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1.
Life Sci ; 257: 118067, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652140

RESUMO

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Diminazena/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Animais , Linhagem Celular , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Diminazena/administração & dosagem , Diminazena/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/tratamento farmacológico , Miocardite/parasitologia , Miócitos Cardíacos/parasitologia , Miosite/tratamento farmacológico , Miosite/parasitologia , Fragmentos de Peptídeos/metabolismo , Ratos , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacologia
3.
Life Sci ; 253: 117749, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32380079

RESUMO

AIM: This work aims to explore the role of diminazene aceturate (DIZE) in the enhancement of angiotensin-converting enzyme-2 (ACE2) to prevent the inflammatory and fibrotic response induced by γ-irradiation through activating the protective axis ACE2/angiotensin (1-7)/Mas receptor (ACE2/Ang(1-7)/Mas). METHODS: Male rats were injected i.p. with 15 mg/kg DIZE daily for 7 days pre and post-irradiation, where 7.5 Gy of γ-radiation as a single dose was used. KEY FINDINGS: Gamma radiation induced a significant elevation of renal biochemical parameters: urea, creatinine and blood urea nitrogen (BUN) in serum with a significant disturbance in oxidative stress markers: elevation in malondialdehyde (MDA) associated with a depletion of reduced glutathione (GSH) and superoxide dismutase (SOD). Beside elevation in the level of angiotensin II (AngII) that lead to remarkably increases in the levels of the renal inflammatory mediators: tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB) and interleukin-1ß (IL-1ß) as well as renal fibrogenic markers: transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and hydroxyproline content in the renal tissues. DIZE caused marked expansion in the expression of ACE2 consequently decreased the expression of AngII and increased the expression of Ang(1-7) which through its Mas receptor ameliorates the biochemical and histopathological damage induced by radiation. SIGNIFICANCE: DIZE-induced stimulation of ACE2 subdues the renal deleterious consequences induced by γ-radiation via activation of ACE2/Ang(1-7)/Mas axis in rats.


Assuntos
Angiotensina II/metabolismo , Diminazena/análogos & derivados , Raios gama/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Angiotensina I/metabolismo , Angiotensina II/administração & dosagem , Animais , Diminazena/farmacologia , Glutationa/metabolismo , Masculino , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
4.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L873-L887, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32160007

RESUMO

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.


Assuntos
Ácido Acético/administração & dosagem , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/genética , Obstrução das Vias Respiratórias/induzido quimicamente , Fibrose Cística/induzido quimicamente , Diminazena/análogos & derivados , Canais Iônicos Sensíveis a Ácido/metabolismo , Obstrução das Vias Respiratórias/tratamento farmacológico , Obstrução das Vias Respiratórias/metabolismo , Obstrução das Vias Respiratórias/patologia , Animais , Animais Recém-Nascidos , Bicarbonatos/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/química , Cloretos/metabolismo , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Diminazena/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Masculino , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucina-5B/genética , Mucina-5B/metabolismo , Depuração Mucociliar/efeitos dos fármacos , Muco/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Suínos , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/patologia
5.
PLoS One ; 15(2): e0228996, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053698

RESUMO

BACKGROUND: The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis. METHODS: In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells. FINDINGS: HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 µM, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 µM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies. CONCLUSION: These results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.


Assuntos
Babesia/efeitos dos fármacos , Eflornitina/efeitos adversos , Eflornitina/farmacologia , Hidroxiureia/efeitos adversos , Hidroxiureia/farmacologia , Theileria/efeitos dos fármacos , Animais , Antineoplásicos , Antiprotozoários/administração & dosagem , Antiprotozoários/farmacologia , Atovaquona/efeitos adversos , Atovaquona/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Clofazimina/efeitos adversos , Clofazimina/farmacologia , Diminazena/efeitos adversos , Diminazena/análogos & derivados , Diminazena/farmacologia , Cães , Prepúcio do Pênis/citologia , Humanos , Masculino , Camundongos , Células NIH 3T3
6.
Eur J Pharmacol ; 872: 172950, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31987711

