ADVANCES IN PHARMACOLOGY AND CHEMOTHERAPY. VOL. 20
Praziquantel ERHARD GROLL Clinical Research Department E. Merck Darmstadt, Federal Republic of Germany
1. Introduction ................................ ............. 11. Pharmacokinetics and Toxicology. . . . . . . . . . . . . . . . . . . . ........................... 111. IV. Mechanism of Action . . . . . .......................... V. Volunteers and Patients. . . . VI. Clinical Trials. . . . . .............................................
VII. VIII.
B. Cestodiasis. . .
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219 220 22 I 222 223 224 225 226 230 23 1 234 235
1. Introduction Praziquantel is the result of joint work between two pharmaceutical firms, Bayer A. G., Leverkusen and E. Merck, Darmstadt, in the Federal Republic of Germany. This collaboration was initiated by the observation that pyrazinoisoquinoline derivatives produce an anthelmintic effect. However, a drug that could be used clinically had not yet been developed. Using a step-by-step procedure, the most effective substance was chosen from a total of approximately 400 compounds. The class of pyrazinoisoquinolines was initially to be used in a completely different medical field. At the beginning of the 1970s, the search for effective tranquilizers with few side effects was still underway in the pharmaceutical industry. The pyrazinoisoquinoline substance group promised not only to be effective but also to have good tolerance. Nevertheless, it was shown that relatively high doses (milligrams/kilogram) had to be used in order to achieve an effect comparable to that of established tranquilizers. As a result, the compounds in this group that were not to be pursued further at E. Merck were then passed on to Bayer A. G. for veterinary screening in accordance with an agreement be219
Copyright 0 19Ei4 by Academic Press. Inc. All rights of reproduction in any form rcservcd. ISBN 0-12.032920-4
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tween the two firms. The methods employed to trace the effect of this substance group on trematodes and cestodes have already been comprehensively described (Andrews et al., 1983). The history of a drug is usually written once the drug has gained a footing in treatment and represents a genuine step forward in the treatment of a disease. As a consequence of very thorough and strict drug legislation in many countries in the world, however, the time between, on the one hand, initial experimental pilot studies and, on the other hand, establishment of a drug in treatment is nowadays 8-10 years. Looking back after 8-10 years, what really happened? Already uncertainties creep in. As the years go by it is not any easier to give exact dates. Diaries kept in the chemical laboratories are consulted, correspondence with experts in all parts of the world is examined, protocols are scrutinized, memoranda noted, and the first administration in man recorded. Currently, the diversification of work involved in developing a new drug in the pharmaceutical industry is routine. Specialists in each branch work according to a network plan that lays down exactly at what time a given co-worker must produce given results. When Paul Ehrlich was working on his Salvarsan, he alone was responsible for all research work. Even during the 1930s,supervision of the developmental work was entirely the responsibility of a small number of people. Recently, the network plan has taken over this function. It can also “remind” itself how the individual steps proceed, eventually resulting in the finished drug. However, if the network plan were to write the history of a drug, the reader would soon be bored. This story of a drug, i.e., praziquantel, is to follow somewhat different paths and points out that, in addition to modem data processing technology, intuition and feeling still play an important role in associating ideas. The scientist who merely feeds machines and reads results cannot indeed be replaced by this technology.
II. Chemistry and Pharmacology Praziquantel, 2-(cyclohexylcarbony1)-1,2,3,6,7,1 lb-hexahydro-W-pyrazino[2,1-a]isoquinolin-4-one,was synthesized by J. Seubert et al. (1977) in the laboratories of E. Merck, Darmstadt.
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It is crystalline and almost colorless, and has a distinctly bitter taste. It is practically insoluble in water. The last two properties, as is shown later, are important in the manufacture of certain galenic forms of the finished drug praziquantel. The effect on cestodes and trematodes was experimentally tested in the laboratories at Bayer A. G., according to reliable methods that have already been described (Thomas et al., 1975a,b; 1976a,b). Later, Thomas and Gonnert (1977) summarized their results on cestodes in experimental animals as follows: single oral or subcutaneous administration of praziquantel proved to be reliably effective against juvenile and adult cestodes in mice and rats. In trials carried out with Hymenolepis nana in mice, it was observed that age, sex, strain, and degree of infestation of the host did not influence the efficacy of praziquantel. The rapid onset of effect of the drug on the cestodes was noted. The parasites are immobilized within 10 minutes, appear to contract, and are excreted with the feces within a few hours. The effect of praziquantel on Schistosoma mansoni, chosen as a test model by Gonnert and Andrews (1977), showed a promising effect in all three hosts (mouse, Mastomys nufalensis,and golden hamster). The dose required to reduce the parasites by 95% depended on the mode of administration and the type of host. An important observation was that praziquantel was also effective in the oral form and that the drug was effective against S . mansoni, Schistosoma hematobium, Schistosoma japonicum, Schistosoma intercalatum, and Schistosoma matthei (Pellegrino et al., 1977; Webbe and James, 1977). These results were confirmed for S . hematobium and S . japonicum in baboons and vervet monkeys (James et al., 1977). AND TOXICOLOGY PHARMACOKINETICS
1. Animal Studies A prerequisite for using a drug in man is study of its toxicology, which must be accompanied by pharmacokinetic and metabolic studies. The pharmacokinetics of praziquantel were studied first in animals: rodents, dogs, monkeys, and sheep. Radioactively labeled praziquantel ([ 14C]praziquantelwith an activity of 23-95.6 pCi/mg), which had been synthesized at the E. Merck Institute for Experimental Drug Research in Grafing (Steiner et al., 1976), was used in the studies. Intravenously administered [ *4C]praziquantelwas distributed quickly in all tissues of the study animals. Unchanged praziquantel and its metabolites were rapidly eliminated from the intravascular phase with half-lives of 3 hours (phase I) and 8 hours (phase II). Praziquantel itself, however, is eliminated more rapidly, i.e., within 1 hour. Praziquantel is almost completely absorbed from the gastrointestinal tract. After 30 minutes to 1 hour, maximum serum concentrations are reached.
