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1.
J Ethnopharmacol ; 247: 111576, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30385423

RESUMO

AIM OF THE STUDY: Because the toxicity and efficacy of arsenic is closely related to its chemical species, we conducted examinations of arsenic species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different arsenic species in the short-term toxicity of realgar. MATERIALS AND METHODS: According to ICH M3 guidelines for non-clinical repeated dose toxicity studies and OECD Test guideline TG407 "Repeated Dose 28-Day oral Toxicity Study in Rodents, the doses of realgar set were 10.6 mg/kg, 40.5 mg/kg and 170 mg/kg. Rats were orally administered with realgar for one-tme and 30 days, respectively. Thereafter, biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine realgar metabolism, arsenic species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated. RESULTS: The absorption, distribution and elimination half-life of total arsenic species in realgar were 3.33 hs, 16.08 hs and 24.65 hs, respectively. After 30 days of oral administration of realgar in rats, no significant drug-related toxicity occurred in the rats. Dimethylarsenic acid (DMA) is the most abundant arsenic species. The DMA contents of the liver and kidney of the high-dose realgar group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group, respectively. The arsenic species (III) was mainly detected in the liver and its content was about 40-fold higher than that of the control group. MMA was mainly detected in rat kidney, and the MMA content of the realgar treatment group was more than 2000 times higher than that of the control group. CONCLUSIONS: Arsenic is rapidly absorbed and distributed over the liver, kidneys and brain, and the distribution and elimination of arsenic in the blood is slow. The realgar doses corresponded to human equivalent doses (HED) of 1.7, 6.4 and 27.2 mg/kg, respectively. Considering that humans are 10 times more sensitive than animals, the realgar dose is equivalent to 0.17, 0.64 and 2.7 mg/kg HED. It can be considered that if patients take no more than 2.7 mg/kg realgar for 2 weeks, there will be no adverse reactions.


Assuntos
Arsenicais/farmacocinética , Sulfetos/farmacocinética , Administração Oral , Animais , Arsenicais/administração & dosagem , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Absorção Gastrointestinal , Meia-Vida , Rim/metabolismo , Fígado/metabolismo , Masculino , Espectrometria de Massas , Ratos , Sulfetos/administração & dosagem , Sulfetos/toxicidade , Distribuição Tecidual , Testes de Toxicidade Aguda
2.
Forensic Sci Int ; 300: e24-e30, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31023496

RESUMO

Realgar (arsenic sulfide) is widely used in combination with other herbs as Chinese patent medicine to treat a variety of diseases in China. As a mineral arsenic, its mild toxicity was also well known. Longtime over-dose usage or wrongly oral intake of realgar can cause chronic arsenic poisoning and/or death, but acute fatal arsenic poisoning resulted from short-term dermal use of realgar-containing medicine was very rare. Here, we present the case of a 35-year-old Chinese man, who was diagnosed with severe psoriasis and died of fatal acute arsenic poisoning after he applied a local folk prescription ointment containing mainly the realgar to the affected skin for about 4 days. The autopsy showed multiple punctate hemorrhages over the limbs, pleural effusion, edematous lungs with consolidation, mild myocardial hypertrophy and normal-looking kidneys. The histopathological examination of renal tissue showed severe degeneration, necrosis and desquamation of renal tubular epithelial cells, presence of protein cast and a widened edematous interstitium with interstitial fibrosis. The presence of arsenic in large amount in the ointment (about 6%), in blood (1.76 µg/mL), and in skin (4.71 µg/g), were confirmed analytically. We also provide the clinical records of the deceased and briefly reviewed 7 similar cases in literature (6 in Chinese and 1 in English) in the past 30 years in China.


Assuntos
Intoxicação por Arsênico/etiologia , Medicina Tradicional Chinesa/efeitos adversos , Sulfetos/envenenamento , Administração Tópica , Adulto , Intoxicação por Arsênico/patologia , Arsenicais/administração & dosagem , Arsenicais/análise , China , Hemorragia/patologia , Humanos , Rim/patologia , Pulmão/patologia , Masculino , Pomadas , Derrame Pleural/patologia , Pele/química , Sulfetos/administração & dosagem , Sulfetos/análise
3.
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
4.
Med Mal Infect ; 49(3): 194-201, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30792037

