RESUMO
Helicobacter pylori infection causes chronic gastric inflammation that contributes to various gastroduodenal diseases, including peptic ulcer and gastric cancer. Despite broad regional variations, the prevalence of resistance to antibiotics used to manage H pylori infection is increasing worldwide; this trend could hinder the success of eradication therapy. To increase awareness of H pylori and improve the diagnosis and treatment of its infection in Hong Kong, our consensus panel proposed a set of guidance statements for disease management. We conducted a comprehensive review of literature published during 2011 and 2021, with a focus on articles from Hong Kong or other regions of China. We evaluated the evidence using the Oxford Centre for Evidence-Based Medicine's 2011 Levels of Evidence and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system and sought consensus through online voting and a subsequent face-to-face meeting, which enabled us to develop and refine the guidance statements. This report consists of 24 statements regarding the epidemiology and burden, screening and diagnosis, and treatment of H pylori. Key guidance statements include a recommendation to use the test-and-treat approach for high-risk individuals, as well as the confirmation that triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin remains a valid first-line option for adults and children in Hong Kong.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Adulto , Criança , Humanos , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/epidemiologia , Hong Kong/epidemiologia , Consenso , Antibacterianos/uso terapêuticoRESUMO
INTRODUCTION: Total ischaemic time should be shortened as much as possible in patients with ST-segment elevation myocardial infarction (STEMI). This study evaluated whether prehospital 12-lead electrocardiogram (ECG) could shorten system delay in STEMI management. METHODS: From November 2015 to November 2017, 15 ambulances equipped with X Series Monitor/ Defibrillator (Zoll Medical Corporation) were used in the catchment area of Queen Mary Hospital, Hong Kong. Prehospital ECG was performed for patients with chest pain; the data were tele-transmitted to attending emergency physicians at the Accident and Emergency Department (AED) for rapid assessment. Data from patients with STEMI who were transported by these 15 ambulances were compared with data from patients with STEMI who were transported by ambulances without prehospital ECG or who used self-arranged transport. RESULTS: Data were analysed from 197 patients with STEMI. The median patient delay for activation of the emergency response system was 90 minutes; 12% of patients experienced a delay of >12 hours. There was a significant difference in delay between patients transported by ambulance and those who used self-arranged transport (P<0.001). For system delay, the use of prehospital ECG shortened the median time from ambulance on scene to first ECG (P<0.001). When performed upon ambulance on scene, prehospital ECG was available 5 minutes earlier than if performed in ambulance compartment before departure. Use of prehospital ECG significantly shortened AED door-to-triage time, AED door-to-first AED ECG time, AED door-to-physician consultation time, and length of stay in the AED (P<0.001 for all comparisons). CONCLUSION: Prehospital ECG shortened ischaemic time prior to hospital admission.
Assuntos
Ambulâncias/estatística & dados numéricos , Eletrocardiografia , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Tempo para o Tratamento , Idoso , Angioplastia Coronária com Balão , Dor no Peito/etiologia , Serviço Hospitalar de Emergência , Feminino , Hong Kong , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , TriagemRESUMO
The potential interaction between chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD), two of the most prevalent liver diseases worldwide, has not been well defined. We performed liver stiffness (LS) and controlled attenuation parameter (CAP) measurements using transient elastography in 1202 CHB patients. Of these, 601 steatotic patients were matched with nonsteatotic controls in a 1:1 ratio by age, gender, nucleoside analogue treatment status, and treatment duration. Severe fibrosis was defined according to EASL-ALEH criteria, and steatosis was defined as CAP ≥222 dB m-1 . Anthropometric measurements and metabolic-related parameters were recorded. The mean age of the 1202 patients (51.4% male) was 51.8 years. 696 patients (57.9%) were on nucleoside analogues for a median duration of 76.2 months. Among treatment-naïve patients, median serum HBV DNA was lower in steatotic individuals than in controls (3.0 vs 3.4 log IU mL-1 , P < .05), with this inverse relationship remaining significant in multivariate analysis (odds ratio 0.859, 95% CI 0.743-0.994, P < .05). With increased steatosis severity, there was a stepwise decrease in median HBV DNA levels (3.1 and 2.6 log IU mL-1 in no steatosis and severe steatosis, respectively, P = .032). Steatosis was associated with a higher median LS (5.4 kPa vs 5.0 kPa, P < .001). Severe steatosis, when compared to mild/moderate steatosis, was associated with an increased percentage of severe fibrosis (23.2% and 12.6%, respectively, P = .005). We conclude that severe steatosis was associated with increased fibrosis in CHB patients. Increasing steatosis was independently associated with lower serum HBV DNA levels, suggesting its potential negative effects on viral replication.
