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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 55 records · Page 3Linked to original sources
PubMed1995

Assessing equivalence of inhaled drugs.

The move to disease management has led to an increase in the practice of drug or formulation substitution on the basis of equivalence. Well established guidelines are available for judging equivalence between oral, but not inhaled, formulations. This article describes the criteria by which equivalence can be assessed and concludes that although traditional issues such as adequate sample size are important, studies also need to be designed in such a way as to avoid the possibility of falsely concluding clinical equivalence.

Administration, Inhalation↗
PubMed1995

The effect of topical fluticasone propionate on intranasal histamine challenge in subjects with perennial allergic rhinitis.

The mechanism of action of topical intranasal steroids is obscure. To investigate this, we have studied the effects of a topical intranasal corticosteroid, fluticasone propionate on nasal airflow resistance (Rnaw), secretions, cytological smears and symptoms. Fluticasone propionate aqueous nasal spray was given to 11 patients with perennial allergic rhinitis in a double-blind, placebo-controlled study. On each day, patients were challenged with ascending doses of histamine. Rnaw, secretion volume, total protein, mucin, lysozyme and albumin were measured. Nasal smears were taken and sneezes counted. Diary card data were collected for both treatment periods. There was a significant, dose-related increase in Rnaw and sneezing on histamine challenge. A single dose of fluticasone had no effect on any parameter. After 4 weeks of treatment, resistance measurements were reduced (post-challenge g.m.2.8 cmH2O/l/s, Q1-Q3 1.6-4.8; placebo 4.2, 2.9-5.3: P < 0.0001) as were baseline secretion volumes (mean 2.4 ml/5 min, c.i.1.9-3.0; placebo 3.3, 2.8-3.8: P < 0.05). Eosinophil counts were suppressed (fluticasone 5.8%, c.i. 4.0-15.7; placebo 23.3%, 12.4-34.1: P < 0.05) and the composite symptom score reduced (P < 0.05). Fluticasone has long-term effects on the nasal response to histamine in perennial allergic rhinitis and part of this effect is likely to be vascular.

Administration, Topical↗
PubMed1995

Postoperative radiation therapy in clinical stage I endometrial cancer: corpus, cervical, and lower uterine segment involvement--patterns of failure.

PURPOSE: To evaluate involvement of the lower uterine segment (LUS) in adenocarcinoma of the endometrium and to identify patterns of treatment failure. MATERIALS AND METHODS: Two hundred four patients, aged 29-92 years, with endometrial carcinoma underwent surgery. Postoperative radiation therapy was administered for adverse histologic criteria, including deep myometrial invasion, high grade, or LUS involvement. RESULTS: The incidence of tumor involvement of the LUS was 19%; of the cervix, 14%; and of the corpus, 67%. Distant metastasis occurred in 3% of patients with LUS involvement and in 17% of patients with cervical involvement. The local recurrence rate was 50% among patients with LUS involvement with no other risk factors and no postoperative radiation therapy and was 3% among those who underwent radiation therapy (P = .023). CONCLUSION: Early local-regional spread may be the primary mechanism of treatment failure in tumor invasion of the LUS. Aggressive local management, including postoperative radiation therapy, may be necessary.

Adenocarcinoma↗
PubMed1995

Abnormal intraepithelial airway nerves in persistent unexplained cough?

Idiopathic persistent nonproductive cough (PNPC) is characterized by enhanced cough sensitivity to inhaled capsaicin, suggesting that capsaicin-sensitive afferent airway nerves are either present in increased numbers or functionally upregulated. In 16 patients with idiopathic PNPC and eight healthy control subjects, we measured cough sensitivity to inhaled capsaicin and the anatomic density in bronchial epithelium of nerves immunoreactive for the general nerve-marker protein gene product (PGP)-9.5 and the sensory neuropeptides calcitonin-gene-related-peptide (CGRP) and substance-P (SP). The log concentrations of capsaicin required to elicit at least two (C2) and five (C5) coughs were significantly lower in patients (P) than in control subjects (C) (median [range] log C2, P = 0.3 [-0.3 to 1.2] microM; C = 1.5 [0.9 to 2.1], p < 0.0005; log C5, P = 0.8 [-0.3 to 2.1]; C = 2.6 [1.8 to 3.0], p < 0.0005). In bronchial epithelium taken from the carina of the right upper lobe (RUL) and a subsegmental carina of the right lower lobe (RLL), total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant. CGRP-immunoreactive nerve density was significantly higher in P than in C in the RUL (median [range] P = 1.05% [0.13 to 5.08]; C = 0.02% [0 to 0.24], p = 0.001) and RLL (P = 0.59% [0.04 to 3.14]; C = 0% [0 to 0.50], p < 0.02). SP-immunoreactive nerves were not significantly different in the two groups. Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Isolation and structure/activity features of halomon-related antitumor monoterpenes from the red alga Portieria hornemannii.

