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Praziquantel

Article  in  Parasitology Research · July 2003

DOI: 10.1007/s00436-002-0751-z · Source: PubMed

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Parasitol Res (2003) 90: S3–S9
DOI 10.1007/s00436-002-0751-z

O R I GI N A L P A P E R

Donato Cioli Æ Livia Pica-Mattoccia

Praziquantel

Published online: 22 November 2002

Springer-Verlag 2002

Abstract Praziquantel is the drug of choice for the

treatment of all forms of schistosomiasis. This review
summarizes the main features of the drug, with special
attention being given to those aspects that may be of
interest to the practicing physician. After a brief mention
of the history, the chemistry, the major available brands
and their costs, doses and administration schedules are
reviewed. Pharmacokinetics and drug interactions are
analyzed and the low toxicity and mild side effects are
stressed. A major weakness of praziquantel is its relative
inefficacy against recent infections, a factor that may
occasionally result in low cure rates in hyperendemic
areas. Recent findings of schistosome isolates with a
decreased sensitivity to praziquantel are discussed in the
broader context of a possible emergence of drug resis-
tance.
Introduction
At present, praziquantel is the drug of choice for the
treatment of all forms of schistosomiasis. The other
antischistosomal drug available on the market, oxa-
mniquine, has an excellent record of efficacy and safety
for the treatment of infections caused by Schistosoma
mansoni (Foster 1987), but is not active against the other
human schistosomes. A third antischistosomal drug,
metrifonate, active only against Schistosoma haemato-
bium, is rarely employed and is no longer available as a
brand product, although it can still be found as a generic
drug.
History
The antiparasitic activity of the pyrazino isoquinoline
ring system – the core structure of praziquantel – was
observed in the early 1970s at the laboratories of Bayer,
Germany (Andrews 1981). When a large series of pyrazino
isoquinoline compounds were synthesized by E. Merck,
Germany (Seubert et al. 1977) as potential tranquillizers,
an agreement between the two firms allowed for the in vivo
screening at Bayer of these chemicals as anthelmintics.
The anticestode and antitrematode activities in animals of
the most effective compound, EMBAY 8440 or praziqu-
antel, were published in 1977 (Thomas and Gönnert 1977;
Gönnert and Andrews 1977) and the first studies on
human volunteers were reported in 1978 (Leopold et al.
1978). In close cooperation with the World Health
Organization, the first clinical trials were carried out in
areas endemic for S. mansoni (Katz et al. 1979), S. hae-
matobium (Davis et al. 1979) and Schistosoma japonicum
(Ishizaki et al. 1979). All of these trials, as well as nu-
merous subsequent ones, were extremely successful and
clearly identified praziquantel as the drug of choice for the
treatment of schistosomiasis. In 1983, the Korean com-
pany, Shin Poong, developed a new method for the syn-
thesis of praziquantel and obtained a process patent for its
product. This started a market competition that rapidly
resulted in conspicuous price reductions. In 1987, EIPICO
started producing praziquantel in Egypt under license
from Shin Poong. This was soon followed by other pro-
ducers in various countries.
Chemistry

