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1.
Internist (Berl) ; 60(11): 1215-1220, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31486859

RESUMO

Janus kinases inhibitors (JAKI) are new orally administrable disease-modifying antirheumatic drugs (DMARD) for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), representing a treatment alternative equally effective as biological DMARD that is also classified equivalent in the guidelines. JAKI reversibly inhibit intracellular signal transduction from the cytokine receptor to the nucleus. Tofacitinib and baricitinib, two JAKI already approved for RA treatment, are taken once or twice a day, respectively, and two more are expected to receive approval next year. Tofacitinib is also approved for PsA. Generally, JAKI are initially used in combination with methotrexate (MTX) but are equally effective as monotherapeutic treatment if MTX is contraindicated. In terms of therapy safety, JAKI and bDMARD are generally comparable with one exception: JAKI are associated with an increased risk of herpes zoster infection. JAKI treatment requires laboratory blood tests, especially blood count, transaminases and creatinine. Due to hepatic metabolization, tofacitinib is associated with certain drug interactions. Altogether JAKI enhance treatment possibilities for diseases such as RA and PsA combining the same effectiveness and safety as bDMARD with the option of oral administration.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Metotrexato/uso terapêutico , Azetidinas/uso terapêutico , Quimioterapia Combinada , Humanos , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento
3.
Drugs ; 79(12): 1321-1335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317509

RESUMO

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn's disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indanos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Mesalamina/uso terapêutico , Oxidiazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Triazóis/uso terapêutico
4.
BMC Vet Res ; 15(1): 204, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208404

RESUMO

BACKGROUND: Mast cell tumours are the most common cutaneous neoplasms in dogs. Other primary sites include visceral organs, such as the gastrointestinal tract, liver, or spleen, and the oral cavity. Frequent metastatic sites include the local lymph nodes, skin, spleen, liver and bone marrow. The thorax is rarely affected by metastatic disease and no such cases have been reported in dogs. Mast cell tumours are usually not considered as a differential diagnosis for lung and intrathoracic chest wall masses in dogs. Chest wall tumours can be primary tumours of the ribs and sternum, an invasion of adjacent tumours into the chest wall, and metastasis from distant tumours. CASES PRESENTATION: A German Shepherd dog presented with a history of persistent cough and a large mass involving the thoracic wall and a small round pulmonary mass. The dog had a history of mammary tumours that were surgically excised. Thoracoscopy revealed a thoracic wall mass involving the internal intercostal muscle and a small mass in the left cranial lung lobe. Cytology and histopathology of the intrathoracic mass confirmed the large mass as a mast cell tumour and the small mass as a carcinoma. Cytology of the sternal lymph nodes showed no involvement. The dog received toceranib for 3 months, which failed to alleviate persistent cough. Radiology indicated that the large mass had a partial response to toceranib. The dog was euthanasied. A Maltese dog presented with a history of chronic regurgitation and cough, and a large mass involving the left caudal lung lobe. Cytology and histopathology of mass confirmed a mast cell tumour. The dog received toceranib for 2 months. Radiology indicated that the large mass had no response to toceranib. The dog was euthanasied. Confirmation of lungs mast cell tumour and the absence of any other Mast cell tumour was achieved by postmortem examination. CONCLUSIONS: The cases discussed are two unusual presentations of intrathoracic mast cell tumours, in the absence of cutaneous mast cell tumours, in dogs.


Assuntos
Doenças do Cão/patologia , Neoplasias Pulmonares/veterinária , Mastócitos/patologia , Neoplasias Torácicas/veterinária , Animais , Antineoplásicos/uso terapêutico , Carcinoma/patologia , Carcinoma/veterinária , Cães , Feminino , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pirróis/uso terapêutico , Neoplasias Torácicas/tratamento farmacológico , Neoplasias Torácicas/patologia , Parede Torácica/patologia
5.
Crit Rev Oncol Hematol ; 140: 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154235

RESUMO

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


Assuntos
Anoikis , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/fisiopatologia , Berberina/farmacologia , Berberina/uso terapêutico , Clorobenzoatos/farmacologia , Clorobenzoatos/uso terapêutico , Feminino , Humanos , Piranos/farmacologia , Piranos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Saponinas/farmacologia , Saponinas/uso terapêutico , Estirenos/farmacologia , Estirenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
6.
Dtsch Med Wochenschr ; 144(11): 748-752, 2019 06.
Artigo em Alemão | MEDLINE | ID: mdl-31163474

