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1.
Br J Haematol ; 196(1): 63-69, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34340260

RESUMO

Sickle cell disease (SCD) is a devastating and under-recognised global child health issue affecting over 300,000 infants annually, with the highest prevalence in India and sub-Saharan Africa. Most affected infants born in low- and middle-income countries (LMIC) lack access to SCD testing and die from complications in the first years of life without a formal diagnosis. The majority of deaths are preventable with early diagnosis and provision of inexpensive interventions. Despite global recognition of the urgent need, expansion of SCD newborn screening (NBS) programmes beyond the pilot stage has been obstructed by a dependence on an expensive and logistically challenging centralised laboratory testing model. Recently, several point-of-care tests (POCT) for SCD have been developed with promising field validation studies. Here, we summarise the state of POCT for SCD, review barriers and unanswered questions, and discuss optimal strategies for utilising POCT to address the growing global burden of SCD. There is an urgent need to prospectively evaluate the ability of POCT to reduce the morbidity and high early mortality of SCD. To impact a sustainable reduction to this end, it is essential to link a diagnosis with comprehensive SCD care, including wide and affordable access to affordable hydroxycarbamide therapy.


Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/epidemiologia , Testes Imediatos , Financiamento de Capital , Análise Custo-Benefício , Diagnóstico Precoce , Avaliação do Impacto na Saúde , Acessibilidade aos Serviços de Saúde , Humanos , Recém-Nascido , Técnicas de Diagnóstico Molecular/economia , Técnicas de Diagnóstico Molecular/instrumentação , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Triagem Neonatal , Testes Imediatos/economia , Testes Imediatos/normas , Prevalência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
Br J Haematol ; 190(5): e274-e276, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32652563
4.
Pharmacotherapy ; 43(5): 430-441, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36906823

RESUMO

Sickle cell disease (SCD) is a common and life-threatening inherited blood disorder that affects more than 300,000 newborns per year. Because of the origins of the sickle gene mutation as a protective mechanism against malaria for those with sickle cell trait, more than 90% of annual SCD births are in sub-Saharan Africa (sSA). Over the past several decades, there have been many important advances in the care of individuals with SCD, including early diagnosis through newborn screening programs (NBS), prophylactic penicillin, the development of vaccines to prevent invasive bacterial infections, and the emergence of hydroxyurea as the primary disease-modifying pharmacologic therapy. These relatively simple and inexpensive interventions have significantly reduced the morbidity and mortality of sickle cell anemia (SCA) such that individuals with SCD can live longer and more complete lives. Unfortunately, although these interventions are relatively inexpensive and evidence-based, they are only readily available for affected individuals living in high-income settings, representing <5% of the global SCD population. In sSA, where >90% of the global SCD burden exists, SCD still results in early mortality with 50-90% of infants likely dying before reaching 5 years of age. Recently, there are an increasing number of efforts in many African countries to prioritize SCA with pilot NBS programs, improved diagnostics, and expanded SCD education for health care professionals and the general public. It is essential to include access to hydroxyurea as a core component of any SCD care program, but there are still many barriers that prevent the widespread global use of hydroxyurea. Here, we summarize what we know about SCD and hydroxyurea use in Africa and discuss a strategy to respond to what we consider to be a public health imperative to maximize access to and appropriate use of hydroxyurea for all individuals with SCD using innovative dosing and monitoring strategies.


Assuntos
Anemia Falciforme , Hidroxiureia , Lactente , Criança , Recém-Nascido , Humanos , Hidroxiureia/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/epidemiologia , África Subsaariana/epidemiologia , Penicilinas
6.
Int J Oncol ; 21(1): 65-72, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12063551

RESUMO

GEM 231, a second-generation antisense oligonucleotide targeted against the RIalpha subunit of protein kinase A (PKA) was co-administered with the chemotherapeutic agent irinotecan, a topoisomerase-I inhibitor, to study the antitumor efficacy of the combination in nude mice bearing various human tumor xenografts. The combination treatment of GEM 231 and irinotecan produced enhanced and prolonged tumor-growth inhibition, compared with irinotecan monotherapy, against human colon (HCT-116), pancreas (Panc-1), prostate (PC3) and lung (SKMES) tumors in mice. The extent of tumor-growth inhibition, however, varied among the different tumor models studied. The tumor-growth inhibition depended on the dose of GEM 231 co-administered with irinotecan. The combination of GEM 231 (20 mg/kg, i.p., 5 days on 2 days off x 7) and irinotecan (50 mg/kg, i.v., qwk x 3) produced significantly longer tumor-growth delay than did irinotecan administered alone. Importantly, the co-administration of irinotecan and GEM 231 did not result in higher toxicity compared with monotherapies in the several tumor models tested. These results suggest that the use of irinotecan in combination with GEM 231 may increase the therapeutic index of irinotecan in cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Peso Corporal/efeitos dos fármacos , Camptotecina/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Relação Dose-Resposta a Droga , Feminino , Humanos , Irinotecano , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Oligonucleotídeos/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Taxa de Sobrevida , Resultado do Tratamento
7.
Algorithms Mol Biol ; 8(1): 20, 2013 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-23849037

RESUMO

BACKGROUND: Kinship inference is the task of identifying genealogically related individuals. Kinship information is important for determining mating structures, notably in endangered populations. Although many solutions exist for reconstructing full sibling relationships, few exist for half-siblings. RESULTS: We consider the problem of determining whether a proposed half-sibling population reconstruction is valid under Mendelian inheritance assumptions. We show that this problem is NP-complete and provide a 0/1 integer program that identifies the minimum number of individuals that must be removed from a population in order for the reconstruction to become valid. We also present SibJoin, a heuristic-based clustering approach based on Mendelian genetics, which is strikingly fast. The software is available at http://github.com/ddexter/SibJoin.git+. CONCLUSIONS: Our SibJoin algorithm is reasonably accurate and thousands of times faster than existing algorithms. The heuristic is used to infer a half-sibling structure for a population which was, until recently, too large to evaluate.

8.
Invest New Drugs ; 20(3): 261-70, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12201489

RESUMO

Methyl-2-benzimidazolecarbamate (carbendazim, FB642) is an anticancer agent that induces apoptosis of cancer cells. In vitro, FB642 demonstrated potent antitumor activity against both the murine B16 melanoma (IC50 = 8.5 microm) and human HT-29 colon carcinoma (IC50 = 9.5 microm) cell lines. FB642 was also highly active against both murine tumor models and human tumor xenografts at varying doses and schedules. In the murine B16 melanoma model, T/C values > 200 were observed. In the human tumor xenograft, FB642 produced tumor growth inhibition of greater than 58% in five of the seven xenograft models evaluated. Partial and complete tumor shrinkage was noted with FB642 against the MCF-7 breast tumor model. Pharmacokinetic studies in rats demonstrated that oral absorption of FB642 was variable and may be saturated at the 2000 mg/kg dose level since higher doses failed to produce a further increase in the area under the time concentration curve. Toxicity of FB642 in vivo appeared to be dose-dependent. Lower doses in the range of 2,000-3,000 mg/kg were better tolerated, while still preserving antitumor activity. Evaluation of FB642 in phase I clinical trials of adult patients with advanced malignancies is currently ongoing.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , Carbamatos , Animais , Antineoplásicos/uso terapêutico , Área Sob a Curva , Benzimidazóis/uso terapêutico , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Leucemia P388/tratamento farmacológico , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Equivalência Terapêutica , Células Tumorais Cultivadas
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