Ten halogenated monoterpenes (2-6 and 8-12) related to the novel antitumor compound halomon (1) or to the carbocyclic analog 7 have been isolated from different geographic collections of the red alga, Portieria hornemannii. Structures were assigned to the basis of spectral analyses (primarily NMR and MS). The absolute configuration of isohalomon (2) was further established by X-ray crystallography. The compounds were comparatively evaluated alongside 1 and 7 in the U.S. National Cancer Institute's in vitro human tumor cell line screening panel. The results provide some interesting initial insights into the structure/activity relationships in this series.

Antineoplastic Agents↗
PubMed1994

Inhibitory actions of salmeterol on human airway macrophages and blood monocytes.

The effect of beta 2-adrenoceptor agonists, salmeterol and salbutamol on thromboxane B2 release from human airway macrophages and peripheral blood monocytes has been examined. Salbutamol (0.1-100 microM) had no inhibitory effect on the release of thromboxane B2 from human airway macrophages. Salmeterol (0.1-100 microM) caused dose-dependent inhibition of thromboxane B2 release from human airway macrophages stimulated by either zymosan or calcium ionophore A23187. This inhibition was not blocked by propranolol (1 microM). The activity of adenylyl cyclase in homogenates of human airway macrophages was increased by NaF (10 mM) by 8.5-fold and salmeterol (100 microM) and isoprenaline (10 microM) by 1.6- and 1.4-fold, respectively. Isoprenaline alone was inhibited by propranolol (1 microM). Salmeterol caused a biphasic inhibition of peripheral blood monocyte thromboxane B2 release. The inhibition at low (10 nM) concentrations of salmeterol was blocked by propranolol and that at higher concentrations (100 microM) was unaffected. The long lipophilic tail of salmeterol had similar inhibitory effects on the airway macrophages to salmeterol itself, and on the peripheral blood monocytes its action resembled that of the highest concentrations of salmeterol used. It is concluded that salmeterol inhibits mediator release from human airway macrophages by a beta-adrenoceptor independent mechanism and from blood monocytes by both beta-adrenoceptor and non-beta-adrenoceptor mechanisms. The latter mechanism may be associated with the lipophilic properties of the salmeterol molecule.

Adenylyl Cyclases↗
PubMed1994

Comparison of the effect of inhaled selective and non-selective adrenergic agonists on cardiorespiratory parameters in chronic stable asthma.

Increased hypoxia has been found after beta 2 adrenoceptor agonists (but not adrenaline) in asthmatics. Combined with hypokalaemia and sympathomimetic stimulation, this may predispose to cardiac arrhythmias. We have compared the effects of nebulized adrenaline and a selective beta 2 agonist (salbutamol) on the arterial oxygen saturation (SaO2), minute ventilation (VE), forced expiratory volume in 1 s (FEV1), plasma potassium and the electrocardiogram (ECG) in patients with chronic stable asthma. Six patients were studied according to a randomized, placebo-controlled, double-blind cross-over protocol. Adrenaline (5 mg), salbutamol (5 mg) and placebo were administered during 4 min tidal breathing using a nebulizer driven by air. There was a fall in SaO2 after both adrenaline (mean % fall (SEM) 3.3 (0.2)) and salbutamol (4.0 (0.7)) associated with an increase in FEV1, with no change in VE. Therefore, the fall in SaO2 must have been caused by increased ventilation-perfusion imbalance. There was an increased heart rate after both adrenaline and salbutamol and ventricular ectopic beats and a short run of parasystole were recorded on the ECG in one patient after adrenaline and in two patients after salbutamol. No change was found in plasma potassium levels. We conclude that both adrenaline and a selective beta 2 agonist salbutamol can cause a fall in SaO2 and ventricular ectopy in some asthmatic patients.

