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1.
Drugs Today (Barc) ; 56(1): 37-46, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32055804

RESUMO

Siponimod fumarate (BAF-312) is a synthetic sphingosine 1- phosphate (S1P) receptor modulator, which exerts immunomodulating effects mediated by B- and T-cell sequestration in secondary lymphoid organs. S1P receptor modulators have consistently shown a significant benefit on relapse rate and other measures of disease activity in patients with relapsing multiple sclerosis (MS), compared with both placebo and active comparator. However, most clinical trials of S1P receptor modulators--as well as other therapies for MS--lack evidence of a significant benefit on disability progression. A phase III trial of siponimod for secondary progressive MS showed a significant effect of the active drug compared with placebo on reduction of disability progression. Siponimod exhibits selective affinity for types 1 and 5 S1P receptors, indicating a possible lower risk of bradycardia and vasoconstriction compared with modulators with type 3 S1P receptor affinity. Current evidence supporting siponimod efficacy for secondary progressive MS is reviewed in the present article.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , /uso terapêutico , Ensaios Clínicos Fase III como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva
3.
Parasit Vectors ; 12(1): 509, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666109

RESUMO

BACKGROUND: Haemaphysalis longicornis is the major tick affecting dogs in most of the East Asia/Pacific region and has recently been detected in a number of areas of the USA. This tick is a vector for a number of pathogens of dogs, other mammals and humans. In this study, the efficacy of a single oral administration of sarolaner (Simparica®, Zoetis) at the minimum label dosage (2 mg/kg) was evaluated against an existing infestation of H. longicornis and subsequent weekly reinfestations for 5 weeks after treatment. METHODS: Sixteen dogs were ranked on pretreatment tick counts and randomly allocated to treatment on Day 0 with sarolaner at 2 mg/kg or a placebo. The dogs were infested with H. longicornis nymphs on Days - 2, 5, 12, 19, 26 and 33. Efficacy was determined at 48 hours after treatment and subsequent re-infestations based on live tick counts relative to placebo-treated dogs. RESULTS: There were no adverse reactions to treatment. A single dose of sarolaner provided 100% efficacy on Days 2, 7, 14 and 21; and ≥ 97.4% efficacy on Days 28 and 35. Considering only attached, live ticks, efficacy was 100% for the entire 35 days of the study. Geometric mean live tick counts for sarolaner were significantly lower than those for placebo on all days (11.62 ≤ t(df) ≤ 59.99, where 13.0 ≤ df ≤ 14.1, P < 0.0001). CONCLUSIONS: In this study, a single oral administration of sarolaner at 2 mg/kg provided 100% efficacy against an existing infestation of H. longicornis nymphs and ≥ 97.4% efficacy (100% against attached ticks) against weekly reinfestation for at least 35 days after treatment.


Assuntos
Antiparasitários/uso terapêutico , Vetores Aracnídeos , Azetidinas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Ixodidae , Compostos de Espiro/uso terapêutico , Infestações por Carrapato/veterinária , Administração Oral , Animais , Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Compostos de Espiro/administração & dosagem , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle
4.
Vet Parasitol ; 276: 108966, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31759192

RESUMO

The aim of this study was to evaluate the larval expulsion, larvicidal effect, retention rate of dead larvae and overall efficacy of sarolaner on the treatment of myiasis caused by New World screwworm Cochliomyia hominivorax in naturally infested dogs. Eight Beagle dogs received a single dose of saroalner 40 mg, with dosage ranging from 2.7 mg/kg to 3.7 mg/kg. Evaluations occurred every 15 min in the first hour, every hour for up to 6 h, and after 24 h of treatment. At 24 h post-treatment, total wound cleaning was performed, including removal and counting of remaining live and dead larvae. The animals received antibiotic, analgesic and wound cleaning support until complete wound healing. The average expulsion of the larvae was 50.9 % occurring mainly after 4 h of treatment. The larvicidal effect was 70.6 % at 6 h after treatment and 100 % at 24 h. The mean retention rate of dead larvae of sarolaner was 33.9 %, The overall efficacy was 100 %, thus making sarolaner an excellent treatment option in myiasis caused by C. hominivorax larvae in dogs.


