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1.
Parasitology ; 150(12): 1158-1166, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37183698

RESUMEN

Parasites and parasitologists have always lived together in good and bad luck in a sort of forced marriage. In recent times bad luck certainly prevailed, because of increasing man-made emergencies such as wars, chemical disasters, but also because of natural disasters, amplified by climate change, that condition more and more parasite­host equilibrium. The symposium at the National Congress of the Italian Society for Parasitology, was a first occasion for Italian parasitologists to reason about 'disaster parasitology' and researchers' responsibilities. Extreme weather events and their impacts on parasites' epidemiology are illustrated, comparing disasters that recently occurred in Italy with literature data. In particular, the Sardinian Island was hit subsequently by fires and floods exacerbating the effects on ecosystems and parasite­host-relationships. Examples of Cryptosporidium outbreaks in man and Fasciola hepatica infections in various hosts after heavy rains are reviewed and effects of droughts on pasture borne parasites, such as gastro-intestinal nematodes of ruminants are discussed. Heavy rains may also cause dissemination of toxic substances released accidentally from chemical plants as happened e.g. in Milan province (IT) after the dioxin hazard. The overlapping effects of strictly man-made disasters with climate change dependent extreme weather events is further challenging the understanding of what are the consequences of disasters on ecosystems and parasite epidemiology.GIS applications combined with AI programs may help to face the complex challenges, allowing the collection and analysis of spatial/temporal data at whatever level desired. Examples illustrated in the article suggest their employment also in a more systematic, prevention-oriented manner.


Asunto(s)
Criptosporidiosis , Cryptosporidium , Parásitos , Animales , Humanos , Tiempo (Meteorología) , Ecosistema , Cambio Climático
2.
Malar J ; 18(1): 35, 2019 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-30736813

RESUMEN

BACKGROUND: Medicinal plant research may contribute to develop new pharmacological control tools for vector borne diseases, such as malaria. METHODS: The effects of methanol extracts (ME) obtained from seed kernel of ripe and unripe Azadirachta indica fruits were studied on erythrocytic proliferation of the rodent malaria parasite Plasmodium berghei strain ANKA and on mice pro-inflammatory response, as evaluated by measuring the matrix-metalloproteinase-9 (MMP-9) and tumour necrosis factor (TNF) plasma levels, in two mouse strains (C57BL/6 and BALB/c) which are considered as prototypical of Th1 and Th2 immune response, respectively. RESULTS: ME obtained from seed kernel of unripe Azadirachta indica fruits decreased by about 30% the proportion of erythrocytes infected with the malaria parasite in C57BL/6 mice in the 4 days suppressive test. In this treatment group, MMP-9 and TNF levels were notably higher than those measured in the same mouse strain treated with the anti-malarial drug artesunate, Azadirachta indica kernel extracts from ripe fruits or solvent. In BALB/c mice, treatment with kernel extracts did not influence parasitaemia. MMP-9 and TNF levels measured in this mouse strain were notably lower than those recorded in C57BL/6 mice and did not vary among treatment groups. CONCLUSIONS: The effects of the ME on the parasite-host interactions appeared to be mouse strain-dependent, but also related to the ripening stage of the neem fruits, as only the unripe fruit seed kernel extracts displayed appreciable bioactivity.


Asunto(s)
Antimaláricos/farmacología , Azadirachta/química , Malaria/tratamiento farmacológico , Parasitemia/tratamiento farmacológico , Extractos Vegetales/farmacología , Plasmodium berghei/efectos de los fármacos , Animales , Sistemas de Liberación de Medicamentos , Eritrocitos/parasitología , Femenino , Inflamación/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Plantas Medicinales/química , Semillas/química
3.
Bioorg Chem ; 93: 103321, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31585261

RESUMEN

Bioassay-guided fractionation of the organic extract obtained from stem barks of the African plant Lophira lanceolata has led to the isolation of seven biflavonoids, including the new α'-chlorolophirone E (5) and 5'-chlorolophirone D (6). Among the isolated compounds, the bichalcone lophirone E was identified as a potent gametocytocidal agent with an IC50 value in the nanomolar range and negligible cytotoxicity (selectivity index = 570). Lophirone E proved to be about 100 times more active against P. falciparum stage V gametocytes than on asexual blood stages, thus exhibiting a unique stage-specific activity profile. The isolation of structural analogues allowed to draw preliminary structure-activity relationships, identifying the critical positions on the chemical scaffold of lophirone E.


