-
Communications Biology Jul 2023Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We...
Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We demonstrate at biomimetic conditions in vitro irreversible inhibition of hematin crystal growth due to distinct cooperative mechanisms that activate at high crystallization driving forces. The evolution of crystal shape after limited-time exposure to both artemisinin metabolites and quinoline-class antimalarials indicates that crystal growth remains suppressed after the artemisinin metabolites and the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour inhibitor pulses inhibit parasite growth with efficacy comparable to that of inhibitor exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that prevent β-hematin growth recovery. Hematin adducts of artemisinins incite copious nucleation of nonextendable nanocrystals, which incorporate into larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both incorporated crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. Nucleation, step bunching, and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for numerous fields that rely on crystalline materials.
Topics: Humans; Hemin; Crystallization; Antimalarials; Quinolines; Malaria
PubMed: 37500754
DOI: 10.1038/s42003-023-05046-z -
PLoS Pathogens Jul 2023Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for...
Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 μM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 μM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.
Topics: Animals; Humans; Praziquantel; Oxamniquine; Schistosomiasis; Schistosoma mansoni; Combined Modality Therapy; Neglected Diseases; Schistosomiasis mansoni; Anthelmintics
PubMed: 37428793
DOI: 10.1371/journal.ppat.1011018 -
Infection Aug 2023Neurocysticercosis is common in regions endemic for Taenia solium. Active-stage neurocysticercosis can be treated with antiparasitic medication, but so far no study on...
PURPOSE
Neurocysticercosis is common in regions endemic for Taenia solium. Active-stage neurocysticercosis can be treated with antiparasitic medication, but so far no study on efficacy and safety has been conducted in Africa.
METHODS
We conducted a prospective cohort study on treatment of neurocysticercosis in Tanzania between August 2018 and January 2022. Patients were initially treated with albendazole (15 mg/kg/d) for 10 days and followed up for 6 months. Additionally in July 2021, all participants who then still had cysts were offered a combination therapy consisting of albendazole (15 mg/kg/d) and praziquantel (50 mg/kg/d). Antiparasitic treatment was accompanied by corticosteroid medication and anti-seizure medication if the patient had experienced epileptic seizures before treatment.
RESULTS
Sixty-three patients were recruited for this study, of whom 17 had a complete follow-up after albendazole monotherapy. These patients had a total of 138 cysts at baseline, of which 58 (42%) had disappeared or calcified by the end of follow-up. The median cyst reduction was 40% (interquartile range 11-63%). Frequency of epileptic seizures reduced considerably (p < 0.001). Three patients had all active cysts resolved or calcified and of the remaining 14, eight received the combination therapy which resolved 63 of 66 cysts (95%). Adverse events were infrequent and mild to moderate during both treatment cycles.
CONCLUSION
Cyst resolution was unsatisfactory with albendazole monotherapy but was very high when it was followed by a combination of albendazole and praziquantel.
Topics: Humans; Neurocysticercosis; Albendazole; Antiparasitic Agents; Praziquantel; Tanzania; Prospective Studies; Cysts; Seizures; Anthelmintics
PubMed: 36961623
DOI: 10.1007/s15010-023-02021-y -
Scientific Reports Oct 2023In this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage,...
In this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage, hemolytic activity and druggability were tested in vitro and in silico, respectively, observing as a result: firstly, compounds showed half-maximal effective concentration (EC) values between 3.6 and 19.3 µM. Likewise, a treatment using the compounds 4a-f caused improvement in most of the treated hamsters and cured some of them. Regarding the antiplasmodial activity, the compounds showed moderate to high activity, although they did not show hemolytic activity. Furthermore, 4e and 4f compounds were not able to control P. berghei infection when administered to animal models. Molecular dynamic simulations, molecular docking and ligand binding affinity indicate good characteristics of the studied compounds, which are expected to be active. And lastly, the compounds are absorbable at the hematoencephalic barrier but not in the gastrointestinal tract. In summary, ADMET properties suggest that these molecules may be used as a safe treatment against Leishmania.
Topics: Animals; Antimalarials; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania; Structure-Activity Relationship
PubMed: 37845281
DOI: 10.1038/s41598-023-43805-4 -
Malaria Journal Sep 2023Concerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya,...
