RESUMEN
Hepatitis B virus (HBV) causes both acute and chronic hepatitis and infects large numbers of individuals worldwide. Unfortunately, prediction of typical clinical outcome is problematic and there is considerable variability in the frequency, duration and severity of disease progression. The mainstay of HBV treatment is directed towards the suppression of HBV replication by nucleos(t)ide analogs (NUCs). The use of immunomodulators such as α-Interferon and thymosin α1 can, in select patients, results in elimination of both HBsAg and HBeAg. Given the observation that viral clearance is most effective in the presence of a strong immune response, this review summarizes data suggesting that the use of a combination of an immune modulator such as Tα1 with a highly effective NUC may result in a more successful therapeutic approach in patients with chronic hepatitis B (CHB). Results from small studies using combination Tα1 and NUCs are encouraging, and ongoing clinical trials combining entecavir with Tα1 are anticipated to provide important data assessing the use of a combination of Tα1 with a NUC to achieve resolution of CHB.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Antivirales/administración & dosificación , Hepatitis B Crónica/terapia , Inmunoterapia/métodos , Timosina/análogos & derivados , Quimioterapia Combinada/métodos , Humanos , Timalfasina , Timosina/administración & dosificación , Resultado del TratamientoRESUMEN
Defining mortality for Caucasians and African American patients with chronic hepatitis C with respect to racial diversity is critical for counselling patients on therapy options. The objective of this study was to define racial diversity influence on mortality and morbidity of 3724 consecutive hepatitis C virus (HCV)-infected patients seen in an urban clinic between 1995 and 2008. Mortality, as of 2011, was defined using the SSA National Death Index and correlated with early visit medical information. The HCV chronically infected patient population consisted of 2879 African Americans (AA), 758 Caucasians and 87 other, and the majority were not treated for their infection prior to 2011. The average time to death from first visit was 5 years, the average age at death was 55 years, and despite racial diversity, AA were just as likely to be reported dead as Caucasians (23% AA vs 22% Caucasians). Cirrhosis and fibrosis (liver biopsy, AST Platelet Ratio Index or Fibrosis-4) at first visit as well as low albumin, diabetes, renal impairment and cardiac symptoms were associated with increased mortality. Treated patients who cleared the virus (sustained viral response (SVR); AA = 59; Caucasians = 40) had lower mortality than patients who were not treated (AA: 5% vs 27%; Caucasians 5% vs 26%). Hence, we find that race is not a factor in the early mortality of patients with chronic HCV infection and achieving a SVR reduced mortality. Unexpectedly, nonresponding AA also benefited by a lower mortality. African American patients with kidney disease and low albumin were at highest risk and should be treated as soon as identified.
Asunto(s)
Negro o Afroamericano , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/mortalidad , Población Urbana , Población Blanca , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
African Americans as a group have a higher incidence of chronic hepatitis C (CHC) than Caucasians but are often under-represented in clinical trials used to define response rates to interferon therapy. The aim of this study was to compare African Americans with Caucasians with respect to end-of-treatment response to interferon. This retrospective study had 61 African Americans and 49 Caucasians with CHC. All patients were treated for at least 12 weeks with interferon-alpha2b (Intron A) thrice weekly. End-of-treatment response was defined as three consecutive nondetectable HCV RNA measurements at least 1 month apart. Sustained response was defined as a negative serum HCV RNA 6 months after end of treatment. Of the 110 patients, 19 achieved an end-of-treatment response (17%) but only four achieved a sustained response (4/110=4%). Of the patients achieving a sustained response, one was genotype 1 (male Caucasian), three were genotype 2/3 with four patients having no follow-up information. The end-of-treatment response was 7% for patients with genotype 1 and 71% for genotype non-1 (P < 0.005 for genotype non-1). The end-of-treatment response was significantly higher in Caucasians (14/49=31%) compared with African Americans (5/61=8%; P < 0.05). A lower response rate in African Americans with genotype 1 in contrast to Caucasians was the primary reason for the difference in end-of-treatment response (1/45=2% vs. 5/33=15%, P < 0.05). Hence, interferon treatment resulted in a poor sustained response rate in the group of patients representative of the urban populations with the highest prevalence of hepatitis C. A genotype other than type 1 was the strongest predictor of end-of-treatment response in patients treated but over 86% of patients in this urban clinic were genotype 1. Caucasians were more likely to respond than African Americans, especially in patients with genotype 1.
