Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.593
Filtrar
1.
Medicine (Baltimore) ; 99(46): e22987, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181661

RESUMO

To investigate the frequency and degree of azole antifungal agents that influence the anticoagulant activity of warfarin to reduce the potential bleeding risk and provide a reference for rational administration of warfarin in clinics.Patients with an abnormal international normalized ratio (INR; INR ≥ 4.5) and treated with warfarin plus azole antifungal agents were screened from February 2011 to July 2016, and their data were extracted.Thirty-two patients treated with warfarin plus azole antifungal agents were included. The INR of all the included patients increased by more than 20% of the INR of warfarin alone, and the warfarin sensitivity index showed an upward trend. The INRs of 21 patients treated with fluconazole (FLCZ) and warfarin was closely monitored for 1 week after the combination treatment, and the interaction between warfarin and the azole antifungal agents peaked on the seventh day. The INRs when warfarin was coadministered with azoles (Y) correlated significantly with those in the absence of azoles (X): FLCZ: Y = 1.2515X + 2.1538, R = 0.8128; and voriconazole Y = 2.4144 X + 2.6216, R2 = 0.7828.The combination of FLCZ and voriconazole will enhance the anticoagulant effect of warfarin. Therefore, it is recommended to detect the genotype of CYP2C9 in patients and evaluate the interaction between the 2 drugs to adjust the warfarin dose. It is also recommended to closely monitor INR within 1 week of the addition of azole antifungal agents.


Assuntos
Anticoagulantes/farmacologia , Antifúngicos/farmacologia , Azóis/farmacologia , Varfarina/farmacologia , Adulto , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Citocromo P-450 CYP2C9/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Erros Inatos do Metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
2.
PLoS One ; 15(11): e0229060, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151938

RESUMO

We assessed the virulence and anti-trypanosomal drug sensitivity patterns of Trypanosoma brucei rhodesiense (Tbr) isolates in the Kenya Agricultural and Livestock Research Organization-Biotechnology Research Institute (KALRO-BioRI) cryobank. Specifically, the study focused on Tbr clones originally isolated from the western Kenya/eastern Uganda focus of human African Trypanosomiasis (HAT). Twelve (12) Tbr clones were assessed for virulence using groups(n = 10) of Swiss White Mice monitored for 60 days post infection (dpi). Based on survival time, four classes of virulence were identified: (a) very-acute: 0-15, (b) acute: 16-30, (c) sub-acute: 31-45 and (d) chronic: 46-60 dpi. Other virulence biomarkers identified included: pre-patent period (pp), parasitaemia progression, packed cell volume (PCV) and body weight changes. The test Tbr clones together with KALRO-BioRi reference drug-resistant and drug sensitive isolates were then tested for sensitivity to melarsoprol (mel B), pentamidine, diminazene aceturate and suramin, using mice groups (n = 5) treated with single doses of each drug at 24 hours post infection. Our results showed that the clones were distributed among four classes of virulence as follows: 3/12 (very-acute), 3/12 (acute), 2/12 (sub-acute) and 4/12 (chronic) isolates. Differences in survivorship, parasitaemia progression and PCV were significant (P<0.001) and correlated. The isolate considered to be drug resistant at KALRO-BioRI, KETRI 2538, was confirmed to be resistant to melarsoprol, pentamidine and diminazene aceturate but it was not resistant to suramin. A cure rate of at least 80% was achieved for all test isolates with melarsoprol (1mg/Kg and 20 mg/kg), pentamidine (5 and 20 mg/kg), diminazene aceturate (5 mg/kg) and suramin (5 mg/kg) indicating that the isolates were not resistant to any of the drugs despite the differences in virulence. This study provides evidence of variations in virulence of Tbr clones from a single HAT focus and confirms that this variations is not a significant determinant of isolate sensitivity to anti-trypanosomal drugs.


Assuntos
Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Virulência/efeitos dos fármacos , Animais , Diminazena/análogos & derivados , Diminazena/farmacologia , Modelos Animais de Doenças , Resistência a Medicamentos/efeitos dos fármacos , Quênia , Masculino , Melarsoprol/farmacologia , Camundongos , Pentamidina/farmacologia , Suramina/farmacologia , Resultado do Tratamento , Tripanossomíase Africana/parasitologia , Uganda
3.
Paediatr Drugs ; 22(6): 645-652, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32885390

