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The efficacy of praziquantel for the treatment of cestode and metacestode infections
INTERNATIONAL JOURNAL OF
Antimierobial Agents ELSEVIER
International Journal of Antimicrobial Agents 4 (1994) 321-324
The efficacy of praziquantel for the treatment of cestode and metacestode infections S. Geerts Institute of Tropical Medicine, Nationalestraat 155, 1t-2000 Antwerp 1, Belgium Accepted 21 March 1994
Abstract The activity of praziquantel against adult and larval cestode infections is reviewed. Praziquantel remains an excellent drug for the treatment of taeniasis and hymenolepiasis. Neurocysticercosis, however, seems to respond better to a treatment with albendazole than to praziquantel, especially when the anthelmintic treatment is combined with steroid drugs. Concerning the treatment of hydatidosis and coenurosis, more research is needed to evaluate the efficacy of praziquantel.
Key words." Praziquantel; Cestodes; Metacestodes; Cysticercosis; Taenia solium; Taenia saginata; Hymenolepis nana
1. Adult cestode infections
Taeniasis Until now the recommended treatment for Taenia saginata and T. solium was a single dose of 5 to 10 mg/kg ofpraziquantel (PZQ) [1,2]. During recent years the efficacy of 10 mg/kg has been confirmed by different authors [3,4]. PZQ was also very effective against the so-called Taiwan Taenia, T. saginata taiwanensis [5]. Recently, however, Pawlowski [6] showed that even a dose of 2.5 mg/kg was 100% effective in 124 patients infected with T. saginata and carefully examined 4 months after treatment. The same author advises 2.5 mg/kg as a safe and more economical and probably still highly effective treatment of T. solium, but admits that its efficacy remains to be confirmed. Indeed, there are few data available on T. solium. A dose rate of 5 mg/kg eliminated T. solium in 33 (94.3%) out of 35 patients (Baranski; Rim cited by Pawlowski [6]). A large-scale mass treatment trial in Ecuador confirmed that this dose is also quite safe, even in a hyperendemic area for neurocysticercosis. After treatment of 10 173 people with an average dose of 5.2 mg/kg (3.4-8.7) only two serious complications were observed: one patient with an epileptic attack and one with an episode of dysentery [7]. Other reports on activation of asymptomatic neurocysticercosis after treatment with PZQ concerned doses of 20 mg/kg or higher [8,9]. 0924-8579/94/$26.00 © 1994 Elsevier ScienceB.V. All rights reserved SSDI 0924-8579(94)00029-T
It is too early to fully evaluate the efficacy of PZQ in controlling the taeniasis--cysticercosis complex and especially neurocysticercosis by 'population oriented chemotherapy', but the first results in Ecuador and Mexico were promising [7,10]. Hymenolepiasis and other cestodoses Although several authors report excellent activity of a single dose of 25 mg/kg PZQ against Hymenolepis nana [1,3,5,11], the efficacy of this dose is sometimes less than 50% [12]. Therefore two doses of 25 mg/kg might be necessary to obtain complete cure, as was already suggested by Kumar et al. [13]. Concerning the efficacy of PZQ against Diphyllobothriurn spp., no new data have become available, so that the recommended treatment still remains a single dose of 10 or 25 mg/kg respectively against D. pacificum and D. latum [1]. A dose rate of about 10 mg/kg seems also to be effective against Dipylidium caninum [14].