Asunto(s)
Población Negra , Hepatitis C Crónica/terapia , Interferones/uso terapéutico , Población Blanca , Adulto , Negro o Afroamericano , Enfermedad Crónica , Femenino , Genotipo , Hepacivirus/genética , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , ARN Viral/análisis , Estudios Retrospectivos , Estados UnidosRESUMEN
This study examines the prevalence of anti-hepatitis C virus by using an enzyme-linked immunoassay test (EIA-2) in 2447 volunteers (including 1560 police, 678 fire, and 209 emergency medical service personnel) and a self-reported questionnaire on potential occupational and non-occupational risk factors. Subjects consisted of 76% men, 54.8% blacks, and 40.3% whites. Twenty-eight individuals (1.1%) tested positive, with prevalence rates of 1.1% and 1.3%, respectively, among blacks and whites. Although firefighters and emergency medical service workers had a higher prevalence (2.3% and 2.8%) than police (0.6%), the overall prevalence was lower than that typical of urban populations. In a multivariate analysis, the most important risk factors were behavioral, with no significant occupational exposure risk observed. Previously reported racial differences were not detected in this study, most likely because the subjects were of similar socioeconomic status.
Asunto(s)
Técnicos Medios en Salud/estadística & datos numéricos , Incendios/estadística & datos numéricos , Hepatitis C/epidemiología , Tamizaje Masivo , Enfermedades Profesionales/epidemiología , Policia/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Adulto , Anciano , Estudios Transversales , Femenino , Indicadores de Salud , Hepatitis C/diagnóstico , Hepatitis C/transmisión , Humanos , Incidencia , Masculino , Michigan/epidemiología , Persona de Mediana Edad , Enfermedades Profesionales/diagnóstico , Enfermedades Profesionales/etiologíaRESUMEN
OBJECTIVES: Administration of vaccine for hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for patients with chronic hepatitis C (CHC) because of the potential for increased severity of acute hepatitis superimposed on existing liver disease. The aim of this study is to determine the prevalence of antibodies directed against HAV and HBV in patients with CHC, analyze demographic and risk factors associated with this prevalence, and develop a cost-effective vaccination strategy. METHODS: We reviewed records from 1092 CHC patients. Demographics and information regarding risk factors were obtained by history and questionnaire administered to all patients. The costs of vaccination and antibody testing were determined, based on standard laboratory and clinic charges at our institution. HAV and HBV markers were correlated to race, age, and risk factors. RESULTS: Of the total population studied (n = 1092), 72% were African-Americans, 27% white, and 1% others. Of 671 CHC patients tested for anti-HAV IgG, 252 (38%) were positive. Of 743 CHC patients tested for HBV antibodies (anti-hepatitis B core IgG or anti-hepatitis B surface), 494 (67%) were positive. African-Americans are more likely to have antibodies to HAV and HBV (67% and 75%, respectively) compared to whites (27% and 20%). The prevalence of anti-HAV was 76% in patients >60 yr, 34% in the 40- to 60-yr-old age group, and 21% in patients <40 yr. The highest prevalence of HBV antibodies was found in patients between the ages of 40-60 yr. No HCV risk factors were associated with increased HAV risk. In CHC patients with HBV antibodies, however, illicit injection drug use was the predominant risk factor. CONCLUSIONS: The prevalence of anti-HAV in patients with CHC was found to be similar to that of the general population in the United States (33% according to recent Centers for Disease Control data), consistent with the hypothesis that the two infections do not share risk factors. Because the prevalence of HAV immunity is low in CHC patients <40 yr, empiric HAV vaccination is cost effective. If two doses of vaccine are to be given, however, antibody testing of all HCV patients is indicated. In the subset of patients >60 yr of age or who are African-American, where the prevalence of HAV exposure is considerably higher, it would be cost effective to check the antibody ($36.00), before vaccination ($97.00). The prevalence of HBV antibodies, however, is significantly increased in patients with CHC compared with the general population (5.3% per the Centers for Disease Control), likely as a result of exposure to similar parenteral risk factors. HBV antibody testing ($26.00 per test) should, therefore, be undertaken in all CHC patients who are hepatitis B surface antigen negative, as this approach is cost-effective compared to empiric HBV vaccination ($438.00 for a three injection course).
