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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 217 records · Page 12Linked to original sources
PubMed1988

The importance of bradykinin and histamine in the skin response to antigen.

On three separate occasions 12 atopic subjects were injected intradermally with two doses of antigen and one of saline as control. Pretreatment with terfenadine 60 mg orally significantly inhibited the flare response to both the lower dose of antigen and to saline (P less than 0.05). Ingestion of enalapril 5 mg orally 3 h before increased the flare response to both doses of antigen. Neither enalapril nor terfenadine affected the weal response when compared with placebo. Both endogenous histamine and bradykinin appear to be released during the intradermal flare response but are not important in the weal reaction to antigen.

Adult↗
PubMed1988

Systemic adrenaline attenuates skin response to antigen and histamine.

Six atopic subjects received either adrenaline (0.3 ml of 1 mg/ml), subcutaneously over the deltoid muscle, or saline on 2 separate days. After 10 min, histamine and antigen were injected intradermally in the forearm. Adrenaline significantly inhibited the flare of histamine and both the flare and weal of antigen (P less than 0.05). This anti-allergic action of adrenaline occurred with a dose that we have previously shown produces plasma concentrations at the upper limit of the physiological range in resting normal subjects.

Adrenergic beta-Agonists↗
PubMed1988

Metabolism of fenfluramine to norfenfluramine in guinea-pigs.

After injection of fenfluramine into guinea-pigs, the N-dealkylated metabolite norfenfluramine was present in brain at higher concentrations and persisted longer than the parent drug, fenfluramine. Contrary to a claim in previous literature, the guinea-pig does metabolize fenfluramine to norfenfluramine, hence the ability of fenfluramine to cause acute and long-term depletion of brain 5-hydroxytryptamine in this species does not prove that fenfluramine, instead of nonfenfluramine, can produce these effects.

Animals↗
PubMed1988

Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans.

To determine the site of action of opiates in humans, we have studied the effect of systemic and inhaled opiates on cough and increase in respiratory resistance (Rrs) caused by inhaled capsaicin. In 13 subjects, a range of doses of capsaicin inhaled in single breaths given in random order produced a reproducible dose-cough response. Inhalation of a dose of capsaicin that caused fewer than two coughs increased Rrs by 28% (21-35, mean 95% confidence interval). Inhaled codeine (50 mg) and morphine (10 mg) did not alter the cough response. In contrast, both drugs increased base-line Rrs by 24% (16-44) and 13% (3-23), respectively, and significantly reduced the increase in Rrs after inhaled capsaicin (P less than 0.05). Oral codeine (60 mg) significantly (P less than 0.05) reduced the number of coughs at 1 and 2 h but did not alter base-line Rrs or its increase after capsaicin. Intravenous morphine (0.15 mg/kg) significantly reduced the sensitivity of the cough response (P less than 0.05), which was reversed by naloxone. However, there was no significant drug effect on either the base-line Rrs or its increase after capsaicin. Systemic dosing of opiates is therefore required to reduce the cough reflex, whereas inhaled opiates may reduce the increase in Rrs after inhaled capsaicin.

Administration, Inhalation↗
PubMed1988

Vasodilatation by calcitonin gene-related peptide and by substance P: a comparison of their effects on resistance and capacitance vessels of human forearms.

A comparison has been made of the effects of the potent vasodilating peptide calcitonin gene-related peptide (CGRP) and substance P (SP) on resistance and capacitance vessels of normal subjects. Brachial artery infusion of 1.25 to 10 pmol/min CGRP and of 0.25 to 1.5 pmol/min SP produced maximal increases in forearm blood flow (177 +/- 75% and 198 +/- 50%, respectively), as measured by venous occlusion plethysmography. The vasodilation due to CGRP was prolonged, with a half-life of biological effect of approximately 18 min, while that due to SP was of short duration, with a half-life of biological effect of approximately 15 sec. There was rapid development of tachyphylaxis to the effects of arterial infusion of SP, but not of CGRP, during a prolonged infusion at one dose. CGRP did not alter the diameter of a superficial hand vein, either at rest or when the vein was constricted by a simultaneous infusion of norepinephrine or by the single deep breath reflex. In contrast, SP caused dilatation of veins preconstricted with norepinephrine, although the effect was only transient and dose-response curves could not be constructed. The venoconstrictor response to a single deep breath was abolished by SP. Simultaneous arterial infusion of both peptides produced at least additive, and possibly synergistic, effects on forearm blood flow. We propose that both CGRP and SP have a role in the regulation of vascular smooth muscle tone.

Adult↗
PubMed1988

Effects of LY104119, a thermogenic weight-reducing compound, on norepinephrine concentrations and turnover in obese and lean mice.