Administration, Inhalation↗
PubMed1994

Fluoxetine at anorectic doses does not have properties of a dopamine uptake inhibitor.

Although fluoxetine is a highly selective inhibitor of serotonin uptake in vitro and in vivo, some investigators have suggested that dopamine uptake inhibition may contribute to anorectic actions of fluoxetine. The present experiments were done to determine fluoxetine's effects in some animal protocols in which dopamine uptake inhibitors have characteristic actions. Mazindol prevented the depletion of striatal dopamine and its metabolites by amphetamine in iprindole-pretreated rats, but fluoxetine had no effect. Mazindol prevented the depletion of striatal dopamine and its metabolites by 6-hydroxydopamine injected intracerebroventricularly into rats, but fluoxetine had no effect. Mazindol enhanced the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain after spiperone injection, but fluoxetine did not cause that effect. Fluoxetine did not mimic amfonelic acid in antagonizing the retention of alpha-methyl-m-tyramine invant striatum after the injection of alpha-methyl-m-tyrosine. These results show that fluoxetine, at doses that are effective in blocking the serotonin uptake carrier and causing anorexia, does not block the dopamine uptake carrier.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo.

Nefazodone (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl- 2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one) has been reported to be effective in the treatment of depression. Antagonism of serotonin type 2A (5HT2A) receptors, as well as inhibition of the serotonin (5HT) uptake carrier, has been suggested to contribute to the antidepressant action of nefazodone in vivo (Eison et al., 1990). Nefazodone weakly antagonized the quipazine-induced rise in rat serum corticosterone levels and the quipazine-induced increase in rat hypothalamic 3-methoxy-4-hydroxy-phenylglycol sulfate, suggesting blockade of 5HT2A receptors in vivo. Nefazodone, however, failed to antagonize the p-chloroamphetamine-induced depletion of mouse or rat brain 5HT, displaying a lack of effect on the 5HT uptake carrier. These data extend previous in vitro and in vivo data (Eison, et al. 1990) reporting nefazodone to be an antagonist at 5HT2A receptors, but fail to show inhibition of the 5HT uptake carrier in the same dose range.

Animals↗
PubMed1994

Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis.

The physiological role of the serotonin transporter on serotonin neuronal membranes apparently is to inactivate serotonin that has been released into the synaptic cleft. Drugs that inhibit the uptake of serotonin increase the amount of serotonin in the synaptic cleft and enhance serotonergic neurotransmission. As an adaptive response to the increased amount of serotonin in the synaptic cleft, serotonin neurons decrease their firing and release of serotonin to limit the magnitude of the increase in extracellular serotonin concentration. The increase in extracellular serotonin in rat brain caused by inhibitors of the serotonin uptake carrier has been characterized by brain microdialysis coupled to liquid chromatography with electrochemical detection. These drugs cause rapid accumulation of extracellular serotonin in several brain regions, although the increase in frontal cortex may be smaller than in other nerve terminal regions or in the cell body-containing raphe region.

5-Hydroxytryptophan↗
PubMed1994

Proposed animal model of attention deficit hyperactivity disorder.

Dopamine (DA) neurons are implicated in the hyperlocomotion of neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Because serotonin (5-HT) neurons mediate some DA agonist effects, we investigated the possible role of 5-HT neurons on locomotor activity. Rats were treated at 3 days after birth with vehicle or 6-OHDA (134 micrograms ICV; desipramine pretreatment, 20 mg/kg IP, 1 h), and at 10 weeks with vehicle or 5,7-dihydroxytryptamine (5,7-DHT; 75 micrograms ICV; pretreatment with desipramine and pargyline, 75 mg/kg IP, 30 min), to destroy DA and/or 5-HT fibers. Intense spontaneous hyperlocomotor activity was produced in rats lesioned with both 6-OHDA and 5,7-DHT. Locomotor time in this group was 550 +/- 17 s in a 600 s session, vs. 127 +/- 13 s in the 6-OHDA group and < 75 s in 5,7-DHT and intact control groups (p < 0.001). Oral activity dose-effect curves established that 5,7-DHT attenuated DA D1 receptor supersensitivity and further sensitized 5-HT2c receptors. Acute treatment with dextroamphetamine (0.25 mg/kg SC) reduced locomotor time in 6-OHDA + 5,7-DHT-lesioned rats to 76 +/- 37 s (p < 0.001). Striatal DA was reduced by 99% and 5-HT was reduced by 30% (vs. 6-OHDA group). Because combined 6-OHDA (to neonates) and 5,7-DHT (to adults) lesions produce intense hyperlocomotion that is attenuated by amphetamine, we propose this as a new animal model of ADHD. The findings suggest that hyperactivity in ADHD may be due to injury or impairment of both DA and 5-HT neurons.