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Nonmetabolized praziquantel has a pronounced first-pass effect in the liver. The serum-protein binding of praziquantel is approximately 80%. The organ distribution of the drug in the rat also was studied using [14C]praziquantel (Steiner and Garbe, 1976). Praziquantel concentrations were higher in the liver and kidneys as well as in the lungs, pancreas, adrenals, and pituitary than in the plasma. In contrast, the concentration of praziquantel in the brain appeared low. Praziquantel is excreted exclusively via its metabolites; unmetabolized praziquantel was not found in the excretion products of any of the animal studies. A number of metabolites, some of which are conjugates of glucuronic and sulfuric acids, are found in the excretion products. 2. Absorption and Elimination in Man
What was clearly observed in animals could also be shown in man (Patzschke et al., 1979; Leopold et al., 1978). Maximum values for the unchanged substance were obtained 1-2 hours after oral administration of 14 and 46 mg/kg [14C]praziquantel.By this time, metabolization is already well underway. The unmetabolized substance is eliminated with a half-life of 1- 1.5 hours, the metabolites having a half-life of approximately 4 hours. Within 4 days, 80435% of the substance leaves the body via the urine. The remainder is excreted with the feces. As in the case of animals, practically no unmetabolized praziquantel is excreted by man.
3 . Metabolism of Praziquantel It therefore appears that unchanged praziquantel cannot be excreted by man. The mixture of glucuronation and sulfation products is only slightly effective against S . mansoni and possesses only 1/400 of the activity of the parent substance (P. Andrews, unpublished results).
111. Toxicology Testing of a new chemotherapeutic must be adapted to the expected and desired mode of administration. For this reason, it would not be practicable and would unnecessarily delay clinical tests if a drug intended for single or I-day administration were to undergo the complete range of toxicology tests in animals. Acute toxicity tests in noninfested mice, rats, and rabbits gave values that indicated a wide range for the therapeutic dose level. The LD,, for oral administration in the mouse was 2454 mg/kg. The dog reacted by vomiting to doses above 200 mg/kg. However, since this response is also observed with other substances, this value could not be included in the evaluation. In female mice infected with S . mansoni, the acute toxicity was found to be within the same range as that for healthy animals (P. Murmann and D. Lorke, unpublished communication). Absorption and excretion of [ 14C]praziquantel
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were slower in mice infected with S. japonicum; the maximum serum values of the substance were lower (Shao et al., 1981). No indication of pathological changes brought about by the substance was found in the rat or dog 4 and 13 weeks, respectively, after the animals had received up to lo00 mg/kg (rat) and 180 mg/kg (dog) praziquantel (Frohberg and Schulze-Schencking, 1981). Reproduction toxicology indicated that praziquantel does not influence the fertility of male and female rats. Even during the organogenesis phase, orally administered praziquantel had no embryotoxic or teratogenous effects on the offspring of the animals thus treated. Carcinogenicity studies were carried out although the substance is only intended for short-term administration. Increasing demands by health authorities with regard to the safety of drugs intended for mass treatment laid particular emphasis on carcinogenicity studies. Extensive mutagenicity studies, however, gave no indication of any mutagenic effect of praziquantel in the test models used with bacteria, yeasts, mammalian cells, and Drosophila. In carcinogenicity studies, oral doses of 100 and 250 mg/kg praziquantel given once weekly for 80 weeks to golden hamsters and over a period of 104 weeks to rats in their food produced no indication that praziquantel might be carcinogenic (Ketkar et al., 1982). Safety pharmacology, which involves the effect of a drug (regardless of its intended use) on important biological functions of the organism, likewise gave no indication of side effects. Neuro- and psychopharmacological effects were found only with very high doses, these effects being explained by the original intention of synthesizing a psychopharmaceutical with praziquantel and its related chemical compounds (Frohberg and Schulze-Schencking, 1981).