Assuntos
Antiparasitários/uso terapêutico , Azetidinas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Miíase/veterinária , Infecção por Mosca da Bicheira/veterinária , Compostos de Espiro/uso terapêutico , Animais , Doenças do Cão/parasitologia , Cães , Miíase/tratamento farmacológico , Infecção por Mosca da Bicheira/tratamento farmacológico
5.
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
6.
Parasit Vectors ; 12(1): 431, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488194

RESUMO

BACKGROUND: The southern African yellow dog tick, Haemaphysalis elliptica, occurs in eastern and southern Africa and adults infest domestic and wild carnivores. This tick species is also a vector of the highly virulent Babesia rossi pathogen, the causative agent of canine babesiosis in sub-Saharan Africa. Sustained high levels of efficacy of a parasiticide are not only important in protecting dogs against the direct effects of tick infestation, but also in reducing the risk of tick-borne diseases. Sarolaner (Simparica™ chewable tablets) has been reported to be effective against the major tick species infesting dogs in Europe and the USA, including representatives from the genera Amblyomma, Ixodes, Rhipicephalus and Dermacentor. Until now no efficacy evaluations have been reported against species of the genus Haemaphysalis. The objective of the study was to confirm the efficacy of a single 2 mg sarolaner/kg oral dose of Simparica™ against induced infestations with H. (R.) elliptica, an important parasite of dogs in southern Africa. METHODS: This blinded, randomised, single centre, placebo controlled efficacy study followed a parallel group design and was conducted on two groups consisting of eight purpose-bred dogs each. Animals were treated orally, once on Day 0, with either a placebo compound (Group 1) or Simparica™ (Group 2). Simparica™ was administered orally at a dose rate of 2 mg sarolaner/kg body weight. The dogs were infested with ticks on Days - 7, - 2, 5, 12, 19, 26 and 33, with removal counts conducted on Days - 5, 2, 7, 14, 21, 28 and 35. RESULTS: A single oral administration of Simparica™ (sarolaner) at a minimum dose of 2 mg/kg resulted in a 100% efficacy against existing infestations of H. (R.) elliptica on dogs and a 100% reduction in live ticks following weekly re-infestations for 35 days. Moreover, the immediate and persistent high levels of efficacy observed in this study for 35 days is consistent with those observed in previous studies against ticks in other genera. CONCLUSIONS: The efficacy of sarolaner (Simparica™), administered orally to dogs at the minimum label dose of 2.0 mg/kg, was demonstrated against existing and weekly re-infestations of H. (R.) elliptica for at least 5 weeks. Efficacy of 100% was achieved against existing infestations as well as weekly re-infestations.


Assuntos
Antiparasitários/uso terapêutico , Azetidinas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Compostos de Espiro/uso terapêutico , Infestações por Carrapato/veterinária , Carrapatos/efeitos dos fármacos , Administração Oral , África Austral , Animais , Doenças do Cão/parasitologia , Cães , Feminino , Masculino , Distribuição Aleatória , Infestações por Carrapato/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento
7.
Medicine (Baltimore) ; 98(34): e15415, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441835

RESUMO

BACKGROUND: Multiple sclerosis is the most common demyelinating disease of the central nervous system with serious social and economic burden. Siponimod is a sphingosine-1-phosphate receptor agonist, and clinical trials in the past decade have shown good prospects for the treatment of multiple sclerosis. But there is a lack of comprehensive understanding of the dose-effect relationship and safety in different subtypes of multiple sclerosis at present. METHODS: We will perform a systematic review and meta-analysis of clinical randomized controlled trials to evaluate the efficacy and safety of siponimod in multiple sclerosis. We will search PubMed, EMBASE, Cochrane Library, Clinical Trials, Cochrane Central Register of Controlled Trials (CENTRAL) using a comprehensive strategy. The reference lists of the articles we select for inclusion will be checked to identify additional studies for potential inclusion. Two reviewers will review all literature independently. Upon inclusion of articles, another 2 reviewers will extract available data using a standardized form and assess the potential bias. Review Manager will be used to conduct data synthesis. There is no requirement of ethical approval and informed consent. RESULT: This is the first systematic assessment of siponimod for the treatment of multiple sclerosis. We predict it will provide high-quality synthesis of existing evidence for the efficacy and safety of siponimod for multiple sclerosis and a relatively comprehensive reference for clinical practice and clinical trials about siponimod to be conducted. CONCLUSION: The results of the systematic review and meta-analysis will provide updated evidence for the use of siponimod for multiple sclerosis. REGISTRATION: The systematic review and meta-analysis is registered in the PROSPERO international prospective register of systematic review (PROSPERO#CRD42018112721).


