Synthesis and biological evaluation of novel imidazolidine derivatives as candidates to schistosomicidal agents

ABSTRACT Introduction: Schistosomiasis is an infectious parasitic disease caused by trematodes of the genus Schistosoma, which threatens at least 258 million people worldwide and its control is dependent on a single drug, praziquantel. The aim of this study was to evaluate the anti-Schistosoma mansoni activity in vitro of novel imidazolidine derivatives. Material and methods: We synthesized two novel imidazolidine derivatives: (LPSF/PTS10) (Z)-1-(2-chloro-6-fluorobenzyl)-4-(4-dimethylaminobenzylidene)-5-thioxoimidazolidin-2-one and (LPSF/PTS23) (Z)-1-(2-chloro-6-fluoro-benzyl)-5-thioxo-4-(2,4,6-trimethoxy-benzylidene)-imidazolidin-2-one. The structures of two compounds were determined by spectroscopic methods. During the biological assays, parameters such as motility, oviposition, mortality and analysis by Scanning Electron Microscopy were performed. Results: LPSF/PTS10 and LPSF/PTS23 were considered to be active in the separation of coupled pairs, mortality and to decrease the motor activity. In addition, LPSF/PTS23 induced ultrastructural alterations in worms, after 24 h of contact, causing extensive erosion over the entire body of the worms. Conclusion: The imidazolidine derivatives containing the trimetoxy and benzylidene halogens showed promising in vitro schistosomicidal activity.

In vitro antischistosomal activity of venom from the Egyptian snake Cerastes cerastes

Abstract INTRODUCTION: We studied the potential in vitro antischistosomal activity of Cerastes cerastes venom on adult Schistosoma mansoni worms. METHODS: Live specimens of the horned viper snake, C. cerastes were collected from the Aswan Governorate (Egypt). Venom was collected from snakes by manual milking. Worms of S. mansoni were obtained from infected hamsters by perfusion and isolated from blood using phosphate buffer. Mortality rates of worms were monitored after 3 days of exposure to snake venom at LC50 and various sublethal concentrations (10, 5, 2.5µg/ml). Scanning electron microscopy was used to investigate tegumental changes in treated worms after exposure to LC50 doses of venom. RESULTS: The LC50 of C. cerastes venom was 21.5µg/ml. The effect of C. cerastes venom on Schistosoma worms varied according to their sex. The mortality rate of male and female worms after 48-h exposure was 83.3% and 50%, respectively. LC50 of C. cerastes venom induced mild to severe tegumental damage in Schistosoma worms in the form of destruction of the oral sucker, shrinkage and erosion of the tegument, and loss of some tubercle spines. CONCLUSIONS: The present study demonstrated that C. cerastes venom exerts potential in vitro antischistosomal activity in a time and dose-dependent manner. These results may warrant further investigations to develop novel schistosomicidal agents from C. cerastes snake venom.

THE SUSCEPTIBILITY OF RECENT ISOLATES OF Schistosoma mansoni TO PRAZIQUANTEL

Introduction: Schistosomiasis is a chronic disease caused by trematode flatworms of the genus Schistosoma and its control is dependent on a single drug, praziquantel (PZQ), but concerns over PZQ resistance have renewed interest in evaluating the in vitro susceptibility of recent isolates of Schistosoma mansoni to PZQ in comparison with well-established strains in the laboratory. Material and methods: The in vitro activity of PZQ (6.5-0.003 µg/mL) was evaluated in terms of mortality, reduced motor activity and ultrastructural alterations against S. mansoni. Results: After 3 h of incubation, PZQ, at 6.5 µg/mL, caused 100% mortality of all adult worms in the three types of recent isolates, while PZQ was inactive at concentrations of 0.08-0.003 µg/mL after 3 h of incubation. The results show that the SLM and Sotave isolates basically presented the same pattern of susceptibility, differing only in the concentration of 6.5 µg/mL, where deaths occurred from the range of 1.5 h in Sotave and just in the 3 h range of SLM. Additionally, this article presents ultrastructural evidence of rapid severe PZQ-induced surface membrane damage in S. mansoni after treatment with the drug, such as disintegration, sloughing, and erosion of the surface. Conclusion: According to these results, PZQ is very effective to induce tegument destruction of recent isolates of S. mansoni.

