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At least 73 records · Page 4Linked to original sources
PubMed1977

Hepatic effect of two hypolipidemic drugs in rats.

Some hepatic effects of the hypolipidemic agents 3,9-di-3-pyridyl-2,4,8,10-tetraoxaspiro-5,5-undecane (compound A) and 2-(4-dibenzofuranyloxy)-2-methylpropionic acid (compound B) were investigated in male rats. The animals were treated orally with these drugs and a reference compound-clofibrate for 10 weeks, the daily doses being 250, 300 and 300 mg/kg body weight respectively. All three drugs caused hepatomegaly with a normal microscopic appearance in liver cells. In rats given compound A, part of some liver cells could be occupied by numerous membranes of smooth endoplasmic reticulum. The hepatocytes of the rats treated with compound B or clofibrate showed a marked increase in microbody profiles and an elevated hepatic catalase activity in comparison to the control animals. Neither the microbodies nor the catalase activity were affected by compound A. Hypolipidemic effects were demonstrated with all three compounds, the most potent activity being shown by compound B. Treatment with this agent resulted in significantly higher catalse activity than with clofibrate.

Animals↗
PubMed1976

Oxindole-3-spiropyrrolidines and -piperidines. Synthesis and local anesthetic activity.

The synthesis and local anesthetic properties of five 1-dealkyloxindole-3-spiropyrrolidines and six 1-dealkyloxindole-3-spiropiperidines are described. The compounds studied include members of all five possible positional isomers of the two classes of spirooxindoles; all showed local anesthetic activity by the rat sciatic nerve block method. The coincidence of the least variability in the relative positions of basic nitrogen, amide carbonyl, and aromatic ring (compounds 1 and 6) with lowest normalized toxicity is noteworthy.

Anesthetics, Local↗
PubMedDate not supplied

Induction of suppressor cell activity in vivo and suppression of lymphoproliferative responses in vitro by SK&F 105.685 in the dog.

SK&F 105.685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in rat models of adjuvant-induced arthritis and experimental autoimmune encephalomyelitis as well as in the murine lupus model. The mechanism of action in these models appears to be the induction of non-specific suppressor cell activity which is measured by the ability of cells from treated animals to partially inhibit the proliferative response of lymphocytes from control animals to concanavalin A (ConA) in a co-culture assay. In this study we have shown that oral administration of 0.1-3 mg/kg/day of SK&F 105.685 to purebred beagle dogs induced suppressor cell activity in the spleen and bone marrow but not in the peripheral blood. In vitro, SK&F 105.685 partially suppressed the proliferative response of dog splenocytes to the mitogens phytohemagglutinin (PHA), ConA and, to a lesser extent, pokeweed mitogen (PWM). Peripheral blood lymphocytes (PBLs) differed from spleen cells in their susceptibility to suppression by SK&F 105.685. While the PWM and ConA responses of PBLs and spleen cells showed similar levels of inhibition, the PHA response of PBLs, in marked contrast to spleen cells, was resistant to suppression by the compound. Our results show that the immunoregulatory effects of SK&F 105,685 are not limited to rodents and that suppressor cell activity in dogs is induced quickly and by relatively low doses of the compound.

Adjuvants, Immunologic↗
PubMed1976

Synthesis and antimineralocorticoid activities of some 7alpha-cyano and 7alpha-alkoxycarbonylamino steroidal spirolactones.

The synthesis and antimineralocorticoid potencies of several steroidal spirolactones bearing novel nitrogenous substituents in the 7alpha position are reported. These substituents include the cyano, the isocyanato, and the alkoxycarbonylamino groupings. The nitrile 1b and the N-carbomethoxy compound 1h showed good antimineralocorticoid potency (MED less than or equal to 0.79 mg) on subcutaneous administration to adrenalectomized rats.

Adrenal Glands↗
PubMed1989

Inhibition of topoisomerases by fredericamycin A.

Fredericamycin is an antibiotic product of Streptomyces griseus that exhibits modest antitumor activity in vivo and in vitro. Because of its unique structure and the absence of a clearly defined mechanism of action, we examined the effects of this compound on L1210 cells in culture as well as on several enzymes that bind to DNA. Fredericamycin exhibits an IC50 of 4.4 microM toward L1210 cells, and its cytotoxicity is a function of the time of exposure as well as drug dose. No DNA breakage was observed in L1210 cells or isolated nuclei following exposure to highly lethal concentrations of fredericamycin. As a first step toward understanding its mechanism of action, we examined the effect of fredericamycin on several enzymes involved in DNA metabolism. The catalytic activity of both DNA topoisomerases I and II were totally inhibited by fredericamycin concentrations of 4.4 and 7.4 microM, respectively. Fredericamycin blocked etoposide-stimulated DNA cleavage by topoisomerase II both in vitro and in isolated nuclei. In addition, the drug inhibits DNA polymerase a in vitro, exhibiting an IC50 of 93 microM. These diverse actions of fredericamycin do not enable us to draw conclusions regarding its mechanism of antitumor effect but clearly identify it as a compound of pharmacologic interest.

Animals↗
PubMed1989

Mutagenicity of oxaspiro compounds with Salmonella.

