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Eur J Med Chem. 2006 Apr;41(4):494-502. Epub 2006 Mar 3.

Air to brain, blood to brain and plasma to brain distribution of

volatile organic compounds: linear free energy analyses.

Abraham MH, Ibrahim A, Acree WE Jr.

Department of Chemistry, University College London, UK.

m.h.abraham@...

Partition coefficients, K(brain), for volatile organic compounds,

VOCs, from air to brain have been collected for 81 compounds (air to

human brain and air to rat brain). For the 81 VOCs a linear free

energy equation (LFER) correlates log K(brain) with R(2) = 0.923 and

S.D. = 0.346 log units. Use of training and test sets gives a

predictive assessment of 0.35-0.40 log units. Combination of log

K(brain) with our previously listed values of log K(blood) enables

blood to brain partition, as log P(b-brain), to be obtained for 78

VOCs. These values can be correlated with R(2) = 0.725 and S.D. =

0.203 log units; use of training and test sets allows a predictive

assessment for log P(b-brain) of 0.16-0.20 log units. Values for air

to plasma were available for 21 VOCs. When these data were combined

with the data on air to blood and air to brain, values for partition

between (blood or plasma) to brain, P(bp-brain), were available for 99

VOCs. A LFER correlates this data with R(2) = 0.703 and S.D.=0.197 log

units; use of training and test sets allows a predictive assessment

for log P(bp-brain) of 0.15-0.20 log units.

PMID: 16516353 [PubMed - indexed for MEDLINE]

Anaesthesist. 2004 Dec;53(12):1177-84.

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[in vitro effects of anaesthetic agents on the blood-brain barrier]

[Article in German]

Fischer S, Renz D, Kleinstück J, Schaper W, Karliczek GF.

Abteilung für Anästhesiologie und Intensivmedizin,

Kerckhoff-Klinik GmbH, Bad Nauheim. s.fischer@...

BACKGROUND: The blood-brain barrier (BBB) forms a selective

barrier between blood and brain and regulates the passage of most

molecules. Pathological conditions such as ischemia lead to breakdown

of the BBB. Vascular endothelial growth factor (VEGF) has been shown

to be responsible for hypoxia-induced hyperpermeability of the BBB in

vivo as well as in vitro. To eliminate factors which alter the

permeability of the BBB in vivo, an in vitro model was used to test

the effects of intravenous and volatile anesthetics on the

permeability and on VEGF expression during normoxia and hypoxia.

METHODS: The in vitro model of the BBB consisted of primary cultures

of porcine brain microvascular endothelial cells (BMEC). The

permeability was measured by the paracellular passage of [3H]inulin

across the BMEC monolayer and the expression of VEGF was determined by

northern blot analysis. RESULTS: All intravenous and volatile

anesthetics tested (etomidate, ketamine, fentanyl, propofol,

midazolam, sodium-gamma-hydroxybutyrate as well as halothane,

enflurane, isoflurane, sevoflurane, desflurane) did not alter the

permeability of the BBB or the expression of VEGF in vitro. Hypoxia (2

vol%) increased the permeability and the VEGF expression significantly

which was not altered in the presence of the anesthetics. CONCLUSION:

The in vitro model represents a suitable model of the BBB to

investigate direct effects of anesthetics on functions of the BBB

independent of hemodynamic factors.

Publication Types:

* English Abstract

PMID: 15597157 [PubMed - indexed for MEDLINE]

Br J Ind Med. 1989 May;46(5):321-8.

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Correlation of tissue, blood, and air partition coefficients of

volatile organic chemicals.

Paterson S, Mackay D.

Institute for Environmental Studies, University of Toronto, Ontario, Canada.