Praziquantel is 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-
hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-one. It is a
white to nearly white crystalline powder of bitter taste,
D. Cioli (&) Æ L. Pica-Mattoccia melting at 136–140C with decomposition. It is stable
Institute of Cell Biology,
C.N.R., 32 Via Ramarini,
under normal conditions and it is practically insoluble in
00016 Monterotondo (RM), Italy water, sparingly soluble in ethanol and soluble in or-
E-mail: dcioli@ibc.rm.cnr.it ganic solvents like chloroform and dimethylsulfoxide.
S4
Praziquantel
Praziquantel possesses an asymmetric center in position
11b (asterisk). The commercial preparation is a racemate
composed of equal parts of ‘‘levo’’ R(–) and ‘‘dextro’’
S(+) isomers. Only the (–)-enantiomer is endowed with
antischistosomal activity, as shown by in vivo and in
vitro experiments (Andrews et al. 1983; Liu et al. 1986;
Xiao and Catto 1989; Wu et al. 1991). The two isomers,
however, have essentially the same toxicity (Liu et al.
1986), and indeed Wu et al. (1991), found that patients
treated with 20 mg/kg (–)-praziquantel had the same
cure rate but fewer side effects than patients treated with
40 mg/kg of the racemic preparation. Also, stereoselec-
tive differences have recently been described in the
metabolism of the drug.
Brands
Praziquantel was initially (and still is) marketed by
Bayer under the name Biltricide for human use and
under the name Droncit for veterinary use. A number
of other brands are now available with various names
in different countries, for instance: Distocide (Shin
Poong, EIPICO), Bilharzid (Pharco, Egypt), Prazitel
(Cosmos, Kenya). Several generic manufacturers also
supply praziquantel and a recent survey was made on
the quality of their products (Doenhoff et al. 2000;
Appleton and Mbaye 2001). Thirty-four praziquantel
samples from different manufacturers were collected at
the user level in different countries and subjected to
quantitative analysis of the active ingredient, purity,
disintegration and dissolution, according to established
pharmacopoeia standards. The results were generally
quite reassuring, since generic and brand products were
equally able to meet such standards. Two of the sam-
ples (from a single manufacturer), however, did not
contain any praziquantel at all (Sulaiman et al. 2001).
Some anomalous features were detectable in the pack-
aging of these samples that could act as a clue to their
spurious nature. From the results of this quality
testing, the use of generic products can be generally
encouraged, but care must be taken over the purchase
of drugs of suspicious appearance.
Praziquantel is usually supplied as oblong tablets
containing 600 mg of active ingredient, with two or three
grooves for the ease of subdivision into segments con-
taining 200 or 150 mg, respectively. In China, however,
praziquantel (also known as Pyquiton) is distributed in
round pills containing 200 mg of the active substance. A
syrup formulation containing 600 mg/5 ml is provided
by some manufacturers (e.g. Epiquentel from EIPICO).
The shelf life is generally 4 years in temperate climates
and 3 years in hot, humid environments.
Since the cost of drugs is often a major obstacle to the
implementation of chemotherapy in many endemic
countries, it may be useful to give a rough indication of
the price of praziquantel. The 2001 ‘‘MSH International
Drug Price Indicator Guide’’ reports an average price of
US$0.1010 per tablet, with the lowest price at
US$0.0751/tablet for a package of 500 tablets (MSH
web site: http://www.msh.org/). The December 2001
catalog of the International Dispensary Association
(Amsterdam) carries a 500-tablet bottle for 41,50 Euro,
or US$0.061/tablet.
Dose and administration
The recommended dose is 40–60 mg/kg body weight, the
lower amount being generally used for S. mansoni and S.
haematobium, while the higher dose (generally split into
two administrations a few hours apart) is especially
recommended for Asian schistosomes (S. japonicum and
Schistosoma mekongi) [World Health Organisation
2002]. In order to avoid the need for a weighing device of
any kind, a useful ‘‘praziquantel tablet pole’’, based on
height rather than weight, has been developed and val-
idated (Hall et al. 1999; Montresor et al. 2001).
It has been repeatedly reported that the bioavail-
ability of praziquantel increases with the concomitant
administration of food (Mandour et al. 1990; Homeida
et al. 1994; Castro et al. 2000), a procedure that should
be considered whenever possible.
Praziquantel has not been formally tested in preg-
nant or lactating women and is therefore released as
‘‘Pregnancy Category B’’, i.e. as a drug that is pre-
sumed to be safe, based on animal studies. Although
administration to pregnant women has been avoided in
general practice (Kusel and Hagan 1999), concerns
have been expressed that withholding treatment may
actually involve more detrimental effects than sub-
stantial risks (Dr. Richard Olds, Milwaukee, Wis.,
USA, personal communication). An ad hoc committee
recently convened by the World Health Organisation
has indeed recommended that praziquantel treatment
be offered to pregnant and lactating women as well
(World Health Organisation 2002).
Pharmacokinetics and clearance
Orally administered praziquantel is rapidly absorbed,
measurable amounts appearing in the blood as early as

