Biomedical subjects

M H Abraham

Publications and source records attributed to M H Abraham.

At least 19 recordsLinked to original sources

PubMed1999

Solute-solvent interactions in micellar electrokinetic chromatography. Characterization of sodium dodecyl sulfate-Brij 35 micellar systems for quantitative structure-activity relationship modelling.

The solvation parameter model has been applied to the characterization of micellar electrokinetic chromatographic (MEKC) systems with mixtures of sodium dodecyl sulfate and Brij 35 as surfactant. The variation in MEKC surfactant composition results in changes in the coefficients of the correlation equation, which in turns leads to information on solute-solvent and solute-micelle interactions. Since the same solvation model can be used to describe many biological processes, particular MEKC surfactant compositions can be selected that model the solute-solvent interactions of some of these processes. Two different MEKC systems have been selected to model the solute-solvent interactions of two processes of biological interest (octanol-water partition and tadpole narcosis).

Animals↗

PubMed1999

Chemosensory detectability of 1-butanol and 2-heptanone singly and in binary mixtures.

Using 1-butanol and 2-heptanone as stimuli, we measured detectability (i.e., psychometric) functions for the odor, nasal pungency, and eye irritation of these two substances alone and in binary mixtures. Nasal pungency responses were tested in subjects lacking olfaction (i.e., anosmics) for whom odors do not interfere. Eye irritation responses were tested in normosmics and anosmics, and found to be similar in both groups so their results were pooled. When all stimuli--single and mixtures--were transformed into concentration units of one (or the other) chemical, a single function could fit all data from the same sensory end point with a correlation coefficient of 0.91 or higher. The outcome lends support, as a first approximation, to the notion of chemosensory agonism, in the sense of dose additivity, between the members of binary mixtures presented at perithreshold levels.

1-Butanol↗

PubMed1999

Hydrogen bonding. 47. Characterization of the ethylene glycol-heptane partition system: hydrogen bond acidity and basicity of peptides.

Twelve measured ethylene glycol-heptane partition coefficients, Peh, have been combined with 20 measured literature values and 44 indirectly determined values to give a set of 76 values. Excluding one value for benzamide, the log Peh values are correlated through our general solvation equation, log Peh = 0.336 - 0.075R2 - 1. 201pi2H - 3.786 Sigmaalpha2H - 2.201 Sigmabeta2H + 2.085Vx with r2 = 0.966, sd = 0.28, and F = 386. The solute descriptor R2 is the excess molar refraction, pi2H is the dipolarity/polarizability, Sigmaalpha2H and Sigmabeta2H are the overall hydrogen bond acidity and basicity, and Vx is the McGowan volume. The log Peh equation has then been used to obtain descriptors for eleven peptides, all of which are end-protected. It is shown that for these end-protected peptides, hydrogen bond basicity makes a greater contribution to log Peh than does hydrogen bond acidity.

Algorithms↗

PubMed1999

Correlation and estimation of gas-chloroform and water-chloroform partition coefficients by a linear free energy relationship method.

A linear free energy relationship, LFER, has been used to correlate 150 values of gas-chloroform partition coefficients, as log Lchl with a standard deviation, sd, of 0.23 log units, a correlation coefficient r2 of 0.985, and an F-statistic of 1919. The equation reveals that bulk chloroform is dipolar/polarizable, of little hydrogen-bond basicity, but as strong a hydrogen-bond acid as bulk methanol or bulk ethanol. However, the main influence on gaseous solubility in chloroform is due to solute-solvent London dispersion interactions. A slightly modified LFER has been used to correlate 302 values of water-chloroform partition coefficients, as log Pchl. The correlation equation predicts log Pchl for a further 34 compounds not used in the equation with sd = 0.17 log units. When the LFER is applied to all 335 log Pchl values, the resulting equation has sd = 0.25, r2 = 0.971, and F = 2218.

Chloroform↗

PubMed1999

The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship.

