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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 91 records · Page 5Linked to original sources
PubMed1993

Effect of 4-(4-methoxy-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,3,6-tetrahydropyridine , an analog of MPTP, on mouse heart norepinephrine and brain catecholamines.

An analog of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with a thiadiazole substituent in place of the phenyl ring was compared to MPTP in mice for its ability to deplete striatal dopamine and its metabolites and norepinephrine in the frontal cortex and heart. One week after the last of 4 daily s.c. injections, MPTP at 20 mg/kg depleted mouse striatal dopamine, DOPAC and HVA as well as norepinephrine in the frontal cortex. One week after 4 daily s.c. doses of 4-(4-methoxy-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,3,6-tetrahydro pyr idine (MZTP) at doses as high as 80 mg/kg, there was no effect on brain catecholamines. A single dose of MPTP (10 mg/kg s.c.) depleted heart norepinephrine concentration 24 h after injection. MZTP had no effect on heart norepinephrine at 10 mg/kg s.c., but did significantly deplete mouse heart norepinephrine 24 h after a dose of 20 mg/kg s.c.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

A chemical screening strategy for the dereplication and prioritization of HIV-inhibitory aqueous natural products extracts.

A relatively high percentage (ca. 15%) of aqueous extracts from terrestrial plants, cyanobacteria, and marine invertebrates and algae has exhibited activity in the National Cancer Institute's primary AIDS-antiviral screen. By removal of anionic polysaccharides in a first stage of dereplication, we have eliminated from further consideration a considerable number of these extracts. However, a still substantial proportion of the active extracts remained, from which we wished to select and prioritize a small percentage for our detailed bioassay-directed fractionation studies. Therefore, a chemical screening protocol, utilizing various solid-phase extraction cartridges, has been developed for a second-stage dereplication and to assist in prioritization of these extracts for our further investigations.

CD4-Positive T-Lymphocytes↗
PubMed1993

Modulation of capsaicin induced airway reflexes in humans: effect of monoamine oxidase inhibition.

1. In animal studies monoamine oxidase (MAO) inhibition has been shown to reduce the cough response through elevation of 5-HT in the central nervous system. In this study the effect of selective inhibition of the two subtypes of MAO (MAO-A and MAO-B) was studied on human airway reflexes. 2. Capsaicin-induced cough and reflex increase in respiratory resistance were measured in nine normal volunteers before and after MDL 72394 (MAO-A inhibitor) 16 mg or MDL 72974A (MAO-B inhibitor) 12 mg. 3. Neither inhibitor altered capsaicin-induced cough. Following treatment with MDL 72394, however, the capsaicin-induced reflex increase in resistance was enhanced, by 5.97 +/- 2.1 fold of the placebo value at 1 h. 4. Thus, neurotransmitters in the central nervous system which are substrate for MAO-A (i.e. noradrenaline, 5-HT) may be involved in the control of capsaicin-induced reflex bronchoconstriction.

Adult↗
PubMed1993

Effect of topical beclomethasone on histamine-induced increases in nasal airflow resistance and secretion in perennial rhinitis.

The effects of topical beclomethasone dipropionate on changes in nasal resistance and secretion induced by topical histamine were studied in eight patients with perennial rhinitis. Patients were studied at enrollment, after 3 weeks of beclomethasone (100 micrograms spray to each nasal cavity twice daily), and after 3 weeks of placebo (saline) treatment administered in a double-blind cross-over trial. Nasal airflow resistance (Rnaw) and total protein, albumin, lysozyme and glycoconjugate secretion in nasal lavage fluids were measured after topical application of histamine to the nasal mucosa. Resistance measurements and secretory parameters were similar for the initial study and after placebo treatment. In those studies, histamine (1 and 10 mg) increased both nasal resistance and secretion of total protein, albumin and glycoconjugates. After beclomethasone treatment the rise in respiratory resistance in response to histamine was significantly attenuated (delta Rnaw, +11.57 cm H2O/l/s with placebo, +5.80 with beclomethasone, P < 0.05). Beclomethasone had no effect on histamine-induced secretion. Because nasal resistance is determined mainly by vascular processes, beclomethasone treatment appears to have a prominent action on the vascular bed to reduce mediator-induced vasodilatation in perennial rhinitis.

Administration, Intranasal↗
PubMed1993

Extracellular 5-hydroxytryptamine concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytryptophan.