15 min after dosing (Valencia et al. 1994) and peak levels
occurring after 1–2 h in normal volunteers (Leopold
et al. 1978). Maximum plasma concentration after a
standard dose of 40 mg/kg shows wide inter-individual
variations in the range of 200–2,000 ng/ml (Mandour
et al. 1990). Praziquantel undergoes a pronounced liver
first pass metabolism, with rapid disappearance from the
circulation and a plasma half-life generally ranging be-
tween 1 and 3 h. Elimination occurs essentially through
the urine and the feces and it is more than 80% complete
after 24 h (Steiner et al. 1976).
The main metabolites of praziquantel are represented
by mono- di- and tri-hydroxylated compounds that
are produced in the liver by microsomal cytochrome
P450, particularly by those isoforms (2B1 and 3A)
that are experimentally inducible by phenobarbitone
(Masimirembwa and Hasler 1994; Giorgi et al. 2001). The
most abundant metabolite is the 4-hydroxycyclohexyl-
carbonyl analog (i.e. the compound with a single hydroxyl
group in the 4¢-position of the cyclohexane ring), which
represents about two thirds of total urinary metabolites.
The bioavailability of praziquantel is increased by the
simultaneous administration of substances that inhibit
cytochrome P450 activities. For instance, cimetidine
causes a 100% increase (Metwally et al. 1995; Jung et al.
1997) and has been used in association with praziquantel
especially for the treatment of neurocysticercosis, where
high drug concentrations are required. Similar increases
can be effected by 17 alpha-ethynylestradiol and diph-
enylhydramine, whereas the opposite effect is observed
after the simultaneous administration of antiepileptics or
corticosteroids, especially carbamazepine, phenytoin or
dexamethasone (Na-Bangchang et al. 1995; Sotelo and
Jung 1998). The hepatic dysfunction accompanying the
late stages of schistosomal disease was found to be
associated with slower praziquantel metabolism and
disposition (El Guiniady et al. 1994).
Concurrent administration of praziquantel and al-
bendazole has been suggested to increase the cost-ef-
fectiveness of large-scale deworming programmes and
the combination has indeed been found to be safe and
effective (Olds et al. 1999), even though praziquantel is
known to significantly increase the bioavailability of
albendazole (Homeida et al. 1994; Sotelo and Jung
1998). The increased bioavailability of praziquantel up-
on simultaneous food administration has been previ-
ously mentioned, an effect that may be mediated by
modifications in microsomal enzyme activities. In trop-
ical areas, praziquantel may be administered together
with the antimalarial chloroquine, an association that
was found to decrease the bioavailability of praziquantel
and to reduce its maximum serum concentration to a
significant extent in rats and in humans (Masimirembwa
et al. 1994).
It is important to recall that the metabolism of pra-
ziquantel occurs in a stereoselective way for the two
enantiomers that constitute all commercial preparations
(Westhoff and Blaschke 1992; Lerch and Blaschke 1998;
Meier and Blaschke 2001). For example, it was shown
S5
that the (–)-trans-4-hydroxypraziquantel in humans is far
more abundant (70:30) than the (+)-isomer (Westhoff
and Blaschke 1992), a relevant fact since the former
metabolite appears to possess antischistosomal activity
(Staudt et al. 1992).
Toxicity studies
In general, the toxicity of praziquantel in animals was
found to be very low, both in acute and long-term ex-
periments (Frohberg 1984). No genotoxic risks could be
demonstrated from various mutagenicity studies in
bacterial, yeast, Drosophila and mammalian systems
(Kramers et al. 1991). Occasional and somewhat con-
flicting reports have claimed either clastogenic (Herrera
et al. 1994), co-clastogenic (Anwar et al. 1989; Anwar
1994) or anticlastogenic (Anwar and Rosin 1993) effects.
No signs of mutagenicity were detected in patients
treated with the high doses employed for neurocystic-
ercosis (Montero et al. 1994).
A wary review of all possibly suspicious data (Mon-
tero and Ostrosky 1997) argues for more genotoxic and/
or carcinogenic studies, based mainly on the consider-
ation that there might be some human genetic poly-
morphism leading to the accumulation of potentially
mutagenic metabolites. Apart from this very broad
concern, however, the latter authors state that the
handful of positive data appear as ‘outlier’ results in the
context of the massive amount of evidence pointing to
praziquantel safety.
Efficacy
The major asset of praziquantel is probably its broad
spectrum of activity. Since the early animal studies, it
was apparent that praziquantel is about equally effective
against S. mansoni, S. hematobium, S. japonicum,
Schistosoma intercalatum and Schistosoma mattheei
(Webbe and James 1977). This has been repeatedly
confirmed by a huge amount of human data collected in
endemic areas around the world.
Using the recommended dosages, cure rates recorded
in a 1984 review (Wegner 1984) were: 75–85% for S.
hematobium; 63–85% for S. mansoni; 80–90% for S.
japonicum; 89% for S. intercalatum and 60–80% for
double infections with S. mansoni and S. hematobium.
Praziquantel is tolerated and effective in patients of all
ages and in the different clinical forms of schistosomiasis,
including advanced hepatosplenic cases (Bassily et al.
1985). Cerebral schistosomiasis caused by S. japonicum
can be treated successfully with praziquantel (Watt et al.
1986) and neurological syndromes caused by S. mansoni
and S. hematobium also respond well, possibly in associ-
ation with corticosteroids (Scrimgeour and Gadjusek
1985). Acute toxemic forms (Katayama fever) are also
