The current status of the chemotherapy of hydatid disease

THE CURRENT STATUS OF THE CHEMOTHERAPY OF HYDATID DISEASE’ William S. Kammerer, M.D.,* and Miguela V. Perez-Esandi, Lit. Q~irn.~

Hydatid disease remains one of the few major parasitic diseases of man for which no adequate chemotherapy exists. However, the development of drug screening programs in laboratory animals provides a rapid, efficient, and economical means for testing potentially effective compounds.

Introduction

Since the chemotherapy of hydatid disease

was last reviewed (I, 2, 3) the further develop-

ment of laboratory animal models (4, 5, 6, 7, 8)

has made it possible to design large-scale drug

screening programs. Previously, testing of

potentially useful drugs was carried out in vitro

or via costly small-scale trials in humans and

domesticated animals.

The difficulties involved in carrying out

controlled clinical trials in humans severely

compromise this method as a screening tech-

nique. In

vitro

testing is theoretically useful for

identifying potentially effective drugs; however,

extrapolation of the results to the situation

in vivo

remains uncertain, due mostly to insuf-

ficient basic information about the metabolism

and permeability characteristics of hydatid

cysts.

The purpose of this article is to point out

certain problems that arise in interpreting the

results of clinical trials in humans reported to

date, and to review the progress of drug

screening programs in laboratory animals.

Human Trials

Several attempts to sterilize or cure hydatid

‘Also

appearing

in Spanish

in

Boletin de la Oficina Sanitaria Panamericana.

aFormerly Parasrtologist,

Pan

American Zoonoses Center, Pan American Health Organization, Ramos Mejia, Buenos Aires, Argentina;

presently Assistant

Professor

of Medicine,

Pennsylvania

State University

Medical School, Hershey Medical Center, Hershey, Pennsylvania.

3Pan Amencan Zoonoses Center, Pan American Health Organization, Ramos Mejia, Buenos Aires, Argentina.

47

cysts through radiation therapy have met with

only limited success (I, 9). Furthermore, the

size of the cysts and the frequently large

numbers involved make it very doubtful that

radiation therapy will prove to be of any

substantial use.

The theoretical rationale behind “biologic

therapy” for hydatid disease and the results of

clinical trials using it have recently been com-

prehensively reviewed (IO, II). As has been

pointed out, no sound experimental or clinical

evidence has emerged to demonstrate the effi-

cacy of this mode of treatment.

Sporadic attempts to develop effective

chemotherapy for hydatid disease over the past

50 years (12, 13, 14, 15) have, with the

exceptions discussed below, encountered little

success.

In 1951, Cuervo Garcia (16) introduced

chemotherapy using iodinized oil of thymol for

treatment of hepatic and pulmonary hydatid

Adult Echinococcus granuiosus tapeworms like this one can infect dogs and various other Canidae. Their larvae can produce cases of hydatidosis involving large internal cysts and ‘a sometimes fatal course in

48 PAHO BULLETIN . Vol. VU, No. 3. I973

FIGURE 1 -The dog-sheep-dog life-cycle of Echi- nococcusgranulosus. E. muftilocularis, the other agent of hydatidosis, is commonly maintained by a fox-vole- fox cycle.

disease;

his reported “cure” of 12 patients was

ascribed to therapy with this compound. A

critical review of this work, however, makes it

difficult to connect the results observed with

the therapy prescribed. The study lacked simul-

taneously matched controls; patient selection

was biased toward those in whom a dramatic

host response

was probably occurring; diagnosis

was often presumptive; and patient follow-up

was uniformly short. Furthermore, as there is

little reliable information on the natural history

of hydatid disease in all of its forms and stages,

it is possible to conclude that the results

obtained by Cuervo Garcia merely represent

the natural course of the disease. The same

comments can be made about subsequent

clinical reports (17, 21) on the efficacy of

iodinized oil of thymol.

More recently, Panaitesco (22) has suggested

long-term therapy with paludrin for the preven-

tion and treatment of secondary hydatidosis.