Healthcare provider and drug dispenser knowledge and adherence to guidelines for the case management of malaria in pregnancy in the context of multiple first-line artemisinin-based combination therapy in western Kenya.
BACKGROUND
Concerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot.
METHODS
From March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests.
RESULTS
Of 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters.
CONCLUSIONS
Knowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.
Topics: Pregnancy; Female; Humans; Case Management; Antimalarials; Kenya; Quinine; Cross-Sectional Studies; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Malaria
PubMed: 37679753
DOI: 10.1186/s12936-023-04692-2 -
PeerJ 2024Malaria has been appraised as a significant vector-borne parasitic disease with grave morbidity and high-rate mortality. Several challenges have been confronting the...
BACKGROUND
Malaria has been appraised as a significant vector-borne parasitic disease with grave morbidity and high-rate mortality. Several challenges have been confronting the efficient diagnosis and treatment of malaria.
METHOD
Google Scholar, PubMed, Web of Science, and the Egyptian Knowledge Bank (EKB) were all used to gather articles.
RESULTS
Diverse biochemical and physiological indices can mirror complicated malaria e.g., hypoglycemia, dyslipidemia, elevated renal and hepatic functions in addition to the lower antioxidant capacity that does not only destroy the parasite but also induces endothelial damage. Multiple trials have been conducted to improve recent points of care in malaria involving biosensors, lap on-chip, and microdevices technology. Regarding recent therapeutic trials, chemical falcipain inhibitors and plant extracts with anti-plasmodial activities are presented. Moreover, antimalaria nano-medicine and the emergence of nanocarrier (either active or passive) in drug transportation are promising. The combination therapeutic trials e.g., amodiaquine + artemether + lumefantrine are presented to safely counterbalance the emerging drug resistance in addition to the Tafenoquine as a new anti-relapse therapy.
CONCLUSION
Recognizing the pathophysiology indices potentiate diagnosis of malaria. The new points of care can smartly manipulate the biochemical and hematological alterations for a more sensitive and specific diagnosis of malaria. Nano-medicine appeared promising. Chemical and plant extracts remain points of research.
Topics: Humans; Antimalarials; Malaria, Falciparum; Artemisinins; Malaria; Plant Extracts
PubMed: 38529311
DOI: 10.7717/peerj.17084 -
EBioMedicine Nov 2023A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome...
BACKGROUND
A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently, we established CHI-S model using single-sex male-only Schistosoma mansoni (Sm) cercariae in Schistosoma-naïve individuals. Given important differences in antigenic profile and human immune responses to schistosomes of different sex, we pioneered a single-sex female-only CHI-S model for future use in vaccine development.
METHODS
We exposed 13 healthy, Schistosoma-naïve adult participants to 10 (n = 3) or 20 (n = 10) female cercariae and followed for 20 weeks, receiving treatment with praziquantel (PZQ) 60 mg/kg at week 8 and 12 after exposure.
FINDINGS
The majority (11/13) participants reported rash and/or itch at the site of exposure, 5/13 had transient symptoms of acute schistosomiasis. Exposure to 20 cercariae led to detectable infection, defined as serum circulating anodic antigen levels >1.0 pg/mL, in 6/10 participants. Despite two rounds of PZQ treatment, 4/13 participants showed signs of persistent infection. Additional one- or three-day PZQ treatment (1 × 60 mg/kg and 3 × 60 mg/kg) or artemether did not result in cure, but over time three participants self-cured. Antibody, cellular, and cytokine responses peaked at week 4 post infection, with a mixed Th1, Th2, and regulatory profile. Cellular responses were (most) discriminative for symptoms.
INTERPRETATION
Female-only infections exhibit similar clinical and immunological profiles as male-only infections but are more resistant to PZQ treatment. This limits future use of this model and may have important implications for disease control programs.
FUNDING
European Union's Horizon 2020 (grant no. 81564).