RESUMO

We have previously demonstrated that the phosphorylation of p38 MAPK, through spinal AT1 receptor activation, is involved in formalin-induced nociception and follows accompanied by the increase in spinal angiotensin (Ang) II levels. We have also found that Ang (1-7), an N-terminal fragment of Ang II generated by ACE2, prevents the Ang II-induced nociceptive behavior via spinal MAS1 and the inhibition of p38 MAPK phosphorylation. Here, we examined whether the ACE2 activator diminazene aceturate (DIZE) can prevent the formalin-induced nociception in mice. The i.t. administration of DIZE attenuated the second, but not the first phase of formalin-induced nociceptive response. An increase in the activity of spinal ACE2 was measured following DIZE administration. The inhibitory effect of DIZE on nociception was abolished by the i.t. co-administration of the MAS1 antagonist A779. The i.t. administration of Ang (1-7) showed a similar effect on the second phase of the response which was also attenuated by A779. Furthermore, DIZE and Ang (1-7) each inhibited the formalin-induced phosphorylation of p38 MAPK on the dorsal lumbar spinal cord. This inhibition was again prevented by A779. ACE2 was expressed in neurons and microglia but absent from astrocytes in the superficial dorsal horn. Our data show that the i.t.-administered DIZE attenuates the second phase of the formalin-induced nociception which is accompanied by the inhibition of p38 MAPK phosphorylation. They also suggest the involvement of MAS1 activation on spinal neurons and microglia in response to the increase in Ang (1-7) following ACE2 activation.


Assuntos
Diminazena/análogos & derivados , Dor/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Medula Espinal/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Angiotensina I/farmacologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Diminazena/administração & dosagem , Modelos Animais de Doenças , Formaldeído/toxicidade , Humanos , Injeções Espinhais , Masculino , Camundongos , Microglia/metabolismo , Neurônios/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Dor/induzido quimicamente , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/metabolismo , Medula Espinal/citologia , Medula Espinal/metabolismo
7.
Trop Anim Health Prod ; 52(4): 1699-1705, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31865537

RESUMO

Co-infections caused by trypanosomes and gastro-intestinal nematodes (GINs) compromise cattle productivity and their control requires a holistic approach. The effectiveness of trypanocides and anthelmintics is compromised by increasing resistance. Use of combined chemotherapeutic products for synergy, mainly practiced in human medicine, is gaining importance in livestock. A trial to evaluate efficacy of VERYL®, containing diminazene diaceturate (3.5 mg/kg body weight) and levamisole chloride (5 mg/kg body weight) for the control of GINs in cattle, was conducted at KALRO-VSRI Muguga, Kenya, between June and August 2016. Thirty-eight cattle aged between 6 and 12 months, naturally infected with GINs, were randomly allocated into two groups; a treatment group received VERYL® intra-muscularly at 10 mL/100 kg bwt and a control group which received Veriben® (Diminazene aceturate) at 3.5 mg/kg bwt. Faecal egg counts (FECs), coproculture, packed cell volume (PCV) and local tolerance at the injection site were measured during the study. FECs were comparable between the treatment and control groups at day 0. However, treatment of cattle with VERYL significantly (p < 0.001) reduced FECs by day 7 and sustained to day 21 post-treatment. Coproculture results for the treatment and control groups revealed presence of Haemonchus, Cooperia, Ostertagia, Trichostrongylus and Oesophagostomum species. Cattle treated with VERYL® had a significant (p < 0.05) reduction in larval recoveries compared to the control group. VERYL® had minimal adverse effects which cleared after a short while and is thus recommended for controlling GINs in cattle.


Assuntos
Anti-Helmínticos/uso terapêutico , Doenças dos Bovinos/tratamento farmacológico , Diminazena/análogos & derivados , Levamisol/uso terapêutico , Infecções por Nematoides/veterinária , Animais , Bovinos , Diminazena/uso terapêutico , Fezes/parasitologia , Haemonchus/isolamento & purificação , Quênia , Infecções por Nematoides/tratamento farmacológico , Contagem de Ovos de Parasitas/veterinária , Distribuição Aleatória , Trichostrongylus/isolamento & purificação
8.
Hypertens Res ; 42(12): 1883-1893, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31506648