Asunto(s)
Antimaláricos/química , Ochnaceae/química , Corteza de la Planta/química , Tallos de la Planta/química , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Línea Celular , Humanos , Concentración 50 Inhibidora , Plasmodium falciparum/efectos de los fármacos , Análisis Espectral/métodos , Relación Estructura-Actividad
4.
J Nat Prod ; 80(10): 2787-2794, 2017 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-28976194

RESUMEN

Phytochemical investigation of the aerial parts of the Tunisian plant Daucus virgatus led to the isolation of eight new germacranolides named daucovirgolides A-H (1-8). The stereostructures of these sesquiterpene lactones, decorated by either one or two angeloyl groups, have been determined by a combination of MS, NMR spectroscopy, chemical derivatization, and comparison of experimental electronic circular dichroism curves with TDDFT-predicted data. Daucovirgolide G (7) proved to be the single member of this family to possess a marked inhibitory activity (92% at 50 µg/mL) on the development of Plasmodium early sporogonic stages, the nonpathogenic transmissible stages of malaria parasites, devoid of general cytotoxicity. The selective activity of daucovirgolide G points to the existence of strict structural requirements for this transmission-blocking activity and therefore of a well-defined, although yet unidentified, biological target.


Asunto(s)
Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Apiaceae/química , Componentes Aéreos de las Plantas/química , Sesquiterpenos de Germacrano/aislamiento & purificación , Sesquiterpenos de Germacrano/farmacología , Antimaláricos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Plasmodium/efectos de los fármacos , Sesquiterpenos de Germacrano/química , Túnez
5.
Molecules ; 22(12)2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29194347

RESUMEN

Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16-53 nM), matched with a high potency against P. vivax field isolates (Mean IC50 29 nM). Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P.berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.


Asunto(s)
Aminoquinolinas/química , Aminoquinolinas/farmacología , Antimaláricos/química , Antimaláricos/toxicidad , Quinolizidinas/química , Quinolizidinas/farmacología , Aminoquinolinas/toxicidad , Animales , Antimaláricos/farmacología , Artemisininas/farmacología , Cloroquina/farmacología , Resistencia a Medicamentos , Células HEK293 , Humanos , Concentración 50 Inhibidora , Malaria/tratamiento farmacológico , Masculino , Ratones , Parasitemia/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Quinolizidinas/toxicidad , Esparteína/análogos & derivados , Esparteína/química , Esparteína/farmacología
6.
Antimicrob Agents Chemother ; 59(9): 5135-44, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26055362

RESUMEN

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.


Asunto(s)
Antimaláricos/farmacología , Ionóforos/farmacología , Piranos/farmacología , Antimaláricos/efectos adversos , Línea Celular , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Hemólisis/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ionóforos/efectos adversos , Estructura Molecular , Monensina/efectos adversos , Monensina/farmacología , Nigericina/efectos adversos , Nigericina/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/patogenicidad , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/patogenicidad , Piranos/efectos adversos
7.
Malar J ; 14: 288, 2015 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-26208861