ULTRASTRUCTURAL CHANGES IN Schistosoma mansoni MALE WORMS AFTER in vitro INCUBATION WITH THE ESSENTIAL OIL OF Mentha x villosa Huds

Introduction: The essential oil Mentha x villosa (MVEO) has a wide range of actions, including antibacterial, antifungal, antiprotozoal and schistosomicidal actions. The present study aimed to investigate the ultrastructural changes of MVEO on the tegument of adult Schistosoma mansoni. Materials and Methods: Different concentrations of MVEO were tested on S. mansoni adult worms in vitro. Ultrastructural changes on the tegument of these adult worms were evaluated using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results: The MVEO caused the death of all worms at 500 μg mL-1 after 24 h. After 24h of 500 μg mL-1 MVEO treatment, bubble lesions were observed over the entire body of worms and they presented loss of tubercles in some regions of the ventral portion. In the evaluation by TEM, S. mansoni adult worms treated with MVEO, 500 μg mL-1, presented changes in the tegument and vacuoles in the syncytial matrix region. Glycogen granules close to the muscle fibers were visible. Conclusion: The ability of MVEO to cause extensive ultrastructural damage to S. mansoni adult worms correlates with its schistosomicidal effects and confirms earlier findings with S. mansoni.

Imatinib activity on Schistosoma mansoni

Imatinib, a drug used for treatment of human chronic myeloid leukaemia, due to its activity against protein kinases, has been also evaluated in vitro against Schistosoma mansoni showing high schistosomicidal activity. In the present experiments imatinib activity in vitro was confirmed at the doses of 25 µM, 50 µM and 100 µM. The first drug activity observed with the lower dose was interruption of egg-laying and with the higher dosages was the death of the worms. In mice infected with S. mansoni no activity was found even with 1,000 mg/kg/day, 500 mg/kg/day, single oral dose or when administered for three consecutive days. This is another example of the difference of results related to in vitro and in vivo trials using S. mansoni worms.

Antischistosomal activity of a calcium channel antagonist on schistosomula and adult Schistosoma mansoni worms

Current schistosomiasis control strategies are largely based on chemotherapeutic agents and a limited number of drugs are available today. Praziquantel (PZQ) is the only drug currently used in schistosomiasis control programs. Unfortunately, this drug shows poor efficacy in patients during the earliest infection phases. The effects of PZQ appear to operate on the voltage-operated Ca2+channels, which are located on the external Schistosoma mansoni membrane. Because some Ca2+channels have dihydropyridine drug class (a class that includes nifedipine) sensitivity, an in vitro analysis using a calcium channel antagonist (clinically used for cardiovascular hypertension) was performed to determine the antischistosomal effects of nifedipine on schistosomula and adult worm cultures. Nifedipine demonstrated antischistosomal activity against schistosomula and significantly reduced viability at all of the concentrations used alone or in combination with PZQ. In contrast, PZQ did not show significant efficacy when used alone. Adult worms were also affected by nifedipine after a 24 h incubation and exhibited impaired motility, several lesions on the tegument and intense contractility. These data support the idea of Ca2+channels subunits as drug targets and favour alternative therapeutic schemes when drug resistance has been reported. In this paper, strong arguments encouraging drug research are presented, with a focus on exploring schistosomal Ca2+channels.