RESUMO

Kawasaki disease (KD) is one of the most common vasculitides of childhood and the main cause of acquired heart disease in developed countries. Intravenous immunoglobulin (IVIG) in association with aspirin represents the main treatment for KD. However, 10-20% of patients fail to respond to standard treatment and have an increased risk of cardiac complications. There is currently no accepted protocol for treatment of resistant cases. Several authors highlighted the role of interleukin-1 (IL-1) as a mediator of inflammation in KD and suggested the possibility of using IL-1 or its receptor as a target of therapy. The use of IL-1 inhibitors in patients with KD has been reported in the scientific literature, but data are largely limited to individual case reports and small case series. We summarized the scientific literature related to the use of anakinra, analyzing preclinical and clinical data. Thirty-eight patients have been described so far, most of them with KD-related complications. Twenty-two were described in case reports and case series, while 16 were patients from the completed KAWAKINRA phase IIa study. Almost all patients received clinical benefit, and no relevant side effects were noted. Based on this evidence, in our opinion, anakinra may be considered as an option after the failure of the first IVIG infusion, especially in patients with coronary involvement.


Assuntos
Antirreumáticos/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Animais , Antirreumáticos/farmacologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Masculino , Camundongos
5.
Sci Rep ; 10(1): 13586, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788636

RESUMO

P-glycoproteins (Pgp) have been proposed as contributors to the widespread macrocyclic lactone (ML) resistance in several nematode species including a major pathogen of foals, Parascaris univalens. Using new and available RNA-seq data, ten different genomic loci encoding Pgps were identified and characterized by transcriptome-guided RT-PCRs and Sanger sequencing. Phylogenetic analysis revealed an ascarid-specific Pgp lineage, Pgp-18, as well as two paralogues of Pgp-11 and Pgp-16. Comparative gene expression analyses in P. univalens and Caenorhabditis elegans show that the intestine is the major site of expression but individual gene expression patterns were not conserved between the two nematodes. In P. univalens, PunPgp-9, PunPgp-11.1 and PunPgp-16.2 consistently exhibited the highest expression level in two independent transcriptome data sets. Using RNA-Seq, no significant upregulation of any Pgp was detected following in vitro incubation of adult P. univalens with ivermectin suggesting that drug-induced upregulation is not the mechanism of Pgp-mediated ML resistance. Expression and functional analyses of PunPgp-2 and PunPgp-9 in Saccharomyces cerevisiae provide evidence for an interaction with ketoconazole and ivermectin, but not thiabendazole. Overall, this study established reliable reference gene models with significantly improved annotation for the P. univalens Pgp repertoire and provides a foundation for a better understanding of Pgp-mediated anthelmintic resistance.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Ascaridoidea/genética , Proteínas de Helminto/genética , Cavalos/parasitologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/classificação , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antiparasitários/farmacologia , Infecções por Ascaridida/tratamento farmacológico , Infecções por Ascaridida/parasitologia , Ascaridoidea/metabolismo , Ascaridoidea/fisiologia , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Proteínas de Helminto/classificação , Proteínas de Helminto/metabolismo , Ivermectina/farmacologia , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Análise de Sequência de RNA/estatística & dados numéricos , Transcriptoma
6.
Sci Rep ; 10(1): 13445, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778698

RESUMO

Fascioliasis is a neglected zoonotic disease that infects humans and ruminant species worldwide. In the absence of vaccines, control of fascioliasis is primarily via anthelminthic treatment with triclabendazole (TCBZ). Parasitic flatworms, including Fasciola hepatica, are active secretors of extracellular vesicles (EVs), but research has not been undertaken investigating EV anthelmintic sequestration. Adult F. hepatica were cultured in lethal and sub-lethal doses of TCBZ and its active metabolites, in order to collect EVs and evaluate their morphological characteristics, production and anthelmintic metabolite content. Transmission electron microscopy demonstrated that F. hepatica exposed to TCBZ and its metabolites produced EVs of similar morphology, compared to non-TCBZ exposed controls, even though TCBZ dose and/or TCBZ metabolite led to measurable structural changes in the treated F. hepatica tegument. qNano particle analysis revealed that F. hepatica exposed to TCBZ and its metabolites produced at least five times greater EV concentrations than non-TCBZ controls. A combined mass spectrometry and qNano particle analysis confirmed the presence of TCBZ and the TCBZ-sulphoxide metabolite in anthelmintic exposed EVs, but limited TCBZ sulphone was detectable. This data suggests that EVs released from adult F. hepatica have a biological role in the sequestration of TCBZ and additional toxic xenobiotic metabolites.


