scholarly journals Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection

2020 ◽  
Author(s):  
Katharine A Collins ◽  
Azrin N Abd-Rahman ◽  
Louise Marquart ◽  
Emma Ballard ◽  
Nathalie Gobeau ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Parasite Clearance ◽  
Clinical Development ◽  
Blood Stage ◽  
Drug Candidate ◽  
Maximum Effect ◽  
Infection Study

Abstract Background Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate. Methods Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility. Results Initial parasite clearance occurred in all participants after artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11–14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4–8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. Conclusions The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria. Clinical Trials Registration NCT02573857.

scholarly journals Defining the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood stage Plasmodium falciparum

2020 ◽  
Author(s):  
James S. McCarthy ◽  
Azrin N. Abd-Rahman ◽  
Katharine A. Collins ◽  
Louise Marquart ◽  
Paul Griffin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Healthy Volunteers ◽  
Antimalarial Activity ◽  
Parasite Clearance ◽  
Clinical Development ◽  
Blood Stage ◽  
Maximum Effect ◽  
Limited Data ◽  
Dose Cohort ◽  
New Treatment

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum. Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3-8 days after dosing, and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single sub-therapeutic dose cohort, a minimum inhibitory concentration of 11.6 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/mL was estimated, and a single 95 mg dose (95% CI: 50-270) was predicted to clear 109 parasites/mL. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of cipargamin as a new treatment for P. falciparum malaria, although the hepatic safety profile of the compound warrants further evaluation.

scholarly journals In VitroandIn VivoActivity of Solithromycin (CEM-101) against Plasmodium Species

2011 ◽  
Vol 56 (2) ◽  
pp. 703-707 ◽  
Author(s):  
Sergio Wittlin ◽  
Eric Ekland ◽  
J Carl Craft ◽  
Julie Lotharius ◽  
Ian Bathurst ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Parasite Clearance ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Asexual Blood Stage ◽  
Content Type

ABSTRACTWith the emergence ofPlasmodium falciparuminfections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potentin vitroactivity against the NF54 strain ofP. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In anin vivomodel ofP. bergheiinfection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promisingin vitroandin vivodata support further investigations into the development of solithromycin as an antimalarial agent.

scholarly journals A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James S. McCarthy ◽  
Thomas Rückle ◽  
Suzanne L. Elliott ◽  
Emma Ballard ◽  
Katharine A. Collins ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Content Type ◽  
Dose Combination ◽  
Combination Study ◽  
Study Support ◽  
New Compounds

ABSTRACT Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.)

scholarly journals Oral Artesunate Dose-Response Relationship in Acute Falciparum Malaria

2002 ◽  
Vol 46 (3) ◽  
pp. 778-782 ◽  
Author(s):  
Brian J. Angus ◽  
Itaporn Thaiaporn ◽  
Kenechanh Chanthapadith ◽  
Yupin Suputtamongkol ◽  
Nicholas J. White
Keyword(s):  
Falciparum Malaria ◽  
Dose Response ◽  
Parasite Clearance ◽  
Multidrug Resistant ◽  
Maximum Effect ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
To Receive ◽  
The Relationship

ABSTRACT The combination of an oral artemisinin derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia ≥1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (E max) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The E max was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

Treatment with synthetic lipophilic tyrosyl ester controls Leishmania major infection by reducing parasite load in BALB/c mice

Parasitology ◽  
2016 ◽  
Vol 143 (12) ◽  
pp. 1615-1621 ◽  
Author(s):  
RABIAA M. SGHAIER ◽  
IMEN AISSA ◽  
HANÈNE ATTIA ◽  
AYMEN BALI ◽  
PABLO A. LEON MARTINEZ ◽  
...  
Keyword(s):  
Immune Responses ◽  
Leishmania Major ◽  
Parasite Load ◽  
Parasite Clearance ◽  
Potential Effect ◽  
Interleukin 4 ◽  
Drug Candidate ◽  
Cytokine Balance

