RESUMO
The objective of the study was to evaluate the in vitro and in vivo schistosomicidal activity of sanguinarine (SA) on Schistosoma mansoni and its in silico pharmacokinetic parameters. ADMET parameters and oral bioavailability were evaluated using the PkCSM and SwissADME platforms, respectively. The activity of SA in vitro, at the concentrations of 1.0-25 µM, was analyzed through the parameters of motility, mortality, and cell viability of the worms at intervals of 3-24 h. Mice were infected with cercariae and treated by gavage with SA (5 mg/kg/day, in a single dose or two doses of 2.5 mg/kg every 12 h for 5 consecutive days) on the 1st (skin schistosomula), 14th (pulmonary schistosomula), 28th (young worms), and 45th (adult worms) days after infection. In vitro and in vivo praziquantel was the control. In vitro, SA showed schistosomicidal activity against schistosomula, young worms, and couples; with total mortality and reduced cell viability at low concentrations and incubation time. In a single dose of 5 mg/kg/day, SA reduces the total worm load by 47.6%, 54%, 55.2%, and 27.1%, and female worms at 52.0%, 39.1%, 52.7%, and 20.2%, respectively, results which are similar to the 2.5 mg/kg/day dose. SA reduced the load of eggs in the liver, and in histopathological and histomorphometric analyses, there was a reduction in the number and volume of hepatic granulomas, which exhibited less inflammatory infiltrate. SA has promising in vitro and in vivo schistosomicidal activity against different developmental stages of S. mansoni, in addition to reducing granulomatous liver lesions. Furthermore, in silico, SA showed good predictive pharmacokinetic ADMET profiles.
Assuntos
Alcaloides , Anti-Infecciosos , Isoquinolinas , Esquistossomicidas , Feminino , Animais , Camundongos , Antiparasitários , Schistosoma mansoni , Benzofenantridinas/farmacologia , Alcaloides/farmacologiaRESUMO
Among all the neglected diseases, schistosomiasis is considered the second most important parasitic infection after malaria. Praziquantel is the most widely used drug for this disease, but its exclusive use may result in the development of drug-resistant schistosomiasis. To increase the control of the disease, new drugs have been developed as alternative treatments, among them 2-(-5-bromo-1-h-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide (LQIT/LT-50), which showed promising schistosomicidal activity in nonclinical studies. However, LQIT/LT-50 presents low solubility in water, resulting in reduced bioavailability. To overcome this solubility problem, the present study aimed to develop LQIT/LT-50 solid dispersions for the treatment of schistosomiasis. Solid dispersions were prepared through the solvent method using Soluplus©, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP K-30) as hydrophilic carriers. The formulations with the best results in the compatibility tests, aqueous solubility and preliminary stability studies have undergone solubility tests and physicochemical characterizations by Fourier-transform infrared spectroscopy (FTIR), x-ray diffractometry (XRD), exploratory differential calorimetry (DSC), thermogravimetry (TG) and Raman spectroscopy. Finally, the schistosomicidal activity was evaluated in vitro. The phycochemical analyzes showed that when using PVP K-30, there was an interaction between the PVP K-30 and LQIT/LT-50, proving the successful development of the solid dispersion. Furthermore, an increase in the solubility of the new system was observed (LQIT/LT-50:PVP K-30) in addition to the improvement in the in vitro shistosomidal activity at 1:4 (w/w) molar ratio (i.e., 20% drug loading) when compared to LQIT/LT-50 alone. The development of the LQIT/LT-50:PVP K-30 1:4 solid dispersion is encouraging for the future development of new pharmaceutical solid formulations, aiming the schistosomicidal treatment.
