Effects of in-vitro treatment of boar spermatozoa with TEPA on the fertilization and development of pig eggs.
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Animals↗
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Damage of DNA and its recovery in AH-109A cells treated with carboquone in vivo.
A single injection of carboquone at a dose of 0.1 mg/kg body weight induced damage of DNA of AH-109A cells as revealed by alkaline and neutral sucrose density gradient centrifugation. A significant decrease in the sedimentation velocity of DNA on alkaline sucrose density gradient centrifugation was observed 15 min after the injection, and it returned to that of control after 60 min. Thereafter, the size of DNA decreased progressively. When the cells were lysed with 2% sodium dodesyl sulfate solution and analyzed on neutral sucrose density gradient centrifugation, a similar change in the sedimentation velocity was observed. The results obtained from the studies of intraperitoneal growth of AH-109A cells pretreated with carboquone in vivo and the survival of host animals well corresponded to the extent of the damage of DNA as revealed by alkaline and neutral sucrose density gradient centrifugation.
Animals↗
Carboquone therapy for hematologic neoplasms.
A daily oral dose of 1-2 mg of Carboquone was administered for remission induction to 38 patients with hematologic malignancy, and the following results were obtained: 2 of the 3 patients with malignant lymphoma, 1 of the 12 patients with multiple myeloma, 13 of the 14 patients with chronic myelogenous leukemia, and all 9 patients with polycythemia vera attained complete remission.
Administration, Oral↗
A chlorodiazirine analog of pentamidine with anti-trypanosomal activity.
A chlorodiazirine derivative of pentamidine was synthesized and tested for anti-trypanosomal activity using EATRO stock 164 trypanosomes in cell culture. Anti-trypanosomal activity was measured as a decrease in [3H]hypoxanthine incorporation by the organisms. The derivative, 3,3'-[1,5-pentanediylbis(oxy-4,1-phenylene)]bis(3-chloro-3H-diazir ine), at a treatment level of 0.1 microM inhibited isotope incorporation by 40-50% compared to nontreated controls. At this concentration, pentamidine inhibited incorporation only 10-15%. The derivative is a nonionic molecule with much different solubility properties than the parent compound and should readily cross the blood-brain barrier.
Animals↗
Solid-liquid extraction and preconcentration of trace nickel using 2-nitroso-1-naphthol-4-sulfonic acid (Nitroso-S) and TDBA onto benzophenone and determination by atomic absorption spectrometry.
Nickel was quantitatively retained by 2-nitroso-1-naphthol-4-sulfonic acid (Nitroso-S) and tetradecyldimethylbenzylammonium chloride (TDBA Cl) onto benzophenone in the pH range 5.0-6.0 from large volumes of aqueous solutions of various samples. After filtration, each solid mass consisting of a nickel complex and benzophenone was dissolved with 5 ml of dimethylformamide (DMF) and the metal was determined by atomic absorption spectrometry (AAS). About 0.6 microg of nickel could be concentrated from 200 ml of an aqueous sample, where its concentration was as low as 3.0 ng/ml. Eight replicate determinations of 2.5 microg/ml of nickel in the final DMF solution gave a mean absorbance of 0.112 with a relative standard deviation of 1.9%. The sensitivity for 1% absorption was 98 ng/ml. The interference of a number of anions and cations was studied and the developed optimized conditions were utilized for the trace determination of nickel in various alloys and biological samples.
Alloys↗
1-Azaadamantanes: pharmacological applications and synthetic approaches.
1-Azaadamantane (1-azatricyclo [3.3.1.1(3,7)]decane) was synthesized in 1953, and the derivatives have been used as rigid models for studies on intramolecular charge transfer phenomena, fluorescence excitation Rydberg states, highly twisted amides, solid electrolyte gas sensors, basicities, and self-organization systems. These structures have also been attracting considerable interest due to their pharmacological activities. The substituted 1-azaadamantanes as conformationally restricted amines have great potential for the therapeutic utilization as anticholinergic agents, serotonergic agents, and squalene synthase inhibitors. However, many steps have been needed for the synthesis of 1-azaadamantanes, and the concise synthetic approaches have been developed. Though double or triple Mannich reactions yield 1-azaadamantanes in moderate yields, the reduction steps are necessary. Our recent research has revealed that trifluoromethanesulfonic anhydride is available for the convenient synthesis of 1-azoniaadamantanes and 1-azaadamantanes without reduction. The new tools for the discovery of novel drugs such as quantitative structure-activity relationship (QSAR) analysis and vibrational circular dichroism (VCD) spectroscopy have also been discussed.