Topics: Adult; Animals; Humans; Male; Female; Schistosomiasis mansoni; Healthy Volunteers; Schistosoma mansoni; Praziquantel; Cytokines; Anthelmintics
PubMed: 37837930
DOI: 10.1016/j.ebiom.2023.104832 -
Molecules (Basel, Switzerland) Apr 2024, a pivotal genus within the family, is renowned for its extensive biological significance and medicinal potential. The genus's sesquiterpene compounds have attracted... (Review)
Review
, a pivotal genus within the family, is renowned for its extensive biological significance and medicinal potential. The genus's sesquiterpene compounds have attracted considerable interest from the scientific community due to their structural complexity and diverse biological activities. These compounds exhibit a range of biological activities, including antimalarial, antibacterial, anti-inflammatory analgesic, and anti-tumor properties, positioning them as promising candidates for medical applications. This review aims to summarize the current knowledge on the variety, species, and structural characteristics of sesquiterpene compounds isolated from plants. Furthermore, it delves into their pharmacological activities and underlying mechanisms, offering a comprehensive foundation for future research.
Topics: Annonaceae; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Sesquiterpenes
PubMed: 38611927
DOI: 10.3390/molecules29071648 -
Parasites & Vectors Jul 2023Helminth infections are an important public health problem in humans and have an even greater impact on domestic animal and livestock welfare. Current readouts for...
BACKGROUND
Helminth infections are an important public health problem in humans and have an even greater impact on domestic animal and livestock welfare. Current readouts for anthelmintic drug screening assays are stage development, migration, or motility that can be subjective, laborious, and low in throughput. The aim of this study was to apply and optimize a fluorometric technique using resazurin for evaluating changes in the metabolic activity of Ascaris suum third-stage larvae (L3), a parasite of high economic relevance in swine.
METHODS
Ascaris suum L3 were mechanically hatched from 6- to 8-week embryonated and sucrose-gradient-enriched eggs. Resazurin dye and A. suum L3 were titrated in 96-well microtiter plates, and resazurin reduction activity was assessed by fluorometry after 24 h of incubation. Fluorescence microscopy was used to localize the resazurin reduction site within the larvae. Finally, we exposed A. suum L3 to various stress conditions including heat, methanol, and anthelmintics, and investigated their impact on larval metabolism through resazurin reduction activity.
RESULTS
We show that the non-fluorescent dye resazurin is reduced inside vital A. suum L3 to fluorescent resorufin and released into the culture media. Optimal assay parameters are 100-1000 L3 per well, a resazurin concentration of 7.5 µg/ml, and incubation at 37 °C/5% CO for 24 h. An intact L2 sheath around the L3 of A. suum completely prevents the uptake of resazurin, while in unsheathed L3, the most intense fluorescence signal is observed along the larval midgut. L3 exposed to methanol or heat show a gradually decreased resazurin reduction activity. In addition, 24 h exposure to ivermectin at 0.625 µM, mebendazole at 5 µM, and thiabendazole from 10 to 100 µM significantly decreased larval metabolic activity by 55%, 73%, and 70% to 89%, respectively.
CONCLUSIONS
Together, our results show that both metabolic stressors and anthelmintic drugs significantly and reproducibly reduce the resazurin reduction activity of A. suum L3, making the proposed assay a sensitive and easy-to-use method to evaluate metabolic activity of A. suum L3 in vitro.
Topics: Humans; Animals; Swine; Ascaris suum; Methanol; Anthelmintics; Xanthenes; Ascariasis; Larva
PubMed: 37468906
DOI: 10.1186/s13071-023-05871-5 -
Cell Chemical Biology Feb 2024Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays,...
Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, assessed the in vitro evolution of resistance, and performed a transcriptome analysis of the most potent peptaibol, HZ NPDG-I. HZ NPDG-I and 2 additional peptaibols were compared for their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content via ultrastructural analysis. HZ NPDG-I demonstrated a stepwise increase in DV pH, impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and 3 independent lines evolved to resist HZ NPDG-I acquired nonsynonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1. Conditional knockdown of PfMDR1 showed varying effects to other peptaibol analogs, suggesting differing sensitivity.
Topics: Humans; Peptaibols; Antimalarials; Membrane Transport Proteins; Cell Membrane Permeability; Malaria, Falciparum
PubMed: 37995692
DOI: 10.1016/j.chembiol.2023.10.025