RESUMO

In Germany, baricitinib and tofacitinib have been approved for the treatment of at least moderately active rheumatoid arthritis after the failure of conventional disease modifying anti-rheumatic drugs in 2017, and tofacitinib also for psoriatic arthritis and ulcerative colitis. Both baricitinib and tofacitinib can be taken orally and reversibly inhibit Janus kinases (JAK) and therefore the signaling of a large number of cytokines via the JAK/STAT pathway. JAK inhibitors have been shown to be at least as efficacious in rheumatoid arthritis as adalimumab and tofacitinib was also efficacious in psoriatic arthritis. Since they inhibit many cytokines, it is likely that in the future they will be applied for the treatment of further chronic inflammatory disorder such as connective tissue diseases and vasculitis. The adverse events of JAK inhibitors are comparable to those observed with biologicals, only herpes zoster is slightly more common. In the placebo-controlled trials, venous thromboembolic events (VTE) were more common in the baricitinib treated patients. The VTE rate does not appear to be elevated in baricitinib treated patients compared to RA cohorts however.In conclusion, JAK inhibitors are a powerful new treatment of RA and likely many other rheumatic diseases and fulfill an unmet need since they may be taken orally.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Azetidinas/uso terapêutico , Alemanha , Humanos , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico
7.
Medicine (Baltimore) ; 98(24): e15860, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192917

RESUMO

BACKGROUND: Vonoprazan, a novel potassium-competitive acid blocking agent, has been used in the management of endoscopic submucosal dissection (ESD)-induced artificial ulcers. This study aimed to perform a systematic review and meta-analysis for the comparison of the effects of vonoprazan and proton pump inhibitors (PPIs) in treating ESD-induced artificial ulcers and preventing delayed bleeding in randomized controlled trial and cohort studies. METHODS: We searched OVID-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, and clinical trial registries in April 2018 to identify all studies that assess and compare the effects of vonoprazan and PPI in treating ESD-induced artificial ulcers and preventing delayed bleeding. Primary outcome of ulcer healing rate and secondary outcomes of shrinkage rate, ulcer size, and delayed bleeding were studied. RESULTS: A total of 1265 patients from 12 studies were included in the final analysis. Healing rate at 4 weeks post-ESD was significantly higher in the vonoprazan group than in the PPI group (relative ratio [RR] 1.20 [1.03-1.40]). However, healing rate at 8 weeks post-ESD was significantly higher in the PPI group than in the vonoprazan group (RR 0.68 [0.48-0.97]).There was no evidence of significant difference between groups in shrinkage rate at 4 weeks post-ESD, shrinkage rate at 8 weeks post-ESD, delayed bleeding, ulcer size at 0 weeks post-ESD, and ulcer size at 8 weeks post-ESD. CONCLUSIONS: There was no substantial difference in ulcer healing and post-ESD bleeding between vonoprazan and PPIs. However, vonoprazan more rapidly and effectively treated artificial ulcers after ESD than did PPIs.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Ressecção Endoscópica de Mucosa/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Úlcera/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Úlcera/etiologia
8.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
9.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
10.
Ter Arkh ; 91(2): 101-108, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-31094180

RESUMO

Major advances in pharmacology of the 21st century include the development of a new class of drugs, which are low-molecular, chemically synthesized molecules (the so-called "small molecules"), the point of application of which is Janus kinase (Janus kinase, JAK) involved in intracellular cytokine signaling. The review examines the molecular aspects of the JAK-STAT signaling pathway, justifying the use of the JAK-kinase inhibitor (tofacitinib) in the treatment of inflammatory bowel disease.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Humanos , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/efeitos dos fármacos
11.
Medicine (Baltimore) ; 98(20): e15701, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096515

RESUMO

BACKGROUND: Endoscopic submucosal dissection (ESD) is a standard procedure for treating gastric neoplasms. However, ESD causes larger artificial ulcers other than mucosal resection methods. We conducted this prospective randomized controlled study to evaluate the effect of stronger acid suppression on ESD ulcers caused by doubling the proton pump inhibitor (PPI) dose and compare the effects of 20-mg (standard dose) and 40-mg (double dose) esomeprazole (EswonampTM, Daewon Pharmaceutical Co., Ltd., Seoul, Korea) on ulcer healing. METHODS: One hundred ninety-seven patients who underwent gastric ESD from July 2017 to December 2017 at Pusan National University Yangsan Hospital were enrolled and randomly assigned to the standard or double-dose group. Change in ulcer size from the day of ESD to 4 weeks after ESD and the scar-change rate were compared between the groups. RESULTS: There were no significant differences in ulcer contraction (84.5% in 20 mg group vs 86.3% in 40 mg group, P = .91) or scar-change rate (30.9% vs 30.6%, P > .99) between the groups. In a multivariate analysis, initial ulcer size [odds ratio (OR) 0.24; 95% confidence interval (CI) 0.11-0.50] and early gastric cancer (OR 0.22, 95% CI 0.08-0.58) were significantly associated with delayed ulcer healing. CONCLUSIONS: Both 40 and 20-mg esomeprazole have similar effects on ESD-induced ulcer area reduction, suggesting that strong acid suppression does not necessarily result in rapid artificial ulcer healing. TRIAL REGISTRATION NUMBER: RCT no.: KCT0002885.