The aqueous solubility of liquids and solids, as log S(W), has been correlated with an amended solvation equation that incorporates a term in Sigma alpha(2)(H) x Sigma beta(2)(H), where the latter are the hydrogen bond acidity and basicity of the solutes, respectively. Application to a training set of 594 compounds led to a correlation equation with a standard deviation, SD, of 0.56 log units. For a test set of 65 compounds, the SD was 0.50 log units, and for a combined correlation equation for 659 compounds, the SD was 0.56 log units. The correlation equations enable the factors that influence aqueous solubility to be revealed. The hydrogen-bond propensity of a compound always leads to an increase in solubility, even though the Sigma alpha(2)(H) x Sigma beta(2)(H) term opposes solubility due to interactions in the liquid or solid. Increase in solute dipolarity/polarizability increases solubility, whereas an increase in solute excess molar refraction, and especially, volume decrease solubility. The solubility of Bronsted acids and bases is discussed, and corrections for the fraction of neutral species in the saturated solution are graphically presented.

Algorithms↗

PubMed1998

Sensory properties of selected terpenes. Thresholds for odor, nasal pungency, nasal localization, and eye irritation.

We tested four normosmics and four anosmics in detection thresholds for six terpenes commonly found indoors: cumene, p-cymene, delta-3-carene, linalool, 1,8-cineole and geraniol. Normosmics provided odor thresholds and anosmics provided nasal pungency thresholds. All subjects provided nasal localization (i.e., right/left nostril) and eye irritation thresholds. Each type of threshold was measured eight times per subject-stimulus combination. Stimuli were presented from squeeze bottles in a two-alternative forced-choice procedure via an ascending method of limits. Odor thresholds ranged between 0.1 and 1.0 parts per million (ppm, by volume). Nasal pungency thresholds lay about three orders of magnitude above odor thresholds. Nasal localization and eye irritation thresholds did not differ between normosmics and anosmics, and fell close to nasal pungency thresholds. Olfactory thresholds could be obtained for all stimuli in all repetitions using the criterion of five correct choices in a row. Trigeminal thresholds (i.e., pungency, localization and eye irritation) could be obtained on all repetitions only for some terpenes using that same criterion. Carene and cineol produced nasal pungency and eye irritation on all repetitions. None of the terpenes could be localized on all repetitions, but cineol was localized a higher percentage of instances than were the other stimuli. At the other extreme, geraniol failed to evoke any of the three trigeminal responses in most instances. Overall, the results indicate that the three trigeminal thresholds produce a uniform view of the potency of these terpenes, with nasal pungency and eye irritation being slightly more sensitive than nasal localization. Furthermore, application of a previously derived linear solvation energy relationship to the results reinforced the view that physicochemical properties can predict the chemesthetic impact of volatile organic compounds.

Eye↗

PubMed1998

Draize eye scores and eye irritation thresholds in man can be combined into one QSAR.

Draize eye scores (DES) of 37 pure organic liquids have been converted into scores for the corresponding vapors, DES/P0, where P0 is the liquid vapor pressure in atmospheres at 298 K. It is shown that there is a constant difference of 6.7 between values of log(DES/P0) and log (1/EIT), where EIT is the eye irritation threshold in parts per million (ppm, by volume) of eight vapors for human subjects. The 37 log(DES/P0) values can be combined with log(1/EIT) values for 17 vapors into one quantitative structure-activity relationship (QSAR) for sensory potency (SP) using our general solvation equation, [formula: see text] where R2 is an excess molar refraction, pi 2H is the compound polarizability/dipolarity, sigma alpha 2H and sigma beta 2H are the compound hydrogen-bond acidity and basicity, and L16 is the gas-hexadecane partition coefficient at 298 K. n is the number of data points, r the correlation coefficient, SD the standard deviation, and F the F-statistic. LogSP is then either [log(DES/P0) - 0.66] or log (1/EIT), confirming the result for the eight common compounds. It is suggested that the equation can be used to predict eye irritancy of organic vapors and pure liquids. It is further suggested that for the compounds in the data set, the main process in eye irritation is transfer of the compound from the vapor or pure liquid to a biological phase, and a number of chemical properties of the biological phase have been mapped out through the equation. These properties are consistent with corresponding properties for a number of organic liquid phases.

Animals↗

PubMed1998

Inhibition of arylesterase by aliphatic alcohols.

