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1.
Colorectal Dis ; 14(12): 1538-45, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22540766

RESUMO

AIM: Completeness and thoroughness of colonoscopy are measured by the caecal intubation rate (CIR) and the adenoma detection rate (ADR). National standards are ≥ 90% and ≥ 10% respectively. Variability in CIR and ADR have been demonstrated but comparison between individuals and units is difficult. We aimed to assess the performance of colonoscopy in endoscopy units in the northeast of England. METHOD: Data on colonoscopy performance and sedation use were collected over 3 months from 12 units. Colonoscopies performed by screening colonoscopists were included for the CIR only. Funnel plots with upper and lower 95% confidence limits for CIR and ADR were created. RESULTS: CIR was 92.5% (n = 5720) and ADR 15.9% (n = 4748). All units and 128 (99.2%) colonoscopists were above the lower limit for CIR. All units achieved the ADR standard with 10 above the upper limit. Ninety-nine (76.7%) colonoscopists were above 10%, 16 (12.4%) above the upper limit and 7 (5.4%) below the lower limit. Median medication doses were 2.2 mg midazolam, 29.4 mg pethidine and 83.3 µg fentanyl. In all, 15.1% of colonoscopies were unsedated. Complications were bleeding (0.10%) and perforation (0.02%). There was one death possibly related to bowel preparation. CONCLUSION: Results indicate that colonoscopies are performed safely and to a high standard. Funnel plots can highlight variability and areas for improvement. Analyses of ADR presented graphically around the global mean suggest that the national standard should be reset at 15%.


Assuntos
Adenoma/diagnóstico , Cateterismo/normas , Neoplasias do Colo/diagnóstico , Colonoscopia/normas , Sedação Profunda/estatística & dados numéricos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Ceco , Competência Clínica , Colonoscopia/efeitos adversos , Colonoscopia/estatística & dados numéricos , Inglaterra , Fentanila , Humanos , Hipnóticos e Sedativos/administração & dosagem , Meperidina , Midazolam , Entorpecentes/administração & dosagem , Guias de Prática Clínica como Assunto , Melhoria de Qualidade
2.
Int J Gynecol Cancer ; 18(6): 1248-57, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18554190

RESUMO

Approximately 90% of human ovarian tumors result from transformation of ovarian surface epithelial cells. It has been hypothesized that repeated destruction of the epithelial cells during ovulation, followed by proliferation and migration of epithelial cells to restore the ovarian surface, renders these cells susceptible to mutagenic events. One of the proteins found to promote ovarian surface epithelial cell survival and proliferation was the transcription factor, cAMP response element-binding protein (CREB). Thus, the objective of this study was to determine whether CREB was also highly expressed in tumor cells originating from the ovarian epithelium. Using an ovarian cancer tissue array, it was observed that approximately 54% of the epithelial-derived human ovarian tumors displayed moderate or high levels of CREB immunostaining, while none of the normal ovarian samples did. Comparison of CREB levels in a human ovarian tumor cell line to those of a normal ovarian epithelial cell line revealed elevated levels of CREB and phosphorylated CREB in the ovarian tumor cells. To determine whether CREB regulated proliferation and/or apoptosis in the ovarian tumor cell line, CREB expression was suppressed using RNA interference. Decreased CREB expression significantly reduced ovarian tumor cell proliferation, while there was no effect on apoptosis in these cells. Finally, we showed that CREB is highly expressed in an in vivo murine model of ovarian tumorigenesis. Therefore, CREB is frequently overexpressed in ovarian cancer where it appears to promote cell proliferation.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adenocarcinoma/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Fosforilação , Análise Serial de Tecidos
3.
J Hum Hypertens ; 19(9): 683-9, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15920451

