PZQ was developed in the 1970s by Bayer and have been proved active against many parasitic platyhelminthes (Vale et al., 2017). PZQ was the first antihelminthic drug to fulfill the requirements of the WHO for community-based chemotherapy of a wide range of parasitic infections, including schistosomiasis (Mutapi et al., 2015).
PZQ is a pyrazino-isoquinoline-derivative (Fig. ). It is a white crystalline powder with a bitter taste. The compound is stable under normal storage conditions. It is hydrophobic compound with poor water solubility, but it is soluble in some organic solvents (Doenhoff et al., 2008; Cupit and Cunningham, 2015).
The commercial form is a mixture of equal parts of dextro (right) and levo (left) isomers. Only the levo isomer has schistosomicidal activity as proved by in-vivo and in-vitro studies (Mutapi, 2015). This means that about half the currently administered pill is unnecessary (Alsaqaby and Lotfy, 2014).
Fig. ( ): Chemical structure of PZQ (Alsaqaby and Lotfy, 2014).
Mechanism of Action
Although PZQ has been the principle treatment for schistosomiasis for many years, its excact mechanism of action has not been established yet (Cupit and Cunningham, 2015).
PZQ is found to be efficacious against adult schistosome worms but not against juveniles, with schistosome cure rates and egg reduction rates typically more than 75% (Mutapi, 2015).
Experimental evidences implicate that PZQ binds to its molecular target followed a rapid influx of calcium (Ca2+), which is considered as the key event in the anti-schistosomal effect of PZQ. Rise of intracellular Ca2+ is then followed by intense muscular contraction and spastic paralysis, in addition to surface modifications in the adult worm (Vale et al., 2017).
Fig. ( ): Mechanism of action of PZQ (You et al., 2015).
Furthermore, in-vitro studies have shown that, PZQ was able to induce vacuolation and blebbing of worm tegumental and subtegumental structures in adult schistosomes but not juveniles (Cupit and Cunningham, 2015). This was followed by disruption of the tegument and exposure of the parasite surface antigens resulting in recognition and parasite clearance by the host immune system (Deribew and Petros, 2013).
However, the exact mechanism by which PZQ disrupts homeostasis in schistosomes remains largely unknown (Vale et al., 2017). Voltage-gated Ca2+ channels have been identified as candidate targets of PZQ. Schistosomes posses two subtypes of Ca2+ channel ? subunit; a conventional subtype similar to ? subunits found in other vertebrates and invertebrates, and a novel variant subtype with unusual structural and functional properties. This unique Ca2+ channel ? subunit may play an essential role in PZQ action (Deribew and Petros, 2013).
Furthermore, many hypotheses suggested that PZQ may mediate its antihelminthic actions through binding to actin and myosin light chains, alteration of membrane fluidity, reducing schistosomal glutathione concentration or inhibiting nucleoside uptake but many of these hypotheses have not been proved yet (Cupit and Cunningham, 2015).
Pharmacokinetic studies in adults with normal renal and liver function show that PZQ is rapidly absorbed from the gastrointestinal tract (Mutapi, 2015).
PZQ is almost completely absorbed is nearly complete (> 80 %), which demonstrates an extensive first-pass hepatic metabolism via hydroxylation of the absorbed drug into inactive metabolites by the action of cytochrome P450, with rapid disappearance of the drug from the circulation (Gouveia et al., 2017; Siqueira et al., 2017; Vale et al., 2017). The drug metabolites are then excreted mainly in the urine (Deribew and Petros, 2013).
PZQ reaches peak concentrations in plasma one to three hours after oral administration. It has low systemic bioavailability with a half-life that ranges between 0.8 and 1.5 hours (Friedman et al., 2018). However, bioavailability of PZQ increases with the concomitant administration of food, especially with fatty diet (Vale et al., 2017).
The recommended dose of PZQ for treatment of schistosomiasis is 40-60 mg/kg body weight. The lower dose have been generally used for S. mansoni and S. haematobium, while the higher dose is recommended for Asian species of schistosomes (S. japonicum and S. mekongi) (WHO, 2002; Deribew and Petros, 2013).