Asunto(s)
Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Hepatovirus/aislamiento & purificación , Inmunidad , Adulto , Envejecimiento/inmunología , Población Negra , Análisis Costo-Beneficio , Femenino , Humanos , Pruebas Inmunológicas/economía , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Vacunación/economíaRESUMEN
Hepatitis C virus (HCV) RNA status and HCV genotype have become important tools in the diagnosis and monitoring of therapy in chronic HCV infection. To establish a database with respect to HCV genotype and serum HCV RNA concentrations in chronic hepatitis C patients in the United States, we analysed 6807 chronic hepatitis C patients who had HCV RNA and HCV genotype tests conducted at a central laboratory. The HCV RNA concentration cut-off for the lower 25th percentile of this population (low titre) was 0.9 x 106 copies ml-1. The median HCV RNA concentration was 3.5 x 106 copies ml-1 and the cut-off for the upper 25th percentile (high titre) was 5 x 106 copies ml-1. Male patients had a median HCV RNA concentration of 3.9 x 106 copies ml-1, which was significantly higher than the median HCV RNA level for females (2.75 x 106 copies ml-1; P < 0.001). HCV genotype 1 was detected in 73% of patients; genotype 2 in 14%; genotype 3 in 8%; mixed genotype in 4%; and genotypes 4, 5 and 6 with a frequency of < 1%. Patients from the Northeast, Southeast and Midwest had significantly (P < 0.001) more infections with genotype 1 than patients from the Western and Southern regions. African-American patients were more likely to be infected with genotype 1 when compared with Caucasian, Hispanic or Asian Pacific Islanders (P < 0.001). Patients infected with HCV genotype 1 and mixed HCV genotypes had significantly higher serum HCV RNA concentrations when compared with HCV genotypes 2 and 3 (P < 0.001 for all comparisons).
Asunto(s)
Genotipo , Hepacivirus/genética , Hepatitis C Crónica/virología , Población Negra , Femenino , Hepacivirus/patogenicidad , Hepatitis C Crónica/sangre , Hepatitis C Crónica/etnología , Humanos , Masculino , ARN Viral/sangre , Estados Unidos , Carga Viral , Población BlancaRESUMEN
Previous clinical trials have suggested that thymosin alpha1 (Talpha1), an immunomodulatory peptide, may be effective in the treatment of chronic hepatitis B (CHB). The aim of this study was to determine the efficacy of Talpha1 in a multicentre, placebo-controlled and double-blind study of 97 patients with serum hepatitis B virus (HBV) DNA- and hepatitis B e antigen (HBeAg)-positive CHB. Patients who had been hepatitis B surface antigen (HBsAg) positive for at least 12 months entered a 3-month screening period prior to randomization. Forty-nine patients received Talpha1 (1.6 mg) and 48 patients received placebo, twice weekly for 6 months, and were followed-up for an additional 6 months. At inclusion, both groups were comparable for age, gender, histological grading, and aminotransferase and HBV DNA levels. A complete response to treatment, defined as a sustained serum HBV DNA-negative status (two negative results at least 3 months apart) during the 12-month study, with negative HBV DNA and HBeAg values at month 12, was seen in seven (14%) patients given Talpha1 and in two (4%) patients treated with placebo (P = 0.084). Five (10%) patients given Talpha1 and four (8%) patients given placebo exhibited a delayed response (defined as sustained serum HBV DNA negativity achieved after the 12-month study period with negative HBV DNA and HBeAg values at the last assessment). A total of 12 (25%) patients given Talpha1 and six (13%) patients given placebo showed a sustained loss of HBV DNA with a negative HBeAg value during or following the 12-month study period (P < 0.11). These results do not confirm observations of treatment efficacy reported in other clinical studies.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Timosina/análogos & derivados , Adyuvantes Inmunológicos/uso terapéutico , Adulto , ADN Viral/sangre , Método Doble Ciego , Femenino , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/aislamiento & purificación , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Timalfasina , Timosina/uso terapéutico , Resultado del TratamientoRESUMEN