IV. Mechanlsm of Action Praziquantel has a rapid effect on Schistosoma. The parasites contract, perhaps as a result of a change in the permeability of their cell membranes (Pax er al., 1978). The reduction in endogenous glycogen, a decrease in alanine, and an increase in lactate release are probably secondary effects (Andrews, 1981). In primates, classical migration of adult Schisrosoma to the liver results (Webbe et al., 1981). The schistosomicidal effect of the drug was confirmed by experimental tests, in which adult S . japonicum, the “most difficult” of all three important Schisrosoma types, proved to be highly sensitive to praziquantel in mice, rabbits, and dogs (Shao et al., 1980). Light and electron microscopic studies on S . mansoni granuloma of the mouse liver were undertaken after administrationof praziquantel. It was observed in the mouse livers that granulocytes penetrated the treated Schisrosoma washed into the liver and triggered phagocytosis of the parasites (Mehlhorn et al., 1982). The rapid effect of praziquantel on Schisrosoma that results in tetanic contraction of the parasite’s muscles was observed also in cestodes, although uptake of praziquantel into these parasites does not occur as quickly as in the case of
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Schistosomu. In the case of H. nana 8 minutes are involved, and in encysted strobilocerci of Taenia taeniaeformis, 20 minutes pass before the concentration of the drug is equal in both the medium and the parasite (Andrews et al., 1980). How praziquantel destroys the parasites with regard to molecular biological events can be described in detail, but the process has not as yet been integrated into the overall biochemical context. Taking Cysricercusfasciolaris as an example (Thomas et al., 1982), it could be shown that praziquantel penetrates the cyst wall. The tegument and scolex are destroyed in the region of the entire pseudostrobila. This effect is comparable with that on adult tapeworms and trematodes. In the final analysis, it would appear that the helminthicidic effect of praziquantel is based on damage to the tegument. Other effects, such as disturbances in glucose intake and leaking of lactate, are probably secondary.
V. Volunteers and Patlents A new drug is first administered to healthy volunteers in order to test the tolerance of the drug in the dose range that is assumed to be therapeutically effective. Time and money are saved when human pharmacokinetics are simultaneously studied. These two objectives were combined in the case of praziquantel, resulting in a considerable logistic task. The pharmacokinetic results have already been outlined. Tolerance in the subject was predominantly uneventful: there was no sign of any toxic effects of praziquantel on the vital functions of the organism. When patients with schistosomiasis were included, the patients’ complaints prior to treatment were carefully recorded. The results are in some cases contradictory. For example, at least 25% of the patients complained of abdominal pain prior to treatment; in the case of S . japonicum, the figure stood at almost 76%. After treatment with praziquantel, the percentage of S . hematobium and S. japonicum patients complaining of abdominal pain in part decreased dramatically whereas an increase was noted for S. mansoni patients. Headache was mentioned by 61% of the S . japonicum patients before and by only 6.5% after treatment. In contrast, vomiting and nausea appeared to occur more frequently after praziquantel than prior to treatment. Side effects of this type did not, however, require any particular treatment and disappeared quickly (Andrews et al., 1983). The advanced stages of S . mansoni infestation are often connected with hepatolienal complications (Ambroise-Thomas et al., 1981; Coutinho et al., 1983; da Silva et al., 1981); nevertheless, the tolerance of praziquantel was equally as good as in uncomplicated cases. Repeated doses of praziquantel are required in liver and lung fluke infestations. Even treatment of cerebral cysticercosis requires 2-week administration of 50 mg/kg/day; this amounts to more than 40 g praziquantel in a patient weighing 60 kg. However, no essential deterioration in tolerance attributable to the drug
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itself ensued. That particular precautionary measures must be observed in neurocysticercosis is connected with the release of foreign protein by dying cysticerci and not with the substance praziquantel as such. Tolerance of praziquantel was particularly good in patients with tapeworm infestations, which may possibly be a consequence of the relatively low single dose of from 5-10 mg/kg (Taenia) to 25 mg/kg ( H . nana).
Vi. Clinical Trials At the beginning of each clinical trial, the question arises as to whether the favorable results from tolerance studies during phase I of the clinical trials will be confirmed in patients, particularly in a large number of patients. The second question, seemingly more important than the first and yet directly connected to the tolerance of the drug, concerns the effective dose. Studying the methods for following up treated patients, cestodiasis appears to be less problematical in comparison to trematode infestations. The excretion of worm eggs in the feces is checked prior to and after treatment, with the times for checking the stool varying according to the type of infestation. In the case of Taenia, checks were carried out 30,60, and 90 days after treatment, and for H.nana, from days 5 to 7 as well as on three consecutive days between days 10 and 14 and 19 and 23. In approximately one-third of the cases, three aliquots were taken from each stool sample since the eggs are not equally distributed in the stool. For Diphyllobothrium latum, the stool was checked on day 21 after treatment and for Diphyllobothrium pacificum, 30, 60,and 90 days subsequently. All investigators had to ascertain the laboratory status of the patients prior to and after completion of treatment. Clinical laboratory examinations also were carried out in a number of Taenia patients when the monthly stool checks were made. The patients also underwent a general examination. A greater problem than that of the stool samples proved to be the search for cestodiasis patients itself. In western Europe, tapeworms are virtually unheard of, although France and Poland have Taenia saginata patients. H . nana is found now and again in southeastern Europe, D . latum occurs now significantly less frequently than in the past in Finland and in only certain regions of Karelia. Infestation with the fish tapeworm depends on eating habits, which in turn depend on the changes in the age structure of the population involved. Raw fish is still consumed by older people whereas the young prefer cooked and fried fish. This destroys the plerocercoids and infestation of the end host (man) can no longer ensue. In patients infested with the fish tapeworm who had been treated with praziquantel, the red blood picture was carefully observed. The occurrence of macrocytic anemia described for D . latum infestations resulting from accumulation of vitamin B,, in the fish tapeworm was not observed in the 200 patients studied. This type of anemia appears to have become very rare, probably