Dopamine (DA) accumulation in interscapular brown adipose tissue (IBAT), heart, and liver was linear for more than 60 min after injection of 1-cyclohexyl-2-mercapto-imidazole (CHMI), a DA beta-hydroxylase inhibitor, into mice and served as an index of the rate of synthesis of norepinephrine (NE) in these tissues. There was a marked diurnal rhythm of DA accumulation in all three tissues of mice fed ad libitum, the rhythm being dampened in obese mice in IBAT and liver but not in heart. LY104119 acutely decreased NE concentration in IBAT, heart and liver, but not in brain, and it also decreased DA accumulation after CHMI in IBAT, heart and liver. Chronic administration of LY104119 at doses that stimulated thermogenesis and reduced body weight decreased NE turnover in heart and liver but increased NE turnover in IBAT. These data suggest that the increased thermogenesis in IBAT after chronic LY104119 treatment may be mediated by increased noradrenergic tone.

2-Hydroxyphenethylamine↗
PubMed1988

Deprenyl antagonizes acute lethality of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

In Charles River CFW mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused lethality with an LD50 of 53.8 mg/kg s.c. In mice pretreated with deprenyl, no lethality occurred with MPTP doses up to 110 mg/kg s.c. MPTP alone at doses of 30 to 90 mg/kg s.c. caused marked salivation, licking and grooming, hyperlocomotion, hyperreactivity and convulsions during the 1st hr, followed by depression, continued salivation and respiratory distress at 2 to 3 hr and at longer times, with death occurring at the higher doses. In deprenyl-pretreated mice, MPTP produced only mild and transient effects. 1-Methyl-4-phenylpyridinium (MPP+) was more potent in causing lethality than was MPTP, and deprenyl did not affect its lethality. MPTP lethality was not antagonized by EXP 561 [4-phenyl-bicyclo-(2,2,2)octan-1-amine hydrochloride monohydrate], an uptake inhibitor that prevented the neurotoxic effects of a lower dose of MPTP on striatal dopamine and cortical norepinephrine neurons. In addition to deprenyl, other monoamine oxidase (MAO) inhibitors effective in inhibiting MAO-B (MD 240928 (R-3-[4-((3-chlorophenyl)methoxy)phenyl]-5-[(methylamino)methyl]-2- oxazolidinone methanesulfonate) and pargyline) protected against MPTP-induced lethality, but LY 51641 (N-[2-(o-chlorophenoxy)ethyl]cyclopropylamine hydrochloride) (a selective inhibitor of MAO-A) did not. The protective effect of deprenyl against MPTP-induced lethality was dose-dependent over a dose range of 0.01 to 10 mg/kg; in this range deprenyl inhibited MAO type B (MAO-B) in brain and liver. A 10-mg/kg i.p. dose of deprenyl antagonized MPTP-induced lethality as long as 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

AL-1576, an aldose reductase inhibitor (ARI), did not prevent the decrease of norepinephrine turnover in diabetic rats.

ONO-2235 [(E)-3-carboxymethyl-5-[(2E)-2-methyl-3-phenyl-propenylidene]rhodanine], an ARI, was reported to prevent significantly the decrease of norepinephrine (NE) turnover in three tissues of streptozotocin (STZ)-diabetic rats (1). To examine whether the partial restoration of NE turnover by ONO-2235 is related to its ARI activity, the effect of another ARI, AL-1576 [spiro(2,7-difluoro-9H-fluoren-9, 4'-imidazoline)-2'5'-dione], on NE turnover in STZ rats was investigated. STZ caused an accumulation of sorbitol in the lens and decreased NE turnover in interscapular brown adipose tissue (IBAT), heart and pancreas. AL-1576 totally prevented the accumulation of sorbitol in the lens but had no effect on the decreased NE turnover in all three tissues. These results suggest that the partial prevention of NE turnover decrease by ONO-2235 may not have been mediated by its ARI activity.

Aldehyde Reductase↗
PubMed1988

Comparative effects of 1-ethyl- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridines on catecholamine concentrations in mouse brain and heart.

The effects of 1-ethyl-4-phenyl-1,2,3,6-tetrahydropyridine (EPTP) on striatal dopamine, cortical norepinephrine and cardiac norepinephrine concentrations in mice were compared to the effects of the 1-methyl analog (MPTP). One week after the last of four daily injections of MPTP into mice, persistent depletion of dopamine and its metabolites in the striatum and of norepinephrine in the frontal cortex was found. EPTP did not produce these effects even at doses up to 4 times those of MPTP. A single dose of MPTP depleted cardiac norepinephrine 24 hrs later in mice. EPTP and the corresponding pyridinium compound (EPP+) depleted cardiac norepinephrine to a similar extent as did MPTP. These results and earlier observations show differences between the characteristics of MPTP-induced depletion of brain catecholamines and those of MPTP-induced depletion of cardiac norepinephrine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Preclinical pharmacology of a new serotonergic receptor antagonist, LY281067.

