Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 37 records · Page 2Linked to original sources

PubMed1996

The influence of fluoxetine on aggressive behavior.

A large body of evidence from studies in humans, in nonhuman primates, and in smaller laboratory animals has supported a role for serotonin in the modulation of aggressive behavior. The evidence shows that diminished serotonergic function can be linked to aggressive behavior and that treatments that increase serotonergic function reduce aggression. Embedded in this large body of data are studies done specifically with fluoxetine, a serotonin uptake-inhibiting antidepressant drug suggested by some individuals charged with criminal aggression and by their attorneys to cause aggressive violence. Contrary to those charges, extensive studies of fluoxetine in animals have shown that fluoxetine decreases aggressive behavior in various species and models of aggression. Clinical studies of fluoxetine in aggressive behavior have been more limited, but findings in those studies seem consistent with the anti-aggressive effects of fluoxetine found in animal studies.

Aggression↗

PubMed1996

Capsaicin cough sensitivity increases during upper respiratory infection.

The mechanism of cough associated with upper respiratory infection (URI) is poorly understood. This paper reports a study of the role of altered sensitivity of capsaicin-sensitive airway nerves. In a prospective study, baseline (B) capsaicin-induced cough and methacholine-induced airway responsiveness were measured in 103 healthy volunteers. During the following year, 31 subjects reattended for challenge testing during URI (I) and after recovery (R). The log concentration of capsaicin required to elicit two coughs (C2) was significantly lower during infection than recovery but not baseline [median (interquartile range) B = 0.59 (0.28-1.20), I = 0.27 (0-0.89), R = 0.89 (0.28-1.49)]. Log C5 (concentration causing five coughs) was lower during infection than baseline and recovery [B = 1.79 (1.20-2.70), I = 1.49 (0.89-2.08), R = 1.79 (1.20-2.40)]. FEV1 and PC15 methacholine values were unchanged during infection compared to baseline. Subjects with dry cough (n = 14) had lower C5 values during infection than both baseline and recovery, and lower C2 values during infection than recovery; in these subjects, increase in capsaicin sensitivity correlated with cough severity score. Subjects with productive cough or no cough showed no consistent changes during infection. Twenty-six control subjects who reattended without URI showed no change in capsaicin sensitivity. Upper respiratory infection may cause cough as a result of increased sensitivity of capsaicin-sensitive afferent airway nerves without affecting airway calibre or responsiveness.

Administration, Inhalation↗

PubMed1996

New pyranocoumarins isolated from Calophyllum lanigerum and Calophyllum teysmannii.

During a chemotaxonomic survey of Calophyllum extracts present in the National Cancer Institute's natural product repository, four new pyranocoumarins were isolated from extracts of C. lanigerum var. austrocoriaceum and C. teysmannii var. inophylloide (King.) P. F. Stevens (Clusiaceae). The structure elucidation and anti-HIV activity of calanolide E2 (4), cordatolide E (5), pseudocordatolide C (6), and calanolide F (9), along with a simple prenylated coumarin precursor (11), are described here.

Antiviral Agents↗

PubMed1996

The asthma death problem revisited.

1. Asthma is a potentially dangerous disease. Asthma deaths occur at varying degrees throughout the world and there is evidence for epidemics occurring in different populations at different times. Such epidemics have been noted as early as last century. Much investigation has been made into the role of inhaled beta-adrenoceptor agonists in these epidemics and indeed there is some evidence fenoterol is implicated. However, evidence for other beta-adrenoceptor agonists is not substantiated. 2. It is also noted that asthma deaths are not all the same, there being at least two types: deaths occurring in chronic severe asthmatics related to disease severity and sudden deaths of an anaphylactic nature that can occur in asthmatics of any disease severity. 3. The important next step in the study of asthma deaths is to concentrate on other important factors rather than the role of therapy which cannot explain all the epidemics and the background instance of asthma death.

Adrenergic beta-Agonists↗

PubMed1996

Pharmacokinetics of intravenous fluticasone propionate in healthy subjects.

1. Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non-compartmental analysis, in healthy male subjects over the 250 to 1000 micrograms dose range. 2. The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body (Vss 3181), rapidly cleared (CL 1.1 l min-1) with a terminal elimination half-life of 7.8 h and a mean residence time of 4.9 h. 3. In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration-time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non-compartmental analysis.

