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Biomedical subjects

U Bicker

Publications and source records attributed to U Bicker.

At least 19 recordsLinked to original sources
PubMed1990

In vivo antitumor activity of ilmofosine.

Ilmofosine is a cytostatic/cytotoxic thioether phospholipid derivative. The in vivo anti-tumour activity of this compound was investigated in a methylcholanthrene (MethA)-induced fibrosarcoma and in the 3Lewis-lung carcinoma systems, respectively. Ilmofosine showed antineoplastic and antimetastatic properties at oral doses ranging from 0.625 to 40 mg/kg/day. Combination of Ilmofosine (p.o.) together with either cyclophosphamide (p.o.) or cis-DDP (i.v.) resulted in synergistic effects in vivo. These results demonstrate the in vivo antitumour activity of Ilmofosine in two tumour systems. The data indicate that direct cytostatic/cytotoxic effects of Ilmofosine are mainly responsible for its antitumour activity in vivo and which are increased by other cytotoxics.

Animals↗
PubMed1990

Drugs in autoimmune diseases.

Autoimmune diseases arise when autoimmunity or the loss of self tolerance results in tissue damages. Many mechanisms have been proposed for the origin of autoimmunity, including immunologic, viral, hormonal and genetic factors. All known parts of the immunological network are involved in causing immunopathologic symptoms. Therefore, more or less specific immunosuppressants are widely used in the treatment of autoimmune disorders which range from organ-specific, i.e. Hashimoto's thyroiditis, to non-organ-specific or systemic diseases, i.e. systemic lupus erythematosus. Unspecifically acting cytostatics do not only suppress autoimmune reactions but also create severe side-effects due to the impairment of immune responses against foreign antigens, leading, for example, to an increased risk of infections. Moreover, the genotoxic activity of cytostatics might induce malignancies. Corticosteroids are clinically well known and very active agents for the management of acute symptoms but different side-effects limit their use in the treatment of chronic diseases. Cyclosporin A has been an important step forward to a more specific prevention of organ transplant rejections and to the therapy of some autoimmune disorders. Modern approaches to immunosuppression include monoclonal antibodies directed against a variety of different determinants on immunocompetent cells. Ciamexone and Leflunomide which are in early clinical and preclinical development, respectively, might be interesting new drugs. Future immunopharmacologic drug research and development should lead to more specific, low molecular weight, orally active and chemically defined immunosuppressive compounds with good tolerability under long-term treatment of autoimmune diseases.

Adrenal Cortex Hormones↗
PubMed1987

Antineoplastic activity of the thioether lysophospholipid derivative BM 41.440 in vitro.

Thioether lysophospholipid derivatives (TLP) inhibited the in vitro uptake of [3H]thymidine into blasts of eight leukemias and cells of 12 different solid tumors of human origin. This effect correlated with trypan blue dye exclusion, which was used to assess cell damage. Cytostatic and cytotoxic effects of TLP were dependent on dosage and incubation time. Destruction of leukemic blasts was completed with greater than 5 micrograms/ml after an incubation of greater than 48 hr, but 10 to 20 micrograms/ml were necessary in solid tumors. Ester-linked 2-lysophosphatidylcholine was ineffective in the same dose range, which points to the requirement of the alkyl moiety in sn-1 and a stable sn-2 substitution of the molecule for the antineoplastic effect. To assess putative antileukemic selectivity, the cytotoxicity (trypan blue dye exclusion) of TLP was compared in human cell samples of 19 non-neoplastic bone marrows and 9 leukemias. Results revealed a significantly higher activity of the TLP BM 41.440 in leukemic blasts.

Antineoplastic Agents↗
PubMed1987

Synthesis of thioether phosphocholine analogues.

The synthesis of thioether phospholipids, which represent a new class of antitumor agents, is reported here. In particular, the route of synthesis of 3-hexadecylmercapto-2-methoxymethylpropyl-2'-trimethylammoni o-ethyl phosphate (BM 41.440, Ilmofosine), one of the most potent cytostatic/cytotoxic derivatives, is described in detail. Starting with diethyl bis-hydroxymethylmalonate, ethyl 2-phenyl-1,3-dioxane-5-carboxylate is formed via diethyl 2-phenyl-1,3-dioxane-5,5-dicarboxylate and 5-ethoxycar-bonyl-2-phenyl-1,3-dioxane-5-carboxylic acid. Reduction of ethyl 2-phenyl-1,3-dioxane-5-carboxylate with LiAlH4 affords 5-hydroxymethyl-2-phenyl-1,3-dioxane. Alkylation with dimethyl sulfate gives 5-methoxymethyl-2-phenyl-1,3-dioxane. The ring structure then is opened by N-bromosuccinimide, resulting in the formation of 3-bromo-2-methoxymethylproply benzoate. Reaction of 3-bromo-2-methoxymethylpropyl benzoate with the sodium salt of hexadecanethiol leads to 3-hexadecylmercapto-2-methoxy-methylpropanol, which is reacted with a cyclic chlorophosphate to give the corresponding phosphorylated 3-hexadecylmercapto-2-methoxymethylpropanol. Treatment with trimethylamine yields BM 41.440. This compound already has been tested in clinical phase I/II trials in West Germany.