RESUMO

The aim of this study was to investigate whether treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with angiotensin-(1-7) during pregnancy could attenuate the development of cardiovascular dysfunction in the adult offspring of spontaneously hypertensive rats (SHRs). For this, pregnant SHRs received DIZE or Ang-(1-7) throughout gestation. The systolic blood pressure (SBP) was measured in the male offspring from the 6th to16th weeks of age by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Samples of the left ventricles (LVs) and kidneys were collected for histology and western blot assay in another batch of adult rat offspring. Maternal treatment with DIZE or Ang-(1-7) during pregnancy attenuated the increase in SBP in adult offspring. In addition, both DIZE and Ang-(1-7) treatments reduced the cardiomyocyte diameter and fibrosis deposition in the LV, and treatment with Ang-(1-7) also reduced the fibrosis deposition in the kidneys. Maternal treatment with DIZE, as well as Ang-(1-7), improved the coronary vasodilation induced by bradykinin in isolated hearts from adult offspring. However, no difference was observed in the contractile function of the LVs of these animals. The expression levels of AT1 and Mas receptors, ACE, ACE2, SOD, and catalase in the LV were not modified by maternal treatment with Ang-(1-7), but this treatment elicited a reduction in AT2 expression. These data show that treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects of attenuating hypertension and cardiac remodeling in adult offspring.


Assuntos
Angiotensina I/farmacologia , Doenças Cardiovasculares/prevenção & controle , Diminazena/análogos & derivados , Ativadores de Enzimas/farmacologia , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Diminazena/farmacologia , Feminino , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Masculino , Contração Miocárdica , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Função Ventricular Esquerda
9.
QJM ; 112(12): 914-924, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393582

RESUMO

OBJECTIVE: To investigate the role of angiotensin-converting enzyme 2 (ACE2) in hyperoxic lung injury. METHODS: Adult mice were exposed to 95% O2 for 72 h to induce hyperoxic lung injury, and simultaneously treated with ACE2 agonist diminazene aceturate (DIZE) or inhibitor MLN-4760. ACE2 expression/activity in lung tissue and angiotensin (Ang)-(1-7)/Ang II in bronchoalveolar lavage fluid (BALF), and the severity of hyperoxic lung injury were evaluated. The levels of inflammatory factors in BALF and lung tissue and the expression levels of phospho-p65, p65 and IkBα were measured. Oxidative parameter and antioxidant enzyme levels in lung tissue were measured to assess oxidative stress. Finally, the expression levels of nuclear factor-erythroid-2-related factor (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were measured using Western blotting. RESULTS: Hyperoxia treatment significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1-7) ratio, while co-treatment with hyperoxia and DIZE significantly increased lung ACE2 expression/activity and decreased the Ang II/Ang-(1-7) ratio. By contrast, co-treatment with hyperoxia and MLN-4760 significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1-7) ratio. Hyperoxia treatment induced significant lung injury, inflammatory response and oxidative stress, which were attenuated by DIZE but aggravated by MLN-4760. The NF-κB pathways were activated by hyperoxia and MLN-4760 but inhibited by DIZE. The Nrf2 pathway and its downstream proteins NQO1 and HO-1 were activated by DIZE but inhibited by MLN-4760. CONCLUSION: Activation of ACE2 can reduce the severity of hyperoxic lung injury by inhibiting inflammatory response and oxidative stress. ACE2 can inhibit the NF-κB pathway and activate the Nrf2/HO-1/NQO1 pathway, which may be involved in the underlying mechanism.


Assuntos
Lesão Pulmonar/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Angiotensina I/análise , Animais , Líquido da Lavagem Broncoalveolar/química , Diminazena/análogos & derivados , Diminazena/farmacologia , Hiperóxia/patologia , Imidazóis/farmacologia , Leucina/análogos & derivados , Leucina/farmacologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/análise
10.
Pharmacol Rep ; 71(5): 958-967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470292

