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At least 181 records · Page 10Linked to original sources
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↗
PubMed1984

Kinetics of irreversible inhibition of choline transport in synaptosomes by ethylcholine mustard aziridinium.

Ethylcholine mustard aziridinium (ECMA) inhibits choline transport in synaptosomes at a half-maximal concentration of about 20 microM. The rate of inhibition falls off rapidly after 10 min and the concentration dependency reaches a plateau at about 100 microM. The inhibition is not removed by washing the synaptosomes, and choline and hemicholinium-3 protect the carrier against attack by the mustard. Choline efflux, particularly that stimulated by choline in the medium (transactivation) is also inhibited by the aziridinium compound. Similarly choline influx activated by preloaded internal choline is inhibited by ECMA. The mustard can enter the synaptosomes in an active form but most of the carrier is alkylated when facing the outside. Prior depolarization of the synaptosomes causes an increase in the rate of inhibition by ECMA which is proportionally about the same as the increase in choline influx also caused by depolarization. At low ECMA concentrations the rate of inhibition is that of a first-order reaction with the carrier but at high ECMA concentrations the translocation of the carrier to the outward-facing conformation controls the rate of inhibition. Using a model of choline transport with some simplifying assumptions it is possible to estimate the amount of carrier; cholinergic synaptosomes carry about six times the concentration of carrier found in noncholinergic ones. In noncholinergic synaptosomes the carrier faces predominately out, the reverse in cholinergic ones. The rate constant of carrier translocation is increased by combination with choline some six- to sevenfold to about 3.5 min-1. The rate constant of ECMA attack on the carrier is about 440 M-1 sec-1.

Animals↗
PubMed1982

Effect of azimexon (BM 12.531) on mouse granulocyte-macrophage and monocyte-macrophage progenitor cells.

Treatment of mice with 25 mg/kg azimexon (BM 12.531) resulted in an increase ln granulocyte-macrophage colony-forming cells (GM-CFC) in spleen and bone marrow after a transient depression in the cell populations. Bone marrow monocyte-macrophage colony-forming cells (MM-CFC) increased at 7 days after treatment, and splenic MM CFC were least affected by azimexon treatment. The increase in granulocytic and monocytic colony-forming cells may play a role in the previously reported protection by azimexon against radiation and drug-induced toxicity.

Animals↗
PubMed1986

Response variability of human brain tumors to AZQ in tissue culture.

In a series of 28 glioma-derived cell cultures and 6 non-gliomatous CNS tumors, AZQ has been found to have varying degrees of growth inhibiting or cytotoxic activity in nearly all lines tested at doses greater than 100 mcg/ml. At dose levels comparable to the clinically achieved levels (1 mcg/ml), AZQ was found to have a cytotoxic effect in 8 of 28 glioma-derived and 2 of 6 non-gliomatous cell lines tested. These findings suggest that AZQ has activity against certain glioma-derived cells in culture at a response ratio similar to that seen in vivo. There, appear to be significant differences in the degree of responsiveness in different patients' tumor cells which can be detected in vitro prior to clinical treatment.

Antineoplastic Agents↗
PubMed1985

Phase II study of aziridinylbenzoquinone (AZQ) in patients with central nervous system malignancies: a Southwest Oncology Group Study.

AZQ, an alkylating agent with lipophilic characteristics allowing CNS penetration was studied in patients with primary CNS malignancies refractory to surgical and radiotherapeutic modalities. Responses were evaluated by three criteria: neurologic examination, performance status and CT scan of the brain. Improvement in all three parameters with stable or decreasing doses of decadron was required for a partial response. Thirty-six poor risk (prior chemotherapy) patients with Grades III and IV astrocytomas were treated with 30 mg/m2. Three patients had a partial response (14, 17, 60 weeks duration). Two patients had mixed responses (worsening of one disease parameter with improvement in another), four had stable disease and one patient had improvement in neurologic parameters with a stable CT scan. Twenty-six patients had increasing disease. Fifteen good risk patients (no prior chemotherapy) with recurrent grades III and IV astrocytomas were treated at a dose of 40 mg/m2 intravenously every three weeks. There were no objective responses in this group of patients. Three patients with nonastrocytomas were treated and no responses observed. The drug was well tolerated. Myelosuppression in the form of leukopenia and thrombocytopenia was the major toxicity. Myelosuppression required dose reductions in eight patients and discontinuation of therapy due to repeated treatment delays in two patients. AZQ at doses of 30 and 40 mg/m2 given on an intermittent bolus schedule is inactive in patients with Grades III and IV recurrent astrocytoma.