Assuntos
Ressecção Endoscópica de Mucosa/efeitos adversos , Esomeprazol/uso terapêutico , Neoplasias Gástricas/cirurgia , Úlcera Gástrica/tratamento farmacológico , Ressecção Endoscópica de Mucosa/métodos , Esomeprazol/administração & dosagem , Feminino , Humanos , Masculino , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , República da Coreia/epidemiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/patologia , Úlcera Gástrica/patologia , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Úlcera/tratamento farmacológico , Úlcera/patologia , Cicatrização/efeitos dos fármacos
12.
Int J Mol Sci ; 20(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121826

RESUMO

OBJECTIVE: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. METHOD: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control. RESULTS: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP. CONCLUSION: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the "crosstalk" between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.


Assuntos
Adiposidade , Heme Oxigenase-1/genética , Obesidade/genética , Obesidade/terapia , Adiposidade/efeitos dos fármacos , Animais , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ativadores de Enzimas/uso terapêutico , Marcação de Genes , Terapia Genética , Masculino , Camundongos Endogâmicos C57BL , Obesidade/patologia , Obesidade/fisiopatologia , Pirazinas/uso terapêutico , Pirróis/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
13.
Pediatrics ; 143(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948682

RESUMO

Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood arthritis accompanied by persistent systemic inflammation. Patients with sJIA often exhibit poor response to conventional disease-modifying antirheumatic drugs, and chronic glucocorticoid use is associated with significant adverse effects. Although biologics used to target interleukin 1 and interleukin 6 are efficacious, the long-term commitment to frequent injections or infusions remains a challenge in young children. Janus-activated kinase (JAK) inhibitors block the signaling of numerous proinflammatory cytokines and are now used clinically for the treatment of rheumatoid arthritis in adults. Whether this new class of medication is effective for sJIA has not been reported. Here, we describe the case of a 13-year-old girl with recalcitrant sJIA characterized by polyarticular arthritis, fever, lymphadenopathy, and serological features of inflammation. She showed minimal response to nonsteroidal antiinflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs, and etanercept. She also developed osteoporosis and vertebral compression fracture as the result of chronic glucocorticoid therapy. Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient experienced steady improvement of both arthritis and systemic features. Complete remission was achieved after 3 months, and no evidence of disease activity or adverse effects was seen through 6 months of follow-up. Our experience reveals the effectiveness of JAK inhibition in a case of refractory sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for children with sJIA, and its efficacy and safety should be further assessed by clinical trial.


Assuntos
Artrite Juvenil/diagnóstico por imagem , Artrite Juvenil/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adolescente , Feminino , Humanos , Resultado do Tratamento
14.
J Headache Pain ; 20(1): 37, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995909

RESUMO

BACKGROUND: In the past decade, migraine research has identified novel drug targets. In this review, we discuss recent data on emerging anti-migraine therapies. MAIN BODY: The development of ditans, gepants and anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of migraine is one of the greatest advances in the migraine field. Lasmiditan, rimegepant and ubrogepant will extend our therapeutic armamentarium for managing acute migraine attacks when triptans are not effective or contraindicated due to cardiovascular disorders. The monoclonal antibodies are migraine specific prophylactic drugs with high responder rates and favorable adverse event profiles. Furthermore, they offer convenient treatment regimens of 4- or 12-week intervals. CONCLUSION: Collectively, novel migraine therapies represent a major progress in migraine treatment and will undoubtedly transform headache medicine.