Assuntos
Fígado Gorduroso/complicações , Fígado Gorduroso/virologia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Carga Viral , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Viral/sangue , Técnicas de Imagem por Elasticidade , Fígado Gorduroso/patologia , Feminino , Hepatite B Crônica/patologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
INTRODUCTION: After ST-segment elevation myocardial infarction (STEMI), it is vital to shorten reperfusion time. This study examined data from a pilot project to shorten the door-to-balloon (D2B) time by using prehospital 12-lead electrocardiogram (ECG). METHODS: Fifteen ambulances equipped with X Series® Monitor/Defibrillator (Zoll Medical Corporation) were deployed to the catchment area of Queen Mary Hospital, Hong Kong, from November 2015 to December 2016. For patients with chest pain, prehospital 12-lead ECG was performed and tele-transmitted to attending physicians at the accident and emergency department for immediate interpretation. The on-call cardiologist was called before patient arrival if STEMI was suspected. Data from this group of patients with STEMI were compared with data from patients with STEMI who were transported by ambulances without prehospital ECG or by self-arranged transport. RESULTS: From 841 patients with chest pain, 731 gave verbal consent and prehospital ECG was performed and transmitted. Of these, 25 patients with clinically diagnosed STEMI required emergency coronary angiogram with or without primary percutaneous coronary intervention. The mean D2B time for these 25 patients (93 minutes) was significantly shorter (P=0.003) than that for 58 patients with STEMI transported by ambulances without prehospital ECG (112 minutes) and that for 41 patients with STEMI with self-arranged transport (138 minutes). However, shorter reperfusion time was only recorded during daytime hours (08:00-17:59). No statistically significant difference in 30-day mortality was found. CONCLUSION: Prehospital ECG is technologically feasible in Hong Kong and shortens the D2B time. However, shorter reperfusion time was only recorded during daytime hours.
Assuntos
Eletrocardiografia/instrumentação , Serviços Médicos de Emergência/normas , Infarto do Miocárdio/diagnóstico , Avaliação de Resultados em Cuidados de Saúde , Idoso , Dor no Peito/etiologia , Árvores de Decisões , Feminino , Hong Kong , Humanos , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Projetos Piloto , Estudos RetrospectivosRESUMO
We examined the relationship between hepatitis B surface and core-related antigens (HBsAg, HBcrAg) and hepatocellular carcinoma (HCC) development in patients with undetectable serum HBV DNA receiving nucleos(t)ide analogue (NA). Seventy-six HBV carriers with undetectable HBV DNA (<20 IU/mL) who subsequently developed HCC were compared with 152 matched controls. Clinical and laboratory parameters (including novel assays to measure linearized HBsAg [HQ-HBsAg] and HBcrAg) were analysed. There were no significant differences in HBsAg/HQ-HBsAg levels between the two groups. There was a significant difference in the median values of both pre- and post-NA HBcrAg levels between the HCC and control groups (pre-treatment: 279.0 vs 35.4 kU/mL, P=.005; post-treatment: 10.2 vs 1.7 kU/mL, P=.005, respectively). For the whole HCC group, a cut-off value of post-treatment HBcrAg level ≥7.8 kU/mL yielded an area under receiver operating curve (AUROC) of 0.61 with a negative predictive value (NPV) of 77.0%. The OR of HCC development was 3.27. For noncirrhotic patients, the median values of post-treatment HBcrAg level of HCC group and controls were 10.2 and 1.0 kU/mL, respectively (P=.001). A cut-off value of HBcrAg level ≥7.9 kU/mL yielded an AUROC of 0.70 with a NPV of 80.6%. The OR of HCC development was 5.95. A higher pre- and post-NA treatment HBcrAg level (but not HBsAg) was associated with an increased risk of HCC development in patients achieving undetectable serum HBV DNA while on NA therapy. HBcrAg may serve as a novel risk marker for HCC in this group of patients.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , DNA , Feminino , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico , Prognóstico , Medição de Risco , Adulto JovemRESUMO
A 66-year-old woman presented to the emergency department after a witnessed cardiac arrest, having had compression-only cardiopulmonary resuscitation initiated by her son on the backseat of his car. She was resuscitated in the emergency department for 1 hour before the return of spontaneous circulation. She then underwent primary percutaneous coronary intervention and therapeutic hypothermia. She was discharged without significant neurological deficit. This case illustrates better survival and neurological outcome can be achieved by prompt implementation of a 'chain of survival' interventions and therapeutic hypothermia.
