PubMed Health⌕ Search

Biomedical subjects

G Dickneite

Publications and source records attributed to G Dickneite.

53 records · Page 3Linked to original sources
PubMed1986

Chemotherapeutics: a questionable or a promising project.

While repository adjuvants are already established drugs for antigen specific immunomodulation, no unspecific active immunomodulator has successfully passed clinical trials in tumor patients in Western countries yet. As this is in striking contrast to the effects seen with unspecific immunomodulators in experimental immunological and tumor test systems, the value of those screening models to predict clinical success may be asked for. To improve the success rate, it is recommended to test compounds for their immunomodulatory effects as broad as possible in ex vivo and in vivo test systems. Subsequently, the prophylactic as well as therapeutic potency of selected immunomodulating drugs should be evaluated in various models of aptitude, such as chronic infection, autoimmune diseases and chronic inflammatory reactions. Those diseases are at least to a certain extent influenced by the immune system, in contrast to the uncertainty in case of tumor diseases. In a battery of chronic infection models we could find that different chemoimmunotherapeutics with very similar immunopharmacological activity behaved quite different. Most compounds were ineffective, a part enhanced chronic diseases and only in a few cases a therapeutic effect could be shown. On the other hand, effectivity in protection against the pathogenicity of subsequently applied, selected microorganisms does not predict the therapeutic potency for the same pathogen. Altogether the data show that activation of cells of the immune system by an immunostimulating drug does not predict its therapeutic potency. Moreover, activation of immune cells may also impair the immune resistance.

Adjuvants, Immunologic↗
PubMed1986

The influence of (+/-)-15-deoxyspergualin on experimental transplantation and its immunopharmacological mode of action.

15-Deoxyspergualin, a novel structure which was described to have anti-tumor activity, was tested on its influence on the survival time of transplanted organs. Prolongation of graft survival was demonstrated in rat skin (LEW----Fischer), islet cells heart and kidney transplantation (DA----LEW) as well as in allogeneic tumor transplantation in mice (C57Bl/6----Balb/c). Especially in the kidney transplantation a long-lasting transplant survival time was observed, indicating induction of tolerance. Examination of its immunopharmacological properties showed that the mononuclear phagocytes and not the lymphocytes are primarily affected by the substance, thus expressing a new mode of action for a substance being effective in transplantation immunology.

Animals↗
PubMed1986

Screening for chemoimmunotherapeutics, success rate and predictivity of models: a five years experience.

While repository adjuvants are already established drugs for antigen specific immunomodulation, no unspecific active immunomodulator has successfully passed clinical trials in tumor patients in western countries yet. As this is in striking contrast to the effects seen with unspecific immunomodulators in experimental immunological and tumor test systems, the value of those screening models to predict clinical success may be asked for. To improve the success rate, it is recommended to test compounds for their immunomodulatory effects as broad as possible in ex vivo and in vivo test systems. Subsequently, the prophylactic as well as therapeutic potency of selected immunomodulating drugs should be evaluated in various models of aptitude, such as chronic infection, autoimmune diseases and chronic inflammatory reactions. Those diseases are at least to a certain extent influenced by the immune system, in contrast to the uncertainty in case of tumor diseases. In a battery of chronic infection models we could find that different chemoimmunotherapeutics with very similar immunopharmacological activity behaved quite differently. Most compounds were ineffective, a part enhanced chronic diseases and only in a few cases a therapeutic effect could be shown. On the other hand, effectivity in protection against the pathogenicity of subsequently applied, selected microorganisms does not predict the therapeutic potency for the same pathogen. Altogether the data show that activation of cells of the immune system by an immunostimulating drug does not predict its therapeutic potency. Moreover, activation of immune cells may also lead to impairness of the immune resistance.

Animals↗
PubMed1985

Tumor growth and metastasis increases the serum concentration of basement membrane proteins.