The inhibition of arylesterase (EC 3.1.8.1) by 11 aliphatic alcohols (one to seven carbon atoms) was studied in blood serum from healthy donors. Inhibition curves were described by the Hill equation, with a Hill coefficient (n) close to unity, except for some alcohols, mainly the lowest. The inhibiting activity of the alcohols was highly dependent on their structure, since the C50 values covered about three orders of magnitude. The least active compound was methanol (C50 approximately 1 M) and the most active was heptanol (C50 approximately 7.4 x 10(-4) M). The A and B isozymes (differing by the amino acid at position 191) had similar inhibition parameters with the alcohols tested. Quantitative structure-activity relationships were computed with either the experimental solvation parameters of Abraham [6] or the theoretical parameters of Wilson and Famini [11]. Both methods gave similar results, with a slight advantage to the empirical parameters in terms of simplicity and statistical significance. The two main determinants of inhibition were identified as molecular volume and lack of polarity. The effect of volume was non-linear, tending to a maximum when the length of the alcohol increased. For a given number of carbon atoms, the best inhibitor was the least polar compound. These results point to a binding site consisting mainly of nonpolar aliphatic amino acids, and located in the depth of the protein molecule.

Carboxylic Ester Hydrolases↗

PubMed1998

Structure-activity relationships of volatile organic chemicals as sensory irritants.

We used a database of 145 volatile organic chemicals for which the sensory irritation potency (RD50) has been reported in mice. Chemicals were first separated into two groups: nonreactive and reactive, using Ferguson's rule. This rule suggests that nonreactive chemicals induce their effect via a physical (p) mechanism (i.e., weak forces or interactions between a chemical and a biological receptor). Therefore, appropriate physicochemical descriptors can be used to estimate their potency. For reactives, a chemical (c) mechanism (i.e., covalent bonding with the receptor) would explain their potency. All chemicals were also separated on the basis of functional groups and subgroups into 24 classifications. Our results indicated that the potency of nonreactive chemicals, regardless of their chemical structure, can be estimated using a variety of physicochemical descriptors. For reactive chemicals, we identified five basic reactivity mechanisms which explained why their potency was higher than that estimated from physicochemical descriptors. We concluded that Ferguson's proposed rule is adequate initially to classify two separate mechanisms of receptor interactions, p vs c. Several physicochemical descriptors can be used to estimate the potency of p chemicals, but chemical reactivity descriptors are needed to estimate the potency for c chemicals. At present, this is the largest database for nonreactive-reactive chemicals in toxicology. Because of the wide variety of c chemicals presented, a semi-quantitative estimate of the potency of new, or not previously evaluated, c chemicals can be arrived at via comparison with those presented and the basic chemical reactivity mechanisms presented.

Acetates↗

PubMed1998

An algorithm for nasal pungency thresholds in man.

Nasal pungency thresholds (NPT) in man have been determined by Cometto-Muniz and Cain for 44 varied compounds, including esters, aldehydes, ketones, alcohols, carboxylic acids, aromatic hydrocarbons and pyridine. With the exclusion of acetic acid, 43 of these NPT values are well correlated through the general linear free energy equation of Abraham, leading to the algorithm, log(1/NPT) = -8.519 + 2.154 pi(2)H + 3.522 sigma alpha(2)H + 1.397 sigma beta(2)H + 0.860 logL16. N = 43, r2 = 0.955, SD = 0.27, F = 201 (i) where the independent variables are solute descriptors: pi(2)H is the dipolarity/polarizability, sigma alpha(2)H and sigma beta(2)H are the overall or effective hydrogen-bond acidity and basicity, and L16 is the solute Ostwald solubility coefficient on hexadecane at 25 degrees C. Surprisingly, the aliphatic aldehydes and carboxylic acids fit the correlation and with respect to nasal pungency thresholds in man for brief (1-3 s) presentations must be regarded as 'nonreactive' compounds. It is suggested mere transport of the compound from the air stream to the receptor area largely determines the potency to produce pungency. Various chemical properties of the receptor area are deduced from the coefficients in Eq. i.

Air Pollutants↗

PubMed1998

Nasal pungency and odor of homologous aldehydes and carboxylic acids.