RESUMO

Recently revised UK and US hypertension guidelines have reduced thresholds for both diagnosis and treatment and differ in their recommendations. We have used data from a random, stratified community-based sample of 4784 people aged 65 years and over to compare the prevalence of treatable hypertension and the potential impact on patients and primary care from using current guidelines. BHS, NICE and JNC7 guidelines were applied to blood pressures obtained from primary care medical records (94%) or measured at a screening clinic (6%). Risk factors were obtained by questionnaire and from medical records, supplemented by epidemiological data. Workload was estimated for a representative practice population of 10 000 patients. Blood pressures were obtained on 4514 patients (94%). Prevalence of treatable hypertension was over 67%. Compared to BHS4, prevalence estimates using NICE guidelines were comparable for men but significantly lower for women (P<0.05). They were significantly higher using JNC7 compared with BHS4 and NICE guidance (P<0.05). A general practice of 10 000 patients could expect 1287 older hypertensive patients using BHS4 guidelines and 1231 patients using NICE guidelines. Under BHS4, an extra 94 patients will require annual, rather than 5-yearly review compared with that using the previous guideline. In conclusion, implementation of BHS4 guidelines, with their revised thresholds for diagnosis, will not add materially to the prevalence of treatable hypertension compared to previous BHS3 guidelines but will have a major impact on practice workload. Use of NICE guidelines in preference to BHS4 will result in GPs treating fewer patients and reviewing untreated patients less often.


Assuntos
Hipertensão/diagnóstico , Hipertensão/epidemiologia , Guias de Prática Clínica como Assunto , Atenção Primária à Saúde , Carga de Trabalho , Idoso , Feminino , Humanos , Hipertensão/terapia , Masculino , Prevalência , Distribuição por Sexo , Reino Unido/epidemiologia
4.
BMJ Open ; 5(4): e007230, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25926146

RESUMO

OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged ≥18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28  days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28  days were measured prospectively. National unit costs were used to value resource use. Initial in-hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in-hospital costs were £2458 (SE=£216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were £391 (£44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be £155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between £143 million and £168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532.


Assuntos
Endoscopia/economia , Transfusão de Eritrócitos/economia , Hemorragia Gastrointestinal/economia , Custos de Cuidados de Saúde , Hospitalização/economia , Qualidade de Vida , Doença Aguda , Análise Custo-Benefício , Endoscopia/estatística & dados numéricos , Transfusão de Eritrócitos/estatística & dados numéricos , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/psicologia , Hospitalização/estatística & dados numéricos , Humanos , Tempo de Internação/economia , Estudos Prospectivos , Reino Unido/epidemiologia
5.
Biochem Pharmacol ; 34(16): 2953-9, 1985 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-4026879

RESUMO

2-Acetylaminofluorene (AAF) produced abnormal, open neural tubes in cultured whole rat embryos only in the presence of an added, NADPH-dependent monooxygenase system. Reactive intermediary metabolites, including N-hydroxy-AAF, N-hydroxy-2-aminofluorene, 2-nitrosofluorene and N-acetoxy-AAF, each elicited embryonic malformations under culture conditions, but a statistically significant increase in the incidence of abnormal neurulation was not observed. Using [14C]AAF and high pressure liquid chromatography (HPLC) separation techniques, the biotransformation of AAF was studied under conditions in which embryos and the monooxygenase system were coincubated. The major metabolites produced cochromatographed with 5-hydroxy-AAF, 7-hydroxy-AAF, 9-hydroxy-AAF and 3-hydroxy-AAF. Other metabolic products also were detected. The embryonic effects of these major AAF metabolites were tested singly and in combination in the embryo culture system. Addition of 7-hydroxy-AAF to the embryo culture system resulted in open neural tubes in the absence of an added monooxygenase system. Other individual ring-hydroxylated metabolites produced retarded growth, but neurulation appeared normal. Ring-hydroxylated metabolites, added to the embryo culture system in combination in the same proportions as were formed during biotransformation in culture, also produced a marked increase in incidence of neural tube defects in the absence of an exogenous (added) biotransforming system. In combination with 3-, 5- and 9-hydroxy-AAF, 7-hydroxy-AAF exposure (86 microM) resulted in a 47% incidence of abnormal, open neural tubes. When tested individually, higher concentrations of 7-hydroxy-AAF (104 microM) produced a lower percentage of malformed embryos (13%). The results suggested that 7-hydroxy-AAF was principally responsible for the neural tube defects caused by AAF following monooxygenase-dependent bioactivation, but that other metabolites also appeared to contribute to the observed effect.