In vitro effects of amodiaquine on paired Schistosoma mansoni adult worms at concentrations of less than 5 µg/mL

In this study, the in vitro effects of amodiaquine (AQ) monotherapy on the egg output of paired adult Schistosoma mansoni worms and their survival during in vitro culture were assessed. In addition, the gross morphological alterations of male and female worms caused by AQ were visually observed under a dissecting microscope. AQ significantly reduced the daily egg output of paired adult S. mansoni worms following incubation for 14 days at 1-5 µg/mL, but not at 0.5 µg/mL, compared with the control group. AQ also reduced the survival of male and female worms at concentrations of 2 and 5 µg/mL, respectively. Moreover, exposure to 5 µg/mL AQ caused severe swelling and/or localisation of black content in the body of all male and female worms within one or two days of incubation; subsequently, shrinkage in the male worms and elongation in the female worms were observed. The initial morphological alterations caused by AQ occurred along the intestinal tract of the male and female worms. To our knowledge, this is the first study to report not only the efficacy of AQ at concentrations lower than 5 µg/mL on paired adult S. mansoni worms, but also the effects of AQ on the intestinal tracts of worms in in vitro culture.

Association of oxamniquine praziquantel and clonazepam in experimental Schistosomiasis mansoni

The antischistosomal activity of clonazepam, when administered alone or in association with oxamniquine and praziquantel, was experimentally evaluated in mice infected with Schistosoma mansoni. The animals were treated 45 days post-infection with a single dose, by oral route, according to three treatment schedules: clonazepam 25 mg/kg and sacrificed 15 min, 1h or 4 h after treatment; clonazepam 1.0, 2.5 or 10.0 mg/kg and sacrificed 15 days post-treatment or with the dose of 10 mg/kg in association with oxamniquine 50 mg/kg or praziquantel 200 mg/kg, single dose, orally, every schedule with a control group. The efficacy of the drugs in vivo was assessed by means of worm counts and their distribution in mesentery and liver, mortality and oogram changes. In the chemotherapeutic schedules used, clonazepam did not present antischistosomal activity and the result of the association of this drug with oxamniquine or praziquantel was not significantly different from the one obtained when these two last drugs were administered alone. In the in vitro experiments, the worms exposed to 0.6 mg/mL clonazepam remained motionless throughout the 8-day-period of observation, without egg-laying, whereas the worms of the control group showed normal movements, egg-laying and hatching of miracidia on the last day of observation. The results obtained in the present study confirm the action of clonazepam on S. mansoni adult worm, in vitro, causing total paralysis of males and females. However, no additive or synergistic effects were observed when clonazepam were used in association with oxamniquine or praziquantel.

The effect of antioxidant properties of aqueous garlic extract and Nigella sativa as anti-schistosomiasis agents in mice / O efeito das propriedades antioxidantes do extrato aquoso do alho e da Nigella sativa como agentes anti-esquistossômicos no camundongo

The aim of this study was to assess the antioxidant and anti-schistosomal activities of the garlic extract (AGE) and Nigella sativa oil (NSO) on normal and Schistosoma mansoni-infected mice. AGE (125 mg kg-1, i.p.) and NSO (0.2 mg kg-1, i.p.) were administrated separately or in combination for successive 28 days, starting from the 1st day post infection (pi). All mice were sacrificed at weeks 7 pi. Hematological and biochemical parameters including liver and kidney functions were measured to assess the progress of anemia, and the possibility of the tissue damage. Serum total protein level, albumin, globulin and cholesterol were also determined. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the liver tissues as biomarkers for oxidative and reducing status, respectively. The possible effect of the treatment regimens on Schistosoma worms was evaluated by recording percentage of the recovered worms, tissue egg and oogram pattern. Result showed that, protection with AGE and NSO prevented most of the hematological and biochemical changes and markedly improved the antioxidant capacity of schistosomiasis mice compared to the infected-untreated ones. In addition, remarkable reduction in worms, tissue eggs and alteration in oogram pattern were recorded in all the treated groups. The antioxidant and antischistosomal action of AGE and NSO was greatly diverse according to treatment regimens. These data point to these compounds as promising agents to complement schistosomiasis specific treatment.

O propósito deste estudo foi verificar os efeitos anti-oxidantes e anti-esquistossômicos do extrato de alho (AGE) e do óleo da Nigella sativa (NSO) em camundongos normais e infectados com S. mansoni. AGE (125 mg/kg, i.p. ) e NSO (0,2 mg/kg, i.p.) foram administrados separadamente ou em combinação por 28 dias sucessivos começando do primeiro dia pós infecção (p.i.). Todos os camundongos foram sacrificados sete semanas p.i. Parâmetros hematológicos e bioquímicos incluindo funções renais e hepáticas foram medidos para avaliar o progresso da anemia e a possibilidade de dano tecidual. O nível total de proteínas séricas, albumina, globulina e colesterol foram também medidos. Níveis de malondialdeído (MDA) e glutationa (GSH) foram determinados em tecido hepático como biomarcações para o estado oxidativo e redutor, respectivamente. O possível efeito dos tratamentos sobre os vermes de Schistosoma foram avaliados através do percentual de vermes recuperados, ovos no tecido e o oograma. Resultados mostraram que a proteção com AGE e NSO preveniu a maior parte das alterações hematológicas e bioquímicas e melhoraram bastante a capacidade anti-oxidante de camundongos com esquistossomose comparados com aqueles infectados e não tratados. Adicionalmente, foi registrado uma acentuada redução nos vermes, ovos no tecido e alterações do oograma. A ação anti-oxidante e anti-esquistossômica do AGE e NSO foi diferente de acordo com os vários tratamentos. Estes dados mostram que estes compostos são agentes promissores para complementar o tratamento específico da esquistossomose.

Antischistosomal and liver protective effects of Curcuma longa extract in Schistosoma mansoni infected mice.

With a view to clarify the induction of the "Crabtree consequence" in liver cells of S. mansoni infected mice, the curative effect of oil extract of C. longa was tested and compared to praziquantel (PZQ) the effective drug against all schistosome species occurring in man. Protein, glucose, glucose-6-phopsphatase, AMP-deaminase, adensoine deaminase, urea concentration, pyravate kinase (PK), phosphoenol pyruvate carboxykinase (PEPCK) and PK/PEPCK ratio were estimated. In addition, worm burden and ova count in mice infected with S. mansoni were elucidated. The result showed that C. longa normalized the concentration of protein, glucose, AMP-deaminase and adenosine deaminase, which were changed by infection. Moreover, it lowered pyruvate kinase level, while PZQ-treatment induced more elevation of this enzyme. PZQ was more effective in lowering worm burden while C. longa extract was more potent in reducing egg count.

The schistosome enzyme that activates oxamniquine has the characteristics of a sulfotransferase

Available evidence suggests that the antischistosomal drug oxamniquine is converted to a reactive ester by a schistosome enzyme that is missing in drug-resistant parasites. This study presents data supporting the idea that the active ester is a sulfate and the activating enzyme is a sulfotransferase. Evidence comes from the fact that the parasite extract loses its activating capability upon dialysis, implying the requirement of some dialyzable cofactor. The addition of the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) restored activity of the dialyzate, a strong indication that a sulfotransferase is probably involved. Classical sulfotransferase substrates like beta-estradiol and quercetin competitively inhibited the activation of oxamniquine. Furthermore, these substrates could be sulfonated in vitro using an extract of sensitive (but not resistant) schistosomes. Gel filtration analysis showed that the activating factor eluted in a fraction corresponding to a molecular mass of about 32 kDa, which is the average size of typical sulfotransferase subunits. Ion exchange and affinity chromatography confirmed the sulfotransferase nature of the enzyme. Putative sulfotransferases present in schistosome databases are being examined for their possible role as oxamniquine activators.