Antineoplastic Agents↗
PubMed1987

Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats.

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a cytotoxic thioether phospholipid analogue that recently has entered phase I trials in cancer patients. The objective of this study was to evaluate the pharmacokinetics of this compound in female rats after administration of a single oral dose (15 mg/kg body weight [bw] ). Furthermore, BM 41.440 serum concentrations were determined under a daily oral treatment of up to 13 weeks. Blood samples were obtained via permanent catheters from the femoral arteries before and after drug administration for a total of 120 hr. Urine was collected in 24 hr-intervals for 120 hr; the volume was measured, and aliquots were stored at -20 C until analytical determination of the thioether derivative. BM 41.440 was assayed in serum and urine by means of a specific, newly developed reverse-phase high pressure liquid chromatography technique. Mean maximum serum concentrations (1.7 micrograms/ml, n = 4 animals) were attained after seven hr. A terminal half-life of ca. 27 hr was calculated from the rate constant for the terminal elimination phase (lambda z approximately 0.026/hr). The mean serum BM 41.440 concentration-time-area-under-the-curve was 52.9 mg X hr/l. The ratio of total body clearance to absorption fraction was 4.7 ml/min X kg bw. Only a small amount of the drug was found in the urine. The quantity excreted in the urine during a 24 hr-interval never exceeded 1.5% of the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Phase I trial of the thioether phospholipid analogue BM 41.440 in cancer patients.

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a new thioether phospholipid, which has been shown to possess antineoplastic, antimetastatic, anti-invasive and immunomodulating properties in several tumor models. The mechanism whereby this compound exerts its direct antineoplastic effect is thought to be related to specific interference with the normal phospholipid metabolism, preferentially of neoplastic cells. BM 41.440 was evaluated in a multicenter phase I study in patients (pts) with refractory cancers. In phase I A, 34 pts were orally treated with doses ranging from 0.5 to 7.0 mg/kg body weight (bw). Three different formulations were tested. The maximum-tolerated dose (MTD) was ca. 5 mg/kg bw. The limiting side effects were nausea and vomiting. There was no evidence for systemic toxicities like myelosuppression, nephro-, neuro-, hepatotoxicity or hematological side effects. The current phase I B is designed to determine the MTD of BM 41.440 administered orally on a daily schedule for at least eight weeks. So far, 19 pts have entered this trial at dose levels ranging from 1.0 to 5.0 mg/kg bw/day. Some pts receiving 1.0 and 2.5 mg/kg bw/day, respectively, have been treated, up to now, for more than nine months. Clinical progress was followed with at-least-weekly blood counts, chemistry profiles, urine analysis, liver function tests and recordings of side effects. Tumor parameters were evaluated at eight-week intervals. In parallel, pharmacokinetic investigations were performed in some pts in phase I A and IB. First results on tolerability and therapeutic efficacy of the long-term BM 41.440 treatment are reported in this intermediate evaluation.

Administration, Oral↗
PubMed1987

Different effect of two immunomodulating agents cyclosporin A and ciamexon on the insulin metabolism of cultured mouse islets.

Ciamexon is a new immunomodulating agent with promising effects in treatment of newly-diagnosed insulin dependent diabetic patients. Ciamexon seems to have fewer adverse toxic properties than Cyclosporin A. Therefore, the effects of both substances on islet cell function were studied. Collagenase-isolated mouse islets were cultured free-floating for 3 or 7 days in medium RPMI 1640 plus 10% fetal calf serum in the presence of Cyclosporin A or Ciamexon (0.1 microgram/ml, 1 microgram/ml). Culture of the islets in the presence of 0.1 microgram/ml Ciamexon neither reduced the number of viable islets nor impaired insulin secretion as was found in Cyclosporin A. These results should be taken into account when treating early Type 1 diabetes or when transplanting islet cells.

Adjuvants, Immunologic↗
PubMed1987

Ciamexon in the low dose streptozotocin induced diabetes of mice.

This article is concerned with suppression of the development of diabetes experimentally induced by multiple injections of subdiabetogenic doses of streptozotocin (4 x 45 mg/kg/d) in mice (CD 1 and C57B16). Streptozotocin injections were followed by hyperglycemia and mononuclear cell infiltration of islets (insulitis). Ciamexon is a new immuno-modulating agent with promising effects in experimental models of autoimmune diseases and practically no toxic side effects. When Ciamexon was given before streptozotocin treatment blood glucose levels in the parenteral glucose tolerance test were suppressed in a dose dependent way. 60 days after streptozotocin application the percentage of islets showing insulitis or even necrosis was reduced in the Ciamexon treated group compared to the streptozotocin only group. In contrast, Cyclosporin A had a detrimental effect on diabetes in this model although blood levels were proved to be in the therapeutic range. From these results we conclude that Ciamexon should be tested for its effect in human type I diabetes.