Assuntos
2-Acetilaminofluoreno/metabolismo , Anormalidades Induzidas por Medicamentos , Embrião de Mamíferos/metabolismo , 2-Acetilaminofluoreno/toxicidade , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , DNA/análise , Relação Dose-Resposta a Droga , Feminino , Defeitos do Tubo Neural/induzido quimicamente , Técnicas de Cultura de Órgãos , Gravidez , Proteínas/análise , Ratos , Ratos Endogâmicos
6.
J Clin Pathol ; 29(8): 704-10, 1976 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-60349

RESUMO

Preparation of human marrow sections has been studied systematically in order to facilitate accurate identification of marrow cells. Both of the methods developed involve embedding marrow cores in methyl methacrylate. In one, acrolein fixation is followed by staining of deplasticized sections with eosine-y followed by azure II; in the other, neutrophilic forms are identified by their esterase-specific reactivity in marrow fixed with neutral-buffered formalin. These preparations are suitable for quantitative studies of marrow cellularity.


Assuntos
Células da Medula Óssea , Medula Óssea , Técnicas Histológicas , Acroleína , Corantes Azur , Medula Óssea/enzimologia , Técnica de Descalcificação , Esterases/metabolismo , Formaldeído , Humanos , Concentração de Íons de Hidrogênio , Metilmetacrilatos , Microtomia , Coloração e Rotulagem , Cloreto de Tolônio
7.
Addiction ; 93(2): 173-81, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9624720

RESUMO

The Victorian temperance movement aimed to eliminate, not reform, public houses, but from 1870 interest began to be taken in promoting an "improved" public house which could promote counter-attractions to drink. Disinterested management, based upon public ownership or a trust company, was advocated as the best means of achieving this. There was, however, an ambiguity about the nature of the "improved" public house. Was the goal an austere establishment where the drinking could be controlled in the public interest, or was it a comfortable leisure centre which would promote civilized drinking? This ambiguity lay unresolved during the period of the Carlisle experiment in state control in the period after 1915. Increasingly during the inter-war years the policies of the state-run Carlisle scheme and the more go-ahead brewers converged. The issue was originally conceptualized as a moral one, then as one of national efficiency and finally as a commercial one.


Assuntos
Consumo de Bebidas Alcoólicas/história , Temperança/história , Consumo de Bebidas Alcoólicas/legislação & jurisprudência , Política de Saúde/história , História do Século XIX , História do Século XX , Humanos , Temperança/legislação & jurisprudência , Reino Unido
8.
Br J Gen Pract ; 47(425): 825-6, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9463986

RESUMO

This study aims to determine whether priority should be given to patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin when selecting which dyspeptic patients to refer for open access gastroscopy. A total of 8156 patients underwent gastroscopy, all of whom had upper gastrointestinal symptoms. Patients taking NSAIDs or aspirin showed no significant differences in the frequency of ulcer disease when age-matched groups were compared. Although NSAIDs and aspirin are frequently implicated in gastrointestinal bleeding in the elderly, patients referred for investigation of dyspepsia show no increase in major endoscopic pathology.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Esofagite/induzido quimicamente , Úlcera Péptica/induzido quimicamente , Adulto , Idoso , Dispepsia/etiologia , Gastroscopia , Humanos , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos
9.
J R Coll Physicians Edinb ; 41(2): 109-13, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21677912