Again, however, the absence of controls makes

it difficult to ascertain a cause-and-effect

rela-

tionship between the therapy employed and the

results observed. And, as in the previous case,

the lack of substantial objective criteria for

determining a cure makes it impossible to state

with certainty that Panaitesco’s

patients were in

fact cured.

For example, the frequency with which

secondary hydatidosis develops after spillage of

cyst contents during surgery is variable. Among

the patients who Panaitesco treated with palu-

drin and followed for 2 years or more, 18 per

cent remained infected. Schiller (23) however,

reported an incidence of only 30 per cent of

secondary hydatidosis in patients who received

no therapy after spillage of cyst contents during

surgery and who were followed for 5 years or

more. Statistically, these results do not differ

significantly (p > 0.40).

Trials in Laboratory Animals

Drug screening programs in laboratory

animals have been easier to design and inter-

pret, in that controls are easily included,

objective criteria exist for judging drug efficacy

at necropsy, and the natural history of infec-

tion in laboratory animal models has been

thoroughly studied (7, 8). To date, the results

of trials testing some 36 different compounds

have been reported.

The results of those trials in which drug

effectiveness was reported are summarized in

Table 1. In addition, Lukashenko (27), in a

review of his work, reports that various acridine

derivatives

(e.g.,

2 methoxy-6-chloro-

9-aminoacridine and 2 methoxy-6-chloro-

9-methylaminoacridine) were effective, both

in vitro

and

in vivo;

but details of the therapy

provided and criteria for evaluating the effect

of these drugs

in vivo

are not given.

TABLE l-Drugs reported to be active against hydatid disease in experimental animals.

Echinococcus Drug and

species reference Dosage

No. of _{Species Infection}

animals agea Sacrificeb Results

E. granulosus Thymol(16) 30 mg/kg in- 1 Sheep tramuscularly, I Rabbits every other day

for 3 months

E. granulosus Quinacrine

(26)

1 ccofa 1: 1000 solu- tion; in tra- peritoneally , once

20 Mice

E. granulosus Rivanol(26) 3-9 diamino- 7ethoxy- acridine

lccofa 1: 1000 solu- tion; intra- peritoneally, once

20 Mice

Months - Sheep: disappearance of cyst;

Rabbits: cyst was converted into a small hard nodule (no controls).

l/2 hour 6 months There were significantly fewer cysts in treated animals, but the same percentage of treated and control animals were infected.

l/2 hour 6 months In comparison to the controls, there were significantly fewer cysts among the treated mice, as well as significantly fewer infected individuals.

E. multilocu- laris

Lucanthone (24)

E. multilocu- laris

E. multilocu- laris

Cyclophos- phamide (24)

Dactinomycin (25)

100 mg/kg; sub- cutaneously twice a week for 7 weeks

50 Mice 1 week 1 week

200 mg/kg; sub- cutaneously, once

91 Mice 1 week 6-12 weeks

0.35 mg/kg; intravenously, once a week for 5 weeks

40 Mice 1 week 1 week

Cyst weight in treated mice was only 40 per cent of average cyst weight in the controls.

Cyst weight in treated mice was only 20 per cent of average cyst weight in the controls.

Cyst weight in treated mice was only 60 per cent of average cyst weight in the controls.

aInfection age when therapy started.

50

PAHO BULLETIN . Vol. VII, No. 3. I973

TABLE 2-Negative results reported in mice, conflicting with results shown in Table 1. (Negative results indicate that there is no statistically significant difference in the number of infected animals or in the size or weight of cysts in treated animals with respect to the control groups.)

Echinococcus

VP. Drug and reference Dosage

No. of Infection Sacrificeb mice agea

E. grunulosus Thymol (3, 28) 50 mg/kg in 1 %, iodinized oil, 12 in&a- 20 l/2 hour 3 months muscular injections, one every other day

64 mg/kg in 1% iodinized oil; intramus- cularly four times a week for 2 weeks 6

4 months 2 months

4

v

E. granulosus Paludrin (28) 5 mg/kg; orally five times a week

for 6 weeks 10 2days 3 months

Y(

E. granulosus Cyclophosphamide (26) 200 mg/kg; one intraperitoneal injec- 20 l/2 hour 6 months tion per day for 3 days

E. granulosus Lucanthone (34) 0.3 mg; subcutaneously twice a week

for 2 months 8 1 month 2months

E. multilocularis Quinacrine (24) 100 mg/kg; subcutaneously twice a week for 6 weeks

25 1 week 1 week

aInfection age when therapy started.

bTime elapsed between end of therapy and sacrifice.

of varying ages before any experimental

therapy in humans is considered. Analogues of

active compounds could then be similarly

studied in an attempt to identify more potent

but less toxic substances.