Cytokine-mediated apoptotic destruction of viral-infected cells, downregulation of virus production and inhibition of anchorage dependent (clonal) cell growth were evaluated using virus-transfected human hepatoblastoma (HepG2) cells. The cytokines evaluated were interferon alpha (IFN-alpha), tumour necrosis factor alpha (TNF-alpha) and thymosin alpha 1 (T alpha 1), all of which have previously been implicated in control of various viral infections. The viruses evaluated were Hepatitis B (HBV) and the transforming virus, SV-40. TNF-alpha-induced apoptosis in the HBV-transfected cell line and the control HepG2 cells but not the HepG2 cells transfected with SV-40 virus. IFN-alpha and T alpha 1 had no effect on apoptosis. TNF-alpha also prevented the clonal growth of the HBV-HepG2 and control HepG2 but enhanced the growth of the SV-40-transfected HepG2 cells. IFN-alpha inhibited the clonal growth of all three cell lines in contrast to T alpha 1 which inhibited the clonal growth of only the HBV-transfected cells. Although TNF-alpha, IFN-alpha, and T alpha 1 when given alone did not significantly inhibit HBV-DNA production in the culture supernatant from HBV-HepG2 cells, the combination of T alpha 1 and IFN-alpha resulted in a statistically significant inhibition of virus production. These studies demonstrate that HepG2 cells transfected with HBV and SV-40 are useful for defining the mechanisms of cytokine activity. The HBV-transfected cells are especially useful in defining possible in vivo differences in responses to cytokines with respect to HBV production, apoptosis and clonal cell growth. Multiple mechanisms through which different cytokines can influence HBV infection and hepatoblastoma growth were identified and the importance of defining effective combinations to improve therapy in vivo demonstrated.
Asunto(s)
Apoptosis , División Celular , Virus de la Hepatitis B/fisiología , Interferón-alfa/farmacología , Virus 40 de los Simios/fisiología , Timosina/análogos & derivados , Factor de Necrosis Tumoral alfa/farmacología , División Celular/efectos de los fármacos , Hepatoblastoma , Humanos , Timalfasina , Timosina/farmacología , Transfección , Células Tumorales CultivadasRESUMEN
Amoxicillin/clavulanic acid is a widely used antibiotic. Hepatic dysfunction is a rare adverse reaction associated with this combination antibiotic. We report the case of a 40-yr-old woman with a somewhat unusual presentation of amoxicillin/clavulanate-related cholestatic hepatotoxicity and multiple duodenal erosions whose diagnosis was delayed until inadvertent rechallenge with the antibiotic combination. The relevant literature is also reviewed and discussed. The diagnosis may be missed because the onset of signs/symptoms may occur several weeks after the cessation of therapy. The hepatic dysfunction, which may be severe and is more prevalent in elderly patients, is usually reversible, although chronic liver disease and deaths have been reported. Immunological hypersensitivity is considered to be the most likely mechanism resulting in liver injury. Amoxicillin/clavulanate should be used with caution in patients with underlying liver disease and in the elderly.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Colestasis/inducido químicamente , Quimioterapia Combinada/efectos adversos , Enfermedad Aguda , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Colestasis/diagnóstico , Femenino , Humanos , Recurrencia , Sinusitis/complicaciones , Sinusitis/tratamiento farmacológicoRESUMEN
BACKGROUND: Thymosin-alpha 1 is a biological response modifier that has been used clinically, alone and in combination with interferon-alpha for the treatment of chronic hepatitis B viral infection. Both immunomodulatory and immediate intracellular mechanisms have been postulated to explain the effect of these two agents on HBV-infected hepatocytes. METHODS: In this study, hepatitis B transfected HepG2 hepatoblastoma cells (HepG2-Nu2), derived from 2.2.15 cells, were used as an in vitro model to determine the efficacy of thymosin-alpha 1 and interferon-alpha, individually and combined, as proliferation inhibitors of HBV-infected cells. For comparison, parental HepG2 cells and an SV40-transfected HepG2 cell line (HepG2P9T2) were also evaluated. RESULTS: In a clonogenic soft agar assay, thymosin-alpha 1 inhibited the anchorage-independent growth of the HepG2-Nu2 cells by 40% compared with untreated controls, but did not inhibit parental HepG2 or HepG2P9T2 clonal growth. The response was dose dependent over concentrations spanning three log units. In comparison, 10000 