. Sarcosomes appear to behave like osmometers when suspended in various aqueous solutions. Solutes which penetrate the membrane show only transient effects in preventing the osmotic entry of water. 6. Under this analysis we find the membrane to be more or less freely permeable to the ions of sodium, potassium, calcium, magnesium, chloride, and phosphate, to non-electrolytes smaller than hexoses, to phosphorylated hexoses, and to several intermediates of the citric acid cycle. 7. The sarcosomal membrane appears to be less permeable to non-electrolytes larger than pentoses, provided that such molecules are not phosphorylated. 8. The membrane shows a higher permeability to ATP than to ADP. The significance of this observation is considered with respect to the ADP-ATP shuttle between sarcosomes and muscle fibrils. 9. Simple solutions of electrolytes or non-electrolytes cause more or less conspicuous changes in the microscopic appearance of sarcosomes. Prolonged preservation was achieved only in more complicated media containing protein. It is concluded that the Donnan equilibrium is the source of the principal osmotic forces regulating the movement of water through the sarcosomal membrane. 10. The optimal medium for the preservation of isolated sarcosomes was an intracellular Ringer solution containing 2.5 per cent crystalline bovine albumin in 0.16 M potassium phosphate buffer at pH 7.0.

Animals↗
PubMed1990

Characterization of 3'-phosphoadenosine 5'-phospho[35S]sulfate transport carrier from rat brain microsomes.

3'-Phosphoadenosine 5'-phospho[35S]sulfate [( 35S]PAPS) specific binding properties of rat brain tissue were studied. [35S]PAPS specific binding was optimal at pH 5.8 in either Tris-maleate or potassium phosphate buffers. Association was maximal at low temperature, reaching equilibrium in 20 min. Dissociation was rapid, with a dissociation time of 80 s. Scatchard analysis of [35S]PAPS specific binding was consistent with a single site having a KD of 0.46 +/- 0.06 microM and a Bmax of 20.8 +/- 2.0 pmol/mg of protein. Low concentrations of Triton X-100 (0.025%) were effective in increasing the number of binding sites to a Bmax of 44.5 +/- 4.6 pmol/mg of protein without affecting the affinity. [35S]PAPS specific binding was enriched in crude synaptic membranes (P2) and microsomes (P3). Regional distribution of [35S]PAPS specific binding was quite homogeneous in all brain structures studied. The pharmacological profile of [35S]PAPS specific binding in rat brain microsomes was consistent with a membrane protein having a high selectivity for the 3'-O-phosphoryl group substitution on the ribose moiety. Thus, 3'-phosphoadenosine 5'-phosphate was more potent than 2'-phosphoadenosine 5'-phosphate in competing for [35S]PAPS specific binding. Adenosine 5'-phosphosulfate was a good inhibitor of [35S]PAPS specific binding. ATP and ADP were also good displacers. Dipyridamole, a highly selective marker for adenosine uptake sites, was ineffective. 4,4-Diisothiocyanostilbene-2,2-disulfonic acid, the chloride transporter inhibitor, showed an IC50 of 36 +/- 5.1 microM for inhibition of [35S]PAPS specific binding. 2,6-Dichloro-4-nitrophenol had a low selectivity in competing for the [35S]PAPS binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1980

The place of oestriol therapy after menopause.

The therapeutic principles covering sex hormone replacement therapy after menopause have undergone profound modification in recent years. Initial optimism regarding benefits, proven and unproven, was followed by deep pessimism because of potential serious adverse effects. Some degree of equilibrium has resulted from the application of risk-benefit and cost-effectiveness formulae to such hormone replacement regimens. Cost-effectiveness analysis in particular has highlighted the fact that different hormones or hormone combinations can markedly affect the therapeutic outcome. The purpose of the present paper is to examine the place of oestriol therapy after menopause based on such risk-benefit analyses. Oestriol, it would appear, has the potential for reduced risk but similar benefit to alternative oestrogen or oestrogen-progestogen combinations. The potential risks and benefits of long-term oestrogen therapy are therefore surveyed from the general standpoint of all oestrogens and the specific role of oestriol alone.

Aged↗
PubMed2000

Optimizing the classical heat engine

A pair of systems at different temperatures is a classic environment for a heat engine, which produces work during the relaxation to a common equilibrium. It is generally believed that a direct interaction between the two systems will always decrease the amount of the obtainable work, due to inevitable dissipation. Here a situation is reported where, in some time window, work can be gained due to the direct coupling, while dissipation is relevant only for much larger times. Thus, the amount of extracted work increases, at the cost of a change of the final state.