RESUMEN

BACKGROUND: Medicinal plants are a validated source for discovery of new leads and standardized herbal medicines. The aim of this study was to assess the activity of Vernonia amygdalina leaf extracts and isolated compounds against gametocytes and sporogonic stages of Plasmodium berghei and to validate the findings on field isolates of Plasmodium falciparum. METHODS: Aqueous (Ver-H2O) and ethanolic (Ver-EtOH) leaf extracts were tested in vivo for activity against sexual and asexual blood stage P. berghei parasites. In vivo transmission blocking effects of Ver-EtOH and Ver-H2O were estimated by assessing P. berghei oocyst prevalence and density in Anopheles stephensi mosquitoes. Activity targeting early sporogonic stages (ESS), namely gametes, zygotes and ookinetes was assessed in vitro using P. berghei CTRPp.GFP strain. Bioassay guided fractionation was performed to characterize V. amygdalina fractions and molecules for anti-ESS activity. Fractions active against ESS of the murine parasite were tested for ex vivo transmission blocking activity on P. falciparum field isolates. Cytotoxic effects of extracts and isolated compounds vernolide and vernodalol were evaluated on the human cell lines HCT116 and EA.hy926. RESULTS: Ver-H2O reduced the P. berghei macrogametocyte density in mice by about 50% and Ver-EtOH reduced P. berghei oocyst prevalence and density by 27 and 90%, respectively, in An. stephensi mosquitoes. Ver-EtOH inhibited almost completely (>90%) ESS development in vitro at 50 µg/mL. At this concentration, four fractions obtained from the ethylacetate phase of the methanol extract displayed inhibitory activity >90% against ESS. Three tested fractions were also found active against field isolates of the human parasite P. falciparum, reducing oocyst prevalence in Anopheles coluzzii mosquitoes to one-half and oocyst density to one-fourth of controls. The molecules and fractions displayed considerable cytotoxicity on the two tested cell-lines. CONCLUSIONS: Vernonia amygdalina leaves contain molecules affecting multiple stages of Plasmodium, evidencing its potential for drug discovery. Chemical modification of the identified hit molecules, in particular vernodalol, could generate a library of druggable sesquiterpene lactones. The development of a multistage phytomedicine designed as preventive treatment to complement existing malaria control tools appears a challenging but feasible goal.


Asunto(s)
Antimaláricos/farmacología , Malaria/transmisión , Extractos Vegetales/farmacología , Plasmodium berghei/efectos de los fármacos , Vernonia/química , Animales , Anopheles/parasitología , Antimaláricos/uso terapéutico , Antimaláricos/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Malaria/tratamiento farmacológico , Malaria/parasitología , Malaria/prevención & control , Masculino , Ratones , Extractos Vegetales/uso terapéutico , Extractos Vegetales/toxicidad
8.
J Nat Prod ; 78(7): 1618-23, 2015 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-26115003

RESUMEN

In addition to known compounds, the leaves of Vernonia amygdalina afforded the new sesquiterpene lactones 14-O-methylvernolide (2), 3'-deoxyvernodalol (6), and vernomygdalin (8). These and related compounds were evaluated for modulation of a series of thiol trapping-sensitive transcription factors (NF-κB, STAT3, and Nrf2), involved in the maintenance of the chronic inflammatory condition typical of human degenerative diseases. Vernolide (1) emerged as a potent inhibitor of STAT3 and NF-κB and showed cytostatic activity toward the prostate cancer cell line DU45, arresting the cell cycle at the S phase. The exomethylene lactones are characterized by multiple Michael acceptor sites, as exemplified by vernolide (1) and vernodalol (5). By using the nuclear magnetic resonance-based cysteamine assay, the most reactive thiophilic site could be identified in both compounds, and competitive experiments qualified vernolide (1) as being more thiophilic than vernodalol (5), in agreement with the results of the pharmacological assays.


Asunto(s)
Lactonas/aislamiento & purificación , Lactonas/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Compuestos de Sulfhidrilo/química , Vernonia/química , Ciclo Celular/efectos de los fármacos , Cisteamina/química , Humanos , Lactonas/química , Estructura Molecular , Factor 2 Relacionado con NF-E2/efectos de los fármacos , FN-kappa B/efectos de los fármacos , Hojas de la Planta/química , Factor de Transcripción STAT3/efectos de los fármacos , Sesquiterpenos/química , Compuestos de Sulfhidrilo/farmacología
9.
J Med Entomol ; 51(4): 831-6, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25118416

RESUMEN

Fecundity, bloodmeal size, and survival are among the most important parameters in the overall fitness of mosquitoes. Impact of an intervention that affects fecundity can be assessed by directly counting the eggs laid by exposed mosquitoes, which is usually done manually. We have developed a macroinstruction, which can be used to count thousands of Anopheles stephensi Liston eggs in a few minutes, to provide an alternative and adaptable method to egg counting as a measure of fecundity. The macro was developed using a scanner and a computer running AxioVision Rel. 4.8 software, a freely accessible software compatible with Windows XP/7/Vista. Using this semiautomated method, it is possible to reduce time, avoid human error and bias, and obtain improved consistency in studies measuring mosquito fecundity.