Assuntos
Analgésicos/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Triptaminas/uso terapêutico , Analgésicos/química , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Humanos , Transtornos de Enxaqueca/diagnóstico , Piridinas/química , Piridinas/uso terapêutico , Pirróis/química , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triptaminas/química
15.
AAPS PharmSciTech ; 20(5): 167, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30993508

RESUMO

Preformulation studies on tofacitinib citrate, a small molecule JAK3 specific inhibitor, have not been previously reported in literature. We therefore conducted several preformulation studies on tofacitinib citrate, and its free base, to better understand factors that affect its solubility, stability, and solid-state characteristics. Further, the results of the preformulation studies helped facilitate the development of a nebulized formulation of tofacitinib citrate for inhalational delivery to house dust mite allergen-challenged, BALB/c mice as a potential treatment for eosinophilic asthma. The preformulation results indicated tofacitinib having a basic pKa of 5.2, with its stability dependent on pH, ionic strength, and temperature. Degradation of tofacitinib follows apparent first-order kinetics. In order to maximize stability of the drug, ionic strength and temperature should be minimized, with an optimal range pH between 2.0 and 5.0. Additionally, our findings demonstrate that tofacitinib citrate can successfully be nebulized at a suitable droplet size for inhalation (1.2 ± 0.2 µm MMAD) through a nose-only chamber. Animals dosed with tofacitinib citrate demonstrated marked reductions in BAL eosinophils and total protein concentrations following HDM challenge. These data suggest that tofacitinib citrate represents the potential to be an effective therapy for eosinophilic asthma.


Assuntos
Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Administração por Inalação , Alérgenos , Animais , Composição de Medicamentos , Estabilidade de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae
16.
Biosens Bioelectron ; 135: 50-63, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30999241

RESUMO

The use of intrinsically conducting polymers (CPs) in wound care and skin tissue engineering presents a novel opportunity for accelerated wound healing, enhanced antibacterial activity and the potential for controlled drug delivery. Through their increased electrical conductivity, CPs can facilitate the application of electrical stimulation directly to the wound area, which has been linked to faster wound healing. The release of drugs or biological agents to the wound site can likewise be modulated through the use of an external electrical stimuli. This review thus summarises the available literature regarding the use of CPs for wound healing and skin tissue engineering applications, in particular the most common CPs, polyaniline (PANI), polypyrrole (PPy), polythiophene (PTh) and their derivates, including poly(3,4-ethylenedioxythiophene) (PEDOT). Results indicated that PANI and PPy, two CPs that have been most extensively studied across a range of applications, including biological, were also most frequently used in wound dressings and hydrogels. PPy was most commonly applied to skin tissue scaffolds. CPs were also frequently combined with biomolecules or biocompatible polymers via doping, the formation of composites, co-polymerisation or blending in order to improve their biocompatibility and physical properties. Overall, CPs offer much potential in terms of promoting enhanced wound healing and in skin tissue engineering.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Polímeros/uso terapêutico , Regeneração , Fenômenos Fisiológicos da Pele , Engenharia Tecidual/métodos , Cicatrização , Compostos de Anilina/química , Compostos de Anilina/uso terapêutico , Animais , Curativos Hidrocoloides , Materiais Biocompatíveis/química , Condutividade Elétrica , Humanos , Polímeros/química , Pirróis/química , Pirróis/uso terapêutico , Pele/citologia , Tiofenos/química , Tiofenos/uso terapêutico , Tecidos Suporte/química
17.
J Vet Med Sci ; 81(6): 821-823, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-30996208

RESUMO

A 12-year-old, male miniature dachshund has an ulcer on the footpad of the right hind limb. Despite treatment for longer than 6 months, the ulcer did not heal. Biopsy of the lesion was done to make a definitive diagnosis. Histologically, there were lumens containing weakly eosinophilic fluid surrounded by tumor cells with a similar circular pale nucleus and distinct nucleoli that showed some variation in size. Immunohistochemically, the tumor cells were positive for cytokeratin (AE1/AE3) and vimentin, were negative for S100 and p63. A poorly differentiated eccrine adenocarcinoma was diagnosed. Treatment was started with toceranib, an anti-angiogenic agent, and enlargement of the lesion was not observed during the administration period.