The physical chemical factors controlling partition coefficients

between air, water, blood, and various tissues are discussed. It is

suggested that improved insights into the relations between partition

coefficients, which are frequently expressed as correlations, may be

obtained by viewing the partition coefficients as ratios of

solubilities or pseudosolubilities. A simple, novel correlation

approach is developed and applied to 24 volatile organic chemicals,

which enables tissue/blood, tissue/air, and blood/air partition

coefficients to be estimated from water solubility and vapour

pressure. An illustration is presented in which these solubilities are

used to calculate the equilibrium distribution of dichloromethane

between air, blood, and various tissues.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 2751930 [PubMed - indexed for MEDLINE]

PMCID: PMC1009775

Drug Metab Dispos. 2004 Jan;32(1):132-9.

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Development of a computational approach to predict blood-brain

barrier permeability.

Liu X, Tu M, RS, Chen C, BJ.

Department of Pharmacokinetics, Dynamics and Metabolism, Groton

Laboratories, Pfizer Global Research and Development, MS 8220-4167,

Eastern Point Road, Groton, CT 06340, USA.

xingrong_liu@...

The objectives of this study were to generate a data set of

blood-brain barrier (BBB) permeability values for drug-like compounds

and to develop a computational model to predict BBB permeability from

structure. The BBB permeability, expressed as permeability-surface

area product (PS, quantified as logPS), was determined for 28

structurally diverse drug-like compounds using the in situ rat brain

perfusion technique. A linear model containing three descriptors,

logD, van der Waals surface area of basic atoms, and polar surface

area, was developed based on 23 compounds in our data set, where the

penetration across the BBB was assumed to occur primarily by passive

diffusion. The correlation coefficient (R(2)) and standard deviation

(S.D.) of the model-predicted logPS against the observed are 0.74 and

0.50, respectively. If an outlier was removed from the training data

set, the R(2) and S.D. were 0.80 and 0.44, respectively. This new

model was tested in two literature data sets, resulting in an R(2) of

0.77 to 0.94 and a S.D. of 0.38 to 0.51. For comparison, four

literature models, logP, logD, log(D. MW(-0.5)), and linear free

energy relationship, were tested using the set of 23 compounds

primarily crossing the BBB by passive diffusion, resulting in an R(2)

of 0.33 to 0.61 and a S.D. of 0.59 to 0.76. In summary, we have

generated the largest PS data set and developed a robust

three-descriptor model that can quantitatively predict BBB

permeability. This model may be used in a drug discovery setting to

predict the BBB permeability of new chemical entities.

Publication Types:

* In Vitro

PMID: 14709630 [PubMed - indexed for MEDLINE]

: Korean J Intern Med. 2007 Mar;22(1):8-12.

Volatile organic compounds contribute to airway hyperresponsiveness.

Jang AS, Choi IS, Koh YI, Park CS.

Department of Internal Medicine, Soonchunhyang University

Hospital, Bucheon, Korea.

BACKGROUND: Volatile organic compounds (VOCs) in concentrations

found in both the work and home environments may influence lung

function. We investigated the prevalence of airway responsiveness in

workers exposed to VOCs. METHODS: We used allergic skin tests,

nonspecific airway hyperresponsiveness testing and questionnaires to

study twenty exposed workers and twenty-seven control subjects. Atopy

was defined as a reactor who showed > 3+ response to one or more

allergens on the skin prick tests. Airway hyperresponsiveness

(BRindex) was defined as log [% fall of FEV1/log (last concentration

of methacholine) +10]. RESULTS: The VOC exposed workers, in comparison

with the control subjects, tended to have a higher BRindex (1.19 +/-

0.07 vs. 1.15 +/- 0.08, respectively). Workers exposed to VOCs with

atopy or smoker, as compared with the workers exposed to VOCs with

non-atopy and who were non-smokers and the control subjects with

non-atopy and who were non-smokers, had a significantly higher BRindex

(1.20 +/- 0.05 vs. 1.14 +/- 0.06 vs. 1.10 +/- 0.03, respectively p <

0.05). The BRindex was not correlated with atopy, the smoking status

or the duration of VOC exposure. CONCLUSIONS: These findings suggest

that VOCs may act as a contributing factor of airway

hyperresponsiveness in workers exposed to VOCs.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 17427638 [PubMed - indexed for MEDLINE]