Assuntos
Fasciola hepatica/metabolismo , Triclabendazol/metabolismo , Triclabendazol/farmacologia , Animais , Anti-Helmínticos/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Fasciolíase/tratamento farmacológico , Ovinos , Doenças dos Ovinos/parasitologia , Triclabendazol/uso terapêutico , Zoonoses/tratamento farmacológico
7.
PLoS One ; 15(8): e0228002, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764831

RESUMO

Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on irinotecan-based therapy in colon cancer. Using differentially expressing CTDSP1 cells, we demonstrated that CTDSP1 contributes to the irinotecan sensitivity by preventing topoI degradation. Retrospective analysis of patients receiving irinotecan with or without rabeprazole has shown the effects of CTDSP1 on irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.


Assuntos
Neoplasias Colorretais/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Rabeprazol/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/fisiopatologia , DNA , DNA Topoisomerases Tipo I/fisiologia , Proteína Quinase Ativada por DNA/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Irinotecano/metabolismo , Irinotecano/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/metabolismo , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol/farmacologia , Estudos Retrospectivos , Inibidores da Topoisomerase I/farmacologia
8.
Lancet Haematol ; 7(8): e613-e623, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735839

RESUMO

Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.


Assuntos
Anticoagulantes/farmacologia , Síndrome Antifosfolipídica/terapia , Resistência a Medicamentos/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Terapia Trombolítica , Trombose/prevenção & controle , Síndrome Antifosfolipídica/patologia , Humanos , Trombose/patologia
10.
Sci Rep ; 10(1): 12238, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699266

RESUMO

Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-α (TNFα) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-α therapy with infliximab (IFX). However, approximately 30-40% of CD patients fail to respond to IFX with still unclear underlying mechanisms. This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. Under basal conditions, the mRNA for the cytokines TNFα, IL-23, IL-1ß and the chemokines CXCL8/IL-8, CCL5/RANTES and CCL2/MCP-1 was up-regulated in monocytes from non-responders than responders. The expression of the same cytokines and CCL2/MCP-1 was higher in non-responders also upon LPS treatment. Moreover, higher secretion of TNFα, IL-1ß, IFNγ and IL-2 proteins occurred in the supernatants of LPS-treated non-responders cells. Resistance to IFX in CD may result from a transcriptional dysregulation of circulating monocytes, leading to hyperactivation of pro-inflammatory pathways. Monocytes' cytokine profile may thus represent a predictive marker of response to IFX. Monocytes were isolated from blood samples of 19 CD patients (11 responders, 8 non-responders) and incubated with or without LPS. Cytokine profiles were assessed by RT-qPCR and, in the supernatants, by ELISA assay.


Assuntos
Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Citocinas/metabolismo , Infliximab/uso terapêutico , Monócitos/metabolismo , Adulto , Idoso , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/fisiologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Transcrição Genética/fisiologia , Regulação para Cima/fisiologia , Adulto Jovem
11.
Neurology ; 95(11): e1461-e1470, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32651292

RESUMO

OBJECTIVE: We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia. METHODS: In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected "off" and "on" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months. RESULTS: The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia. CONCLUSION: Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach.


Assuntos
Antiparkinsonianos/uso terapêutico , Dopaminérgicos/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Tremor/tratamento farmacológico , Acelerometria , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Resistência a Medicamentos/fisiologia , Feminino , Seguimentos , Humanos , Hipocinesia/diagnóstico por imagem , Hipocinesia/tratamento farmacológico , Hipocinesia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Resultado do Tratamento , Tremor/diagnóstico por imagem , Tremor/fisiopatologia
13.
J Clin Psychiatry ; 81(4)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32603560

RESUMO

OBJECTIVE: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. METHODS: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). RESULTS: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). CONCLUSIONS: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adolescente , Adulto , Antidepressivos/uso terapêutico , Aripiprazol/uso terapêutico , Bupropiona/uso terapêutico , Transtorno Depressivo Maior/complicações , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Transtornos de Estresse Pós-Traumáticos/complicações , Adulto Jovem
15.
PLoS One ; 15(6): e0234864, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555706

RESUMO

The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Escala de Resultado de Glasgow/normas , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Clozapina/sangue , Clozapina/uso terapêutico , Estudos Transversais , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Hospitais Psiquiátricos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Psicometria/métodos , Reprodutibilidade dos Testes , Inquéritos e Questionários
16.
Biochem J ; 477(10): 2007-2026, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32391551