2. Metacestode infections
Cysticercosis In the past many reports have been published which did not allow an unequivocal evaluation of the efficacy of PZQ for the treatment of neurocysticercosis due to the
322
S. Geertsl International Journal of Antimicrobial Agents 4 (1994) 321~324
lack of control patients or the use of PZQ in combination with other drugs, the possibility of spontaneous cure, etc. [2,15,16]. Well designed studies including a sufficient number of untreated control patients, however, have provided clearcut answers on the efficacy of PZQ against different types and different locations of cysticerci. Treatment with 50 mg/kg PZQ per day for 15 days significantly decreased the number of cysts and also the frequency of seizures in comparison with untreated patients [17-19]. Vasquez and Sotelo [20] examined a large retrospective series of 240 patients (follow-up during 92 _+7 months) and showed very conclusively that treatment with albendazole, PZQ or both caused an 82% reduction in the mean number of brain cysts and a 95% reduction in the mean frequency of seizures (from 11.3 to 0.6 per year; 54% seizure-free after 3 years), whereas the untreated patients (without inflammation around the cysts) averaged 10.9 seizures per year and none became seizurefree. Spontaneous cure or satisfactory control of the disease without anthelmintic treatment, however, is possible in patients with inflammation around the cysts and in children. Actively inflamed acute lesions, which are very common in the age group below 20 years, generally resolve completely in 2 to 9 months time [16,21-24]. There are strong indications that albendazole (15 mg/ kg per day for 30 days) is superior to PZQ (50 mg/kg per day for 15 days) for the treatment of neurocysticercosis patients. Up to now, however, prospective, double-blind, placebo-controlled trials comparing both drugs are still lacking. After the first report by Escobedo et al. [25], the excellent activity of albendazole was confirmed by different research groups in Mexico, Brazil and Ecuador [19,20,26,27]. When few or no steroids are used simultaneously, the difference in the efficacy of PZQ and albendazole is not very pronounced [27,28]. In combination with prednisolone, however, albendazole gives a much better overall improvement than PZQ: 84% against 62% in a series of 50 patients treated with each of the drugs [26]. Retrospective evaluation of a large number of patients, only 22% of whom were treated with dexamethasone, confirmed the better activity of albendazole, resulting in 80% reduction of the total number of cysts against only 65% reduction with PZQ [20]. These authors also found a higher risk of persistent seizures after treatment with PZQ than albendazole (odds ratio 2.3). The improved activity of albendazole when combined with steroids is due to an increase of the plasma level of the drug by 50% [29], whereas just the opposite occurs when PZQ is combined with steroids. In patients simultaneously treated with PZQ and dexamethasone PZQ plasma levels were 50% lower than in those treated with PZQ alone [30]. The bioavailability of PZQ, however, can be increased by a factor of 2.5 through coadministration with cimetidine, an inhibitor of the P450 cytochrome metabolic pathway [31]. The current treatment schemes for cysticercosis using
albendazole or PZQ have been determined empirically and only very few studies were set up to optimise these schemes. Sotelo et al. [18] compared four treatment regimens: 50 mg/kg PZQ for 15 or 8 days and 15 mg/kg albendazole for 30 or 8 days. Surprisingly they found that the short treatment scheme with albendazole was as effective as the long one. It caused disappearance of the lesions in 85% of the patients, whereas the short and the long scheme with PZQ caused a reduction of only 48 and 60% respectively. The same authors recommend to start treatment of neurocysticercosis with a short course using albendazole. In patients showing a partial response to albendazole after 3 months, the treatment can be continued with a 15-day course using PZQ. Indeed, some cysts seem to respond better to PZQ, whereas others respond better to albendazole. Several reports mention the disappearance of cysticerci with albendazole after unsuccessful treatment with PZQ [25,32,33]. Another treatment schedule was tried by Bittencourt et al. [34]. They used 100 mg/kg PZQ for 10 days. Although there was a disproportionally higher concentration of the drug in blood and CSF than with the usual dose, these authors could not find any correlation between serum and CSF concentration of PZQ and disease outcome [35]. Similarly, the optimal treatment schedule for muscular and subcutaneous cysticercosis has not yet been determined. Usually 25 mg/kg PZQ is used for 3 to 4 days [2]. Gascon et al. [36], however, obtained good results using three doses of 20 mg/kg PZQ at 4-h intervals. The advantage of this schedule is that treatment of patients in rural regions can be finished in one day. Further research is absolutely necessary to identify minimum drug concentrations to kill cysticerci in vitro and to determine consequently optimal treatment dosages in vivo. Concerning the indications for treatment of neurocysticercosis with either PZQ or albendazole, there is general agreement that both drugs are most effective against scattered living intraparenchymal, subcutaneous or muscular cysts. They are less effective in patients with intraventricular, spinal, racemose or disseminated cysts, chronic meningitis and acute encephalitis and are even contra-indicated for intraocular cysts [37-39].