Assuntos
Esquistossomose , Esquistossomicidas , Humanos , Esquistossomicidas/farmacologia , Química Farmacêutica/métodos , Povidona/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Naftalenos , Água , Indóis/farmacologia , Difração de Raios X , Portadores de Fármacos/químicaRESUMO
Probiotics contribute to the integrity of the intestinal mucosa and preventing dysbiosis caused by opportunistic pathogens, such as intestinal helminths. Bacillus cereus GM obtained from Biovicerin® was cultured to obtain spores for in vivo evaluation on experimental schistosomiasis. The assay was performed for 90 days, where all animals were infected with 50 cercariae of Schistosoma mansoni on the 15th day. Three experimental groups were formed, as follows: G1-saline solution from the 1st until the 90th day; G2-B. cereus GM (105 spores in 300 µL of sterile saline) from the 1st until the 90th day; and G3-B. cereus GM 35th day (onset of oviposition) until the 90th day. G2 showed a significant reduction of 43.4% of total worms, 48.8% of female worms and 42.5% of eggs in the liver tissue. In G3, the reduction was 25.2%, 29.1%, and 44% of the total number of worms, female worms, and eggs in the liver tissue, respectively. G2 and G3 showed a 25% (p < 0.001) and 22% (p < 0.001) reduction in AST levels, respectively, but ALT levels did not change. ALP levels were reduced by 23% (p < 0.001) in the G2 group, but not in the G3. The average volume of granulomas reduced (p < 0.0001) 65.2% and 46.3% in the liver tissue and 83.0% and 53.2% in the intestine, respectively, in groups G2 and G3. Th1 profile cytokine (IFN-γ, TNF-α, and IL-6) and IL-17 were significantly increased (p < 0.001) stimulated with B. cereus GM in groups G2 and G3. IL-4 showed significant values when the stimulus was mediated by ConA. By modulating the immune response, B. cereus GM reduced the burden of worms, improved some markers of liver function, and reduced the granulomatous inflammatory reaction in mice infected with S. mansoni, especially when administered before infection.
Assuntos
Probióticos , Esquistossomose mansoni , Esquistossomose , Feminino , Animais , Camundongos , Esquistossomose mansoni/parasitologia , Bacillus cereus , Schistosoma mansoni , Esquistossomose/parasitologia , Fígado/parasitologiaRESUMO
Schistosomiasis is a parasitic disease that can be asymptomatic, but it can progress and cause serious damage, such as hospitalization and death. This work aimed to characterize and carry out the in vivo pharmacological test of the dry extract of Morinda citrifolia and obtain a pharmaceutical dosage form based on this extract for the treatment of schistosomiasis. The aqueous extract was characterized based on the evaluation of pH, dry residue and density. The aqueous extract was dried through the freeze-drying process. The obtained dry extract was characterized through phytochemical screening, rheological analysis, acute toxicity and in vivo pharmacology. Additionally, the pre-formulation development of a pharmaceutical dosage form was pursued with the dry extract. Through the HPLC chromatogram, characteristic rutin peaks were identified. The rheological behavior of the dry extract did not show good characteristics. Acute toxicity, at a dose of 2000 mg/kg, showed excitatory activity in the central and autonomous nervous system. The in vivo pharmacological test of the dry extract showed that, at a dose of 400 mg/kg, it was possible to reduce 67.5% of the total adult worms, 66% of female worms and 60% of the number of eggs. The pharmaceutical dosage form obtained was an oral solution that was clear, transparent, without the presence of lumps and precipitates, having a density of 1.1276 g mL-1 and pH of 5.92. The results obtained will provide parameters for the production of suitable pharmaceutical formulations, as well as for the quality control of products based on M. citrifolia, with promising schistosomicidal activity.
