Effect of artemether administered alone or in combination with praziquantel to mice infected with Plasmodium berghei or Schistosoma mansoni or both

The artemisinins have become key drugs for the treatment and control of malaria, particularly within artemisinin-based combination therapies. Since the artemisinins also exhibit antischistosomal properties, their use in areas where malaria and schistosomiasis are co-endemic may have an effect on both diseases and co-infection might alter drug efficacy. We assessed the antimalarial and antischistosomal efficacies of artemether in mice infected with Plasmodium berghei or Schistosoma mansoni or both parasites concurrently. Three oral doses of 400 mg/kg artemether at 14-day intervals reduced total and female S. mansoni worm burdens by 98.7-100%, regardless of a concurrent P. berghei infection. When four daily doses of 55 mg/kg artemether were administered, which is a standard treatment schedule to cure P. berghei-infected mice, significantly lower total and female S. mansoni worm burden reductions were observed (73.1-89.2%). Artemether, administered at both of the above-mentioned treatment schemes, showed excellent antimalarial efficacy with no indications of delayed clearance of P. berghei or recrudescence, also in mice co-infected with S. mansoni. Co-infection with P. berghei had no effect on S. mansoni worm burden reductions following artemether-praziquantel combinations. Our findings point to the need for epidemiological studies in areas where malaria and schistosomiasis co-exist and where artemisinin-based combination therapies are introduced, since artemisinin-based combination therapies as part of a malaria control package may have ancillary benefits against schistosomiasis.     

Evaluation of the anthelmintic effects of artesunate against experimental Schistosoma mansoni infection in mice using different treatment protocols

The therapeutic effects of artesunate against experimental Schistosoma mansoni infection in mice were analyzed. Previous studies showed that artesunate is highly effective against S. japonicum infection, but the action of this drug against S. mansoni remained uncovered. The present study examines the optical conditions for artesunate against S. mansoni and evaluates the effects of inhibiting the sexual maturation of adult worms. Mice infected with S. mansoni were orally administered with artesunate according to different schedules. Four consecutive administrations of 300 mg/kg of artesunate at 2-week intervals conferred almost total protection without the development of pathological lesions in the liver. The significant reduction in the number of eggs produced by surviving worms and the status of egg maturation suggested that artesunate inhibits sexual maturation. Electron microscopy revealed that artesunate caused morphological damage, especially on the worm tegument. Artesunate was also very effective in iron-deficient mice. Furthermore, the efficacy of artesunate was equal to or better than that of artemether against S. japonicum infection. Considering that artemether is more toxic, artesunate is currently one of the most efficient drugs against immature S. mansoni.     

Effect of artemether alone and in combination with grapefruit juice on hepatic drug-metabolising enzymes and biochemical aspects in experimental Schistosoma mansoni

Artemether is an efficacious antimalarial drug that also displays antischistosomal properties. Grapefruit juice increases the oral availability of a variety of the CYP3A4 substrates. This study was designed to evaluate the effect of repeated administration of grapefruit juice with artemether on the hepatic activities of cytochrome P-450 (CYP450) and cytochrome b5 (cyt b5), on the serum levels of some biochemical enzymes and antischistosome efficacy. Results showed that administration of grapefruit juice alone induced more inhibition in the hepatic activities of CYP450 and cyt b5 than that produced by Schistosoma mansoni infection. Moreover, it enhanced degeneration of eggs and accelerated healing of the pathological granulomatous lesions. Treatment of S. mansoni-infected mice with artemether at a total dose of 300 mg/kg resulted in total and female worm burden reductions of 66.7 and 90.1%, respectively, hence protecting the host from damage induced by schistosome eggs. Treatment of S. mansoni-infected mice with artemether at 150 mg/kg reduced the total and female worm numbers by 43.3 and 54.4%, respectively, thus somewhat ameliorating hepatic granulomatous lesions compared with the infected untreated group. This was associated with no change in the hepatic activities of CYP450 and cyt b5 and in the serum levels of total protein, albumin, globulin and alanine aminotransferase compared with the uninfected control group. Coadministration of grapefruit juice with the lower dose (150 mg/kg) of artemether eliminated eggs and granulomatous reactions. In this group, the inhibitory effects of grapefruit juice on CYP450 and cyt b5 were apparent but serum liver enzymes were unchanged compared with the uninfected control group. Coadministration of grapefruit juice with artemether achieved complete protection of the host from damage induced by schistosomal infection.     

