RESUMO
The snake genus Daboia (Viperidae: Viperinae; Oppel, 1811) contains five species: D. deserti, D. mauritanica, and D. palaestinae, found in Afro-Arabia, and the Russell's vipers D. russelii and D. siamensis, found in Asia. Russell's vipers are responsible for a major proportion of the medically important snakebites that occur in the regions they inhabit, and their venoms are notorious for their coagulopathic effects. While widely documented, the extent of venom variation within the Russell's vipers is poorly characterised, as is the venom activity of other species within the genus. In this study we investigated variation in the haemotoxic activity of Daboia using twelve venoms from all five species, including multiple variants of D. russelii, D. siamensis, and D. palaestinae. We tested the venoms on human plasma using thromboelastography, dose-response coagulometry analyses, and calibrated automated thrombography, and on human fibrinogen by thromboelastography and fibrinogen gels. We assessed activation of blood factors X and prothrombin by the venoms using fluorometry. Variation in venom activity was evident in all experiments. The Asian species D. russelii and D. siamensis and the African species D. mauritanica possessed procoagulant venom, while D. deserti and D. palaestinae were net-anticoagulant. Of the Russell's vipers, the venom of D. siamensis from Myanmar was most toxic and D. russelli of Sri Lanka the least. Activation of both factor X and prothrombin was evident by all venoms, though at differential levels. Fibrinogenolytic activity varied extensively throughout the genus and followed no phylogenetic trends. This venom variability underpins one of the many challenges facing treatment of Daboia snakebite envenoming. Comprehensive analyses of available antivenoms in neutralising these variable venom activities are therefore of utmost importance.
Assuntos
Hemolíticos/química , Venenos de Víboras/química , Venenos de Víboras/toxicidade , Animais , Antivenenos , Ásia , Fator X/análise , Hemolíticos/análise , Humanos , Plasma/efeitos dos fármacos , Protrombina/análise , Daboia , Mordeduras de Serpentes , Venenos de Víboras/análise , ViperidaeRESUMO
Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline-containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4·6% after 3-5 cycles of R-CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate.
Assuntos
Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Insuficiência Cardíaca/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Arritmias Cardíacas/mortalidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/mortalidade , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dinamarca/epidemiologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Imunoterapia/efeitos adversos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Rituximab , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto JovemRESUMO
Pomalidomide is a next-generation immunomodulatory agent with activity in relapsed light chain (AL) amyloidosis, but real world outcomes are lacking. We report the experience of the UK National Amyloidosis Centre. All patients with AL amyloidosis treated with pomalidomide between 2009 and 2017 were included. Data was collected on treatment toxicity and clonal response. Survival was calculated by the Kaplan-Meier method and outcomes reported on an intent-to-treat (ITT) basis. A total of 29 patients treated with pomalidomide were identified. Haematological responses at 3 months were: complete response (CR) nil, very good partial response (VGPR) 10 (35%), partial response (PR) 9 (31%), stable or progressive disease 7 (24%), unevaluable 3 (10%). On an ITT basis (n = 28), responses at 6 months were: CR- nil, VGPR-11 (39%), PR-2 (7%) and the remaining patients were non-responders 15 (53%). Median overall survival was 27 months (95% confidence interval 15·7-38·1 months). Median progression free survival (PFS) was 15 months (95% confidence interval 6·24-23·77). In conclusion, pomalidomide has activity in patients with relapsed AL amyloidosis. Responses are rapid and early responses may be predictive of a sustained overall response. Deep responses (VGPR or better) are seen in only a third of all patients and combination therapy needs to be explored.
Assuntos
Amiloidose de Cadeia Leve de Imunoglobulina , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Talidomida/administração & dosagemRESUMO
Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/efeitos adversos , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Síndromes Mielodisplásicas/induzido quimicamente , Segunda Neoplasia Primária/induzido quimicamente , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Fatores de Tempo , Resultado do TratamentoAssuntos
Radioisótopos do Iodo/administração & dosagem , Linfoma Folicular/terapia , Radioimunoterapia , Rituximab/administração & dosagem , Gerenciamento Clínico , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioimunoterapia/métodos , Resultado do TratamentoRESUMO
Background: The World Health Organization estimates that there are approximately 5.4 million snakebites and 1.8-2.7 million cases of envenomation, with 81 410-137 880 deaths each year worldwide. Aims: To estimate the prevalence of neurotoxic and haemotoxic snakebite envenomation through a comprehensive systematic review and meta-analysis. Methods: We searched Medline/PubMed, Scopus and Cochrane Library up to January 2021 using keywords such as snakebite and snake envenomation. Bibliographic and random searches were also performed. Prospective or retrospective observational studies and randomized controlled trials were included for the review. Results: We included 271 of 9711 studies published between 1963 and 2020. The pooled prevalence of snakebite from 188 studies with a total of 207 235 participants showed the highest prevalence in North America (69.20%; 95% confidence interval, CI: 57.06-81.34%) and lowest in Africa (28.10%; 95% CI: 22.22-33.98%). There was a pooled prevalence of 24.94% (95% CI: 22.84-27.03%) for haemotoxicity, with a highest prevalence of coagulopathy (43.76%; 95% CI: 33.15-54.37%). The overall prevalence of neurotoxicity was 38.20% (95% CI: 31.88-44.53%), with a highest prevalence of ptosis (53.57%; 95% CI: 38.51-68.62%). Conclusion: There was a higher prevalence of snakebites in North America. The most prevalent haemotoxicity and neurotoxicity were coagulopathy and ptosis, respectively. The overall quality of evidence was good with a non-significant publication bias.
Assuntos
Mordeduras de Serpentes , Humanos , Mordeduras de Serpentes/complicações , Mordeduras de Serpentes/epidemiologia , Estudos Retrospectivos , Estudos Prospectivos , Prevalência , ÁfricaRESUMO
The Ethiopian endemic snake of the species Bitis parviocula, recognized for its colorful patterns, might be more interesting as we look deeper into the venom activity. We assayed the effects of venoms from the most widespread venomous African Bitis arietens and closely related species Bitis parviocula using The Hen's Egg Test-Chorioallantoic membrane test (HET-CAM) and Chicken embryotoxicity screening test (CHEST), acetylcholinesterase (AChE) analysis, cytotoxicity assay performed on cell lines and protein analysis of selected venoms. Our results indicated that B. parviocula venom contains vasoactive compounds that have a direct effect on blood vessels. The AChE analysis showed significant ability inhibiting AChE activity in embryonic tissue. Cytotoxicity observed on A549 ATCC® CCL-185™ cells indicates the possible presence of cytotoxic agents in B. parviocula venom. We proved previously described differences in the composition of venom obtained from B. arietans and B. parviocula by using electrophoresis and total protein concentration. Based on similarities in vasoactive effects observed after administration of venoms onto a chicken chorioallantoic membrane, we suggest that venom from B. arietans and B. parviocula might share certain venom proteins responsible for haemotoxicity. The main active components of B. parviocula venom are unknown. Our results suggest that it might be worth performing proteomic analysis of B. parviocula venom as it might contain medically valuable compounds.