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Biomedical subjects

H Kupper

Publications and source records attributed to H Kupper.

At least 19 recordsLinked to original sources
PubMed2003

Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study.

OBJECTIVES: To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). METHODS: During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. RESULTS: Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p</=0.01). Additionally, ACR responses with adalimumab were achieved more rapidly than with placebo, with 82/115 (71%) of the ultimate ACR20 response rate to adalimumab treatment achieved at week 2. At week 12, for adalimumab 20, 40, and 80 mg, ACR20 response rates were 50.7%, 57.1%, and 54.2%, respectively, versus 10.0% for placebo (p</=0.001 for all comparisons); ACR50 rates were 23.9%, 27.1%, and 19.4%, respectively, versus 1.4% for placebo (p</=0.001 for all comparisons); and ACR70 rates were 11.3%, 10.0%, and 8.3%, respectively, versus 0.0% for placebo (p</=0.05 for all comparisons). All adalimumab doses significantly improved all ACR core criteria at all assessments. The 40 mg and 80 mg doses provided similar benefit. Adalimumab at all doses was generally well tolerated, with only mild or moderate adverse events. Completion rates were 87% for adalimumab and 67% for placebo. CONCLUSIONS: Adalimumab given as monotreatment to patients with longstanding, severe RA refractory to traditional DMARDs produced a rapid, sustained response and was safe and well tolerated, with no dose limiting side effects.

Adalimumab↗
PubMed2001

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.

OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

APACHE↗
PubMed2000

Relationship between interleukin-6 plasma concentration in patients with sepsis, monocyte phenotype, monocyte phagocytic properties, and cytokine production.

Monocyte phenotype, their phagocytic capacity as well as the cytokine production from 10 patients with sepsis with low interleukin-6 (IL-6) serum concentrations (<1000 pg/mL) and 8 patients with sepsis with high IL-6 (> or = 1000 pg/mL) plasma concentrations were investigated within 24 hours of fulfilling the criteria for sepsis. Monocytes from patients with high IL-6 levels had higher levels of human leukocyte antigen (HLA)-DR, HLA-ABC, CD64, and CD71, and the production of tumor necrosis factor-alpha (TNF-alpha) and IL-8, as well as the capacity of monocytes to phagocytose, was significantly elevated. Of 8 patients with high levels of plasma IL-6, 4 patients died. In contrast, all 10 patients with low plasma IL-6 concentrations survived until day 28. Patients who died had constant high IL-6 concentrations during the first 3 days, whereas IL-6 levels in patients who survived decreased by 88%. Our data indicate that IL-6 levels are a better prognostic parameter in the early phase of sepsis than the monocyte HLA-DR expression.

Adult↗
PubMed1998

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer.

Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase II trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m(-2) i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 microg ml[-1] h[-1], P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 microM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, CI 5-39%, s.e.P 0.079). The remissions lasted 3, 8, 11 and 11+ months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.

Adult↗
PubMed1995

Dexverapamil to overcome epirubicin resistance in advanced breast cancer.

Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.

Adult↗
PubMed1995

Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma.

Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined-treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 microM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Dexverapamil as resistance modifier in acute myeloid leukaemia.

In order to evaluate dexverapamil as a resistance modifier in acute myeloid leukaemia, we have added dexverapamil (4 x 300 mg/d orally) to DA chemotherapy (daunorubicin, cytosine arabinoside) in six patients with acute myeloid leukaemia. Two patients (1 first and 1 second relapse) achieved complete remission and two patients (1 refractory disease, 1 third relapse) showed some improvement. One patient in first relapse died due to disease progression and one drug-refractory patient remained refractory. The peak plasma levels of dexverapamil and nordexverapamil ranged from about 600 to 4100 ng/ml and from 450 to 1130 ng/ml, respectively. Major sideeffects were hypotension and sinus bradycardia. These results show the need for further evaluation of dexverapamil as a resistance modifier in acute myeloid leukaemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

[Characterization of a T-cell subpopulation with a new monoclonal antibody BL-TSub/2].

The mab BL-TSub/2 binds to a majority (80%) of thymocytes. The antigen isolated from these cells has an apparent molecular weight of about 170 kDa. The mab BL-TSub/2 recognized antigen is expressed on approximately 50% of mature T cells in peripheral blood. The mab BL-TSub/2 does not bind to monocytes, granulocytes, platelets and CD16+NK cells. The antigen is possibly present on a part of peripheral B cells in very low density. Double labelling experiments showed that about 30% of CD4+ and 60% of CD8+ cells react with the mab BL-TSub/2. This BL-TSub/2+ subset is not identical with T-cell subpopulations till now defined. Within the CD4+ subset the majority of BL-TSub/2+ cells is included in the CD45RO+ subset while only a small proportion is CD45RA+. However, the CD8+ BL-TSub/2+ cells are mostly CD45RA+ with only few cells belonging to the CD45RO+ subset.

Antibodies, Monoclonal↗
PubMed1991

[Epitope analysis of CD68 antigens].

Different epitopes of CD68 antigen are detectable by three new generated monoclonal antibodies (MABs) BL-M68/1-3 (all mouse IgM). The MAB BL-M68/3 reacts with an epitope, which is stable also in formalin-fixed paraffin-embedded tissues. In immunohistochemical blocking experiments using the own biotinylated MABs and six CD68 MABs from the IV. Workshop on Human Leucocyte Differentiation Antigens two new epitopes could be defined. The number of known CD68 epitopes increases at least up to seven.