Fluoxetine (10 mg kg-1, i.p.) caused a three- to fourfold increase in extracellular 5-hydroxytryptamine (5-HT) concentration measured by microdialysis in hypothalamus of freely moving rats. The addition of L-5-hydroxytryptophan at 20 or 40 mg kg-1, i.p. doses, magnified the increase in extracellular 5-HT to as much as 16 times basal levels, although these doses of L-5-hydroxytryptophan alone had only small effects on extracellular 5-HT. The increased formation of 5-HT following L-5-hydroxytryptophan administration appears to overcome homeostatic mechanisms that limit the increases in extracellular 5-HT caused by uptake inhibition.

5-Hydroxytryptophan↗
PubMed1993

Effect of an oral potassium channel activator, BRL 38227, on airway function and responsiveness in asthmatic patients: comparison with oral salbutamol.

BACKGROUND: Potassium (K+) channel activators, such as cromakalim, open ATP sensitive K+ channels and relax airway smooth muscle in vitro and inhibit induced bronchoconstriction in vivo in animals. The prolonged half life of cromakalim gives it potential as an oral bronchodilator. The effect of orally administered BRL 38227 (the active enantiomer of cromakalim), at doses of 0.125, 0.25, and 0.5 mg, on airway function and airway responsiveness to histamine and methacholine has been investigated in asthmatic patients. METHODS: Seventeen patients with asthma were studied in three separate randomised double blind, placebo controlled studies. In the first study eight patients with moderately severe asthma were given 0.125, 0.25, and 0.5 mg of BRL 38227 or placebo, and responses to histamine were assessed before and five hours after treatment. In the second study responses to methacholine were measured before and five hours after 0.125 and 0.5 mg of BRL 38227 or placebo were given to nine patients with mild asthma. In the third study the effect of 0.5 mg of BRL 38227 or placebo was assessed in eight patients with mild asthma. Responses to histamine were measured before treatment and two and five hours after treatment. To provide a positive control study eight subjects who had taken part in studies 1 and 3 were also given oral salbutamol (8 mg) in a placebo controlled, double blind study. Responses to histamine were assessed before and two hours after treatment. RESULTS: BRL 38227 did not cause significant bronchodilatation or changes in airway responsiveness in any of the studies. Headache was reported in 19 of 25 of patients receiving (in some cases twice) 0.5 mg of BRL 38227. By contrast, oral salbutamol gave significant protection against histamine challenge (geometric mean 2.23 doubling dilutions). CONCLUSIONS: After a single oral dose of BRL 38227 no beneficial effect on airway function was detected, despite a high incidence of side effects, which indicates that the orally administered K+ channel activator BRL 38227 may not be useful in the management of asthma.

Adult↗
PubMed1993

Decrease of histamine induced bronchoconstriction by caffeine in mild asthma.

BACKGROUND: While high doses of caffeine may affect pulmonary function and bronchial challenge tests in patients with mild asthma, the effects of lower doses (< or = 5 mg/kg) are less well documented. Specific recommendations exist for withholding theophylline, but not caffeine, before bronchoprovocation and pulmonary function testing. METHODS: To assess the effect of a single oral dose of caffeine (5 mg/kg) on FEV1 and bronchial responsiveness to histamine a double blind, placebo controlled study was performed in eight patients with mild stable asthma. RESULTS: While caffeine had no effect on FEV1, mean (95% confidence interval) log PC20 histamine was significantly higher 150 minutes [caffeine = 0.99 (0.2) mg/ml, placebo = 0.53 (0.29)] and 240 minutes [caffeine = 0.89 (0.24), placebo = 0.44 (0.26)] after administration of caffeine than after placebo. CONCLUSIONS: Caffeine should be excluded from the diet for a period of more than four hours before bronchial provocation testing. The exact length of time for which it must be excluded requires further study.

Adult↗
PubMed1993

Effects of 5-hydroxytryptamine and 5-hydroxytryptophan infusion on the human cough reflex.