Adult↗

PubMed1996

A comparison of the effects of an alpha-agonist, an anti-muscarinic agent and placebo on intranasal histamine challenge in allergic rhinitis.

Autonomic receptors play a part in the physiology and pathology of the nasal mucosa. The effect of an alpha-agonist and an anti-muscarinic agent on histamine-challenge was examined on patients with perennial allergic rhinitis. Nine patients received saline, oxitropium bromide 0.075%, or xylometazoline hydrochloride 0.1% in a double-blind fashion. Sequential challenge with increasing doses of histamine were given and resistance changes, sneezes and volume and content of secretion measured. Histamine challenge produced dose-related increases in nasal resistance (P < 0.0001), lavage fluid volume (P < 0.01) and total protein (P < 0.01). Following xylometazoline, histamine produced little increase in resistance compared with saline and oxitropium bromide (P < 0.0001). The latter reduced the dose-related increase in resistance (P < 0.01) and nasal lavage fluid volume (P = 0.0007) and total protein (P = 0.023) seen with saline. These results confirm the importance of alpha-adrenergic and muscarinic receptors in the human nasal mucosa and suggest mechanisms of action for these drugs in perennial allergic rhinitis.

Adrenergic alpha-Agonists↗

PubMed1996

On the in-vivo modulation of neostriatal dopamine release by fluoxetine and 5-hydroxy-L-tryptophan in conscious rats.

To help determine the nature of serotonergic regulation of dopamine activity in the brain an in-vivo microdialysis study has been performed in conscious rats to investigate the modulation of dopamine release in the neostriatum by 5-hydroxytryptamine (5-HT). The 5-HT uptake inhibitor, fluoxetine, and the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), were used to produce an increase in extracellular 5-HT concentration Systemic administration of fluoxetine (10 mg kg-1, s.c.) produced a 2- to 3-fold increase in extracellular 5-HT concentration but did not change extracellular dopamine concentration in the neostriatum. Co-administration of fluoxetine and 5-HTP (40 mg kg-1, s.c.; 60-90 min after fluoxetine) caused a highly significant tenfold increase in extracellular 5-HT concentration in the neostriatum with a slight but non-significant decrease in extracellular dopamine concentration. Pergolide, a dopamine D2 agonist, given systemically caused a dramatic decrease in extracellular dopamine concentration demonstrating the responsiveness of the neurons. These results demonstrate that high concentrations of extracellular 5-HT do not modulate dopamine release in the neostriatum. The possibility that different 5-HT receptor subtypes may mediate different regulation of dopamine release remains to be explored.

5-Hydroxytryptophan↗

PubMed1996

Serum corticosterone increases reflect enhanced uptake inhibitor-induced elevation of extracellular 5-hydroxytryptamine in rat hypothalamus.

The increase in extracellular 5-hydroxytryptamine (5-HT) in rat hypothalamus following administration of fluoxetine, a 5-HT-uptake inhibitor, was enhanced by the injection of LY206130(1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-prop ano l maleate), a 5HT1A receptor antagonist, or by L-5-hydroxytryptophan (L-5-HTP), the 5-HT precursor. Elevation of serum corticosterone, measured as a functional output of hypothalamic 5-HT pathways, was greater in rats treated with fluoxetine plus LY206130 or with fluoxetine plus L-5-HTP than in rats treated with the agents alone. Synergism between effects of fluoxetine and L-5HTP has often been reported, but this is the first report of an increased functional effect when a 5-HT1A receptor antagonist is combined with a 5-HT uptake inhibitor to augment the increase in extracellular 5-HT.

5-Hydroxytryptophan↗

PubMed1996

Dopamine and 5-HT receptor sensitivity does not correlate with neostriatal dopamine or 5-HT content.

To explore associations of neostriatal (NST) endogenous levels of dopamine (DA) and serotonin (5-HT) with sensitivity of their receptors, graded doses of 6-hydroxydopamine HBr (0 to 400 micrograms, ICV; 6-OHDA; desipramine pretreatment, 20 mg/kg IP) were given to rats between birth (P 0) and P 42. Numbers of vacuous chewing movements (VCMs) induced by SKF 38393 or m-chlorophenylpiperazine (m-CPP), respective DA D1 and 5-HT2 agonists, were subsequently determined. Enhanced SKF 38393-induced VCMs occurred when NST DA was reduced 97%-98% by high dose 6-OHDA (100-134 micrograms) at P 0 or P 3, but not in rats with 95%-97% loss in DA produced by 6-OHDA at P7 (134 micrograms) or P3 (67 micrograms). Enhanced m-CPP-induced VCMs occurred even when NST 5-HT content was not elevated after 6-OHDA (134 micrograms at P 10). Accordingly, D1 and 5-HT receptor sensitivity is not correlated with respective NST DA and 5-HT contents. The stage of ontogeny at the time of DA denervation may be the governing influence on receptor sensitivity.

