RESUMO
Tangier disease is one of the most severe forms of familial high-density lipoprotein (HDL) deficiency. Since its discovery it has been diagnosed in about 100 patients and is characterized by severe plasma deficiency or absence of HDL, apolipoprotein A-I (apoA-I, the major HDL apolipoprotein) and by accumulation of cholesteryl esters in many tissues throughout the body. The biochemical signs of this condition are plasma HDL concentrations less than 5 mg/dL, low total plasma cholesterol (below 150 mg/dL), and normal or high plasma triglycerides. Tangier disease is caused by mutations in the 'ATP-Binding Cassette transporter A1' (ABCA1) gene, which encodes the membrane transporter ABCA1. This transporter plays a key role in the first step of reverse cholesterol transport, through which the efflux of free cholesterol from peripheral cells is transferred to lipid-poor apoA-I. The Tangier disease clinical phenotype is inherited as an autosomal recessive trait, the biochemical phenotype is inherited as an autosomal co-dominant trait. Nearly all the children affected by Tangier disease were identified on the basis of large, yellow-orange tonsils, while half of the adult patients affected by Tangier disease came to medical attention because of symptoms of neuropathy. Diagnosis in the remaining subjects was related to the clinical features of hepatomegaly, splenomegaly, premature myocardial infarction (about 30% of Tangier disease cases) or stroke, thrombocytopenia, anemia, gastrointestinal disorders, corneal opacities, hypocholesterolemia, low HDL cholesterol, or following a familial screening of Tangier patients. To date there is no specific treatment for Tangier disease. Old and recently designed drugs, known to increase HDL levels, have been shown to be ineffective in Tangier patients. The possible and more realistic therapeutic strategy should be designed to obtain a selective increase of mature HDL concentration to restore cholesterol efflux. Recently designed drugs like the cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib and reconstituted forms of HDL could be considered until the development of gene therapy.
Assuntos
Apolipoproteína A-I/sangue , Lipoproteínas HDL/sangue , Doença de Tangier/terapia , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Amidas , Animais , Criança , Colesterol/sangue , Ésteres do Colesterol/metabolismo , Desenho de Fármacos , Ésteres , Humanos , Mutação , Oxazolidinonas/uso terapêutico , Compostos de Sulfidrila/uso terapêutico , Doença de Tangier/epidemiologia , Doença de Tangier/fisiopatologia , Triglicerídeos/sangueAssuntos
Anticolesterolemiantes/uso terapêutico , Quinolinas/uso terapêutico , Compostos de Sulfidrila/uso terapêutico , Amidas , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/fisiologia , Ensaios Clínicos como Assunto , Indústria Farmacêutica/economia , Indústria Farmacêutica/tendências , Ésteres , Humanos , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Compostos de Sulfidrila/efeitos adversosAssuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Lipoproteínas HDL/fisiologia , Amidas , Animais , Anticolesterolemiantes/uso terapêutico , Azetidinas/efeitos adversos , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Colesterol/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Ensaios Clínicos como Assunto , Ésteres , Ezetimiba , Glucose/metabolismo , Humanos , Insulina/metabolismo , Lipase/fisiologia , Niacina/efeitos adversos , Niacina/farmacologia , Niacina/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Medição de Risco , Fatores de Risco , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/uso terapêuticoRESUMO
BNCT causes selective damage to tumor cells by neutron capture reactions releasing high LET-particles where (10)B-atoms are present. Neither the (10)B-compound nor thermal neutrons alone have any therapeutic effect. Therefore, the development of BNCT to a treatment modality needs strategies, which differ from the standard phase I-III clinical trials. An innovative trial design was developed including translational research and a phase I aspect. The trial investigates as surrogate endpoint BSH and BPA uptake in different tumor entities.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias/radioterapia , Adenocarcinoma/metabolismo , Adenocarcinoma/radioterapia , Adenocarcinoma/secundário , Boroidretos/farmacocinética , Boroidretos/uso terapêutico , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Neoplasias Colorretais , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Masculino , Neoplasias/metabolismo , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Estudos Prospectivos , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/uso terapêutico , Compostos de Sulfidrila/farmacocinética , Compostos de Sulfidrila/uso terapêutico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/radioterapia , Distribuição TecidualRESUMO
OBJECTIVE: The primary objective of this study was to investigate the drug-drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitro and clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone. RESEARCH DESIGN AND METHODS: Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC(50) for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug-drug interaction studies were conducted in healthy males: dalcetrapib 900 mg plus the Cooperstown 5 + 1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900 mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed. RESULTS: In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC(50) values ranged from 1.5 +/- 0.1 microM for CYP2C8 to 82 +/- 4 microM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900 mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900 mg on activity of CYP2C8. Dalcetrapib was generally well tolerated. CONCLUSIONS: Although in vitro studies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900 mg dose, which is higher than the 600 mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/enzimologia , Compostos de Sulfidrila/farmacologia , Adolescente , Adulto , Idoso , Amidas , Hidrocarboneto de Aril Hidroxilases/metabolismo , Ensaios Clínicos Fase II como Assunto , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Quimioterapia Combinada , Inibidores Enzimáticos/metabolismo , Ésteres , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Rosiglitazona , Compostos de Sulfidrila/farmacocinética , Compostos de Sulfidrila/uso terapêutico , Tiazolidinedionas/metabolismo , Adulto JovemRESUMO
The potential for chemical intervention (chemoprevention) as a means of halting or delaying the process of carcinogenesis is assessed as a strategy for reducing the incidence of human cancer. The process of carcinogenesis is dissected into its constituent steps, thereby exposing sites for intervention. These sites are then critically discussed with regard to the existence of chemicals active at these sites using data gained from the laboratory and from epidemiological studies, intrinsic problems or advantages associated with intervention at specific sites in the carcinogenic process, and practical aspects of intervention in humans. The design and potential long-term positive and negative consequences of chemoprevention clinical trials are critically discussed, with the objective of exposing the major differences that exist between clinical trials in cancer chemoprevention and those in cancer chemotherapy. Results of completed prevention trials and details of ongoing trials are presented and discussed. Based on the laboratory, epidemiological, and clinical evidence presented, it is concluded that chemoprevention offers excellent prospects as a means of reducing cancer incidence. Among currently available agents, the retinoids possess the best combination of properties. However, much more research is needed to optimize drugs and protocols and to develop interim end points for assessing response. The authors finally caution that overambitious claims for the prospects for chemoprevention may lead to reduced emphasis on the need for changes in life-style (principally in smoking and diet) that are viewed as having the greatest potential for reducing cancer incidence.