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Since the early phase of severe trichinosis were prepared by adding drugs to finely
is accompanied by various phenomena sug- ground mouse chow and mixing thoroughly.
gestive of hypersensitivity, it was thought Medicated and nonmedicated diets were pro-
to be of interest to administer to Trichinella- vided ad libitum.
infected mice a drug which might be expected Mice were exposed to T. spiralis larvae
to exert a suppressive action on a wide vari- harvested from other mice by peptic diges-
ety of hypersensitive states. The drug used tion and washed once by sedimentation in
was 1-methyl-4- (5dibenzo- [ a,e] -cyclohepta- saline. The concentration of larvae in a
trienylidine)-piperidine hydrochloride mono- freshly-digested suspension was estimated by
hydrate (generic name: cyproheptadine) . a sampling technique, the aliquots being with-
This compound is unusual in that it possesses drawn while the suspension was stirred. The
both antihistamine and antiserotonin proper- concentration of larvae was adjusted so that
ties (Stone et al., 1961). When cyprohepta- the requisite number of larvae could be given
dine was found to have a definite effect on to mice in volumes of 0.5 or 1.0 ml. The
the intestinal phase of the disease, two other larvae were introduced into the stomach of
drugs, one having antihistamine activity, the the mice by means of a syringe and dosing
other having antiserotonin activity, were needle; the suspens&n was stirred while the
similarly tested. Data obtained with all three inocula were withdrawn.
drugs are presented in this report. The following method was used to estimate
the average number of adult Trichinella per
MATERIALS AND METHODS
mouse. The mice of a group or subgroup were
Male albino mice were used; they were killed, and their small intestines were slit
approximately 5 weeks of age and weighed open and cut into lengths of a few centi-
20-25 gm at the time of exposure to TriGhi- meters. These fragments were incubated at
nella. Nontreated mice were fed a diet of 37’C for about 1 hour in saline. Sufficient
commercial mouse chow. Medicated diets 0,40J0 NaOH was then added to give a final
23
24 CAMPBELL, HARTMAN, AND CUCKLER
TABLE II
Results of Experiments 2 and 4”
Initial
Worms per mouse, day 17
number Number mice
Treatment mice necropsied Rangea Mean”
Experiment 2
None 50 50 198-239 221(+ 8.4)
Cyproheptadine, 0.025% 49 28 317-424 374(f 9.8)
Experiment 4
None 31 21a 59-79 69(+ 10.0)
Cyproheptadine, O.O2S% 19 18 104-127 116(k 11.5)
B.A.S., 0.2% 19 13 111-148 130(+ 18.5)
Chlorpheniramine, 0.2% 19 13 133-152 143 (-c 9.5)
a Numbers of Trichtnek recovered from the intestine of mice on day 17 after exposure to infection. Mice
unaccounted for in necropsy figures died during the experiment.
b Range of the means of the sub-groups into which each group was divided.
C Mean of the means of the sub-groups; Standard Error in parentheses.
d The other 10 mice necropsied on-day-7f see text.
TABLE III
Results of Experiment 3a
Treatment
Cyproheptadine
Day None 0.0125-0.025%
Day 7
Number mice necropsied 12 12
Worms per mouse, mean 280 319
Day 21
Number mice necropsied 39 39
Worms per mouse, range* 53-87 124-147
Worms per mouse, meant 70(+- 8.1) 137(& 5.1)
Day 28
Number mice necropsied 40 35
Worms per mouse, rangeb 5-17 30-73
Worms per mouse, mean0 13(& 2.6) 42(-1- 10.5)
Larvae per gram, range* 4262-5439 5039-6993
Larvae per gram, mean0 4668(+-262) 6238(*425)
a Numbers of Trichinella recovered from intestine and musculature of mice on days 7, 21, and 28
after exposure to infection. Mice unaccounted for in necropsy figures died during the experiment.
* Range of the means of the sub-groups.
0 Mean of the means of the sub-groups; Standard Error in parentheses.
6 Necropsy performed before start of medication,
(Table II). The mice were exposed to 850 is statistically significant (p < 0.05 and p <
larvae each. Administration of each drug was 0.01).
begun on day 4 of infection and continued DISCUSSION
until day 17. One of the characteristics of T. spiralis in-
The results of the fourth experiment are fections is the rather sudden elimination of
summarized in Table II. Ten untreated mice, most of the adult worms from the intestine
killed on day 7 after exposure, harbored an of the host within a few weeksafter infection.
