Drug Praziquantel Research Articles

In silico REPOSITIONING OF NEW DRUGS AGAINST Schistosoma mansoni

Schistosomiasis is a neglected tropical disease caused by parasites of the genus Schistosoma. In Brazil only Schistosoma mansoni causes this disease. The World Health Organization estimated in 2012 approximately 249 million people at risk of acquiring this disease around the world. The main strategy to control this disease is praziquantel treatment of individuals living in endemic areas. The drug praziquantel is used on a large scale in the treatment of schistosomiasis and currently there are reported cases of resistance, indicating the need to discover new drugs. In silico drug repositioning is a time and cost reducing strategy in the search for anti-Schistosoma agents. This work used bioinformatic tools to identify potential schistosomicidal drugs. A list was compiled of S. mansoni potential targets that are part of essential processes in the database TDR and the targets that are part of the tegument were obtained in the scientific literature. The file with S. mansoni targets contained 1,376 targets, and of these only 61 targets associated with 399 drugs had homology with drug targets. After removal of duplicate drugs, drugs found in previous studies and after the analysis of the conservation of the binding site, only 28 S. mansoni targets associated with 102 drugs had 60% or more of the active site conserved. Some of the drugs had activity and are interesting to validate this study such as: artemether, lumefantrine, meloxicam. Among the drugs found 18 drugs were selected to be tested in prospective experimental assays according to the following criteria: low toxicity in vivo, off-patent status, and logP <5.0.

Efficacy of Ozoroa pulcherrima Schweinf methanolic extract against Schistosoma mansoni-induced liver injury in mice

The roots of Ozoroa pulcherrima Schweinf are used in traditional medicine to treat intestinal helminthiasis. The aim of this study was to assess the effect of Ozoroa pulcherrima roots methanolic extract (OPME) on liver injury induced by Schistosoma mansoni in mice. A preliminary phytochemical study of OPME was conducted. OPME was given daily and orally to S. mansoni-infected mice at 100, 200 or 400 mg/kg for 28 days, starting from the 36th day post-infection. Praziquantel was used as reference drug. Non-infected and infected-untreated mice served as controls. Worm burden and egg output, transaminases, total bilirubin, alkaline phosphatase and total protein; as well as malondialdehyde, catalase and reduced glutathione were evaluated. In OPME, total phenolic was 79.61 ± 0.25 mg gallic acid equivalent/g, while total flavonoid was 7.98 ± 0.04 mg rutin equivalent/g. Treatment of S. mansoni-infected mice with OPME produced significant reduction of worm burden and ova count in the faeces, liver and intestine. Significant reduction of alanine aminotransferase activity (p < 0.001) as well as significant increase of total protein content (p < 0.001) was recorded after OPME treatment at all doses. Total bilirubin level was also reduced (p < 0.01). Administration of OPME at all doses corrected the high malondialdehyde level (p < 0.001) induced by the infection. At 200 mg/kg, catalase activity and reduced glutathione concentration were significantly increased (p < 0.001). OPME at 200 mg/kg showed moderate schistosomicidal effect, but was effective as the standard drug praziquantel in restoring the liver function after S. mansoni infection.

Schistosomiasis.

Schistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms (blood flukes) of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia and, particularly, in sub-Saharan Africa. Infective larvae grow in an intermediate host (fresh-water snails) before penetrating the skin of the definitive human host. Mature adult worms reside in the mesenteric (Schistosoma mansoni and Schistosoma japonicum) or pelvic (Schistosoma haematobium) veins, where female worms lay eggs, which are secreted in stool or urine. Eggs trapped in the surrounding tissues and organs, such as the liver and bladder, cause inflammatory immune responses (including granulomas) that result in intestinal, hepato-splenic or urogenital disease. Diagnosis requires the detection of eggs in excreta or worm antigens in the serum, and sensitive, rapid, point-of-care tests for populations living in endemic areas are needed. The anti-schistosomal drug praziquantel is safe and efficacious against adult worms of all the six Schistosoma spp. infecting humans; however, it does not prevent reinfection and the emergence of drug resistance is a concern. Schistosomiasis elimination will require a multifaceted approach, including: treatment; snail control; information, education and communication; improved water, sanitation and hygiene; accurate diagnostics; and surveillance-response systems that are readily tailored to social-ecological settings.