Drugs reported to be without effect in

laboratory animal infections include: arseno-

benzol (29), kamala (3U), prednisolone (31),

thiabenzadole (32), neosalvarsan (33), chloro-

quin, sodium antimony mercaptosuccinate,

neguvon and tiguvon (24), trimethoprim, pyri-

methamine, metronidazole, diethylcarbamasine,

hycanthone, colchicine, Hoechst S-201 and

S-6 16 (experimental schistosomicides), hydro-

xyurea, vincristine and vinblastine (25), 6-

mercaptopurine (26), gentian violet, ampho-

tericin B, griseofulvin, emetine hydrochloride

(3), astiban and endoxan (34).

Conclusions

At the present time, surgery remains the

only remedy for patients with hydatid disease.

However, many patients are inoperable due to

the extensiveness of their disease, while others

are ineligible for surgery because of medical

contraindications. Furthermore, surgical re-

moval of hydatid cysts is a costly and time-

consuming procedure, and even in the most

experienced hands it is a hazardous under-

taking. At the same time, improved diagnostic

techniques, and increased awareness of the

disease as a result of epidemiologic surveys and

national control campaigns, are bringing more

and more patients to medical attention. Clearly,

if effective chemotherapy were developed it

would find immediate application.

SUMMARY

If an effective chemotherapeutic treatment application. Among other things, there is

for hydatid disease were discovered, there are currently no sure remedy for hydatidosis

good reasons to believe it would find immediate except surgery, diagnostic techniques have re-

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4

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4 A.

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Kammerer and Phez-Esandi . CHEMOTHERAPY OF HYDATID DlSEASE 51

cently improved, and there is increasing aware- recent work with laboratory animal models has ness of the disease as a result of epidemiologic made it possible to conduct large-scale drug surveys and national control campaigns. screening programs. This article reviews the Initial efforts to test the effects of drugs on results obtained from trials testing over 30 the disease were limited to small-scale trials in different compounds.

humans and domesticated animals. However,

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BUBONIC PLAGUE IN THE UNITED STATES OF AMERICA

Human and animal plague has been controlled in the United States to a point where it is now primarily a rural or wilderness area problem. Only rarely does it pose the sort of threat to large urban centers that it did in the early part of this century. Nevertheless, a record 13 cases of human bubonic plague associated with rural exposure were reported in the United States during 1970; two more were detected in 1971, another was found in 1972, and two more occurred in June and July 1973.

Plague activity has remained high among wild rodent populations in those states where human cases have often occurred, notably Arizona, California, Colorado, and New Mexico. During the first half of 1973 epizootic plague was reported among wild rodents from three widely separated California counties: Siskiyou, Tulare, and Riverside. An epizootic among wood rats at Siskiyou

County’s Lava Beds National Monument, detected in March, forced temporary

closure of visitor facilities until vector control measures could be implemented by state officials. In New Mexico, an epizootic among prairie dogs near Shiprock, San Juan County, necessitated vector control operations over a 5,000-acre tract in order to protect the resident Navajo population. This latter

situation was directly related to epizootics among prairie dogs of southwestern Colorado in 1971-1972.

Because it is sporadic and uncommon, human plague is easily overlooked or mistakenly diagnosed. Since it is readily treatable with appropriate antibiotics, recognizing the current status of wild animal plague and the consequent potential for human exposure should provide a basis for suspecting and appropriately handling sporadic cases. [Morbidity and Mortality, weekly report of the U.S. Center for Disease Control, Vol. 22, Nos. 25, 30, and 32, 1973.1

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