1955_Horita_139_1.pdf

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ABSTRACTS OF PAPERS
Francisco
22. This paper covers the initial phases
of a study designed to correlate the neurotoxic
effects of a series of triorthotolylphosphate
de-
rivatives with their structure. An attempt also
was made to correlate anticholinesterase activity
with the production of flaccid paralysis. White
Leghorn cockerels and their tissues were used
exclusively, and 18 of the compounds in the series
are reported on.
Tests
in vitro
by Michel's method, using acetyl-
choline as substrate, showed that the compounds
did not inhibit the cholinesterase activity of brain
or plasma at concentrations as high as 10-
2
11J.
Tests run
24
hours after injection into cockerels
showed that plasma cholinesterase was more com-
monly inhibited than that of brain or cord. Brain
cholinesterase was never extremely
«
50% nor-
mal activity) inhibited. Only one compound, tri-
orthotolylphosphite,
caused extreme inhibition
of cord cholinesterase. The compounds causing
extreme inhibition of pseudocholinesterase
of
plasma were: triorthotolylphosphate,
diortho-
t
olylmonoparatolylphosphatc,
monoorthotolydi-
parut.olylphospha.te , triorthotolylphosphite,
and
diethoxymonoorthotolylphosphate.
The first three
named were the only ones in the series which
caused flaccid paralysis. Trimetatolyl- and tri-
paratolylphosphate;
2,4-, 2,5-, 2,6-, and 3,5-
dimethylphenylphosphates;
and triorthophenyl-
phenylenephosphate showed little or no anticho-
linesterase activity as well as no paralytic effect.
Results obtained so far indicate that paralytic
and anticholinesterase effects are not related. In
this series paralysis has been caused only by a fully
aromatic-substituted
phosphate with a single
methyl group in the ortho-position on one or more
of the rings.
(Supported in part by grants from the
Shell Development Company and the Shell Oil
Company.)
The pyretogenic effect of lysergic acid diethyl-
amide. AKIRA HORITA AND JAxlES M. DILLE.
*
Dept. of Pharmacology,
Univ. of Washington
School of Medicine, Seattle.
The administration of
lysergic acid diethylamide (LSD) intravenously
or subcutaneously to rabbits, cats, and dogs pro-
duces a rise in body temperature. Most experi-
ments were carried out on rabbits which proved
to be the most responsive. Body temperature was
measured rectally with a mercury thermometer.
Dose levels ranged between 0.5 and 50 microgm./
kg. Maximum rise in temperature occurred at
about the end of one hour and the total duration
of the effect was six to eight hours.
Measurement of surface temperature of the skin
and ear by means of a McKesson "Dermalor" in-
dicated that the skin temperature did not change
29
whereas the ear temperature fell markedly. The
fall of the ear temperature outlasted the rise of
the rectal temperature. The effect of LSD on the
surface temperature of the ear appears to be un-
related to the pyretogenic effect of LSD.
In an attempt to find a mechanism for the
pyretogenic effect of LSD, cervical spinal sec-
tions were made in rabbits. This abolished the
pyretogenic effect. The administration
of
d-
tubocurarine or sodium pentobarbital also abol-
ished the pyretogenic effect. The administration
of antipyrine, Dibenamine, dihydroergotamine,
or Hydergine did not modify the effect of LSD.
The administration of morphine augmented the
pyretogenic effect of LSD. There is an indication
that the pyretogenic effect is central in origin.
Epinephrine induced ventricular fibrillation in
animals treated with Harman methosulphate.
D.
E.
HUTcHEo"" A. SCRL,"BI",E* ",DA.
L.
RA-
A
l'UZZI*.Research
Laboratories, Chas.
Pfizer
&
Co.,
Inc., Brooklyn, N. Y.
Experimental cardiac ar-
rhythmias were found to be induced in cats and
dogs under sodium pentobarbital anesthesia by
Harman methosulphate
(3-6
mg. per kg.) and
epinephrine (5--30 microgm. per kg.). These ar-
rhythmias ranged in severity from nodal rhythm
and ventricular
extrasystoles
to ventricular
tachycardia and fibrillation. Several practical
differences between Harman methosulphate and
the hydrocarbon inhalation anesthetics, which
predispose the heart to ventricular fibrillation,
were: (1) smaller doses of epinephrine were
effective after Harman methosulphate, (2) epi-
nephrine resulted in a higher incidence of ven-
tricular fibrillation after Harman methosulphate
than after cyclopropane or petroleum ether, (3)
fibrillation may be induced by epinephrine up to
one hour after Harman methosulphate and, (4)
the onset of action appeared to be slower than
after petroleum ether. There was no evidence of a
relation between the development of fibrillation
and the initial blood pressure level. On the eat's
papillary muscle, Harman methosulphate
in
4
caused a slight
concentrations of 0.3 to 0.7 X 10-
increase in the force of contraction whereas the
hydrocarbon anesthetics are known to depress the
myocardium. In concentrations of 1.4 to 1.6 X 10-
4
the substance initiated rhythmic contractions
which continued without electrical stimulation.
A relationship was suggested between this ability
of Harman methosulphate to produce automa-
ticity in the isolated papillary muscle and its
action in predisposing the heart to ventricular
fibrillation.
(T). Addiction liability of 4-4-diphenyl-6-di-
methylamino-hexanone-3.
H. ISBELL ANDH. F.

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