RESUMO

AIM: Endoscopic retrograde cholangio-pancreatography (ERCP) is an important tool for the management of pancreato-biliary disease. The aim of this study was to compare the current practice of ERCP in North East England against the key 2004 National Confidential Enquiry Report into Patient Outcome and Death (NCEPOD) recommendations and the standards set by the Joint Advisory Group on Gastrointestinal Endoscopy (JAG). METHODS: This was a prospective multicentre study involving all hospitals in North East England, coordinated through the Northern Regional Endoscopy Group (NREG). RESULTS: Fourteen endoscopy units submitted data for 481 ERCPs. Mean dose of midazolam was 3.24 mg (standard deviation 1.35; range 1-8 mg). Coagulation profile results were available on 469 patients (97%). Radiological investigations were documented in 96% of the procedures (463 of 481) prior to ERCP. The most common indication for ERCP was related to choledocholithiasis and its complications. All procedures were performed with a therapeutic intent. A total of 84% of all patients were either American Society of Anesthesiologists grade I or II. The selective biliary cannulation rate was 87.3%. The total completion rate of all procedures was 80.2% (381 of 475) and completion of therapy was 89.5% (425 of 475). The 30-day mortality rate was 2% (ten patients) and procedure-related complications occurred in 5% of patients. There were no deaths directly as a result of ERCP; all deaths were related to underlying medical conditions. CONCLUSIONS: The practice of ERCP in North East England adheres to the key recommendations of the NCEPOD and the standards set by JAG. The rates of complications compare favourably with those reported internationally.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica/normas , Coledocolitíase/terapia , Padrões de Prática Médica , Idoso , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/mortalidade , Ducto Colédoco/diagnóstico por imagem , Inglaterra , Feminino , Fidelidade a Diretrizes , Hospitais de Distrito , Hospitais Gerais , Humanos , Pacientes Internados/classificação , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Ductos Pancreáticos/diagnóstico por imagem , Guias de Prática Clínica como Assunto , Estudos Prospectivos
10.
J Oncol ; 2010: 586905, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20671917

RESUMO

Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.

11.
J Oncol ; 2010: 514310, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20182531

RESUMO

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.

14.
Teratology ; 16(2): 131-6, 1977 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-929430

RESUMO

Cytochalasin D, a mold metabolite identified in food, was injected intraperitoneally in doses of 0.4 to 0.9 mg per kilogram on gestational days 7 through 11 and produced evidence of teratogenicity in two out of three strains of mice. Exencephaly, hypognathia and axial skeletal defects were found in strains C57BL/6J and BALB/c while no increase in defects was observed in the Swiss Webster strain. In all three strains, a significantly increased resorption rate was found. Oral doses of approximately 7.0 mg per kg on days 7 through 11 in the BALB/c produced exencephaly in the offspring. Autoclaved cytochalasin D retained its teratogenic potential.


Assuntos
Anormalidades Induzidas por Medicamentos , Anormalidades Múltiplas/induzido quimicamente , Citocalasinas/efeitos adversos , Anormalidades Teratoides Graves/induzido quimicamente , Animais , Anoftalmia/induzido quimicamente , Osso e Ossos/anormalidades , Encéfalo/anormalidades , Fissura Palatina/induzido quimicamente , Citocalasinas/administração & dosagem , Feminino , Hérnia Umbilical/induzido quimicamente , Injeções Intraperitoneais , Rim/anormalidades , Troca Materno-Fetal , Camundongos , Gravidez
15.
Teratology ; 31(3): 373-80, 1985 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-4012646

RESUMO

Day 10 rat embryos were exposed in vitro to [chloroethyl 3H] cyclophosphamide (3H-CP) at 4 micrograms/ml over a 24-hour period and the uptake and binding of labeled drug were monitored autoradiographically and biochemically. Autoradiographic analysis revealed that embryos exposed to 3H-CP and a complete activating system exhibited radioactivity distributed throughout the embryo. Subsequent analysis indicated that the distribution of autoradiographic grains on a per cell basis ranged from 7.7 in surface ectoderm to 13.4 in the neuroepithelium. No correlation was found between the sensitivity of various embryonic tissues to the cytotoxic effects of CP and the number of grains per cell. Direct radiochemical analysis of the amount of tritium taken up and bound by embryos under bioactivating conditions (3H-CP + S-9 + cofactors) confirmed the autoradiographic analysis. Autoradiographic and radiochemical analyses demonstrate that embryos exposed under bioactivating conditions take up and bind approximately three times more tritium than embryos exposed under nonactivating conditions (3H-CP + S-9 without cofactors). Additional studies have demonstrated that uptake and binding of tritium from bioactivated 3H-CP only are linear over the first 10 hours of incubation with no detectable increases thereafter.