Adamantane↗
The influence of diaziquone free radicals on the in vitro activity of diaziquone.
1. The influence of the free radical of diaziquone on inhibition of cell growth in vitro was studied using P388 murine leukaemia cells and a mixture of AZQH2 + AZQ. This mixture generates the AZQ free radical by the disproportionation-comproportionation reaction AZQH2 + AZQ in equilibrium with 2AZQH. 2. Reduced AZQ (AZQH2) was produced electrochemically under anaerobic conditions. This colourless solution was added anaerobically to a solution of AZQ at a 9:1 ratio of AZQH2 to AZQ. The free radical (AZQH) generated was detected by electron spin resonance (ESR) and amounted to about 7% of the concn of AZQH2 + AZQ. The AZQ free radical was stable enough to treat cells in culture. 3. Aerobic suspensions of P388 murine leukaemia cells treated with AZQH experienced a surge of free radicals lasting approx. 30 min at concn near 10 times that of the AZQ free radicals generated by P388 cells. 4. Cell growth inhibition indicates that the concentration of AZQ required to arrest the growth of P388 cells by 50% (IC50) is twice that of the AZQ free radical generating mixture. The mechanism of action of AZQ probably does not exclusively involve AZQ free radicals, but they appear to play an important role.
Animals↗
Molecular orbital calculations on tumour-inhibitory phenyl aziridines: QSARs.
1. Molecular orbital calculations, by the MINDO/3 method, on tumour-inhibitory phenyl aziridines are reported. 2. The generation of quantitative structure-activity relationships (QSARs) shows that biological activity, chemical reactivity and hydrophobicity can be explained in terms of theoretically-derived electronic structural parameters.
Antineoplastic Agents↗
The metabolism of biological alkylating agents.
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Acetylcysteine↗
The influence of ascorbic acid on the free-radical metabolism of xenobiotics: the example of diaziquone.
Diaziquone (AZQ) is a quinone-containing alkylating agent undergoing trials as an antitumor drug. The quinone moiety of this compound places it among a group of compounds whose activity is believed to be modulated by a redox cycle that activates the compounds to their free radicals (e.g., adriamycin). AZQ is unique among these compounds in that it can be reduced to its free radical (AZQH) by a variety of cells in culture, including human and murine cancer cells. Red blood cells (RBC) were also observed to reduce AZQ to its free radical. Using electron spin resonance (ESR), we observed that soon after the AZQ free radical appeared, it decayed and was replaced by a doublet with ESR parameters that suggested the presence of the ascorbyl radical (AH). The identity of AH was confirmed by adding exogenous ascorbic acid to AZQ free radicals generated by a suspension of L1210 murine leukemia cells. The endogenous ascorbic acid was shown to arise mostly from the "buffy coat" of an RBC preparation which contained leukocytes. Leukocytes are second only to the adrenals in level of ascorbic acid in humans. Cyclic voltammetry of ascorbic acid, AZQ, and adriamycin in Hank's Balanced Salt Solution (HBSS pH 7.5), the buffer used for biological measurements, showed that the oxidation peak potential for ascorbic acid (Eap = +0.43 V) is closer to the reduction peak potential for AZQ (Ecp = -0.36 V) than that for adriamycin (Ecp = -0.67 V). This may explain why the ascorbic acid redox system interacts with that of AZQ but not with that of ADR.
Animals↗
Treatment of metastatic breast cancer with AZQ: a phase II trial.
Seventeen patients with metastatic breast cancer who had failed prior chemotherapy were treated with intravenous AZQ at a dose of 15-20 mg/m2 weekly for four consecutive weeks followed by a two-week rest period. No responses were observed. Myelosuppression was the dose-limiting toxicity. One patient experienced massive liver infarction possibly related to AZQ. Our data suggest that this agent at the schedule and dosage used is of no benefit in pretreated breast cancer patients.
Antineoplastic Agents↗
The immunomodulatory effect on BM 12.531 (azimexon) on normal or tumored mice: in vitro and in vivo studies.
The effect of BM 12.531 (BM) treatment on normal or tumored mice was studied under both in vitro and in vivo experimental conditions. It was found that BM treatment of mice that received 500 R of whole body irradiation caused a highly significant (P < 0.001) increase in the prolongation of the mean survival time. BM was found to significantly increase (P < 0.01) the delayed-type hypersensitivity reaction of normal mice. BM treatment was found to moderately increase both in vivo and in vitro activated macrophages. However, BM was found to be extremely effective in significantly increasing the mean survival times of lung carcinoma-bearing or leukemic mice.
