Biomedical subjects

H Wagner

Publications and source records attributed to H Wagner.

At least 307 records · Page 17Linked to original sources

PubMed1993

Immunomodulatory effects of ultra-low-dose interleukin-2 in cancer patients: a phase-IB study.

High-dose interleukin-(IL-2) has been broadly studied in tumor therapy, yet it may be inhibitory to T-cell-dependent immunity. Therefore immune and tumour responses mediated by low-dose IL-2 were studied systematically with respect to the feedback organisation of immune responses. IL-2 was administered once daily at three dose levels: 0.18, 0.9, 4.5 MIU/m2 according to three different schedules requiring subcutaneous (s.c.) injection once weekly (four doses, stratum I), thrice weekly every other day (nine doses, stratum II), or five times weekly every other week (ten doses, stratum III). A total of 46 patients with advanced cancer were randomly assigned to one of the nine treatment groups. Systemic effects were induced at doses as low as 0.18 MIU/m2 IL-2 s.c. as demonstrated from measurable IL-2 serum levels, induction of circulating IL-6, a transient lymphopenia, and stimulation of delayed-type hypersensitivity (DTH) responses of the skin. Analysis of the different IL-2 schedules demonstrated (a) prolonged effects of once-weekly injections on DTH responses, lymphocyte and eosinophil counts, and (b) maximum increase of eosinophil counts and preferential expansion of activated NK cells with repeated injections every 48 h or 72 h (stratum II), while sequential treatment according to stratum III was found to be more potent in increasing the number of activated T cells. A tumour response was observed in 1/15 patients with renal cell carcinoma who experienced more than 50% tumour regression for 8 months; 12 patients had stable disease for 4 months (median). These data demonstrate prolonged immunological effects of ultra-low doses of s.c. IL-2 despite its short half-life. Furthermore, scheduling of IL-2 was found to affect immune responsiveness specifically as demonstrated by the differential effects on natural killer and T cell populations.

Adult↗

PubMed1993

Bryodin, a single-chain ribosome-inactivating protein, selectively inhibits the growth of HIV-1-infected cells and reduces HIV-1 production.

Bryodin, a single-chain ribosome-inactivating protein (RIP) isolated from Bryonia cretica ssp dioica (cucurbitaceae), was found to selectively inhibit the growth of persistently HIV-1-infected T lymphoma cells (KE37/1) and human lung fibroblast when used in concentrations from 2-20 micrograms/ml. Uninfected KE37/1 cells remained unaffected at the same doses of bryodin. In addition, bryodin reduced HIV production in the surviving infected cells. Two isoforms of bryodin were purified by dye ligand chromatography. Both isoforms exerted the growth-inhibiting influence and reduced HIV production. Trichosanthin, another member of the RIP family, had similar inhibitory effects on the growth of HIV-1 infected cells and on HIV-1 production. Bryodin and trichosanthin were effective in about the same dose range. No selective effects for HIV-infected cells were observed with the RIPs gelonin and ricin.

Cells, Cultured↗

PubMed1993

Anti-inflammatory and immunologically active polysaccharides of Sedum telephium.

Two major polysaccharides, rhamnogalacturonans with mean M(r)s of 13,500 and 13,000, were isolated from dried leaves of Sedum telephium by column chromatography on DEAE-Sepharose CL-6B and gel filtration on Fractogel TSK HW-50 (S) and Sephacryl 200 HR. The structures were determined mainly by NMR spectroscopy, methylation analysis and GC-MS of the partially methylated alditol acetates, carboxyl reduction and by analysis of acidic and enzymatic degradation products. Both polysaccharides exert an anticomplementary effect in vitro, induce TNF-alpha-production, enhance phagocytosis in vitro and in vivo, and exhibit anti-inflammatory activity.

Animals↗

PubMed1993

Squarroside A, a biologically active triterpene saponin from Acanthophyllum squarrosum.