Adult↗
PubMed1980

Kinetics of cellular proliferation in regenerating mouse liver pretreated with the alkylating drug dipin.

The effect of prior exposure to the alkylating drug 1,4-Bis[N,N'-di(ethylene)-phosphamide] piperazine (Dipin) on the cell cycle progression in a regenerating mouse liver is reported, using cytological, autoradiographical and DNA-cytophotometrical methods. In Dipin-treated animals 3H-TdR pulse labelled nuclei appeared 22 h after the partial hepatectomy, followed by a rapid rise in labelling index to a very high level between 43-54 h, and then by a gradual decline to 72 h. Four injections of 3H-thymidine at 16 h intervals resulted in 89% labelling of hepatocytes at 72 h. The DNA-synthesis time was assessed by DNA photometry combined with 3H-TdR autoradiography on the same nucleus. The DNA-content in Dipin-pretreated nuclei was doubled after 26 h, approximately three times longer than in the controls. Mitoses were completely absent during the first 2-4 days. They were observed subsequently for up to 2 months but with varying frequency. The frequency of binucleated hepatocytes remained constant during liver regeneration. Hence, pretreatment of resting liver with Dipin altered the kinetics of cell proliferation following partial hepatectomy. Delay in division resulted primarily from an increase in the DNA-synthesis time and a prolonged block of the transition from G2 to mitosis. No changes in the duration of the prereplicative period and in the size of the proliferative pool were noticed. The increase of the mitotic cycle time led to synchronization of the cell population. About a half of the hepatocytes were seen in the S phase by the end of the second day and by the end of the third day about 80% of the cells had passed into the G2 phase.

Alkylating Agents↗
PubMed1985

A carbene-yielding amino acid for incorporation into peptide photoaffinity reagents.

3-[p-[3-(Trifluoromethyl)-3H-diazirin-3-yl]phenyl]alanine has been prepared in 10 steps from p-bromobenzyl alcohol. The alcohol was converted to 3-(alpha-iodo-p-tolyl)-3-(trifluoromethyl)-3H-diazirine, which was used to alkylate N-(diphenylmethylene)glycine ethyl ester. After deprotection the amino acid was obtained with an overall yield of 18%. The D- and L-isomers of 3-[p-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl]alanine have also been resolved, and 3-[p-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl]alanine labeled with tritium has been prepared. The advantages of using this amino acid as a building block for peptide photoaffinity reagents is discussed.

Affinity Labels↗
PubMed1991

Radiolabeling of the hydrophobic components of lung surfactant with 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine.

Studies of the metabolism and distribution of lung surfactant are aided by use of radiolabeled surfactant or surfactant components. These studies have often made use of [3H]- or [14C]phosphatidylcholine. Analysis of the lung content of surfactant containing these beta-emitting labels usually requires tissue digestion, use of scintillation fluids, and significant correction for quenching of photon production. Because use of a gamma-emitting isotope would obviate these requirements, we have investigated the use of 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine ([125I]TID), a lipophilic photoactivatable compound, to radiolabel pulmonary surfactant. Our results indicate that, during photoactivation, products of [125I]TID are produced that result in radiolabeling of both the lipid and protein components of extracted porcine surfactant. Separation of radiolabeled surfactant from hydrophobic nonlabelling photolysis products was accomplished by gel chromatography. Exposure of surfactant (34 mumol/ml) to [125I]TID under labeling conditions resulted in incorporation of 45.3 +/- 5.1% of the radiolabel. Incorporation of radiolabel in the various phospholipids of lung surfactant was approximately equivalent. Lipophilic surfactant apoproteins were also radiolabeled. Finally, both in vitro and in vivo testing of radiolabeled surfactant (0.1 microCi/mg) revealed full retention of surface tension lowering ability.