5,7-Dihydroxytryptamine↗
PubMed1994

Cucurbitacins: differential cytotoxicity, dereplication and first isolation from Gonystylus keithii.

A characteristic pattern of differential cytotoxicity of extracts of Iberis amara seeds, predominantly toward renal tumor, brain tumor, and melanoma cell lines in the NCI human disease-oriented tumor screening panel, was traced to cucurbitacins E [1] and I [2]. This same differential cytotoxicity profile was detected in extracts of Begonia plebeja and Gonystylus keithii. Computer-assisted recognition of these profiles was followed by a rapid chemical fractionation, thus permitting the efficient dereplication of those extracts containing cucurbitacins B [3] and D [4], respectively. This is the first report of cucurbitacins from the genus Gonystylus.

Antineoplastic Agents, Phytogenic↗
PubMed1994

The effect of topical sodium cromoglycate on intranasal histamine challenge in allergic rhinitis.

Topical sodium cromoglycate is used to treat allergic diseases of the upper and lower airways. To investigate its mechanisms of action, intranasal histamine challenge was used in nine subjects with perennial allergic rhinitis. After a preliminary day where subjects' reactivity thresholds (D100) for histamine were determined, intranasal sodium cromoglycate was administered in a double-blind, placebo-controlled fashion. Graded (D100/3, D100, D100X3), sequential challenges were performed on days 1 and 21 of each course, and responses measured by changes in nasal airway resistance, sneezes, secretion volume and secretion content: total protein, lysozyme and mucin. After a single dose of sodium cromoglycate, there was no change in resistance, but secretion volumes fell significantly (3.12 ml/5 min c.i. 2.83-3.4; placebo 3.61, c.i. 3.32-3.90: P = 0.026). After a 3-week-course, there was a significant fall in resistance (4.29 cm H2O/l/s, c.i. 3.85-4.72; placebo 5.45, c.i. 5.01-5.88: P < 0.0001). No change in other parameters was observed. Thus, in perennial allergic rhinitis, intranasal sodium cromoglycate has both short- and long-term effects on nasal reactivity to histamine challenge. Acutely, there is a reduction in nasal lavage fluid volume which may be the result of reduced irritant receptor activity. After a 3-week course, there is a reduction in nasal resistance responses, a possible anti-inflammatory effect.

Administration, Intranasal↗
PubMed1994

Comparative 5-HT2-receptor antagonist activity of amesergide and its active metabolite 4-hydroxyamesergide in rats and rabbits.

Amesergide is an orally active ergoline amide, 5-HT2-receptor antagonist with a long duration of action. Since a major metabolite of amesergide is 4-hydroxyamesergide, we questioned whether the formation of this metabolite might contribute to the pharmacological activity and long duration of action observed after oral administration of amesergide. 4-Hydroxyamesergide was a potent 5-HT2-receptor antagonist with an affinity equal to or greater than amesergide under in-vitro conditions as measured by blockade of vascular 5-HT2 receptors, and 5-hydroxytryptamine (5-HT)-amplified ADP-induced rabbit platelet aggregation. Furthermore, 4-hydroxyamesergide, like amesergide, inhibited the pressor response to 5-HT after its intravenous administration to rats and was about 3-fold more potent than amesergide in this regard. 4-Hydroxyamesergide was also a potent inhibitor of vascular 5-HT2 receptors after oral administration to rats. After oral administration, 4-hydroxyamesergide had a similar or slightly greater duration of activity than the parent molecule. 4-Hydroxyamesergide, again like amesergide, also blocked central 5-HT2 receptors after its in-vivo administration to rats as measured by its ability to inhibit quipazine-induced increases in serum corticosterone. Thus, the formation of 4-hydroxyamesergide after oral administration of amesergide to animals and man may contribute to the potency and long duration of action of amesergide as a 5-HT2-receptor antagonist.

Adenosine Diphosphate↗