The spiro attachment of an epoxide group to a tetrahydropyran ring in the trichothecene mycotoxins has prompted this study of the mutagenicity and alkylation rates of the trichothecene, anguidine, and 5 related model oxaspiro compounds. While the model compounds were weak alkylating agents of 4-(4-nitrobenzyl)pyridine as a test nucleophile, anguidine lacks such activity. Also, while mutagenicity was not established for anguidine in Salmonella TA100, 3 of the oxaspiro compounds were weakly mutagenic and 2 compounds were toxic to the bacteria. The toxicity and mutagenicity of the model compounds are more related to their polarity than to their alkylation rates.

Alkylating Agents↗
PubMed1979

Absorption and fluorescence of fluram-labelled lysozyme and peroxidase solutions.

The absorption spectra of fluram, lysozyme, horse-radish peroxidase, and mixtures of lysozyme + fluram and peroxidase + fluram and the fluorescence and fluorescence excitation spectra of the mixtures in 0.05 M phosphate buffer with 1 per cent dioxane are determined. Due to formation of a protein-fluram compound, the absorption spectra of the mixtures are not algebraic sums of the components. From the fluorescence intensities the number of bonding sites is found 6 in both cases. The fluorescence spectrum of the peroxidase-fluram compound has maxima at 305, 350, 400, 450 nm due to peroxidase and at 480 nm originating from fluram. In mixtures of 10(-5) M lysozyme + 10(-4) M fluram, 3/4 of the excitation energy is transferred from lysozyme to fluram within the compound under 280 nm excitation. Under similar conditions 4/5 of the excitation energy is transferred from peroxidase to fluram.

Binding Sites↗
PubMed1978

Formation of spirodilactone of 4-(2'-carboxyphenyl)-4,4-dihydroxybutyrate from 2-succinylbenzoate in cell-free extracts of Micrococcus luteus.

The enzyme mediated ATP- and, to a lesser extent, CoASH-dependent synthesis of the spirodilactone of 4-(2'-carboxyphenyl)-4,4-dihydroxybutyrate from 2-succinylbenzoate has been demonstrated in membrane-free extracts of Micrococcus luteus and Escherichia coli. The suggestion is made that the spirodilactone is the product of an aberrant reaction involving a compound that is normally an intermediate in the conversion of 2-succinylbenzoate to 1,4-dihydroxy-2-naphthoate.

Adenosine Triphosphate↗
PubMed1976

Derivatization of compounds at the origin of thin-layer plates with fluorescamine.

A method has been developed for the detection of compounds with primary amino groups on thin-layer chromatography (TLC) plates with fluorescamine. The compounds dissolved in buffer were applied to TLC plates and derivatized at the origin by developing with or dipping into an acetone-hexane solution of fluorescamine. Virtually all fluorescamine derivatives stayed at the origin, and they were subsequently separated using appropriate solvent systems. As little as 10 pmoles of fluorescamine-derivatized compound could be detected when viewed under a long-wave (366 nm) ultraviolet lamp. The method was applied to the analysis of peptides, amino acids and amines.

Amines↗
PubMed1990

[Intramolecular aromatic alkylation. 28. Synthesis and pharmacological testing of homologized and hydroxylated 3,4-dihydro-1'-methylspiro[naphthalin-1(2H),4'-piperidine].

The compounds 4, 8, and 10, prepared by standard methods, are converted to the phenylpyridylakanes 9; their methoiodides 11 are reduced to yield the tetrahydropyridines 12. Whereas the cyclisation of 12a gives the isomers 1f and 1g, 12b furnishes only the isomer 1i or 1k, respectively. H3PO4 is found to be more suitable than HBr to cyclize 12c and 12d to the homologues 1l and 1m. Treatment of 12c and 12d affords the bromides 13a and 13b by HBr-addition, which are isolated for the first time. Compounds 1l, 1b, 1c, and 1a exhibit a notable activity in the writhing test, whereas the hydroxylated derivatives 1h, 1e, and 1f are definitely less active. The homologue 1m is inactive.

Analgesics↗
PubMed1989

Inhibition of animal models of autoimmune disease and the induction of non-specific suppressor cells by SK&F 105685 and related azaspiranes.

SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride), administered orally to adjuvant arthritic (AA) rats inhibited immune-mediated hindpaw inflammation with an ED50 of 20 mg/kg/day. Both prophylactic and therapeutic administration were effective in this model. In addition, SK&F 105685 inhibited skin wheal responses to purified protein derivative (PPD) of tuberculin in AA rats and the development of hindleg paralysis associated with experimental allergic encephalomyelitis (EAE). Spleens of normal rats treated with SK&F 105685 were found to contain a population(s) of suppressor cells (SC) which inhibited the response of normal cells to Concanavalin A (Con A) in co-culture assays. The association between SC induction and anti-arthritic activity was determined by evaluating a series of chemically related azaspiranes in the AA rat model and for SC induction in normal rats. A statistically significant correlation was demonstrated (r = 0.79, P less than 0.001), indicating that SC induction may be responsible for the therapeutic activity of these compounds.

Adjuvants, Immunologic↗