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Malaria Journal Aug 2023Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum...
Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Chad: clinical and genetic surveillance.
BACKGROUND
Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum infections in Chad. This study assessed the efficacy of these artemisinin-based combinations, proportion of day 3 positive patients, proportions of molecular markers associated with P. falciparum resistance to anti-malarial drugs and variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).
METHODS
A single-arm prospective study assessing the efficacy of AS-AQ and AL at three sites (Doba, Kelo and Koyom) was conducted between November 2020 to January 2021. Febrile children aged 6 to 59 months with confirmed uncomplicated P. falciparum infection were enrolled sequentially first to AS-AQ and then AL at each site and followed up for 28 days. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples collected on day 0 were analysed for mutations in pfkelch13, pfcrt, pfmdr-1, pfdhfr, pfdhps genes and deletions in pfhrp2/pfhrp3 genes.
RESULTS
By the end of 28-day follow-up, per-protocol PCR corrected ACPR of 97.8% (CI 95% 88.2-100) in Kelo and 100% in Doba and Kayoma were observed among AL treated patients. For ASAQ, 100% ACPR was found in all sites. All, but one patient, did not have parasites detected on day 3. Out of the 215 day 0 samples, 96.7% showed pfkelch13 wild type allele. Seven isolates carried nonsynonymous mutations not known to be associated artemisinin partial resistance (ART-R). Most of samples had a pfcrt wild type allele (79% to 89%). The most prevalent pfmdr-1 allele detected was the single mutant 184F (51.2%). For pfdhfr and pfdhps mutations, the quintuple mutant allele N51I/C59R/S108N + G437A/540E responsible for SP treatment failures in adults and children was not detected. Single deletion in the pfhrp2 and pfhrp3 gene were detected in 10/215 (4.7%) and 2/215 (0.9%), respectively. Dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, were observed in 5/215 (2.3%) isolates.
CONCLUSION
The results of this study confirm that AS-AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance. Trial registration ACTRN12622001476729.
Topics: Adult; Female; Pregnancy; Humans; Artesunate; Antimalarials; Amodiaquine; Artemether, Lumefantrine Drug Combination; Chad; Prospective Studies; Artemether; Malaria, Falciparum; Artemisinins
PubMed: 37612601
DOI: 10.1186/s12936-023-04644-w -
Scientific Reports Jul 2023Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing...
Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing antimalarial therapies has complicated the problem, and the emergence of resistance to artemisinin derivatives is even more concerning. It is increasingly difficult to cure malaria patients due to the limited availability of effective antimalarial drugs, resulting in an urgent need for more efficacious and affordable treatments to eradicate this disease. Herein, new nucleoside analogues including morpholino-nucleoside hybrids and thio-substituted nucleoside derivatives were prepared and evaluated for in vitro and in vivo antiparasitic activity that led a few hits especially nucleoside-thiopyranoside conjugates, which are highly effective against Pf3D7 and PfRKL-9 strains in submicromolar concentration. One adenosine derivative and four pyrimidine nucleoside analogues significantly reduced the parasite burden in mouse models infected with Plasmodium berghei ANKA. Importantly, no significant hemolysis and cytotoxicity towards human cell line (RAW) was observed for the hits, suggesting their safety profile. Preliminary research suggested that these thiosugar-nucleoside conjugates could be used to accelerate the antimalarial drug development pipeline and thus deserve further investigation.
Topics: Animals; Mice; Humans; Antimalarials; Nucleosides; Sugars; Plasmodium falciparum; Malaria; Malaria, Falciparum; Plasmodium berghei
PubMed: 37507429
DOI: 10.1038/s41598-023-39541-4 -
PLoS Neglected Tropical Diseases Nov 2023Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of paromomycin/miltefosine/liposomal amphotericin B combinations for the treatment of post-kala-azar dermal leishmaniasis in Sudan: A phase II, open label, randomized, parallel arm study.
BACKGROUND
Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for ≥ 6 months) or grade 3 PKDL, aged 6 to ≤ 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 87% of patients were ≤12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-LAmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in PM/MF arm and 28/55 (50.9%) in LAmB/MF arm, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported.
CONCLUSIONS/SIGNIFICANCE
The PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955 ClinicalTrials.gov ClinicalTrials.gov.
Topics: Humans; Child; Paromomycin; Leishmaniasis, Visceral; Antiprotozoal Agents; Leishmaniasis, Cutaneous; Phosphorylcholine; Treatment Outcome
PubMed: 37988402
DOI: 10.1371/journal.pntd.0011780 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2023Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine...
Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and β-carboline alkaloid harmine against cancer cell lines and . The hybrids were prepared from the corresponding amines by 1,1'-carbonyldiimidazole (CDI)-mediated synthesis. evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 ( = 5.48 ± 3.35 μmol L). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the life cycle identified CQ-based UT harmiquine as a novel antiplasmodial hit because it displayed low values in the submicromolar range against CQ-sensitive and resistant strains ( 0.06 ± 0.01, and 0.19 ± 0.02 μmol L, respectively), and exhibited high selectivity against , compared to mammalian cells (SI = 92).
Topics: Humans; Antimalarials; Cell Line, Tumor; Chloroquine; Mefloquine; Parasitic Sensitivity Tests
PubMed: 38147482
DOI: 10.2478/acph-2023-0035 -
Tropical Animal Health and Production Sep 2023Haemonchus contortus (H. contortus) is one of the most prevalent gastrointestinal nematodes, causing health problems and economic losses in ruminants. Nanotechnology...
Emerging alternatives to traditional anthelmintics: the in vitro antiparasitic activity of silver and selenium nanoparticles, and pomegranate (Punica granatum) peel extract against Haemonchus contortus.
Haemonchus contortus (H. contortus) is one of the most prevalent gastrointestinal nematodes, causing health problems and economic losses in ruminants. Nanotechnology holds great promise as a field of science, with potential applications in veterinary medicine. This study investigated the in vitro anthelmintic activity of silver nanoparticles (AgNPs), selenium nanoparticles (SeNPs), and pomegranate peel extract (Punica granatum; PPE) on different stages of H. contortus: eggs, larvae, and adults. The in vitro anthelmintic efficacy was evaluated using the egg hatching inhibition assay (EHA), the third larval stage paralysis assay (LPA), and the adult worm motility inhibition assay (WMI). Six dilutions of PPE were utilized for EHA, LPA, and WMI, ranging from 0.25 to 6 mg/ml. AgNPs dilutions ranged from 0.00001 to 1.0 μg/ml for EHA and LPA and 1 to 25 μg/ml for WMI. SeNPs were utilized at dilutions of 1, 5, 10, and 15 μg/ml for EHA, LPA, and WMI. The results showed that the lowest concentration of AgNPs, SeNPs, and PPE significantly inhibited egg hatching. To further assess larvicidal activity, AgNPs at the highest concentration of 1 μg/ml induced a strong larvicidal effect, as did SeNPs at the lowest concentration. On the contrary, PPE displayed a significant larvicidal effect at 1 mg/ml compared to the control. The percentage mortality of adult H. contortus was measured as follows (mortality (%) = the number of dead adult H. contortus/total number of adult H. contortus per test × 100). The death of the adult H. contortus was determined by the absence of motility. Adult H. contortus mortality percentage was also significantly affected by all three agents when compared to the control. The AgNPs, SeNPs, and PPE have effective antiparasitic activity on gastrointestinal parasitic nematodes. These results provide evidence of the excellent antiparasitic properties of AgNPs, SeNPs, and PPE, demonstrating their effectiveness in controlling eggs, larvae, and adult H. contortus in vitro.
Topics: Animals; Pomegranate; Antiparasitic Agents; Selenium; Haemonchus; Silver; Metal Nanoparticles; Ovum; Anti-Infective Agents; Anthelmintics; Larva; Plant Extracts
PubMed: 37737938
DOI: 10.1007/s11250-023-03722-0 -
Medecine Tropicale Et Sante... Jun 2023In 2022 as in 1884, the clinical presentation of uncomplicated malaria is unspecific: fever of variable intensity, continuous or rhythmic, chills, flu syndrome,...