New imidazolidinic bioisosters: potential candidates for antischistosomal drugs

The emergence of strains of Schistosoma resistant to praziquantel has drawn attention to the search for new schistosomacide drugs. Imidazolidinic derivatives have performed outstandingly against adult S. mansoni worms when evaluated in vitro. The molecular modification of imidazolidine by way of bioisosteric replacement gives rise to variations in its biological response. This study verifies the potential of substituent groups in the derivatives (Z)3-benzyl-5-(2-fluoro-benzylidene)-imidazolidine-2,4-dione NE4, 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin -2-ona PT5, 3-benzyl-5-(3-fluoro-benzylidene)-1-methyl-2-thioxo-imidazolidin-4-one JT53; 3-benzyl-1-methyl-5-(4-methyl-benzylidene)-2-thioxo-imidazolidin-4-one JT63; 3-benzyl-1-methyl-5-(4-methoxi-benzylidene)-2-thioxo -imidazolidin-4-one JT68; 3-(4-chloro-benzyl)-1-methyl-5-(4-methoxi-benzylidene)-2-thioxo-imidazolidin-4-one JT69; 3-(4-phenyl-benzyl)-1-methyl-5-(4-methoxi-benzylidene)-2-thioxo-imidazolidin-4-one JT72 by determining the viability in vitro of adult S. mansoni worms in the presence of these derivatives. The susceptibility of the worms obtained from mice and kept in culture in the presence of different concentrations was determined by way of schistosomacide kinetic, observed every 24 h over a period of eight days. The results show that the worms were more sensitive to the PT5 derivative at a concentration of 58 æM which killed 100 percent of the worms after 24 h of contact, also giving rise to alterations in the tegument surface of the worms with the formation of bubbles and peeling. These observations suggest a strong electronic contribution of the arylazo grouping in the biological response.

Does Cleome droserifolia have anti-schistosomiasis mansoni activity? / Cleome droserifolia tem atividade anti-esquistossomose mansônica?

The present study was undertaken to assess the effect of the crude extract of Cleome droserifolia (CD) leaves on experimentally infected mice with Schistosoma mansoni. Two groups of mice, showing a patent infection of S. mansoni, one of them was daily treated with an alcoholic extract of CD leaves (0.31 g kg-1 body weight, i.p.) for 21 days. The schistosomicidal activity of the CD extract was evaluated, three weeks post-treatment, on some parasitological and histopathological aspects including worm load, oogram pattern, faecal eggs releasing and granuloma formation. In addition, serum thyroid hormones levels (tri-iodothyronine; T3 and tetra-iodo-thyronin; T4), serum total protein contents and hepatic reduced glutathione (GSH) were evaluated. Treatment using CD extract resulted in a weak reduction in worm burden (32.46 percent) and affected the viability of both mature and immature eggs as indicated by the increase in the percentage of dead eggs and the decrease in the percentage of live ones. In addition, a week post-treatment, eggs elimination was observed in the stool of the infected-treated group which was low compared to the infected group. There was a suppressive effect of the extract on granuloma formation that could be due to the antioxidant effect of the extract. These data are confirmed by increasing hepatic GSH, serum total proteins and thyroid hormone levels in the infected-treated group as compared to the infected group. Treatment significantly enhanced b globulin fractions of the protein. Based on these assumptions, CD extract has beneficial effects on thyroid hormones status and anti-schistosomiasis activity. The beneficial effects of CD extract could be related to its direct effects on the parasite, and secondary to its effect on the antioxidant capacity of the host. The present study could emphasize the precise mechanism (s) of CD extract protection.