RESUMO

OBJECTIVE: An empirical treatment of infectious vaginitis is justified because of its multiple etiologies, the frequent uncertainty of clinical diagnosis and limits of microbiological analysis. Our aim was to comparatively investigate nystatin-neomycin-polymyxin B combination (NNP, Polygynax®) and miconazole. PATIENTS AND METHODS: In this European multicenter, double-blind PRISM trial, participating women presenting with infectious vaginitis were randomized to receive one vaginal capsule containing either NNP for 12 days or miconazole for 3 days followed by 9 days of placebo. RESULTS: The clinical success rate was higher in the NNP group (n=302) than the miconazole group (n=309), with a difference between groups close to statistical significance (91.1% vs. 86.7%, P=0.0906). The risk of treatment failure was 36% lower in the NNP group (odds ratio, 0.64; 95% confidence interval, 0.38-1.07). Vaginal burning on Day 2 and vaginal discharge on Day 4 were significantly less intense in the NNP group than in the miconazole group (39.1 vs. 42.3, P=0.031 and 34.6 vs. 37.6, P=0.031, respectively). Adverse drug reactions were reported by 1.2% and 2.1% of patients in the NNP and miconazole group respectively, with the ratio of adverse drug reactions relative to total adverse events significantly higher in the miconazole group (20.3% vs. 6.9%, P=0.022). CONCLUSION: The widespread use of NNP for several decades and its good efficacy and safety profile, as well as the frequent diagnostic uncertainties due to the various pathogens sustain the initiation of this broad-spectrum empirical treatment in infectious vaginitis.


Assuntos
Arsenicais/administração & dosagem , Miconazol/administração & dosagem , Neomicina/administração & dosagem , Nistatina/administração & dosagem , Polimixinas/administração & dosagem , Vaginite/tratamento farmacológico , Adolescente , Adulto , Arsenicais/efeitos adversos , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/epidemiologia , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Miconazol/efeitos adversos , Pessoa de Meia-Idade , Neomicina/efeitos adversos , Nistatina/efeitos adversos , Polimixinas/efeitos adversos , Resultado do Tratamento , Vaginite/epidemiologia , Vaginite/microbiologia , Vaginose Bacteriana/tratamento farmacológico , Vaginose Bacteriana/epidemiologia , Adulto Jovem
6.
Eur J Gastroenterol Hepatol ; 31(2): 183-186, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30499784

RESUMO

BACKGROUND: Mesalazine-refractory ulcerative proctitis is common, with a significant proportion of the patients requiring escalation to immunomodulators or biological therapy. Three small preliminary cohort studies suggested good clinical efficacy for the organic arsenic derivative acetarsol in the management of proctitis. Our aim was to describe our experience on the use of acetarsol in proctitis and to review all existing evidence on its safety and efficacy. PATIENTS AND METHODS: We retrospectively reviewed clinical records of all ulcerative colitis patients exposed to acetarsol at Nottingham University Hospitals since 2012. Clinical response was determined basing on physicians' global assessments and patients' improvement over the baseline (reduction in stool frequency and rectal bleeding). Clinical remission was defined as total resolution of symptoms including bleeding cessation. Serum arsenic, C-reactive protein and faecal calprotectin levels reviewed when available. Nonparametric analysis performed. RESULTS: Twenty-eight (16 males) patients with median (range) age 39 (35) and 9 (19) years disease duration received acetarsol suppositories for proctitis. All had failed mesalazine or corticosteroid topical therapy, with 50% having additionally failed immunomodulators. Median treatment duration was 70 (64) days. 16/28 were prescribed acetarsol more than once. 67.9% achieved clinical response and 46.4% clinical remission. 32.1% required treatment escalation to steroids, thiopurines or antitumour necrosis factor agents. 6/28 patients stopped acetarsol due to side effects. CONCLUSION: Acetarsol could be an effective and safe option in the management of refractory proctitis. A definitive trial with long-term safety follow-up is required to investigate the efficacy and safety of this promising drug.


Assuntos
Anti-Inflamatórios/administração & dosagem , Arsenicais/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Mesalamina/administração & dosagem , Proctocolite/tratamento farmacológico , Centros de Atenção Terciária , Administração Retal , Adulto , Anti-Inflamatórios/efeitos adversos , Arsenicais/efeitos adversos , Resistência a Medicamentos , Substituição de Medicamentos , Registros Eletrônicos de Saúde , Inglaterra , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Masculino , Mesalamina/efeitos adversos , Proctocolite/diagnóstico , Indução de Remissão , Estudos Retrospectivos , Supositórios , Fatores de Tempo , Resultado do Tratamento
7.
Chin J Integr Med ; 25(5): 354-359, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29500545

RESUMO

OBJECTIVE: To explore the effect of Qinghuang Powder (QHP,()combined with Bupi Yishen Decoction (BPYS, ) on myelodysplastic syndromes (MDS) patients with refractory cytopenia with multilineage dysplasia (RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. METHODS: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count (ANC), hemoglobin (Hb), platelets (PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation. Gene Ontology (GO) and Pathway analysis were applied to analyze the methylation data. RESULTS: The overall MDS response rate to QHP was 61.68% (190/360) including hematologic improvement-neutrophil (HI-N) or hematologic improvement-erythroid (HI-E) or hematologic improvement-platelet (HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia (55.88% vs 31.54% or 55.88% vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. CONCLUSIONS: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement (HI-N, HI-P or HI-E) and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.


Assuntos
Arsenicais/uso terapêutico , Linhagem da Célula , Metilação de DNA/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos Leucocíticos/tratamento farmacológico , Transtornos Leucocíticos/genética , Arsenicais/administração & dosagem , Arsenicais/farmacologia , Linhagem da Célula/efeitos dos fármacos , Desmetilação , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Pós , Resultado do Tratamento
8.
Parasit Vectors ; 11(1): 671, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587225

RESUMO

BACKGROUND: The American Heartworm Society currently recommends the use of a monthly macrocyclic lactone, a 28-day course of 10 mg/kg doxycycline BID, and the 3-dose protocol of melarsomine dihydrochloride for the treatment of canine heartworm disease. Doxycycline is necessary for the reduction of the bacterium Wolbachia, found in all heartworm life-stages. Previous price increases and decreasing availability prompted us to evaluate alternative tetracycline antibiotics, i.e. minocycline, for the reduction of Wolbachia during canine heartworm treatment. METHODS: Thirty-two heartworm-positive dogs were randomized to receive 10 mg/kg or 5 mg/kg of either doxycycline or minocycline for 28 days BID, for a total of 8 dogs per experimental group. All dogs received 6 months of Heartgard Plus® (ivermectin/pyrantel) and the 3-dose protocol of 2.5 mg/kg melarsomine dihydrochloride. Blood samples were collected prior to the initiation of treatment, every 7 days throughout tetracycline treatment, and then monthly thereafter until the dog tested negative for the presence of heartworm antigen. DNA was isolated from circulating microfilarial samples and qPCR was performed on each sample. RESULTS: A greater number of dogs in the 10 mg/kg doxycycline and minocycline treated groups experienced gastrointestinal side effects as compared to the 5 mg/kg doxycycline and minocycline treated groups. All eight dogs in the 10 mg/kg doxycycline-treated group tested negative for the presence of Wolbachia DNA by 28 days post-tetracycline treatment. A total of two dogs in both the 5 mg/kg doxycycline- and 10 mg/kg minocycline-treated groups and three dogs in the 5 mg/kg minocycline-treated group remained positive for the presence of Wolbachia DNA by the end of tetracycline treatment. CONCLUSIONS: No lung pathology was assessed in this clinical trial, therefore the clinical effect of the remaining Wolbachia DNA in the 10 mg/kg minocycline-, 5 mg/kg doxycycline- and 5 mg/kg minocycline-treated groups cannot be determined. Owner compliance in the proper administration of these tetracyclines may be impacted by the increased severe gastrointestinal side effects reported for the 10 mg/kg doxycycline- and minocycline-treated groups. We recommend that veterinarians prescribe the recommended 10 mg/kg doxycycline for canine heartworm treatment and reduce the dosage to 5 mg/kg in cases of severe gastrointestinal side effects in order to improve owner compliance in administration of medications.


Assuntos
Antibacterianos/administração & dosagem , Arsenicais/administração & dosagem , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Doxiciclina/administração & dosagem , Filaricidas/administração & dosagem , Minociclina/administração & dosagem , Triazinas/administração & dosagem , Wolbachia/efeitos dos fármacos , Animais , Dirofilaria immitis/microbiologia , Dirofilaria immitis/fisiologia , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Doxiciclina/efeitos adversos , Quimioterapia Combinada , Feminino , Masculino , Minociclina/efeitos adversos , Wolbachia/genética , Wolbachia/fisiologia
9.
Int J Nanomedicine ; 13: 5937-5952, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323584

RESUMO

Background: The Traditional Chinese Medicine, arsenic trioxide (ATO, As2O3) could inhibit growth and induce apoptosis in a variety of solid tumor cells, but it is severely limited in the treatment of glioma due to its poor BBB penetration and nonspecifcity distribution in vivo. Purpose: The objective of this study was encapsulating ATO in the modified PAMAM den-drimers to solve the problem that the poor antitumor effect of ATO to glioma, which provide a novel angle for the study of glioma treatment. Methods: The targeting drug carrier (RGDyC-mPEG-PAMAM) was synthesized based on Arg-Gly-Asp (RGDyC) and αvß3 integrin targeting ligand, and conjugated to PEGylated fifth generation polyamidoamine dendrimer (mPEG-PAMAM). It was characterized by nuclear magnetic resonance, fourier transform infrared spectra, Nano-particle size-zeta potential analyzer,etc. The in vitro release characteristics were studied by dialysis bag method. MTT assay was used to investigate the cytotoxicity of carriers and the antitumor effect of ATO formulation. In vitro blood-brain barrier (BBB) and C6 cell co-culture models were established to investigate the inhibitory effect of different ATO formulation after transporting across BBB. Pharmacokinetic and antitumor efficacy studies were investigated in an orthotopic murine model of C6 glioma. Results: The prepared RGDyC-mPEG-PAMAM was characterized for spherical dendrites, comparable size (21.60±6.81 nm), and zeta potential (5.36±0.22 mV). In vitro release showed that more ATO was released from RGDyC-mPEG-PAMAM/ATO (79.5%) at pH 5.5 than that of pH 7.4, during 48 hours. The cytotoxicity of PEG-modified carriers was lower than that of the naked PAMAM on both human brain microvascular endothelial cells and C6 cells. In in vitro BBB model, modification of RGDyC heightened the cytotoxicity of ATO loaded on PAMAM, due to an increased uptake by C6 cells. The results of cell cycle and apoptosis analysis revealed that RGDyC-mPEG-PAMAM/ATO arrested the cell cycle in G2-M and exhibited threefold increase in percentage of apoptosis to that in the PEG-PAMAM/ATO group. Compared with ATO-sol group, both RGDyC-mPEG-PAMAM/ATO and mPEG-PAMAM/ATO groups prolonged the half-life time, increased area under the curve, and improved antitumor effect, significantly. While the tumor volume inhibitory of RGDyC-mPEG-PAMAM/ATO was 61.46±12.26%, it was approximately fourfold higher than the ATO-sol group, and twofold to the mPEG-PAMAM/ATO group. Conclusion: In this report, RGDyC-mPEG-PAMAM could enhance the antitumor of ATO to glioma, it provides a desirable strategy for targeted therapy of glioma.


Assuntos
Arsenicais/uso terapêutico , Dendrímeros/química , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Oligopeptídeos/química , Óxidos/uso terapêutico , Polietilenoglicóis/química , Animais , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/administração & dosagem , Arsenicais/farmacocinética , Arsenicais/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Glioma/patologia , Humanos , Masculino , Camundongos , Óxidos/administração & dosagem , Óxidos/farmacocinética , Óxidos/farmacologia , Coelhos , Ratos , Eletricidade Estática , Resultado do Tratamento
10.
Mol Med Rep ; 18(5): 4733-4738, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30221721

RESUMO

The aim of the present study was to investigate the acute effect and mechanism of tumor necrosis factor (TNF) on basolateral 50 pS K channels in the thick ascending limb (TAL) of the rat kidney. The TAL tubules were isolated from the rat kidney, and the activity of the 50 pS K channels was recorded using the patch­clamp technique. The results indicated that the application of TNF (10 nM) significantly activated the 50 pS K channels and the TNF effect was concentration­dependent. Inhibition of protein kinase A, phospholipase A2 and protein tyrosine kinase using pathway inhibitors (H89, AACOCF3 and Herbimycin A, respectively) did not abolish the stimulatory effect of TNF, indicating that none of these pathways mediated the TNF effect. By contrast, the phenylarsine oxide inhibitor against protein tyrosine phosphatase (PTP) decreased the activity of the 50 pS K channels and blocked the stimulatory effect of TNF on these channels. Furthermore, western blot analysis demonstrated that the application of TNF (10 nM) in the TAL increased the phosphorylation of PTP, an indication of PTP activity stimulation. Thus, it was concluded that the acute application of TNF may stimulate the basolateral 50 pS K channel in the TAL and the stimulatory effect of TNF may be mediated by the PTP­dependent pathway.


Assuntos
Túbulos Renais/metabolismo , Rim/metabolismo , Canais de Potássio/genética , Fator de Necrose Tumoral alfa/metabolismo , Animais , Ácidos Araquidônicos/administração & dosagem , Arsenicais/administração & dosagem , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Isoquinolinas/administração & dosagem , Rim/efeitos dos fármacos , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Alça do Néfron/efeitos dos fármacos , Alça do Néfron/metabolismo , Masculino , Técnicas de Patch-Clamp , Inibidores de Fosfolipase A2/administração & dosagem , Fosfolipases A2/genética , Canais de Potássio/metabolismo , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Rifabutina/administração & dosagem , Rifabutina/análogos & derivados , Sulfonamidas/administração & dosagem , Fator de Necrose Tumoral alfa/administração & dosagem
11.
PLoS Negl Trop Dis ; 12(9): e0006790, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30208034

RESUMO

BACKGROUND: Trypanosoma evansi is mechanically transmitted by biting flies and affects camels, equines, and other domestic and wild animals in which it causes a disease called surra. At least two types of Trypanosoma evansi circulate in Ethiopia: type A, which is present in Africa, Latin America and Asia, and type B, which is prevalent in Eastern Africa. Currently, no information is available about the drug sensitivity of any Ethiopian T. evansi type. METHODOLOGY/PRINCIPAL FINDINGS: This study was conducted with the objective of determining the in vivo drug sensitivity of two T. evansi type A and two type B stocks that were isolated from camels from the Tigray and Afar regions of Northern Ethiopia. We investigated the efficacy of four trypanocidal drugs to cure T. evansi infected mice: melarsamine hydrochloride (Cymelarsan), diminazene diaceturate (Veriben and Sequzene), isometamidium chloride (Veridium) and homidium chloride (Bovidium). Per experimental group, 6 mice were inoculated intraperitoneally with trypanosomes, treated at first peak parasitemia by daily drug injections for 4 consecutive days and followed-up for 60 days. Cymelarsan at 2 mg/kg and Veriben at 20 mg/kg cured all mice infected with any T. evansi stock, while Sequzene at 20 mg/kg caused relapses in all T. evansi stocks. In contrast, Veridium and Bovidium at 1 mg/kg failed to cure any T. evansi infection in mice. CONCLUSIONS/SIGNIFICANCE: We conclude that mice infected with Ethiopian T. evansi can be cured with Cymelarsan and Veriben regardless of T. evansi type. In contrast, Veridium and Bovidium are not efficacious to cure any T. evansi type. Although innate resistance to phenanthridines was previously described for T. evansi type A, this report is the first study to show that this phenomenom also occurs in T. evansi type B infections.


Assuntos
Fenantridinas/administração & dosagem , Tripanossomicidas/administração & dosagem , Trypanosoma/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Animais , Arsenicais/administração & dosagem , Diminazena/administração & dosagem , Diminazena/análogos & derivados , Modelos Animais de Doenças , Etiópia , Feminino , Injeções , Camundongos , Recidiva , Resultado do Tratamento , Trypanosoma/isolamento & purificação
12.
Ann Hematol ; 97(10): 1797-1802, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29951912

RESUMO

Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21-128 months), the 4-year OS probability was 0.85 (95% CI 0.61-0.94), DFS was 0.74 (95% CI 0.49-0.88), and EFS 0.68 (95% CI 0.45-0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
13.
Hematology ; 23(10): 756-764, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29724147

RESUMO

OBJECTIVES: Catastrophic hemorrhage remains the main cause of acute promyelocytic leukemia (APL) treatment failure. This study was aimed to study the pathogenesis of coagulopathy in patients with APL. METHODS: Multiple procoagulant and profibrinolytic parameters in plasma and peripheral leukocytes from 24 patients with newly diagnosed APL accompanied by coagulopathy before and after arsenic trioxide (ATO) treatment were evaluated. RESULTS: Prior to the treatment, the patients had elevated D-dimer and decreased fibrinogen levels. Plasma urokinase-type plasminogen activator receptor (uPAR) and plasmin-ɑ2 antiplasmin complexes (PAP) levels, plasmin (Pn) activity, and cell surface levels of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were significantly higher; plasma plasminogen activator inhibitor-1 (PAI-1) levels and plasminogen (Pg) activity were significantly decreased; plasma plasminogen activator (PA) activity, uPA and tPA levels; and cell surface levels of uPAR and annexin II were not significantly different from levels in the control group. During ATO treatment, both patients' plasma PA activity and uPAR on leukocytes gradually increased, annexin II on leukocytes increased initially and decreased afterwards, and tPA and uPA on leukocytes remained consistently higher in the patients than in the controls. Other parameters gradually tended toward normal values. CONCLUSIONS: In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.


Assuntos
Arsenicais/administração & dosagem , Transtornos da Coagulação Sanguínea/sangue , Proteínas Sanguíneas/metabolismo , Fibrinólise , Leucemia Promielocítica Aguda , Proteínas de Neoplasias/sangue , Óxidos/administração & dosagem , Adulto , Idoso , Trióxido de Arsênio , Feminino , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
14.
BMJ Case Rep ; 20182018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29724869

RESUMO

Leukaemia cutis or cutaneous infiltration of neoplastic myeloid or lymphoid cells is usually seen in the acute myelomonocytic and acute monocytic variants of acute myeloid leukaemia. Here, we report a case of acute promyelocytic leukaemia who achieved remission, presenting with skin lesions, the biopsy of which revealed leukaemia cutis, heralding the relapse of the disease. After establishing the diagnosis with bone marrow analysis, the patient was started on daunorubicin chemotherapy along with arsenic trioxide and all-trans retinoic acid. Afterwards, the skin lesions resolved, and the patient is planned for consolidation with bone marrow transplantation.


Assuntos
Leucemia Promielocítica Aguda/patologia , Infiltração Leucêmica/patologia , Pele/patologia , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Biópsia , Quimioterapia de Consolidação , Daunorrubicina/administração & dosagem , Feminino , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Infiltração Leucêmica/tratamento farmacológico , Óxidos/administração & dosagem , Tretinoína/administração & dosagem
15.
J Toxicol Sci ; 43(5): 291-298, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29743440

RESUMO

Organic arsenic diphenylarsinic acid (DPAA[V]) accumulates at high concentrations in the liver of primates after its subchronic administration. However, no studies on the hepatic effects of organic arsenic compounds, including DPAA(V), on primates have been reported to date. To clarify the toxicokinetics of DPAA(V) in the liver of primates, hepatic tissue specimens were collected from cynomolgus monkeys (n = 32) at 5, 29, 170, and 339 days after repeated administration of DPAA(V) for 28 days. Four histopathological changes in the specimens were observed and pathologically evaluated. Atypical ductular proliferation was found in the DPAA(V)-exposed liver throughout the period. Inflammatory cell infiltration in Glisson's capsules and lipid droplets were seen at earlier periods after administration. Conversely, inflammatory cell infiltration in liver lobules was seen later after administration. In this experiment, we did not confirm the hepatic dysfunction of DPAA(V)-exposed monkeys by blood chemistry tests. To compensate for this, we further investigated the blood from a patient who exhibited several neurological symptoms after DPAA(V) exposure. Her blood chemistry test values for aspartate transaminase, alanine transaminase, and lactate dehydrogenase were elevated, suggesting that her liver may have been damaged by DPAA(V) exposure. Together, these findings suggest that the accumulation of DPAA(V) may induce differential histopathological changes in primate hepatocytes, resulting in decreased liver function. This is the first report to investigate the liver of primates pathologically after exposure to organic arsenic DPAA(V). Our findings will help expand our knowledge regarding the effect of DPAA(V) on the liver of primates.


Assuntos
Arsenicais/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/patologia , Alanina Transaminase/sangue , Animais , Arsenicais/administração & dosagem , Arsenicais/farmacocinética , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Criança , Feminino , Humanos , Gotículas Lipídicas/metabolismo , Fígado/metabolismo , Hepatopatias/diagnóstico , Macaca fascicularis , Fatores de Tempo
16.
Talanta ; 184: 446-451, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29674067

RESUMO

Arsenic in hair and nails has been used to assess chronic exposure of humans to environmental arsenic. However, it remains to be seen whether it is appropriate to evaluate acute exposure to sub-lethal doses of arsenic typically used in therapeutics. In this study, hair, fingernail and toenail samples were collected from nine acute promyelocytic leukemia (APL) patients who were administered intravenously the daily dose of 10 mg arsenic trioxide (7.5 mg arsenic) for up to 54 days. These hair and nail samples were analyzed for arsenic species using high performance liquid chromatography separation and inductively coupled plasma mass spectrometry detection (HPLC-ICPMS). Inorganic arsenite was the predominant form among water-extractable arsenicals. Dimethylarsinic acid (DMAV), monomethylarsonic acid (MMAV), monomethylarsonous acid (MMAIII), monomethylmonothioarsonic acid (MMMTAV), and dimethylmonothioarsinic acid (DMMTAV) were also detected in both hair and nail samples. This is the first report of the detection of MMAIII and MMMTAV as metabolites of arsenic in hair and nails of APL patients.


Assuntos
Arsênico/análise , Arsenicais/uso terapêutico , Cabelo/química , Leucemia Promielocítica Aguda/tratamento farmacológico , Unhas/química , Óxidos/uso terapêutico , Adulto , Trióxido de Arsênio , Arsenicais/administração & dosagem , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Adulto Jovem
17.
Int J Mol Sci ; 19(4)2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29617346

RESUMO

Despite the success of arsenic trioxide (ATO) in treating haematological malignancies, its potential to treat solid tumours has not been fully exploited, owing to its dose-limiting toxicity and poor pharmacokinetics. In order to overcome this hurdle, liposomal encapsulation of the drug with different surface charges (neutral, negative, and positive) and sizes (100, 200 and 400 nm) were synthesised and tested on human papilloma virus (HPV)-positive HeLa and HPV-negative HT-3 cervical cancer cell lines. Two epithelial cell lines-human keratinocytes (HK) and human colon cells (CRL-1790)-were used as controls. The synthesised liposomes were tested for their physico-chemical characteristics, drug loading efficiency, and toxicity on the studied cell lines. Neutral liposomes of 100 nm in size were the chosen formulation for delivering ATO into the studied cells, as they showed the least intrinsic cytotoxicity and the highest loading efficiency. The findings demonstrated that the optimised formulation of liposomes was an effective drug delivery method for HPV-infected cervical cancer cells. Furthermore, the toxicity vs. uptake ratio was highest for HeLa cells, while a reduced or minimal toxic effect was observed for non-HPV-infected cervical cancer cells and control cells. These findings may provide a promising therapeutic strategy for effectively managing cervical cancers.


Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Sistemas de Liberação de Medicamentos , Lipossomos , Óxidos/administração & dosagem , Antineoplásicos/química , Trióxido de Arsênio , Arsenicais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Feminino , Humanos , Óxidos/química , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Tamanho da Partícula , Eletricidade Estática , Neoplasias do Colo do Útero/etiologia
18.
Dig Dis Sci ; 63(4): 1011-1015, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29457211

RESUMO

BACKGROUND: Management of proctitis refractory to conventional therapies presents a common clinical problem. The use of acetarsol suppositories, which are derived from organic arsenic, was first described in 1965. Data concerning clinical efficacy and tolerability are very limited. AIM: To examine the efficacy of acetarsol suppositories for the treatment of refractory proctitis. METHODS: A retrospective analysis was performed on patients with inflammatory bowel disease treated with acetarsol suppositories between 2008 and 2014 at Addenbrooke's Hospital, Cambridge, United Kingdom. Clinical response was defined as resolution of symptoms back to baseline at the time of next clinic review. RESULTS: Thirty-nine patients were prescribed acetarsol suppositories between March 2008 and July 2014 (29 patients with ulcerative colitis, nine with Crohn's disease, and one with indeterminate colitis). Thirty-eight were included for analysis. The standard dose of acetarsol was 250 mg twice daily per rectum for 4 weeks. Clinical response was observed in 26 patients (68%). Of the 11 patients who had endoscopic assessment before and after treatment, nine (82%) showed endoscopic improvement and five (45%) were in complete remission (Wilcoxon signed-rank test p = 0.006). One patient developed a macular skin rash 1 week after commencing acetarsol, which resolved within 4 weeks of drug cessation. CONCLUSION: Acetarsol was effective for two out of every three patients with refractory proctitis. This cohort had failed a broad range of topical and systemic treatments, including anti-TNFα therapy. Clinical efficacy was reflected in significant endoscopic improvement. Adverse effects of acetarsol were rare.


Assuntos
Anti-Infecciosos/administração & dosagem , Arsenicais/administração & dosagem , Doenças Inflamatórias Intestinais/complicações , Proctite/tratamento farmacológico , Supositórios , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proctite/etiologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
Medicine (Baltimore) ; 97(8): e9657, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29465554

RESUMO

RATIONALE: Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. APL is currently treated with combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) resulting in the induction of apoptosis and differentiation of the leukemic cells. Differentiation syndrome (so-called ATRA syndrome) is the main life-threatening complication of induction therapy with these differentiating agents. PATIENT CONCERNS: Herein, we report the case of a 49-year-old woman diagnosed with APL with, concomitantly, a bulky cutaneous lesion of 10 cm diameter with a red-to-purple background and a necrotic center, localized on her abdomen. DIAGNOSES: After 10 days of treatment, the cutaneous lesion became purulent. Fluorescence in situ hybridization (FISH) analysis performed on this pus confirmed the presence of malignant features in the involved granulocytes proving their origin from the differentiation of leukemic APL cells, as all the analyzed nuclei showed 2 promyelocytic leukemia (PML)-retinoic acid receptor-a (RARA) fusions signals. INTERVENTION: The association by ATRA and ATO was continued. OUTCOME: Eventually, the evolution was favorable with healing in three weeks. LESSONS: This case report therefore highlights the differentiation phenomenon of promyelocytic blasts within promyelocytic sarcoma with the ATRA-ATO combination and the efficacy of this drug association in resolving both the malignant sarcoma and a secondary local infection.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arsenicais/efeitos adversos , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/efeitos adversos , Sarcoma Mieloide/tratamento farmacológico , Tretinoína/efeitos adversos , Abdome/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Sarcoma Mieloide/induzido quimicamente , Sarcoma Mieloide/patologia , Supuração/induzido quimicamente , Tretinoína/administração & dosagem
20.
Complement Ther Med ; 36: 59-62, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29458932

RESUMO

BACKGROUND: Among the post-immunization adverse events, especially of Diphtheria-Pertusis-Tetanus (DPT), fever is a common systemic reaction. There is anecdotal support for the use of the homeopathic medicine Arsenicum album in preventing post-vaccination fever. The investigators intended to evaluate its efficacy in preventing febrile episodes following vaccination. METHODS: In the community medicine out-patient of Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, West Bengal, India, between August 2014 and January 2017, a double-blind, randomized, placebo-controlled trial was conducted on 120 children (verum: 60, placebo: 60) who presented for the 2nd and 3rd dose of DPT-HepB-Polio vaccination and reported febrile episodes following the 1st dose. Intervention used was Arsenicum album 30cH 6 doses or placebo (indistinguishable from verum), thrice daily for two subsequent days. Parents were advised to report any event of febrile attacks within 48h of vaccination, either directly or over telephone. RESULTS: The groups were comparable at baseline. Children reporting fever after the 2nd dose was 29.8% and 30.4% respectively for the homeopathy group and control group respectively [Relative Risk (RR)=1.008] with no significant difference (P=0.951) between groups. Again after the 3rd dose, children reporting fever were 31.5% and 28.3% respectively for the homeopathy group and control group respectively (RR=0.956) with no significant difference (P=0.719) between groups. CONCLUSION: Empirically selected Arsenicum album 30cH could not produce differentiable effect from placebo in preventing febrile episodes following DPT-HepB-Polio vaccination. [Trial registration: CTRI/2017/02/007939].


Assuntos
Arsenicais/uso terapêutico , Febre , Materia Medica/uso terapêutico , Vacinação/efeitos adversos , Arsenicais/administração & dosagem , Criança , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Método Duplo-Cego , Febre/tratamento farmacológico , Febre/epidemiologia , Febre/prevenção & controle , Vacinas contra Hepatite B/efeitos adversos , Homeopatia , Humanos , Índia , Materia Medica/administração & dosagem , Vacinas contra Poliovirus/efeitos adversos
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