PubMed Health⌕ Search

Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 145 records · Page 8Linked to original sources
PubMed1991

Pergolide: a dopamine agonist at both D1 and D2 receptors.

Pergolide is a potent, direct-acting dopamine agonist used in treating Parkinson's disease. It is an agonist found recently to have high affinity for D3 receptors. The affinity of pergolide for D1 receptors is lower than for D2 receptors, and there have been some reports that it may not interact with D1 receptors in vivo at doses used to activate D2 receptors. A growing body of evidence suggests that pergolide does occupy and activate D1 receptors in vivo, although the relevance to therapeutic efficacy in Parkinson's disease needs further study.

Animals↗
PubMed1991

Pharmacology of inhaled capsaicin in humans.

Inhaled capsaicin in humans causes cough and transient increase in airways resistance: both these effects appear to be through stimulation of sensory nerves in the airway. It has therefore been possible to study the effect of pharmacological agents on these two reflexes. The induced cough can be modulated by using opiates and local anaesthetics and the increase in airways resistance by anticholinergic agents. The use of inhaled capsaicin has therefore proved a useful human model for the study of novel treatments of cough.

Administration, Inhalation↗
PubMed1991

The effect of 443C81, a mu opioid receptor agonist, on the response to inhaled capsaicin in healthy volunteers.

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male volunteers. Using a randomised, double-blind crossover design, each subject inhaled either saline, 1 mg ml-1 443C81 or 4 mg ml-1 443C81 for 10 min from an ultrasonic nebuliser. The cough response to a range of doses of inhaled capsaicin and the increase in Rrs caused by inhalation of a single subtussive dose of capsaicin were measured before and after each treatment. There was no evidence of an effect of either 1 or 4 mg ml-1 443C81 on cough or increase in Rrs produced by capsaicin when compared with the saline placebo. It is concluded that inhalation of this mu opioid receptor agonist had no effect on capsaicin-induced cough or reflex bronchoconstriction in healthy volunteers.

Administration, Inhalation↗
PubMed1991

Human responses to inhaled capsaicin are not inhibited by granisetron.

Cough is a common respiratory symptom, the mechanism of which is poorly understood. In this study the role of 5-HT3 receptors was investigated. Capsaicin-induced cough and increase in airways resistance were measured in six male volunteers before and after infusion with granisetron 160 micrograms kg-1 or placebo. Neither cough nor the increase in respiratory resistance was altered by the active treatment. These results suggest that 5-HT3 receptors are not involved in these two respiratory responses to inhaled capsaicin in humans.

Administration, Inhalation↗
PubMed1991

Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin-1.

1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF 1 alpha and 2,3-dinor-6-oxo-PGF 1 alpha (products of PGI2) at 24 h. 3. Interleukin-1 (IL-1 beta; 5 micrograms) alone caused an increase in PGI2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4. Pretreatment of rats with IL-1 beta before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1 beta alone. 5. The cyclo-oxygenase inhibitor, ibuprofen (10 mgkg-1 i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/IL-1 beta. 6. We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Potent vasoactive properties of endothelin 1 in human skin.

The effect of the endothelial cell-derived peptide endothelin 1 was investigated in human skin. Intradermal injection of endothelin 1 (1-100 pmol) caused a dose-dependent area of pallor that was associated with a significant reduction in basal skin blood flow, measured by laser-Doppler blood flowmeter (with 1 pmol endothelin, P = 0.012, analysis of variance). The coadministration of endothelin 1 (1-100 pmol) with the neuropeptide vasodilator calcitonin gene-related peptide (CGRP) inhibited the vasodilator response to CGRP (10 pmol) by up to 82.7 +/- 9.2% (with 100 pmol endothelin, P less than 0.001). The response of the prostanoid vasodilator prostaglandin E2 (10 pmol) was inhibited by endothelin in a similar manner. In addition to the vasoconstrictor effects, endothelin 1 produced a dose-dependent flare that surrounded the area of pallor, and this was associated with a significant increase in blood flow (P less than 0.05) within the flare area. The H1 antagonist terfenadine (120 mg po) significantly reduced the flare area associated with endothelin 1: flare 5 min after intradermal endothelin (10 pmol, placebo treated), 668 +/- 405 mm2; terfenadine treated, 201 +/- 257 mm2 (P less than 0.05). The flare was also significantly attenuated when endothelin (10 pmol) was injected into local anesthetic-treated skin. Thus intradermal injection of endothelin in humans causes long-lasting vasoconstriction at the site of injection and a surrounding flare. Results suggest that the flare component is partially histamine dependent and the result of an axon reflex. This study demonstrates the potent activity of endothelin in human skin. It is possible that endothelin could be relevant to the local response of skin to injury.