O presente estudo foi realizado para verificar o efeito do extrato cru de folhas de Cleome droserifolia (CD) em camundongos experimentalmente infectados com Schistosoma mansoni. Em dois grupos de camundongos mostrando infecção patente por S. mansoni, um deles foi tratado diariamente com extrato alcoólico de folhas de CD (0.31g kg-1 por peso corporal, i.p.) por 21 dias. A atividade esquistossomicida do extrato de CD foi avaliada, três semanas após o tratamento, em alguns aspectos parasitológicos e histopatológicos incluindo carga parasitária, padrão de oograma, eliminação fecal de ovos e formação de granuloma. Além disto, níveis séricos de hormônio tireoideano (tri-iodotironina: T3 e tetra-iodotironina: T4), conteúdo sérico total de proteínas e glutatione hepático reduzido (GSH) foram avaliados. Tratamento usando extrato de CD resultou em fraca redução da carga de vermes (32,46 por cento) e afetou a viabilidade de ovos maduros ou não, como indicado pelo aumento na porcentagem de ovos mortos e o descrécimo na porcentagem de ovos viáveis. Além disso, uma semana após o tratamento, a eliminação de ovos foi observada nas fezes do grupo infectado-tratado que foi baixa comparada ao grupo infectado. Houve efeito supressivo do extrato sobre a formação de granuloma que poderia ser devido ao efeito antioxidante do extrato. Estes dados são confirmados pelo aumento do GSH hepático, soro total de proteínas e níveis dos hormônios tireoideanos no grupo infecto-tratado quando comparado com o grupo infectado. O tratamento aumentou significativamente as frações beta-globulina da proteína. Baseado nestas afirmativas o extrato de CD tem efeitos benéficos sobre o nível dos hormônios tireoideanos e da atividade anti-esquistossomica. Os efeitos benéficos do extrato de CD poderiam estar relacionados com seu efeito direto sobre o parasita, e secundariamente por seus efeitos na capacidade anti-oxidante do hospedeiro. O presente trabalho poderia enfatizar o(s) mecanismo(s) preciso(s) desta proteção do extrato de CD.

Efficacy of Citrus reticulata and Mirazid in treatment of Schistosoma mansoni

This work has been carried out to investigate the effect of Schistosoma mansoni infection on mice livers after treatment with the ethanolic extract of Citrus reticulata root or the oleo-resin extract from Myrrh of Commiphora molmol tree (Mirazid), as a new antishistosomal drug. Marker enzymes for different cell organelles were measured; succinate dehydrogenase (SDH); lactate dehydrogenase (LDH) and its isoenzymes; glucose-6-phosphatase (G-6-Pase); acid phosphatase (AP) and 5'- nucleotidase. Liver function enzymes; aspartate aminotransferase (AST); alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were also estimated. Parasitological studies through ova count and worm burden will also be taken into consideration. The results showed a marked reduction in SDH, LDH, AST, and ALT enzyme activities and a significant increase in G-6-Pase, AP, 5'- nucleotidase, and ALP after S. mansoni infection. A noticeable alteration in LDH subunits were also noticed. Treatment with C. reticulata or Mirazid improved all the previous enzyme activities with a noticeable reduction in ova count and worm burden.

Sativa seeds against Schistosoma mansoni different stages

The schistosomicidal properties of Nigella sativaseeds were tested in vitro against Schistosoma mansoni miracidia, cercariae, and adult worms. Results indicate its strong biocidal effects against all stages of the parasite and also showed an inhibitory effect on egg-laying of adult female worms. In the present work we also studied the effects of crushed seeds on some antioxidant enzymes; which have a role in protection of adult worms against host oxidant killing; as well as some enzymes of glucose metabolism; which have a crucial role in the survival of adult worms inside their hosts. The data revealed that the used drug induce an oxidative stress against adult worms which indicated by a decrease in the activities of both antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and glutathione reductase and enzymes of glucose metabolism, hexokinase and glucose-6-phosphate dehydrogenase. Disturbing of such enzymes of adult worms using N. sativa seeds could in turn render the parasite vulnerable to damage by the host and may play a role in the antischistosomal potency of the used drug.

Genetic analysis of praziquantel resistance in Schistosoma mansoni.

To determine the genetic basis of the resistance of Schistosoma mansoni to praziquantel (PZQ) and to understand whether the resistance is dominant or recessive trait, a schistosome cross was undertaken between a PZQ-susceptible and a PZQ-resistant isolate using infections of the single-sex cercariae which were identified by a direct W1-specific PCR technique. The resistances of F1 and F2 generation to PZQ were evaluated using in vitro egg, miracidial and cercarial tests. The F1 hybrid progeny from crosses between the susceptible and resistant isolates were resistant to PZQ. The resistant phenotype reappeared in the F2 progeny. It can thus be considered that the PZQ resistance behaves like a dominant trait.