Hydatidosis and coenurosis In their recently published book, Morris and Richards [40] review the activity of PZQ and conclude that 'the drug has not been anything like as successful as in vitro and animal experiments had suggested it would'. Indeed, several authors proved PZQ to be a strong protoscolicidal agent in vitro both for Echinococcus granulosus [41] and for E. multiloeularis [42]. PZQ, however, is less effective in inhibiting cyst growth in laboratory animals and sheep [40,43]. PZQ alone did not show very promising activity in the small number of patients with hydatid disease treated up to now [44,45]. A combination of al-
s. Geerts/ lnternational Journal of Antimicrobial Agents 4 (1994) 321-324 b e n d a z o l e (50 m g / k g p e r d a y ) a n d P Z Q (500 m g / k g p e r d a y ) f o r 1 m o n t h , o n the o t h e r h a n d , was significantly m o r e effective t h a n either d r u g a l o n e in a p r o p h y l a c t i c t r e a t m e n t o f E. granulosus cysts in gerbils [46]. It m i g h t be w o r t h w h i l e to f u r t h e r e x p l o r e c o m b i n a t i o n t h e r a p y . P r o m i s i n g results were o b t a i n e d with a c o m b i n a t i o n o f m e b e n d a z o l e a n d P Z Q in p a t i e n t s unsuccessfully t r e a t e d with m e b e n d a z o l e [47]. M o n t h l y o r 6-weekly m a s s t r e a t m e n t s o f d o g s respectively infected with E. multilocularis o r E. granulosus using P Z Q are very effective in r e d u c i n g the risk o f h u m a n h y d a t i d o s i s in h y p e r e n d e m i c areas. This was nicely s h o w n b y R a u s c h et al. [48] in A l a s k a for E. multilocularis a n d in several E u r o p e a n c o u n t r i e s a n d in N e w Z e a l a n d for E. granulosus [49]. T h e activity o f P Z Q a g a i n s t c e r e b r a l c o e n u r o s i s in sheep at t o t a l d o s a g e s o f 100-500 m g / k g was reconfirmed [50]. U p to n o w n o d a t a are a v a i l a b l e a b o u t treatm e n t o f h u m a n c o e n u r o s i s cases, b u t one r e p o r t m e n tions s o m e success o f P Z Q a g a i n s t a b d o m i n a l c o e n u r i in a spectacled l a n g u r [51].
3. Conclusion To s u m m a r i z e , it c a n be c o n c l u d e d t h a t P Z Q r e m a i n s the d r u g o f choice to t r e a t a d u l t cestode infections. F o r the t r e a t m e n t o f T. solium cysticerci in the b r a i n p a r e n c h y m a , a l b e n d a z o l e seems to be s u p e r i o r to P Z Q , cert a i n l y when steroid d r u g s are used simultaneously. T h e o p t i m a l schedules for the t r e a t m e n t o f n e u r o - c y s t i c e r c o sis a n d for m u s c u l a r cysticercosis using either P Z Q o r a l b e n d a z o l e have still to be identified. C o n c e r n i n g the use o f P Z Q f o r the t r e a t m e n t o f h u m a n h y d a t i d o s i s o r coenurosis, the a v a i l a b l e d a t a are r a t h e r d i s a p p o i n t i n g .
References [1] Groll E. Praziquantel for cestode infections in man. Acta Trop 1980;37:293. [2] Brandt JR, Kumar V, Geerts S. In: Peterson PK, Verhoef J, eds. Antimicrobial Agents Annual 1. Amsterdam: Elsevier Sci Publ, 1986;287-294. [3] Bouree P. Efficacy of a single dose of praziquantel as treatment for Taenia saginata and Hyrnenolepis nana. Pathol Biol Paris 1988;36:759-761. [4] Tesfa YTM. Observations on self-induced Taenia saginata infection. Ethiop Med J 1990;28:91-93. [5] Fan PC, Chung WC, Chan CH et al. Studies on taeniasis in Taiwan. V. Field trial on evaluation of therapeutic efficacy of mebendazole and praziquantel against taeniasis. Southeast Asian J Trop Med Publ Health 1986;17:82-90. [6] Pawlowski ZS. Efficacy of low doses of praziquantel in taeniasis. Acta Trop 1990;48:83-88. [7] Cruz M, Davis A, Dixon H, Pawlowski ZS, Proano J, Operational studies on the control of Taenia solium taeniasis/cysticercosis in Ecudaor. Bull WHO 1989;67:401-407.
