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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 cysts through radiation therapy have met with only limited success(I, 9). Furthermore, the Since the chemotherapy of hydatid disease size of the cysts and the frequently large was last reviewed (I, 2, 3) the further develop- numbers involved make it very doubtful that ment of laboratory animal models (4, 5, 6, 7, 8) radiation therapy will prove to be of any has made it possible to design large-scaledrug substantial use. screening programs. Previously, testing of The theoretical rationale behind “biologic potentially useful drugs was carried out in vitro therapy” for hydatid diseaseand the results of or via costly small-scaletrials in humans and clinical trials using it have recently been com- domesticatedanimals. prehensively reviewed (IO, II). As has been The difficulties involved in carrying out pointed out, no sound experimental or clinical controlled clinical trials in humans severely evidence has emergedto demonstratethe effi- compromise this method as a screening tech- cacy of this mode of treatment. nique. In vitro testing is theoretically useful for Sporadic attempts to develop effective identifying potentially effective drugs;however, chemotherapy for hydatid diseaseover the past extrapolation of the results to the situation in 50 years (12, 13, 14, 15) have, with the vivo remains uncertain, due mostly to insuf- exceptions discussedbelow, encountered little ficient basic information about the metabolism success. and permeability characteristics of hydatid In 1951, Cuervo Garcia (16) introduced cysts. chemotherapy using iodinized oil of thymol for The purpose of this article is to point out treatment of hepatic and pulmonary hydatid certain problems that arise in interpreting the results of clinical trials in humans reported to date, and to review the progress of drug screeningprograms in laboratory animals.

Human Trials Severalattempts to sterilize or cure hydatid

‘Also appearingin Spanishin Boletin de la Oficina Sanitaria Panamericana. aFormerlyParasrtologist, Pan American Zoonoses Center, Pan American Health Organization, Ramos Mejia, Buenos Aires, Argentina; presentlyAssistant Professorof Medicine,Pennsylvania State University Medical School, Hershey Medical Center, Hershey, Adult Echinococcus granuiosus tapeworms like this Pennsylvania. one can infect dogs and various other Canidae. Their 3Pan Amencan Zoonoses Center, Pan American larvae can produce cases of hydatidosis involving Health Organization, Ramos Mejia, Buenos Aires, large internal cysts and ‘a sometimes fatal course in Argentina. man. 47 48 PAHO BULLETIN . Vol. VU, No. 3. I973

FIGURE 1 -The dog-sheep-dog life-cycle of Echi- with certainty that Panaitesco’spatients were in nococcusgranulosus. E. muftilocularis, the other agent fact cured. of hydatidosis, is commonly maintained by a fox-vole- fox cycle. For example, the frequency with which secondary hydatidosis developsafter spillage of cyst contents during surgery is variable. Among the patients who Panaitescotreated 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 secondaryhydatidosis in patients who received no therapy after spillageof 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, disease;his reported “cure” of 12 patients was objective criteria exist for judging drug efficacy ascribed to therapy with this compound. A at necropsy, and the natural history of infec- critical review of this work, however, makesit tion in laboratory animal models has been difficult to connect the results observedwith thoroughly studied (7, 8). To date, the results the therapy prescribed.The study lacked simul- of trials testing some 36 different compounds taneously matched controls; patient selection have been reported. was biased toward those in whom a dramatic The results of those trials in which drug host responsewas probably occurring; diagnosis effectivenesswas reported are summarized in was often presumptive; and patient follow-up Table 1. In addition, Lukashenko (27), in a was uniformly short. Furthermore, as there is review of his work, reports that various acridine little reliable information on the natural history derivatives (e.g., 2 methoxy-6-chloro- of hydatid diseasein all of its forms and stages, 9-aminoacridine and 2 methoxy-6-chloro- it is possible to conclude that the results 9-methylaminoacridine) were effective, both in obtained by Cuervo Garcia merely represent vitro and in vivo; but details of the therapy the natural course of the disease.The same provided and criteria for evaluating the effect comments can be made about subsequent of thesedrugs in vivo are not given. clinical reports (17, 21) on the efficacy of It should also be noted that conflicting iodinized oil of thymol. results have been reported by other investi- More recently, Panaitesco(22) has suggested gators with respectto oil of thymol, cyclophos- long-term therapy with paludrin for the preven- phamide, quinacrine and paludrin (Table 2). tion and treatment of secondary hydatidosis. Resultswith the remaining compounds(rivanol, Again, however, the absenceof controls makes lucanthone, and dactinomycin) have yet to be it difficult to ascertain a cause-and-effectrela- confirmed. If these latter results are confirmed, tionship between the therapy employed and the dose responsecurves should first be established; results observed. And, as in the previous case, trials should then be run in a variety of the lack of substantial objective criteria for laboratory and domestic animals having both determining a cure makesit impossible to state primary and secondary hydatidosis infections TABLE l-Drugs reported to be active against hydatid disease in experimental animals.