Besides its high cure rate, PZQ decreases worm burden and egg production in those who are not cured. Patients with continuous shedding of viable eggs should be re-treated with the same dose; the second treatment is usually successful (Alsaqabi and Lotfy, 2014). For the treatment of some cestode infections as cystic echinococcosis, repeated administrations of PZQ in high doses over a longer period are required (Campos et al., 2013).
PZQ is a well-tolerated drug; few adverse effects have been recorded, including fatigue, urticaria, gastrointestinal and abdominal pains, nausea, vomiting, headache, and dizziness (Mutapi, 2015). These reactions may be attributed to dying worms and to the release of their products and the consequent host immune reaction. Thus, the most severe side effects are encountered mainly in high intensity areas (Alsaqabi and Lotfy, 2014).
The major drawback of PZQ is being ineffective against sexually immature larval stages that are present in systemic circulation in the first 2–4 weeks after infection. In addition, PZQ rarely affects 100% cure rate, resulting in failure of mass treatment to control schistosomiasis (Cupit and Cunningham, 2015). This failure has been attributed to the fact that therapy is not sufficiently long-lasting (El-Feky et al., 2015). This effect may be attributed to the poor bio¬availability and short plasma half-life of PZQ (Campos et al., 2013).
Low solubility in biological fluid restricts the delivery of the drug after oral administration. In addition, PZQ undergoes fast hepatic metabolism, rendering the drug less effective against immature worms present in the systemic circulation, as they are less exposed to PZQ. Eventually, schistosomulae exposed to insufficient drug concentrations become mature and may be responsible for the poor cure rates of the drug. Furthermore, large doses with extra costs are required in order to achieve adequate concentrations at larval tissue (El-Feky et al., 2015). Morever, it has been reported that PZQ does not prevent re-infection (Gray et al., 2010).
Since the global control strategies of schistosomiasis have been solely based on large-scale administration of PZQ in numerous countries for many years, reports of drug resistance have raised an intense alarm (Elridi and Tallima, 2012).
Resistance to PZQ is defined as the genetically transmitted loss of susceptibility in worm populations that were previously susceptible to PZQ (Pinto-Almeida et al., 2015). However, the exact mechanism involved in the phenomenon of resistance to PZQ is not yet fully understood. Many hypotheses have been postulated to explain schistosome resistance to PZQ (Pinto-Almeida et al., 2016).
Resistance is assumed to be genetically inherited. There is a common supposition that S. mansoni has a capacity to develop resistance to therapeutic doses of a determined drug, especially when the parasitic population is under continuous pressure from that schistosomacides (Alsaqabi and Lotfy, 2014). It is worth saying that, sublethal PZQ concentration is a major factor that facilitated the emergence of PZQ resistant strains (El-Feky et al., 2015).
A further problem with PZQ is the tablet itself that has a large size and a bitter taste, with difficult administration to school-aged children, knowing that they represent a large pool of the target of schistosomiasis control programs (Cupit and Cunningham, 2015).
Furthermore, PZQ is still categorized by the United States Food and Drug Administration (FDA) as class B regarding its use in pregnancy. However, in 2006, WHO last published a recommendation on the use of PZQ in pregnant and breastfeeding women in the second and third trimesters or at a total dose of 60 mg per kg at 12–16 weeks’ gestation. On the other hand, the safety during the first trimester has not been well assessed (Friedman et al., 2018).
In addition, severe side effects associated with treatment of patients with a relatively high level of infection have been observed but are often transient due to allergic reactions caused by the significant increase in circulating parasite antigens (Cupit and Cunningham, 2015).
Analysis of the genotoxicity of PZQ has been extensively performed using diverse in-vitro and in-vivo assays, however results are contradictory and not conclusive (Eid et al., 2014). Although, In most cases, the effectiveness and safety of PZQ have been confirmed, there are few concerns about the the mutagenicity and genotoxicity of the drug (Ali, 2006).
Morever, PZQ proved to aggrevate the infection induced oxidative stress, along with some degree of genotoxicity compared with infected untreated controls (Eid et al., 2014).
These problems reveal the urgent need for a controlled drug delivery system. This enables the drug to be always maintained at effective concentrations during the course of therapy, reducing its side effects or improving undesireable physico¬chemical and biopharmaceutical properties (Campos et al., 2013).