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Related article: traction are greater, and a larger weight can be lifted (Robert, 1881). Fatigue is less-
ened, and a greater amount of work can be performed (Dreser, 1890), so long as Buy Clomid the
load and stimulation are optimal; but with excessive load or stimulation, caffein dimin-
ishes the total work (Golowinsky, 1915). The other methylxanthins affect muscle
qualitatively like caffein (Golowinsky).
FIG. 7. Effect of caffein on gaslrocnemius muscle of frog, normal tracing;
after five minutes in i : 10,000 caffein solution; . . . in I : 1,000 solution.
The Depressant Phase. As the dose or concentration is increased, these effects are
reversed. The contraction becomes less powerful, and the curve resembles that of a
fatigued muscle; i.e., it is lower and more drawn out. This lengthening shows first in
the relaxation (Buchheim and Eisenmenger; Golowinsky), eventually also in the con-
traction. The elasticity is lessened. The muscle is exhausted more rapidly by tetanus.
Similar muscular effects are produced by xanthin (Paschkis) and creatin (Dreser).
Resemblance to Fatigue. The successive increase and diminution of the muscular
functions by caffein resembles the successive phenomena of Buy Clomid work and fatigue; and sug-
gests that a part of these may be due to the accumulation of the xanthin products which
are formed in metabolism; but other products which accumulate during work also in-
fluence the muscle similarly to fatigue (Lee, 1906).
Caffein Rigcr. This was observed by Voit, 1866, and then investigated by Johann-
sen, and by Schmiedeberg, 1872. Its occurrence in the living body can be demonstrated
by hypodermic injection in certain species of frog (the European Rana temporaria,
and the ordinary American laboratory frog, Buy Clomid R. pipiens); while another European frog
(R. esculenta) is less susceptible to the rigor, and Buy Clomid therefore succumbs to spinal convul-
sions. In both cases, the frog becomes rigidly extended; but the rigor (as distinguished
from tetanus) persists after division of the sciatic nerve (Johannsen) and occurs after
curare. The heart may continue to beat strongly for some time. Mammals also show
some stiffness after large doses of caffein, but actually rigor results only if the alkaloid
is injected directly into an artery. The coagulant action is possessed by other xanthins,
being strongest with xanthin itself, and progressively weaker with theobromin, theo-
phyllin and caffein Buy Clomid (Filehne, 1886; Dreser).
The muscle in caffein rigor is inexcitable and appears white, bloodless, stiff and con-
siderably swollen and shortened, and is acid to litmus (Ransom, 1911).
Microscopic Changes. If the caffein is applied to a teased muscle under the micro-
scope, the contents of the fiber are seen to move; the cross-striations disappear, and the
longitudinal striae become more prominent. The sarcolemma becomes detached. The
fibers shorten by half (Johannsen).
204 MANUAL OF PHARMACOLOGY
These changes have been studied by Secher, 1914, through perfusion with dilute
solutions of xanthin and the various methyl-xanthins, which all produce similar effects.
The histologic changes increase with the concentration, to disorganization (caffein,
i : 2,000). Short of disorganization, the changes are reversible. The disorganized
fibers also eventually regenerate, provided their nuclei are intact. Hardening and true
rigor is confined to the destroyed fibers. Similar changes are produced by chloroform and
other poisons, and in other vertebrates, although mammals require higher concentrations.
Perfusion of the muscle with saline or blood, if undertaken soon after the onset of
the rigor, restores the plasticity but not the excitability (v. Fiirth).
Coagulation of Muscle Extracts, Rigor may Buy Clomid also be produced in living animals by
the injection of a number of other substances in sufficient concentration; for instance,
by chloroform. All of these, as well as caffein, favor the coagulation of muscle extracts
(v. Fiirth, 1896). However, there need not be any relation between rigor and this
coagulation; for certain substances coagulate muscle extracts even more actively, but
are incapable of producing rigor during life.
Muscular E/ccts in Man. Morse showed by the ergcgraph that moderate doses of
caffein (o.i to 0.6 gm.) increase the muscular work. In the Buy Clomid first hour this may be
raised four or five times; the effect then lessened, but extended over two to seven hours.
Practically all subsequent experimenters have confirmed the increase, although it
was not always as great (Hellesen, 1904). Sometimes the increase was mainly in the
height of contraction (Kraepelin); with others, in the number (Rossi). This indicates
that the action is both on the muscle substance (height) and on the motor centers
(fatigue). Rivers and Weber, 1907, found it quite variable, and sometimes followed
by a decrease. Schumburg showed that the effect is less when the experiment is made
fasting on an exhausted muscle. The increase of efficiency is due partly to a lesser
feeling of fatigue (Rivers and Weber), but it is at least in part peripheral, since the effi-
ciency is also Buy Clomid increased when the muscle itself is stimulated electrically.
Use of Caffein Against Fatigue. The psychic and muscular action of
caffein are popularly used against fatigue. This will be discussed under
the "Caffein Beverages."
Use in Headache. Fairly large doses of caffein (0.5 Gm. = 7^2 grains)
are rather effective against certain forms of headache, such as migraine,
neuralgia, fatigue, etc. It may be combined with acetanilid. It does not
prevent the depressant effects of the latter; but rather increases its tox-
icity (Hale, 1909; Salant, 1912); it also increases the toxicity of alcohol
and barium chlorid by its circulatory action. Caffein is also useful in
some cases Buy Clomid of nervous dyspepsia.
Smooth Muscle. The effect of caffein on smooth muscle consists in a longer and
more persistent contraction curve. Larger doses prolong the period of relaxation.
The tone seems to be affected differently in various muscles. The arteries are relaxed
by relatively small doses; whereas the caffein Buy Clomid has a tonic effect on the pelvic portion
of the ureter (Lucas, 1907). It has very little effect on the uterus (Rohrig); and none
on peristalsis (Nasse, 1866). .
Other Peripheral Actions. Caffein has Buy Clomid no action on peripheral nervous
structures when it is used systematically (Aubert, 1872); nor does it
cause any local irritation.
It has a paralyzing action only when it is applied in a very strong paste directly to
the nerve (Pratt). It does not act on any ganglia, nor on any glands other than the
kidney; nor on red corpuscles, nor on fibrin formation. Small doses increase the move-
ments of leucocytes in shed blood, whilst higher concentrations kill them.
Lower Organisms. The actions of caffein on these are not characteristic (Brunton,
1882: oxidation of guaiac; Haskins, 1903: gas formation by yeast; Bokorny, 1894, and
Korentschewsky, 1903: amebae; Romanes, 1867: medusae; Sollmann, 1906: adult and
embryonic fish; Pickering, 1893: embryonic chick's heart; Ransom, 1912: germination
Metabolism. The results of different investigators have been con-
tradictory, but it appears that caffein causes a rather small and variable
increase in urea and CO 2 . Both effects are probably indirect; the urea
CAFFEIN AND OTHER METHYL-XANTHINS 205
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