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Compostos de Benzil/administração & dosagem , Compostos de Benzil/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Esclerose Múltipla/classificação , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
9.
J Zoo Wildl Med ; 50(2): 470-473, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260217

RESUMO

Two nonrelated Goeldi's monkeys (Callimico goeldii) from the same enclosure developed multifocal alopecia with hyperkeratotic to ulcerative skin lesions on the lower abdomen and inner thighs. Necropsy samples of the first animal showed hyperplastic dermatitis together with in situ carcinoma and intralesional Demodex organisms. The second monkey developed similar lesions 2.5 yr later. Skin scrapings and biopsies also revealed Demodex mites within hyperplastic dermatitis. Long-term treatment with ivermectin, imidacloprid-moxidectin, and sarolaner resolved the demodicosis but skin lesions progressed to actinic keratosis and carcinoma. Both cutaneous neoplasia and demodicosis are rarely described in New World monkeys and these are the first reported cases in Goeldi's monkeys. Since the animals had access to ultraviolet (UV) light, as recommended for indoor-housed callitrichids, the skin tumors were likely UV-induced and the mites have settled particularly within impaired regions. Thus, apparent demodicosis can indicate cutaneous immunosuppression and might alert caretakers to adjust the UV regime.


Assuntos
Callimico , Carcinoma de Células Escamosas/veterinária , Infestações por Ácaros/veterinária , Doenças dos Macacos/etiologia , Neoplasias Cutâneas/veterinária , Raios Ultravioleta/efeitos adversos , Animais , Animais de Zoológico , Antibacterianos/uso terapêutico , Antiparasitários/administração & dosagem , Antiparasitários/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/uso terapêutico , Carcinoma de Células Escamosas/patologia , Combinação de Medicamentos , Feminino , Fluoroquinolonas/uso terapêutico , Inseticidas/administração & dosagem , Inseticidas/uso terapêutico , Ivermectina/uso terapêutico , Macrolídeos/administração & dosagem , Macrolídeos/uso terapêutico , Masculino , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/parasitologia , Doenças dos Macacos/parasitologia , Doenças dos Macacos/patologia , Neonicotinoides/administração & dosagem , Neonicotinoides/uso terapêutico , Nitrocompostos/administração & dosagem , Nitrocompostos/uso terapêutico , Neoplasias Cutâneas/etiologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/uso terapêutico
11.
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
12.
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
13.
Drugs ; 79(9): 1009-1015, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31144287

RESUMO

Siponimod (Mayzent®) is an oral selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1PR1,5) modulator being developed by Novartis Pharmaceuticals for the treatment of multiple sclerosis (MS) and intracerebral haemorrhage. In March 2019, siponimod received its first global approval in the USA, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Siponimod is under regulatory review in the EU and Japan for secondary progressive MS. This article summarizes the milestone in the development of siponimod leading to this first global approval for MS in the USA.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Aprovação de Drogas , Esclerose Múltipla/tratamento farmacológico , United States Food and Drug Administration/legislação & jurisprudência , Administração Oral , Adulto , União Europeia , Humanos , Japão , Resultado do Tratamento , Estados Unidos
14.
Pediatr Rheumatol Online J ; 17(1): 19, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046790

RESUMO

BACKGROUND: CANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the ß5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib. CASE PRESENTATION: We report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease. CONCLUSIONS: CANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.


Assuntos
Azetidinas/uso terapêutico , Dermatite/tratamento farmacológico , Febre/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Lipodistrofia/tratamento farmacológico , Neutropenia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Criança , Doença Crônica , Dermatite/complicações , Febre/complicações , Humanos , Lipodistrofia/complicações , Masculino , Neutropenia/complicações , Complexo de Endopeptidases do Proteassoma/imunologia , Síndrome , Resultado do Tratamento
16.
Stroke ; 50(5): 1224-1231, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31009359

RESUMO

Background and Purpose- The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods- Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results- Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions- For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Acidente Vascular Cerebral/tratamento farmacológico , Fatores Etários , Animais , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento
17.
Int J Surg Pathol ; 27(6): 669-677, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30942107