Effect of artemether against Schistosoma haematobium in experimentally infected hamsters

The drug, artemether, has been shown to be active against the juvenile stages of Schistosoma japonicum and Schistosoma mansoni in experimentally infected animals, while it is less effective on adult worms. These findings have been confirmed in randomised controlled trials in humans. Consequently, it could be expected that artemether is also active against Schistosoma haematobium. We present here the first results from experiments assessing the effect of artemether on S. haematobium. Hamsters with a single infection received intra-gastrically an initial dose of 300 mg/kg artemether on day 14, 21 or 28, followed by further doses at varying treatment regimens. In all the treatment groups, the total and female worm reduction rates were highly significant, and ranged from 78 to 100% in hamsters harbouring juvenile schistosomes. Hamsters infected three times with S. haematobium, on days 0, 4 and 9, and repeatedly treated with artemether at the same dose as above, showed highly significant total and female worm reduction rates of between 94 and 99%. Artemether was also active against 77-day-old adult S. haematobium, since its administration on two consecutive days resulted in highly significant total and female worm reduction rates of 76-89%. Our findings confirm that artemether is also active against S. haematobium, especially the schistosomules. These results provide a basis for clinical trials in humans, for further assessment of the potential of artemether for schistosomiasis control.     

Effect of praziquantel together with artemether on Schistosoma japonicum parasites of different ages in rabbits

The efficacy of combined treatment with praziquantel and artemether against infection with Schistosoma japonicum was tested on infected rabbits, in which 7-to 14-day-old schistosomules and 42-day-old adult schistosomes were simultaneously present. Rabbits were treated orally with praziquantel and artemether using various dosages and schedules. The therapeutic effects were evaluated by estimating the mean total worm burden (TWB) and female worm burden (FWB) and comparing them with the worm burdens in control animals treated with praziquantel or artemether alone. When the rabbits received praziquantel in a single dose (50 mg/kg), or daily for 2-6 days (30-60 mg/kg), the TWB was reduced by 28-66% and the FWB by 26-65%. In rabbits treated with artemether the reductions were 44-56% and 35-54%, respectively. Treatment with praziquantel in combination with artemether resulted in a significantly greater reduction of worm burden than was found for the groups treated with praziquantel or artemether alone, using the same dosages and schedules. TWB was reduced by 79-92%, and FWB by 80-93%. The results demonstrated that when rabbits infected simultaneously with schistosomules and adult schistosomes were treated with praziquantel in combination with artemether, the effects of the individual drugs could be increased significantly.     

Tegumental changes in adult Schistosoma mansoni harbored in mice treated with artemether

A detailed temporal examination was made of alterations induced by artemether in the tegument of adult Schistosoma mansoni worms using scanning electron microscopy (SEM). Mice infected with S. mansoni cercariae 42 days previously were treated intragastrically with artemether at a single dose of 400 mg/kg. Groups of 3 mice were killed at 24 hr, 72 hr, and 7 days after treatment; the worms were collected by perfusion and examined by SEM. Twenty-four hours after artemether treatment, focal damage to the tubercles on the tegumental surface of male worms was seen. In both male and female worms, there was focal swelling and fusion of tegumental ridges, and sometimes peeling. After 72 hr, the damage to the tegument had increased, especially in female worms, with extensive swelling, fusion, and peeling of the tegumental ridges. In the most severely damaged worms, host leukocytes were seen to be adhered to the damaged tegument. Damage to the oral sucker was also occasionally seen in both male and female worms. Seven days after treatment, the appearance of the tegument had returned to normal in some male and female worms, whereas others still showed apparent damage. The results demonstrate that artemether damages the tegument of adult S. mansoni, and the intensity of damage is more severe in female worms than in males.     

