Prediction of the corneal permeability of drug-like compounds.

Purpose: To develop a computational model for optimisation of low corneal permeability, which is a key feature in ocular drug development.

Methods: We have used multivariate analysis to build corneal permeability models based on a structurally diverse set of 58 drug-like compounds.

Results: According to the models, the most important parameters for permeability are logD at physiologically relevant pH and the number of hydrogen bonds that can be formed.

Defibrillation and the quality of layperson cardiopulmonary resuscitation-dispatcher assistance or training?

Aims Of The Study: To examine whether basic life support-defibrillation (BLS-D) training of laypersons enhances the speed of defibrillation and the quality of cardiopulmonary resuscitation (CPR) during a simulated ventricular fibrillation scenario compared with a situation where the care provider has no previous BLS-D training but receives dispatcher assistance with the use of an automated external defibrillator (AED) and the performance of CPR.

Methods: Fifty-two military conscripts of the Finnish Defence Forces who without previous medical education had been tested in a simulated cardiac arrest scenario with dispatcher assistance and thereafter received a 4-h BLS-D training. Six months later they were randomly divided to form teams of two and again tested in a similar scenario but without dispatcher assistance.

Can untrained laypersons use a defibrillator with dispatcher assistance?

Objectives: Automated external defibrillators (AEDs) provide an opportunity to improve survival in out-of-hospital cardiac arrest by enabling laypersons not trained in rhythm recognition to deliver lifesaving therapy. This study was performed to examine whether untrained laypersons could safely and effectively use these AEDs with telephone-guided instructions and if this action would compromise the performance of cardiopulmonary resuscitation (CPR) during a simulated ventricular fibrillation out-of-hospital cardiac arrest.

Methods: Fifty-four conscripts without previous medical education were recruited from the Western Command in Finland.

Reduction of dopamine synthesis inhibition by dopamine autoreceptor activation in striatal synaptosomes with in vivo reserpine administration.

In an attempt to clarify the mechanisms by which dopamine (DA) autoreceptor activation inhibits DA synthesis, the efficacy and potency of the D2 DA agonists bromocriptine, lisuride, and pergolide, and the D1-D2 DA agonist apomorphine were studied in rat striatal synaptosomes, in which the rate of DA synthesis (formation of 14CO2 from L-[1-14C]tyrosine) was increased 103% by treating the animals from which the synaptosomes were obtained with reserpine (5 mg/kg i.p. twice, 24 and 2 h before they were killed), using the striatal total homogenate as the standard synaptosomal preparation.

Synaptosomal dopamine autoreceptors: sensitivity changes after in vitro and in vivo treatments.

Dopamine (DA) synthesis in rat striatal synaptosomes was approximately doubled either by treating the animals from which the synaptosomes were obtained with reserpine, or by treating the preparations in vitro with d-amphetamine, ouabain or dibutyryl cyclic AMP. The concentration-response curve of DA synthesis inhibition by apomorphine was shifted to the right after treatment with all these compounds. The inhibitory effect of bromocriptine on DA synthesis was reduced completely after treatment with all the above compounds with the exception of dibutyryl cyclic AMP.

Autoreceptors mediate the inhibition of dopamine synthesis by bromocriptine and lisuride in rats.

The administration of bromocriptine and lisuride to rats caused a decrease in striatal dopamine (DA) synthesis, as measured by 3,4-dihydroxy-phenylalanine (DOPA) accumulation after decarboxylase inhibition. DOPA formation was inhibited by a maximum of about 60% of control values by bromocriptine and lisuride, 5.0 and 0.

Inhibition of dopamine synthesis in striatal synaptosomes by lisuride: stereospecific reversal by (-)-sulpiride.

Lisuride, an ergot D2 dopamine receptor agonist inhibited dopamine synthesis in striatal synaptosomes concentration-dependently. Significant inhibition was detected at 10(-8) M, and the inhibition by 10(-4) M lisuride was 50%. The inhibitory effect of lisuride was reversed by more than 50% not only by the D1-D2 dopamine receptor blocker haloperidol but also by the D2 dopamine receptor blocker(-)-sulpiride.