S6
treated with praziquantel (Monson 1987; Farid et al.
1987), but Harries and Cook (1987) reported three cases
in which worm elimination had worsened the situation.
The major weakness of praziquantel is its lack of effi-
cacy against juvenile schistosomes. This has been clearly
shown in experimental animals (Gönnert and Andrews
1977; Sabah et al. 1986; L. Pica-Mattoccia unpublished
data) as well as in in vitro tests (Xiao et al. 1985) and it has
been confirmed by clinical data (Gryseels et al. 2001). The
sensitivity of schistosomes to praziquantel has a peculiar
biphasic profile, with the earliest stages (from cercariae to
the first few days after infection) being susceptible, fol-
lowed by progressive insensitivity down to very low levels
around weeks 3–4 after infection. From this point on,
schistosomes gradually regain susceptibility until they are
fully affected by the drug, beginning around weeks 6–7
after infection. This age-dependence of activity is proba-
bly the source of most treatment ‘failures’ experienced
with praziquantel in clinical practice. In endemic areas
with active transmission of schistosomiasis, any patient at
the time of treatment has a given probability of having
been infected in the previous 3–5 weeks. Such a patient
would thus harbor immature schistosomes that are not
killed by praziquantel and that will mature and deposit
eggs in the subsequent weeks, thus resulting in an appar-
ent drug failure. This might raise the suspicion that failure
is due to drug resistance. To overcome this problem, a
protocol has been proposed that contemplates two pra-
ziquantel doses spaced 3 weeks apart and a follow-up
examination 2 weeks after the second dose (Renganathan
and Cioli 1998). Another possibility would be to admin-
ister praziquantel together with artemether, a drug that
has been found to be active against immature schisto-
somes, with an age-activity profile that is exactly com-
plementary to that of praziquantel (De Clercq et al. 2000;
Utzinger et al. 2001).
Side effects
After the administration of praziquantel, side effects
are observed in a relatively large percentage of
patients (30–60%), but these are usually mild and
transient, disappearing within 24 h (Jaoko et al. 1996;
Berhe et al 1999). The most commonly reported effects
are headache, nausea, anorexia, vomiting, abdominal
pain, epigastric pain, diarrhea with or without blood
and/or mucus, lassitude, fever, myalgia, dizziness,
sleeplessness, sleepiness, and – more rarely – a skin
rash with edema.
It has been repeatedly observed that the frequency and
the severity of the side effects is directly correlated with the
intensity of infection, as measured by the number of pre-
treatment eggs. Thus, it appears that a proportion of the
reactions are likely to be due to dying schistosomes and to
the release of their products. This may well be the case
with the most severe side effects, like bloody diarrhea or
edematous urticaria, which are encountered mainly in
high-intensity areas (Polderman et al. 1984).
Other diseases
In addition to its antischistosomal effects, praziquantel
is the drug of choice for infections due to other human
trematodes: Opisthorchis (Clonorchis) sinensis, Opis-
thorchis viverrini, Paragonimus spp., Fasciolopsis buski,
Heterophyes heterophyes and Metagonimus yokogawai
(Wegner 1984). Treatment of these infections is usually
carried out by administering three daily praziquantel
doses of 25 mg/kg for 3 days .
The use of praziquantel to treat veterinary cestode
infections predates its use as a human schistosomicide
(Thomas and Gönnert 1977). Regarding human ces-
todes, Hymenolepis spp., Taenia saginata and Diphyllo-
bothrium latum are easily eradicated with a single low
dose of praziquantel (Bouree 1991). In hydatid disease
caused by Echinococcus spp., praziquantel is adminis-
tered preoperatively (up to 75 mg/kg per day for
15–20 days), often in combination with albendazole
(Cobo et al. 1998). The cysticercus stage of Taenia
solium, especially in its localization in the brain (neuro-
cysticercosis), can be treated with high doses of
praziquantel (50 mg/kg/day for 15 days), usually in
combination with corticosteroids (Bale 2000) and
possibly associated with cimetidine (Overbosch 1992).
Mode of action
The detailed molecular mechanism of action of praziqu-
antel has not yet been elucidated (Day et al. 1992; Cioli
2000), but a few phenomena connected with its effects are
well known. The most obvious and immediate modifica-
tion that can be observed in schistosomes exposed to the
drug either in vitro or in vivo is a spastic paralysis of the
worm musculature. This contraction is accompanied –
and probably caused – by a rapid Ca2+ influx inside the
schistosome (Pax et al. 1978). Another early effect of
praziquantel consists in morphological alterations that
can be observed in the worm tegument, initially repre-
sented by vacuolization at the base of the tegumental
syncytium and blebbing at the surface (Becker et al. 1980;
Mehlhorn et al. 1981). These morphological alterations
are accompanied by an increased exposure of schistosome
antigens at the parasite surface (Harnett and Kusel 1986).
Some of the drug exposed antigens have been identified
and appear to be connected with the host immune re-
sponse that is required for the complete activity of pra-
ziquantel (Doenhoff et al. 1987; Brindley et al. 1989).
An interesting recent report drew attention to schis-
tosome calcium channels as the possible molecular tar-
get of praziquantel (Kohn et al. 2001). The b-subunits of
these channels appear to have a different structure from
other known b-subunits and, when expressed together