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[8] Torres JR, Noya O, De Noya BA, Mondolfi A. Seizures and praziquantel. A case report. Rev Inst Mexi Trop Sao Paulo 1988;30:433-436. [9] Torres JR. Use of praziquantel in populations at risk of neurocysticercosis. Rev Inst Med Trop Sao Paulo 1989;31:290. [10] Diaz Camacho SE Candil Ruiz A, Suate Peraza Vet al. Epidemiologic study and control of Taenia solium infections with praziquantel in a rural village of Mexico. Am J Trop Med Hyg 1991;45:522-531. [11] Schenone H. Praziquantel in the treatment of Itymenolepis nana infections in children. Am J Trop Med Hyg 1980;29:320. [12] Castillo RM, Grados P, Carcamo C et al. Effect of treatment on serum antibody to Hymenolepis nana detected by enzyme-linked immunosorbent assay. J Clin Microbiol 1991;29:413-414. [13] Kumar V, Geerts S, Bran& JRA. Praziquantel. In: Peterson PK, Verhoef J, eds. Antimicrobial Agents Annual 2. Amsterdam: Elsevier Sci Publ, 1987;282-287. [14] Wijesundera MD. The use ofpraziquantel in human infection with Dipylidium. Trans R Soc Trop Med Hyg 1989;83:383. [15] Earnest ME Relier LB, Filley CM, Grek AJ. Neurocysticercosis in the United States: 35 cases and a review. Rev Infect Dis 1987;9:961-979. [16] Moodley M, Moosa A. Treatment of neurocysticercosis: is praziquantel the new hope. Lancet 1989;1:262-263. [17] Sotelo J, Escobedo F, Penagos P. Albendazole vs praziquantel for therapy of neurocysticercosis. A controlled trial. Arch Neurol 1988;45:532-534. [18] Sotelo J, Del Brutto OH, Penagos P, Escobedo F et al. Comparison of therapeutic regimen of anticysticercal drugs for parenchyreal brain cysticercosis. J Neurol 1990;237:69-72. [19] Takayanagui OM, Jardim E. Therapy for neurocysticercosis. Comparison between albendazole and praziquantel. Arch Neurol 1992;49:290-294. [20] Vasquez V, Sotelo J. The course of seizures after treatment for cerebral cysticercosis. N Engl J Med 1992;327:696-701. [21] Thomson AJ, De Villers JC, Moosa A, Van Dellen JR. Cerebral cysticercosis in children in South Africa. Ann Trop Pediatr 1984;4:67-77. [22] Kalra V, Paul VK, Marwah RK, Kochhar GS, Bhargava S. Neurocysticercosis in childhood. Trans R Soc Trop Med Hyg 1987;81:371-373. [23] Antoniuk SA, Bruck I, Wittig E, Accorsi A. Neurocysticercosis in childhood. II. Computed tomography of 24 patients according to symptomatic and praziquantel treatment. Arq Neuropsiquiatr 1991 ;49:47-51. [24] Mitchell WG, Crawford TO. lntraparenchymal cerebral cysticercosis in children: diagnosis and treatment. Pediatrics 1988;82:7682. [25] Escobedo F, Penagos P, Rodriguez J, Sotelo J. Albendazole therapy for neurocysticercosis, Arch Intern Med 1987;147:738741. [26] Cruz M, Cruz I, Horton J. Albendazole versus praziquantel in the treatment of cerebral cysticercosis: clinical evaluation. Trans R Soc Trop Med Hyg 1991;85:244-247. [27] Jung H, Hurtado M, Sanchez M, Medina MT, Sotelo J. Plasma and CSF levels of albendazole and praziquantel in patients with neurocysticercosis. Clin Neuropharmacol 1990;13:559-564. [28] Sotelo J, Escobedo F, Penagos P. Albendazole vs praziquantel for therapy for neurocysticercosis. A controlled trial. Arch Neurol 1988;45:532-534. [29] Jung H, Hurtado M, Medina MT, Sanchez M, Sotelo J. Dexamethasone increases plasma levels of albenduzole. J Neurol 1990;237:279-280. [30] Vasquez ML, Jung H, Sotelo J. Plasma levels of praziquantel decrease when dexamethasone is given simultaneously. Neurol 1987;37:1561- 1562. [31] Overbosch D. Neurocysticercosis. An introduction with special