Asunto(s)
Anopheles , Insectos Vectores , Control de Mosquitos/métodos , Animales , Femenino , Fertilidad , Ratones , Ratones Endogámicos BALB C , Control de Mosquitos/instrumentación , Recuento de Huevos de Parásitos/instrumentación , Recuento de Huevos de Parásitos/métodos
10.
Photochem Photobiol Sci ; 11(2): 294-301, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22011789

RESUMEN

The increasing use of photosensitized processes for disinfection of microbiologically polluted waters requires a precise definition of the factors controlling the degree of photosensitivity in target and non-target organisms. In this regard, tests with protozoa and invertebrates which have a natural habitat in such waters may be used as first screening methods for the assessment of possible hazards for the ecosystem. A new cationic porphyrin, namely meso-tri(N-methyl-pyridyl)mono(N-dodecyl-pyridyl)porphine (C12), is tested in this work on the protozoan Ciliophora Colpoda inflata and Tetrahymena thermophila and the Crustacea Branchiopoda Artemia franciscana and Daphnia magna. The protocol involved 1 h incubation with porphyrin doses in the 0.1-10.0 µM range and subsequent irradiation with visible light at a fluence rate of 10 mW cm(-2). The results indicate that C12 porphyrin has a significant affinity for C. inflata and T. thermophila; this is also shown by fluorescence microscopic analyses. C. inflata cysts were resistant to the phototreatment up to a porphyrin dose of 0.6 µM. The effects of C12 on cysts have been evaluated at 3 and 24 h after the end of the phototreatment; a delay in the excystment process was observed. T. thermophila was fairly resistant to the phototreatment with C12 porphyrin. The data obtained with the two crustaceans indicated that the effects of dark- and photo-treatment with C12 need to be closely examined for every organism. A. franciscana is more resistant, probably owing to its ability to adapt to extreme conditions, while the high level of photosensitivity displayed by Daphnia magna represents a potential drawback, as this organism is often selected as a reference standard for assessing the environmental safety. Thus, while C12 photosensitisation can represent a useful tool for inducing a microbicidal or larvicidal action on polluted waters, the irradiation protocols must be carefully tailored to the nature of the specific water basin, and in particular to its biotic characteristics.


Asunto(s)
Artemia/efectos de los fármacos , Daphnia/efectos de los fármacos , Agua Dulce/microbiología , Insectos Vectores/efectos de los fármacos , Porfirinas/farmacología , Tetrahymena thermophila/efectos de los fármacos , Contaminación Química del Agua/prevención & control , Animales , Antiinfecciosos/farmacología , Artemia/efectos de la radiación , Cilios/efectos de los fármacos , Cilios/efectos de la radiación , Daphnia/efectos de la radiación , Oscuridad , Ecosistema , Control de Insectos , Insectos Vectores/efectos de la radiación , Fármacos Fotosensibilizantes/farmacología , Compuestos de Piridinio , Tetrahymena thermophila/citología , Tetrahymena thermophila/efectos de la radiación , Trofozoítos/efectos de los fármacos , Trofozoítos/efectos de la radiación
11.
Eur J Med Chem ; 215: 113227, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33601312

RESUMEN

Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite's digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes.


Asunto(s)
Antimaláricos/farmacología , Compuestos de Bencidrilo/farmacología , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Animales , Anopheles , Antimaláricos/síntesis química , Compuestos de Bencidrilo/síntesis química , Cloroquina/farmacología , Diseño de Fármacos , Farmacorresistencia Microbiana/efectos de los fármacos , Femenino , Células Hep G2 , Humanos , Proteínas de Transporte de Membrana , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Células 3T3 NIH , Pruebas de Sensibilidad Parasitaria , Isoformas de Proteínas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Xenopus
12.
Malar J ; 9: 66, 2010 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-20196858