Artemether, an effective new agent for chemoprophylaxis against shistosomiasis in China: its in vivo effect on the biochemical metabolism of the Asian schistosome.

Conventional drug chemotherapy against human schistosomiasis currently relies on treatment with praziquantel to eliminate adult schistosome worm pairs. The use of praziquantel for control purposes is limited, however, by high rates of post-treatment re-infection with subsequent parasite egg deposition and host end-organ damage. Artemether, a methyl ether derivative of the anti-malarial drug quinghaosu, was discovered recently to also have anti-schistosomal properties. Because artemether selectively targets the larval migratory stages of the parasite, known as schistosomulae, it blocks the development of ovipositing adult schistosome worm pairs in the vasculature. On this basis, we have since shown in clinical trials conducted in China that artemether has proven benefit as an agent for chemoprophylaxis. In vivo studies using laboratory animals suggest that artemether causes damage to the tegument and musculature of schistosomulae. Artemether may exert its helminthotoxic effect through synergy with hemin or related heme-containing compounds. Schistosomes recovered from artemether treated laboratory animals have increased glycogen phosphorylase activity, but decreased glucose uptake. These findings may account for their decreased glycogen content, relative to schistosomes recovered from untreated laboratory animals. The artemether-damaged schistosomes also have decreased activities of a number of enzymes and enzyme systems, including glycolysis. This might suggest common pathways by which artemether may target human parasites that live in the bloodstream.

Schistosoma mansoni: testis alterations induced by antischistosomal drug ro15-5458

Effects of the administration of curative and sub-curative doses of antischistosomal drug [Ro15-5458*] on the testis of Schistosoma mansoni were studied using electron microscopy. Worms were recovered from mice one and seven days after treatment. Testis alterations included disintegration of the non-germinal cells, detachment of the muscle fibers from the basal lamina, cellular shrinkage, disorganization of the germ cells, vacuolation within the testis and regression of spermatocytes. Degrees of lesion intensity were clearly depending on the period of recovery after treatment and on the dosage

Experimental studies on early treatment of schistosomal infection with artemether.

An early treatment with artemether given in appropriate regimens was tested in mice, rabbits and dogs for prevention purposes. Artemether was administered intragastrically (ig) to the hosts on day 7 after infection with Schistosoma japonicum cercariae at a single dose, and the same dose of artemether was repeated every 1 or 2 weeks for 2-4 times. As a result, most of the female worms were killed before their oviposition with female worm reduction rates of 90-100%, resulting in protection of the host from damage induced by schistosome eggs. When rabbits were treated ig with artemether 10 mg kg-1 on day 7 after infection, followed by repeated dosing every week for 4 times, some parameters related to acute schistosomiasis, such as temperature, eosinophil count and eggs in the feces were negative, and low specific antigen and antibody levels in serum were seen. Further study showed that the appropriate regimens of Artemether were also effective in early treatment of reinfection with cercariae. When rabbits infected with 48-52 cercariae once every other day for 5 times were treated ig with artemether 15 mg kg-1, followed by repeated dosing every 1 or 2 week for 2- 3 times, the female worm reduction rates were 92.1-98.4%. Histopathological examination of the livers showed that the above-mentioned early treatment with Artemether exhibited a promising protective effect on dogs and rabbits. The major features included normal appearance of the liver resembling those of uninfected dogs and rabbits; few or no dispersed miliary egg tubercles appeared on the surface of the liver; the structure of the hepatic lobules was normal with normal arrangement of the liver bundles; few or no eggs appeared in the portal vein area and there was apparent diminution of total egg granuloma, comprising inflammatory, fibrous or scarred egg granuloma. On the basis of above-mentioned results, early treatment with Artemether could be recommended for field trial for controlling acute schistosomiasis, reducing infection rate and intensity of infection.