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emphasis on new developments in pharmacotherapy. Schweiz Med Wochenschr 1992;122:893-898. [32] Sotelo J, Penagos P, Escobedo F, Del Brutto OH. Short course of albendazole therapy for neurocysticercosis. Arch Neurol 1988;45:1130-1133. [33] Cohen L, Belec L, Sanson M, Pierrot Deseilligny C, Signoret JL. Selective sensitivity of cysts to praziquantel and albendazole in a case of cerebral cysticercosis. Rev Neurol Paris 1992;148:58-61. [34] Bittencourt PR, Gracia CM, Gorz AM, Mazer S, Oliveira TV. High dose praziquantel for neurocysticercosis: efficacy and tolerability. Eur Neurol 1990;30:229-234. [35] Bittencourt PR, Gracia CM, Gorz AM, Oliveira TV. High dose praziquantel for neurocysticercosis: serum and CSF concentrations. Acta Neurol Scand 1990;82:28-33. [36] Gascon J, Corachan M, Ramirez J. 5 cases of cysticercosis in Rwanda. Med Trop 1989;49:77-80. [37] Bryan RT. Current issues in cysticercosis: proteins, proglottids, pigs and privies. In: Walker DH, ed. Global Infectious Diseases. Prevention, Control and Eradication. Springer-Verlag, Vienna, 1992;181-203. [38] Del Brutto OH, Sotelo J. Neurocysticercosis: an update. Rev Inf Dis 1988;6:1075-1085. [39] Welsh NH, Peters AL, Crewe-Brown W, Blignaut P, Donnoli P, Da Souza BS, Javary Y. Ocular cysticercosis. A report of 13 cases. S Afr Med J 1987;71:719-722. [40] Morris DL, Richards KS. Hydatid Disease. Current Medical and Surgical Management. Butterworth Heinemann, 1992. [41] Morris DL, Taylor D, Daniels D, Richards KS. Determination of minimum effective concentration of praziquantel in in vitro cultures of protoscoleces of Echinococcus granulosus. Trans R Soc Trop Med Hyg 1987;81:494~497.
[42] Taylor DH, Morris DL. In vitro culture ofEchinococcus multilocularis: protoscolicidal action of praziquantel and albendazole sulphoxide. Trans R Soc Trop Med Hyg 1988;82:265-267. [43] Morris DL, Richards KS, Clarkson MJ, Taylor DH. Comparison of albendazole and praziquantel therapy of Echinococcus granulosus in naturally infected sheep. Vet Parasitol 1990;36:83-90. [44] Piens MA, Persat F, May F, Mojon M. Praziquantel in human hydatidosis. Evaluation by preoperative treatment. Bull Soc Pathol Exot 1989;82:503 512. [45] Henriksen TH, Klungsoyr P, Zerihun D. Treatment of disseminated peritoneal hydatid disease with praziquantel. Lancet 1989; 1:272. [46] Taylor DH, Morris DL. Combination therapy is more effective in postspillage prophylaxis for hydatid disease than either albendazole or praziquantel alone. Br J Surg 1989;76:954. [47] Salto E, Juarez E, Roiz MP, Abad J. Combined chemotherapy (mebendazole plus praziquantel) in patients with hydatidosis. Enferm Infecc Microbiol Clin 1991;9:527-529. [48] Rausch RL, Wilson JF, Schantz PM. A programme to reduce the risk of infection by Echinococcus multiloeularis: the use of praziquantel to control the cestode in a village in the hyperendemic region of Alaska. Ann Trop Med Parasitol 1990;84:239-250. [49] Gemmell MA, Lawson JR, Roberts MG. Towards global control of cystic and alveolar hydatid diseases. Parasitol Today 1987;3:144~151. [50] Verster A, Tustin RC. Treatment of cerebral coenurosis in sheep with praziquantel. J S Afr Vet Assoc 1990;61:24-26. [51] Price TC, Dresden MH, Alvarado T, Flanagan J, Chapall CL. Coenuriasis in a spectacled langur (Presbytis obscura): praziquantel treatment and the antibody response to cyst antigens. Am J Trop Med Hyg 1989;40:514-520.