Assuntos
Ciclofosfamida/metabolismo , Feto/metabolismo , Teratogênicos/metabolismo , Animais , Autorradiografia , Biotransformação , Feminino , Cinética , Troca Materno-Fetal , Gravidez , Ratos , Distribuição Tecidual
16.
Toxicol Appl Pharmacol ; 69(1): 81-8, 1983 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-6857691

RESUMO

The teratogenicity of the semisynthetic antibiotic rifampin (RIF) was investigated in rat embryos cultured from Days 10 to 11. Comparisons were made between the teratogenicity of RIF alone and RIF plus a rat liver fraction and cofactors for cytochrome P-450-mediated monooxygenation. Both groups were compared to vehicle controls. Rifampin without the metabolizing system caused significant retardation of growth but no significant increase in incidence of abnormalities (neural tube defects). Metabolism did not alter the growth-retarding action of the drug but did significantly increase the frequency of neural tube malformation. Exposure to RIF at concentrations from 12.5 to 100 micrograms/ml medium in the presence of the metabolizing system resulted in concentration-dependent decreases in embryo length, somite number, and protein content. The addition of metyrapone, an inhibitor of cytochrome P-450 activity, failed to prevent growth retardation but did reduce the incidence of malformations to a rate equal to that produced by the unmetabolized drug. No significant increases in malformation incidence or growth retardation were observed when embryos were cultured with the RIF metabolites, 3-formyl rifamycin, 25-deacetyl rifampin, or rifampin quinone.


Assuntos
Rifampina/toxicidade , Teratogênicos , Animais , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/patologia , Microssomos Hepáticos/metabolismo , Técnicas de Cultura de Órgãos , Gravidez , Ratos , Ratos Endogâmicos/embriologia
17.
Teratology ; 26(2): 135-43, 1982 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7157190

RESUMO

Chlorambucil, a bifunctional alkylating agent and antitumor drug, is a potent teratogen in rodents and possibly teratogenic in humans. Unlike cyclophosphamide, a related bifunctional alkylating agent, chlorambucil is a direct-acting cytotoxic agent. However, several studies indicate that the cytotoxic potential of chlorambucil is enhanced by metabolism of the parent compound. Using day-10 rat embryos cultured in vitro, we have demonstrated that chlorambucil is a direct acting teratogen but that its teratogenicity can be enhanced by the addition of rat liver S-9 preparations to culture medium containing the drug. Our data also suggest that this enhancement is not related to cytochrome P-450 monooxygenases. This conclusion is based upon three lines of evidence. First, enhancement occurs under culture conditions which lack cofactors necessary for cytochrome P-450 monooxygenases. Second, metyrapone, a known inhibitor of cytochrome P-450, did not abolish the enhancement. Third, induction of cytochrome P-450 by two specific inducers of monoxygenase activity had no effect on the observed enhancement. We postulate that the observed enhancement of chlorambucil teratogenicity is related to the beta-oxidation of the butyric acid side chain of chlorambucil generating the more cytotoxic (teratogenic) metabolite, phenylacetic acid mustard. Finally, our data indicate that the teratogenic effects elicited by chlorambucil are indistinguishable from those elicited by cyclophosphamide.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Clorambucila/efeitos adversos , Animais , Biotransformação , Clorambucila/metabolismo , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Metirapona/farmacologia , Microssomos Hepáticos/metabolismo , Gravidez , Ratos , Ratos Endogâmicos
18.
Toxicol Appl Pharmacol ; 80(1): 155-65, 1985 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-4024103