units/ml of interferon-alpha inhibited parental HepG2, HepG2-N4Z and HepG2P9T2 by 33%, 41% and 87%, respectively. The combination of thymosin-alpha 1 and interferon-alpha consistently inhibited HepG2-Nu2 clonal growth more effectively than either treatment alone, reaching maximum inhibition levels of 51%. CONCLUSIONS: Thymosin-alpha 1 specifically inhibits the tumorigenic growth of HBV-transfected HepG2 cells in contrast to the general inhibition displayed by interferon-alpha. This panel of cell lines may be an important resource for dissecting the mechanism by which thymosin, alone or in combination with other drugs, influences HBV-infected hepatocytes and/or HBV-associated carcinoma.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Hepatoblastoma/tratamiento farmacológico , Interferón-alfa/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Timosina/análogos & derivados , Adyuvantes Inmunológicos/administración & dosificación , Antivirales/administración & dosificación , División Celular/efectos de los fármacos , Transformación Celular Viral , ADN Viral/biosíntesis , ADN Viral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Ensayo de Inmunoadsorción Enzimática , Virus de la Hepatitis B/genética , Hepatoblastoma/virología , Humanos , Interferón-alfa/administración & dosificación , Neoplasias Hepáticas/virología , Timalfasina , Timosina/administración & dosificación , Timosina/farmacología , Transfección , Células Tumorales Cultivadas , Replicación Viral/efectos de los fármacosRESUMEN
The immune system plays a crucial role in the control and eventual clearance of hepatitis B virus (HBV) infection. Immune mechanisms are now believed to participate in the pathogenesis of the hepatitis C virus (HCV) and to account perhaps for the high frequency of progression from acute to chronic disease. Although IFN-alpha has been proven effective in the treatment of viral chronic hepatitis B and C, response rates are low, reactivation of disease is appreciable and side effects of treatment are frequent. Both antiviral and immune modulatory activity have been ascribed to IFN-alpha and are believed to account for its therapeutic effect. Immune-active peptides including those derived from the thymus have also been evaluated over the past 15 years for the treatment of viral chronic hepatitis. This review summarizes clinical studies and experimental observations which provide the rationale for the use of these agents in the treatment of chronic hepatitis associated with HBV and HCV. Primary attention is focused on thymosin-alpha (T alpha 1), a synthetic peptide, which has been evaluated in clinical trials. T alpha 1 has in vivo and in vitro immune-modulatory activity on lymphoid populations as well as the potential of more direct antiviral activity. Preliminary results of clinical trials utilizing combinations of T alpha 1 with various IFN preparations are also reviewed.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Hepatitis Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Hormonas del Timo/uso terapéutico , Ensayos Clínicos como Asunto , Hepatitis B/inmunología , Hepatitis C/inmunología , Hepatitis Crónica/inmunología , HumanosRESUMEN
BACKGROUND: Monotherapy for chronic hepatitis C using interferon (IFN) results in a very small proportion of patients exhibiting a sustained response. Clinical trials assessing the benefit of combination drug therapy may provide evidence of improved treatment response over that seen with single drug treatment. AIM: To assess the response in patients with chronic hepatitis C to one year of combination treatment: thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU thrice weekly. PATIENTS AND METHODS: Fifteen patients with serum HCV RNA positive chronic hepatitis C were studied. Eleven patients were treatment naive and four had failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b. All patients were given combination T alpha 1 and L-IFN therapy for one year with a six month follow up period. RESULTS: Six months after initiation of treatment seven patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA. CONCLUSIONS: The results of this open label trial suggest that there may be a potential benefit to combining an immune modulator (T alpha 1) with an antiviral (IFN) in the treatment of chronic hepatitis C. Verification of the observations in this study require completion of a randomised controlled study.