Airborne substances can stimulate both the olfactory and the trigeminal nerve in the nose, giving rise to odor and pungent (irritant) sensations, respectively. Nose, eye, and throat irritation constitute common adverse effects in indoor environments. We measured odor and nasal pungency thresholds for homologous aliphatic aldehydes (butanal through octanal) and carboxylic acids (formic, acetic, butanoic, hexanoic, and octanoic). Nasal pungency was measured in subjects lacking olfaction (i.e., anosmics) to avoid odor biases. Similar to other homologous series, odor and pungency thresholds declined (i.e., sensory potency increased) with increasing carbon chain length. A previously derived quantitative structure-activity relationship (QSAR) based on solvation energies predicted all nasal pungency thresholds, except for acetic acid, implying that a key step in the mechanism for threshold pungency involves transfer of the inhaled substance from the vapor phase to the receptive biological phase. In contrast, acetic acid - with a pungency threshold lower than predicted - is likely to produce threshold pungency through direct chemical reaction with the mucosa. Both in the series studied here and in those studied previously, we reach a member at longer chain-lengths beyond which pungency fades. The evidence suggests a biological cut-off, presumably based upon molecular size, across the various series.

Adult↗

PubMed1998

Trigeminal and olfactory chemosensory impact of selected terpenes.

In Experiment 1, four normosmics and four anosmics (three congenital, one idiopathic) provided odor and nasal pungency thresholds, respectively, for the following terpenes: delta3-carene, p-cymene, linalool, 1.8-cineole, and geraniol, plus the structurally related compound cumene. Additionally, all subjects provided nasal localization (i.e., right/left) and eye irritation thresholis. Trigeminally mediated thresholds (i.e., nasal pungency, nasal localization, and eye irritation) lay about three orders of magnitude above odor thresholds, which ranged between 0.1 and 1.7 ppm. The results implied uniform chemesthetic sensitivity across tasks and sites of impact. In Experiment 2, normosmics and anosmics provided odor and nasal pungency thresholds, respectively, for three pairs of isomeric terpenes: alpha- and gamma-terpinene, alpha- and beta-pinene, and R(+)- and S(-)-limonene. Odor thresholds ranged between 1.4 and 19 ppm, that is, about an order of magnitude higher than those of the previous terpenes, with no substantial differences between odor thresholds of members of a pair. Regarding chemesthetic impact, only alpha-terpinene evoked nasal pungency. The overall outcome suggests comparable trigeminal chemosensitivity between nose and eyes and between normosmics and anosmics, as shown before for homologous n-alcohols. It also lends support to a previously derived solvation model of the chemesthetic potency of airborne substances, and indicates the likely importance of certain molecular-size restrictions for effective trigeminal impact.

Acyclic Monoterpenes↗

PubMed1998

A theoretical approach to the Ferguson principle and its use with non-reactive and reactive airborne chemicals.

The Ferguson principle has been widely used in toxicology to separate or indicate possible mechanisms for acute toxic effects of chemicals. However, this principle has never been adequately tested because of the lack of a database containing a sufficient number of both types of chemicals, non-reactive and reactive, that the Ferguson principle purports to separate. Such a database is now available. In this report a theoretical framework for the Ferguson principle is presented, regarding one of the acute toxicological effects of volatile airborne chemicals: sensory irritation. Previously obtained results on series of non-reactive and reactive chemicals are then used to demonstrate that the Ferguson principle can be extended to reactive chemicals by adding chemical reactivity descriptors to the physicochemical descriptors required by the Ferguson principle. This approach can be successful, provided that specific chemical reactivity mechanisms can be identified for the reactive chemicals of concern. The findings suggest that it is possible to replace the empirical Ferguson principle by formal mechanistic equations which will provide a better foundation for the understanding of the mechanisms by which airborne sensory irritants exert their action.

Air Pollutants↗

PubMed1997

On the partition of ampholytes: application to blood-brain distribution.

Partition coefficients in the water-octanol, -cyclohexane, and -dichloromethane systems were determined as a function of pH for three non-zwitterionic ampholytes (nitrazepam, albendazole sulfoxide, and sulfadimidine) and three zwitterionic ampholytes (morphine, difloxacin, and niflumic acid). From known macro- and microprotonation constants in water, the concentration of cation, anion, neutral form, and zwitterion can be found, and partition coefficients can then be calculated for the partition of the neutral form in water to the neutral form in the organic solvent for all six compounds. These micropartition coefficients were then used to obtain descriptors for the neutral form in the general linear free energy (LFER) equation of Abraham. Knowledge of the descriptors enables a number of physicochemical and biochemical properties of the neutral form to be estimated; a detailed analysis is given of the estimation of the blood-brain distribution ratio for the process of going from the neutral form in blood to the neutral form in brain. A related procedure leads to an estimation of the distribution ratio for the process of going from the zwitterion in blood to the neutral form in brain.