High levels of Schistosoma mansoni infections among schoolchildren in central Sudan one year after treatment with praziquantel

A longitudinal study was conducted to evaluate the impact of praziquantel (PZQ) for the treatment of Schistosoma mansoni infection among schoolchildren in Al Gunaid in Central Sudan. A cohort of schoolchildren (6-15 years of age) was investigated before and 1 year after treatment with a single dose of PZQ 40?mg/kg. Parasitological examinations for S. mansoni were performed before and after treatment, and prevalence and intensity of infection were analysed. Of 2741 schoolchildren recruited from six elementary schools at baseline, 2521 were successfully traced and re-examined at follow-up, with two complete sets of longitudinal parasitological data on S. mansoni. Boys showed significantly higher prevalence of S. mansoni infection than girls. A single dose of PZQ reduced the overall prevalence of S. mansoni infection by 36.7% (from 59.1 to 37.4%) and the intensity of infection by 41.1% (from 116.7 to 68.7 eggs per gram of stool) 1 year after treatment. The reduction in prevalence was significantly higher among the group of children with heavy infections (by 76.1%, from 6.7 to 1.6%) and among girls (by 54.1%, 42.3 to 19.4%) at 1 year after treatment. Thus, in spite of a significant reduction in the prevalence and intensity of S. mansoni infection 1 year after PZQ treatment, the prevalence of the disease was still high and further research is needed on this topic.     

Cross-resistance between Schistosoma mansoni and Fasciola hepatica in sheep

Five sheep were exposed to 5,000 S. mansoni cercariae percutaneously and the stools examined for 20 wk to determine patency. The sheep were found to be partially susceptible to a primary infection and showed great individual variations in their pathophysiological responses. All of the sheep acquired a patent infection with S. mansoni and eggs were first seen in feces 9 wk postexposure with no eggs detected after 14 wk. At necropsy 20 wk postexposure only dead S. mansoni worms were found. KOH digests revealed that tissue egg counts were low, ranging from 0 to 133 in the liver, and 0 to 257 in the intestine. Primary infection of sheep with S. mansoni followed by oral infection with F. hepatica metacercariae 10 wk later resulted in a reduction of 51% in F. hepatica worms recovered over controls infected with F. hepatica for 10 wk. All 5 of the S. mansoni-infected/F. hepatica-challenged sheep developed 71 or less F. hepatica worms. In contrast, 3 of the 5 F. hepatica-infected sheep developed 113-197 worms. However, although the experimental mean worm burden was lower than the control group, the variability in the control group was too great to obtain significance between the groups. There was a clear tendency toward normocytic normochromic anemia following a primary infection with S. mansoni; however, blood values were more reduced in the F. hepatica challenge controls than in the animals that received primary infection with S. mansoni.     

Ultrastructural alterations in adult Schistosoma mansoni caused by artemether

Progress has been made over the last decade with the development and clinical use of artemether as an agent against major human schistosome parasites. The tegument has been identified as a key target of artemether, implying detailed studies on ultrastructural damage induced by this compound. We performed a temporal examination, employing a transmission electron microscope to assess the pattern and extent of ultrastructural alterations in adult Schistosoma mansoni harboured in mice treated with a single dose of 400 mg/kg artemether. Eight hours post-treatment, damage to the tegument and subtegumental structures was seen. Tegumental alterations reached a peak 3 days after treatment and were characterized by swelling, fusion of distal cytoplasma, focal lysis of the tegumental matrix and vacuolisation. Tubercles and sensory organelles frequently degenerated or collapsed. Typical features of subtegumental alterations, including muscle fibres, syncytium and parenchyma tissues, were focal or extensive lysis, vacuolisation and degeneration of mitochondria. Severe alterations were also observed in gut epithelial cells and vitelline cells of female worms. Our findings of artemether-induced ultrastructural alterations in adult S. mansoni confirm previous results obtained with juvenile S. mansoni and S. japonicum of different ages.     

Repeated exposure induces periportal fibrosis in Schistosoma mansoni-infected baboons: role of TGF-beta and IL-4

Recently, we observed that repeated Schistosoma mansoni infection and treatment boost Th2-associated cytokines and TGF-beta production in baboons. Other studies have shown that some chronically infected baboons develop hepatic fibrosis. Because TGF-beta, IL-2, and IL-4 have been shown to participate in development of fibrosis in murine schistosomiasis, the present study examined whether repeated exposure stimulates hepatic fibrosis in olive baboons. To test this hypothesis, animals were exposed to similar numbers of S. mansoni cercariae given once or repeatedly. After 19 wk of infection, animals were cured with praziquantel and reinfected once or multiple times. Hepatic granulomatous inflammation and fibrosis were assessed from serial liver biopsies taken at weeks 6, 9, and 16 after reinfection and egg Ag (schistosome egg Ag)-specific cytokine production by PBMC were measured simultaneously. Periportal fibroblast infiltration and extracellular matrix deposition (fibrosis), angiogenesis, and biliary duct hyperplasia developed in some animals. The presence and amount of fibrosis directly correlated with the frequency of exposure. Fibrosis was not associated with adult worm or tissue egg burden. The amount of fibrosis correlated with increased schistosome egg Ag-driven TGF-beta at 6, 9, and 16 wk postinfection (rs = 0.9, 0.8, and 0.54, respectively, all p < 0.01) and IL-4 production (p = 0.02) at 16 wk postinfection and not IFN-gamma, IL-2, IL-5, or IL-10. These data suggest that repeated exposure is a risk factor for periportal fibrosis by a mechanism that primes lymphocytes to produce increased levels of profibrotic molecules that include TGF-beta and IL-4.     