RESUMEN

BACKGROUND: The wide use of gametocytocidal artemisinin-based combination therapy (ACT) lead to a reduction of Plasmodium falciparum transmission in several African endemic settings. An increased impact on malaria burden may be achieved through the development of improved transmission-blocking formulations, including molecules complementing the gametocytocidal effects of artemisinin derivatives and/or acting on Plasmodium stages developing in the vector. Azadirachtin, a limonoid (tetranortriterpenoid) abundant in neem (Azadirachta indica, Meliaceae) seeds, is a promising candidate, inhibiting Plasmodium exflagellation in vitro at low concentrations. This work aimed at assessing the transmission-blocking potential of NeemAzal(R), an azadirachtin-enriched extract of neem seeds, using the rodent malaria in vivo model Plasmodium berghei/Anopheles stephensi. METHODS: Anopheles stephensi females were offered a blood-meal on P. berghei infected, gametocytaemic BALB/c mice, treated intraperitoneally with NeemAzal, one hour before feeding. The transmission-blocking activity of the product was evaluated by assessing oocyst prevalence, oocyst density and capacity to infect healthy mice. To characterize the anti-plasmodial effects of NeemAzal(R) on early midgut stages, i.e. zygotes and ookinetes, Giemsa-stained mosquito midgut smears were examined. RESULTS: NeemAzal completely blocked P. berghei development in the vector, at an azadirachtin dose of 50 mg/kg mouse body weight. The totally 138 examined, treated mosquitoes (three experimental replications) did not reveal any oocyst and none of the healthy mice exposed to their bites developed parasitaemia. The examination of midgut content smears revealed a reduced number of zygotes and post-zygotic forms and the absence of mature ookinetes in treated mosquitoes. Post-zygotic forms showed several morphological alterations, compatible with the hypothesis of an azadirachtin interference with the functionality of the microtubule organizing centres and with the assembly of cytoskeletal microtubules, which are both fundamental processes in Plasmodium gametogenesis and ookinete formation. CONCLUSIONS: This work demonstrated in vivo transmission blocking activity of an azadirachtin-enriched neem seed extract at an azadirachtin dose compatible with 'druggability' requisites. These results and evidence of anti-plasmodial activity of neem products accumulated over the last years encourage to convey neem compounds into the drug discovery & development pipeline and to evaluate their potential for the design of novel or improved transmission-blocking remedies.


Asunto(s)
Limoninas/farmacología , Oocistos/efectos de los fármacos , Extractos Vegetales/farmacología , Plasmodium berghei/efectos de los fármacos , Animales , Anopheles/genética , Anopheles/inmunología , Anopheles/parasitología , Azadirachta/química , Femenino , Insectos Vectores/genética , Insectos Vectores/inmunología , Insectos Vectores/parasitología , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica , Oocistos/ultraestructura , Oviposición/efectos de los fármacos , Plasmodium berghei/crecimiento & desarrollo , Semillas
13.
J Nat Prod ; 73(8): 1448-52, 2010 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-20669933

RESUMEN

Eight known and two new triterpenoid derivatives, neemfruitins A (9) and B (10), have been isolated from the fruits of neem, Azadirachta indica, a traditional antimalarial plant used by Asian and African populations. In vitro antiplasmodial tests evidenced a significant activity of the known gedunin and azadirone and the new neemfruitin A and provided useful information about the structure-antimalarial activity relationships in the limonoid class.


Asunto(s)
Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Azadirachta/química , Plantas Medicinales/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Antimaláricos/química , Burkina Faso , Frutas/química , Limoninas/química , Limoninas/farmacología , Relación Estructura-Actividad , Triterpenos/química
14.
Malariaworld J ; 11: 1, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-34532220