Assuntos
Reanimação Cardiopulmonar/métodos , Hipotermia Induzida/métodos , Parada Cardíaca Extra-Hospitalar/terapia , Intervenção Coronária Percutânea/métodos , Idoso , Serviços Médicos de Emergência , Feminino , Humanos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND Bronchiectasis is a common respiratory disease complicated by periodic exacerbations. The association with different degrees of gastric acid suppression has not been well studied.METHODS A retrospective cohort study of 350 patients was conducted to investigate the association of different gastric acid suppressants with bronchiectasis exacerbation that required hospitalisation. Components of FACED (FEV1% predicted, age, chronic colonisation by Pseudomonas aeruginosa, radiological extent of the disease, and dyspnoea) were adjusted in multivariate analysis.RESULTS Among patients with exacerbation of bronchiectasis, 52 (14.9%) required hospitalisation. Prescription of a high-dose of proton pump inhibitors (PPI) was associated with increased risk of bronchiectasis exacerbation requiring hospitalisation (adjusted OR 2.77, 95% CI 1.01-7.59; P = 0.05). There was no significant association with use of a histamine-2 receptor antagonist (H2RA) (OR 1.28, 95% CI 0.32-5.06) or low-dose PPI (OR 1.47, 95% CI 0.42-5.13). Nonetheless, patients prescribed a high dose of PPI required a significantly longer hospital stay for exacerbation (13.1 ± 1.4 days) than patients not prescribed a gastric acid suppressant (8.2 ± 2.6 days) or those on a low dose PPI (8.3 ± 1.3 days) and H2RA (6.50 ± 1.50 days).CONCLUSIONS Risk of bronchiectasis exacerbation requiring hospitalisation was increased among high-dose PPI users, but not those prescribed an H2RA or low-dose PPI.
Assuntos
Bronquiectasia , Inibidores da Bomba de Prótons , Bronquiectasia/tratamento farmacológico , Histamina , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Hospitalização , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non-invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core-related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB. AIM: To examine the virological aspect and clinical application of HBcrAg with respect to the natural history and treatment of CHB. METHODS: We reviewed all papers published in the PubMed journal list and abstracts from major international meetings that included the keyword "HBcrAg" or "hepatitis B core-related antigen" until March 2017. Selected studies were compared and summarised on the basis of existing theories, as well as the authors' experience. RESULTS: HBcrAg exhibited good correlation with intrahepatic (ih) cccDNA, ih total hepatitis B virus (HBV) DNA, serum HBV DNA and to a lesser extent HBV surface antigen (HBsAg). In situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved, HBcrAg can still be detectable. This marker is helpful in differentiation of HBeAg-negative chronic hepatitis from HBeAg-negative chronic infection, predicting spontaneous or treatment-induced HBeAg seroconversion, sustained response to nucleos(t)ide analogue (NA), risk of HBV reactivation in occult HBV infection under immunosuppressive therapies, and risk of hepatocellular carcinoma (HCC) development as well as post-operative HCC recurrence. CONCLUSIONS: HBcrAg is a potential surrogate marker of cccDNA. It may soon become a useful marker for disease monitoring, predicting treatment response and disease outcome of chronic hepatitis B.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/virologia , Biomarcadores/sangue , Biópsia , Carcinoma Hepatocelular/virologia , DNA Circular , DNA Viral/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/virologiaRESUMO
The effects on some host defenses of murine cytomegalovirus (MCMV) and(or) EL(4), a mouse ascites homograft, were studied in mice. Assays of cellular and humoral immunity in response to either or both of these perturbations were carried out by quantitation of various immune activities.Limited studies demonstrated no effect of EL(4) inoculation on the host response to MCMV by organ viral titer, duration of viral persistence, or anti MCMV complement-fixing antibody titer. Prior infection with MCMV, however, resulted in greatly reduced numbers of splenocytes, the source in this study of immune effector cells. Residual splenocytes demonstrated less response to both phyto-hemagglutinin and