SUMMARYSynthesized lipophilic tyrosyl ester derivatives with increasing lipophilicity were effective against Leishmania (L.) major and Leishmania infantum species in vitro. These findings prompted us to test in vivo leishmanicidal properties of these molecules and their potential effect on the modulation of immune responses. The experimental BALB/c model of cutaneous leishmaniasis was used in this study. Mice were infected with L. major parasites and treated with three in vitro active tyrosyl esters derivatives.Among these tested tyrosylcaprate (TyC) compounds, only TyC10 exhibited an in vivo anti-leishmanial activity, when injected sub-cutaneously (s.c.). TyC10 treatment of L. major-infected BALB/c mice resulted in a decrease of lesion development and parasite load. TyC10 s.c. treatment of non-infected mice induced an imbalance in interferon γ/interleukin 4 (IFN-γ/IL-4) ratio cytokines towards a Th1 response. Our results indicate that TyC10 s.c. treatment improves lesions’ healing and parasite clearance and may act on the cytokine balance towards a Th1 protective response by decreasing IL-4 and increasing IFN-γ transcripts. TyC10 is worthy of further investigation to uncover its mechanism of action that could lead to consider this molecule as a potential drug candidate.

scholarly journals Immunohistochemical Investigations of Treatment with Ro 13-3978, Praziquantel, Oxamniquine, and Mefloquine in Schistosoma mansoni-Infected Mice

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Gordana Panic ◽  
Marie-Thérèse Ruf ◽  
Jennifer Keiser
Keyword(s):  
T Cells ◽  
B Cells ◽  
Schistosoma Mansoni ◽  
Parasite Clearance ◽  
Drug Candidate ◽  
Minimal Cell ◽  
Onset Of Action ◽  
Content Type

ABSTRACT To date, there is only one drug in use, praziquantel, to treat more than 250 million people afflicted with schistosomiasis, a debilitating parasitic disease. The aryl hydantoin Ro 13-3978 is a promising drug candidate with in vivo activity superior to that of praziquantel against both adult and juvenile Schistosoma mansoni organisms. Given the drug's contrasting low activity in vitro and the timing of its onset of action in vivo, it was postulated that immune-assisted parasite clearance could contribute to the drug's in vivo activity. We undertook histopathological studies to investigate this hypothesis. Infected mice were treated with an effective dose of Ro 13-3978 (100 mg/kg of body weight) and were dissected before and after the drug's in vivo onset of action. The veins and livers were excised, paraffin-embedded, and sectioned, and macrophages (IBA-1), neutrophils (Neutro), B cells (CD45R), and T cells (CD3) were stained by immunohistochemistry. For comparison, samples from infected untreated mice and mice treated with effective doses of praziquantel (400 mg/kg), oxamniquine (200 mg/kg), and mefloquine (200 mg/kg) were examined. At 24 h after treatment with Ro 13-3978, significant macrophage recruitment to the veins was observed, along with a modest increase in circulating B cells, and at 48 h, neutrophils and T cells are also present. Treatment with praziquantel and oxamniquine showed similar patterns of recruitment but with comparatively higher cellular levels, whereas mefloquine treatment resulted in minimal cell recruitment until 3 days posttreatment. Our study sheds light on the immediate immune responses to antischistosomal treatment in mice and provides further insight into immune effector mechanisms of schistosome clearance.

scholarly journals Artemisinin Therapy for Malaria in Hemoglobinopathies: A Systematic Review

2018 ◽  
Vol 66 (5) ◽  
pp. 799-804 ◽  
Author(s):  
Sri Riyati Sugiarto ◽  
Brioni R Moore ◽  
Julie Makani ◽  
Timothy M E Davis
Keyword(s):  
Clinical Studies ◽  
Antimalarial Activity ◽  
Artemisinin Combination Therapy ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Convincing Evidence ◽  
Hemoglobin E ◽  
Artemisinin Derivatives