with heterologous a-subunits, can confer to the latter a
previously nonexistent sensitivity to praziquantel.
Resistance
The first alarming reports of possible praziquantel resis-
tance came from an intensive focus in northern Senegal,
where the drug had produced very low cure rates
(18–39%) (Gryseels et al. 1994; Stelma et al. 1995). The
most common interpretation of these findings is that they
were mainly due to the peculiar epidemiological situation
of the focus, i.e. high numbers of worms present in each
patient, high probability of immature parasites and rapid
reinfection (Cioli 2000; Gryseels et al. 2001). It should be
mentioned, however, that oxamniquine was found to be as
effective as normal in the same population (Stelma et al.
1997) and that snails collected in the area carried a
schistosome strain that, when tested in the laboratory,
proved to have a decreased susceptibility to praziquantel
(Fallon et al. 1995; Liang et al. 2001).
Additional evidence for resistance to praziquantel was
collected in Egypt, where a number of schistosome iso-
lates were established in the laboratory from the eggs ex-
creted by patients who had been unsuccessfully treated
(three times) with praziquantel (Ismail et al. 1996). Some
of the isolates obtained from easily cured patients showed
a decreased sensitivity to praziquantel in vivo (Bennett
et al. 1997) and in vitro (Ismail et al. 1999). Differences in
ED50 between sensitive and resistant schistosomes are
relatively small (two- to sixfold), and no practical clinical
problems have been detected so far in the area.
Finally, schistosomes have been repeatedly subjected
to drug pressure in the laboratory and the worms
emerging from this selection process have been found to
be less sensitive to praziquantel than the original uns-
elected strain (Fallon and Doenhoff 1994; Liang et al.
2001).
Conclusions
In summary, the existence of schistosomes with a de-
creased susceptibility to the action of praziquantel has
been repeatedly demonstrated. Active monitoring of the
phenomenon is needed in the field, while urgent efforts
should be made towards the development of new antis-
chistosomal drugs (Doenhoff et al. 2002).
Acknowledgements The authors are currently supported by an
INCD-DEV grant (ICA4-CT-2001-10079) from the European
Commission. This review is dedicated to our colleague and friend
Franco Tatò.
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