RESUMEN

BACKGROUND: Current efforts towards malaria elimination include the discovery of new transmission blocking (TB) drugs and identification of compounds suitable to replace primaquine, recommended as transmission blocking post treatment after artemisinin combination therapy (ACT). High through put screening of compound libraries has allowed to identify numerous compounds active in vitro against gametocytes and insect early sporogonic stages, but few studies have been performed to characterize TB compounds in vivo. Here we propose a double TB drug Direct Feeding Assay (2TB-DFA), suitable to assess the combined effects of TB compounds. MATERIALS AND METHODS: Plasmodium berghei GFPcon (PbGFPcon), BALB/c mice and Anopheles stephensi mosquitoes were used. Artemisinin (ART) and artesunate (AS) served as examples of artemisinins, NeemAzal® (NA), as a known TB-product with sporontocidal activity. DFA experiments were performed to assess the appropriate time point of administration before mosquito feeding and estimate suitable sub-optimal doses of the three compounds that allow combination effects to be appreciated. RESULTS: Suboptimal dosages, that reduce about 50% of oocyst development, were recorded with ART in the range of 16-30 mg/ kg, AS 14-28 mg/kg and NA 31-38mg/kg. Ten hours before mosquito feeding (corresponding to 3.5 days after mouse infection) was determined as a suitable time point for mouse treatment with ART and AS and 1 hour for post-treatment with NA. ART given at 35 mg/kg in combination with NA at 40 mg/kg reduced oocyst density by 94% and prevalence of infection by 59%. Similarly, the combination of ART at 25 mg/kg plus NA at 35 mg/kg decreased oocyst density by 95% and prevalence of infection by 34%. In the 2TB-DFA, conducted with AS (20 mg/kg) and NA (35 mg/kg) the combination treatment reduced oocyst density by 71% and did not affect prevalence of infection. Applying 'Highest Single Agent' analysis and considering as readout oocyst density and prevalence of infection, cooperative effects of the combination treatments, compared with the single compound treatments emerged. CONCLUSION: This study suggests the 2TB-DFA to be suitable for the profiling of new TB candidates that could substitute primaquine as a post-treatment to ACT courses.

15.
Drug Des Devel Ther ; 14: 1593-1607, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32425505

RESUMEN

PURPOSE: Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages. METHODS: Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions. RESULTS: Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07-0.13 µM. They were also active against mature stage V gametocytes with IC50 values below 5 µM (range: 3.43-4.42 µM). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 µM. CONCLUSION: Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials.


Asunto(s)
Antimaláricos/farmacología , Malaria/tratamiento farmacológico , Fenilhidrazinas/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/administración & dosificación , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Malaria/transmisión , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Fenilhidrazinas/administración & dosificación , Relación Estructura-Actividad
16.
Phytochemistry ; 174: 112336, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32192964

RESUMEN

Targeting the transmissible stages of the Plasmodium parasite that develop in the human and mosquito host is a crucial strategy for malaria control and elimination. Medicinal plants offer a prolific source for the discovery of new antimalarial compounds. The recent identification of the gametocytocidal activity of lophirone E, obtained from the African plant Lophira lanceolata (Ochnaceae), inspired the evaluation of the plant also against early sporogonic stages of the parasite development. The bioassay-guided phytochemical study led to the isolation of two known lanceolins and of a new glycosylated bichalcone, named glucolophirone C. Its stereostructure, including absolute configuration of the bichalcone moiety, was elucidated by means of NMR, HRMS, ECD and computational calculations. Lanceolin B proved to be a potent inhibitor of the development of Plasmodium early sporogonic stages indicating that the plant produces two different stage-specific antimalarial agents acting on transmissible stages in the human and mosquito host.


Asunto(s)
Antimaláricos , Malaria , Ochnaceae , Animales , Humanos , Corteza de la Planta , Extractos Vegetales , Plasmodium falciparum
17.
Malariaworld J ; 6: 9, 2019 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-31293898

RESUMEN

BACKGROUND: About 30 million insecticide treated mosquito nets have been distributed in Kenya since 2001 and ownership is approaching full coverage. As a consequence of this achievement, Kenya is faced with the challenge of disposing old mosquito nets that are no longer in use. The study aimed at investigating ways of disposal and re-use of old and torn nets by end users. MATERIALS AND METHODS: A formative study was conducted in the former Malindi District, which is comprised of Malindi and Magarini sub-counties of Kilifi County in Coastal Kenya. A total of 6 Focus Group Discussions, 10 Key Informant Interviews and 9 transect walks/drives were undertaken. Data from the different sources were analysed separately and triangulated for similarities and differences. RESULTS: There were variations in disposal and re-use of old nets between urban and rural or peri-urban residents. In all settings, people adopted innovative and beneficial ways of re-using old, expired nets, and those that were damaged beyond repair. Common causes of damage were fire, children, domestic animals sharing the sleeping room and friction from the bed poles while hanging or tacking it in under a sleeping mat. Re-use was most prominent in farming activities (78%) and less to for use in mosquito control, like window screening (15%). The remaining 8% was related to making ropes, swings, footballs, goal posts and fishing nets. Advantageous texture and nature of the netting material, perceived economic benefit and lack of guidelines for disposal were the main reasons cited by residents for re-using old nets. CONCLUSIONS: It is important that re-use and disposal of old mosquito nets is distinguished from misuse of newly distributed mosquito nets. Alternative uses of old nets as opposed to misuse of new nets was found to be common in our study.