RESUMO

BACKGROUND: Neprilysin inhibitors (NEPi) are assisting the renin-angiotensin system (RAS) inhibitors in halting diabetic cardiomyopathy (DCM). Away from conventional tactic, a recent report revealed the renoprotective potential of NEPi and angiotensin-converting enzyme (ACE2) activator combination therapy against diabetic nephropathy. However, this combination so far not evaluated against DCM, thus the present investigation aiming the same. METHODS: Streptozotocin-induced (55 mg/kg, ip) type 1 diabetic (T1D) male Wistar rats were treated with either monotherapy of thiorphan (0.1 mg/kg/day, po) or diminazene aceturate (5 mg/kg/day, po), or their combination therapy, for four weeks. After hemodynamic measurements, all the rats' heart and plasma were collected for biochemistry, ELISA, histopathology, and immunoblotting. RESULTS: Metabolic perturbations and failing cardiac functions associated with diabetes were markedly attenuated by combination therapy. Besides, unfavourable alterations in RAS and natriuretic peptides system (NPS) were corrected by combination therapy. Interestingly, combination therapy significantly increased plasma and heart cGMP levels compared to T1D and monotherapy receiving rats. Moreover, rats receiving combination therapy exhibited significant inhibition of activated NF-κB, TGF-ß and apoptotic signalling, and a notable reduction in cardiac fibrosis when compared to T1D rats. Expressions of posttranslational histone modifications markers; H3K4Me2 and its methyltransferases (SET7/9 and RBBP5) were significantly enhanced in T1D hearts, which were significantly reduced by combination therapy. CONCLUSIONS: The NEPi and ACE2 activator combination therapy effectively prevented DCM by normalising RAS and NPS activities, increasing cGMP, inhibiting inflammatory, pro-fibrotic and apoptotic signalling, and reversing H3K4Me2 and its methyl transferases expressions.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Diminazena/administração & dosagem , Diminazena/análogos & derivados , Diminazena/uso terapêutico , Quimioterapia Combinada , Ativação Enzimática/efeitos dos fármacos , Masculino , Ratos Wistar , Estreptozocina , Tiorfano/administração & dosagem , Tiorfano/uso terapêutico
11.
Carbohydr Res ; 482: 107742, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310940

RESUMO

Glycosaminoglycans (GAGs) is a particular class of linear anionic periodic polysaccharides, which play a key role in many cell signaling processes in the extracellular matrix by direct interactions with multiple proteins targets. Because of their periodic nature resulting in experimental challenges to study these molecules, computational approaches recently proved to be successful in complementing the experiments aimed to understand GAG interactions. However, the aspect of GAG binding of small, pharmacologically active molecules is still essentially understudied despite its significance. In this work, we apply computational approaches to rigorously characterize the interactions between GAGs and two trypanosoma active DNA targeting agents, berenil and pentamidine, which mainly differ in the structure of their intramolecular linkers connecting two benzamidine moieties. We thoroughly analyze their binding to heparin and chondroitin 6-sulfate in terms of dynamics, energetics and properties of π-stacked oligomeric structures of the drug molecules formed upon GAG association. Our work contributes to the general understanding of biologically relevant interactions between GAGs and small molecules which has potential impact in drug pharmacology and related therapeutic modalities.


Assuntos
Antiprotozoários/metabolismo , Sulfatos de Condroitina/metabolismo , Simulação por Computador , Diminazena/análogos & derivados , Heparina/metabolismo , Pentamidina/metabolismo , Diminazena/química , Diminazena/metabolismo , Ligação de Hidrogênio , Conformação Molecular , Simulação de Dinâmica Molecular , Pentamidina/química , Teoria Quântica , Termodinâmica
12.
Rev Bras Parasitol Vet ; 28(2): 320-324, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31188944

RESUMO

Trypanosomiasis caused by Trypanosoma evansi can seriously affect both domestic and wild animals. This article reports on an outbreak of canine trypanosomiasis on a farm in the Pantanal region of Brazil. The farm had 38 dogs, 20 of which died before receiving veterinary care. The remaining 18 dogs were underwent anamnesisn, clinical examination, hematological and biochemical evaluations. Blood smears and PCR analysis were performed for the diagnosis. The treatment protocols used according to the clinical recovery or parasitological cure of the dogs, using diminazene diaceturate, isometamidium chloride or quinapyramine sulfate. Post-treatment parasitological evaluation was performed by the microhematocrit technique. 7/18 dogs were PCR positive for T. evansi (confirmed by sequencing). There was clinical findings, which were consistent with both the acute and chronic stages of the disease in dogs. The infected dogs all exhibited at least one clinical sign of the disease. The hematological findings were compatible with trypanosomiasis, highlighting the hypochromic microcytic anemia as the main outcome. No treatment protocol was fully effective and the prolonged use of diminazene diaceturate caused the death of an animal. The trypanosomiasis can cause high rates of morbidity and mortality in dogs and difficulty in establishment an effective and safe therapeutic protocol.