Antimierobial Agents ELSEVIER
International Journal of Antimicrobial Agents 4 (1994) 321-324
The efficacy of praziquantel for the treatment of cestode and metacestode infections S. Geerts Institute of Tropical Medicine, Nationalestraat 155, 1t-2000 Antwerp 1, Belgium Accepted 21 March 1994
Abstract The activity of praziquantel against adult and larval cestode infections is reviewed. Praziquantel remains an excellent drug for the treatment of taeniasis and hymenolepiasis. Neurocysticercosis, however, seems to respond better to a treatment with albendazole than to praziquantel, especially when the anthelmintic treatment is combined with steroid drugs. Concerning the treatment of hydatidosis and coenurosis, more research is needed to evaluate the efficacy of praziquantel.
Key words." Praziquantel; Cestodes; Metacestodes; Cysticercosis; Taenia solium; Taenia saginata; Hymenolepis nana
1. Adult cestode infections
Taeniasis Until now the recommended treatment for Taenia saginata and T. solium was a single dose of 5 to 10 mg/kg ofpraziquantel (PZQ) [1,2]. During recent years the efficacy of 10 mg/kg has been confirmed by different authors [3,4]. PZQ was also very effective against the so-called Taiwan Taenia, T. saginata taiwanensis [5]. Recently, however, Pawlowski [6] showed that even a dose of 2.5 mg/kg was 100% effective in 124 patients infected with T. saginata and carefully examined 4 months after treatment. The same author advises 2.5 mg/kg as a safe and more economical and probably still highly effective treatment of T. solium, but admits that its efficacy remains to be confirmed. Indeed, there are few data available on T. solium. A dose rate of 5 mg/kg eliminated T. solium in 33 (94.3%) out of 35 patients (Baranski; Rim cited by Pawlowski [6]). A large-scale mass treatment trial in Ecuador confirmed that this dose is also quite safe, even in a hyperendemic area for neurocysticercosis. After treatment of 10 173 people with an average dose of 5.2 mg/kg (3.4-8.7) only two serious complications were observed: one patient with an epileptic attack and one with an episode of dysentery [7]. Other reports on activation of asymptomatic neurocysticercosis after treatment with PZQ concerned doses of 20 mg/kg or higher [8,9]. 0924-8579/94/$26.00 © 1994 Elsevier ScienceB.V. All rights reserved SSDI 0924-8579(94)00029-T
It is too early to fully evaluate the efficacy of PZQ in controlling the taeniasis--cysticercosis complex and especially neurocysticercosis by 'population oriented chemotherapy', but the first results in Ecuador and Mexico were promising [7,10]. Hymenolepiasis and other cestodoses Although several authors report excellent activity of a single dose of 25 mg/kg PZQ against Hymenolepis nana [1,3,5,11], the efficacy of this dose is sometimes less than 50% [12]. Therefore two doses of 25 mg/kg might be necessary to obtain complete cure, as was already suggested by Kumar et al. [13]. Concerning the efficacy of PZQ against Diphyllobothriurn spp., no new data have become available, so that the recommended treatment still remains a single dose of 10 or 25 mg/kg respectively against D. pacificum and D. latum [1]. A dose rate of about 10 mg/kg seems also to be effective against Dipylidium caninum [14].