Sensitivity and specificity of point-of-care circulating Cathodic antigen test before and after praziquantel treatment in diagnosing Schistosoma mansoni infection in adult population co-infected with human immunodeficiency virus-1, North-Western Tanzania

BackgroundThe effect of Human Immunodeficiency Virus-1 (HIV-1) on CD4+ Th2 cells is hypothesized to affect parasitological diagnosis of Schistosoma mansoni using Kato Katz technique. Thus, the use of more sensitive technique such as Point-of-Care Circulating Cathodic Antigen (POC-CCA) test is recommended. However, the sensitivity of this diagnostic test in diagnosing S.mansoni infection and the usefulness of it in monitoring efficacy of praziquantel drug in presence of HIV-1 co-infection remains inconclusive. The Primary objective of the present study was to assess accuracy of the POC-CCA test in diagnosing S.mansoni infection before and after praziquantel treatment in adult population co-infected with HIV -1.MethodsA prospective longitudinal study was conducted among individuals aged 15–55 years at Igalagala village, north-western Tanzania. At baseline and 4 weeks after treatment, a single stool and urine samples were collected from each participants. Kato Katz (KK) technique and Point-of-Care Circulating Cathodic Antigen tests were used for diagnosis of Schistosoma mansoni.ResultsAt baseline, based on KK and POC-CCA, the prevalence of S.mansoni was 57.8% (95%CI: 52.9–62.4) and 87.5% (95%CI: 83.9–90.4). Based on KK technique and POC-CCA test, 3.6% and 5.7% of the study participants were co-infected with S.mansoni and HIV-1. At baseline, in the general population, the sensitivities of POC-CCA test using KK technique and combine gold standard were 96.3%(95%CI: 93.1–98.3) and 97.6%(95%CI:95.5–98.9) respectively. In the HIV-1 seropositive group, at baseline, the sensitivities of POC-CCA test using KK technique and combined gold standards, were 93.3%(95%CI:68.1–99.8) and 96%(95CI%:79.6–99.9). Four weeks after treatment, in general population, the sensitivities of POC-CCA test using KK technique and combined gold standards were 47.8%(95%CI:26.8–69.4) and 84.4%(95%CI:74.4–91.7). In the HIV-1 seropositive group, using KK technique, the sensitivity was 100% (95%CI:2.5–100).ConclusionThe sensitivity of POC-CCA in diagnosing S.mansoni infection was higher than KK technique in adult individuals likely to have low infection intensity and co-infected with HIV-1. However, its sensitivity decreases following praziquantel treatment but remained higher than Kato Katz technique. If the goal of the post-treatment is to identify uncured individuals, then POC-CCA test offers the best choice.

English

Schistosomiasis, a neglected and most prevalenttropical diseases after malaria, have been a threat to people living in endemic areas. With regards to possible resistance to the popular drug (praziquantel) use for treatment of schistosomiasis, the need for a permanent vaccinating approach has been justified. This study uses an in silico approach to identify potential target vaccine candidate or T cell epitopes (T cell response activating epitope) for the treatment of schistosomiasis. This research therefore identified some candidate T cell epitopes from Sm23 protein of Schistosma mansoni using immunoinformatics tools. Nonameric epitopes like 85YMYAFFLVV93, 83MLYMYAFFL91, 8MRCLKSCVF16, 41SQYGDNLHK49 and 104VAVVYKDRI112 was found to exhibit strong binding affinity with some human leukocyte antigen (HLA). The predicted epitope was found to have no similarity with human proteome, a good attribute that is conferred on any good vaccine candidate. The predicted epitopes provide promising drug candidates and could be tested by wet laboratory as targeted vaccine against S. mansoni infection. Key words: Schistosomiasis, T-cell epitopes, human leukocyte antigen (HLA), vaccines.

The effectiveness of water treatment processes against schistosome cercariae: A systematic review.