average of 199 worms each. By day 17 of In mice a substantial loss of worms generally
infection the three groups of treated mice occurs at the end of the second week of in-
were in poor physical condition, and a con- fection. The occurrence of an acute cellular
siderable number had died. The control mice process in the intestinal mucosa shortly be-
weighed an average of 24.7 gm; the average fore the expulsion of Trichinella from the
weight of the mice treated with cyprohepta- intestine of the mousehas been described by
dine, B.A..%, and chlorpheniramine maleate, Larsh and Race, 1954. This processis inflam-
was 22.2, 16.5, and 19.1 gm, respectively. The matory in nature and can be reduced by ad-
mice treated with cyproheptadine yielded 1.7 ministration of cortisone, under which condi-
times as many worms, on average, as did the tions the worms remain longer in the intestine
control mice; the difference, in this particular (Coker, 1955). As might be expected, such
experiment, was of borderline statistical sig- prolongation of the intestinal phase results
nificance. The mice treated with B.A.S. in an increasein the number of larvae in the
and chlorpheniramine maleate, respectively, host musculature (Markell, 19.58). Adreno-
yielded 1.9 and 2.1 times as many worms as cortical steroids are capable of blocking anti-
did the controls; the difference, in each case, body synthesis (Robinson, 1960), and cor-
tisone might therefore suppress the inflam- techniques. Most of these responses could
matory process indirectly by blocking a pre- be considered to be of the “immediate” vari-
requisite antigen-antibody reaction. ety (Andrews, 1962). Stewart (1955) has
In the present study, cyproheptadine, and reported that the phenomenon of “self-cure”
two other drugs, significantly reduced the in hemonchosis in sheep results from hyper-
number of adult Trichinella which were ex- sensitivity of the abomasal mucosa and can
pelled from the gut of mice by day 17 or 21 be suppressed by antihistamine drugs. Mar-
of infection. It is presumed that this effect kell and Lewis (1957) suggested that the
was due either to a delay in the onset of the cellular reaction of mice to the presence of
cellular reaction which is responsible for the intestinal Trichinella represented a state of
expulsion of the worms, or to a cellular reac- “delayed” hypersensitivity and was inde-
tion of diminished intensity. In view of the pendent of circulating antibodies. There is
well-known anti-inflammatory property of abundant evidence, however, that humoral
antihistamine drugs, the present findings add antibodies play a role in providing protection
strength to the belief that the expulsion of against reinfection with Trichinella (Culbert-
Trichinella is caused by the inflammatory son, 1942; Larsh, 1953).
response of the host’s intestinal mucosa. In The prolongation of the intestinal phase of
the mouse, serotonin has been shown to have trichinosis, following administration of anti-
a histaminelike action (Page, 1958). The histamine or antiserotonin compounds, does
activity of B.A.& in Experiment 4, was not indicate whether the cellular response is
therefore not unexpected. an allergic phenomenon. The observation
The inflammatory reaction of mouse in- does suggest that the cellular response is
testinal mucosa occurs much earlier in pre- mediated, to some extent, by histamine. How-
viously infected mice than in mice with a first ever, in view of the weight loss recorded in
infection, and Larsh and Race (1954) have all groups of treated mice in Experiment 4,
proposed that the response is, in both cases, the experimental findings might reflect a
stimulated by the interaction between the reduced antibody production, resulting from
worms and the humoral antibodies which stress and/or lack of protein resources.
they, or their by-products, have elicited. If In Nippostrongylus infections in mice,
this be true, the very rapid onset of the inflammation of the mucosa was associated
response in immunized rats and mice (within with an increase in the number of mast cells
3-12 hours after challenge, according to but no increase in the level of free histamine
McCoy, 1940, and Larsh and Race, 1954) in the tissue; this was attributed to the
could be attributed either to the immediate destruction of histamine by substances re-
availability of circulating antibody or to the leased from the eosinophils which were pre-
hypersensitivity of the host’s mucosa. Indeed, sent in large numbers (Wells, 1962). Perhaps
both factors may well be involved, i.e., in the eosinophilia characteristic of trichinosis
immune mice the mucosa may be hypersen- similarly serves to diminish histamine activ-
sitive, not only to the challenge worms or ity.
their by-products, but to a complex formed In Experiment 2, since the majority of
by the combination of antigen from the chal- worms had been expelled from both the cy-
lenge infection with residual antibody from proheptadine-treated and the untreated mice
a previous infection. within 21 days after exposure, it is not sur-
Conditions of hypersensitivity are well prising that there was so little difference be-
known in helminthic infections and have tween the estimated number of larvae in the
formed the basis of many immunodiagnostic muscles of treated and nontreated mice. In
28 CAMPBELL, HARTMAN, AND CUCKLER
preliminary experiments, in which very high LARSH, J, E. 1953. Studies in old mice to test the
mortality occurred in infected cyprohepta- hypotheses of local and general immunity to
Trichinella spiralis. Journal of Infectious Dis-
dine-treated mice, the few surviving treated eases 93, 282-293.
mice harbored fewer larvae in their muscles LARSH, J. E., AND RACE, G. J. 1954. A histopatho-
than did nontreated mice. This may simply logical study of the anterior small intestine of
be due to the fact that these few mice sur- immunized and non-immunized mice infected
vived because their infections had been ex- with Tn’chinella spiralis. Journal of Infectious
Diseases 94, 262-272.
ceptionally light.
MARKELL, E. K. 1958. The effect of cortisone
Inflammatory processes are important in treatment upon the longevity and productivity
the elimination, not only of infecting orga- of Trichinella spiralis in the rat. Jourmzl of In-
nisms, but also of their noxious by-products. fectious Diseases 102, 158-161.
MARKELL, E. K., AND LEWIS, W. P. 1957. Effect
The unexpectedly high mortality of the of cortisone treatment on immunity to subse-
treated mice in these experiments may be quent re-infection with Trichinella in the rat.
due to decreased tolerance of the infected American Journal of Tropical Medicine and
mice to the drugs used, but may on the other Hygiene 6, 553-561.
hand reflect the failure of the host to elimi- MCCOY, 0. R. 1940. Rapid loss of Trichinella
larvae fed to immune rats and its bearing on
nate toxins produced by the parasites.
the mechanism of immunity. American Journal
of Hygiene 32, 105-116.
PAGE, I. H. 1958. Serotonin. Phwioloaical
_ - Re-
The authors thank Dr. R. W. Schayer for his &ems 36, 277.
helpful comments and for suggesting the use of ROEINSON, H. J. 1960. Adrenal steroids and resis-
chlorpheniramine and B.A.% in this study. Statistical tance to infection. Antibiotics and Chemo-
analysis of the data was performed by Mr. A. G. therapy 7, 199.
Itkin. STEWART, D. F. 1955. “Self-cure” in nematode
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