Antibodies, Monoclonal↗
PubMed1991

[Immunohistologic investigations of paraffin-embedded lymph nodes after bone marrow transplantation in autopsy samples].

A histological and immunohistochemical analysis of paraffin-embedded lymph nodes from 31 autopsies after bone marrow transplantation (BMT) was performed (20 allogeneic, 10 autologous, 1 syngeneic). Monoclonal antibodies against CD 45RB, CD 20, CD 21, CD 35. CD 43, CD 45RO, CD 76 and Ki-B3, and antisera for detection of S 100-protein and immunoglobulin isotypes were used. None of the lymph nodes showed a regular reconstitution. The lymphoid cells, scattered in a diffuse pattern, were mainly CD 43-positive. Most of them also expressed the CD 45RO antigen. CD 20- and Ki-B3 positive lymphoid cells were nearly absent within the first 100 days after BMT. After that time B cell follicles were detectable in a few cases. Surprisingly, in nearly all cases with infectious complications, numerous plasma cells could be found. The origin of this plasma cells is discussed.

Antibodies, Monoclonal↗
PubMed1989

[Secondary follicles in the thymus. Immunohistologic characterization of B lymphocytes using monoclonal antibodies].

Studies were conducted into the incidence of secondary follicles in individuals without autoimmune disease. Thymic tissue specimens were obtained from 20 children, aged between 6 months and 14 years who had undergone cardiac surgery and had been chosen at random. These specimens were immunohistologically investigated, using monoclonal anti-B cell antibodies (CD19 to CD23, CD37) and anti-immunoglobulin antibodies. Follicular structures were found in 7 cases. They were localized in thymic medullary regions. Immunohistologically, the secondary follicles in the thymus exhibited staining patterns similar to those recordable from follicles in other lymphatic tissues, such as tonsils. Formation of follicular structures from the potential of normally detectable scattered B cells in the thymus appears to be quite common also in cases without autoimmune diseases.

Adolescent↗
PubMed1988

[Uses of monoclonal antibodies in the immunohistochemistry of lymphatic organs].

The paper describes the value of immunohistological screening in the production of monoclonal antibodies against leukocyte membrane antigens. Some examples are given of unexpected findings in this screening. It is shown also the application of characterized antibodies for the differentiation of lymphocytes in various lymphatic tissues (thymus, tonsil, spleen).

Antibodies, Monoclonal↗
PubMed1987

Involvement of the central nervous system in malignant lymphomas of mice.

19% of the male and 49% of the female AKR mice with spontaneously developed lymphomas show an involvement of the central nervous system (CNS) in the form of a tumor cell infiltration of the leptomeninx. A significantly higher rate of lymphomas was achieved by syngeneic transplantation of lymphoma cells (intraperitoneal inoculation) in the CNS with 87% in both sexes. Morphologically, there were no differences between the leptomeningeal infiltrations in spontaneously developed and transplanted lymphomas. Spontaneous and induced lymphomas of the AKR mouse may be suitable as a simple model for investigations on CNS lymphomas in experimental oncology.

Age Factors↗
PubMed1986

[Detection of thymocyte antigens by monoclonal antibodies of the BL series].

The reactivity of 4 monoclonal pan T cell antibodies and 6 pan leukocyte antibodies was detected with human thymocytes. The study was performed with single cell suspensions and cryostat sections using immunofluorescence and immunoperoxidase techniques. Monoclonal antibodies with T cell specificity react with different percentages of thymocytes. The antibody BL-T1, which is directed against the sheep erythrocyte receptor, reacts with 90% of thymocytes. These cells were found uniform in the thymus cortex and medulla. On the other hand, the antibodies e.g. BL-T2 and T3 react only with 20% of the thymocytes, identified mainly in the medulla. Pan leukocyte antibodies are also suitable for the detection of different thymocyte membrane antigens. In single cell suspensions, it was found a reactivity of the used antibodies with 20, or 40, or 95% of the cells. The immunohistological findings are described.

Antibodies, Monoclonal↗
PubMed1986

Double staining technique using a combination of indirect and direct immunofluorescence with monoclonal antibodies.

A simple method for double staining by immunofluorescence is described. If for double staining using monoclonal antibodies of the same species only one antibody is conjugated with FITC or TRITC, a combination of indirect and direct immunofluorescence is possible. For cell staining the following incubation steps are carried out: Monoclonal antibody I (unlabelled, mouse), anti-mouse immunoglobulin serum FITC- or TRITC-conjugated, normal mouse serum for blocking of free binding sites of the anti-mouse immunoglobulin, and monoclonal antibody II (mouse) which is conjugated with an alternative fluorochrome. The use of this method is demonstrated for investigation of single cell suspensions (performed as a slide test) and of cryostat sections.

Animals↗
PubMed1985

[Characterization of monoclonal antibodies to human monocytes].

A set of monoclonal antibodies reacting with human peripheral blood monocytes is characterized. Two of these antibodies also bind to a fraction of granulocytes (BL-M/G-1) respectively to all of them (BL-M/G-2). On the other hand the BL-M-3 appears to be specific for monocytes only. All three monoclonals do not react with enriched B and T lymphocytes, platelets, erythrocytes and several lymphoid or erythroid permanent cell lines. The antigens recognized by all three monoclonals are expressed by monoblastic cell line U-937, whereas the myeloid line HL-60 and the cell line KG-1 express only antigen recognized by monoclonal antibody BL-M/G-2.

Animals↗