BackgroundSchistosomiasis is one of the most disabling neglected tropical diseases, ranking second in terms of years lived with disability. While treatment with the drug praziquantel can have immediate beneficial effects, reinfection can occur rapidly if people are in contact with cercaria-infested water. Water treatment for schistosomiasis control seeks to eliminate viable cercariae from water, thereby providing safe alternative water supplies for recreational and domestic activities including laundry and bathing. This provision may reduce contact with infested water, which is crucial for reducing reinfection following chemotherapy and cutting schistosome transmission.MethodologyA qualitative systematic review was carried out to summarize the existing knowledge on the effectiveness of water treatment in removing or inactivating human schistosome cercariae. Four online databases were searched. Studies were screened and categorized into five water treatment processes: storage, heating, chlorination, filtration, and ultraviolet (UV) disinfection.ConclusionsAll five water treatment methods can remove or inactivate cercariae in water, and hence produce cercaria-free water. However, reliable design guidelines for treating water do not exist as there are insufficient data. Overall, the review found that cercariae are inactivated when storing water for 10–72 hours (depending on temperature), or with chlorination values of 3–30 mg-min/l. UV fluences between 3–60 mJ/cm2 may significantly damage or kill cercariae, and sand filters with 0.18–0.35 mm grain size have been shown to remove cercariae. This systematic review identified 67 studies about water treatment and schistosomiasis published in the past 106 years. It highlights the many factors that influence the results of water treatment experiments, which include different water quality conditions and methods for measuring key parameters. Variation in these factors limit comparability, and therefore currently available information is insufficient for providing complete water treatment design recommendations.

Insights into the mode of action of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89) against adult Schistosoma mansoni worms

Control of morbidity associated with schistosomiasis via chemotherapy largely relies on the drug praziquantel. Repeated therapy with praziquantel has created concerns about the possible selection of resistant worms and necessitated the search for novel drugs to treat schistosomiasis. Here, a murine model was infected with Schistosoma mansoni and treated with oral 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89), which caused a significant reduction in fecundity and egg burden and reduced morbidity when administered at 5-weeks post-infection.The analysis showed that the mode of action occurred through the ingestion of activated N-89 by the worms, and that there was no direct external effect on the S. mansoni worms. Ultrastructural analysis of the treated worms showed disruptions in the gut lumen and the presence of large volumes of material, suggestive of undigested blood meals or red blood cells. In addition, there were reduced vitelline cells in female worms and damage to sub-tegmental musculature in male worms. Eggs recovered from the treated mice showed both damage to the eggs and the production of immature eggs. Expression of mRNA responsible for gut and digestive function and egg production was also significantly affected by N-89 treatment, whereas control genes for musculature showed no significant changes.Thus, N-89 drastically affected the total digestive function and egg production of S. mansoni worms. Physiological processes requiring heme uptake such as egg production and eggshell formation were subsequently affected, suggesting that the compound could be a possible therapeutic drug candidate for schistosomiasis control.

Cosmetic and pharmaceutical qualifications of Egyptian bentonite and its suitability as drug carrier for Praziquantel drug

The aim of this paper is to characterize and evaluate newly discovered bentonite deposits in Egypt for pharmaceutical and cosmetic applications as well as its suitability as carrier for Praziquantel drug. The study was performed for the raw bentonite sample, purified bentonite sample and alkali activated purified bentonite sample. The raw bentonite sample composed mainly of montmorillonite contaminated by little amounts of quartz and calcite, while the purified sample composed of montmorillonite without detected mineral impurities and matches the mineralogical properties of Wyoming bentonite as an international standard. Geochemically, the studied raw and purified samples appear to high purity with a chemical composition close to those of Wyoming bentonite and match the pharmacopeia specifications. The chemical properties in addition to the textural properties of the surface area, porosity, particle size distribution qualify the bentonite products to use as a function in powder, emulsion and creams. Investigation of pharmacopeia properties of pH, sedimentation volume and swelling capacity revealed the suitability of the raw and purified samples for pharmaceutical and cosmetic applications. Moreover, the microbiological tests indicated that the samples free from harmful microbial pathogens. At the optimum conditions of time (240 min), bentonite dose (250 mg) and reaction temperature (60 °C), the obtained encapsulation percentages of Praziquantel drug are 62%, 78.4% and 93.2% for raw bentonite, purified and alkali activated bentonite, respectively. The releasing percentage of the drug using an intestinal buffer at pH 7.4 is more efficient and the maximum obtained values were obtained after 420 min. The obtained releasing values are 71%, 79.2% and 87.4% for raw bentonite, purified bentonite and alkali activated bentonite, respectively

Praziquantel Interaction with Mammalian Targets in the Spotlight

Chan et al. recently demonstrated that the antischistosomal drug praziquantel has a potent and specific interaction with human 5-HT2B receptors, and that the drug also elicits contraction of mouse mesenteric vasculature apparently mediated by the same receptor subtype We consider what this might mean about the drug's molecular therapeutic targets in both the worm and the host.

