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PubMedDate not supplied

Morphology of spontaneous and induced tumors in the bronchiolo-alveolar region of F344 rats.

The morphology of spontaneous and chemically-induced metastasizing carcinomas and adenomas in the bronchiolo-alveolar region of F-344 rats was studied. Histologically, the tumors were tubulo-papillary. Ultra-structurally, they consisted of cells which formed and secreted osmiophilic lamellated inclusion bodies, a marker of alveolar type II cells. Mitotic tumor cells also demonstrated such bodies. No cells of bronchial or bronchiolar origin were found in the tumors. We conclude that in F344 rats, lung tumors located in the bronchioloalveolar region consist of alveolar type II cells exclusively and are, therefore, alveolar cell adenomas and carcinomas, respectively.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1983

Potencies and channel properties induced by semirigid agonists at frog nicotinic acetylcholine receptors.

Structure-activity relationships were investigated in a series of semirigid nicotinic agonists. Three of the agonists, (-)-ferruginine methiodide, arecoline methiodide, and its ketonic analogue arecolone methiodide, were cyclic analogues of anatoxin-a, a potent, naturally occurring, bicyclic alkaloid. Two other cyclic agonists, (-)-cytisine and (+/-)-muscarone, and the simplest agonist, the tetramethylammonium ion, were also tested. Arecolone methiodide and (-)-ferruginine methiodide have been tested as nicotinic agonists for the first time. Relative potency was assayed by contracture on the rectus abdominis muscle of the frog Rana pipiens. Natural, (+)-anatoxin-a, the most active of all of the agonists, was more than twice as potent as racemic anatoxin-a. Arecolone methiodide ranked after anatoxin-a in potency, being 8.6 times more potent than carbamycholine. A correlation between nicotinic potency and steric requirements probably involves the position of positively charged groups out of the plane defined by the carbonyl group and its two substituents. Channel properties induced by the agonists were evaluated by Fourier analysis of the end-plate current noise that resulted when the agonists were iontophoretically applied to frog sartorius muscle fibers. Average channel lifetimes were exponential functions of membrane potential, but the voltage sensitivity of channel lifetime seemed to vary among the agonists. Channel conductance, which was independent of membrane potential, also varied significantly among the agonists. The average charge traversing the membrane through each open channel, calculated from the product of average channel lifetime and current, did not correlate with potency. Therefore, the dominant component of potency is the frequency of channel opening. No clear relationship between the structure of the agonist and channel lifetime or conductance was evident.

Alkaloids↗
PubMed1978

[Ephedrine, salsoline and cytisine derivatives as substrates and inhibitirs of cholinesterases].

25 iodomethylates of acetic, propionic, butyric, isobutyric and valeric esters of N-(beta-hydroxyethyl)-derivatives of ephedrine (I) pseudo-ephedrine (II), salsoline (III), salsolidine (IV) and cytisine (V) are studied as substrates and inhibitors of acetylcholine esterase (EC 3.1.1.8) from human erythrocytes and butyrylcholine esterase (EC 3.1.1.8) from horse serum. Butyrylcholine esterase found to increase the hydrolysis rate of all the alkaloid esters studied with the increase of acyl radical either to valerates (for ephedrine and pseudo-ephedrine derivatives), or to butyrates (for the rest alkaloids) and then it did not considerably change under further elongation of carbon chain up to valerate. Isobutyrates were observed to be similar to propionates in their hydrolysis rates. Acetylcholine esterase hydrolyzed acetates with the highest rate, while butyrates of ephedrine and pseudoephedrine derivatives were hydrolyzed by the enzyme 2,5-3-fold as slow as acetates. The rate of choline esterase hydrolysis decreased in the row: ephedrine--salsoline--cytisine with the volumetric increase of the cationic group. The decrease was almost 10-fold for butyrylcholine esterase, while a transition from "poor" substrates to reversible inhibitors was observed for acetylcholine esterase (3 of 5 cytisine esters were reversible inhibitors of the enzyme). The data obtained are compared with literary data on other cyclic choline esterase substrates; they are discussed from the viewpoint of unproductive binding hypothesis and on the basis of the structure of active centres of acetyl- and butyrylcholine esterases.