Curative and protective activity in rabbits after reinfection with Schistosoma mansoni: a new model of immunity?

New Zealand rabbits were infected on day 1 and challenged on days 15, 30, and 60 with 1,000 Schistosoma mansoni cercariae/animal/infection. Challenged and control rabbits were perfused 60 days after each infection, corresponding to days 75, 90, and 120 after the first exposure. No decrease in number of adult schistosomes occurred in animals reinfected 15 days after primary infection, but, when the rabbits were challenged 30 and 60 days after the first infection, worm burden reduction of 61.4% and 92.6%, respectively, was observed as compared to infection controls. These data indicate that rabbits submitted to reinfection are able to kill the worms from their primary infection, besides being protected against challenge parasites.     

Dominant antibody responses to Fucalpha1-3GalNAc and Fucalpha1-2Fucalpha1-3GlcNAc containing carbohydrate epitopes in Pan troglodytes vaccinated and infected with Schistosoma mansoni

The development of the humoral anti-glycan immune response of chimpanzees, either or not vaccinated with radiation-attenuated Schistosoma mansoni cercariae, was followed during 1 year after infection with S. mansoni. During the acute phase of infection both the vaccinated and the control chimpanzees produce high levels of immunoglobulin G (IgG) antibodies against carbohydrate structures that are characteristic for schistosomes carrying the Fucalpha1-3GalNAc and Fucalpha1-2Fucalpha1-3GlcNAc motifs, but not to the more widespread occurring structures GalNAcbeta1-4GlcNAc, GalNAcbeta1-4(Fucalpha1-3)GlcNAc, and Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(x)). In addition, high levels of IgM antibodies were found against the trimeric Lewis(x) epitope. Apparently, the schistosome-characteristic carbohydrate structures are dominant epitopes in the anti-glycan humoral immune response of the chimpanzees. All chimpanzees showed an increase in the level of antibodies against most of the carbohydrate structures tested directly after vaccination, peaking at challenge time and during the acute phase of infection. With the exception of anti-F-LDN antibody responses, the anti-carbohydrate antibody responses upon schistosome infection of the vaccinated animals were muted in comparison to the control animals.     

Toxoplasma gondii and Schistosoma mansoni synergize to promote hepatocyte dysfunction associated with high levels of plasma TNF-alpha and early death in C57BL/6 mice.

To address the question of how the murine host responds to a prototypic type 1 cytokine inducer while concurrently undergoing a helminth-induced type 2 cytokine response, C57BL/6 strain animals with patent schistosomiasis mansoni were orally infected with the cystogenic Toxoplasma gondii strain ME49. Schistosoma mansoni infection resulted in a significantly higher mortality rate when mice were subsequently orally infected with ME49, and these animals displayed a defective IFN-gamma and NO response relative to animals infected with T. gondii alone. Plasma levels of TNF-alpha and aspartate transaminase in double-infected mice were greatly elevated relative to mice infected with either parasite alone. Consistent with the latter observation, these animals exhibited severe liver pathology, with regions of coagulative necrosis and hepatocyte vacuolization unapparent in mice carrying either infection alone. Interestingly, mean egg granuloma size was approximately 50% of that in mice with S. mansoni infection alone. The exacerbated liver pathology in coinfected mice did not appear to be a result of uncontrolled tachyzoite replication, because both parasite-specific RT-PCR analysis and immunohistochemical staining demonstrated a low number of tachyzoites in the liver. We hypothesize that mortality in these animals results from the high level of systemic TNF-alpha, which mediates a severe liver pathology culminating in death of the animal.     