lipopolysaccharide, particularly in the 2-3-wk interval after infection. Similarly, responder cells in mixed lymphocyte cultures were less reactive when derived from infected animals. Lymphocyte-mediated cytolysis of EL(4) was significantly less in mice infected on the day of and 7, 14, and 21 days before the tumor homograft with a return to control levels by 28 days. 90% of the cell-mediated cytolysis could be eliminated by treatment with anti-theta serum. Serum-mediated cytolysis of EL(4) was also reduced in infected animals. No suppressor cells or serum inhibitory factors could be identified in infected animals. Although alternative explanations exist, this study suggests that in infected animals there is a significant reduction in both the number and function of bone marrow-derived and thymus-derived cells directed against the alloantigens in EL(4).
Assuntos
Infecções por Citomegalovirus/imunologia , Imunidade Celular , Neoplasias Experimentais/imunologia , Imunologia de Transplantes , Animais , Anticorpos Antivirais , Formação de Anticorpos , Células Cultivadas , Citomegalovirus/imunologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/microbiologia , Feminino , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Biológicos , Transplante de Neoplasias , Baço/citologia , Transplante HomólogoRESUMO
BACKGROUND: Psychological morbidity is commonly found in medical students. AIMS: The Mental Health Support Group (MSG), a student-initiated and student-run web-based peer support service aims to provide mental health information, e mail counseling and an online forum for medical students. METHODS: The development process of MSG is described in the paper with presentation of preliminary evaluation results. RESULTS: Preliminary evaluation shows promising results. Student members of MSG acquired valuable skills in counseling, communication, webpage design and maintenance of an online forum. CONCLUSIONS: Future challenges include succession issues, strategies to keep up the momentum, enhancement of publicity and further diversification of service to meet the needs of our students.
Assuntos
Informação de Saúde ao Consumidor/métodos , Promoção da Saúde/métodos , Saúde Mental , Estudantes de Medicina/psicologia , Informação de Saúde ao Consumidor/tendências , Feminino , Hong Kong , Humanos , Internet , Masculino , Transtornos Mentais/psicologia , Grupo Associado , Avaliação de Programas e Projetos de Saúde , Fatores Sexuais , Apoio Social , Estresse Psicológico/psicologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The temporal relationship between nucleoside analogue therapy for chronic hepatitis B (CHB) and liver cancer development has not been evaluated at a population level. AIM: To investigate the impact of nucleoside analogue prescription on liver cancer incidence in a CHB-prevalent region. METHODS: We obtained territory-wide nucleoside analogue prescription data from 1999, when nucleoside analogue was first available in Hong Kong, to 2012 and the population-based liver cancer incidence data from 1990 to 2012. We compared the liver cancer incidences from 1990 to 1998 and 1999 to 2012 with adjustment for local hepatitis B surface antigen seroprevalence. RESULTS: Nucleoside analogue prescription patient headcount increased from 2006 per year in 1999 to 26 411 in 2012. Prescription volume in 2012 was highest among 55-64 years (30.3%), higher than 65-74 years (13.0%) and ≥75 years (5.8%). Age-standardised liver cancer incidence 1999-2012 decreased by 1.88%/year (95% CI 3.34% to 0.42%/year). NA therapy was associated with decline in age-adjusted liver cancer incidence (2.7 per 100 000 persons, P < 0.001, 95% CI 1.4-4.0 per 100 000 persons). Fifty-five to sixty-four years age group had the most significant decline (men: 24.0 per 100 000 persons, P = 0.001, 95% CI 11.4-36.6 per 100 000 persons; women: 8.5 per 100 000 persons, P = 0.009, 95% CI 2.3-14.6 per 100 000 persons). No significant association was noted in age groups 65-74 years and ≥75 years (both P > 0.05). CONCLUSIONS: Nucleoside analogue prescription was associated with a reduction of overall liver cancer incidence in a CHB-prevalent region. The lack of association among individuals of ≥65 years was consistent with the low nucleoside analogue prescription volume in elderly patients, mitigating the impact of CHB treatment on liver cancer.