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because food is nowadays enriched with vitamins. Today it is extraordinarily difficult to find pernicious anemia patients who have not undergone pretreatment. Clinical testing concentrated on the Latin American states, South Korea, and Egypt for Taenia and H . nana as the number of cases required would have been difficult to obtain in Europe. With trematode infestations, especially schistosomiasis, it was imperative that the investigators agreed on a method catalog. It was necessary to employ double-blind methods as well as the obligatory detection of eggs in the feces or urine in order to look into side effects. The symptomatology of schistosomiasis sometimes resembles the side effects that occur directly after treatment. For these reasons, the planners of the trials found a demarcation in phase 11-A even more important. Schistosomiasis can be connected with wide variations in egg excretion. An agreement had to be reached as to how to define mild, moderate, and severe infestation. It was already known that children are not as successfully treated for schistosomiasisas adults and this also had to be considered in the planning. How would the three types of schistosomiasis, i.e., S . hematobium, S . mansoni, and S . japonicum, respond to a defined single dose of praziquantel? Would 1-day administration with two or three doses be more likely to eliminate the infestation than a single dose? How would the hepatolienal cases and the patients with double infestations by S . hematobium and S . mansoni react? The investigators involved with phase 11-Aof the clinical trials came to agreements in comprehensive and sometimes awkward discussions held in a small workshop. A consensus was necessary in order to guarantee the comparability of the results expected. An appreciation of this preliminary work for praziquantel was described by the “Clinical Monitor” from Bayer A.G. as clinical testing stands or falls with the planning, particularly when the follow-up of patients involves several months (Wegner, 1981). A consensus also had to be reached regarding the methods to be used for clinical trials on cestodes. The clinical investigators were invited to join in a workshop in which parasitologists also took part. The problems involved with cestodes are not so much defining the follow-up observation periods but rather the difficulty in persuading the patients to deliver their stool samples at the times given. In contrast to trematode tests, all cestode tests were carried out on an open basis; parasitological cure was evaluated solely by egg excretion. A. CLINICAL EFFWACYIN TREMATODE INFESTATION 1. Schistosoma hematobium
The first trial was carried out in Zambia (Davis et al., 1979). It was designed as a dose-finding study using doses of 1 X 20, 2 X 20, or 3 x 20 mg/kg in patients with minimum egg excretion of 50/dl urine. At a later stage, 3 X 20 mg/kg (20 mg/kg tds) was compared with a single dose of 50 mg/kg. All dose
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levels administered showed a high therapeutic effect. It must also be mentioned, however, that infestations with an egg excretion of 54-135/d1 urine were only mild to moderate. The doses were changed in later clinical trials: 30 mg/kg was compared with 40 mg/kg as a single dose (McMahon and Kolstrup, 1979). The higher dose did not result in any significant increase in efficacy; the authors also report that there are no serious side effects with doses over and above 50 mg/kg. Clinical trials in Nigeria (Oyediran et a f . , 1981) confirm that there was no difference between the dose groups 30 and 40 mg/kg as a single dose and 2 X 20 mg/kg as 1-day treatment. The same experimental design was used in Senegal. High efficacy was achieved there with a parasitological cure rate of 95.8%, and again no differences between the treatment groups could be ascertained (Diallo et a f . , 1981). On the occasion of the Fifth International Congress for Parasitology in Toronto (1982), D. H. G. Wegner referred to 2061 patients afflicted with S . hematobium who were treated with praziquantel and followed up. The dose that was eventually agreed upon by the investigators and monitors was 40 mg/kg. 2. Schistosoma mansoni Again the investigators began with a dose-finding study initially using single doses ranging from 30 to 50 mg/kg, two doses per day being administered, each with half of the daily dose. The egg loads in these studies were considerably higher than in the case of S . hematobium so that classification into three groups was required (group I, 150-500; group 11, 501-1000; group 111, 1000+/dl urine). No significant difference between the dose groups 40 mg/kg as a single dose and 2 X 25 mg/kg as a daily dose was observed (McMahon, 1981). In Mali (Ranque et a f . , 1981) and Kenya (Smith et a f . , 1981), trials were carried out in village populations in which 40 mg/kg was administered as a single dose. S . mansoni is a problem not only in Africa; other endemic areas exist in South America in Brazil and, to a lesser extent, in Venezuela. Clinical trials that initially proceeded within the initial test concept as a dose-finding study (Katz et a f . , 1979) came up with a possible dose range of approximately 40 mg/kg as a single dose, a value similar to that in African cases. More extensive studies, however, had widely varying results. A dose of 30 mg/kg resulted in parasitological cure for 36.5-50% in children and 45-75% in adults (Prata et a f . , 1978). It became more and more evident that children responded to a lesser extent to praziquantel with regard to S . mansoni infestation than did adults. This is a phenomenon that had already been observed in studies with oxamniquine (Lambertucci et al., 1980). A cure rate of only 45% was achieved with an oral dose of oxamniquine in 11 children 55-77 days after treatment, even though the administered dose of 20 mg/kg was higher than for adults (15 mg/kg). With parented administration, the cure rate was much better (Katz et al., 1973). However, as praziquantel is virtually insoluble in water, it cannot be administered parenterally