Assuntos
Morinda , Esquistossomose , Animais , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Morinda/química , Composição de Medicamentos , Água , Frutas/químicaRESUMO
Schistosomiasis affects about 260â million people worldwide and the search for new schistosomicidal compounds is urgent. In this study we evaluated the inâ vitro effect of barbatic acid against schistosomulae and young worms of Schistosoma mansoni. The barbatic acid was evaluated through the bioassay of motility and mortality, cellular viability and ultrastructural analysis of juvenile stages through Scanning Electron Microscopy. Barbatic acid showed a schistosomicidal effect against schistosomulae and young worms of S. mansoni after 3â h of exposure. At the end of 24â h, barbatic acid showed 100 %, 89.5 %, 52 % and 28.5 % of lethality for schistosomulae at the concentrations of 200, 100, 50 and 25â µM, respectively. For young worms, barbatic acid showed 100 % and 31.7 % of lethality at the concentrations of 200 and 100â µM, respectively. Motility changes were observed at all sublethal concentrations. There was a significant reduction in the viability of young worms after exposure to barbatic acid at 50, 100 and 200â µM. Extensive damage to the schistosomulae and young worm's tegument, was observed from 50â µM. This report provides data showing the schistosomicidal effect of barbatic acid on schistosomulae and young worms of S.â mansoni, causing death, motility changes and ultrastructural damage to worms.
Assuntos
Anti-Helmínticos , Ácidos Ftálicos , Esquistossomicidas , Animais , Schistosoma mansoni , Anti-Helmínticos/farmacologia , Ácidos Ftálicos/farmacologia , Esquistossomicidas/farmacologia , Microscopia Eletrônica de VarreduraRESUMO
BACKGROUND: Snails of the genus Biomphalaria are intermediate hosts of Schistosoma mansoni, the main etiological agent of schistosomiasis mansoni, which affects about 236.6 million people in tropical and subtropical regions of the world. The World Health Organization recommends the population control of vector snails as one of the strategies to reduce the prevalence and incidence of schistosomiasis. In this study, molluscicidal and antiparasitic activities of plumbagin, a naturally sourced naphthoquinone with a range of biological effects, were evaluated against B. glabrata and cercariae of S. mansoni. RESULTS: After 24 h of exposure, plumbagin demonstrated molluscicidal activity at low concentrations against embryos (LC50 of 0.56, 0.93, 0.68, 0.51 and 0.74 µg mL-1 for the blastula, gastrula, trochophore, veliger and hippo stage, respectively) and adult snails (LC50 of 3.56 µg mL-1 ). There were no changes in exposed snails' fecundity or fertility; however, plumbagin was able to increase the frequency of DNA damage and the number of hemocytes, with apoptosis and binucleation being the main hemocyte alterations. In addition, plumbagin showed death of S. mansoni cercariae in the concentration of 1.5 µg mL-1 in 60 min, while showing moderate toxicity to Artemia salina. CONCLUSION: Plumbagin proved to be a promising substance for the control of B. glabrata population, intermediate host of S. mansoni, as well as the cercariae, infective stage for humans (definitive host), while being moderately toxic to A. salina, a crustacean widely used in ecotoxicity tests. © 2022 Society of Chemical Industry.
Assuntos
Biomphalaria , Naftoquinonas , Esquistossomose mansoni , Animais , Humanos , Biomphalaria/parasitologia , Naftoquinonas/farmacologia , Dano ao DNARESUMO
To obtain usnic acid potassium salt (PS-UA), the usnic acid (UA) was extracted and purified from the lichen Cladonia substellata, and modified to produce PS-UA. The structure was determined by 1H-NMR, IR and elemental analysis, ratified through computational models, as well as identification the site of K+ insertion in the molecule. Antinociceptive activity was detected through contortions in mice induced by acetic acid and formalin (phases I and II) after treatments with 10 and 20 mg/kg of PS-UA, indicating interference in both non-inflammatory and inflammatory pain. After oral administration at doses of 500, 1000 and 2000 mg/kg, no deaths of mice with treatments below 2000 mg/kg were observed. Except for body weight gain, food and water consumption decreased with treatments of 1000 and 2000 mg/kg, and the number of segmented leukocytes was higher for both treatments. Regarding serum levels, cholesterol and triglycerides decreased, however, there was an increase in hepatic transaminases with both treatments. Liver and kidney histological changes were detected in treatments of 2000 mg/kg, while the spleen was preserved. The PS-UA demonstrated antinociceptive activity while the acute toxicity at the concentration of 2000 mg/kg was the only dose that presented morphological changes in the liver and kidney.