Assuntos
Antivirais/uso terapêutico , Prescrições de Medicamentos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Hepatite B Crônica/diagnóstico , Hong Kong/epidemiologia , Humanos , Incidência , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Estudos Soroepidemiológicos , Resultado do TratamentoRESUMO
Replication in vitro of murine cytomegalovirus was found to be enhanced in lymphoid cells from leukemic (AKR/J) mice as compared with similar cells from nonleukemic animals. Prolonged productive murine cytomegalovirus infection in lymphoid organs in vivo was demonstrable only in leukemic AKR/J mice. Latent nonproductive murine cytomegalovirus infection established in young nonleukemic AKR/J mice was invariably reactivated and expressed in salivary glands and lymphoid organs after these animals became leukemic.
Assuntos
Citomegalovirus/genética , Leucemia Experimental/microbiologia , Linfócitos/microbiologia , Animais , Animais Recém-Nascidos/microbiologia , Camundongos , Glândulas Salivares/microbiologia , Baço/citologia , Baço/microbiologia , Timo/citologia , Timo/microbiologia , Replicação ViralRESUMO
BACKGROUND: Factors influencing changes in liver stiffness measurements during long-term nucleoside analogue therapy for chronic hepatitis B (CHB) have not been thoroughly investigated. AIM: To identify determinants of on-treatment fibrosis regression in CHB. METHODS: We performed follow-up liver stiffness and controlled attenuation parameter measurements on nucleoside analogue-treated CHB patients with severe liver fibrosis, according to EASL-ALEH criteria, diagnosed by transient elastography in 2006-2008. Anthropometric measurements and different metabolic parameters were recorded. RESULTS: Among 257 patients with severe liver fibrosis by initial transient elastography, 123 (47.9%) were recruited for reassessment. Median treatment duration was 87.5 (interquartile range 75.3-102.2) months; 97.5% had undetectable HBV DNA. There was a significant reduction in median liver stiffness from 14.6 to 8.3 kPa (P < 0.001). A total of 29.3% had fibrosis regression, with lower rates of 17.9%, 14.9% and 11.5% noted in patients with body-mass index (BMI) ≥25 kg/m2 , metabolic syndrome and diabetes, respectively. Absence of BMI ≥25 kg/m2 , diabetes and metabolic syndrome, when compared with presence of any one of these three factors, was associated with increased fibrosis regression (43.1% vs. 16.9%, P = 0.001). Multivariate analysis found a lower BMI to be the only factor independently associated with fibrosis regression (P = 0.034, odds ratio 0.68, 95% CI 0.48-0.97). No association was noted between controlled attenuation parameter measurements and fibrosis regression (P > 0.05). CONCLUSION: An increased BMI hindered fibrosis regression in patients with chronic hepatitis B during nucleoside analogue treatment, suggesting that control of metabolic risk factors, in addition to virologic suppression via antiviral therapy, might be needed to halt the fibrogenic process in chronic hepatitis B.