Albendazole↗

PubMed1997

Molecular factors influencing drug transfer across the blood-brain barrier.

A recently reported approach to the prediction of blood-brain drug distribution uses the general linear free energy equation to correlate equilibrium blood-brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; pi2H, solute dipolarity or polarizability; alpha2H and beta2H, the hydrogen bond acidity or basicity, and Vx, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood-brain barrier in the rat. The permeability (logPS) of the blood-brain barrier to a chemically diverse series of compounds was measured using a short duration vascular perfusion method. LogPS data were correlated with calculated solute descriptors, and octanol-water partition coefficients (logP(oct)) for comparison. It is shown that a general linear free energy equation can be constructed to predict and interpret logPS values. The utility of this model over other physicochemical descriptors for interpreting logPS and logBB values is discussed.

2-Propanol↗

PubMed1997

Algorithms for skin permeability using hydrogen bond descriptors: the problem of steroids.

Several algorithms that use hydrogen bond descriptors have been published for the permeation of compounds from aqueous solution through human stratum corneum. In the present work, all the skin permeability coefficients, Kp in cm s-1, used in these algorithms for non-steroids have been correlated through the Abraham equation to give a new algorithm: [equation: see text] where n is the number of solutes, r is the correlation coefficient, s.d. is the standard deviation, and F is the F-statistic. The solute descriptors are: R2 an excess molar refraction, pi 2H the dipolarity/polarizability, sigma alpha 2H and sigma beta 2H the overall or effective hydrogen-bond acidity and basicity, and Vx the McGowan characteristic volume. Equation 1 is a reasonably good predictor of log Kp values for steroids as given by Johnson et al, but not for those given by Scheuplein.

Algorithms↗

PubMed1996

An analysis of nasal irritation thresholds using a new solvation equation.

In the present paper we have developed a quantitative structure-activity relationship (QSAR) equation for nasal pungency caused by nonreactive volatile organic compounds (VOCs). Our QSAR was developed upon previously published nasal pungency thresholds in anosmics, i.e., patients lacking a sense of smell and thus responding only to sensory irritation evoked by trigeminal nerve stimulation. The reported solvation equation, which fits the data with considerable precision, describes sensory potency in terms of interaction via electron pairs, dipolarity/polarizability, hydrogen bond acidity and basicity, and hydrophobicity. It correspondingly suggests relevant physicochemical properties of the biophase where the sensory response is brought about. The equation implies that in the range of molecular size where nonreactive VOCs can produce any pungency, transport from the air to the biophase strictly determines potency. In this respect, the potency of nasal pungency shares characteristics with the ability of VOCs to cause narcosis and anesthesia.

Adult↗

PubMed1996

Sensory irritation mechanisms investigated from model compounds: trifluoroethanol, hexafluoroisopropanol and methyl hexafluoroisopropyl ether.

Quantitative structure-activity relationships (QSAR) have suggested the importance of hydrogen bonding in relation to activation of the sensory irritant receptor by nonreactive volatile organic chemicals. To investigate this possibility further, three model compounds with different hydrogen bond acidity, trifluoroethanol, hexafluoroisopropanol and methyl hexafluoroisopropyl ether, were selected for study. The potency of each chemical is obtained from the concentration necessary to reduce respiratory rate in mice by 50% (RD50). The RD50 values obtained were: methyl hexafluoroisopropyl ether (> or = 160,000 ppm), trifluoroethanol (11,400-23,300 ppm), and hexafluoroisopropanol (165 ppm). QSAR showed that trifluoroethanol and methyl hexafluoroisopropyl ether behaved as predicted as nonreactive sensory irritants, whereas hexafluoroisopropanol was much more potent than predicted. The higher than predicted potency of hexafluoroisopropanol could be due to a coupled reaction, involving both strong hydrogen bonding and weak Brönsted acidity. A concerted reaction could thus be more efficient in activation of the receptor. Hydrogen bonding properties and concerted reactions may be important in the activation of the sensory irritant receptor by nonreactive volatile organic chemicals.

1-Propanol↗