Acetates↗
PubMed1981

Epithelial focus assay for early detection of carcinogen-altered cells in various organs of rats exposed in situ to N-nitrosoheptamethyleneimine.

The purpose of these studies was to determine a) whether epithelial cells with altered in vitro growth capacity occur not only after topical application of 7-12-dimethylbenz [a]-anthracene but also after systemic administration of a carcinogenic nitrosamine, and b) whether such cells can be isolated from tissues other than tracheal mucosa. AT 3 and 20 weeks following intragastric administration of 150, 300, or 600 mg N-nitrosohepatamethyleneimine (NHMI)/kg, cells were harvested from tracheas, esophagi, and lungs (target tissues for NHMI) of inbred F344 rats and seeded into culture dishes. Normal cells from nonexposed organs produced no proliferative epithelial foci (EF). Of those tracheas sampled 3 weeks following exposure to 150 and 300 mg/kg 10 and 20%, respectively, contained one or more EF that could be subcultured. Of these tracheas harvested 3 weeks post exposure to 600 mg/kg or 20 weeks post exposure to 150-600 mg/kg, 80-100% contained EF that could be subcultured. Twenty weeks after 600 mg NHMI/kg, the incidence of tracheas harboring cell populations with neoplastic potential (agarose-positive EF) was 80%, whereas the tracheal tumor incidence determined at 24 months was only 29%. Epithelial focus-forming units with various abnormal in vitro growth potentials were also detected in esophagi and lungs of NHMI-exposed rats.

Animals↗
PubMedDate not supplied

The total alkaloid and anagyrine contents of some bitter and sweet selections of lupin species used as food.

The total alkaloid and anagyrine contents of bitter and sweet Lupinus luteus, Lupinus angustifolius, Lupinus albus, Lupinus mutabilis, Lupinus polyphyllus, and Lupinus perennis were analyzed by gas chromatography (GC) and mass spectrometry. No anagyrine was detected in any of the samples. The GC peak in some of the samples which corresponded to anagyrine in retention of time seems to be identical to 17-oxolupanine. The alkaloid content of samples ranged from 3.17 to 0.003 percent.

Alkaloids↗
PubMed1980

Derivatives of 1,2,3,3-tetramethyl-2-azabicyclo[2,2,2]octan-5-trans-ol with antiarrhythmic and other activities. V.

A series of N,N-dialkyl 5-trans-carbamoyloxy-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octanes was prepared by reaction of 1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octan-5-trans-ol with phosgene, followed by aminolysis of the resulting chlorocarbonate with aliphatic secondary amines. 5-Chloro-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2] octane (cis/trans mixture) was isolated as by-product of the reaction. A number of urethanes showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

Anesthetics, Local↗
PubMed1980

Derivatives of 1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octan-5-trans-ol with antiarrhythmic and other activities. III.

A new series of aliphatic and aromatic esters of 1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octan-5-trans-ol is described. A number of these compounds showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to that of lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

Anesthetics, Local↗
PubMed1980

Derivatives of 1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octan-5-trans-ol with antiarrhythmic and other activities. IV.

A new series of aliphatic and aromatic amides of 5-trans-(3-aminopropoxy)-1,2,3,3-tetramethyl-2-azabicyclo[2.2.2] octane is described. A number of these compounds showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to that of lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

Anesthetics, Local↗
PubMed1994

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: I. In vitro characterization.