Assuntos
Antivirais/uso terapêutico , Índice de Massa Corporal , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Nucleosídeos/uso terapêutico , Idoso , Diabetes Mellitus/tratamento farmacológico , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Síndrome Metabólica/tratamento farmacológico , Pessoa de Meia-Idade , Razão de Chances , Fatores de RiscoRESUMO
Dermatan sulphate proteoglycans have been extracted from bovine lung with 2.0 M CaCl2 and isolated using CsCl density gradient centrifugation, DEAE ion-exchange chromatography, gel chromatography and preparative sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Ultrastructurally these proteoglycans are specifically associated with collagen fibrils. Dermatan sulphate (Mr 15.10(3)-35.10(3), with a strong prevalence for the higher Mr) is link via an O-glycosidic bond to a protein core, which is rich in Asx, Glx and Leu. Of the total uronic acid, 91% is iduronic acid. A part of the glucuronic acid residues is located near the protein core and a large cluster of disaccharides is devoid of glucuronic acid residues. An inhibition enzyme immunoassay has been developed to quantitate the proteoglycan. A model for the interaction between dermatan sulphate proteoglycans and collagen fibrils is proposed.
Assuntos
Proteoglicanas de Sulfatos de Condroitina/isolamento & purificação , Condroitina/análogos & derivados , Colágeno/metabolismo , Dermatan Sulfato/isolamento & purificação , Pulmão/análise , Proteoglicanas/isolamento & purificação , Aminoácidos/análise , Animais , Bovinos , Cromatografia por Troca Iônica , Técnicas Imunoenzimáticas , Microscopia Eletrônica , Peso MolecularRESUMO
The effectiveness of acycloguanosine (acyclovir) and trifluorothymidine (TFT) as inhibitors of cytomegalovirus (CMV) infection was tested using a plaque-reduction assay. Two laboratory strains and seven clinical isolates were employed. The results indicated that both acyclovir and TFT were ineffective in inhibiting viral cytopathic effect (CPE) below the concentration of 50 microM. At concentrations of 100 microM or more, greater than a 50 percent inhibition was achieved by both acyclovir and TFT on all clinical isolates. Although complete inhibition of plaque formation was seldom achieved even at a drug concentration as high as 200 microM, a reduction of plaque size was consistently observed at drug concentrations above 100 microM. When a low dose of virus was used for infection, ED50 could be achieved at an acyclovir concentration of 50 microM. Laboratory strains of CMV were found to be more resistant than the clinical isolates to inhibition of acyclovir.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Guanina/análogos & derivados , Timidina/análogos & derivados , Trifluridina/farmacologia , Aciclovir , Linhagem Celular , Citomegalovirus/crescimento & desenvolvimento , Efeito Citopatogênico Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanina/farmacologia , Humanos , Ensaio de Placa ViralRESUMO
A large number of structurally diverse di- and tripeptides containing the alanine racemase inactivator beta-chloro-L-alanine (beta-Cl-LAla) have been synthesized, and their antibacterial properties in vitro have been evaluated. The dipeptides 1, 3-6, and 8-17 and the tripeptide 20 are all broad-spectrum antibacterial agents with considerable potency against both Gram-positive and Gram-negative species, but none of these peptides improves dramatically on the antibiotic efficacy of the previously described beta-Cl-LAla-beta-Cl-LAla, 9 (Cheung, K. S.; Wasserman, S. A.; Dudek, E.; Lerner, S. A.; Johnston, M. J. Med. Chem. 1983, 26, 1733). Gram-negative microorganisms, such as Escherichia coli, Hemophilus influenzae, Shigella flexneri, and Enterobacter species are consistently resistant to any haloalanyl peptide containing an alanyl residue, such as the dipeptide LAla-beta-Cl-LAla (2) and the tripeptides LMet-LAla-beta-Cl-LAla (7), LAla-LAla-beta-Cl-LAla (18), and LVal-LAla-beta-Cl-LAla (19). Correspondingly, these same organisms are protected from the bactericidal effects of 9 by supplementation of the growth medium with LAla or LAla-LAla. Escherichia coli JSR-O exposed to 9, but protected from lysis by sucrose stabilization, has only about 10% the normal level of intracellular alanine racemase activity. But when these cells are cultured in the presence of 9 with LAla supplementation, or in the presence of 2 with no supplementation, the alanine racemase levels are only about 20-30% below control values. These findings suggest that the resistance of Gram-negative species to chloroalanyl peptides containing alanyl units arises from the ability of LAla to protect the targeted racemase from inactivation by beta-Cl-LAla in vivo, an event which otherwise leads to cell death and lysis. Inactivation of alanine racemase in Gram-positive organisms appears not to be the cellular event that confers sensitivity of these species to a haloalanyl peptide.