Abstract Artemisinin derivatives are widely used antimalarial drugs. There is some evidence from in vitro, animal and clinical studies that hemoglobinopathies may alter their disposition and antimalarial activity. This review assesses relevant data in α-thalassemia, sickle cell disease (SCD), β-thalassemia and hemoglobin E. There is no convincing evidence that the disposition of artemisinin drugs is affected by hemoglobinopathies. Although in vitro studies indicate that Plasmodium falciparum cultured in thalassemic erythrocytes is relatively resistant to the artemisinin derivatives, mean 50% inhibitory concentrations (IC50s) are much lower than in vivo plasma concentrations after recommended treatment doses. Since IC50s are not increased in P. falciparum cultures using SCD erythrocytes, delayed post-treatment parasite clearance in SCD may reflect hyposplenism. As there have been no clinical studies suggesting that hemoglobinopathies significantly attenuate the efficacy of artemisinin combination therapy (ACT) in uncomplicated malaria, recommended artemisinin doses as part of ACT remain appropriate in this patient group.

scholarly journals In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

2015 ◽  
Vol 11 (2) ◽  
pp. e1004598 ◽  
Author(s):  
Henrique Borges da Silva ◽  
Raíssa Fonseca ◽  
Alexandra dos Anjos Cassado ◽  
Érika Machado de Salles ◽  
Maria Nogueira de Menezes ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Phase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Cd4 T Cell ◽  
Blood Stage Malaria

scholarly journals Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes

2007 ◽  
Vol 51 (4) ◽  
pp. 1463-1472 ◽  
Author(s):  
Françoise Benoit-Vical ◽  
Joël Lelièvre ◽  
Antoine Berry ◽  
Caroline Deymier ◽  
Odile Dechy-Cabaret ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Mice Model ◽  
Additional Advantage ◽  
Antimalarial Agents ◽  
Hybrid Molecules ◽  
Resistant Strains ◽  
Antimalarial Chemotherapy

ABSTRACT Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

scholarly journals In Vivo and In Vitro Efficacy of Amodiaquine Monotherapy for Treatment of Infection by Chloroquine-Resistant Plasmodium vivax

2008 ◽  
Vol 53 (3) ◽  
pp. 1094-1099 ◽  
Author(s):  
A. R. Hasugian ◽  
E. Tjitra ◽  
A. Ratcliff ◽  
H. Siswantoro ◽  
E. Kenangalem ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Plasmodium Vivax ◽  
Inhibitory Concentration ◽  
Rank Correlation ◽  
Early Treatment Failure ◽  
Rural Clinic ◽  
Treatment Of Infection

ABSTRACT Amodiaquine retains efficacy against infection by chloroquine-resistant Plasmodium falciparum; however, little information is available on its efficacy against infection by chloroquine-resistant Plasmodium vivax. Patients presenting to a rural clinic with a pure P. vivax infection that recurred after recent antimalarial treatment were retreated, this time with amodiaquine monotherapy, and the risk of further recurrence within 4 weeks was assessed. Of the 87 patients with pure P. vivax infection, 15 patients did not complete a full course of treatment, 4 of whom were intolerant to treatment. In the 72 patients completing treatment, 91% (63 of 69) had cleared their parasitemia within 48 h with no early treatment failure. Follow-up to day 28 or recurrent parasitemia was achieved for 56 patients (78%). The cumulative incidence of treatment failure by day 28 was 22.8% (95% confidence interval, 7.3 to 38%). The in vitro sensitivity profile was determined for a separate set of isolates from outpatients with pure P. vivax infection. The median 50% inhibitory concentration of amodiaquine was 11.3 nM (range, 0.37 to 95.8) and was correlated significantly with that of chloroquine (Spearman rank correlation coefficient, 0.602; P < 0.001) Although amodiaquine results in a rapid clinical response, the risk of recurrence by day 28 is unacceptably high, reducing its suitability as an alternative treatment of infection by chloroquine-resistant P. vivax in this region.

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