Assuntos
Diminazena/análogos & derivados , Doenças do Cão/diagnóstico , Fenantridinas/uso terapêutico , Compostos de Quinolínio/uso terapêutico , Tripanossomíase/diagnóstico , Animais , Brasil/epidemiologia , Diminazena/uso terapêutico , Surtos de Doenças , Doenças do Cão/tratamento farmacológico , Doenças do Cão/epidemiologia , Cães , Feminino , Masculino , Reação em Cadeia da Polimerase/veterinária , Tripanossomíase/tratamento farmacológico , Tripanossomíase/epidemiologia
13.
Prev Vet Med ; 168: 103-107, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076189

RESUMO

This study was conducted from May 08 to June 08, 2017 in Gidami District, Kellem Wollega Zone, Oromia Regional State, Ethiopia. The objective of the study was to assess the occurrence of trypanocidal drug resistance in naturally infected cattle in identified hot spots villages of Gidami district. An initial cross-sectional prevalence study was conducted in seven villages from November 2015 to June 2016. Based on the outcome of the cross-sectional study, Kellem and Gry Sonka villages with highest trypanosome prevalence (28% and 30.85%) respectively were selected. An abbreviated 28-day field prototocol study was used to estimate resistance to 1 mg/kg bw isometamidium chloride (ISM) and 7.0 mg/kg bw diminanzene aceturate (DA). In this study, 100 purposively selected trypanosome positive cattle were ear-tagged and allocated into two treatment groups: a group I were treated with 2% solution of 1 mg/kg bw ISM and a group II were treated with 7% solution of 7 mg/kg bw DA. The treatment day was considered as day 0 and the treated cattle were monitored for trypanosomes and packed cell volume (PCV) levels on days 14 (for DA and ISM) and 28 (for ISM) post treatment. A treatment failure rate of 25% of the cattle in the ISM treated group on days 14 and 28 were indicative of resistance, whereas in the DA treated group the response was assessed only on day 14 post-treatment. The results of the study confirmed the presence of drug resistance to the maximum recommended doses of ISM and DA in Giray Sonka and Kellem villages of Gidami district. Out of 50 trypanosome positive cattle treated with ISM, 68% had persistent infections on day 28 post-treatment. Similarly, of the 50 trypanosome positive cattle treated with 7 mg/kg bw DA, 36% had persistent trypanosomes on day 14 post treatment. Of all ISM and DA treatment failures T. congolense accounted for (70.59%; 66.67%), T. vivax (23.53%; 27.78%) and T. brucei (5.88%; 5.55%) respectively. Drug resistance has indeed been a considerable threat in all villages of Gidami district, but the situation is magnified in Giray Sonka and Kellem villages. Thus, an integrated control approach of trypanosomosis should be conducted to ensure sustainable animal health and production in the area. In addition beside tsetse control, rational use of trypanocidal drugs and control of co-infections to exploit self-cure against resistant trypanosome populations are recommended. Furthermore, extensive data on trypanocidal drug sensitivity tests using advanced molecular techniques considered as elucidative.


Assuntos
Doenças dos Bovinos/tratamento farmacológico , Diminazena/análogos & derivados , Resistência a Medicamentos , Fenantridinas/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma/efeitos dos fármacos , Tripanossomíase/veterinária , Animais , Bovinos , Doenças dos Bovinos/parasitologia , Diminazena/uso terapêutico , Etiópia/epidemiologia , Tripanossomicidas/farmacologia , Tripanossomíase/tratamento farmacológico , Tripanossomíase/epidemiologia
14.
PLoS One ; 14(5): e0216078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048849

RESUMO

African trypanosomiasis remains a lethal disease to both humans and livestock. The disease persists due to limited drug availability, toxicity and drug resistance, hence the need for a better understanding of the parasite's biology and provision of alternative forms of therapy. In this study, the in vitro effects of phenolic acids were assessed for their trypanocidal activities against Trypanosoma brucei brucei. The effect of the phenolic acids on Trypanosoma brucei brucei was determined by the alamarBlue assay. The cell cycle effects were determined by flow cytometry and parasite morphological analysis was done by microscopy. Effect on cell proliferation was determined by growth kinetic analysis. Reverse Transcriptase quantitative Polymerase Chain Reaction was used to determine expression of iron dependent enzymes and iron distribution determined by atomic absorption spectroscopy. Gallic acid gave an IC50 of 14.2±1.5 µM. Deferoxamine, gallic acid and diminazene aceturate showed a dose dependent effect on the cell viability and the mitochondrion membrane integrity. Gallic acid, deferoxamine and diminazene aceturate caused loss of kinetoplast in 22%, 26% and 82% of trypanosomes respectively and less than 10% increase in the number of trypanosomes in S phase was observed. Gallic acid caused a 0.6 fold decrease, 50 fold increase and 7 fold increase in the expression levels of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes respectively while treatment with deferoxamine and diminazene aceturate also showed differential expressions of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes. The data suggests that gallic acid possibly exerts its effect on T. brucei via iron chelation leading to structural and morphological changes and arrest of the cell cycle. These together provide information on the cell biology of the parasite under iron starved conditions and provide leads into alternative therapeutic approaches in the treatment of African trypanosomiasis.