RESUMO

The emergence of drug resistance is a major concern for combating against Cutaneous Leishmaniasis, a neglected tropical disease affecting 98 countries including India. Miltefosine is the only oral drug available for the disease and Miltefosine transporter proteins play a pivotal role in the emergence of drug-resistant Leishmania major. The cause of resistance is less accumulation of drug inside the parasite either by less uptake of the drug due to a decrease in the activity of P4ATPase-CDC50 complex or by increased efflux of the drug by P-glycoprotein (P-gp, an ABC transporter). In this paper, we are trying to allosterically modulate the behavior of resistant parasite (L. major) towards its sensitivity for the existing drug (Miltefosine, a phosphatidylcholine analog). We have used computational approaches to deal with the conservedness of the proteins and apparently its three-dimensional structure prediction through ab initio modeling. Long scale membrane-embedded molecular dynamics simulations were carried out to study the structural interaction and stability. Parasite-specific motifs of these proteins were identified based on the machine learning technique, against which a peptide library was designed. The protein-peptide docking shows good binding energy of peptides Pg5F, Pg8F and PC2 with specific binding to the motifs. These peptides were tested both in vitro and in vivo, where Pg5F in combination with PC2 showed 50-60% inhibition in resistant L. major's promastigote and amastigote forms and 80-90% decrease in parasite load in mice. We posit a model system wherein the data provide sufficient impetus for being novel therapeutics in order to counteract the drug resistance phenotype in Leishmania parasites.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/farmacologia , Regulação Alostérica/efeitos dos fármacos , Leishmania major/metabolismo , Fosforilcolina/análogos & derivados , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/toxicidade , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/farmacologia , Transportadores de Cassetes de Ligação de ATP/toxicidade , Animais , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Linhagem Celular , Biologia Computacional/métodos , Resistência a Medicamentos/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Aprendizado de Máquina , Camundongos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Biblioteca de Peptídeos , Peptídeos/síntese química , Fosforilcolina/metabolismo , Fosforilcolina/farmacologia
17.
Sci Rep ; 10(1): 7299, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350366

RESUMO

Diabetic macular edema (DME) refractory to anti-VEGF drugs is a socioeconomic burden. In this retrospective study, we investigated the relationship between DME remission and hyperreflective walls in foveal cystoid spaces, a novel finding on spectral domain optical coherence tomography (SD-OCT) images in DME. In a cross-sectional study, we assessed the relationship between hyperreflective walls in foveal cystoid spaces and other OCT findings in 110 eyes of 110 DME patients. Hyperreflective walls were delineated in 27 of 171 foveal cystoid spaces. Eyes with hyperreflective walls in foveal cystoid spaces had poorer visual acuity and more severe photoreceptor disruption than did those without such findings (P = 0.008 and P < 0.001, respectively). In the other longitudinal study, we evaluated the relationship between this finding and the remission in 54 eyes of 51 DME patients treated with as-needed ranibizumab injections for 24 months. Foveal cystoid spaces with hyperreflective walls were often persistent, and the cumulative rates of DME remission among eyes with and without the hyperreflective walls were 7.7% (1 eye) and 48.8% (20 eyes) at 18 months (hazard ratio, 0.092; P = 0.025). We characterized hyperreflective walls in foveal cystoid spaces and designated them as a predictor of no DME remission under ranibizumab injections.


Assuntos
Retinopatia Diabética , Resistência a Medicamentos/efeitos dos fármacos , Fóvea Central/diagnóstico por imagem , Edema Macular , Ranibizumab/administração & dosagem , Tomografia de Coerência Óptica , Adulto , Idoso , Biomarcadores , Estudos Transversais , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/tratamento farmacológico , Feminino , Humanos , Edema Macular/diagnóstico por imagem , Edema Macular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
18.
Vet Parasitol ; 281: 109121, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32361524

RESUMO

The search of novel strategies for anthelmintic control is a crucial need considering the widespread increase in resistant parasitic populations in livestock. Bioactive phytochemicals may contribute to improve parasite control by enhancing the effect of existing anthelmintic drugs. The aim of the current work was to evaluate the in vivo and in vitro pharmaco-chemical interaction and the in vivo efficacy of the combination of albendazole (ABZ) with thymol (TML) in lambs naturally infected with resistant gastrointestinal nematodes. Thirty (30) lambs were allocated into three experimental groups. Each group was treated orally with either ABZ (5 mg/kg), TML (150 mg/kg, twice every 24 h) or the co-administration of both compounds. Blood samples were collected between 0 and 51 h post-treatment and TML, ABZ and its metabolites were measured by HPLC. Individual faecal samples were collected at days -1 and 14 post-treatment to perform the faecal egg count reduction test. Additionally, the effect of TML on the sulphoreduction and sulphonation of ABZ sulphoxide was assessed in vitro using ruminal content and liver microsomes, respectively. The metabolism of TML in the ruminal content was very low and the monoterpene exhibited a low degree of association with the particulate phase of the ruminal content. No changes in the pharmacokinetic behavior of ABZ sulphoxide were observed in the presence of the natural product (TML). In contrast, the ABZ sulphone Cmax and AUC were lower (P 0.002 and 0.001 respectively) in the co-administered animals (0.16 ±â€¯0.07 µg/mL and 3.63 ±â€¯1.21 µg.h/mL) compared with those that received ABZ alone (0.45 ±â€¯0.15 µg/mL and 9.50 ±â€¯2.84 µg.h/mL). TML was detected in the bloodstream between 1 and 48 h post-treatment, which indicates the time of target nematodes being exposed to the bioactive monoterpene. However, the in vivo efficacy of TML was 0% and the presence of this terpene did not increase the efficacy of ABZ. The presence of TML significantly inhibited the ruminal sulphoreduction (P 0.001) and the hepatic sulphonation (P 0.001) of ABZ sulphoxide. These observations point out that in vivo pharmaco-parasitological studies are relevant to corroborate the adverse kinetic/metabolic interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics.