A diversity of nicotinic acetylcholine receptor (nAChR) subtypes has been identified in mammalian brain using recombinant DNA technology. Alterations in the activity of these acetylcholinegated ion channels have been implicated in a number of central nervous system disorders including Alzheimer's disease (AD). The potential therapeutic usefulness of (-)-nicotine [(S)-3-(1-methyl-2-pyrrolidinyl) pyridine], the prototypic agonist at nAChRs, is severely limited by side effects that are the result of activation of both cholinergic and noncholinergic pathways in the central and peripheral nervous systems. This study sought to determine the in vitro selectivity of (S)-3-methyl-5-(1methyl-2-pyrrolidinyl)isoxazole (ABT 418), a novel analog of (-)-nicotine in which the pyridine ring was replaced with an isoxazole bioisotere, to activate nAChRs. ABT 418 was a potent inhibitor of [3H]-cytisine binding to nAChR in rat brain (Ki = 3 nM) but was inactive (Ki > 10,000 nM) in 37 other receptor/neurotransmitter-uptake/enzyme/transduction system binding assays, including those for alpha-bungarotoxin, muscarinic and 5-hydroxytryptamine3 receptors. In PC12 cells, patch-clamp studies indicated that ABT 418 was an agonist with an EC50 value of 209 microM, a potency to activate cholinergic channel currents some 4-fold less than that of (-)-nicotine (52 microM). Channel current responses elicited by ABT 418 were prevented by the cholinergic channel blocker, mecamylamine. ABT 418 was also approximately 10-fold less potent (EC50 value = 380 nM) than (-)-nicotine (40 nM) in increasing [3H]-dopamine release from rat striatal slices, an effect that was blocked by the nAChR antagonist, dihydro-beta-erythroidine (10 microM).2+ In contrast, ABT 418 appeared equipotent with (-)-nicotine in enhancing 86Rb+ flux from mouse thalamic synaptosomes. ABT 418 demonstrated an in vitro pharmacological profile of cholinergic channel activation that was robust at some nAChR, but not others. The reasons for this are unclear. However, a nAChR subtype selectivity may account for the in vitro potency differences of ABT 418 on various neurotransmitter systems, and the substantial separation between the cognitive enhancement/anxiolytic benefits, and the reduced central nervous system side-effect liabilities seen in vivo. ABT 418 represents the first neuronal nAChR ligand that differentiates the toxicities/liabilities and other negative aspects normally associated with liabilities and other negative aspects normally associated with (-)-nicotine from the potential pharmacological benefits of selective cholinergic channel activation.

Alkaloids↗
PubMed1995

A primate model of polydrug abuse: cocaine and heroin combinations.

Abuse of cocaine-opiate combinations ("speedballs") reported clinically was simulated in a rhesus monkey model of simultaneous cocaine and heroin self-administration. The reinforcing effects of nine cocaine-heroin combinations (cocaine [0.001, 0.01 and 0.10 mg/kg per injection i.v.] and heroin [0.0001, 0.001 and 0.01 mg/kg per injection i.v.]) were evaluated for 10 days on a second-order fixed ratio of 4 (variable ratio of 16:S) schedule and compared with self-administration of cocaine and heroin alone. Dose-effect curves for cocaine-heroin combinations usually were similar to those for cocaine and heroin alone, and intermediate doses maintained equivalent high levels of drug self-administration. No toxic effects were observed. In drug discrimination studies, cocaine (0.004-1.3 mg/kg) substitution resulted in a dose-dependent generalization to the training dose (0.4 mg/kg i.m.) in all five monkeys. Heroin substitution (0.01-1.0 mg/kg i.m.) resulted in dose-dependent and complete generalization to cocaine in three of five monkeys. Heroin pretreatment (0.1-0.18 mg/kg i.m.) did not change the cocaine discrimination dose-effect curve. Pretreatment with an opiate antagonist, quadazocine (0.1 mg/kg i.m.), had no effect on the discriminative stimulus effects of cocaine but antagonized the cocaine-like discriminative stimulus effects of heroin. Pretreatment with a dopamine antagonist, flupenthixol (0.018 mg/kg), antagonized the discriminative stimulus effects of cocaine but did not affect the cocaine-like effects of heroin. These findings demonstrate the feasibility of maintaining self-administration of cocaine-heroin combinations and suggest that cocaine and heroin have similar reinforcing and discriminative stimulus effects in rhesus monkeys.

Animals↗
PubMed1979

In vivo autoradiography and nitrosoheptamethyleneimine carcinogenesis in hamsters.

Quantitative autoradiograms were made, in vivo, in European hamsters with the use of [14C]nitrosoheptamethyleneimine (260 muCi/animal; time between administration of nitrosamine and killing of animals, 6 hr). In this species, the lung is the principal target, and radioactivity was found in the Clara cells of the bronchial epithelium and in the nitrosoheptamethyleneimine-induced tumors which derive from these cells. Tumors are not induced in the liver, which can metabolize this compound, and labeling is found principally in the cytoplasm, whereas in the target cells there is a high degree of labeling in both the cytoplasm and the nuclei.

Animals↗