2. Metacestode infections
Cysticercosis In the past many reports have been published which did not allow an unequivocal evaluation of the efficacy of PZQ for the treatment of neurocysticercosis due to the
322
S. Geertsl International Journal of Antimicrobial Agents 4 (1994) 321~324
lack of control patients or the use of PZQ in combination with other drugs, the possibility of spontaneous cure, etc. [2,15,16]. Well designed studies including a sufficient number of untreated control patients, however, have provided clearcut answers on the efficacy of PZQ against different types and different locations of cysticerci. Treatment with 50 mg/kg PZQ per day for 15 days significantly decreased the number of cysts and also the frequency of seizures in comparison with untreated patients [17-19]. Vasquez and Sotelo [20] examined a large retrospective series of 240 patients (follow-up during 92 _+7 months) and showed very conclusively that treatment with albendazole, PZQ or both caused an 82% reduction in the mean number of brain cysts and a 95% reduction in the mean frequency of seizures (from 11.3 to 0.6 per year; 54% seizure-free after 3 years), whereas the untreated patients (without inflammation around the cysts) averaged 10.9 seizures per year and none became seizurefree. Spontaneous cure or satisfactory control of the disease without anthelmintic treatment, however, is possible in patients with inflammation around the cysts and in children. Actively inflamed acute lesions, which are very common in the age group below 20 years, generally resolve completely in 2 to 9 months time [16,21-24]. There are strong indications that albendazole (15 mg/ kg per day for 30 days) is superior to PZQ (50 mg/kg per day for 15 days) for the treatment of neurocysticercosis patients. Up to now, however, prospective, double-blind, placebo-controlled trials comparing both drugs are still lacking. After the first report by Escobedo et al. [25], the excellent activity of albendazole was confirmed by different research groups in Mexico, Brazil and Ecuador [19,20,26,27]. When few or no steroids are used simultaneously, the difference in the efficacy of PZQ and albendazole is not very pronounced [27,28]. In combination with prednisolone, however, albendazole gives a much better overall improvement than PZQ: 84% against 62% in a series of 50 patients treated with each of the drugs [26]. Retrospective evaluation of a large number of patients, only 22% of whom were treated with dexamethasone, confirmed the better activity of albendazole, resulting in 80% reduction of the total number of cysts against only 65% reduction with PZQ [20]. These authors also found a higher risk of persistent seizures after treatment with PZQ than albendazole (odds ratio 2.3). The improved activity of albendazole when combined with steroids is due to an increase of the plasma level of the drug by 50% [29], whereas just the opposite occurs when PZQ is combined with steroids. In patients simultaneously treated with PZQ and dexamethasone PZQ plasma levels were 50% lower than in those treated with PZQ alone [30]. The bioavailability of PZQ, however, can be increased by a factor of 2.5 through coadministration with cimetidine, an inhibitor of the P450 cytochrome metabolic pathway [31]. The current treatment schemes for cysticercosis using
albendazole or PZQ have been determined empirically and only very few studies were set up to optimise these schemes. Sotelo et al. [18] compared four treatment regimens: 50 mg/kg PZQ for 15 or 8 days and 15 mg/kg albendazole for 30 or 8 days. Surprisingly they found that the short treatment scheme with albendazole was as effective as the long one. It caused disappearance of the lesions in 85% of the patients, whereas the short and the long scheme with PZQ caused a reduction of only 48 and 60% respectively. The same authors recommend to start treatment of neurocysticercosis with a short course using albendazole. In patients showing a partial response to albendazole after 3 months, the treatment can be continued with a 15-day course using PZQ. Indeed, some cysts seem to respond better to PZQ, whereas others respond better to albendazole. Several reports mention the disappearance of cysticerci with albendazole after unsuccessful treatment with PZQ [25,32,33]. Another treatment schedule was tried by Bittencourt et al. [34]. They used 100 mg/kg PZQ for 10 days. Although there was a disproportionally higher concentration of the drug in blood and CSF than with the usual dose, these authors could not find any correlation between serum and CSF concentration of PZQ and disease outcome [35]. Similarly, the optimal treatment schedule for muscular and subcutaneous cysticercosis has not yet been determined. Usually 25 mg/kg PZQ is used for 3 to 4 days [2]. Gascon et al. [36], however, obtained good results using three doses of 20 mg/kg PZQ at 4-h intervals. The advantage of this schedule is that treatment of patients in rural regions can be finished in one day. Further research is absolutely necessary to identify minimum drug concentrations to kill cysticerci in vitro and to determine consequently optimal treatment dosages in vivo. Concerning the indications for treatment of neurocysticercosis with either PZQ or albendazole, there is general agreement that both drugs are most effective against scattered living intraparenchymal, subcutaneous or muscular cysts. They are less effective in patients with intraventricular, spinal, racemose or disseminated cysts, chronic meningitis and acute encephalitis and are even contra-indicated for intraocular cysts [37-39].