In 2022 as in 1884, the clinical presentation of uncomplicated malaria is unspecific: fever of variable intensity, continuous or rhythmic, chills, flu syndrome, headache, respiratory and digestive disorders. At any time, it can evolve into a severe form (ex-pernicious attack or cerebral malaria) or even lethal. By reading again Alphonse Laveran's book on malarial fevers, we realized to what extent the observations made at that time allowed for a methodical and orderly description of the clinical forms of malaria, very close to what we can still observe today. No symptom or sign is pathognomonic of the disease. Only the detection of plasmodia or "malaria microbes" by direct or immuno-chromatographic methods allows for diagnostic confirmation, which is a prerequisite for the implementation of a curative treatment.Serendipity, synthetic chemistry and traditional medicine are the three methods that led to the discovery and large-scale production of antimalarial drugs. Serendipity for quinine, synthetic chemistry for chloroquine, and research conducted around traditional Chinese medicine for artemisinin and its derivatives. The latter have marked a real revolution in the management of malaria, both in its uncomplicated and severe forms. However, as with other antimalarial drugs, its medium- and long-term efficacy is compromised by the emergence and spread of resistance in malaria parasites, particularly The control and eradication of malaria therefore require continued research in both prevention and therapy.The disease so well described by Alphonse Laveran has not yet said its last word….
Topics: Humans; Antimalarials; Plasmodium; Quinine; Chloroquine; Malaria, Cerebral
PubMed: 37525671
DOI: 10.48327/mtsi.v3i2.2023.378 -
ACS Infectious Diseases Jun 2024Antiparasitic drug development stands as a critical endeavor in combating infectious diseases which, by affecting the well-being of humans, animals, and the environment,... (Review)
Review
Antiparasitic drug development stands as a critical endeavor in combating infectious diseases which, by affecting the well-being of humans, animals, and the environment, pose significant global health challenges. In a scenario where conventional pharmacological interventions have proven inadequate, the One Health approach, which emphasizes interdisciplinary collaboration and holistic solutions, emerges as a vital strategy. By advocating for the integration of One Health principles into the R&D pharmaceutical pipeline, this Perspective promotes green chemistry methodologies to foster the development of environmentally friendly antiparasitic drugs for both human and animal health. Moreover, it highlights the urgent need to address vector-borne parasitic diseases (VBPDs) within the context of One Health-driven sustainable development, underscoring the pivotal role of medicinal chemists in driving transformative change. Aligned with the Sustainable Development Goals (SDGs) and the European Green Deal, this Perspective explores the application of the 12 Principles of Green Chemistry as a systematic framework to guide drug discovery and production efforts in the context of VBPD. Through interdisciplinary collaboration and a constant commitment to sustainability, the field can overcome the challenges posed by VBPD while promoting global and environmental responsibility. Serving as a call to action, scientists are urged to integrate One Health concepts and green chemistry principles into routine drug development practices, thereby paving the way for a more sustainable R&D pharmaceutical pipeline for antiparasitic drugs.
Topics: Antiparasitic Agents; Humans; Green Chemistry Technology; One Health; Animals; Drug Discovery; Parasitic Diseases; Drug Development; Vector Borne Diseases; Sustainable Development
PubMed: 38724015
DOI: 10.1021/acsinfecdis.4c00172 -
Infection and Immunity Jul 2023Cystic echinococcosis (CE) is a disease caused by the infection of Echinococcus granulosus. We sought to investigate the effects of dihydroartemisinin (DHA) against CE...
Cystic echinococcosis (CE) is a disease caused by the infection of Echinococcus granulosus. We sought to investigate the effects of dihydroartemisinin (DHA) against CE under and conditions. Protoscoleces (PSCs) from were divided into control, DMSO, ABZ, DHA-L, DHA-M, and DHA-H groups. PSC viability after DHA treatment was determined based on the eosin dye exclusion test, alkaline phosphatase content detection, and ultrastructure observation. DNA oxidative damage inducer hydrogen peroxide (HO), reactive oxygen species (ROS) scavenger mannitol, and the DNA damage repair inhibitor velparib were used to explore the anti-CE mechanism of DHA. The anti-CE effects and CE-induced liver injury and oxidative stress of DHA at different doses (50, 100, and 200 mg/kg) were assessed in CE mice. DHA showed antiparasitic effects on CE in both and experiments. DHA could elevate the ROS level and induce oxidative DNA damage in PSCs, thereby destroying hydatid cysts. DHA could inhibit the growth of cysts in a dose-dependent manner and reduce the content of biochemical parameters associated with liver injury in CE mice. It also significantly reversed oxidative stress in CE mice, which was characterized as the decreased tumor necrosis factor alpha and HO content, as well as the increase of the ratio of glutathione/oxidized glutathione and total superoxide dismutase content. DHA showed antiparasitic effects. DNA damages induced by oxidative stress played important roles in this process.