Assuntos
Adenocarcinoma/veterinária , Doenças do Cão/diagnóstico , Neoplasias das Glândulas Sudoríparas/veterinária , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Animais , Biópsia/veterinária , Doenças do Cão/tratamento farmacológico , Cães , Membro Posterior/patologia , Imuno-Histoquímica , Indóis/uso terapêutico , Queratinas/metabolismo , Masculino , Pirróis/uso terapêutico , Neoplasias das Glândulas Sudoríparas/diagnóstico , Neoplasias das Glândulas Sudoríparas/tratamento farmacológico , Vimentina/metabolismo
18.
J Drugs Dermatol ; 18(3): s115-s116, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30909355

RESUMO

Hypopigmentation and depigmentation of the skin can be due to multiple causes and has a broad differential diagnosis. The most common cause of depigmentation worldwide is vitiligo. This disorder affects 1-2% of the world's population and is seen in all races. Vitiligo is an autoimmune disorder in which the predominant cause is an attack by CD8+ cytotoxic T cells on melanocytes in the epidermis. This condition can have a significant negative impact on the quality of life of affected individuals. Treatment options currently include psychological counseling, topical therapy, systemic therapy, phototherapy, surgical therapy, and depigmentation. In patients with stable, refractory disease, successful repigmentation has been achieved using mini-punch grafting, blister grafting, and non-cultured epidermal suspension (NCES) grafting. Emerging therapies include the Janus kinase (JAK) inhibitors ruxolitinib and tofacitinib. Further studies exploring the pathogenesis of vitiligo are warranted in order to optimize treatment for affected patients. J Drugs Dermatol. 2019;18(3 Suppl):s115-116.


Assuntos
Doenças Autoimunes/terapia , Qualidade de Vida , Vitiligo/terapia , Administração Cutânea , Administração Oral , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Doenças Autoimunes/psicologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Aconselhamento/métodos , Fármacos Dermatológicos/uso terapêutico , Diagnóstico Diferencial , Epiderme/transplante , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Melanócitos/transplante , Micose Fungoide/diagnóstico , Fototerapia/métodos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/imunologia , Tinha Versicolor/diagnóstico , Vitiligo/diagnóstico , Vitiligo/imunologia , Vitiligo/psicologia
19.
Dermatol Clin ; 37(2): 137-141, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850035

RESUMO

The treatment of hair loss is a challenge for all dermatologists. New medications are needed due to lack of efficacy of many treatments or their side-effect profile. This article discusses the most recent literature updates on the use of retinoids in frontal fibrosing alopecia, platelet-rich plasma in androgenetic alopecia, and JAK inhibitors in alopecia areata.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/terapia , Inibidores de Janus Quinases/uso terapêutico , Plasma Rico em Plaquetas , Retinoides/uso terapêutico , Alopecia em Áreas/tratamento farmacológico , Azetidinas/uso terapêutico , Humanos , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico
20.
Medicine (Baltimore) ; 98(8): e14381, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813139

RESUMO

BACKGROUND: Vonoprazan is a potassium-competitive acid blocker (P-CAB). It is often used in Japan for Helicobacter pylori (H pylori) eradication, gastroesophageal reflux disease, and endoscopic submucosal dissection (ESD) ulcers and bleeding. This meta-analysis aims to evaluate whether vonoprazan has better therapeutic effect on ESD-induced ulcers and bleeding than proton pump inhibitors (PPIs) at different length of treatment periods (2, 4, and 8 weeks). METHODS: This meta-analysis will include both randomized controlled trials (RCTs) and observational studies discussing the effectiveness of vonoprazan and PPIs on ESD-induced ulcers and bleeding. Information of studies will be collected from PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar. Studies will be selected according to the eligibility criteria and data will be extracted by 2 people and compared with each other to keep in consistency. Cochrane risk of bias tool will be used to assess RCTs and the Newcastle-Ottawa Quality Assessment Scale will be used to assess the observational studies. Meta-analysis based on the random-effects model will be conducted to compare the differences of ulcers' shrinkage ratios (%) and the odds ratios (OR) of scars' stages and delayed bleeding. Publication bias will be evaluated using funnel plots and Egger's regression test. Heterogeneity will be assessed with the I statistics. Sensitivity analysis will be conducted on follow-up periods. The evidential quality of the findings will be assessed with the Grading of Recommendations Assessment Development and Evaluation (GRADE) profiler. DISCUSSION: The findings of the present systematic review will be critical for physicians, patients, and policymakers regarding the use of vonoprazan in ESD-induced ulcers. STUDY REGISTRATION: PROSPERO registration number: CRD42018116855.


Assuntos
Ressecção Endoscópica de Mucosa/efeitos adversos , Hemorragia Gastrointestinal/prevenção & controle , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Úlcera Gástrica/tratamento farmacológico , Sulfonamidas/uso terapêutico , Estudos Epidemiológicos , Humanos , Complicações Pós-Operatórias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Neoplasias Gástricas/cirurgia , Fatores de Tempo
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