A new bioactive saponin has been isolated from the roots of Acanthophyllum squarrosum. Based on spectroscopic data, especially direct and long-range heteronuclear 2D NMR analysis, and on chemical transformations, the structure of this new compound was elucidated as 3-O-beta-D-galactopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->3)]-beta- D-glucuronopyranosyl gypsogenin 28-O-beta-D-xylopyranosyl-(1-->4)-alpha-L- rhamnopyranosyl-(1-->2)-[alpha-L-arabinofuranosyl-(1-->3)]-beta-D-4-O- acetylfucopyranoside for which we proposed the name squarroside A. This molecule showed a concentration dependent immunomodulatory effect in the in vitro lymphocyte transformation test.

Carbohydrate Conformation↗

PubMed1993

Polysaccharides isolated from plant cell cultures of Echinacea purpurea enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes.

Polysaccharides (EP) isolated from large scale plant cell cultures of Echinacea purpurea, have been shown to activate human and murine phagocytes. In this study we investigated the influence of EP on the nonspecific immunity in immunodeficient mice. EP was effective in activating peritoneal macrophages isolated from animals after administration of cyclophosphamide (CP) or cyclosporin A (CsA). EP-treated macrophages exhibited increased production of tumor necrosis factor-alpha (TNF) and enhanced cytotoxicity against tumor target WEHI 164 as well as against the intracellular parasite Leishmania enrietti. After a CP-mediated reduction of leukocytes in the peripheral blood, the polysaccharides induced an earlier influx of neutrophil granulocytes as compared to PBS-treated controls. EP treatment of mice, immunosuppressed with CP or CsA, restored their resistance against lethal infections with the predominantly macrophage-dependent pathogen Listeria monocytogenes and predominantly granulocyte-dependent Candida albicans. Further, the effects of EP in allogeneic bone marrow chimeric mice are discussed. These findings may have therapeutical implications in prophylactic treatment of opportunistic infections.

Animals↗

PubMed1993

Leading structures of plant origin for drug development.

This review summarizes the most important results of a plant screening program performed in the author's laboratory during the last 10 years. The screening program was initiated to search for new plant constituents with potential pharmacological activity in the field of inflammation in general, allergic asthma, immunodeficiencies and cardiovascular diseases. The test program mainly utilised in vitro assays, and particular attention was given to the key enzymes of the prostaglandin metabolism, cellular and humoral targets of the unspecific immune system, an in vitro ACE-inhibition test system, and an in vivo plethysmographic system as an inhibitory model of bronchial obstruction. The results of structure-activity relationship studies are also described.

Animals↗

PubMed1993

A dammarane-type saponin from the roots of Ampelozizyphus amazonicus.

A new C31 dammarane-type triterpenoid saponin has been isolated from the roots of Ampelozizyphus amazonicus. Its structure was elucidated to be ampelozigenin-15 alpha-O-acetyl- 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside by 1D and 2D NMR spectroscopic methods, and by chemical transformations. Ampelozigenin is a novel triterpene, (20R,22R)-16 beta,22:16 alpha, 30-diepoxydammar-24(24')- methylene-3 beta, 15 alpha, 20-triol.

Carbohydrate Sequence↗

PubMed1993

Superantigen mediated shock: a cytokine release syndrome.

Treatment of animals with superantigens results in profound immunological changes. A major fraction of all peripheral T cells becomes activated in vivo. Subsequently, successive waves of cytokines are produced with TNF playing a central pathophysiologic role. In addition, if the liver is damaged by an as yet poor defined mechanism the consequences of the cytokine syndrome are life threatening. However, TNF alone is not sufficient to cause death, instead synergizing interactions with cytokines like IL-1, IL-6, and IFN-gamma are probably involved. On the other hand, certain experimental conditions prevent these waves of cytokines and consequently lethal shock. Furthermore, a significant fraction of SA reactive T cells are deleted by programmed cell death 10 to 24 hours after treatment. Thereafter the surviving cells proliferate vigorously until day 2 or 3, followed by a second wave of apoptosis resulting in reduced SA reactive T cell numbers as compared to pretreatment levels. Of course, many aspects of the complicated events are only marginally understood and deserve further investigation.

Animals↗

PubMed1993

Crystal structure of artemisinic acid: a possible biogenetic precursor of antimalarial artemisinin from Artemisia annua.