Animals↗

PubMed1995

Persistence of long-lasting serotonin depletion by p-chloroamphetamine in rat brain after 6-hydroxydopamine lesioning of dopamine neurons.

In rats that had been treated neonatally with 6-hydroxydopamine (6OHDA) to deplete striatal dopamine more than 95%, a single injection of p-chloroamphetamine (pCA) (5 or 10 mg/kg, i.p.) resulted in depletion of striatal and hippocampal serotonin at 1 week to a similar extent as in control rats. These findings suggest that striatal dopamine is not essential to the long-lasting depletion of brain serotonin by pCA in rats.

Animals↗

PubMed1995

Decreased hypothalamic epinephrine concentration by quipazine and other serotonin agonists in rats.

Epinephrine concentrations in rat hypothalamus were decreased after the injection of quipazine, a direct-acting serotonin (5-HT) agonist. The decrease was statistically significant and dose-dependent from 0.1 to 10 mg/kg, s.c., was apparent within 1 hr, and persisted for 8 hr but not 24 hr. There was no decrease in epinephrine concentrations in rat medulla oblongata, a region containing epinephrine cell bodies. Epinephrine concentrations in rat hypothalamus were also decreased by 1-(m-trifluoromethylphenyl)-piperazine (TFMPP) and by 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), other direct-acting 5-HT agonists, and by d-fenfluramine, a 5-HT-releasing drug. The decrease evoked by quipazine was prevented by pretreatment with metergoline, ketanserin or LY53857 (6-methyl-1-[methylethyl]-ergoline-8-carboxylic acid 2-hydroxy-1-methyl-propyl ester), centrally acting 5-HT antagonists. The lowering of rat hypothalamic epinephrine concentrations by 8-OH-DPAT was prevented by pretreatment with pindolol, a centrally acting 5-HT1A receptor antagonist. These data suggest that serotonergic drugs affect epinephrine concentrations in rat hypothalamus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1995

Loss of response to beta-adrenoceptor agonists during the maturation of human monocytes to macrophages in vitro.

We have previously reported that human airway macrophages do not respond to the beta-adrenoceptor agonist isoprenaline. The airway macrophage is known to be derived from the blood monocyte. In this study we have assessed the effect of beta-adrenoceptor stimulation on human monocytes matured into macrophages in vitro, to determine whether the lack of response previously observed in the airway macrophage may be a consequence of differentiation. The release of thromboxane B2 (TXB2) from freshly isolated monocytes stimulated by opsonized zymosan (OPZ) was inhibited by 39.3 +/- 5.5% in the presence of isoprenaline (10(-7) M). However, the response was lost in the monocyte-derived macrophage (MDM), where isoprenaline (10(-7) M) caused only 4.0 +/- 9.3% inhibition of OPZ-stimulated TXB2 release. In contrast forskolin (10(-5) M) inhibited MDM TXB2 release by 36.4 +/- 17.3%, indicating that the adenylyl cyclase was functional. Measurement of adenylyl cyclase activity showed that there was a reduction in the basal level, 17.03 +/- 4.1 to 7.9 +/- 4.6 cyclic AMP pmol/min/mg protein, and NaF (10(-2) M)-induced activity, 116.3 +/- 32.1 to 21.9 +/- 12.6 cyclic AMP pmol/min/mg protein, between freshly isolated monocytes and MDMs, respectively. In addition, there was no change in MDM basal adenylyl cyclase activity on exposure to isoprenaline. Thus we have demonstrated the loss of beta-adrenoceptor function during the maturation of human monocytes to macrophages in vitro, despite a functional adenylyl cyclase system. In this respect the monocyte-derived macrophage is like the airway macrophage.

Acetylglucosaminidase↗

PubMed1995

Serotonin uptake inhibitors: uses in clinical therapy and in laboratory research.