Animals↗
Effect of the immune modulators BM 12.531 (azimexone) and BM 41.332 on the subsets of T-lymphocytes in mice.
The immunomodulating 2-cyanaziridine derivatives BM 12.531 (azimexone) and BM 41.332 have no effects on the total amount of T-lymphocytes in the spleen of mice but increase dose-dependently the percentage of Ly1-, 2+, 3+ T-lymphocytes (killer/suppressor) and decrease the percentage of Ly1+, 2-, (helper) cells. These investigations were carried out by means of specific monoclonal antibodies and fluorescence-activated cell sorting. The increase in Ly2+-cells is mainly due to increased suppressor activity.
Adjuvants, Immunologic↗
Reduction of the immunosuppressive action of chemotherapeutics in patients with mammary carcinoma by Azimexon.
Patients treated by aggressive cytostatic treatment exhibit marked deficiencies in cell-mediated immunity. Our investigations were performed in order to find out whether these immunosuppressive effects could be diminished by supportive treatment with the new synthetic immunomodulating compound BM 12.531, INN: AZIMEXONE. After inducing remission in ten patients with metastasizing breast cancer by a combination chemotherapy given for about one year, leucocytes, T- and B-lymphocytes and reactivity of peripheral lymphocytes to different mitogens were determined at weekly intervals before (8 X), during (8 X while on 100 mg i.v. weekly, then 4 X while on 400 mg i.v. weekly) and after (4 X) treatment with AZIMEXONE. Chemotherapy-induced immunosuppression could be markedly diminished during the administration of AZIMEXONE. A significant increase in the peripheral leucocyte count and mitogen-induced lymphocyte transformation could be achieved without any marked influence on the percentages of T- and B-cells. No severe side-effects of AZIMEXONE were observed.
Aziridines↗
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↗
Modulation of myelopoiesis by CSF or CSF-inducing biological response modifiers.
We have compared the effects on number and function of bone marrow progenitors and peripheral effector cells of the myelomonocytic lineage of treatment with the 2-cyanaziridine compounds Azimexone and BM 41.332 to those of maleic anhydride divinyl ether copolymer (MVE-2) or granulocyte-macrophage colony stimulation factor (GM-CSF). Within a few hours after i.p. injection of either Azimexone or BM 41.332, there was a dose-dependent increase in serum CSF levels, CSF secretion by mononuclear bone marrow cells (BMC) and macrophages (M phi), which was followed by an increase in granulocyte-M phi committed stem cells (GM-CFU-C), nucleated BMC, and peripheral blood leukocytes. Optimal effects occurred 3 days after 50 mg/kg Azimexone or 25 mg/kg BM 41.332. Three i.p. injections of 50 mg/kg Azimexone into mice pretreated with cyclophosphamide (CY) (150 mg/kg) were able to significantly restore suppressed bone marrow cellularity (GM-CFU-C and nucleated BMC). Azimexone also increased the number of peripheral M phi in normal or CY-treated mice, without inducing detectable tumoricidal activity. These M phi, however, retained their capacity to become fully activated (cytotoxic) by appropriate activation signals such as IFN or LPS. Analogous to the 2-cyanaziridines. MVE-2 (at 25 mg/kg) had similar stimulatory effects on myeloid functions in normal mice. MVE-2 induced, in addition, a significant augmentation of cytoxicity by both M phi and NK cells. In contrast, single or multiple injections of semipurified GM-CSF into normal mice (1000 U or 5000 U per mouse) failed to detectably stimulate myelopoietic growth and differentiation. 2-cyanaziridine compounds thus offer the potential of selectively augmenting growth and differentiation of myelomonocytic cells in normal and bone marrow-depressed mice without appreciably affecting their immunological status.
Adjuvants, Immunologic↗
The influence on the formation of unstable haemoglobin by the immunomodulating 2-cyanaziridines azimexone and BM 41.332 in mice.
Azimexone causes in mice the formation of unstable haemoglobins after a single dose of 20 mg/kg. BM 41.332, another immunomodulating drug of the 2-cyanaziridine class, induces these unstable haemoglobins only after a single oral administration of 500 mg/kg. Subsequently to the formation of unstable haemoglobins we observed a development of Heinz bodies. These effects of the 2-cyanaziridines were elicited neither by methaemoglobin formation nor by an impairment of the components protecting haemoglobin against oxidation (G6PD, catalase, glutathione). The elimination of the altered haemoglobin in the spleen could be followed by measurement of the rise in the iron content of the spleen.
Adjuvants, Immunologic↗
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↗