Adjuvants, Immunologic↗
PubMed1987

BM 41.440: a new antineoplastic, antimetastatic, and immune-stimulating drug.

Alkyllysophospholipids are analogs of the cell membrane component lysophosphocholine. The thioether lysophospholipid BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is already in use in phase I and II trials in human cancer therapy. A direct antitumor effect of this new compound has been shown in vitro using 35 different cell types of murine and human origin. All normal cells investigated were not affected in the concentration range (1-10 micrograms/ml) that was cytotoxic for most tumor cells studied. In vivo, antimalignant and antimetastatic actions have been documented in the Meth A sarcoma, L1210 leukemia, B 16 melanoma and the 3Lewis-lung carcinoma tumor models, respectively. Murine, bone marrow-derived macrophages (M phi), preincubated with BM 41.440, showed an increased cytotoxicity in vitro. Addition of syngeneic spleen cells and low doses of BM 41.440 to this system enhanced tumor cell destruction 20- to 100-fold compared to controls dependent on the target cells used (YAC, ABLS-8.1, L1210, and P815). In vivo, Meth A sarcoma growth was dose and time dependently reduced in CB6F1 mice under therapeutic IV application of BM 41.440-activated M phi. The mean survival time of DBA mice, treated once IP with BM 41.440 4 days before L1210 challenge, increased from 24 to 38 days.

Alkaline Phosphatase↗
PubMed1986

Ciamexone, a highly selective immunomodulator--a tool for autoimmune diseases?

Both organ-specific diseases such as insulin dependent diabetes mellitus as well as non organ-specific disorders such as rheumatoid arthritis are thought to be autoimmune in origin. Both T-cell and B-cell mediated immune responses are involved in these diseases. More or less specific immunosuppressants are therefore widely used drugs in the treatment of autoimmune diseases which, however, suppress the immune reactions not only against autoantigens but also against foreign antigens. Cyclosporine (Cyclosporin A) has been a tremendous step forward in a more specific direction but it creates problems in the long term treatment of autoimmune diseases due to the impairment of immune reactions against foreign antigens as well as to compound specific side effects. Ciamexone, a new highly selective immunomodulator, might be an interesting new approach in the treatment of autoimmune diseases. The compound has had effect in different experimental autoimmune situations such as the diabetic BB-rat and experimentally-induced arthritis in mice or rats. The compound does not show antiproliferative activity on T-lymphocytes or B-lymphocytes. The immune response against foreign antigens, e.g. foreign major histocompatibility complex, viral or fungal antigens is not impaired. On the other hand, however, Ciamexone suppresses the antibody production in different animal systems. It is likely that Ciamexone exhibits its immunosuppressive property via the induction of regulating mechanisms. Due to its remarkably good tolerance, Ciamexone has been used in first pilot trials in different human autoimmune situations such as rheumatoid arthritis and insulin dependent diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Formation↗
PubMed1986

Suppression of spontaneous insulin-dependent diabetes in BB rats by administration of ciamexone.

BB rats spontaneously develop an insulin dependent diabetes which resembles in many features human type I diabetes. We have tested the effect of the immunomodulatory drug Ciamexone, a 2-cyan-aziridine-derivative, on the development of diabetes in BB rats. Ciamexone was given once daily during 6 days per week beginning with the age of 42 or 50 days up to 120 days. For comparison cyclosporin A (10 mg/kg) was applied following the same protocol. At 1 mg/kg ciamexone administration led to complete prevention of diabetes in females but was not beneficial in males. At 10 mg/kg the drug caused significant suppression of diabetes development in males but more pronounced in females. Both, a reduction of the incidence of diabetes and a delay in the onset of hyperglycaemia was observed only in females. After administration of cyclosporin A none of the animals developed diabetes. Ciamexone treatment did not affect granulocyte and lymphocyte counts and subsets in the peripheral blood except for a tendency to suppress eosinophilia. The growth of animals was not retarded. It is concluded that ciamexone seems to influence the autoimmune state of the BB rat resulting in partial suppression of the disease.

Aging↗
PubMed1985

Ciamexone--a new highly selective immunosuppressive compound.

A local graft versus host reaction between lymphocytes of Balb-c mice and its F-1-generation CB6F1 can be induced because of differences in products of the class II of the major histocompatibility complex (Ir). In this local mixed lymphocyte reaction mainly T-helper cells and B-cells are involved. An induction of a delayed type hypersensitivity reaction with oxazolon significantly decreases the local graft versus host reaction. Cyclosporin A depresses the local graft versus host reaction and the delayed type hypersensitivity in mice whereas Ciamexone, a 2-cyanaziridine derivative, very selectively only suppresses the local graft versus host reaction and increases the delayed type hypersensitivity.

Animals↗