Serum concentrations of two basement membrane proteins, laminin and collagen type IV, were studied in three spontaneously metastasising experimental tumors: 3LL Lewis Lung and B16 melanoma of the mouse and R3230 adenocarcinoma of the rat. In the Lewis Lung tumor the mass of the primary tumor or the degree of metastasis correlated well with the concentration of serum laminin. In B16 melanoma the level of serum laminin was only significantly raised when the tumor had metastasised to the lung. No correlation between tumor mass and serum laminin was found in the R3230 adenocarcinoma. The serum concentrations of collagen IV, however, were raised to a certain extent during primary tumor growth and metastasis. Immunofluorescent staining for laminin in the Lewis Lung tumor demonstrated positive reactions in the primary tumor and in metastases of the lung. The data indicate the possibility of using similar tests for clinical tumor diagnosis.

Adenocarcinoma↗
PubMed1984

The influence of Aclacinomycin A on the immune response and on experimental immune disorders.

The anti-cancer drug Aclacinomycin A (ACM) was able to inhibit the humoral immune response of mice against sheep red blood cells. This could be demonstrated in the formation of antibody secreting cells (PFC) and serum antibody titers, when ACM was administered either together with the antigen or three days after antigen application. Cellular immunity was not affected by the drug. In two murine Graft-vs-Host (GvH) disease models leading to two different B cell dependent auto-immune diseases (immune complex glomerulonephritis and immune hemolytic anemia) a protective effect of ACM was observed when it was administered at the time of the graft. The application of ACM in the induction phase mitigated the development of glomerulonephritis and prevented animals from dying due to hemolytic anemia. Only a slight therapeutical effect was observed when ACM was given after the appearance of clinical symptoms. In a T cell induced auto-immune disease (experimental allergic encephalomyelitis (EAE], ACM had no discernible effect on the course of the disease. It seems that the therapeutic effects of ACM on GvH-diseases are mediated via suppression of B-lymphocytes.

Aclarubicin↗
PubMed1984

Stimulation of cell-mediated immunity by bestatin correlates with reduction of bacterial persistence in experimental chronic Salmonella typhimurium infection.

The effect of bestatin, a low-molecular-weight immunomodulating drug isolated from Streptomyces olivoreticuli, on Salmonella typhimurium infection was elaborated. Bestatin enhanced the delayed-type hypersensitivity reaction against S. typhimurium in a dose- and time-dependent manner. Parallel to the activation of delayed-type hypersensitivity reaction, bestatin reduced the amount of persistent bacteria in livers and spleens as well as the amount of necrotic foci found in these organs. This was shown when bestatin was given either prophylactically or therapeutically. The therapeutic effect of bestatin was even seen when the drug was given in the chronic phase of the infection, i.e., 6 days after inoculation of the animals with the infectious agent. No influence of bestatin, however, could be observed on the initial multiplication rate of S. typhimurium and concomitantly on the initial mortality rate of the infected mice. As bestatin has no direct antibiotic effect on S. typhimurium, it must be concluded that the therapeutic effects of the drug on chronic infection must be solely contributed to elevation of the host's own defense mechanisms.

Abscess↗
PubMed1984

Cefodizime, an aminothiazolyl cephalosporin. IV. Influence on the immune system.

Studies concerning the activity of cefodizime (HR 221), on certain aspects of the immune response, were conducted. It was found that lymphocytes from Balb/c mice treated with 3 and 30 mg/kg/day of cefodizime display increased responsiveness to B-cell mitogens and specific antigens. Also, the amount of antigen specific antibody producing plaque forming cells was increased in these mice and was accompanied by a rise in the specific IgG haemagglutinin titer. These effects were not observed in lymphocytes obtained from NMRI mice that had been treated with cefodizime. Peritoneal macrophages from NMRI mice, treated with cefodizime prior to harvesting of the cells, contained increased levels of lysosomal enzymes, developed enhanced chemiluminescent reaction to stimuli and showed elevated pinocytosis rates. Furthermore, NMRI mice treated with cefodizime during the immunization, developed enhanced DTH-reaction, when challenged with the antigen (SRBC). The prophylactic treatment of Balb/c mice with cefodizime (2 X 30 mg/kg/day ip for 4 days) significantly prolonged the mean survival time of the animals after intravenous infection with Candida albicans 200/175 (16.7 days as against 3.5 days in the case of the controls). This stimulatory effect of cefodizime on the host defence system was not observed for NMRI mice. Treatment with latamoxef or cefoperazone under the same experimental conditions did not reduce the susceptibility of mice to C. albicans. The protective activity of cefodizime against C. albicans in Balb/c mice, may be due to the immuno-stimulatory activity of this agent.