RESUMO

Undifferentiated sarcoma has been hypothesized as an intermediate step in the progression of malignant melanoma to rhabdomyosarcoma. The current report describes a new case of rhabdomyosarcomatous transformation in a malignant melanoma and documents the temporal progression of the malignant melanoma to rhabdomyosarcoma in different metastatic sites via undifferentiated sarcoma. A 65-year-old female with a past medical history of malignant melanoma presented with a new lung mass. A core biopsy revealed a malignant spindle cell neoplasm that was negative for all melanocytic markers, suggesting the possibility of a primary pulmonary sarcomatoid carcinoma or sarcoma. The subsequent lobectomy demonstrated an undifferentiated spindle cell neoplasm with areas of rhabdomyoblastic differentiation. Review of the skin lesion and lymph nodes confirmed the diagnosis of the primary cutaneous malignant melanoma, but also revealed that the nodal metastases had largely transformed into an undifferentiated sarcoma with similar morphology as the spindle cell neoplasm in the lung. Molecular studies demonstrated an identical BRAFV600E mutation in both the primary malignant melanoma and the lung tumor. Interestingly, the metastatic malignant melanoma with rhabdomyosarcomatous transformation was the single metastasis resistant to anti-BRAF therapy, whereas other metastases displayed dramatic clinical responses. The case report provides further supportive evidence that undifferentiated sarcoma is an intermediate step in the progression of malignant melanoma to rhabdomyosarcoma. Pathologists should be aware of this phenomenon as proper documentation of an undifferentiated sarcoma or newly acquired phenotypic variations in a malignant melanoma could considerably improve diagnostic accuracy and therapeutic management of subsequent recurrences.


Assuntos
Neoplasias Pulmonares/diagnóstico , Pulmão/patologia , Melanoma/diagnóstico , Rabdomiossarcoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Diagnóstico Diferencial , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Pulmão/cirurgia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Melanoma/secundário , Melanoma/terapia , Terapia Neoadjuvante/métodos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pneumonectomia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Rabdomiossarcoma/secundário , Rabdomiossarcoma/terapia , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico
18.
Nature ; 567(7749): 521-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867592

RESUMO

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.


Assuntos
Azetidinas/uso terapêutico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/enzimologia , Histiocitose/tratamento farmacológico , Histiocitose/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/uso terapêutico , Azetidinas/farmacologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Histiocitose/genética , Histiocitose/patologia , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Piperidinas/farmacologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética
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.
Trials ; 20(1): 182, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902094

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is associated with significantly diminished health-related quality of life. Patient-reported outcomes (PROs) are considered important in RA; however, some symptoms such as morning joint stiffness (MJS) and fatigue that are considered important by patients are not captured by the American College of Rheumatology "core set" measures for RA trials. The US Food and Drug Administration has endorsed electronic capture of clinical trial data including PROs, and electronic PRO (ePRO) systems may lead to more accurate and complete data capture, improved compliance, and patient acceptance compared with paper-based methods. Our objective was to assess the implementation of ePRO measures of Duration and Severity of MJS, Severity of Worst Tiredness, and Severity of Worst Joint Pain in baricitinib RA-BEAM and RA-BUILD phase 3 randomized clinical trials (RCTs). METHODS: A daily electronic diary (handheld device; Invivodata®, Inc.) was utilized to capture PRO data in the RCTs. Three "reporting window" options were incorporated to accommodate differences in patients' routine daily schedules, and alarms were programmed for each reporting window. Duration of MJS was recorded in "hours and minutes," and Severity of MJS, Worst Tiredness, and Worst Joint Pain were captured on a 0 to 10 rating scale, with a higher score indicating more severe symptoms. The patients and site staff were trained to use the daily electronic diary. RESULTS: Patients with moderately to severely active RA used the daily electronic diary in the RA-BEAM study (N = 1305) and RA-BUILD study (N = 684). The average compliance, calculated as total days completed by patients compared with total days expected to complete the diary, through Week 12 was high (RA-BEAM 94% patients; RA-BUILD 93% patients), potentially attributable to appropriate training, clarity of instructions, simple user interface, and electronic device design. Identified process challenges included non-timely issuance of the device, low battery, inadequate training of patients before data collection, inappropriate diary set-up, and first response entry 1 day after the baseline visit. CONCLUSIONS: High compliance rates support the use of the daily electronic PRO diary in large RCTs. Despite the anticipated issues, the daily electronic diary is expected to reduce recall bias and improve the quality of PRO data collection. TRIAL REGISTRATION: RA-BEAM ( NCT01710358 ) and RA-BUILD ( NCT01721057 ).


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Ensaios Clínicos Fase III como Assunto/instrumentação , Computadores de Mão , Coleta de Dados/instrumentação , Medidas de Resultados Relatados pelo Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto/instrumentação , Sulfonamidas/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/psicologia , Atitude Frente aos Computadores , Azetidinas/efeitos adversos , Nível de Saúde , Humanos , Medição da Dor , Cooperação do Paciente , Qualidade de Vida , Índice de Gravidade de Doença , Sulfonamidas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
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