Assuntos
Hidroxibenzoatos/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Diminazena/análogos & derivados , Diminazena/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Ácido Gálico/farmacologia , Humanos , Ferro/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma/efeitos dos fármacos , Trypanosoma brucei brucei/patogenicidade , Tripanossomíase Africana/parasitologia
15.
Trop Anim Health Prod ; 51(7): 2091-2094, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30997632

RESUMO

African animal trypanosomiasis is a major cause of mortality and economic losses for the livestock industry in Nigeria. Chemotherapy has been the most reliable option for cattle herders, and the most commonly found drug on the market is diminazene aceturate. To ascertain the long-term efficacy of this compound, we sampled a cattle herd in Ogun State, Nigeria, 2 months after they were treated with diminazene aceturate. The ITS-PCR results revealed 19 positives for trypanosome DNA out of the 79 samples tested (24.1%, 95% CI 16.0-34.5). Seventeen out of the total 19 positives were Trypanosoma congolense (21.5%, 95% CI 13.9-31.8). Mixed infections were also observed. Therefore, the persistence of bovine trypanosomiasis at this Nigerian cattle farm despite treatment could be due to diminazene aceturate resistant trypanosomes being present in the herd.


Assuntos
Diminazena/análogos & derivados , Tripanossomicidas/uso terapêutico , Trypanosoma congolense/genética , Tripanossomíase Africana/veterinária , Tripanossomíase Bovina/tratamento farmacológico , Animais , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , DNA Intergênico , Diminazena/farmacologia , Resistência a Medicamentos , Fazendas , Nigéria , Reação em Cadeia da Polimerase
16.
Protein Pept Lett ; 26(7): 523-531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30950337

RESUMO

BACKGROUND: Angiotensin Converting Enzyme (ACE) 2 is an important modulator of the Renin Angiotensin System (RAS) and the RAS plays a central role in renovascular hypertension. Very few studies investigated the role of components of the counterregulatory RAS axis (ACE2, Ang-(1-7) and Mas receptor) in renovascular hypertension and the results are controversial. OBJECTIVE: The aim of this study was to investigate the effects of Diminazene Aceturate (DIZE) administration on renal function and renal inflammation parameters in 2K1C hypertensive rats. METHODS: Male Wistar rats were divided into three experimental groups: sham-operated animals, 2K1C+saline and 2K1C+DIZE orally (1 mg/kg/day). At the end of the 30 days of treatment, renal function was analyzed and kidneys from all the groups were collected and processed separately for measurement of N-acetyl-beta-D-glucosaminidase (NAG) and Myeloperoxidase (MPO) activities, cytokines, chemokines and nitric oxide levels. RESULTS: Oral DIZE administration for 4 weeks in hypertensive rats attenuated renal dysfunction and reduced the levels of MPO and NAG, cytokines and chemokines (IL1ß, IL-6, TNF-α and MCP-1) and increased urinary nitrate/nitrite levels in 2K1C hypertensive rats. CONCLUSION: Our findings showed that ACE2 activation may effectively improve renal alterations and inflammation induced by renovascular hypertension.


Assuntos
Diminazena/análogos & derivados , Ativadores de Enzimas/farmacologia , Hipertensão Renovascular/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Acetilglucosaminidase/metabolismo , Angiotensina I/metabolismo , Animais , Citocinas/metabolismo , Diminazena/farmacologia , Diminazena/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Peroxidase/metabolismo , Ratos Wistar
17.
Biosensors (Basel) ; 9(2)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013753