Artemisinic acid [1], a possible biogenetic precursor of the antimalarial artemisinin [2], was isolated from the hexane extract of Artemisia annua. X-ray crystallography of the dimer of artemisinic acid shows that the cyclization during intermolecular hydrogen bonding occurs by the opposite orientation of the alpha, beta-methylene group in each molecule. Complete spectroscopic data of 1 are also given.

Antimalarials↗

PubMed1993

[Biological standardization of Ginkgo extracts].

The determination of the inhibition of PAF (platelet-activating factor)-induced platelet aggregation has been proposed as a biological standardization method for commercially available Ginkgo biloba extracts by measuring the characteristic pharmacological effect of ginkgolides in vitro. The determination is specific for ginkgolides A, B, C, and J and is not influenced by other constituents present in Ginkgo biloba extracts. IC50 values of ginkgolide B can be used to standardize various Ginkgo extracts produced by special extraction methods with respect to equi-effective ginkgolide B contents. In order to compare values obtained by a chemical-analytical procedure with those obtained by the biological assay, the equi-effective total ginkgolide content of each Ginkgo extract had to be calculated. Accordingly, the concentrations of the individual ginkgolides in the various Ginkgo extracts were determined chromatographically by assaying ginkgolides as trime-thylsilyl derivatives. Their individual contributions towards the measured in vitro effects were derived from their respective IC50 values. The calculated equi-effective total ginkgolide contents of the Ginkgo extracts were in good agreement with those obtained by gas chromatography. The results demonstrate that, in addition to a chemical standardization, the biological standardization of Ginkgo extract preparations is also feasible.

Lactones↗

PubMed1993

Tetragalloylquinic acid, the major antiasthmatic principle of Galphimia glauca.

In the search for antiasthmatic principles in plant drugs, a bioguided fractionation of an alcoholic extract of Galphimia glauca was performed using a plethysmographic in vivo model. Tetragalloylquinic acid (G1), which was found together with other compounds (gallic acid, methyl gallate, ellagic acid, and flavonoid acylglycosides), showed the highest activity against bronchial hyperreactivity and allergic reactions. Using mass and NMR spectroscopy in combination with energy calculations, the structure G1 was elucidated as tetra-O-galloylquinic acid. Depending on the solvent used, the quinic acid skeleton can occupy a fixed conformation or several interconverting ones on the NMR time scale.

Animals↗

PubMed1993

Induction of unresponsiveness to the superantigen staphylococcal enterotoxin B: cyclosporin A resistant split unresponsiveness unfolds in vivo without preceding clonal expansion.

The continuous presence of antigen and powerful immune responses (exhaustive cell proliferation) of ligand reactive T cells are currently thought to condition clonal deletion and/or induction of unresponsiveness to endogenous or exogenous superantigens (SAg). Here we report that in vivo induction of unresponsiveness to the SAg staphylococcal enterotoxin B (SEB) can be an immediate process. Within ours a large portion of ligand reactive V beta 8+ T cells becomes clonally deleted by apoptosis. In parallel, the remaining V beta 8+ T cells are unresponsive to SEB, yet at the same time express functional IL-2 receptors (IL-2R) and thus are highly responsive to the growth promoting effects of IL-2. In a subsequent step refractory IL-2R+V beta 8+ T cells undergo a wave of cell proliferation for 48 h, presumably driven by IL-2. Thereafter a large proportion of V beta 8+ T cells succumb to apoptosis, the remaining cells display the hallmarks of split unresponsiveness, i.e. they display a selective failure to produce IL-2 upon SEB stimulation in vitro combined with a preserved capability to express functional IL-2R. Early deletion and induction of unresponsiveness to SEB are cyclosporin A (CsA) resistant, while clonal expansion with subsequent cell deletion is blocked by CsA, yet the development of split unresponsiveness is not impaired by CsA. The results suggest that IL-2 driven growth of refractory T cells may mimic powerful immune responses of ligand reactive V beta 8+ T cells. Since unresponsiveness to SEB precedes in vivo expansion, the results as such question the concept of 'exhaustive cell proliferation' as a prerequisite for induction of unresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Evidence that functional deletion of donor-reactive T lymphocytes in kidney allograft recipients can occur at the level of cytotoxic T cells, IL-2-producing T cells, or both. A limiting dilution study.