Topics: Animals; Mice; Hydrogen Peroxide; Reactive Oxygen Species; Echinococcosis; Echinococcus granulosus; Antiparasitic Agents
PubMed: 37310215
DOI: 10.1128/iai.00470-22 -
International Journal of Nanomedicine 2024Nowadays, recycling agricultural waste is of the utmost importance in the world for the production of valuable bioactive compounds and environmental protection. Olive...
BACKGROUND
Nowadays, recycling agricultural waste is of the utmost importance in the world for the production of valuable bioactive compounds and environmental protection. Olive leaf bioactive compounds have a significant potential impact on the pharmaceutical industry. These compounds possess remarkable biological characteristics, including antimicrobial, antiviral, anti-inflammatory, hypoglycemic, and antioxidant properties.
METHODS
The present study demonstrates a green synthetic approach for the fabrication of nickel oxide nanoparticles (NiO-olive) using aqueous wasted olive leaf extract. Calcination of NiO-olive at 500°C led to the fabrication of pure NiO nanoparticles (NiO-pure). Different techniques, such as thermal gravimetric analysis (TGA), Fourier-transform infrared spectra (FTIR), ultraviolet-visible spectra (UV-Vis), X-ray diffraction (XRD), scanning electron microscopy (SEM) fitted with energy-dispersive X-ray analysis (EDX), and transmission electron microscopy (TEM), were used to characterize both NiO-olive and NiO-pure. The extract and nanoparticles were assessed for antiparasitic activity against adult ticks () and antimicrobial activity against .
RESULTS
From XRD, the crystal sizes of NiO-olive and NiO-pure were 32.94 nm and 13.85 nm, respectively. TGA, FTIR, and EDX showed the presence of olive organic residues in NiO-olive and their absence in NiO-pure. SEM and TEM showed an asymmetrical structure of NiO-olive and a regular, semi-spherical structure of NiO-pure. UV-Vis spectra showed surface plasmon resonance of NPs. Antiparasitic activity showed the highest mortality rate of 95% observed at a concentration of 0.06 mg/mL after four days of incubation. The antimicrobial activity showed the largest inhibition zone diameter of 33 ± 0.2 mm against the strain.
CONCLUSION
Nanoparticles of NiO-olive outperformed nanoparticles of NiO-pure and olive leaf extract in both antiparasitic and antimicrobial tests. These findings imply that NiO-olive may be widely used as an eco-friendly and effective antiparasitic and disinfection of sewage.
Topics: Antiparasitic Agents; Metal Nanoparticles; Anti-Infective Agents; Plant Extracts; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction; Anti-Bacterial Agents; Microbial Sensitivity Tests; Olea
PubMed: 38380146
DOI: 10.2147/IJN.S443965 -
Lipids in Health and Disease Dec 2023Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and...
BACKGROUND
Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and promote fascial adipogenesis, and this effect is related to the structure of heparin. Regarding the structural and physiological properties of the negatively charged polymers, hexasulfonated suramin, a centuries-old medicine that is still used for treating African trypanosomiasis and onchocerciasis, is assumed to be a heparin-related analog or heparinoid. This investigation aims to elucidate the influence of suramin on the adipogenesis.
METHODS
To assess the influence exerted by suramin on adipogenic differentiation of primary white adipocytes in rats, this exploration was conducted both in vitro and in vivo. Moreover, it was attempted to explore the role played by the sulfonic acid groups present in suramin in mediating this adipogenic process.
RESULTS
Suramin demonstrated a dose- and time-dependent propensity to stimulate the adipogenic differentiation of rat preadipocytes isolated from the superficial fascia tissue and from adult adipose tissue. This stimulation was concomitant with a notable upregulation in expression levels of pivotal adipogenic factors as the adipocyte differentiation process unfolded. Intraperitoneal injection of suramin into rats slightly increased adipogenesis in the superficial fascia and in the epididymal and inguinal fat depots. PPADS, NF023, and NF449 are suramin analogs respectively containing 2, 6, and 8 sulfonic acid groups, among which the last two moderately promoted lipid droplet formation and adipocyte differentiation. The number and position of sulfonate groups may be related to the adipogenic effect of suramin.
CONCLUSIONS
Suramin emerges as a noteworthy pharmaceutical agent with the unique capability to significantly induce adipocyte differentiation, thereby fostering adipogenesis.
Topics: Rats; Animals; Adipogenesis; Suramin; Antiparasitic Agents; Cell Differentiation; Adipocytes, White; Heparin
PubMed: 38093311
DOI: 10.1186/s12944-023-01980-3