Assuntos
Analgésicos/farmacologia , Benzofuranos/farmacologia , Benzofuranos/toxicidade , Testes de Toxicidade Aguda , Animais , Comportamento Animal/efeitos dos fármacos , Benzofuranos/química , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Feminino , Camundongos , Conformação Molecular , Especificidade de Órgãos/efeitos dos fármacosRESUMO
The main pathology associated with Schistosomiasis mansoni is granulomatous inflammation that may develop into hepatosplenic disease with fibrosis and hepatoesplenomegaly. It is known that N-acetyl-L-cysteine (NAC) reduces tissue damage in chronic liver diseases owing to its anti-inflammatory, antioxidant, and detoxifying properties. In this study, we investigated the imunohistopathological changes in murine schistosomiasis mansoni under the influence of NAC, in combination with Praziquantel (PZQ) or not. Three groups of mice were formed to evaluate the effects of NAC during infection in the acute, intermediate, and chronic phases. Each group was further subdivided into four subgroups: NAC, PZQ, NAC + PZQ and control (without treatment). Oral administration of NAC (200 mg/kg/day) was carried out on the first day after infection for the acute phase and on the 45th for the intermediate and chronic phases for 59 and 45, 75 days, respectively. PZQ (100 mg/kg/day), was given orally by gavage from the 45th to 49th day after infection. Histopathological analysis of liver tissue provided evidence that combined NAC + PZQ treatment reduced the development of granulomas observed in the chronic phase. Animals treated with NAC and/or PZQ showed a reduction in the size of granulomas and all those treated with NAC exhibited a lower degree of fibrosis. In all groups, NAC decreased the synthesis of interferon-γ and nitric oxide, while increasing the levels of interleukin-10, but it did not influence the production of interleukin-4. On the whole, NAC treatment induced an immunomodulatory effect and reduced liver damage during the granulomatous inflammation in S. mansoni-infected mice.
Assuntos
Acetilcisteína/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/patologia , Administração Oral , Animais , Anti-Helmínticos/administração & dosagem , Modelos Animais de Doenças , Feminino , Granuloma/patologia , Histocitoquímica , Imuno-Histoquímica , Fígado/patologia , Masculino , Camundongos , Praziquantel/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Portal hypertension in the mucosa of the intestine and the presence of granulomas in the wall of this organ can alter digestive function in patients with schistosomiasis. Citrulline is a potential marker of intestinal function in some diseases that affect the morphometry of the mucosa because of its close association with enterocytes. The aims of the present study were to determine serum citrulline concentrations in mice with hepatosplenic schistosomiasis, analyze the morphologic repercussions for the mucosa of the small intestine, correlate citrulline concentrations with morphometric changes in the intestinal mucosa, and evaluate the effect of splenectomy on citrulline concentration. METHODS: After approval from the local ethics committee, 46 adult female albino Swiss mice were divided into two groups: Control (23 healthy mice) and experimental (23 mice with hepatosplenic schistosomiasis). Blood samples were collected for the analysis of plasma citrulline before and after splenectomy. A segment of the jejunum was resected for morphometric analysis. RESULTS: The average body mass in the control group was greater than that in the experimental group (p = 0.00062). The average citrulline concentration in the control group was greater than that in the experimental group both before and after splenectomy (p < 0.001). In the experimental group, the villi had less height and area, and there was a smaller perimeter of the mucosal surface (p = 0.003, <0.001, and p = 0.001, respectively). There was a direct correlation between citrulline concentration and the height and area of the villi (p = 0.003 and 0.04, respectively). There was no correlation between citrulline concentration and the perimeter of the surface of the jejunal mucosa. After splenectomy, there was a reduction in the mean citrulline concentration in the experimental group (p = 0.009). CONCLUSIONS: Serum citrulline concentrations were reduced in mice with schistosomiasis, and a direct correlation was found between the citrulline concentration and the morphometry of the jejunal villi. Moreover, there was a reduction in the plasma concentration of citrulline after splenectomy.