Effect of (-)-epicatechin, a flavonoid on the NO and NOS activity of Raillietina echinobothrida

(-)-Epicatechin, a natural flavonoid reportedly has huge pharmacological properties. In this study the cestocide effect of (-)-epicatechin is demonstrated in Raillietina echinobothrida. Although the antiparasitic activity of (-)-epicatechin has been demonstrated against protozoa, helminths and ectoparasites, in the present study the cestocide activity of (-)-epicatechin is shown to be related to a decrease in nitric oxide synthase (NOS) activity and nitric oxide (NO) production. On exposure to 0.53mg/ml each of epicatechin, reference drug praziquantel and Ѡ Nitro-l- Arginine Methyl Ester (NOS inhibitor), the parasites attained paralysis at 10.15, 0.27 and 11.21h followed by death at 30.15, 1.21 and 35.18h respectively. Biochemical analysis showed a significant decrease in activity of NOS (57.360, 36.040 and 44.615%) and NO (41.579, 19.078 and 24.826%) in comparison to the controls. NADPH-diaphorase histochemical staining (a selective marker for NOS in neuronal tissue) demonstrated a pronounced decline in the visible staining activity in the tegument, subtegument and the peripheral nerve regions following exposure to the treatments. Strong binding affinity of (-)-epicatechin with NOS protein was also revealed through docking studies. The results strongly define the probable anthelmintic activity of our compound through its influence on the NOS activity.

The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer — (R)-PZQ — which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.

TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis.

BackgroundNeurocysticercosis (NCC) is an infection of the brain with the larval cyst of the tapeworm, Taenia solium. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN), an anti-tumor necrosis factor agent, or dexamethasone (DEX), a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ).Methodology/Principal findingsWe followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9), pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6), and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6). The fourth group remained untreated (n = 3). As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB) (a measure of blood brain barrier dysfunction) compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA)4, interleukin (IL)-13 and transforming growth factor (TGF)-β; the tissue remodeling genes matrix metalloprotease (MMP)1 and 9, tissue inhibitors of metalloproteases (TIMP)1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF)1, angiopoietin (Ang)1, Ang 2, and platelet endothelial cell adhesion molecule (PECAM)-1. In contrast, transcription was only modestly decreased in the DEX pretreated pigs compared to PZQ alone, and only for TNF-α, IL-6, IFN-γ, TGF-β and Ang1. IL-10 was not affected by either ETN or DEX pretreatments. The degree of inflammation, assessed by semi-quantitative inflammatory scores, was modestly decreased in both ETN and DEX pretreated animals compared to PZQ treated pigs whereas cyst damage scores were moderately decreased only in cysts from DEX pretreated pigs. However, the proportion of cysts with EB extravasation was not significantly changed in ETN and DEX pretreated groups.Conclusions/SignificanceOverall, TNF-α blockade using ETN treatment modulated expression of a large variety of genes that play a role in induction and control of inflammation and structural changes. In contrast the number of inflammatory cells was only moderately decreased suggesting weaker effects on cell migration into the inflammatory capsules surrounding cysts than on release of modulatory molecules. Taken together, these data suggest that TNF-α blockade may provide a viable strategy to manage post-treatment pericystic inflammation that follows antiparasitic therapy for neurocysticercosis.

The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel

Praziquantel is the most effective anthelminthic drug for the treatment of schistosomiasis, an infectious disease caused by the platyhelminth Schistosoma mansoni. While praziquantel is known to trigger calcium influx into schisostomes, followed by spastic paralysis of the worms and tegumental disruption, the mechanism of action of the drug is not completely understood. Although relatively well tolerated, praziquantel has been reported to cause mild adverse effects, including nausea, abdominal pain and headaches. As a number of putative Transient Receptor Potential (TRP) channel genes have recently been predicted in S. mansoni, we sought to investigate the effect of praziquantel on three mammalian TRP channels, TRP melastatin type 8 (TRPM8), TRP vanilloid type 1 (TRPV1) and TRP ankyrin type 1 (TRPA1). Using calcium microfluorimetry and the patch clamp technique, we recorded the effect of praziquantel on HEK293T cells expressing recombinant TRPM8, TRPV1 or TRPA1, as well as on cultured dorsal root ganglion (DRG) neurons from wild type and TRPM8 null mutant mice. We discovered that praziquantel is a relatively potent and selective partial agonist of the mammalian and avian cold and menthol receptor TRPM8. The activation of cultured DRG neurons by clinically relevant concentrations of praziquantel is predominantly mediated by TRPM8. Our results may provide clues to a better understanding of praziquantel's mechanism of action and its adverse effects.