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and a trial using injections was subsequently not possible. Thus, oral doses of praziquantel had to be increased for children. Oxamniquine (20 mg/kg) was compared to 65 mg/kg praziquantel as a single oral dose in children in an endemic area (Minas Gerais, Brazil). Most of the egg loads were between 90 and 500/g feces, although there were children who had between 1001 and 2500 S. mansoni eggs/g stool. The cure rate after praziquantel was 76% and that after oxamniquine 65%. A statistically significant difference could not be determined due to the relatively low number of cases (Katz and Rocha, 1982). In another double-blind trial in children, the authors determined that, in different age groups between 6 and 14 years treated with praziquantel single-dose levels of 50 and 70 mg/kg, it was not the age classification that influenced the cure rate but rather the different dose levels. Cure rates were 59% for patients treated with 50 mg/kg and almost 74% with 70-mg/kg patients (Emanuel and Prata, 1983). For older patients, a study carried out with soldiers aged 18-19 years showed that 15 mg/kg oxamniquine taken as a single dose was comparable to 2 X 25 mg/kg praziquantel as a 1-day dose with regard to effect and, with limitations, the type of side effects (Katz et al., 1983). The hepatolienal form of S . mansoni was a special target group for clinical trials. The drug concentrations increase considerably in patients with pathological changes in the liver and spleen in comparison to patients without such complications, so that side effects as a result of unmetabolized substances, particularly in the central nervous system, are frequent. This type of patient was the subject of a study in Sio Paulo in which a single dose of 40 mg/kg praziquantel was administered (da Silva et al., 1981), whereas in Recife, 1 X 30 mg/kg was compared with 2 x 25 mg/kg (Coutinho et al., 1983). EEG and ECG before and after treatment as well as laboratory tests showed no major alterations. Praziquantel can therefore be administered to patients with hepatolienal complications. Patients with infestations of oxamniquine- and hycanthone-resistant S . munsoni were peculiarities of the Brazilian schistosomiasistrials. Such treatment-refractorycases have been found more frequently in recent times in Venezuela and Brazil. It is apparently possible to cure such patients of parasites using praziquantel (Carmago, 1982; Berti and Schmidt-Dommerque, 1981; Pedro et a f . , 1980). Clinical trial in S . mansoni infestations in Venezuela gave practically identical results for oxamniquine and praziquantel, these results giving a cure rate of approximately 93% (Berti et al., 1979). Results from 1956 African and 1392 Latin American cases of S . munsoni infestation were summarized by D. H. G. Wegner in Toronto in 1982. 3. Mixed Infestations of S . hemutobium and S . mansoni
The Occurrence of S. hemutobium together with S . mansoni is being observed more frequently in Africa. In Sudan, this type of mixed infestation represented a
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problem for treating larger groups of the population, as, to date, two different drugs had to be given on such occasions. With praziquantel both infestations in one patient can be eliminated with a 1-day dose of 2 X 20 mg/kg (Saif and Abdel-Maguid, 1981; Omer, 1981; El-Alamy et al., 1981). 4. Schistosoma intercalatum
Experiences in Cameroon (Ripert et al., 1981) indicate a response to praziquantel by S . intercalatum infestations equally favorable to that by S. mansoni. The dose should be chosen accordingly.
5 . Schistosoma japonicum This Schistosoma is generally considered to be the most difficult to treat. A dose level of 2 X 30 mg/kg administered as 1-day treatment was found to be effective in clinical trials. Whereas the results obtained from clinical trials carried out by Bayer A. G. were based on a limited number of patients (Ishizaki et al., 1979) publications from the People's Republic of China appeared soon thereafter in which large treatment collectives were involved (Xu, 1981; Chen, 1981). Chinese treatments gave an even better result than those obtained initially, i.e., an almost 100% cure rate. Nevertheless, a comparison can hardly be drawn because the conditions for diagnosis and follow-up have not been exactly specified. Nevertheless, the Chinese initiative of carrying out mass treatment with praziquantel indicates that the effect of the drug is superior to that ot schistosomicides used to date. 6. Other Trematode Infestations a. Clonorchiasis. Clonorchis sinensis incidence is frequently underestimated in the Far East. In Korea there are areas in which two-thirds of the population are infested (Kim, 1974). As children are usually infected-according to H.-J. Rim, 40% in the age group younger than 9 years in one community-and since the parasite infestation tends to increase with increasing age, treatment must commence in children. The average number of eggs per g feces ( E X ) in the population group quoted was 10,698, but EPGs of 30,000or more have been observed. In the province of Kwangtung in China, in Hong Kong and Taiwan, and in many areas of China as well as in Vietnam, patients are infested with the Chinese liver fluke. Treatment has now become very much simpler. H.-J. Rim et al. (1981) carried out treatment with 25 mg/kg tds as 1-day administration; results were convincingly positive. b. Opisthorchiasis.The cat liver fluke (Opisthorchis)in Southeast Asia, particularly Thailand and Laos, can be very easily treated with praziquantel in the doses given for C. sinensis with high prospects of successful treatment (Bunnag and Harinasuta, 1981). As the illness also occurred in recent years in Europe as a
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result of the large number of immigrants, treatment results from Germany also are available (Loscher et al., 1981; Horstmann et al., 1981), the dose levels administered being 20-30 mg/kg over 2 to 3 days. Further clinical tests will show whether 1-day treatment also is sufficient. c . Paragonimiasis. The lung fluke Paragonimus, in contrast to Clonorchis and Opisrhorchis infestations, is found in very isolated regions. It would appear that not all types of paragonimiasis have yet been accurately classified. Paragonimus ecuadoriensis is possibly identical to Paragonimus peruvianus but results from specific studies are as yet unavailable. Paragonimus westermani, as in the case of the South American infestations, can be eliminated with 25 mg/kg tds over 2 days. The fact that 2-day treatment is more effective against this fluke than 1-day treatment may be connected to the different type of tegument of these parasites. This applies in particular to Fasciola hepatica, the large liver fluke, which was initially considered to be “nonresponsive to praziquantel” (D. H. G. Wegner, personal communication). The situation has changed, however: apparently, praziquantel in a dose level of 25 mg/kg tds must be administered not for 1 or 2 days only but for approximately 1 week. The first few cases suggest that successful treatment of this parasitosis also is to be expected.