Animals↗
PubMed1984

Immunosuppression as a desired pharmacological effect.

The immunosuppressive efficacy of the antineoplastic antibiotic Aclacinomycin A (ACM) was assayed in several test models for humoral and cellular immune response. Humoral immune response, measured as splenic plaque forming cells (PFC) in vitro and in vivo was markedly inhibited by ACM. Suppression of PFC in vivo could be observed when ACM was administered together with the antigen, or three days later. Concomitantly a decrease of circulating antibodies to SRBC was obtained. No effect on T-cell mediated immune response - DTH reaction and allogeneic cytotoxic lymphocytes - or on skin transplantation or a T-cell mediated autoimmune disease, EAE, was observed. ACM beneficially influenced the course of the disease in two GvH-models (hemolytic anemia and immune complex glomerulonephritis) which lead to a B-cell mediated autoimmune disease with fatal outcome. It was concluded that the therapeutic effect of ACM on GvH-disease is mediated via its suppression of the B-cell response.

Aclarubicin↗
PubMed1984

Studies on the mechanisms of action of the immunomodulator Bestatin in various screening test systems.

The effects of Bestatin, a low molecular weight metabolite of Streptomyces olivoreticuli on the human and mouse/rat immune system, have been studied in detail. To describe the activity of the immunomodulating dipeptide, it has been tested in vitro, ex vivo and in vivo in various experimental models. Bestatin simultaneously applied with selected antigens to mice was able to enhance the DTH response against a challenge injection of the respective antigen given into the footpad. Serum antibody levels against those antigens were uneffected. However, an increase of PFC could be found in those mice given high doses of Bestatin. On natural killer cell activity against Yac-1 tumor cells the dipeptide had no effect in low responder (DBA2/J) mice. In high responder mice (CBA/JCr), however, a significant increase of NK cell activity of spleen cells could be found, when the drug was given on day 0 or on days 0 to 3 and the test was performed on day 4. Bestatin had no effect on the generation of allogeneic cytotoxic T-lymphocytes in vivo or in vitro and even a suppressive effect on the induction of syngeneic antitumor CTL. Contrary to this suppressive effect, Bestatin increases in the popliteal lymph node assay the weights in a dose-dependent way. When mouse macrophages or human monocytes were either incubated in vitro with Bestatin or mice were treated with the dipeptide parenterally or orally and the macrophages from those mice were investigated, Bestatin induced in vitro and in vivo a dose-dependent increase in pinocytic uptake of radioactive colloidal gold. Also the oxidative metabolism was dose-dependently augmented as measured by chemiluminescence. Bestatin modulates the macrophage mediated cytotoxicity. In vitro or in vivo activated mononuclear phagocytes exhibited a dose-dependent increase in cytotoxic activity for several tumor target cells. A minimum ratio of 50:1 effector to target cells was necessary for this cytotoxic effect. A similar degree of activation was observed in macrophages from athymic nu/nu-mice or from endotoxin resistant C3H/HeJ-mice. Other parameters of macrophage activation were determined by measuring secretion of lysosomal enzymes and liberation of prostaglandins. Bestatin interacts with macrophages in vivo and in vitro by increasing their secretory activity of acid hydrolases (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-D-glucosaminidase). This release was dose- and time-dependent and not associated with any sign of cell death. Another class of mediators produced by macrophages after stimulation with Bestatin were the prostaglandins E2 and F2a.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗
PubMed1984

Chronic bacterial infection models for BRM screening.

Models of chronic infections have been established to test the therapeutic and prophylactic potency of biological response modifiers (BRM). As an example for a BRM the immunostimulating drug Bestatin was tested. It is of dipeptide nature and was purified from culture supernatants of Streptomyces olivoreticuli. In two chronic bacterial infection models, induced by the inoculation of NRMI mice with Salmonella typhimurium or with a nephropathogenic strain of Escherichia coli, Bestatin acted prophylactically as well as therapeutically. This could be seen from the reduction of bacterial organ colonization and the inhibition of organ lesion formation. Bestatin could be shown to stimulate macrophage activity and to potentiate delayed type hypersensitivity, but not be effective on the humoral immune response.