Asunto(s)
Hepatitis C/terapia , Hepatitis Crónica/terapia , Interferón-alfa/uso terapéutico , Timosina/análogos & derivados , Adulto , Anciano , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Genotipo , Hepacivirus/genética , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN Viral/análisis , Timalfasina , Timosina/uso terapéuticoRESUMEN
This open label study was initiated to assess the safety and efficacy of lymphoblastoid interferon-alpha (IFN-alpha) and thymosin alpha 1 (T alpha 1) in the treatment of 11 patients with chronic hepatitis B, who had failed to respond to standard IFN-alpha 2b therapy, and in four interferon naive patients. These fifteen hepatitis B surface antigen (HBsAg) positive and serum hepatitis B virus (HBV) DNA positive patients were given T alpha 1 (1 mg) subcutaneously (s.c.) on 4 consecutive days. Low-dose lymphoblastoid IFN-alpha (3 MU) was administered intramuscularly (i.m.) on the fourth day. Beginning with the second and for the subsequent 25 weeks, patients self-administered T alpha 1 twice weekly in the morning followed, 12 h later, by 3 million units (MU) lymphoblastoid IFN-alpha. Patients were followed-up for 12 months. Nine (60%) of the 15 patients, including six (55%) of the 11 patients previously treated with IFN-alpha 2b, responded by losing serum HBV DNA and normalizing alanine aminotransferase (ALT) values. Six of the nine responders seroconverted to HBsAg negativity. Significant improvements in the Knodell histological activity index were observed in the responders and no significant adverse effects were observed. Combination low-dose lymphoblastoid IFN-alpha and T alpha 1 treatment may provide a safe and potentially effective therapeutic approach in chronic hepatitis B. These results require confirmation in future randomized controlled studies.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Timosina/uso terapéutico , Adulto , Anciano , Alanina Transaminasa/análisis , Antivirales/administración & dosificación , Biopsia , Enfermedad Crónica , ADN Viral/análisis , Femenino , Antígenos de Superficie de la Hepatitis B/análisis , Virus de la Hepatitis B/genética , Humanos , Interferón-alfa/administración & dosificación , Hígado/patología , Masculino , Persona de Mediana Edad , Autoadministración , Timosina/administración & dosificaciónRESUMEN
Thymosin alpha 1 (T alpha 1) is an immune modulatory peptide which has been evaluated in a variety of clinical trials. Although no in vivo adverse effects, including enhancement of tumor growth, have been noted, in vitro studies suggesting a role for T alpha 1 in cell growth have been reported. The studies presented in this report evaluated both exogenously added T alpha 1 and endogenously expressed T alpha 1 as factors which could either promote growth of tumor cells or induce transformation. No effect of exogenous T alpha 1 on cell growth was found. NIH-3T3 cells transfected with cDNA for the precursor ProThymosin alpha (Pro T alpha) expressed elevated levels of authentic T alpha 1 but did not demonstrate either enhanced proliferation in liquid culture or transformation as defined by the loss of contact inhibition or anchorage independent growth in soft agar. Thus these studies argue against the hypothesis that T alpha 1 is either an intracellular or extracellular growth promoter.
Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Sustancias de Crecimiento/farmacología , Precursores de Proteínas/farmacología , Timosina/análogos & derivados , Células 3T3 , Adenocarcinoma/patología , Animales , Neoplasias de la Mama/patología , Neoplasias del Ciego/patología , División Celular/efectos de los fármacos , Neoplasias del Colon/patología , Neoplasias del Íleon/patología , Ratones , Timosina/farmacología , Células Tumorales CultivadasRESUMEN
At the present time, interferon is considered the only effective therapeutic approach in the treatment of both chronic hepatitis B and chronic hepatitis C. It is clear that the disappointing response rates in both chronic hepatitis B and C place added emphasis on efforts to identify alternative forms of therapy. In addition to the development of other antiviral agents including the nucleoside analogs which might prove more effective and have fewer associated side-effects, other agents currently under investigation include thymic peptides such as thymosin alpha 1. In the future, the therapeutic approach to the treatment of chronic hepatitis B and C may consist of combination therapy using perhaps an immune modulator and an antiviral agent or, several antiviral drugs. Alternatively, there is indication that cellular targeting systems with delivery of the toxic material to the specific cell containing the virus may be more effective, while minimizing side-effects. Finally, there are agents such as ursodeoxycholic acid which perhaps, makes bile less toxic and can be used as adjunctive therapy with improvement in liver chemistry values. The treatment of chronic hepatitis B and chronic hepatitis C has shifted in emphasis form the concept of treating liver disease towards that of treating viral infections which happen to effect primarily the liver.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Adyuvantes Inmunológicos/uso terapéutico , Ácidos y Sales Biliares/uso terapéutico , Enfermedad Crónica/tratamiento farmacológico , Humanos , Interferones/uso terapéutico , Nucleósidos/uso terapéutico , Péptidos/uso terapéutico , Timosina/uso terapéutico , Timo/químicaRESUMEN
Liver regeneration is regulated by the orderly activation of growth-related genes. Although ethanol impairs induction of liver regeneration by partial hepatectomy, we have not identified ethanol-associated differences in the hepatic mRNA levels of several proto-oncogenes, including c-myc, which peaks 3-6 hr post-partial hepatectomy. Prothymosin alpha, a gene encoding a ubiquitous nuclear protein, is activated by c-myc in resting fibroblasts and has been implicated as a regulator of cell proliferation. Prothymosin alpha mRNA levels reportedly increase 12-32 hr post-partial hepatectomy, several hours after c-myc induction. We sought to determine if chronic ethanol intake alters the expected induction post-partial hepatectomy of prothymosin alpha steady-state mRNA expression and protein levels. Comparing rats chronically fed ethanol with pair-fed controls, we found no significant differences in steady-state levels of prothymosin alpha mRNA; however, we did see a delay in the increase of prothymosin immunoreactive peptide in rats chronically fed alcohol. This suggests that the inhibition in protein levels in ethanol fed rats is not due to lower steady-state mRNA levels, but may occur post-transcriptionally. Further data are needed to determine if this finding is important in the inhibition in cell growth following partial hepatectomy in rats chronically fed ethanol.
Asunto(s)
Alcoholismo/genética , Regeneración Hepática/efectos de los fármacos , Precursores de Proteínas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Timosina/análogos & derivados , Animales , División Celular/genética , Sondas de ADN , Etanol/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Regeneración Hepática/genética , Masculino , ARN Mensajero/genética , Ratas , Ratas Endogámicas WF , Timosina/genéticaRESUMEN
Accumulating evidence suggests that prothymosin alpha has an as yet undefined intracellular, perhaps intranuclear, function related to cell proliferation. Prothymosin alpha mRNA and/or peptide levels increase when cells are stimulated to proliferate. Because proliferation and differentiation events are often inversely correlated, we examined prothymosin alpha gene expression during proliferation and differentiation of HL-60 myeloid leukemia cells. Steady-state levels of prothymosin alpha mRNA, which are high in exponentially growing HL-60, decrease within hours after induction of HL-60 to differentiate along the neutrophil pathway with dimethylsulfoxide (DMSO) or along the macrophage lineage with either tetradecanoylphorbol acetate (TPA) or bryostatin 1. The decline in prothymosin alpha mRNA in response to these differentiation signals parallels that of c-myc mRNA under the same conditions. We then determined whether the downregulation of prothymosin alpha and c-myc mRNA were due to differentiation or cessation or proliferation. Recombinant human gamma-interferon induces monocytic differentiation of HL-60, but permits continued proliferation, and, under these conditions, expression of prothymosin alpha, as well as of c-myc, mRNA remains elevated. We conclude that prothymosin alpha and c-myc expression are coregulated in differentiating HL-60 and that their expression correlates with the proliferative state of HL-60 cells, rather than with the differentiated state.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Promielocítica Aguda/metabolismo , Precursores de Proteínas/genética , Timosina/análogos & derivados , Diferenciación Celular/efectos de los fármacos , División Celular , Dimetilsulfóxido/farmacología , Genes myc , Humanos , Interferón gamma/farmacología , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , ARN Mensajero/análisis , ARN Neoplásico/análisis , Acetato de Tetradecanoilforbol/farmacología , Timosina/genética , Células Tumorales CultivadasRESUMEN
OBJECTIVE: The thymus-derived peptides, thymosin alpha 1 and thymosin beta 4, are believed to contribute to the maintenance of immune homeostasis. They are also associated with the hypothalamic-pituitary-adrenal-gonadal axis and may play a role in reproduction. STUDY DESIGN: Patients were recruited from a university hospital setting. Eligible candidates were 24 to 38 years old who were being seen in an ovulation induction and in vitro fertilization program. Serial maternal serum thymosin alpha 1 and beta 4 levels were assayed preconceptual and then twice in the first trimester by ELISA in 28 women with known ovulation dates who successfully conceived as demonstrated by positive serum beta human chorionic gonadotropin (hCG). Thymosin alpha 1 and beta 4 serum levels for viable pregnancies (group I; N = 19) were compared to pregnancies that aborted (group II; N = 9) using repeated measures of multivariate analysis of variance (MANOVA). Periconceptional (preovulatory and early pregnancy) thymosin alpha 1 and beta 4 values between groups I and II were compared using repeated measure one-way ANOVA. RESULTS: Thymosin alpha 1 levels from pregnancies that remained viable were significantly higher than those from pregnancies that spontaneously aborted. Preovulation thymosin alpha 1 levels also tended to be lower in pregnancies that subsequently aborted. Thymosin beta 4 levels were similar between the two groups. CONCLUSION: Decreased maternal serum thymosin alpha 1 levels may be associated with periconceptional endocrine and/or immune disturbances preceding miscarriage.
Asunto(s)
Aborto Espontáneo/etiología , Embarazo/sangre , Timosina/análogos & derivados , Adulto , Femenino , Humanos , Timalfasina , Timosina/sangre , Timosina/fisiologíaRESUMEN
Enzyme linked immunosorbent assays were used to measure serum levels of immunoreactive thymosin alpha 1 and thymosin beta 4 in 681 healthy adults (range 18 yr-101 yr). Immunoreactive thymosin alpha 1 was found to occur at a geometric mean of 540 pg/ml with a range from 252 to 1158 pg/ml. There were no differences in the levels when analyzed according to race, sex or age. Immunoreactive thymosin beta 4 was measured at a geometric mean of 12.6 ng/ml with a range from 6.9 to 23.0 ng/ml. There were no differences in the levels when analyzed according to race or sex, however, there was a slight upward trend with increasing age. This data may be useful as a reference when monitoring clinical studies, determining the kinetics of drug metabolism and distinguishing patient groups with elevated levels of either of these peptides.
Asunto(s)
Timosina/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Timalfasina , Timosina/sangreRESUMEN
To evaluate the effects of a gonadotropin-releasing hormone agonist on non-reproductive systems, we administered [D-Leu6,Des-gly10]-GnRH ethylamide (leuprolide; 5 micrograms/day) for 21 days to female Sprague-Dawley rats. In Experiment 1, continuous infusion (Alzet minipumps sc) was compared to injection. Increased thymus and body weights and decreased estradiol and uterine weights were noted for both administration methods. Spleen weight increased only in rats treated by continuous infusion. Ovary, kidney and liver weights did not change. Only leuprolide-injected rats had elevated LH with decreased corticosterone and ACTH levels, possibly related to the injection process. Glucose, insulin, progesterone, FSH and corticosterone/ACTH were not different. In Experiment 2, intact and ovariectomized rats were implanted with minipumps delivering leuprolide or 0.9% NaCl. Body and thymus weights increased, whereas uterine weight and estradiol declined in both leuprolide-treated and ovariectomized rats. No synergism between leuprolide and ovariectomy was noted. Thymosin alpha 1, but not thymosin beta 4, increased in leuprolide-treated ovariectomized rats. Peripheral white blood cell count was elevated in leuprolide-treated intact rats and ovariectomized rats. In bone marrow, non-nucleated cell count declined in leuprolide-treated intact rats, contributing to the decreased total cell count in this group. Nucleated cell count was unaffected. Therefore, thymus weight gain was accompanied only in some cases by functional changes. Our results demonstrate that leuprolide affects non-reproductive systems, in a similar manner to ovariectomy. We suggest that such alterations may be due to the hypoestrogenic environment produced by leuprolide.