B . CESTODIASIS 1. Taenia saginata
Infestations with T. saginata were cured by 10 mg/kg in 376 of 387 patients. This success rate of 97% contrasts with 96.6% (141/146) after a 5-mg/kg dose level. However, the two schemes were not tested on a double-blind basis and, in a number of the cases, randomization of patients into one of the two treatment groups of 5 or 10 mg/kg was carried out. Successful treatment was checked by investigating the stool (Groll, 1980). The pork tapeworm Taenia solium was more difficult to find and define, particularly compared to T. saginata. The success rate for T . solium in South America was 619 = 66.6% with 5 mg/kg and 33/33 = 100% with 10 mg/kg. A randomized trial with the two dose levels has been carried out by Rim in Korea where T. solium is today contracted more frequently than in the past. Rim carried out a prevalence study in some areas of South Korea where a Taenia spp. infestation rate of 2.1% was found. Of 151 cases of Taenia in Seoul traced by checking stool, 59 (39.1%) were T. solium infestations, a remarkably high rate for a city of one million inhabitants. A higher percentage of students was infestated with T . solium than other citizens (Rim et al., 1980). The cure rate with 5 mg/kg in Korea was 96.2% and with 10 mg/kg, 100% (Rim et al., 1979). Therefore, infestation with Taenia can definitely be cured with 10 mg/kg as a single dose.
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2. Hymenolepis nana Praziquantel can be classified only as “probably equally effective as niclosamide” from results of the clinical trials with praziquantel in the large Taenia since there is no comparative study with niclosamide. Nevertheless, the results of the H . nana trials lead to the conclusion that praziquantel is the drug of choice. A single dose of 25 mg/kg, even for children who are most often affected by this infestation, is a simple procedure (Schenone, 1980). It is important, however, that all inhabitants of children’s homes, schools, and barracks be simultaneously treated, otherwise the infestation spreads again after a short period of time. Whereas in Schenone’s patients the dose dependency of the effect on H. nana was marked-98.5% success with 25 mg/kg, 76% with 15 mg/kg-the lower 15-mg dose level was not considered to have any clear advantage in the overall summary. The recommendation of prescribing 25 mg/kg may also be supported by the good tolerance of this dose (Groll, 1980). 3 . Diphyllobothrium
The trial in Finland was based on patients who were undergoing stationary treatment on account of other disorders and who gave a positive result for D . latum eggs in routine stool tests. It was thus possible to observe the clinical laboratory results (macrocytic anemia). The dose of 25 mg/kg was set down by experimental data by Bylund et al. (1977) in which case it had to be assumed that this dose was more toward the lower effective limit. It was shown, however, that the 25-mg/kg dose was exceptionally effective: 52 of 54 patients were cured of Diphyllobothrium when treated on an inpatient basis in the clinic and 151 of 159 of those patients treated on an outpatient basis were cured. In Peru, the frequently occumng infestation with D . pacificum was eliminated in all 52 patients treated (Lumbreras et a f . , 1982; Espejo, 1977). If there had been more cases of D . latum in Finland, a comparative study of 10 vs 25 mg/kg would have been of interest. However, this was not possible.