Tegumental alterations in juvenile Schistosoma haematobium harboured in hamsters following artemether treatment

We report the findings of a detailed temporal study on tegumental alterations in juvenile Schistosoma haematobium, induced by artemether, using scanning electron microscopy. Hamsters infected with S. haematobium cercariae for 28 days were treated intragastrically with a single dose of 300 mg/kg artemether. Groups of two hamsters were killed 24 h, 72 h and 7 days after treatment, and schistosomula were recovered from livers by perfusion and subsequent systematic examination of the tissue, before routinely processing for scanning electron microscopic examination. Most schistosomula collected 24 h after artemether administration showed severe tegumental damage, usually including swelling, fusion, vesiculation, peeling and collapse of enlarged sensory structures. After 72 h, tegumental damage had increased and schistosomula generally showed contraction with extensive swelling, erosion and peeling of the tegument. Seven days post-treatment, severe tegumental damage was only seen in a single male specimen with swelling of the worm body and destruction of the oral sucker. The other schistosomula showed only light to moderate damage, suggesting that schistosomula surviving the treatment began to recover. Our findings of tegumental damage following artemether treatment correlate with the efficacy of this novel antischistosomal drug in killing the juvenile stages of S. haematobium and complement recent findings with S. japonicum and S. mansoni.     

Evidence for the activation of the endogenous opiate system in hamsters infected with human blood flukes, Schistosoma mansoni

Nociceptive thresholds were investigated in golden hamsters infected with the human blood fluke, Schistosoma mansoni. Increases in thermal thresholds suggestive of analgesia were evident by 20-25 days of infection. These increased further during a 40-42 day period. The altered responses were suppressed by the opioid antagonist naloxone. Non-invasive inhibition of the activity of the pineal gland by exposure to light also reduced nocturnal analgesia in schistosome infected animals. Naloxone antagonism and pineal inhibition of morphine- induced analgesia was obtained similarly in control, uninfected animals. Taken together, these findings suggest strongly that infection with S. mansoni results in a chronic activation of the endogenous opiate system.     

Schistosoma mansoni heat shock protein 70 elicits an early humoral immune response in S. mansoni infected baboons

A study was undertaken to search for DNA recombinant Schistosoma mansoni proteins responsible for eliciting an antibody response from the host at a very early phase after infection. A S. mansoni adult worm cDNA expression library was screened using pooled sera from baboons with four weeks of infection. Based on their specific reactivity with the S. mansoni infected sera and no reactivity when tested against the pre-infection sera from the same baboons, four clones were selected for further studies. Sequence analysis revealed that they were homologous to the S. mansoni heat shock protein 70 (hsp70). The insert sizes of the four selected clones varied from 1150 to 2006 bp. The preliminary characterization for antibody reactivity against a panel of baboon sera showed that the longest clone was the most reactive, eight out of eight acute and three out of four chronic sera reacting positively to this clone. The shortest clone was the least reactive. Our results suggest that the S. mansoni hsp70 elicits an early and strong antibody response in baboons and that antibodies to this protein can be detected in chronically infected animals. Therefore S. mansoni hsp70 may be a valid target for immunodiagnosis. However further studies are needed to identify the portion of the hsp70 that best fits the requirements for a valuable diagnostic antigen.     

Modulation of macrophage activation and resistance by suppressor T lymphocytes in chronic murine Schistosoma mansoni infection

Activated macrophages (M phi) appear responsible for at least part of the concomitant resistance in mice infected with Schistosoma mansoni. We found that as murine S. mansoni progressed from acute (8 to 12 wk of infection) to chronic (16 to 24 wk) stages, acquired resistance decreased (57% resistance to challenge with cercariae at 8 wk vs 28% by 24 wk, p less than 0.05), as did macrophage activation (21% +/- 2 killing of schistosomula by 8 wk M phi vs 8% +/- 2 for 24 wk M phi, p less than 0.01). T cells from the spleens of 8 wk-infected mice were capable of activating M phi from naive animals when stimulated with worm antigens (24% +/- 2 killing vs 8% +/- 2 induced by normal T cells, p less than 0.01); T cells obtained from 24 wk-infected mice did not activate M phi (13% +/- 2 killing). Furthermore, T cells from 24 wk-infected animals suppressed activation of M phi by 8 wk T cells. The addition of 10(5) 24 wk T cells to 3 X 10(5) antigen-stimulated 8 wk T cells reduced subsequent M phi killing from 27% +/- 4 to 13% +/- 2 (p less than 0.05). Week 24 T cells (3 X 10(5] reduced this additionally to 9% +/- 1 (p less than 0.01), a value no greater than that of unstimulated M phi. The subpopulation of T cells responsible for suppression of M phi activation was Lyt-2+1- nonadherent T cells. Cyclophosphamide treatment of chronically infected mice resulted in enhanced resistance (41%), M phi activation (18% +/- 1 killing), and T cell activation of naive M phi (10% +/- 1 killing). Thus, during chronic S. mansoni infection, resistance to reinfection wanes in parallel to and perhaps because of development of suppressor T cells that interfere with T-dependent M phi activation.     