Fluoxetine, zimelidine, sertraline, paroxetine, fluvoxamine, indalpine and citalopram are the selective inhibitors of serotonin uptake that have been most widely studied. Some of these compounds are or have been used clinically in the treatment of mental depression, obsessive-compulsive disorder and bulimia, and therapeutic benefit has been claimed in additional diseases as well. By blocking the membrane uptake carrier which transports serotonin from the extracellular space to inside the serotonin nerve terminals, these compounds increase extracellular concentrations of serotonin and amplify signals sent by serotonin neurons. Because serotonin neurons are widespread in the central nervous system, the functional consequences of blocking serotonin uptake are diverse, but are generally subtle. Animals treated with serotonin uptake inhibitors look normal in gross appearance, but effects such as reduced aggressive behavior, decreased food intake and altered food selection, analgesia, anticonvulsant activity, endocrine changes and neurochemical changes have been demonstrated and characterized. Serotonin uptake inhibitors have helped in revealing some dynamics of serotonin neurons; for example, when uptake is inhibited and extracellular serotonin concentration increases, presynaptic as well as postsynaptic receptors for serotonin are activated to a greater degree. A consequence of increased activation of autoreceptors on serotonin cell bodies and nerve terminals is a reduction in firing of serotonin neurons and a decrease in serotonin synthesis and release. The result is a limit on the degree to which extracellular serotonin and serotonergic neurotransmission are increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

(R)-thionisoxetine, a potent and selective inhibitor of central and peripheral norepinephrine uptake.

Inhibitors of neuronal norepinephrine (NE) uptake are useful for the treatment of a variety of diseases including depression and urinary incontinence. In the present study, we synthesized and evaluated a novel analog of the potent and selective NE uptake inhibitor, nisoxetine. Thionisoxetine more potently inhibited the uptake of [3H]-NE into hypothalamic synaptosomes and [3H]-nisoxetine binding to the NE transporter than (R)-nisoxetine. The (R) enantiomer of this compound was significantly more potent than the (S) enantiomer, having a Ki of 0.20 nM in [3H]-nisoxetine binding. The (R) enantiomer was approximately 70-fold more potent in inhibiting [3H]-NE uptake when compared to [3H]-5HT uptake. In rats, (R)-thionisoxetine prevented hypothalamic NE depletion by 6-hydroxydopamine with an ED50 of 0.21 mg/kg. Depletion of NE in peripheral nerves was accomplished by the administration of metaraminol to rats. In this paradigm, (R)-thionisoxetine prevented the depletion of heart NE with an ED50 of 3.4 mg/kg and urethral NE with an ED50 of 1.2 mg/kg. Thus, (R)-thionisoxetine is a potent and selective inhibitor of NE uptake in both central and peripheral tissues.

Animals↗

PubMed1995

Tissue distribution, metabolism and effects of bufotenine administered to rats.

Bufotenine (N, N-dimethyl-5-hydroxytryptamine) is a serotonin analog reported to be hallucinogenic. Bufotenine concentrations were measured by liquid chromatography with electrochemical detection after the s.c. injection of bufotenine (1, 30 or 100 mg/kg) into rats. At 1 hr, bufotenine was high in lung, heart and blood and lower in brain and liver. No N-monomethyl-5-hydroxytryptamine was detected, but 5-hydroxyindoleacetic acid (5HIAA) was increased due to bufotenine metabolism. Bufotenine disappeared nearly completely by 8 hr. Bufotenine concentrations were slightly higher in hypothalamus and brain stem than in striatum or cortex; serotonin was slightly decreased, and 5HIAA was increased in these brain regions. Pargyline reduced concentrations of 5HIAA in blood and tissues after bufotenine injection; LY51641 but not deprenyl mimicked pargyline, suggesting type A not type B monoamine oxidase metabolizes bufotenine. Bufotenine injection increased serum corticosterone concentration, an effect not blocked by metergoline at a dose that blocked a similar increase elicited by quipazine. Although only 2% of the serotonin was found in platelet-poor plasma, more than 99% of the bufotenine was found in platelet-poor plasma, indicating that bufotenine is not stored in platelets. These experiments indicate that bufotenine is rapidly eliminated, in part by type A monoamine oxidase, after its injection into rats and that bufotenine penetrates the blood-brain barrier poorly.