RESUMO

Development of technologies for rapid screening of DNA secondary structure thermal stability and the effects on stability for binding of small molecule drugs is important to the drug discovery process. In this report, we describe the capabilities of an electrochemical, microdevice-based approach for determining the melting temperatures (Tm) of electrode-bound duplex DNA structures. We also highlight new features of the technology that are compatible with array development and adaptation for high-throughput screening. As a foundational study to exhibit device performance and capabilities, melting-curve analyses were performed on 12-mer DNA duplexes in the presence/absence of two binding ligands: diminazene aceturate (DMZ) and proflavine. By measuring electrochemical current as a function of temperature, our measurement platform has the ability to determine the effect of binding ligands on Tm values with high signal-to-noise ratios and good reproducibility. We also demonstrate that heating our three-electrode cell with either an embedded microheater or a thermoelectric module produces similar results. The ΔTm values we report show the stabilizing ability of DMZ and proflavine when bound to duplex DNA structures. These initial proof-of-concept studies highlight the operating characteristics of the microdevice platform and the potential for future application toward other immobilized samples.


Assuntos
Técnicas Biossensoriais/métodos , DNA/química , Técnicas Eletroquímicas/métodos , Diminazena/análogos & derivados , Diminazena/química , Ligantes , Proflavina/química , Temperatura de Transição
18.
Rev. bras. parasitol. vet ; 28(2): 320-324, Apr.-June 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1042503

RESUMO

Abstract Trypanosomiasis caused by Trypanosoma evansi can seriously affect both domestic and wild animals. This article reports on an outbreak of canine trypanosomiasis on a farm in the Pantanal region of Brazil. The farm had 38 dogs, 20 of which died before receiving veterinary care. The remaining 18 dogs were underwent anamnesisn, clinical examination, hematological and biochemical evaluations. Blood smears and PCR analysis were performed for the diagnosis. The treatment protocols used according to the clinical recovery or parasitological cure of the dogs, using diminazene diaceturate, isometamidium chloride or quinapyramine sulfate. Post-treatment parasitological evaluation was performed by the microhematocrit technique. 7/18 dogs were PCR positive for T. evansi (confirmed by sequencing). There was clinical findings, which were consistent with both the acute and chronic stages of the disease in dogs. The infected dogs all exhibited at least one clinical sign of the disease. The hematological findings were compatible with trypanosomiasis, highlighting the hypochromic microcytic anemia as the main outcome. No treatment protocol was fully effective and the prolonged use of diminazene diaceturate caused the death of an animal. The trypanosomiasis can cause high rates of morbidity and mortality in dogs and difficulty in establishment an effective and safe therapeutic protocol.


Resumo A tripanossomíase causada por Trypanosoma evansi pode acometer gravemente os animais domésticos e selvagens. Este artigo relata um surto de tripanossomíase canina em uma fazenda na região do Pantanal, Brasil. Na fazenda havia 38 cães, 20 dos quais morreram antes de receber cuidados veterinários. Os 18 cães restantes foram submetidos a anamnese, exame clínico, avaliação hematológica e bioquímica. Esfregaços de sangue e análise da PCR foram realizados para o diagnóstico. Os protocolos de tratamento foram utilizados de acordo com a recuperação clínica ou cura parasitológica dos cães, utilizando diaceturato de diminazeno, cloreto de isometamídio ou sulfato de quinapiramina. A avaliação parasitológica pós-tratamento foi realizada pela técnica de microhematócrito. 7/18 cães foram PCR positivos para T. evansi (confirmado por sequenciamento). Os achados clínicos encontrados, foram consistentes com os estágios agudo e crônico da doença em cães. Todos os cães infectados exibiram pelo menos um sinal clínico da doença. Os achados hematológicos foram compatíveis com a tripanossomíase, destacando a anemia microcítica hipocrômica como principal consequência. Nenhum protocolo de tratamento foi totalmente eficaz e o uso prolongado de diaceturato de diminazeno causou a morte de um animal. A tripanossomíase pode causar altas taxas de morbidade e mortalidade em cães e dificultar o estabelecimento de um protocolo terapêutico eficaz e seguro.