Assuntos
Alanina Racemase/antagonistas & inibidores , Alanina/análogos & derivados , Alanina/farmacologia , Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/farmacologia , Dipeptídeos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Oligopeptídeos/farmacologia , beta-Alanina/análogos & derivados , Antibacterianos/síntese química , Bactérias Gram-Negativas/enzimologia , Oligopeptídeos/síntese química , Transaminases/antagonistas & inibidores , beta-Alanina/farmacologiaRESUMO
A set of dipeptides containing the amino acid residues beta-chloroalanine and propargylglycine, which are mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine gamma-synthase, respectively), have been synthesized, and their antibacterial properties in vitro have been evaluated. Dipeptides containing a single beta-chloro-L-alanyl residue (e.g., 3, 5, 9, and 10) or a single L-propargylglycyl residue (e.g., 12 and 15) are potent antibacterials. The in vitro antibiotic activity of beta-chloro-L-alanine and of L-propargylglycine is increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contain only a single enzyme-inactivating amino acid together with a second L-alanyl residue (3, 5, 12, and 15) have a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis are sensitive. However, peptides that contain two suicide-substrate residues [e.g., beta-Cl-LAla-beta-Cl-LAla (8) or LppGly-LppGly (18)] are broad-spectrum antibacterials; as many as 12 different species of the 16 surveyed are sensitive. Dipeptides that contain an amino-terminal L-methionyl (9) or an L-norvalyl (10) residue and a carboxy-terminal beta-chloro-L-alanyl unit are also effective against a large number of organisms; the spectra of activity are like those seen for 8 and 18. A "mixed" dipeptide [beta-Cl-LAla-LppGly, (21)] gives apparent synergism of antibiotic action of beta-chloro-L-alanine and of L-propargylglycine when these two residues are incorporated into a single structure. Peptides of the D,D configuration (4, 6, 13, 16, and 20) and ones of L,D stereochemistry (e.g., 7) are not antibacterials. Peptides containing one (11 and 14) and two (17) D,L-propargylglycyl residues are unresolved sets of diastereomers; the mixtures of compounds are between two- and fourfold less active than the correspondingly resolved L,L dipeptides (12, 15, and 18). These findings are consistent with a mechanism of action for these antibiotics involving stereoselective processing of the peptidyl unit in vivo.
Assuntos
Alanina/análogos & derivados , Alcinos/farmacologia , Antibacterianos/síntese química , Dipeptídeos/farmacologia , Glicina/análogos & derivados , beta-Alanina/análogos & derivados , Dipeptídeos/síntese química , Enterobacteriaceae/efeitos dos fármacos , Glicina/farmacologia , beta-Alanina/farmacologiaRESUMO
Tritrichomonas foetus relies primarily on the salvage of hypoxanthine to supply purine nucleotides. Mycophenolic acid disrupts T. foetus growth by specifically inhibiting inosine-5'-monophosphate (IMP) dehydrogenase, thereby blocking the biosynthesis of guanine nucleotides from hypoxanthine. We have cloned a T. foetus strain (mpar) that was 50-fold more resistant to mycophenolic acid than wild type (IC50 = 1 mM for mpar vs 20 microM for wild type). None of the usual mechanisms of drug resistance could be identified. IMP dehydrogenase isolated from T. foetus mpar was indistinguishable from the wild type enzyme. No difference in mycophenolic acid uptake or metabolism was detected between the wild type and mpar strains. Mycophenolic acid (100 microM) completely blocked the conversion of adenine and hypoxanthine to guanine nucleotides in T. foetus mpar, although no inhibition of T. foetus mpar growth was observed at this concentration. These observations indicate that the major purine salvage pathways must be altered in T. foetus mpar so that guanine nucleotide biosynthesis no longer requires IMP dehydrogenase. T. foetus mpar incorporated xanthine more efficiently into the nucleotide pool relative to hypoxanthine and guanine than wild type. Xanthine incorporation via XMP provided an IMP dehydrogenase independent route to guanine nucleotides that would enable the parasite to become mycophenolic acid resistant. No difference could be detected between wild type and mpar hypoxanthine-guanine-xanthine phosphoribosyltransferases, the key enzyme in purine base incorporation into nucleotides. Two alterations were identified in the purine salvage network of mpar: it was deficient in hypoxanthine transport and had diminished adenine deaminase activity. The apparent net result of these two changes was to lower the intracellular concentration of hypoxanthine in mpar. Hypoxanthine and adenine inhibited the incorporation of xanthine into the nucleotide pool in wild type T. foetus, but not in mpar. The mpar strain, therefore, can salvage xanthine more efficiently from a mixture of purines and thus bypass the drug block at IMP dehydrogenase.