Urogenital Schistosomiasis—Evidence-Based Benefits of Treatment Initiated Early During Childhood

Urogenital schistosomiasis, caused by the helminth parasite Schistosoma haematobium, is one of the most important childhood public health problems in Africa, compromising child growth and development and usually causing irreversible damage in life leading to increased susceptibility to HIV coinfection in adulthood. Naturally acquired immunity develops slowly, and with no vaccine available, infection and morbidity are controlled by treatment with the antihelminthic drug praziquantel. Treatment is believed to accelerate development of protective immunity. In our recent research, we demonstrated that morbidity occurs in young children and that the markers of morbidity can be used for diagnosis, while development of pathology is reduced by a single antihelminthic treatment. Many gaps exist in the control efforts of schistosomiasis that could be initiated during early years of growth to avoid childhood schistosomiasis with immense benefits in adulthood susceptibility or increased HIV transmission. Treating urogenital schistosomiasis infection during earlier childhood age is a relatively cheap strategy to benefit child health and provide opportunity to develop protective immune responses. Studies on the association of urogenital schistosomiasis with HIV transmission indicate that prevention and protective immunity could be achieved by administering treatment earlier during childhood.

A palladium-catalyzed intramolecular Heck/Hydrogenation approach towards the synthesis of praziquantel

Starting from 3-methoxy N-acylpyrazinium salts, a new approach towards the synthesis of the antischistosomal drug praziquantel (PZQ) has been developed. Utilization of a palladium-catalyzed intramolecular Heck reaction to form dehydro-PZQ followed by a Hydrogenation step, in a stepwise or one-pot manner, allowed for the gram scale synthesis of PZQ in 4 or 5 steps and in good overall yields. This methodology proved to be well suited for generating the pyrazino[1,2-a] isoindole and pyrazino[1,2-a] benzazepine analogues of PZQ.

Assessment of efficacy and safety of praziquantel in the treatment of &lt;i&gt;Schistosoma haematobium&lt;/i&gt; in school-aged children, Ogun State, Nigeria

Praziquantel (PZQ) remains the drug of choice for treatment of schistosomiasis in infected persons. This study assessed the efficacy and safety of PZQ in school-aged children in four communities’ endemic for schistosomiasis. Urine samples (10 ml) were collected from 300 primary school children aged 5-16 years in Ibaro Oyan, Imala Odo, Apojola and Abule Titun communities located in parts of Ogun State, Nigeria. The urine was examined for the presence of haematuria and ova of S. haematobium . All pupils were also treated with a single dose of PZQ at 40 mg/kg. Urine samples were collected from positive pupils 21 days later to determine the Cure Rate (CR) and Egg Reduction Rate (ERR). Survey forms were also used to collect information on safety of the drug, documenting observed adverse reaction. Results showed that prevalence by haematuria was 147 (69%). Assessing haematuria with ova of S. haematobium revealed that 132 (44%) were positive for haematuria using dip-stick and eggs of S. haematobium simultaneously. Two hundred and nine pupils (69.7%) were infected with S. haematobium with mean egg count of 16.23 eggs/10 ml of urine. Males (73%) were more infected than females (66.7%). The highest prevalence (72.8%) was observed among the age-group 9-12 years and the least prevalence among age-group 5-8 years. The presence of S. haematobium was neither age nor sex dependent ( p >0.05). On location and intensity, school children located in Imala Odo Community had the highest prevalence of 89.2%, but pupils in Ibaro had the highest Geometric Mean (GM) of 18.31 eggs/10 ml. At 21 days post-treatment the cure-rate (CR) was 96.1%. The anthelminthic drug Praziquantel efficacy was satisfactory with an Egg Reduction Rate (ERR) of 98.5%. Most of the adverse effects occurred within 4-24 hours after PZQ administration but abdominal pains were the most common adverse visible micro effects complained by the school-children. Keywords: Efficacy, praziquantel; Schistosoma haematobium ; school-aged children; Ogun State; Nigeria

Anti-Inflammatory Effect of Hostacortin (Steroidal) or Vioxx (Non-Steroidal) on Mice Infected with Schistosoma Mansoni and Treated with Praziquantel