Journal Article↗
PubMed1996

Antibody characteristics for a continuous response fiber optic immunosensor for theophylline.

A self-contained fiber optic immunosensor was developed to measure continuously theophylline concentrations. The analytical signal was derived from the non-radiative energy transfer quench of fluorescence following binding of a fluorescence donor, B-phycoerythrin labeled theophylline, to an energy acceptor, Texas Red labeled antibody. Increases in free theophylline analyte concentrations resulted in a shift in antibody binding equilibrium between labeled and unlabeled theophylline that elicited a proportional increase in the fluorescence. The selection criteria for a monoclonal antibody as a molecular recognition element, and the optimization of labeling conditions to maximize the dynamic range and minimize sensor response time are described. Under one or more Texas Red labeling conditions, five antibody clones exhibited significant quenching when mixed with labeled analyte and also demonstrated 95% or greater reversible binding to labeled analyte. Two clones failed to exhibit fluorescence quenching when mixed with labeled analyte. The response time of the indicator chemistry system was dependent on the dissociation rate constant of the antibody. The equilibrium response time of intact sensors was limited by analyte diffusion across the containment membrane.

Antigen-Antibody Reactions↗
PubMed1991

Kinetic parameters of enzymatic reactions in states of maximal activity; an evolutionary approach.

A theoretical investigation is presented which allows the calculation of states of maximal reaction rates for single enzymes and for unbranched enzymatic chains. As an extension to previous papers (Heinrich & Holzhütter, 1985, Biomed. biochim. Acta 44, 959-969; Heinrich et al., 1987, Bull. math. Biol. 49, 539-595) a detailed enzymatic mechanism was taken into consideration. Conclusions are drawn for the optimal values of the microscopic rate constants as well as of the maximal activities and Michaelis constants. Ten solutions are found which depend on the equilibrium constant as well as on the concentrations of substrates and products. It is shown that for high equilibrium constants one of the solutions applies to a very large range of the concentrations of the outer reactants. This solution is characterized by maximal values of the rate constants of all forward reactions and by non-maximal values of the rate constants of all backward reactions. In contrast to previous assumptions (Albery & Knowles, 1976b, Biochemistry 15, 5631-5640; Burbaum et al., 1989, Biochemistry 28, 9293-9305) states of maximal reaction rate are not always characterized by the highest possible values of the second-order rate constants which are related to the diffusion of the substrate and the product to the active site of the enzyme. Predictions are made concerning the ratios of maximal activities in optimal states as well as for the adaptation of the Michaelis constants to the concentrations of the outer reactants. Using metabolic control analysis it is shown that the solutions obtained for single enzymes may also be applied in multi-enzyme systems.

Animals↗
PubMed1994

Effects of modulations of the energetic metabolism on the mortality of cultured cells.

Since cells are open systems which exchange material with their surroundings, they can be considered as open systems far from equilibrium and in this way, they follow the principles of thermodynamics of open systems. This approach stresses the fact that cells optimize their use of energy according to their functions. However, with time and/or under environmental challenges, cells can reorganize themselves at other lower levels of energy production and utilization (Toussaint et al. (1991) Mech. Ageing Dev. 61, 45-64). Considered as optimized systems, cells can adapt their behaviours according to the balance between, on one side, their energetic potential and the level of their defence systems, and on the other side, the intensity of the stress. Mainly three types of behaviour can be theoretically predicted. If the stresses are very low, the damages generated are instantaneously repaired and the cellular system remains at its steady state of energy production and utilization. If the stresses are of an intermediary intensity, it is predicted that the cell can leave its steady state of energy production and utilization and find a new one characterized by a lower level of entropy production and a higher level of errors. Third, if the stresses are of a very high intensity which can be cytotoxic, the level of the energetic potential of the cell is directly related to cell survival. We tested the latter prediction in the present work in two ways. First, the level of energy production was lowered by partially uncoupling the mitochondria. Then the effect of stresses under tert-butylhydroperoxide or ethanol was investigated in order to look for a synergistic effect on cell death with the mitochondria uncoupling. Secondly, the effect of a modification of the energetic sources during the stress was tested. Besides a protective effect found with specific defence systems, the presence of energetic metabolites such as D-glucose, pyruvate/malate, glutamate/malate, was tested and found to be protective. The effect of a stimulator of the energetic metabolism, naftidrofuryl oxalate, was also investigated and found protective. The experimental data provide good evidence that energetic factors can modulate the resistance of cells to various stresses.

Adenosine Triphosphate↗