RESUMO

Adriamycin (ADR) is a widely used and highly valued antineoplastic agent but chronic treatment is limited by cardiotoxicity. To investigate its embryotoxic potential, cultured rat embryos were exposed to ADR at concentrations ranging from 0.4 to 1.2 microM. Within this range, ADR elicited decreases in growth parameters (somite numbers, embryonic length, and protein and DNA content), malformations involving the prosencephalic region, and embryolethality at the higher concentrations. Embryotoxicity was significantly increased (p less than 0.05) when cultures included cofactors for cytochrome P-450-dependent biotransformation and a hepatic microsomal preparation (S-9) prepared from animals pretreated with 3-methylcholanthrene or a mixture of polychlorinated biphenyls (Aroclor 1254). When S-9 from control animals or from rats pretreated with phenobarbital was used, significant increases in ADR-elicited embryotoxicity were not observed. Substitution of NADH for NADPH as a cofactor reduced the incidence of malformations from 100 to 60% at ADR concentrations of 0.5 microM. Increasing O2 concentrations partially counteracted the embryotoxic effects of ADR. Several other agents [including various antioxidants, compounds bearing free sulfhydryl groups, coenzyme Q10, and superoxide dismutase (with or without catalase)] that prevent or reduce the cardiotoxicity of ADR without impairing its antineoplastic properties, failed to modify the embryotoxicity significantly. This suggested that the embryopathic and antineoplastic properties of ADR may share a common mechanism which is distinct from that responsible for cardiotoxicity.


Assuntos
Anormalidades Induzidas por Medicamentos , Doxorrubicina/toxicidade , Embrião de Mamíferos/efeitos dos fármacos , Animais , Doxorrubicina/metabolismo , Feminino , NAD/farmacologia , Técnicas de Cultura de Órgãos , Oxigênio/farmacologia , Ratos , Ratos Endogâmicos
19.
Toxicol Appl Pharmacol ; 82(2): 307-15, 1986 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3945955

RESUMO

A series of nitroheterocyclic compounds with antimicrobial and radiosensitizing properties was tested for embryotoxicity in cultured Sprague-Dawley rat embryos, and their effects were compared with various other five-membered heterocycles. Nifuroxime, furazolidone, nitrofurazone, niridazole, 2-nitroimidazole, and ronidazole each elicited a striking malformation characterized by asymmetrical, right-sided hypoplasia when coincubated with embryos for 26 hr. Minimum concentrations required to elicit this unusual defect ranged from 0.01 mM with nifuroxime and furazolidone to 0.5 mM with ronidazole and were roughly correlated with single electron redox potentials; i.e., agents with relatively high redox potentials were generally more effective than those with low potentials. Nitrofurantoin failed to elicit this unusual malformation but exhibited an extremely steep dose-response curve for embryolethality. Metronidazole and 4-nitroimidazole, nitroheterocyclic agents with relatively low redox potentials, did not produce the asymmetric abnormality nor were they highly embryotoxic, even at concentrations up to 2 mM. 2-Amino-5-nitrothiazole and 4'-methylniridazole also failed to evoke the asymmetric malformation but produced significant embryotoxicity as manifested by decreased growth parameters and elicitation of other kinds of malformations. Heterocyclic compounds not bearing a nitro group (furosemide, 2-aminothiazole, and 2-aminoimidazole) failed to elicit axial asymmetry at concentrations up to 1.0 mM but produced other signs of embryotoxicity at the highest concentrations tested. The results suggest that the presence of a reducible nitro group is critical for generation of the unusual malformation and that the single-electron redox potential of the nitro group plays a dominant but not exclusive role in the capacity of these chemicals to evoke axial asymmetry in cultured rat embryos.


Assuntos
Anormalidades Induzidas por Medicamentos , Compostos Heterocíclicos/toxicidade , Nitrocompostos/toxicidade , Animais , Técnicas de Cultura , Feminino , Niridazol/análogos & derivados , Niridazol/toxicidade , Oxirredução , Gravidez , Ratos , Ratos Endogâmicos
20.
Postgrad Med J ; 72(848): 367-8, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8758020

RESUMO

We describe two cases of digoxin toxicity presenting with clinical and electroencephalographic evidence of encephalopathy without other features of digoxin toxicity.


Assuntos
Encefalopatias/induzido quimicamente , Digoxina/intoxicação , Idoso , Encefalopatias/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Intoxicação/diagnóstico
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