Animals↗
PubMed1983

Head group and structure specific interactions of enkephalins and dynorphin with liposomes: investigation by hydrophobic photolabeling.

The interaction of the opioid enkephalins and endorphins with lipid bilayers is largely unknown. Such interactions might, however, be important for understanding the molecular mechanisms of biological action. We have therefore studied the interaction of several enkephalins and of dynorphin-(1-13)-tridecapeptide (dynorphin1-13) with model membrane systems, using the extremely hydrophobic photolabel of J. Brunner and G. Semenza, (Biochemistry 20, 7174-7182 (1981)) 3-trifluoromethyl-3-(m[125I]iodophenyl)diazirine. By observing several limitations of the method, it was possible to characterize hydrophobic interactions of opioid peptides with liposomes prepared from egg yolk phosphatidylcholine (PC) plus dipalmitoylphosphatidic acid (PA), from brain phosphatidylserine (PS) alone, and from brain cerebroside sulfate (CS) alone, Dynorphine1-13 exhibited strong hydrophobic interactions through its N-terminal "message" segment which were potentiated by the "address" that itself remained in the aqueous phase. This behavior was consistent with the reported pharmacological potentiation. The enkephalins were generally weakly labeled in the PC/PA and PS systems. However, in the CS systems the preferentially mu agonists were labeled very strongly whereas the preferentially delta agonists were labeled more weakly yet. The kappa agonist, dynorphin1-13, was strongly, but more equally labeled in the three systems. Thus, there was a head group specificity that, in our series of compounds, correlated with opiate receptor sub-type specificity. The results were consistent with the behavior of the mu agonist, morphine.

Amino Acid Sequence↗
PubMed1988

Rat brain hexokinase: the hydrophobic N-terminus of the mitochondrially bound enzyme is inserted in the lipid bilayer.

Mitochondrially bound rat brain hexokinase was labeled with the photoactivatable reagent, 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine. This highly hydrophobic reagent is strongly partitioned into the hydrophobic environment of the membrane core, and thus selectively labels segments of a protein that penetrate this region of the membrane. Labeling of hexokinase was shown to be restricted to the N-terminal region of the molecule. Approximately 80% of the radiolabel was removed by treatment of the enzyme with chymotrypsin, which preferentially cleaves a hydrophobic 9-residue sequence at the extreme N-terminus of the enzyme, and it is considered likely that the remaining 20% was associated with two additional hydrophobic residues, immediately adjacent to this segment but not susceptible to cleavage by chymotrypsin. Labeling of the enzyme was shown to be dependent on maintenance of the association with the membrane. These results are consistent with a model in which binding of hexokinase involves insertion of an 11-residue hydrophobic N-terminal "tail," possibly existing in alpha-helical secondary structure, into the hydrophobic core of the membrane.

Affinity Labels↗
PubMed1989

Penetration and fusion of phospholipid vesicles by lysozyme.

The lysozyme-induced fusion of phosphatidylserine/phosphatidylethanolamine vesicles as studied at a wide range of pH is found to correlate well with the binding of this protein to the vesicles. An identical 6000 molecular weight segment of lysozyme at the N-terminal region is found to be protected from tryptic digestion when initially incubated with vesicles at several pH values. Only this segment is labeled by dansyl chloride, which is partitioned into the bilayer. These results suggest the penetration of one segment of lysozyme into the bilayer. Photoactivated labeling of the membrane-penetrating segment of lysozyme with 3-(trifluoromethyl)-3-([125I]iodophenyl)diazirine ([125I]TID) and subsequent identification of the labeled residues by Edman degradation and gamma-ray counting indicate that four amino acids from the N-terminal are located outside the hydrophobic core of the bilayer. Although treatment of the membrane-embedded segment with aminopeptidase failed to cleave any amino acids from the N-terminal, it appears that a loop of lysozyme segment near the N-terminal penetrates into the bilayer at acidic pH. A helical wheel diagram shows that the labeling is done mainly on one surface of the alpha-helix. The penetration kinetics as studied by time-dependent [125I]TID labeling coincide with the fusion kinetics, strongly suggesting that the penetration of the lysozyme segment into the vesicles is the cause of the fusion.

Amino Acid Sequence↗