Background: Schistosoma mansoni, a helminthic parasite induces granulomatous inflammation following deposition of the eggs in the liver. The present study was conducted to evaluate the efficacy of two anti-inflammatory drugs; Hostacortin (steroidal) and Vioxx (non-steroidal) in ameliorating the damaging effects of S. mansoni infection in mice. The effects of the two anti-inflammatory drugs after treatment of schistosomiasis mansoni with praziquantel (PZQ) in mice were assessed for management of S. mansoni infection. Materials and Methods: The PZQ drug was administered to 6-weeks S. mansoni infected mice at one oral dose of 685 mg/kg body weight. The anti-inflammatory activity of the two drugs was evaluated at dose levels of 10, 50,100 and 200 mg/kg body weight in mice infected with 80 S.mansoni cercariae / mouse and treated for 10 consecutive days after 6-weeks of infection. Some biochemical parameters indicating the hepatic function as enzymatic activity of transaminases; alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and alkaline phosphatase (ALP) in liver as well as serum albumin and liver total protein were performed to evaluate the possible anti-inflammatory effect of any of the two used anti-inflammatory drugs in ameliorating the severity of the disease. In addition, some parasitological parameters as worm burden, liver egg count, hepatic granuloma size and hepato-somatic index were performed to evaluate the possible anti-inflammatory effect of any of the two used anti-inflammatory drugs in ameliorating the severity of the disease. Results: The results indicated that Hostacortin had no marked effect on the parasite burden and liver egg count. However, it caused a percentage decrease by 14.9 in the elevated ALP activity and pronounced increases by 33.2% and 11.3% in ALAT and ASAT activities, respectively, in liver tissue homogenate. Also, a significant reduction in granuloma size by 22.5% and 31.6% for doses 100 and 200 mg/kg, respectively, was recorded. Hostacortin treatment with PZQ improved the liver status as indicated by a significant reduction in number of worms, eggs count and size of the liver granuloma. However, Vioxx did not affect the parasite burden and liver egg count, it caused high reduction in the enzymatic activities of ALAT, ASAT, and ALP in liver tissue homogenate. In contrast with Hostacortin, Vioxx significantly increased the granuloma size by 27.6% at a dose level of 200 mg/kg. Conclusion: the treatment with Hostacortin, after PZQ treatment, ameliorates to some extent the severity of the disease, but Vioxx treatment causes additional hepatotoxicity in the S. mansoni infected mice after treatment with PZQ.

Synthesis and anthelmintic activity of arctigenin derivatives against Dactylogyrus intermedius in goldfish

To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10mg/L. Compared to traditional drug praziquantel (EC50=2.69mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC50 values of 2.48 and 1.52mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC50 values of 2.13 and 2.07mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs.

Elimination of Schistosoma mansoni in infected mice by slow release of artemisone

The current treatment of schistosomiasis is based on the anti-helminthic drug praziquantel (PZQ). PZQ affects only the adult stages of schistosomes. In addition, resistance to PZQ is emerging. We suggest a drug, which could serve as a potential alternative or complement to PZQ, and as a means of treating infections at earlier, pre-granuloma stage. Derivatives of the peroxidic antimalarial drug artemisinin have been indicated as alternatives, because both plasmodia and schistosomes are blood-feeding parasites. The mechanism of action of artemisinins is related to oxidative effects of the artemisinins on intracellular reductants leading to formation of cytotoxic reactive oxygen species. We used artemisone, which has improved pharmacokinetics and anti-plasmodial activity, and reduced toxicity compared to other artemisinins in clinical use against malaria. We infected adult mice by subcutaneous injection of S. mansoni cercariae (about 200) and treated them at various times post infection by the following methods: i. artemisone suspension administered by gavage (400–450 mg/kg); ii. subcutaneous injection of a gel containing a known concentration of artemisone (115–120 mg/kg); iii. subcutaneous insertion of the drug incorporated in a solid polymer (56–60 mg/kg); iv. intraperitoneal injection of the drug solubilized in DMSO (115–120 mg/kg). Drug administration in polymers was performed to enable slow release of the artemisone that was verified in vivo and in vitro bioassays using drug-sensitive malaria parasites. We found superior strong anti-schistosome effects up to a total reduction of worm number, mainly following repetitive treatments with the drug absorbed in the polymers (73.1% and 95.9% reduction in mice treated with artemisone in gel 7 and 14, and 21, 28 and 35 days post infection, respectively). The results indicate that artemisone has a potent anti-schistosome activity. Its main importance in this context is its effectiveness in treating hosts harboring juvenile schistosomes, before egg-deposition and induction of deleterious immune responses.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance.

Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.