VII. Larval Cestode Infestations in Man Cysticercosis in man is not such a rare disease as European neurology textbooks would imply. Of the 1079 pages of text of the standard work of German neurological literature by W. Scheid (1980), only one and a half pages are devoted to cysticercosis. Epidemiologists in the Third World, however, see the occurrence of the disease, in particular neurocysticercosis, quite differently. In an editorial in Salud Publica de Mexico (1982), C. Robles estimated that there were 2 million cases of cysticerci infestations in Mexico, of which, however, only a minority showed clinical symptoms. Ecuador, Peru, Columbia, Chile, and Brazil are also affected. In Venezuela and Korea, neurocysticercosisis not a rare
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occurrence, and even in Europe this infestation of the CNS has been recently diagnosed. It must remain open as to whether the appearance of neurocysticercosis in central Europe is a consequence of worldwide European tourism or immigration from the Third World to European countries, or whether it is a consequence of greatly improved diagnostic procedures as a result of computer tomography (Markwalder et al., 1983). Even the United States has problems with neurocysticercosis, as a result of immigration from Mexico and Central American countries. No effective chemotherapy was previously available; treatment was effective only when the single, isolated cysts could be removed by neurosurgery. However, such a favorable prerequisite is rare since multiple infestation is often the rule, particularly in the parenchyma. The ventricular system is often infested, resulting in hydrocephalus and increased cerebral pressure. A possible treatment involves introduction of an efferent shunt and treatment with dexamethasone, which relieve the life-threatening consequences of intraventricular cysticercosis but do not change the basic infestation. M. Chavarria in Mexico was the frst to consider treating cysticercosis in man, and this was pursued by C. Robles when it was shown that 50 mg/kg praziquantel administered over a period of 15 days was able to eliminate cysticerci in the pig. An acutely ill child who could not be helped by neurosurgery was saved by the dose level given above, the infestation being cured without any clinical consequences (Robles and Chavarria, 1980). In December 1977, H.-J. Rim et al. (1980) had treated their first patient afflicted with dermal- and neurocysticercosis. They administered a higher daily but lower total dose: 25 mg/kg tds over 3-4 days. The results were encouragingly successful, although some patients had to be treated twice. Brink et al., (1980) reported from Chile similarly promising experiences, while Botero and Castaiio (1981, 1982) initially approached treatment of neurocysticercosis with caution, later using higher doses as used by C. Robles, who had treated more than 100 patients with 50 mg/kg over a period of 2 weeks. A. Spina-Franca et al. (1982) treated 40 patients, beginning with doses of 20 mg/kg which were later increased to 50 mg/kg when undesired side effects on the CNS as a consequence of the dying parasites were rarely observed. The authors also lengthened the treatment time to 3 weeks. The work of Robles, who at present is monitoring more than 400 cases of praziquantel treatment, may be used to illustrate the benefits and necessity of concomitant corticosteroid treatment, as was originally indicated. Corticosteroid treatment is a precautionary measure and can prevent, or at least relieve, cerebral pressure. But steroids can also alter the symptoms of the infestation so that the therapeutic value and side effect spectrum of chemotherapy with praziquantel becomes unclear. It has become gradually apparent that there are a number of matters to be considered in praziquantel treatment of neurocysticercosis. First,
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parenchymal cysts are clearly better influenced by praziquantel treatment than intraventricularcysts or those occurring in the spinal column. Second, it has also been shown that concomitant treatment with corticosteroids, which was originally thought to be indispensable, is not required in every case. Third, 2 weeks of treatment appear to be necessary. L. Lombardo et af. (1983) were able to show that the cysts in the CNS do begin to disintegrate at the end of the first week but in the case of giant cysts, treatment should cover 4 rather than 2 weeks. Of his 12 patients, 2 had giant cysts which disappeared only after the second treatment phase. All cysts, and up to 20 were detected by computer tomography, disappeared in the other patients after 2 weeks of treatment with 50 mg/kg. The authors are of the opinion that other publications that have appeared since 1980 on cysticercosis and its treatment with praziquantel do not pay enough attention to one of the principles of clinical testing, i.e., if at all possible, no concomitant treatment should be used if the clinical value of a new drug is being assessed. From the pharmacologist’s standpoint this is a completely correct opinion. The conclusion that praziquantel has a cysticidal effect must also make it possible to reach the conclusion from follow-up observation of the patients that disappearance of the cysts is accompanied by essential improvement or disappearance of the clinical symptoms. This is, however, not the case in all patients. Lombardo also made this assertion in his conclusions. In immunodiagnostics studies by Lombardo, antibodies could be detected by immunoelectrophoresisin only 6 of 12 patients although computer tomography (CT) and clinical tests verified the diagnosis in almost 100% of the cases. This immune test can therefore not replace the new technique of CT and its further development. Immune diagnostics are likewise of only limited value in followup observation of the patients. Even here, the clinician is often faced with values that mean nothing to him. He prefers to rely on CT and his cliniconeurological findings. Praziquantel has a marked cysticidal effect on human cysticercosis. Whether it can always cure neurocysticercosis is a different matter. Totally calcified neurocysticercosis does not respond to this treatment, which is also logical considering the pathologicoanatomical substrate. Early treatment is therefore desirable. This depends on first-class CT diagnostics, which in turn largely depend on finances: CT is expensive and often almost beyond the means of Third World countries. By way of conclusion, another word on dermal cysticercosis: it is in itself not dangerous but rather cosmetically unpleasant. On the other hand, it can also indicate that a careful neurological examination is required. Praziquantel even in smaller doses also has a reliable effect on the dermal form of the parasitosis. The dermal cysts usually disappear after 25 mg/kg tds over 3-4 days. H.-J. Rim et af. (1982) had patients with more than 100 cysts, of which only a few persisted. In 1 patient, who initially had 89 cysts, only 70 remained after 3 months and after 12 months a mere 2. In 28 cases treated in Seoul,
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cerebral involvement was present in 15. M. C. Baranski (1981) came up with similar results but he administered lower daily doses (60 mglkg, later 30 mglkg) over 6 days. The tolerance of praziquantel during treatment of neurocysticercosis was very good. If neurological complications, which are usually manifested by cerebral pressure, arise, an inflammatory reaction of the meninges to the dying cysticerci must be considered. This complication can be effectively treated with dexamethasone. On account of this unforeseeable biological reaction, treatment of neurocysticerosis should be carried out only on an inpatient basis. Other side effects such as headache and dizziness occur particularly in the first week of treatment, but it is difficult to distinguish them from the symptoms of neurocysticercosis.