Animals↗

PubMed1995

Novel halogenated analogs of tomoxetine that are potent and selective inhibitors of norepinephrine uptake in brain.

Halogenated analogs of the potent norepinephrine (NE) uptake inhibitor, tomoxetine, were synthesized and their affinities for the serotonin (5HT) and NE uptake sites evaluated. One of the most potent was the 2-iodo substituted analog (289306) that inhibited [3H]tomoxetine binding to rat cerebral cortex with a Ki of 0.37 nM. The compound also inhibited the uptake of [3H]NE into rat hypothalamic synaptosomes with a Ki of 3.5 nM. This analog was significantly less potent at the 5HT uptake site, as exhibited by a Ki of 25 nM in the inhibition of [3H]paroxetine binding and a Ki of 121 nM in [3H]5HT uptake. The resolved (R) enantiomer (303926) was 10 times more potent as a [3H]NE uptake inhibitor and 29 times more potent as an inhibitor of [3H]tomoxetine binding than the (S) enantiomer (303884). Administration of 289306 to rats prior to an i.c.v. injection of 6-hydroxydopamine prevented the depletion of hypothalamic NE and Epi with ED50 values of 0.28 and 0.47 mg/kg, respectively. Thus, 289306 was a potent inhibitor of NE uptake in vitro and in vivo. In addition, these compounds provide structures for potential ligands for the study of NE uptake sites by autoradiography, PET or SPECT imaging.

Adrenergic Uptake Inhibitors↗

PubMed1995

Comparison of desmethylsertraline with sertraline as a monoamine uptake inhibitor in vivo.

1. Desmethylsertraline, a metabolite of the antidepressant drug sertraline, was compared with sertraline for its ability to produce effects characteristic of inhibitors of the serotonin transporter in vivo. Desmethylsertraline antagonized brain serotonin depletion by p-chloroamphetamine, a depletion dependent upon the serotonin transporter, being less potent than sertraline in rats but almost as potent as sertraline in mice. Desmethylsertraline was a weak antagonist of 6-hydroxydopamine-induced depletion of heart norepinephrine in mice; sertraline had no effect at the doses studied. 2. Desmethylsertraline decreased brain concentrations of 5-hydroxyindoleacetic acid (5HIAA) in rats as did sertraline, the duration of the effect after both drugs being at least 24 hrs but less than 48 hrs. 3. After sertraline injection, desmethylsertraline was present in rat brain at higher concentrations than the parent drug at 8 hrs and thereafter. 4. In rats, repeated injections of sertraline, at doses previously shown to diminish beta-adrenergic receptor-mediated responses, led to marked accumulation of desmethylsertraline in brain and to inhibition of the catecholamine transporters. 5. In mice, brain concentrations of desmethylsertraline were higher than those of parent drug within 7 hrs after sertraline injection and probably contributed importantly to the antagonism of p-chloroamphetamine effects. 6. These data show that desmethylsertraline is less potent than sertraline as a serotonin uptake inhibitor in vivo, as the in vitro data would have predicted, but that desmethylsertraline may nonetheless contribute to the prolonged inhibition of the serotonin transporter after sertraline administration, perhaps more in mice than in rats.

1-Naphthylamine↗

PubMed1995

Eicosanoid release in allergen-induced bronchoconstriction in dogs. Its relationship to airways hyperreactivity and pulmonary inflammation.

In vitro studies have demonstrated the release of histamine, PGD2, TXB2, PGE2, PGF2 alpha, 6-keto-PGF1 alpha and the peptidoleukotrienes from sensitized lung. We have assessed the release of these mediators following antigen challenge in vivo. Antigen challenge of allergic dogs resulted in an acute bronchoconstriction and an increase in bronchial reactivity to histamine and an increase in neutrophil and eosinophil numbers recovered by bronchoalveolar lavage (BAL), 2 and 24 h later. The acute response was associated with histamine and PGD2 release but there was no increase in the levels of other eicosanoids in recovered BAL. Bronchial hyperreactivity and pulmonary inflammation, 2 and 24 h post-challenge was not associated with a concommitant (antigen specific) increase in BAL fluid eicosanoid levels. We conclude that although PGD2 is released during the acute response to antigen the subsequent changes (hyperreactivity and inflammation) are not characterised by a maintained elevation in eicosanoid levels detectable by BAL.

Airway Resistance↗