Increase of dopamine synthesis in synaptosomes from rats treated with neuroleptics or reserpine.

Dopamine (DA) synthesis in rat striatum was increased three- to four-fold by in vivo treatment with gammabutyrolactone (GBL), reserpine, haloperidol and (-)sulpiride. DA synthesis in striatal synaptosomes (measured by formation of 14CO2 from labelled tyrosine) did not change after GBL and only doubled after reserpine and neuroleptic administration. The increase of synaptosomal DA synthesis was proportional to and probably due to kinetic activation of tyrosine hydroxylase which, after neuroleptic drugs, remained activated for at least 15 min in synaptosomal incubations at 37 degree C.

Ultrastructure of neurosecretosomes sedimented in the nuclear fraction from the posterior pituitary of the rat.

Subcellular fractions of the posterior pituitary of the rat were isolated by differential and density gradient centrifugation, and microsamples prepared for electron miscroscopy by KMnO4 or glutaraldehyde-OsO4 fixation. The nuclear fraction, P1 (1000 g x 7 min), was the main neurosecretosome (NSS) fraction and contained nuclei and mitochondria in addition to NSS (60%). The crude mitochondrial fraction, P2 (10,000 g x 20 min), contained free mitochondria (70%), NSS, unidentified membrane particles, fat droplets derived from pituicytes, neurosecretory granules (NSG) and synaptosomes, identified by the presence of synaptic membrane thickenings.

Foot-shock stress accelerates non-striatal dopamine synthesis without activating tyrosine hydroxylase.

Electric foot-shock stress (20 min) increases DOPAC content in the frontal cortex (by about 80%) and in the nucleus accumbens (by 35%) but not in the striatum. However, foot shock stress failed to modify the kinetic properties of tyrosine hydroxylase (Vmax, Km for DMPH4 cofactor) in any of the above areas. Similar results were obtained in rats in which noradrenergic terminals in the n.

Ultrastructure of synaptosomes from fetal rat brain.

The crude mitochondrial fraction P2 and subfractions of P2 were prepared from the brain stem, hemispheres and whole brain of 19-day-old fetal rats. Samples were fixed in glutaraldehyde-osmium, NaMnO4 or by Tranzer's triple fixation method (aldehydr-chromate-dichromate-osmium) and examined by electron microscopy. The C-fraction from whole brain was the main synaptosome fraction, containing 3.

Ultrastructural identification of monoaminergic synaptosomes from one day old rat brain.

Synaptosomes from one day old and adult rat brain were studied. Specific cytochemical methods for demonstrating monoaminergic (MA) nerve endings were used. Permanganate fixation after preincubation with 5-OHDA or alpha-methyl-NA demonstrated MA synaptosomes.

Synaptosomes containing large agranular vesicles isolated from developing rat brain.

Using the subcellular fractionation technique the fine structure of the isolated nerve endings (synaptosomes) from the hemispheres and brain stem of the 1-day old and adult rat was examined. In the synaptosomal fractions of the brain of 1-day old rats we observed a new type of nerve endings containing predominantly large agranular vesicles about 1,000 A in diameter. After incubation with alpha-methylnoradrenaline or 5-hydroxydopamine these vesicles remained agranular.

Pharmacological and ultrastructural maturation of serotonergic synapses during ontogeny.

Studies were made on the course of maturation of serotonergic synapses during ontogeny in rat brain. Mature synaptosomes containing the same five types of synatic vesicles as in the adult, including small dense core vesicles, could be isolated in low proportion from the brain of 1-day-old rats. Although the buoyant density of these synaptosomes varied more than in the adult, the 5-hydroxytryptamine (5-HT) synaptosomes at the two age groups had similar sedimentation characteristics.