The interactions of bromocriptine and lergotrile with dopamine and α-adrenergic receptors

Summary Bromocriptine and lergotrile, which are clinically used as antiparkinsonian (AP) agents, compete for the binding of H³-dopamine, H³-apomorphine, and H³-haloperidol to striatal membrane sites. Lergotrile has a higher affinity for the H³-dopamine binding to bovine striatal membranes than bromocriptine. Lergotrile and bromocriptine are almost equipotent in competing for the binding of H³-apomorphine to rat striatal membranes, but bromocriptine is more potent in competing for the binding of H³-haloperidol than lergotrile. These results indicate that lergotrile and bromocriptine are mixed putative agonist-antagonist with respect to the postsynaptic dopamine receptors. Lergotrile and bromcriptine at higher concentrations inhibit synaptosomal tyrosine hydroxylase activity, and reverse the apomorphine elicited enzyme inhibition. Thus, these ergot alkaloids behave as mixed agonist-antagonist also with respect to the presynaptic dopamine receptors. Bromocriptine and lergotrile, as well as other tested DH-ergot alkaloids and neuroleptics, compete for the binding of the-antagonist H³-WB-4101 to rat cerebral cortical membranes. The displacing potencies of the tested DH-ergot alkaloids and of the neuroleptics indicate that they have a high affinity for the-adrenoreceptors in the CNS.     

Diarrheal deaths in the United States, 1979 through 1987. A special problem for the elderly

OBJECTIVE.--Diarrhea is an important cause of death among young children in both developing and developed countries, but little is known about diarrheal death among adults. In this study, we examined trends in diarrheal deaths among all age groups in the United States. DESIGN/SETTING/PARTICIPANTS.--We reviewed national mortality data complied by the National Center for Health Statistics, Hyattsville, Md, which consists of information from all death certificates filed in the United States for the period 1979 through 1987. A death for which diarrhea was listed as an immediate or underlying cause was considered a "diarrheal death" and included in the analysis. RESULTS.--We found that 28,538 persons died of diarrhea cited as either an immediate or the underlying cause of death during the 9-year period. A majority of diarrheal deaths occurred among the elderly (older than 74 years of age, 51%), followed by adults 55 to 74 years of age (27%), and young children (younger than 5 years of age, 11%). For the elderly, adjusted risk factors for dying of diarrhea included being white, female, and residing in a long-term care facility. Only the elderly and young children had clear, distinct winter peaks of diarrheal deaths, suggesting that the diarrhea may, in part, be infectious in origin. CONCLUSION.--For the elderly, more directed studies of those at risk, such as nursing home residents, are needed to determine if oral rehydration therapy, vaccines, or other preventive measures might benefit this population.     

Local secretion of a chimeric anti-CD4 antibody protects against graft rejection in the NOD mouse

BACKGROUND: Engineering a graft to secrete its own immunosuppressive antibodies may minimize the risks associated with current high dose systemic immunosuppression. METHODS AND RESULTS: A beta cell insulinoma cell line (NIT-1) was transfected with genes encoding a chimeric anti-CD4 antibody. The NIT-1 cells secreted functional chimeric anti-CD4 antibody that bound to the CD4 molecule on mouse thymocytes and inhibited in vitro proliferation of CD4+ve T cells. Both test and control transfected cell lines grew at a similar rate in immunodeficient mice. In immunocompetent NOD mice, NIT-1 cells are normally rejected by a cellular immune response against the SV40 T antigen. Although control transfected NIT-1 cells were rapidly rejected by NOD mice, anti-CD4 secreting NIT-1 cells grew significantly better and were able to form tumors at the site of injection. CONCLUSIONS: The local secretion of chimeric anti-CD4 antibody from transfected cells can contribute to graft survival in our transplantation model.     

HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study.

PURPOSE: Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen. PATIENTS AND METHODS: Three hundred and forty nine patients had estrogen receptor (ER)-positive breast cancer and received daily tamoxifen as initial therapy for advanced disease. HER-2 gene amplification, detected by fluorescence in situ hybridization, and HER-1 expression, evaluated by immunohistochemistry, was determined on 136 and 204 patients, respectively. RESULTS: HER-2 amplification was correlated with lower ER (P = 0.02), HER-1 positivity (P = 0.004), and HER-2 protein overexpression (P < 0.00001). The response rate was 56% for HER-2 non-amplified versus 47% for HER-2 amplified tumors (P = 0.38), and 58% for HER-1-negative versus 36% for HER-1-positive (P = 0.05). Time to treatment failure (TTF) was 7 months for non-amplified HER-2 tumors and 5 months (P = 0.007) for amplified HER-2 tumors, and there was a trend toward a better overall survival (OS) in patients with non-amplified HER-2 tumors (median 31 versus 25 months, respectively, P = 0.07). For positive versus negative HER-1 tumors, TTF was 4 versus 8 months (P = 0.08) and median survival was 24 versus 31 months (P = 0.41). Combining HER-1 expression and HER-2 gene status, patients with both negative HER-1 expression and non-amplified HER-2 had longer TTF (P = 0.001) and OS (P = 0.03) than if either were positive. In multivariate analysis, HER-2 was not an independent factor for TTF and OS, although HER-1 was significant for TTF only (P 相似文献   