18.
Malariaworld J ; 8: 21, 2019 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-31338302

RESUMEN

BACKGROUND: Since 2000, a decrease in malaria burden has been observed in most endemic countries. Declining infection rates and disease burden and reduction in asymptomatic carriers are the outcome of improved quality of care and related health system factors. These include improved case management through better diagnosis, implementation of highly effective antimalarial drugs and increased use of bednets. We studied communities' and health workers' perceptions of indicators and drivers in the context of decreasing malaria transmission in Malindi, Kenya. MATERIALS AND METHODS: A variety of qualitative methods that included participatory rural appraisal (PRA) tools such as community river of life and trend lines, focus group discussions (FGDs) and key informant interviews were used. Studies took place between November 2013 and April 2014. RESULTS: Providing residents with bednets contributed to malaria reduction, and increasing community awareness on the causes and symptoms of malaria and improved malaria treatment were also perceived to contribute to the decline of malaria. The study identified three perceived drivers to the reported decline in malaria: a) community health workers' enhanced awareness creation towards household owners regarding malaria-related activities through visitations and awareness sessions, b) Women involvement in Savings Internal Lending Community was perceived to have increased their financial base, thereby improving their decision-making power towards the care of their sick child(ren), c) Non Governmental Organizations (NGOs) and partners played a promoter part in health and general economic development initiatives. CONCLUSIONS: To achieve the goal of malaria elimination, collaboration between governmental and NGOs will be crucial when improving the financial base of women and enhancing participation of community health workers.

19.
Fitoterapia ; 137: 104188, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31158428

RESUMEN

Repeated chromatographic purifications of aerial parts of the Tunisian plant Daucus virgatus led to the isolation of four new germacranolides, named daucovirgolides I-L (2-5), along with the Plasmodium transmission-blocking agent daucovirgolide G. The chemical structures of the new compounds were defined as mono- or di-angeloylated germacrane-type sesquiterpenoids by spectroscopic (mainly 1D and 2D NMR) and spectrometric methods (ESIMS). The low potency exhibited by daucovirgolides I-L further supports the observation that strict structural requirements do exist for the Plasmodium transmission blocking activity in the daucovirgolide series. In particular, the endocyclic double bond system seems to be crucial for bioactivity.


Asunto(s)
Antimaláricos/farmacología , Apiaceae/química , Plasmodium berghei/efectos de los fármacos , Sesquiterpenos de Germacrano/farmacología , Antimaláricos/aislamiento & purificación , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Componentes Aéreos de las Plantas/química , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/aislamiento & purificación , Túnez
20.
J Am Mosq Control Assoc ; 34(4): 311-314, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-31442140

RESUMEN

Detoxifying pathways of mosquitoes against the neem (Azadirachta indica) extracts are still unclear. The aim of the present study was to investigate the role of adenosine triphosphate-binding cassette (ABC) transporters in this process in Anopheles stephensi, one of the main malaria vectors in southern Asia. Third-stage larvae of An. stephensi were fed with fish food alone or in combination with neem extract at 0.5%, 1%, 5%, and 10%. Six ABC-transporter genes from 3 different subfamilies (B, C, and G) were analyzed to assess their relative expression compared with controls. A bioassay was also performed to assess larval mortality rate at different concentrations and in combination with verapamil, an ABC-transporter inhibitor. No significant variation in the expression levels of any transporter belonging to the B, C, and G subfamilies was detected. Furthermore, the use of verapamil did not induce an increase in mortality at any of the tested neem extract concentrations, indicating that ABC transporters are not involved in the detoxification of neem extracts in An. stephensi larvae.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Anopheles/metabolismo , Azadirachta/química , Proteínas de Insectos/metabolismo , Fase I de la Desintoxicación Metabólica , Extractos Vegetales/química , Animales , Anopheles/crecimiento & desarrollo , Larva/metabolismo
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