The preclinical pharmacologic activity of LY281067 shows it to be a potent and highly selective serotonergic (5-HT2) receptor antagonist. Based upon binding studies with 5-HT2 receptors in brain cortical membranes and block of 5-HT-induced contractions in the rat jugular vein, LY281067 showed high affinity at 5-HT2 receptors with a dissociation constant of approximately 1 nM. Furthermore, LY281067 was a highly selective 5-HT2 receptor antagonist without appreciably binding to 5-HT1, D1 or D2 receptors or interacting with histamine (H1), cholinergic, beta adrenergic or alpha-1 adrenergic receptors in smooth muscle. LY281067 had modest affinity at alpha-2 receptors with a dissociation constant of approximately 100 nM. Oral bioavailability of LY281067 in spontaneously hypertensive rats was excellent with an oral to i.v. dose ratio approximating 4, based upon blockade of pressor responses to 5-HT as an in vivo estimate of 5-HT2 receptor antagonist activity. Furthermore, LY281067 blocked quipazine-induced increase in serum corticosterone concentration, an increase thought to be mediated by activation of central 5-HT receptors. After oral administration to rats, LY281067 antagonized vascular 5-HT2 receptors with a relatively long duration of action (greater than 6 hr), an observation likely to be related to plasma concentrations of both the parent and an active metabolite. Lastly, LY281067 was relatively nontoxic, possessing a therapeutic index of approximately 1000 after oral administration to rats. In summary, LY281067 is a potent and highly selective, orally active 5-HT2 receptor antagonist with a relatively long duration and wide margin of therapeutic safety.

Animals↗
PubMed1987

p-Chloroamphetamine formation responsible for long-term depletion of brain serotonin after N-cyclopropyl-p-chloroamphetamine injection in rats.

After the injection of N-cyclopropyl-p-chloroamphetamine (N-cyclopropyl-PCA) into rats, p-chloroamphetamine (PCA) was identified in brain by high performance liquid chromatography with UV detection and was quantitated by that method and by spectrofluorometric analysis involving reaction with fluorescamine. The identity of PCA in brains of rats treated with N-cyclopropyl-PCA was confirmed by mass spectrometry. The peak concentrations of PCA in brain occurred 4 hrs after N-cyclopropyl-PCA injection. Brain concentrations of PCA and of N-cyclopropyl-PCA were measured at 1 or 4 hrs, respectively, after the injection of various doses of PCA or of N-cyclopropyl-PCA into rats. The depletion of brain serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was measured 1 week after injection of those same doses of PCA or N-cyclopropyl-PCA. Comparing peak concentrations of PCA with the degree of depletion of brain serotonin supported the interpretation that PCA formed metabolically accounted for the long-term depletion of brain 5-hydroxyindoles after injection of N-cyclopropyl-PCA in rats.

Amphetamines↗
PubMed1987

Ventilatory effects of inhaled capsaicin in man.

Nebulised capsaicin (10(-7) M) was inhaled by 8 normal subjects to study its effects on the pattern of breathing. When compared to the diluent alone capsaicin increased mean inspiratory flow, a reflection of central inspiratory drive (mean increase: 25 +/- 6%, SEM, p less than 0.01), with a trend to increasing ventilation through more rapid but not more shallow breathing. If capsaicin selectively stimulates non-myelinated fibres in the lung in man as it does in dogs, these results suggest that such stimulation in man can alter the pattern of breathing.

Adult↗
PubMed1987

Selective cytotoxicity of a system L specific amino acid nitrogen mustard.

The synthesis and characterization of DL-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid and DL-2-amino-5-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-napthoic+ ++ acid were accomplished. The correct assignment of the site of attachment of the bis(2-chloroethyl)amino side chain was ascertained by selective proton decoupling of the 13C NMR spectra performed on the corresponding nitrospirohydantoin precursors 2 and 3, which were obtained from the nitration of beta-tetralone hydantoin. The two target compounds 6 and 7 were designed as tumor-specific agents capable of being selectively transported into tumor cells by the leucine-preferring transport system (system L). Inhibition analysis of the initial rate of transport of the system L specific substrate 2-amino-bicyclo[2.2.1]heptane-2-carboxylic acid (BCH) by 6 and 7 indicated that the 7-substituted isomer 6 was an extremely potent competitive inhibitor of that transport system in murine L1210 leukemic cells (Ki = 0.2 microM). Evaluation of the selectivity of this compound indicated that it possessed enhanced in vitro antitumor activity and reduced myelosuppressive activity when compared to its prototype amino acid nitrogen mustard, L-phenylalanine mustard (L-PAM). In addition to being more selectively toxic to tumor cells, this compound differs from L-PAM in having a 2-3-fold shorter half-life (t1/2).

2-Naphthylamine↗