Assuntos
Humanos , Masculino , Feminino , Cães , Fenantridinas/uso terapêutico , Compostos de Quinolínio/uso terapêutico , Tripanossomíase/diagnóstico , Diminazena/análogos & derivados , Doenças do Cão/diagnóstico , Tripanossomíase/terapia , Tripanossomíase/epidemiologia , Brasil/epidemiologia , Reação em Cadeia da Polimerase/veterinária , Surtos de Doenças , Diminazena/uso terapêutico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/epidemiologia
19.
Can J Physiol Pharmacol ; 97(7): 638-646, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30840489

RESUMO

Myocardial infarction is a major cause of cardiac dysfunction. All components of the cardiac renin-angiotensin system (RAS) are upregulated in myocardial infarction. Angiotensin-converting enzyme (ACE) and ACE2 are key enzymes involved in synthesis of components of RAS and provide a counter-regulatory mechanism within RAS. We compared the cardioprotective effect of the ACE2 activator diminazene aceturate (DIZE) versus the ACE inhibitor enalapril on post acute myocardial infarction (AMI) ventricular dysfunction in rats. Adult male rats received subcutaneous injections of either saline (control) or isoproterenol (85 mg/kg) to induce AMI. Rats with AMI confirmed biochemically and by ECG, were either left untreated (AMI) or administered DIZE (AMI + DIZE) or enalapril (AMI + enalapril) daily for 4 weeks. DIZE caused a significant activation of cardiac ACE2 compared with enalapril. DIZE caused a significantly greater enhancement of cardiac hemodynamics. DIZE also caused greater reductions in heart-type fatty acid binding protein (H-FABP), ß-myosin heavy chain (ß-MYH), and in heart mass to total body mass ratio. These results indicated that activation of cardiac ACE2 by DIZE enhanced the protective axis of RAS and improved myocardial function following AMI, whereas enalapril was not sufficient to restore all cardiac parameters back to normal.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiotônicos/farmacologia , Diminazena/análogos & derivados , Enalapril/farmacologia , Infarto do Miocárdio/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Doença Aguda , Animais , Diminazena/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Masculino , Infarto do Miocárdio/complicações , Ratos , Ratos Wistar
20.
PLoS Negl Trop Dis ; 13(3): e0007175, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30901321

RESUMO

BACKGROUND: Globally, working equines have a continued and growing socioeconomic role in supporting the livelihoods of between 300-600 million people in low income countries which is rarely recognised at a national or international level. Infectious diseases have significant impact on welfare and productivity in this population and equine trypanosomiasis is a priority disease due to its severity and prevalence. Strategies are required to improve the prevention, diagnosis, management and treatment of trypanosomiasis in equines and more data are required on the efficacy and safety of current trypanocidal drugs. METHODS: A prospective randomised, open-label non-inferiority trial was performed in The Gambia on horses and donkeys that fulfilled 2/5 clinical inclusion criteria (anaemia, poor body condition, pyrexia, history of abortion, oedema). Following randomised trypanocidal treatment (diminazene diaceturate, melarsomine dihydrochloride or isometamidium chloride), animals were observed for immediate adverse drug reactions and follow-up assessment was performed at 1 and 2 weeks. Blood samples underwent PCR analysis with specific Trypanosoma sp. primers. Treatment efficacy was assessed by measuring changes in clinical parameters, clinicopathological results and PCR-status post-treatment after evaluating for bias. Using PCR status as the outcome variable, non-inferiority of isometamidium treatment was determined if the upper bound limit of a 2-sided 95% CI was less than 10%. RESULTS: There was a significant beneficial effect upon the Trypanosoma sp. PCR positive population following trypanocidal treatment for all groups. The findings of clinical evaluation and PCR status supported a superior treatment effect for isometamidium. Melarsomine dihydrochloride efficacy was inferior to isometamidium. There were immediate, self-limiting side effects to isometamidium in donkeys (26%). Diminazene had the longest duration of action as judged by PCR status. CONCLUSIONS: The data support the continued use of isometamidium following careful dose titration in donkeys and diminazene for trypanosomiasis in equines using the doses and routes of administration reported.


Assuntos
Diminazena/análogos & derivados , Equidae/parasitologia , Doenças dos Cavalos/tratamento farmacológico , Fenantridinas/administração & dosagem , Tripanossomicidas/administração & dosagem , Trypanosoma/efeitos dos fármacos , Tripanossomíase/veterinária , Animais , Arsenicais/administração & dosagem , Arsenicais/efeitos adversos , Diminazena/administração & dosagem , Diminazena/efeitos adversos , Feminino , Gâmbia/epidemiologia , Doenças dos Cavalos/epidemiologia , Doenças dos Cavalos/parasitologia , Cavalos , Masculino , Fenantridinas/efeitos adversos , Estudos Prospectivos , Distribuição Aleatória , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Tripanossomicidas/efeitos adversos , Tripanossomíase/tratamento farmacológico , Tripanossomíase/epidemiologia , Tripanossomíase/parasitologia
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