Infection Echinococcus Drug and Dosage No. of Species Sacrificeb Results species reference animals agea

E. granulosus Thymol(16) 30 mg/kg in- 1 Sheep Months - Sheep: disappearance of cyst; tramuscularly, I Rabbits Rabbits: cyst was converted into a small hard nodule every other day (no controls). for 3 months E. granulosus Quinacrine 1 ccofa 20 Mice l/2 hour 6 months There were significantly fewer cysts in treated animals, (26) 1: 1000 solu- but the same percentage of treated and control tion; in tra- animals were infected. peritoneally , once E. granulosus Rivanol(26) lccofa 20 Mice l/2 hour 6 months In comparison to the controls, there were significantly 3-9 diamino- 1: 1000 solu- fewer cysts among the treated mice, as well as 7ethoxy- tion; intra- significantly fewer infected individuals. acridine peritoneally, once

E. multilocu- Lucanthone 100 mg/kg; sub- 50 Mice 1 week 1 week Cyst weight in treated mice was only 40 per cent of laris (24) cutaneously average cyst weight in the controls. twice a week for 7 weeks E. multilocu- Cyclophos- 200 mg/kg; sub- 91 Mice 1 week 6-12 weeks Cyst weight in treated mice was only 20 per cent of laris phamide (24) cutaneously, average cyst weight in the controls. once E. multilocu- Dactinomycin 0.35 mg/kg; 40 Mice 1 week 1 week Cyst weight in treated mice was only 60 per cent of laris (25) intravenously, average cyst weight in the controls. once a week for 5 weeks

aInfection age when therapy started. bTime elapsed between end of therapy and sacrifice.. 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.) 4

Echinococcus Drug and reference Dosage No. of Infection Sacrificeb v VP. 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- 6 4 months 2 months cularly four times a week for 2 weeks Y( E. granulosus Paludrin (28) 5 mg/kg; orally five times a week 10 2days 3 months for 6 weeks 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 8 1 month 2months for 2 months

E. multilocularis Quinacrine (24) 100 mg/kg; subcutaneously twice a 25 1 week 1 week week for 6 weeks aInfection age when therapy started. bTime elapsed between end of therapy and sacrifice.

of varying ages before any experimental Conclusions i therapy in humans is considered.Analogues of active compounds could then be similarly At the present time, surgery remains the r studied in an attempt to identify more potent only remedy for patients with hydatid disease. but lesstoxic substances. However, many patients are inoperable due to Drugs reported to be without effect in the extensivenessof their disease,while others 4 laboratory animal infections include: arseno- are ineligible for surgery because of medical benzol (29), kamala (3U), prednisolone (31), contraindications. Furthermore, surgical re- thiabenzadole (32), neosalvarsan(33), chloro- moval of hydatid cysts is a costly and time- . quin, sodium antimony mercaptosuccinate, consuming procedure, and even in the most neguvon and tiguvon (24), trimethoprim, pyri- experienced hands it is a hazardous under- methamine,metronidazole, diethylcarbamasine, taking. At the sametime, improved diagnostic 4 hycanthone, colchicine, Hoechst S-201 and techniques, and increased awareness of the A. S-616 (experimental schistosomicides),hydro- diseaseas a result of epidemiologic surveysand xyurea, vincristine and vinblastine (25), 6- national control campaigns,are bringing more 4 mercaptopurine (26), gentian violet, ampho- and more patients to medical attention. Clearly, tericin B, griseofulvin, emetine hydrochloride if effective chemotherapy were developed it ‘( (3), astiban and endoxan (34). would find immediate application.

SUMMARY If an effective chemotherapeutic treatment application. Among other things, there is 4 for hydatid diseasewere discovered, there are currently no sure remedy for hydatidosis . good reasonsto believe it would find immediate except surgery, diagnostic techniques have re- 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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f BUBONIC PLAGUE IN THE UNITED STATES OF AMERICA

Human and animal plague has been controlled in the United States to a point 4 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 4 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