Adult↗
PubMed1991

Inhaled PAF stimulates leukotriene and thromboxane A2 production in humans.

Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.

Administration, Inhalation↗
PubMed1991

Thromboxane A2 biosynthesis in acute asthma and after antigen challenge.

Thromboxane A2 is a potent bronchial smooth muscle spasmogen in vitro, and it has been implicated in airway inflammation and in the genesis of bronchial hyperresponsiveness in asthma. We have examined the urinary excretion of a variety of products derived from thromboxane A2 (thromboxane B2, 2,3-dinor, and 11-dehydro-thromboxane B2) and prostacyclin (6-oxo-PGF1 alpha and 2,3-dinor-6-oxo-PGF1 alpha) using gas chromatography-mass spectrometry in patients admitted acutely to hospital with severe asthma and in atopic volunteers after bronchial antigen challenge. Urinary excretion of all thromboxane-derived products was markedly increased in a number of patients with severe acute asthma compared with that in a nonsmoking control population, in some cases approaching those previously described in myocardial infarction: TXB2, 31.6 +/- 12.0 versus 6.5 +/- 0.9; 2,3-dinor-TXB2, 79.0 +/- 19.2 versus 29.5 +/- 2.7; and 11-dehydro-TXB2, 234.3 +/- 65.3 versus 25.0 +/- 2.1 ng/mmol creatinine (p less than 0.001). Urinary prostacyclin-derived products were also significantly raised in acute asthma. In contrast, after inhaled allergen challenge in atopic volunteers, which caused significant bronchoconstriction, urinary excretion of thromboxane-derived products was not significantly elevated: TXB2, 5.6 +/- 1.1 versus 5.7 +/- 1.0; 2,3-dinor-TXB2, 41.2 +/- 12.5 versus 28.5 +/- 6.9; and 11-dehydro-TXB2, 69.8 +/- 17.6 versus 39.7 +/- 11.2 ng/mmol creatinine. In a separate experiment, less than 2% of exogenously administered TXB2 to the airway appeared as urinary thromboxane-derived products, suggesting that production of greater than or equal to 1 microgram of TXA2 in vivo would be required to increase urinary thromboxane excretion twofold.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1991

Effect of inhaled furosemide and bumetanide on adenosine 5'-monophosphate- and sodium metabisulfite-induced bronchoconstriction in asthmatic subjects.

Inhaled furosemide, a high ceiling diuretic, inhibits bronchoconstrictor responses to sodium metabisulfite (MBS) and other indirect challenges by unknown mechanisms. Furosemide acts by inhibition of Na+/Cl- transport in renal tubules and may exert similar effects on asthmatic airways. To evaluate this hypothesis we compared the effects of nebulized furosemide with those of bumetanide, another high ceiling diuretic that inhibits Na+/Cl- transport, on bronchial challenge with adenosine 5'-monophosphate (AMP) and MBS in 16 asthmatic subjects. We also studied the effects of furosemide on histamine-induced bronchoconstriction in seven of these subjects. Nine subjects inhaled furosemide (30 mg) or placebo (P) 30 min before challenge with nebulized AMP (0.39 to 400 mg/ml). Seven returned for similar study with histamine (0.125 to 32 mg/ml). In another study, seven subjects inhaled bumetanide (2 mg) or P 5 and 30 min before AMP and MBS (0.3 to 80 mg/ml) challenge. The provocative concentration causing a 20% fall in FEV1 (logPC20) was calculated by linear interpolation of log dose-response curves. Furosemide (F) significantly attenuated responses to AMP: mean +/- SEM logPC20, 1.59 +/- 0.24 (geometric mean PC20 [GM], 39.0 mg/ml) after F and 0.98 +/- 0.29 (GM, 9.5 mg/ml) after P (p less than 0.01), but it did not alter responsiveness to histamine: logPC20, 0.09 +/- 0.17 (GM 1.2 mg/ml) after F and 0.09 +/- 0.20 (GM, 1.2 mg/ml) after P.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1991

Action of budesonide on asthmatic bronchial hyperresponsiveness. Effects on directly and indirectly acting bronchoconstrictors.