Assuntos
IMP Desidrogenase/antagonistas & inibidores , Cetona Oxirredutases/antagonistas & inibidores , Ácido Micofenólico/farmacologia , Tritrichomonas/efeitos dos fármacos , Adenina/metabolismo , Animais , Clonagem Molecular , Resistência a Medicamentos/genética , Guanina/metabolismo , Nucleotídeos de Guanina/metabolismo , Hipoxantina , Hipoxantina Fosforribosiltransferase/metabolismo , Hipoxantinas/metabolismo , Mutação , Ácido Micofenólico/metabolismo , Tritrichomonas/genética , Tritrichomonas/metabolismo , Xantina , Xantinas/metabolismoRESUMO
Some solvents for antiepileptics were tested, for 4 consecutive days, in a rat model (the WAG/Rij inbred strain) for absence epilepsy. Electroencephalogram registrations and behavioral observations suggested that both Tween-80 and a mixture of saline/ethanol/propylene glycol caused an increase in the number of epileptic phenomena. This increase was not significant and restricted to injection day 1 with Tween-80 but was significantly present during all 4 injection days with the saline/ethanol/propylene glycol mixture. Furthermore, with this latter solvent the increase became larger during consecutive days. Because of the proepileptic potencies and the differential time effects of these solvents, their usage should be seriously questioned.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Tipo Ausência/induzido quimicamente , Solventes/toxicidade , Animais , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Epilepsia Tipo Ausência/fisiopatologia , Etanol/toxicidade , Feminino , Masculino , Polissorbatos/toxicidade , Propilenoglicóis/toxicidade , Ratos , Ratos EndogâmicosRESUMO
The individual anaerobic threshold (IAT) is defined as the highest metabolic rate where blood lactate (La) concentrations are maintained at a steady-state during prolonged exercise. The asymptote of the hyperbolic relationship between power output and time to fatigue has been defined as the critical power (CP), which, in theory, represents the highest metabolic rate where a steady-state response can be achieved during prolonged exercise. Since IAT and CP may define the same power output, the purpose of this study was to compare the gas exchange, blood La, and acid-base responses during exercise at the metabolic rates defined as IAT and CP. Fourteen males performed a maximal incremental cycle exercise test that was followed by a light active recovery period to determine IAT. Subsequently, subjects exercised to fatigue at five power outputs (calculated to elicit from 90% to 110% VO2max) to determine CP. IAT occurred at a significantly lower power output and VO2 (235 +/- 44 W and 2.97 +/- 0.47 l.min-1, respectively) compared with CP (265 +/- 39 W and 3.35 +/- 0.41 l.min-1, respectively). During 30 min of exercise at IAT, blood La levels increased during the initial 10 min to 3.9 +/- 1.9 mmol.l-1 but did not change during the final 15 min. Blood pH decreased to 7.32 +/- 0.04 at 5 min and did not change thereafter, while PCO2 fell from 41.5 +/- 3.2 mm Hg at 5 min to 36.2 +/- 3.6 mm Hg at 30 min. Only one subject completed 30 min of exercise at CP.(ABSTRACT TRUNCATED AT 250 WORDS)