Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics

Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.     

前列腺特异抗原研究进展与挑战(摘要)

前列腺特异抗原(ＰＳＡ)发现四分之一世纪以来,已成为诊断前列腺癌最有价值的肿瘤标志物。前列腺癌在男性癌症发病中占首位。自从80年代中期第一代检测ＰＳＡ的方法问世以来,前列腺癌的发病率有了显著改变。这部分归功于ＰＳＡ检测的增加,从而使前列腺癌得到早期诊断,这有利于将癌症控制在发病早期,增加治愈的可能性。虽然ＰＳＡ是一个有效的肿瘤标志物,并具有器官特异性,但其癌症特异性不高。ＰＳＡ升高也可见于其他良性前列腺疾病,尤其当ＰＳＡ浓度在4～10μｇ/Ｌ时。这个浓度范围被称为“诊断灰色区域”。对ＰＳＡ分子结构的研究主要集中…     

Establishment of a human acute promyelocytic leukemia-ascites model in SCID mice

Acute promyelocytic leukemia (APL) is an interesting model for cancer research because of the presence of the specific PML-RARalpha fusion gene associated with the clinical response to retinoic acid differentiation therapy. To better understand and improve differentiation induction with retinoic acid, we have established a human APL-ascites model in SCID mice using the NB4 human APL cell line. NB4 (1 x 10(6) cells) were transplanted into the peritoneum (IP) of SCID mice for 1 month. NB4 ascites cells (A-NB4) appeared, which were then engrafted in SCID mice periodically for 18 passages at an interval of 3 to 4 weeks with a 100% success rate of tumor induction. The mean survival times of SCID mice transplanted with 1 x 10(6) A-NB4 cells was 21.6 +/- 2.3 days. Analysis of the biologic characteristics of ninth passage NB4 ascitic cells was performed and they were found to have the morphologic, immunologic, cytogenetic, and molecular features of cultured NB4 cells. Furthermore, A-NB4 cells were capable of differentiating when treated with all-trans retinoic acid (ATRA), as manifested by enhanced NBT reduction and CD11b expression. In vivo treatment with ATRA in SCID mice for 4 days also increased NBT reduction by A-NB4 cells. ATRA treatment significantly prolonged survival time in the group after transplantation (28.1 +/- 6.8 to 29.1 +/- 8.4 days) compared with the control (P < .001). Furthermore, treatment with adriamycin, an effective chemotherapeutic drug in APL, had a strong growth suppressive effect on A-NB4 cells. These results demonstrate that this SCID-APL (NB4 ascites cells) model is a useful preclinical system for evaluating new or known drugs in the treatment of APL.     

Microdroplet fluorochromatic assay for the enumeration of white cells (WBCs) in WBC-reduced blood components: validation and application for evaluating newly developed WBC-reduction filters

BACKGROUND: Sensitive and accurate counting methods are required to assess the residual white cells (WBCs) in WBC-reduced blood components. The Nageotte hemocytometer, widely used for this purpose, is cumbersome, and its efficacy is dependent upon the skill of the operator. The performance of a simple fluorochromatic assay using tissue-typing microdroplet trays is presented here. STUDY DESIGN AND METHODS: Undiluted samples of blood components were mixed with a fluorochromatic dye in trays. WBCs were counted under an epifluorescence microscope. The accuracy and sensitivity of this method were compared with those of the reference Nageotte hemocytometer method by using serial dilution of samples of platelets and red cells containing known concentrations of WBCs and by calculating the standard curves. The Nageotte hemocytometer and the microdroplet fluorochromatic assay (MFA) were also compared in terms of count correlation and reproducibility in 320 paired counts of plateletpheresis samples. MFA was used to evaluate a newly developed WBC-reduction red cell filter. RESULTS: The MFA for platelets and red cells was linear to 0.1 and 0.03 WBCs per microL, respectively. The linear regression line of log10 MFA versus log10 Nageotte method had a slope of 0.963, intercept of -0.04, and r2 of 0.968. The Nageotte method gave an estimation of WBC content 12 to 20 percent greater than that of the MFA. The MFA, with a larger neat sample volume, showed precision comparable to that of the Nageotte method. The filters demonstrated a median WBC reduction of 4.8 log10. CONCLUSION: The MFA is a sensitive and accurate method for quality control processes to assess the residual WBCs in WBC-reduced blood components.     

Human parvovirus B19-induced epidemic acute red cell aplasia in patients with hereditary hemolytic anemia

From March to August 1984, 26 patients with hereditary hemolytic anemia in northeastern Ohio developed acute, profound red cell aplasia. The patients included 14 males and 12 females 2 to 23 years old, with sickle cell anemia (20 cases), hemoglobin SC-disease (4 cases), sickle- beta-thalassemia (1 case), or hereditary spherocytosis (1 case). All had an acute onset of severe reticulocytopenia and anemia and prodromal symptoms of illness including fever, abdominal symptoms, headache, and arthralgias. Twenty-two received transfusions. Reticulocytosis occurred spontaneously within 2 to 14 days of presentation. In five acute-phase sera, 10(8) to 10(12) viral particles/mL were detected by electron microscopy. Human parvovirus B19 DNA was demonstrated in high concentration by hybridization in the same five acute-phase sera and in low concentration in sera of eight additional patients. The five highly viremic sera inhibited erythroid colony formation in vitro. B19- specific IgM was detected in sera of 24/26 patients, and B19-specific IgG in 21 of 22 patients tested. Our results indicate that human parvovirus B19 was the etiologic agent in this large epidemic of life- threatening acute red cell aplasia in patients with hereditary hemolytic anemia.     

Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.     

Defective T suppressor-inducer cell function in human immune deficiency virus-seropositive hemophilia patients

In human immune deficiency virus (HIV)-seropositive hemophilia patients, a low number of CD4 + lymphocytes is found, as well as a low CD4+/CD8+ ratio. In previous studies, it has been shown that antigen- specific T-helper cell (CD4+) function was present and no excessive antigen-specific T-suppressor cell (CD8+) function could be demonstrated. In this report, we studied another activity of CD4+ cells, namely the capacity to induce T-suppressor cell activity. The results clearly show a selective dysfunction of CD4+ suppressor-inducer (Tsi) cell function. Since these HIV-seropositive hemophilia patients showed the presence of activated B cells in the peripheral circulation refractory to antigen-specific T-helper cell signals and secreting specific antibodies spontaneously, we raised the hypothesis that the activated B cells in the patients activate the Tsi cells in vivo. This constant activation leads to a functional exhaustion of the Tsi cell pool.     

Meniscal injuries: detection using MR imaging

Both retrospective and blinded analyses of thin-section, high-resolution magnetic resonance (MR) images of the knee joint, produced using a solenoid surface coil, indicate that MR imaging is an effective technique for evaluating meniscal injuries. Images of 49 patients were evaluated, and the results were correlated with those of subsequent arthroscopy. A grading scale was developed to rate the index of suspicion of a meniscal tear based on the MR images. Overall, approximately 80% of menisci rated grade 4 (definite tear) or 3 (probable tear) were found to have corresponding tears at arthroscopy. In many other patients with a grade 4 or 3 meniscus in whom a corresponding tear was not found arthroscopically, meniscal tears at other sites or other abnormalities were correctly diagnosed using MR. A majority of the false-positive MR images involved the posterior horns of the menisci, the sites of most false-negative arthroscopic diagnoses. The predictive value of a negative MR image was almost 100%. Even in patients with moderate-to-large effusions, the menisci were accurately evaluated. The results imply that MR imaging is useful in the preoperative evaluation of suspected meniscal tears.