The frequencies of circulating donor-reactive cytotoxic lymphocyte precursors (CLP) and Il-2-producing helper lymphocyte precursors (HLP) were determined by limiting dilution analysis in 19 kidney allograft recipients before and at various intervals (up to 2 years) after transplantation. A significant, selective, and stable reduction of the frequencies of donor-reactive (but not of third party-reactive) CLP and/or HLP was observed in some patients beginning 3 to 6 months after transplantation. One patient developed reduced frequency of CLP only, 3 patients reduced frequencies of HLP only, and 2 patients reduced frequencies of both CLP and HLP. The selective reduction of donor-reactive CLP and/or HLP frequencies ranged from 5-25-fold when compared with the pretransplantation level and was associated with stable graft function. These data indicate that functional deletion of circulating donor-reactive T cells can occur at the level of cytotoxic T lymphocytes, Il-2-producing helper T lymphocytes, or both. Implications of these findings for the individualization of immunosuppressive regimens will be discussed.

Humans↗

PubMed1993

Concurrent radiation therapy and chemotherapy for locally unresectable squamous cell head and neck cancer: an Eastern Cooperative Oncology Group pilot study.

PURPOSE: The feasibility and success of an intensive chemoradiotherapeutic protocol for patients with locally advanced, unresectable squamous cell head and neck cancer was tested in this limited-institution, Eastern Cooperative Oncology Group phase II pilot study. MATERIALS AND METHODS: Between December 1987 and September 1989, 57 patients were entered onto this trial. The treatment protocol consisted of three courses of a 4-day continuous fluorouracil infusion, a single cisplatin bolus injection, and concurrent split-course radiotherapy. After 30 Gy of radiation and two chemotherapy courses, patients were evaluated for response and for the possibility of surgical resection. RESULTS: Fifty-five of 57 registered patients are assessable for toxicity and 52 are assessable for response and survival. Toxicity was significant, but tolerable, although there were three toxic deaths. A complete response to this treatment was ultimately achieved by 77% of patients. Twenty-four patients remain relapse-free. The projected Kaplan-Meier 4-year relapse-free survival rate is 45% and the overall survival rate is 49%. Median relapse-free and overall survival durations are 26 and 37 months, respectively. Of the 28 treatment failures, 79% were locoregional. Fourteen patients underwent surgery. Six remain relapse-free. CONCLUSION: This aggressive concurrent chemoradiotherapy protocol appears feasible within a cooperative group. Treatment results are promising and appear durable. A randomized phase III clinical trial is currently underway.

Adult↗

PubMed1993

Alternating chemotherapy and twice-daily thoracic radiotherapy in limited-stage small-cell lung cancer: a pilot study of the Eastern Cooperative Oncology Group.

PURPOSE: This pilot study was undertaken to determine the efficacy and feasibility of alternating cisplatin and etoposide with multiple daily fractions of thoracic radiotherapy (TRT) in patients with limited-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS: Thirty-four SCLC patients received four courses of cisplatin (30 mg/m2/d x 3) plus etoposide (120 mg/m2/d x 3) (PE) every 3 weeks. TRT was administered twice daily (1.5 Gy per fraction) for 5 consecutive days in the week after cycles 1, 2, and 3 of chemotherapy (total TRT dose, 45 Gy). Patients who achieved a complete response (CR) received one course of late-intensification (LI) treatment consisting of cyclophosphamide (4 g/m2) and etoposide (900 mg/m2). Prophylactic cranial irradiation (PCI) was optional. RESULTS: Nineteen of 32 assessable patients achieved a CR (59%) and 12 had a partial response (38%), for an overall response rate of 97% (95% confidence interval [CI], 84% to 99%). Median survival was 18 months, while 2-year progression-free survival was 47%. Leukopenia < or = 1,000/microL occurred in 12% of induction treatment cycles. Severe esophagitis was uncommon. Pulmonary fibrosis that was asymptomatic or minimally symptomatic was observed in eight patients (25%). There was one episode of adult respiratory distress syndrome (ARDS) during LI chemotherapy. Life-threatening neutropenia (< or = 500/microL) developed in all patients who underwent LI chemotherapy, with a median duration of 10 days (range, 8 to 19). Two patients died of sepsis during LI chemotherapy. CONCLUSION: Alternating PE and TRT as performed in this trial is an effective brief induction regimen for limited-stage SCLC. However, this particular regimen did not appear to be substantially different in terms of efficacy or toxicity compared with regimens using concurrent chemotherapy and standard-fraction TRT. LI chemotherapy was associated with unacceptable toxicity and did not appear to have a favorable impact on survival.