Adjuvants, Immunologic↗
PubMedDate not supplied

Influence of recombinant hirudin on tissue-factor-induced activation of coagulation in rabbits.

Uncontrolled activation of the tissue-factor (TF)-dependent extrinsic pathway of coagulation can lead to severe impairment of the hemostatic balance. AS thrombin plays the central role in the initiation of clotting, we used the highly specific thrombin inhibitor recombinant hirudin to prevent TF-induced coagulation activation in a rabbit model. Infusion of 0.5 micrograms.kg-1.h-1 TF in rabbits for 7 h led to a decrease in fibrinogen and platelets, to an increase in fibrin monomers and to a prolongation of TT, aPTT and PT. Recombinant hirudin was administered in doses of 0.5, 1 and 2 mg.kg-1 body weight (intravenous bolus), the protocol included a pre-TF (recombinant hirudin given at t = 0) and a post-TF study group (recombinant hirudin given at t = 2 h after the start of the TF infusion). Fibrinogen plasma levels, platelet counts and recombinant hirudin plasma levels were measured at baseline (t = 0) at 0.5, 1, 2, 3, 4, 5, 6, and 7 h; the deceleration rate of fibrinogen and platelets per hour was calculated for the control and the recombinant-hirudin-treated groups. The deceleration rate for fibrinogen in the TF group was -0.227 g.l-1.h-1 and was reduced by recombinant hirudin to -0.119, -0.116 and -0.095 g.1-1.h-1 for 0.5, 1 or 2 mg.kg-1, respectively (significant differences to control group, Jonckheere-Terpstra test). The inhibitor similarly prevented the decrease of platelets dose-dependently. Recombinant hirudin was cleared from plasma with a terminal half-life of about 100 min; however, even after its clearance from plasma, recombinant hirudin significantly prevented the fibrinogen and platelet drop. Recombinant hirudin was effective when given in the pre-TF as well as in the post-TF phase.

Animals↗
PubMedDate not supplied

Prevention of gynaecological adhesions using haemostatic fleece in a rabbit model.

This pre-clinical study was performed to investigate the ability of the haemostatic fleece TachoComb to prevent adhesion formation following uterine surgery. Thirty rabbits were randomized to receive TachoComb or no intervention following incision to the right uterine horn. After 14 days, the animals were killed and examined for the presence of adhesion. The lengths of any adhesions were measured and the severity was recorded as a score (0, no adhesion; 1, adhesion easy to lyse; 2, adhesion lysed with traction; 3, adhesion separated by sharp dissection). The incidence of adhesions was 100% in the control group compared with 33% in the TachoComb-treated animals. The mean adhesion score was significantly lower (0.7 versus 2.2) and the mean adhesion length category was significantly shorter (0.4 versus 2.0) with TachoComb than in the control group. This study indicates that TachoComb is a well-tolerated and effective means of preventing adhesion following gynaecological surgery.

Animals↗
PubMedDate not supplied

Preparation and evaluation of PEG-bound thrombin inhibitors based on 4-amidinophenylalanine.

The dipeptide Mtr-Asp-D-Adf-Pip 10 represents a potent thrombin inhibitor. In comparison to NAPAP, 10 exhibited improved tolerability and a longer half-life in vivo, i.e., 20 +/- 5 min. We have coupled aminopolyethyleneglycolmonomethylether of various molecular weights to the carboxyl moiety of 10 and evaluated their biological properties. First, Mtr-Asp-OBut was coupled to the amino group of the PEG employing TOTU as an activating agent. This was followed by the removal of the OBut protecting group and coupling of D-Adf-Pip using TOTU as well. The PEG-bound thrombin inhibitors showed inhibition constants vs. thrombin in the subnanomolar range, i.e., they were more active than the parent molecule 10. Moreover, the pegylated inhibitors exhibited a longer lasting effect in vivo. In rats the half-life of Mtr-Asn (PEG10000-OMe)-D-Adf-Pip 14 was determined to be 63 min. Mtr-Asn(PEG10000-OMe)-D-Adf-Pip 14 showed a half-life of 120 min in pigs. It could be concluded that these PEG-bound thrombin inhibitors may be employed as versatile drugs for parenteral administration in treating thrombotic disorders.

Animals↗