We have investigated the effects of inhaled budesonide on the bronchial responsiveness to both directly and indirectly acting spasmogens in man. Following treatment with budesonide or placebo for three weeks in a double-blind, crossover trial with a three-week washout, the response to histamine and bradykinin was determined in ten patients with mild asthma. After treatment with budesonide, the response to both inhaled histamine and bradykinin was decreased when compared with placebo. The PD35 histamine was increased by 1.95 doubling doses and PD35 bradykinin by 2.1 doubling doses. Daily (PEF) recordings were significantly increased during budesonide therapy, the morning PEF by 34.8 +/- 14.1 L/min and evening by 50.3 +/- 23.1 L/min. Baseline laboratory lung function on the study days was not altered by budesonide nor were symptom records altered significantly. Inhaled budesonide therefore inhibits to the same extent the exaggerated response to both directly acting histamine and bradykinin which acts through airway nerves.

Adolescent↗
PubMed1991

Role of serotonin in therapy of depression and related disorders.

Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.

Aggression↗
PubMed1991

Role of norfluoxetine in the inhibition of desipramine metabolism and in the inhibition of serotonin uptake after fluoxetine administration to rats.

Fluoxetine, a serotonin uptake inhibitor, is known to inhibit the metabolism of some drugs including desipramine, resulting in increased brain and blood levels of desipramine when the drugs are co-administered to rats. Norfluoxetine, the N-desmethyl metabolite of fluoxetine, was found to be less potent than fluoxetine in increasing brain and blood levels of desipramine in rats. Norfluoxetine was essentially equipotent to fluoxetine in decreasing brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) as a consequence of serotonin uptake inhibition. After the injection of fluoxetine into rats, brain levels of fluoxetine predominated over those of norfluoxetine at 1 hour, but at longer times (out to 24 hours), norfluoxetine levels were higher in brain (and in liver) than fluoxetine levels. Brain levels of 5-HIAA were decreased for at least 24 hours after fluoxetine injection, due apparently to the persistence of and inhibition of serotonin uptake by norfluoxetine. When desipramine was injected 16 hrs after fluoxetine injection, brain levels of desipramine were no longer elevated. The results suggest that norfluoxetine contributes in a major way to the inhibition of serotonin uptake after fluoxetine administration but contributes less, if at all, to the inhibition of desipramine metabolism.

Animals↗
PubMed1991

The effect of altering airway tone on the sensitivity of the cough reflex in normal volunteers.

Cough is frequently the presenting symptom of bronchial asthma, although cough can result from a wide variety of other respiratory disease. Treatment of chronic cough has proved extremely difficult. It has been suggested that treatment with bronchodilators may reduce the symptom of cough. In this study the effect of altering airway tone on the sensitivity of the cough reflex was determined. Twelve normal, healthy volunteers took part. The number of coughs following inhalations of single breaths of doubling concentrations of capsaicin (1.95-500 microM) was recorded before and after doses of salbutamol, methacholine and saline which altered forced expiratory volume in one second (FEV1) by 6.2 +/- 2.6%, -8.8 +/- 3.2% and -0.18 +/- 1.38%, respectively. In a further study the cough response was recorded before and after doses of salbutamol and ipratropium bromide, both of which reduced baseline respiratory resistance and resistance measured after capsaicin. Ipratropium bromide, salbutamol and methacholine, despite having significant effects on airway tone, did not change the sensitivity of capsaicin-induced cough. Thus, if bronchodilator drugs are antitussive in non-asthmatic patients, then this is unlikely to be due to an effect on the sensitivity of the cough reflex.

Adult↗
PubMed1991

Cough.

Cough, although the most common respiratory symptom, is poorly understood by doctors. It is still widely believed that all cough occurs as part of mucociliary clearance and thus should only be inhibited with caution. However, it is now known that some and perhaps most cough occurs as a consequence of increased sensitivity of the cough reflex and therefore could be suppressed with safety.

Cough↗
PubMed1990

Drugs affecting serotonin neurons.

Advances in serotonin pharmacology, the development of drugs that intervene at specific sites to modify serotonergic function, have accompanied advances in the understanding of physiologic roles of serotonin present in neurons and elsewhere and of serotonin receptors that are widely distributed in brain and many peripheral tissues. The pharmacologic advances have sometimes been stimulated by developments in serotonin physiology, such as the recognition of multiple serotonin receptor subtypes, and in other cases have been a major factor in providing new insights into physiologic roles of serotonin. Drugs that modify serotonin function have a variety of therapeutic applications currently and many more potential therapeutic uses to be explored in the future. Having drugs that act with high specificity or selectivity on particular enzymes in serotonin biosynthesis, on particular serotonin receptors, or at other sites such as uptake carriers for serotonin not only offers the hope of improved clinical therapy in diseases caused by abnormal serotonergic function or in which alteration of serotonergic function can alleviate symptoms, but also provides valuable pharmacologic tools for learning more about serotonin physiology and probing the functional status of serotonergic systems. The next few years promise to yield important new serotonergic drugs.

Animals↗