Aged↗

PubMed1993

Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin's lymphoma.

PURPOSE: To determine the toxicity, response, and survival rate of orally administered combination chemotherapy in patients with AIDS-related intermediate- and high-grade non-Hodgkin's lymphoma. Secondary objectives included prospective quality-of-life assessment and quantitation of cell-associated p24 antigen (p24 Ag) by flow cytometry. PATIENTS AND METHODS: Eighteen patients with biopsy-proven lymphoma were treated with oral chemotherapy consisting of lomustine (CCNU) 100 mg/m2 on day 1, etoposide 200 mg/m2 on days 1 through 3; cyclophosphamide 100 mg/m2 on days 22 through 31, and procarbazine 100 mg/m2 on days 22 through 31 at 6-week intervals. A variety of clinical assessments were performed: prospective quality-of-life assessment using the Functional Living Index-Cancer (FLIC) and Brief Symptom Inventory (BSI) instruments; indirect immunofluorescence with flow cytometry to measure cell-associated p24 antigen; and price of the oral regimen compared with two other intravenous combination chemotherapy regimens. RESULTS: The overall objective response rate using Eastern Cooperative Oncology Group (ECOG) criteria was 61% (95% confidence interval, 39% to 84%), with seven complete remissions (39%) and four partial remissions (22%). The median survival duration was 7 months, with a range of 11 days to 36 months. The treatment-related mortality rate was 11%. One patient developed CNS progression. Myelosuppression was the most frequent and severe toxicity encountered. Predictor variables of performance status (PS), prior history of thrush, and CD4 lymphocyte count were found to be of prognostic value. In a separate analysis, scores on the three subscales of the BSI were also found to be predictive of complete response. The price of this regimen is several thousand dollars less than that of other intravenous combination chemotherapy regimens. CONCLUSION: This regimen is active in patients with AIDS-related non-Hodgkin's lymphoma. Because it is important to design systemic cytotoxic chemotherapy regimens that are cost-effective, considerate of quality-of-life issues, and efficacious in this patient population, this approach should be compared with standard intravenous combination chemotherapy regimens in randomized controlled clinical trials.

Adult↗

PubMed1993

In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1-infected patients.

Several mutations are associated with resistance to zidovudine (3'-azido-3'-deoxythymidine, AZT) in cultured human immunodeficiency virus type 1 (HIV-1) isolates. Little is known as to what extent drug resistance occurs in vivo and whether its development within the CNS differs from that in peripheral blood. We therefore performed comparative nucleotide sequence analysis of the HIV-1 reverse transcriptase (RT) gene in proviral DNA obtained from blood and CSF of three patients, all of whom had progressed to AIDS under long-term zidovudine treatment. Six to 11 individual proviral copies per patient and compartment were analyzed by polymerase chain reaction (PCR)-mediated direct sequencing. In all samples, mutations associated with zidovudine resistance could be identified. They occurred in multiple HIV-1 copies in both blood and CSF, indicating that molecular determinants of resistance are reflected in most individual proviruses in vivo. Comparable positions and frequencies of mutations in isolates derived from both compartments do not argue for independent development of zidovudine resistance in CSF.

Acquired Immunodeficiency Syndrome↗

PubMed1993

[Teratoma of the umbilical cord. Case report with literature review].

A rare case of teratoma of the umbilical cord is reported. It is differentiated from acardius amorphus and compared with the nine cases reported in the literature since the first description in 1878. The clinical consequences for pregnancy of the tumour's influence on the circulation are discussed. For the first time, non-radioactive in situ hybridization of the interphase nucleus was performed in a teratoma of the umbilical cord. The results are presented and different histogenetic pathways, e.g. parthenogenetic origin of the teratoma, are debated.

Cell Transformation, Neoplastic↗