Additive efficacy of CTLA4Ig and OX40Ig secreted by genetically modified grafts

BACKGROUND: The use of systemic immunosuppressive drugs have been paramount in the success in transplantation, but there are serious deleterious effects. Genetic modification of grafts to secrete immunomodulators locally may be a way to reduce the need for systemic immunosuppression. METHODS AND RESULTS: An insulinoma cell line, NIT, having the nonobese diabetic (NOD) genotype but also expressing the SV40 large T Ag, was transfected with CTLA4Ig or OX40Ig in an attempt to block signals in the costimulatory/adhesion pathways. The extracellular domains of these molecules have been fused to the Fc of IgG2c derived from the NOD mouse strain. This resulted in secreted and dimerized proteins. SV40 T Ag is potent at inducing graft rejection. Test and control transfectants were transplanted subcutaneously into young NOD mice to determine whether secretion of CTLA4Ig and OX40Ig would promote survival of the insulinoma graft. In immunodeficient mice, cell growth was similar for all transfectants. However, in immunocompetent NOD mice, the survival/growth of test grafts was significantly better than that of controls. By combining test transfectants, we found that graft survival was enhanced in an additive and significant fashion. In vitro, there was a significant reduction in immune responses-compared with control-when purified fusion proteins were added to mixed leukocyte reaction cultures. CONCLUSIONS: We conclude that blockade of individual costimulatory/adhesion signals by graft manipulation can contribute to transplantation success and that blockade of combinations of signals in these pathways enhances this success. Successful immunomodulation by the graft itself can be achieved.     

Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501.

PURPOSE: To determine the efficacy of combination fludarabine and mitoxantrone (FN) in untreated stages III and IV low-grade lymphoma. The major end point was to estimate progression-free survival (PFS) in all eligible patients. PATIENTS AND METHODS: Seventy-eight eligible patients were registered. Chemotherapy courses were administered every 4 weeks with mitoxantrone 10 mg/m2 on day 1 and fludarabine 25 mg/m2 on days 1, 2, and 3 for a total of six to eight cycles. Pneumocystis carinii prophylaxis was required. RESULTS: Seventy-three patients (94%) attained an objective response. Complete remission was demonstrated in 34 patients (44%) and partial remission was demonstrated in 39 patients (50%). With a median follow-up time of 5.5 years, the median PFS was 32 months, with a 4-year PFS rate of 38%. Median survival has not been reached and 88% of all patients are alive at 4 years. The application of the International Prognostic Index and serologic staging showed significant differences in PFS in all risk groups, whereas overall survival was markedly worse for the highest-risk group in either prognostic model. Three prior Southwest Oncology Group trials using a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone or a combination of prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone in similar patient populations demonstrated comparable clinical outcome, although the 4-year survival for FN was better. FN was well tolerated, but mild to severe reversible myelosuppression was noted. Other complications were rare. CONCLUSION: FN is an effective, safe chemotherapy combination for patients with advanced-stage, low-grade lymphoma. Clinical outcomes were comparable to prior published data using anthracycline-based regimens.     

Free radical pathways in CNS injury

Free radicals are highly reactive molecules implicated in the pathology of traumatic brain injury and cerebral ischemia, through a mechanism known as oxidative stress. After brain injury, reactive oxygen and reactive nitrogen species may be generated through several different cellular pathways, including calcium activation of phospholipases, nitric oxide synthase, xanthine oxidase, the Fenton and Haber-Weiss reactions, by inflammatory cells. If cellular defense systems are weakened, increased production of free radicals will lead to oxidation of lipids, proteins, and nucleic acids, which may alter cellular function in a critical way. The study of each of these pathways may be complex and laborious since free radicals are extremely short-lived. Recently, genetic manipulation of wild-type animals has yielded species that over- or under-express genes such as, copper-zinc superoxide dismutase, manganese superoxide dismutase, nitric oxide synthase, and the Bcl-2 protein. The introduction of the species has improved the understanding of oxidative stress. We conclude here that substantial experimental data links oxidative stress with other pathogenic mechanisms such as excitotoxicity, calcium overload, mitochondrial cytochrome c release, caspase activation, and apoptosis in central nervous system (CNS) trauma and ischemia, and that utilization of genetically manipulated animals offers a unique possibility to elucidate the role of free radicals in CNS injury in a molecular fashion.     

Renal abnormalities in sickle cell disease

Renal abnormalities in sickle cell disease. Sickle cell nephropathy is indicated by sickled erythrocytes, with the consequent effects of decreased medullary blood flow, ischemia, microinfarct and papillary necrosis. Impaired urinary concentrating ability, renal acidification, hematuria, and potassium secretion are also found. There may be a causal relationship between an increase in nitric oxide synthesis and experimental sickle cell nephropathy, and some studies have indicated that the progression of sickle cell nephropathy is hemodynamically mediated. Although there are many studies showing that proteinuria, nephrotic syndrome, chronic progressive renal failure, and acute renal failure syndromes are the outcome of this disease, the pathogenic mechanism(s) and potential therapies remain to be elucidated. Survival of patients with sickle cell nephropathy who progress to end-stage renal disease (ESRD) is equal to non-diabetic ESRD patients, and graft survival rates are also similar for those who undergo renal transplantation. This article presents a historical review of the glomerular and tubular disorders associated with sickle cell nephropathy, and reviews therapeutic indications to slow its progression. Further research is needed.