Assuntos
Albendazol/administração & dosagem , Resistência a Medicamentos/efeitos dos fármacos , Gastroenteropatias/tratamento farmacológico , Helmintíase Animal/tratamento farmacológico , Doenças dos Ovinos/tratamento farmacológico , Timol/administração & dosagem , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Quimioterapia Combinada , Gastroenteropatias/parasitologia , Helmintíase Animal/parasitologia , Compostos Fitoquímicos/farmacologia , Ovinos , Doenças dos Ovinos/parasitologia , Resultado do Tratamento
19.
PLoS One ; 15(5): e0233500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421749

RESUMO

BACKGROUND: Meta-analyses on impact of isoniazid-resistant tuberculosis informed the World Health Organization recommendation of a levofloxacin-strengthened rifampicin-based regimen. We estimated the effect of initial rifampicin resistance (Rr) and/or isoniazid resistance (Hr) on treatment failure or relapse. We also determined the frequency of missed initial and acquired Rr to estimate the impact of true Hr. METHODS: Retrospective analysis of 7291 treatment episodes with known initial isoniazid and rifampicin status obtained from individual patient databases maintained by the Damien Foundation Bangladesh over 20 years. Drug susceptibility test results were confirmed by the programme's designated supra-national tuberculosis laboratory. To detect missed Rr among isolates routinely classified as Hr, rpoB gene sequencing was done randomly and on a sample selected for suspected missed Rr. RESULTS: Initial Hr caused a large recurrence excess after the 8-month regimen for new cases (rifampicin for two months), but had little impact on rifampicin-throughout regimens: (6 months, new cases; 3.8%; OR 0.8, 95%CI:0.3,2.8; 8 months, retreatment cases: 7.3%, OR 1.8; 95%CI:1.3,2.6). Rr was missed in 7.6% of randomly selected "Hr" strains. Acquired Rr was frequent among recurrences on rifampicin-throughout regimens, particularly after the retreatment regimen (31.9%). It was higher in mono-Hr (29.3%; aOR 3.5, 95%CI:1.5,8.5) and poly-Hr (53.3%; aOR 10.2, 95%CI 4.4,23.7) than in susceptible tuberculosis, but virtually absent after the 8-month new case regimen. Comparing Bangladesh (low Rr prevalence) with a high Rr prevalence setting,true Hr corrected for missed Rr caused only 2-3 treatment failures per 1000 TB cases (of whom 27% were retreatments) in both. CONCLUSIONS: Our analysis reveals a non-negligible extent of misclassifying as isoniazid resistance of what is actually missed multidrug-resistant tuberculosis. Recommending for such cases a "strengthened" regimen containing a fluoroquinolone provokes a direct route to extensive resistance while offering little benefit against the minor role of true Hr tuberculosis in rifampicin-throughout first-line regimen.


Assuntos
Resistência a Medicamentos , Isoniazida/farmacologia , Rifampina/farmacologia , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Bangladesh , Erros de Diagnóstico , Resistência a Medicamentos/efeitos dos fármacos , Fluoroquinolonas/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Recidiva , Estudos Retrospectivos , Rifampina/uso terapêutico , Falha de Tratamento , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos
20.
Arthritis Res Ther ; 22(1): 65, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228698

RESUMO

OBJECTIVES: Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). METHODS: We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. RESULTS: The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0-10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. CONCLUSIONS: Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.


Assuntos
Cromonas/uso terapêutico , Aplicação de Novas Drogas em Teste/métodos , Nefrite Lúpica/tratamento farmacológico , Terapia de Salvação/métodos , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Estudos de Coortes , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/uso terapêutico , Quimioterapia de Indução/métodos , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA