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1.
Chemotherapy ; 64(2): 57-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31484176

RESUMO

Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose/terapia , Transplante de Células-Tronco Hematopoéticas , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/genética , Aspergillus fumigatus/isolamento & purificação , DNA Fúngico/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Tórax/diagnóstico por imagem , Transplante Homólogo/efeitos adversos
2.
Int J Clin Pharmacol Ther ; 57(11): 567-570, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31496508

RESUMO

OBJECTIVE: Hyperuricemia is an independent risk factor for renal dysfunction, cardiovascular events, and gouty arthritis. Xanthine oxidoreductase (XOR) inhibitors inhibit uric acid (UA) production and may be treatment options for hyperuricemia patients. I aimed to evaluate the effects of topiroxostat on circulating lipid concentrations in patients with hyperuricemia. MATERIALS AND METHODS: 83 hyperuricemic patients taking topiroxostat were enrolled into this retrospective study. RESULTS: Serum UA significantly decreased, total cholesterol (TC) decreased, and low-density lipoprotein cholesterol (LDL-c) decreased between baseline and 24 weeks. CONCLUSION: Topiroxostat may have the potential to lower serum UA, TC, and LDL-c concentrations in hyperuricemic patients.


Assuntos
Hiperuricemia/sangue , Lipídeos/sangue , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Colesterol/sangue , LDL-Colesterol/sangue , Humanos , Hiperuricemia/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Úrico/sangue
3.
Chem Pharm Bull (Tokyo) ; 67(7): 699-706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257325

RESUMO

In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (4) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)amino]propanenitrile (27) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 (5) and talampanel (1).


Assuntos
Anticonvulsivantes/síntese química , Nitrilos/química , Receptores de AMPA/antagonistas & inibidores , Administração Oral , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/veterinária , Relação Estrutura-Atividade
4.
Adv Mater ; 31(33): e1901965, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237375

RESUMO

Antibacterial photocatalytic therapy has been reported as a promising alternative water disinfection technology for combating antibiotic-resistant bacteria. Numerous inorganic nanosystems have been developed as antibiotic replacements for bacterial infection treatment, but these are limited due to the toxicity risk of heavy metal species. Organic semiconductor photocatalytic materials have attracted great attention due to their good biocompatibility, chemically tunable electronic structure, diverse structural flexibility, suitable band gap, low cost, and the abundance of the resources they require. An all-organic composite photocatalytic nanomaterial C3 N4 /perylene-3,4,9,10-tetracarboxylic diimide (PDINH) heterostructure is created through recrystallization of PDINH on the surface of C3 N4 in situ, resulting in enhanced photocatalytic efficiency due to the formation of a basal heterostructure. The absorption spectrum of this composite structure can be extended from ultraviolet to near-infrared light (750 nm), enhancing the photocatalytic effect to produce more reactive oxygen species, which have an excellent inactivation effect on both Gram-negative and positive bacteria, while demonstrating negligible toxicity to normal tissue cells. An efficient promotion of infectious wound regeneration in mice with Staphylococcus aureus infected dermal wounds is demonstrated. This all-organic heterostructure shows great promise for use in wound disinfection.


Assuntos
Antibacterianos/química , Imidas/química , Nitrilos/química , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Semicondutores , Animais , Antibacterianos/uso terapêutico , Antibacterianos/toxicidade , Catálise , Sobrevivência Celular , Escherichia coli/efeitos dos fármacos , Feminino , Luz , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanoestruturas/química , Nitrilos/uso terapêutico , Nitrilos/toxicidade , Perileno/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/toxicidade , Porfirinas/uso terapêutico , Porfirinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia
5.
Vet Parasitol ; 267: 4-8, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30878083

RESUMO

The objective of present studies was to evaluate and compare the anticoccidial activity of triazine compounds in broiler chickens infected with E. tenella, E. necatrix, E. acervulina, E. maxima, and two field mixed Eimeria species. The anticoccidial efficacy was evaluated using the anticoccidial index (ACI). The results showed that Aminomizuril (AZL) and Ethanamizuril (EZL) were active metabolites of nitromezuril, which demonstrated excellent effectiveness against E. tenella, E. necatrix, E. acervulina, E. maxima, and the field Eimeria isolates in broiler chickens at a dosage of 10 mg/kg in feed. The anticoccidial activities of AZL and EZL at dose 10 mg/kg were roughly equivalent to the parent nitromezuril at a dosage of 3 mg/kg in feed. The decrease in metabolite anticoccidial activity is probably due to an increasing polarity of compounds in the metabolic processes. The sensitivity of two field Eimeria isolates to triazines EZL, diclazuril and toltrazuril was tested using 4 indices including anticoccidial index (ACI), percent of optimum anticoccidial activity (POAA), reduction of lesion scores (RLS) and relative oocysts production (ROP). Results showed that the sensitivity of EZL treatment against the two field Eimeria isolates were relatively superior to that of diclazuril and toltrazuril treatment. The field Eimeria isolates from Gansu Province was determined to be slightly, moderately and highly resistant to EZL, diclazuril and toltrazuril respectively. The field Eimeria isolates from Zhejiang Province was slightly, highly and slightly resistant to EZL, diclazuril and toltrazuril respectively. The results above indicated that the anticoccidial activity of metabolites was lower than that of the parent nitromezuril and there was partial cross-resistance among triazines EZL, diclazuril and toltrazuril. However the field Eimeria isolates had higher sensitive to EZL than the triazines diclazuril and toltrazuril. It was suggested that the site of C4 substituents of phenol of triazine anticoccidials may have important biological functions and the metabolite EZL would be a potential novel anticoccidial agent worthy of more attention.


Assuntos
Coccidiose/veterinária , Eimeria/efeitos dos fármacos , Doenças das Aves Domésticas/tratamento farmacológico , Triazinas/uso terapêutico , Animais , Galinhas/parasitologia , Coccidiose/tratamento farmacológico , Resistência a Medicamentos , Nitrilos/uso terapêutico , Oocistos/efeitos dos fármacos , Doenças das Aves Domésticas/parasitologia
6.
Mycoses ; 62(6): 534-541, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30851214

RESUMO

BACKGROUND: Isavuconazole use in the real-world setting has not been extensively described. Subgroups of patients with particular prognostic significance, such as previous triazole prophylaxis or treatment and the important subgroup treated empirically for invasive fungal infection, have beforehand been excluded from trials. OBJECTIVES: We aimed to determine treatment response and safety in these patients at a large US transplant and cancer centre. PATIENTS/METHODS: We conducted a retrospective cohort study of all adult inpatients administered ≥3 doses of isavuconazole between June 2015 and October 2017. RESULTS: Ninety-one adults were identified. Six (7%) received primary prophylaxis, 10 (11%) treatment then secondary prophylaxis and 75 (82%) treatment only. Overall treatment response was 62%. Six-week mortality was 24%. Sixty-three per cent of 32 patients treated with isavuconaozle following prophylaxis with another antifungal agent exhibited a treatment response. Among 49 patients switched from treatment with another agent, 53% had a treatment response. Thirty-four patients received isavuconazole empirically, and 65% demonstrated a treatment response. Individuals given isavuconazole prophylaxis developed no breakthrough invasive fungal infections. One patient discontinued isavuconazole due to hepatotoxicity. CONCLUSIONS: Real-world isavuconazole use appears safe and is associated with treatment responses in varied patients including critically important subgroups previously unreported.


Assuntos
Antifúngicos/uso terapêutico , Quimioprevenção/métodos , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Centros Médicos Acadêmicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Substituição de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversos , Estados Unidos
7.
Med Oral Patol Oral Cir Bucal ; 24(2): e172-e180, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818309

RESUMO

BACKGROUND: Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation. MATERIAL AND METHODS: Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library. RESULTS: Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides. CONCLUSIONS: Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candidíase Bucal/tratamento farmacológico , Administração Intravenosa , Administração Oral , Administração Tópica , Anfotericina B/uso terapêutico , Anidulafungina/uso terapêutico , Azóis/uso terapêutico , Caspofungina/uso terapêutico , Clotrimazol/uso terapêutico , Bases de Dados Factuais , Interações de Medicamentos , Equinocandinas/uso terapêutico , Fluconazol/uso terapêutico , Humanos , Miconazol/uso terapêutico , Nitrilos/uso terapêutico , Nistatina/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico
8.
Ann Clin Microbiol Antimicrob ; 18(1): 13, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894179

RESUMO

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efficacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efficacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole. METHODS: This single center retrospective matched cohort study evaluated adults between January 2015 and December 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost. RESULTS: A total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was different between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p = 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p = 0.029) were different between the three groups. No differences in mortality, length of stay, readmission, or infection recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not different between treatments (p = 0.36). CONCLUSIONS: Patients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not significantly different between the treatment therapy options.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Voriconazol/uso terapêutico , Centros Médicos Acadêmicos/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Infecções Fúngicas Invasivas/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
9.
BMC Infect Dis ; 19(1): 134, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744563

RESUMO

BACKGROUND: Voriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden. METHODS: The cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs. RESULTS: The base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%. CONCLUSIONS: This model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective.


Assuntos
Antifúngicos/economia , Aspergilose/economia , Infecções Fúngicas Invasivas/economia , Nitrilos/economia , Piridinas/economia , Triazóis/economia , Voriconazol/economia , Adulto , Anfotericina B , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Estudos de Casos e Controles , Análise Custo-Benefício , Árvores de Decisões , Feminino , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Mucormicose/tratamento farmacológico , Mucormicose/economia , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Suécia , Triazóis/uso terapêutico , Voriconazol/uso terapêutico
10.
BMC Vet Res ; 15(1): 65, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808423

RESUMO

BACKGROUND: A previous six-week (wk) study demonstrated the potential of the sodium-glucose linked transport inhibitor velagliflozin as a novel treatment for equine insulin dysregulation. The present study examined the safety and efficacy of velagliflozin over 16 wk. of treatment, and over 4 wk. of withdrawal. Twenty-four insulin dysregulated ponies were selected, based on their hyper-responsiveness to a diet challenge meal containing 3.8 g non-structural carbohydrates (NSC)/kg bodyweight (BW). Ponies with serum insulin > 90 µIU/mL either 2 or 4 h after feeding were enrolled, and randomly allocated to receive either velagliflozin (0.3 mg/kg BW orally once daily, n = 12), or a placebo (n = 10-12) for 16 wk. The subjects were fed 7.5 g NSC/kg BW/day to maintain a fat body condition. Safety was assessed through daily monitoring, veterinary examination, and the measurement of fasting blood glucose, biochemistry and haematology. Efficacy at reducing post-prandial hyperinsulinemia was assessed using a diet challenge every 8 wk. during treatment and 4 wk. after withdrawal. RESULTS: Velagliflozin was well accepted by all subjects and caused no adverse effects or hypoglycaemia. Post-prandial serum insulin (insulin Cmax) did not change significantly in the control animals over the entire study period (P = 0.101). In contrast, insulin Cmax (mean ± SE) concentrations fell over time in the velagliflozin-treated group from 205 ± 25 µIU/mL in wk. 0, to 119 ± 19 µIU/mL (P = 0.015) and 117 ± 15 µIU/ml (P = 0.029) after 8 and 16 wk. of treatment, respectively. Although the insulin Cmax in this group was not significantly lower than in controls at wk-8 (P = 0.061), it was lower at wk-16 (P = 0.003), and all 12 treated ponies were below the previously-determined risk threshold for laminitis at this time. After 4 wk. withdrawal, the insulin Cmax returned to 199 ± 36 µIU/mL in the treated group, with no rebound effect. CONCLUSIONS: Velagliflozin appears to be a promising and safe treatment for equine insulin dysregulation, bringing post-prandial insulin concentrations below the laminitis risk threshold, albeit without normalising them.


Assuntos
Doenças dos Cavalos/tratamento farmacológico , Hiperinsulinismo/veterinária , Nitrilos/uso terapêutico , Animais , Doenças dos Cavalos/sangue , Cavalos , Hiperinsulinismo/sangue , Hiperinsulinismo/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Distribuição Aleatória , Resultado do Tratamento
11.
J Neuroinflammation ; 16(1): 1, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606213

RESUMO

BACKGROUND: Despite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation. METHODS: Intramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing. RESULTS: BCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity. CONCLUSION: The NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.


Assuntos
Astrócitos/metabolismo , Dor do Câncer/patologia , Quimiocina CXCL1/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Receptores de Interleucina-8B/metabolismo , Analgésicos/uso terapêutico , Animais , Anticorpos/uso terapêutico , Neoplasias Ósseas/complicações , Antígenos CD11/metabolismo , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Carcinoma/complicações , Linhagem Celular Tumoral , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/etiologia , Hiperalgesia/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Nitrilos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/imunologia , Sulfonas/uso terapêutico
12.
Transpl Infect Dis ; 21(2): e13048, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30636363

RESUMO

Invasive fungal infections are a common complication in immunocompromised patients, such as organ transplant recipients. Isavuconazole is a broad-spectrum azole antifungal for the treatment of aspergillosis and mucormycosis. The package insert for isavuconazole recommends against opening the capsule for administration through enteral feeding tubes. We describe the case of a 68-year-old man with a complex post-lung transplant course receiving isavuconazole for presumed invasive aspergillosis (bronchial alveolar lavage galactomannan index of >3.75) therapy administered through a gastrostomy-jejunostomy tube (G-J tube). Therapeutic drug monitoring was performed to ensure appropriate absorption. Peak and trough concentrations were measured in the early and late phases of the treatment course and resulted in trough levels of 2.7 mcg/mL and 4.0 mcg/mL, which is consistent with previously published trough concentrations of isavuconazole when the capsule was administered intact. This case report suggests that opening isavuconazole capsules and administration through a G-J tube results in appropriate absorption and serum drug levels comparable to intact capsules.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Nitrilos/administração & dosagem , Nitrilos/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Idoso , Cápsulas/administração & dosagem , Monitoramento de Medicamentos , Nutrição Enteral/métodos , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Transplante de Pulmão/efeitos adversos , Masculino
13.
Vector Borne Zoonotic Dis ; 19(4): 274-283, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30668280

RESUMO

Sylvatic plague affects many species in North American prairie ecosystems. Deltamethrin is commonly used to manage fleas in potential outbreak areas. Understanding the role of small mammals and their ectoparasites in sylvatic plague maintenance is pertinent to understanding the ecology of plague and its persistence in nature. This study examined the effects of plague management using deltamethrin on communities of small mammals, their flea faunas, and Yersinia pestis prevalence. We trapped small mammals from 2014 to 2016 on the Lower Brule Indian Reservation (LOBR), South Dakota, and analyzed the effects of deltamethrin treatment on small mammal populations, flea loads, and Y. pestis prevalence. We collected higher flea loads from small mammals on sites not treated with deltamethrin (1.10 fleas per animal) than from deltamethrin-treated sites (1.03 fleas per animal). We observed significant negative trends in mean flea load per animal between pre- and post-treatment collections. We detected no significant effects of deltamethrin treatment on animal captures pre- and post-treatment, but observed significant differences in animal captures by experimental unit. We detected no serological evidence for the presence of Y. pestis antibodies in small mammals and 1.2% Y. pestis prevalence across all sampled fleas. Although there is little overlap in the species of fleas infesting small mammals and prairie dogs, the occurrence of flea spillover has been documented. In our study, treatment with deltamethrin reduced flea loads on small mammals by up to 49%. Our data suggest that although the efficacy of deltamethrin on the LOBR-a mixed-grass system-may not be as high as that found in a comparable study in a short-grass system, deltamethrin is still a useful tool in the management of plague.


Assuntos
Ectoparasitoses/veterinária , Infestações por Pulgas/veterinária , Nitrilos/uso terapêutico , Peste/veterinária , Piretrinas/uso terapêutico , Doenças dos Roedores/parasitologia , Sifonápteros/efeitos dos fármacos , Animais , Antígenos de Bactérias , Ectoparasitoses/tratamento farmacológico , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/epidemiologia , Inseticidas/uso terapêutico , Peste/epidemiologia , Peste/prevenção & controle , Dinâmica Populacional , Doenças dos Roedores/microbiologia , Doenças dos Roedores/prevenção & controle , Roedores/parasitologia , South Dakota/epidemiologia , Yersinia pestis
16.
Medicine (Baltimore) ; 97(44): e13038, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30383669

RESUMO

This retrospective study investigated the efficacy and safety of letrozole for patients with polycystic ovary syndrome (PCOS).Totally, 136 cases of infertility women with PCOS were analyzed. Of those, 68 patients received letrozole, and were assigned to Letrozole group. The other 68 cases received clomiphene, and were assigned to clomiphene group. Patients in both groups were treated up to 5 treatment cycles. The primary endpoint included infant outcomes. The secondary endpoints consisted of the number of women in conception, pregnancy, pregnancy loss, and ovulation. In addition, any kinds of adverse events were also recorded.Cases in the Letrozole group did not show better outcomes neither in primary endpoint (live birth, P = .11; birth weight, P = .95; infant gender, P = .85), nor in secondary endpoints (the number of women in conception, P = .07; pregnancy, P = .12; pregnancy loss, P = .47; pregnancy loss in first trimester, P = .70; and ovulation, P = .09), compared with cases in the clomiphene group. Moreover, no adverse events differ significantly between 2 groups.This study demonstrated that the efficacy of letrozole is not superior to the clomiphene in patients with PCOS.


Assuntos
Inibidores da Aromatase/uso terapêutico , Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Nitrilos/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Triazóis/uso terapêutico , Adulto , Inibidores da Aromatase/efeitos adversos , Clomifeno/efeitos adversos , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Infertilidade Feminina/tratamento farmacológico , Letrozol , Nitrilos/efeitos adversos , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Triazóis/efeitos adversos
17.
Oxid Med Cell Longev ; 2018: 3509091, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405876

RESUMO

The Toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway is vital in the pathogenesis of hepatic ischemia/reperfusion (HIR) injury. Dipeptidyl peptidase-4 (DPP4) inhibitors exert protective effects on IR injury of the kidney, heart, and lung; however, their effect on the liver is still unknown. Thus, the purpose of this study was to examine whether pretreatment with vildagliptin (Vilda), a DPP4 inhibitor, produces hepatic protection against IR injury and to investigate its influence on TLR4/NF-κB signaling in a rat model. Thirty male Wistar rats were divided into 3 groups: the sham group: subjected to a sham operation and received normal saline; the HIR group: subjected to HIR and received normal saline; and the Vilda + HIR group: subjected to HIR with pretreatment of 10 mg/kg/day Vilda for 10 days intraperitoneally. Hepatic ischemia lasted for 45 minutes followed by 3-hour reperfusion; then blood and liver samples were collected for biochemical and histopathological examination. The HIR group produced a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) levels and a significant reduction in the hepatic catalase level in comparison to the sham group. Moreover, a significant upregulation of gene and protein expressions of TLR4, NF-κB, and high-mobility group box-1 (HMGB1) along with caspase-3 protein expression was observed in the HIR group when compared with the sham group. Histopathological examination of the liver from the HIR group showed necrosis, sinusoidal congestion, hemorrhage, and hepatocyte degeneration. Administration of Vilda ameliorated the biochemical and histopathological changes caused by HIR. Vildagliptin showed for the first time a hepatoprotective effect in HIR injury through downregulation of TLR4/NF-κB/HMGB1 and caspase-3 hepatic expressions.


Assuntos
Adamantano/análogos & derivados , Fígado/irrigação sanguínea , NF-kappa B/metabolismo , Nitrilos/uso terapêutico , Pirrolidinas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Receptor 4 Toll-Like/metabolismo , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , NF-kappa B/genética , Nitrilos/farmacologia , Nitrosação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pirrolidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/fisiopatologia , Receptor 4 Toll-Like/genética , Vildagliptina
18.
Reprod Biol Endocrinol ; 16(1): 89, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217209

RESUMO

BACKGROUND: Letrozole is widely employed as ovulation induction agent in women with PCOS, but its use in mild stimulation (MS) protocols for IVF is limited. Aim of the present study was to evaluate the feasibility of a MS protocol with letrozole plus hMG in non-obese PCOS women undergoing IVF after a metformin pre-treatment. METHODS: We retrospectively evaluated the data of 125 non-obese PCOS undergoing MS with letrozole plus hMG, 150 IU as starting dose, (group 1, N = 80) compared to those undergoing a conventional IVF stimulation protocols (CS) (group 2, N = 45) prior to IVF. All patients had received metformin extended release 1200-2000 mg daily for three to six months before IVF. GnRH antagonist was administered in both groups when the leading follicles reached 14 mm. RESULTS: Both groups were comparable for age, BMI and ovarian reserve markers. Both groups showed lower than expected AFC and AMH values as a consequence of metformin pre-treatment. Letrozole-treated patients required a significantly lower amount of gonadotropins units (p < 0.0001), and showed significantly lower day 5, day 8 and hCG day E2 levels compared to patients undergoing the CS protocol (p < 0.0001, p < 0.0001 and p = 0.001 respectively). The oocyte yield, in terms of total (6, IQR 3, vs 6, IQR 4 respectively,) and MII oocytes (5, IQR 3, vs 5, IQR 3, respectively) number, did not differ among groups; the number of total (3, IQR 2, vs 3, IQR 1 respectively) and good quality embryos (2, IQR1 vs 2, IQR 1,5 respectively) obtained was comparable as well in the two groups. The number of fresh transfers was significantly higher in group 1 compared to group 2 (80% vs 60%, p = 0.016). A trend for higher cumulative clinical pregnancy rate was found in women undergoing MS compared to CS (42.5%vs 24,4%, p = 0.044), but the study was not powered to detect this difference. CONCLUSIONS: The present study suggests that the use of letrozole as adjuvant treatment to MS protocols for IVF may be an effective alternative to CS protocols for non-obese PCOS patients pre-treated with metformin, as it provides comparable IVF outcome without requiring high FSH dose, and avoiding supraphysiological estradiol levels.


Assuntos
Infertilidade Feminina/terapia , Metformina/uso terapêutico , Nitrilos/uso terapêutico , Síndrome do Ovário Policístico/complicações , Triazóis/uso terapêutico , Adulto , Feminino , Gonadotropinas/uso terapêutico , Humanos , Letrozol , Recuperação de Oócitos , Síndrome de Hiperestimulação Ovariana , Indução da Ovulação/métodos , Projetos Piloto , Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Injeções de Esperma Intracitoplásmicas
19.
J Cancer Res Ther ; 14(5): 909-915, 2018 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30197324

RESUMO

Aim of Study: This review aims to highlight that bosutinib represents a valuable alternative for patients already treated unsuccessfully with one or more other tyrosine kinase inhibitors (TKIs). Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm associated with a specific genetic abnormality resulting in a fusion protein with an active tyrosine kinase region. Therefore, TKIs were developed as a suitable treatment option. Methods: Full-text articles, abstracts, and meta-analysis comparing the efficacy and safety of the five TKIs were included in the review. Efficacy of these enhanced therapies is estimated on the basis of achievement of a complete cytogenetic response (CCyR) and this outcome is an important goal as a surrogate marker for improved survival. Results: Bosutinib's efficacy is comparable to that of imatinib in the first-line setting and with dasatinib and nilotinib as second-line therapy, while its safety profile is distinctly different. Most therapeutic guidelines for CML recommend an initiation of therapy with imatinib and application of dasatinib and nilotinib as subsequent lines. Conclusion: Bosutinib is generally not recommended despite its demonstrated efficacy and manageable toxicity. However, resistance, intolerance, specific mutations, as well as disease progression are often the reasons for the lack of sufficient response to therapy registered by the lower rates or complete absence of CCyR. Treatment options are limited for these patients.


Assuntos
Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Compostos de Anilina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bulgária/epidemiologia , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Nitrilos/efeitos adversos , Quinolinas/efeitos adversos , Resultado do Tratamento
20.
J Food Sci ; 83(9): 2369-2374, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30070707

RESUMO

The risk for breast and colon cancer may be lowered in part by high intake of fruits and vegetables. Fruits such as grapes are abundant in bioactive compounds such as anthocyanins. The potential anticancer activity of anthocyanins may be limited by their metabolism in the gut and liver. One metabolic transformation is due to the enzyme catechol-O-methyltransferase (COMT), which methylates polyphenols such as anthocyanins. Entacapone is a clinically used inhibitor of COMT, and has been shown to modulate the methylation of food-derived polyphenols. In this study, we compared the effect of entacapone on the cell viability of colon (Caco-2 and HT-29) and breast (MDA-MB-231) cancer cell lines treated with anthocyanins. Cells were treated with either cyanidin-3-glucoside, delphinidin-3-glucoside, or an anthocyanin-rich grape extract, in the absence or presence of entacapone. Cell viability was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Entacapone in combination with the anthocyanins had a greater than additive effect on growth inhibition of the Caco-2 cells. In the MDA-MB-231 cell line, entacapone similarly enhanced the growth inhibitory activity of the anthocyanin extract. Entacapone also had antiproliferative effects when used as a single treatment. Total hydroperoxides was quantified in the cell culture media. Greater concentrations of the treatments resulted in higher levels of total hydroperoxides, indicating that oxidative stress may be an important mechanism for growth inhibition. In conclusion, the antiproliferative activity of fruit-derived anthocyanins was improved in human cancer cell lines by the clinically used drug entacapone. The efficacy and mechanisms of entacapone/anthocyanin combinations should be carefully studied in vivo. PRACTICAL APPLICATION: Chemical components of grapes are good for our health and have been shown to lower risk for certain cancers. Their beneficial health effects could also be enhanced by consuming other molecules that improve their bioavailability.


Assuntos
Antocianinas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Catecóis/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Nitrilos/uso terapêutico , Vitis/química , Antocianinas/metabolismo , Antocianinas/farmacologia , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Células CACO-2 , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecóis/farmacologia , Proliferação de Células , Sinergismo Farmacológico , Feminino , Frutas/química , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Células HT29 , Humanos , Metilação , Nitrilos/farmacologia , Estresse Oxidativo , Fitoterapia , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Sais de Tetrazólio , Tiazóis
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