Schistosoma japonicum: effect of artemether on glutathione S-transferase and superoxide dismutase

Glutathione S-transferase (GST) and superoxide dismutase (SOD) are major antioxidant enzymes of schistosomes that are involved in detoxification processes. To study the effect of artemether on these enzymes, mice infected with adult Schistosoma japonicum, were treated with artemether either at a subcurative (100 mg/kg) or a curative dose (300 mg/kg). Schistosomes were recovered 24-72 h post-treatment separated by sex and used for GST and SOD activity measurements. Female worms showed consistently higher GST inhibitions than males. For instance, 24 h after administration of 100 mg/kg artemether, GST activities of female worms were inhibited by 23.3%, as compared to 12.7% in males. Both activities were significantly lower when compared to worms recovered from untreated mice. Slightly higher inhibitions were observed at the higher dose of artemether, which gradually increased to levels of 52.5-55.1%, 72 h post-treatment. GST inhibitions could be reversed by application of 1,4-dithiothreitol at a concentration of 10 mmol/L. Adding L-cysteine also reduced GST inhibitions, but in female worms, GST activities remained significantly higher than in worms from untreated animals. Administration of 300 mg/kg artemether resulted in significant reductions of SOD activities in both sexes. In conclusion, these results suggest that the inhibition of GST and, to a lesser extent also SOD enzymes, could lead to increased schistosome susceptibility to oxidant attacks and might be linked with the antischistosomal action of artemether.     

In vitro killing of schistosomula of Schistosoma mansoni by BCG and C. parvum-activated macrophages.

Resistance to Schistosoma mansoni infection in the mouse has been induced either specifically by a primary infection with this parasite or nonspecifically by a variety of immunostimulants such as BCG. In the present study we developed an in vitro system to examine the effector mechanism of nonspecifically induced resistance. Activated macrophage monolayers obtained from BCG- or Corynebacterium parvum treated mice killed a respective mean 32 +/- 6% and 48 +/- 5% of schistosomula after 24 hr incubation. The killing of the parasites was verified by their inability to mature to adult worms upon injection into normal mice. The activated macrophage-mediated killing was related to cell:parasite ratio, and was partially lost if the macrophage monolayers were kept in cultures for 24 hr before incubation with the organism. Supernatants of macrophages cultured in the presence of schistosomula killed a mean of 51 +/- 3% of the organisms whereas those from cells cultured alone resulted in a mean killing of 25 +/- 3%. Furthermore, toxic supernatants could be generated equally well on incubation with S. mansoni schistosomula or Trichinella spiralis larvae. Our data show that activated macrophage monolayers through soluble mediators destroy a significant proportion of the multicellular parasite S. mansoni schistosomula in vitro.     

Schistosoma mansoni: effects on tryptophan metabolism in mice

In mice, infection with 20-30 cercariae of Schistosoma mansoni resulted in a considerable reduction in the formation of 14CO2 from [14C]tryptophan. Infected animals excreted significantly lower amounts of kynurenine, kynurenic acid, and methyl pyridone carboxamide than did uninfected controls. There was no difference in the ability of hepatocytes isolated from infected or control animals to metabolise [14C]tryptophan. Hepatocytes from infected animals synthesized less NAD(P), but more niacin and N1-methyl nicotinamide from tryptophan. They showed no greater accumulation of kynurenine metabolites than did cells from control animals. The hepatocyte content of pyridoxal phosphate and the erythrocyte aspartate aminotransferase activation coefficient were the same in both groups of mice, suggesting that infection with S. mansoni does not deplete vitamin B6. The impairment of tryptophan metabolism in vivo was apparently not due to impaired hepatic metabolism. Rather, it seems likely that the parasites or their eggs take up tryptophan avidly from the host's circulation. Studies of parasite and egg metabolism of tryptophan may suggest novel approaches to the chemotherapy of bilharzia.