VIM. Conclusion The title of this book is “Advances in Pharmacology and Chemotherapy.” What advances are to be found in praziquantel therapy? From a purely historic point of view, one can return to the beginning of praziquantel chemotherapy in man and list the advances expected after the experiment: in the case of schistosomiasis, it could be assumed for the three important types, S . hematobiurn, S . mansoni, and S . japonicum, that single or 1-day treatment was possible, and this actually held true. This was also the case for S . intercalatum and S . matthei as well as for the mixed infestation of S . mansoni and S . hematobium. The latter is gaining in importance with regard to different epidemiology in regions with dramatic changes in the economics of water supply and distribution as a result of man-made lakes. Here advances play an obvious role, as it is considerably simpler to cure two infestations with one drug than to organize two different campaigns with different drugs. The success of praziquantel in treating S . japonicum infestation has exceeded expectations; this type of schistosomiasis had always been a problem and met with only limited therapeutic success. The efficacy of praziquantel in treating liver and lung flukes has crystallized since 1979. The last type of trematode whose treatment with different doseslonger administration is meant here-lead to clinical success was F . hepatica. It remains to be seen whether initial nonresponse of the parasite to single doses is simply a result of the parasite’s tegument being particularly thick, thus requiring a longer reaction time for praziquantel to eliminate F. hepatica. On account of the difficulty in treating, particularly, this parasitic infestation in part with toxic drugs (dehydroemetine), praziquantel would represent true progress. The efficacy of praziquantel in human cestode infestations with adult parasites was expected. The range of cestode infestations covers all important parasitoses by adult worms. The efficacy of the quantitites of praziquantel that are usually
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administered as single doses lies almost exclusively within the range 95 to 100%. There are no direct comparative studies with the most important cestode drug to date, niclosamide. This product also has very respectable cure rates, but praziquantel is obviously superior to niclosamide in treatment of H.nana. Successful treatment results were not expected for dermal cysticercosis and still less for neurocysticercosis, although the efficacy of praziquantel in the larval stages of the pork tapeworm had already been noted in experiments. The step from dermal cysticercosis with cerebral involvement to direct treatment of neurocysticercosis was logical. Praziquantel has a clearly cysticidal effect: it kills the cysticerci in the cerebral parenchyma and in the ventricular system of the CNS, although the latter is by far less certain. The reason for this is probably to be found in the pharmacokinetics of the drug, which is detected in far lower concentrations in the cerebrospinal liquor than in the parenchyma. This assumption elicits great expectations for successful chemotherapy of spinal cysticercoses. However, praziquantel often represents the only possible treatment of cysts localized in the parenchyma especially if they are multiple and consequently inoperable. The agreement of zoological classification-trematodes and cestodes-with the action spectrum of praziquantel is striking. The drug has a convincing effect within the two classes of Platyhelminthes. It has no effect on the Nemathelminthes. In comparison, mebendazole is predominantly effective against nematode infestations, whereas its effect on cestodes is moderate. Nevertheless, apart from flubendazole, it represents the only chemotherapeutic hope for Echinococcus in man (Van den Bossche et al., 1982). The effects of mebendazole and other benzimidazoles cannot be described or precisely defined within the zoological classes as can those for praziquantel. The fact that praziquantel is effective against the two helminthic classes Trematoda and Cestoda does not prove their metabolic or structural similarities but rather points out how closely Carl von LinnC observed nature and how biologically exact his classification was. REFERENCES Ambroise-Thomas, P., Goullier, A., and Wegner, D. H. G. (1981). Bull. SOC. Park Exor. 74, 426-433. Andrews, P. (1981). Arzneim. Forsch. 31, 538-541. Andrews, P., Thomas, H., and Weber, H. (1980). J . Parasirol. 66, 920-925. Andrews, P., Thomas, H.. Pohlke, R . , and Seubert, J. (1983). Med. Res. Rev. 3, 147-199. Baranski, M. C. (1981). “Praziquantel in Human Cysticercosis.” Paper presented at the Workshop, Mexico, D. F. April 25-26, 1981. Berti, J . J . , and Schmidt-Dommerque, F. S. (1981). Trib. MPd. (Venezuela) 54, 6-7. Berti, 1. J., Paezde Molina, B., and Schmidt-Dommerque, F. S. (1979). Trib. Mkd. (Venezuela) 11, 47-48. Botero, D. R., and Castaiio, M. S. (1981). Trib. MPd. (Colombia)63, 31-36.
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