Hydatidosis and coenurosis In their recently published book, Morris and Richards [40] review the activity of PZQ and conclude that 'the drug has not been anything like as successful as in vitro and animal experiments had suggested it would'. Indeed, several authors proved PZQ to be a strong protoscolicidal agent in vitro both for Echinococcus granulosus [41] and for E. multiloeularis [42]. PZQ, however, is less effective in inhibiting cyst growth in laboratory animals and sheep [40,43]. PZQ alone did not show very promising activity in the small number of patients with hydatid disease treated up to now [44,45]. A combination of al-
s. Geerts/ lnternational Journal of Antimicrobial Agents 4 (1994) 321-324 b e n d a z o l e (50 m g / k g p e r d a y ) a n d P Z Q (500 m g / k g p e r d a y ) f o r 1 m o n t h , o n the o t h e r h a n d , was significantly m o r e effective t h a n either d r u g a l o n e in a p r o p h y l a c t i c t r e a t m e n t o f E. granulosus cysts in gerbils [46]. It m i g h t be w o r t h w h i l e to f u r t h e r e x p l o r e c o m b i n a t i o n t h e r a p y . P r o m i s i n g results were o b t a i n e d with a c o m b i n a t i o n o f m e b e n d a z o l e a n d P Z Q in p a t i e n t s unsuccessfully t r e a t e d with m e b e n d a z o l e [47]. M o n t h l y o r 6-weekly m a s s t r e a t m e n t s o f d o g s respectively infected with E. multilocularis o r E. granulosus using P Z Q are very effective in r e d u c i n g the risk o f h u m a n h y d a t i d o s i s in h y p e r e n d e m i c areas. This was nicely s h o w n b y R a u s c h et al. [48] in A l a s k a for E. multilocularis a n d in several E u r o p e a n c o u n t r i e s a n d in N e w Z e a l a n d for E. granulosus [49]. T h e activity o f P Z Q a g a i n s t c e r e b r a l c o e n u r o s i s in sheep at t o t a l d o s a g e s o f 100-500 m g / k g was reconfirmed [50]. U p to n o w n o d a t a are a v a i l a b l e a b o u t treatm e n t o f h u m a n c o e n u r o s i s cases, b u t one r e p o r t m e n tions s o m e success o f P Z Q a g a i n s t a b d o m i n a l c o e n u r i in a spectacled l a n g u r [51].
3. Conclusion To s u m m a r i z e , it c a n be c o n c l u d e d t h a t P Z Q r e m a i n s the d r u g o f choice to t r e a t a d u l t cestode infections. F o r the t r e a t m e n t o f T. solium cysticerci in the b r a i n p a r e n c h y m a , a l b e n d a z o l e seems to be s u p e r i o r to P Z Q , cert a i n l y when steroid d r u g s are used simultaneously. T h e o p t i m a l schedules for the t r e a t m e n t o f n e u r o - c y s t i c e r c o sis a n d for m u s c u l a r cysticercosis using either P Z Q o r a l b e n d a z o l e have still to be identified. C o n c e r n i n g the use o f P Z Q f o r the t r e a t m e n t o f h u m a n h y d a t i d o s i s o r coenurosis, the a v a i l a b l e d a t a are r a t h e r d i s a p p o i n t i n g .
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