In some species serotonin (5-HT) has been shown to act as a central modulator of the cough reflex. To investigate whether serotonergic mechanisms influence the control of the human cough reflex, we have induced cough responses before and during infusions of 5-HT; its precursor 5-hydroxytryptophan (5-HTP), which, in contrast to 5-HT, crosses the blood-brain barrier; and saline control. At the start of each study day, eight normal male volunteers were challenged with a single inhalation of a solution lacking chloride ions (0.15 M sodium bicarbonate) and a single breath of capsaicin during a sham infusion. After 3 h they received repeat cough challenges during experimental infusions of 5-HT, 5-HTP, or saline control, which were given randomly and single blind. Heart rate, respiratory rate, and blood pressure were measured before, during, and after each infusion. Both 5-HT and 5-HTP reduced cough responses to the chloride-deficient solution (P = 0.035 and P = 0.017, respectively) with respect to saline control, whereas neither infusion reduced responses to capsaicin. 5-HT caused a transient increase in heart rate that was not observed with a similar dose of 5-HTP or saline (P < 0.01). Respiratory rate and blood pressure were not affected by experimental infusions but rose during cough challenge. We conclude that 5-HT exerts an inhibitory influence over the human cough reflex at peripheral and possibly central sites.

5-Hydroxytryptophan↗
PubMed1993

Sodium cromoglycate: evidence of tachykinin antagonist activity in the human skin.

The mechanism of action of the antiasthmatic drug sodium cromoglycate (SCG) is unclear. One possibility is that SCG antagonizes the effects of the tachykinin substance P (SP), an agent known to cause airway edema. However, when SP is inhaled by humans, it has no demonstrable effect on airway function; therefore, the possibility that SCG prevents SP-induced changes in microvascular permeability was examined in human skin in vivo where potent edema-producing effects are seen. SCG (5-500 nmol) caused significant (P < 0.05) dose-dependent inhibition of SP-induced edema (wheal) formation when coadministered by intradermal injection. There was no effect on the nonreceptor-mediated flare response. SCG also significantly (P < 0.05) inhibited the wheal response to the related tachykinin neurokinin B but had no inhibitory effect on the cutaneous responses to histamine and prostaglandin E2. In addition, SCG (0.1-10 mM) caused dose-dependent inhibition of binding of SP labeled with 125I-labeled Bolton-Hunter to a number of tissues known to contain SP binding sites, as assessed by autoradiography. These concentrations were equivalent to the final concentrations of SCG found to inhibit the wheal response in the skin. The possibility that SCG interacted with SP was investigated both by gel filtration and high-performance liquid chromatography. No strong interaction was demonstrated with an 8,000 M excess of SCG under both hydrophobic and hydrophilic conditions. These results raise the possibility that SCG may have tachykinin antagonist properties.

Adult↗
PubMed1993

Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion.

Allergen challenge is associated with an increased excretion of urinary leukotriene E4. The source of this increase is unknown, although the lack of effect of inhaled beta-agonists and sodium cromoglycate suggests that airway mast cells may not be involved. We investigated this further using a new and topically potent inhaled glucocorticoid, fluticasone propionate (FP). A group of 10 mild atopic asthmatic subjects (6 males; FEV1 > 60% of predicted; PC20 histamine < or = 8 mg/ml; and on inhaled beta 2-agonists only) were studied before and after a 2-wk period of FP (1,000 micrograms/day) or placebo administered by metered-dose inhalers as two puffs twice per day through a large-volume spacer. Treatments were assigned in a double-blind crossover fashion separated by a 3-wk washout period. The PC20 histamine was measured at the start and end of each treatment when subjects also received a bronchial allergen challenge. Urine was collected for 4 h after allergen challenge for determination of LTE4 using HPLC-RIA, and 2 h later the PC20 histamine measurement was repeated. The 2-wk treatment with FP significantly inhibited both early and late responses to allergen: the maximum % fall in FEV1 during the early (0 to 2 h) and late response (2 to 6 h) was 32.6 +/- 3.4 and 19.6 +/- 5.2, respectively, following placebo versus 19.5 +/- 4.5 and 3.6 +/- 2.6 following FP (both p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Intranasal histamine challenge in normality and allergic rhinitis.

A series of investigations was performed in which histamine challenge was used to compare nasal responsiveness in 20 normal subjects and 20 with allergic rhinitis. There was found to be a lower threshold of reactivity (D100) to histamine in allergic subjects as measured by resistance changes (geometric mean, 0.53 mg/ml; normal subjects, 2.15: p = 0.022). This may represent increased number or sensitivity of histamine receptors on the nasal capacitance vessels. The loss of a laser Doppler response to a supramaximal histamine stimulus (normal subjects, 102% increase in flux at 3 minutes; p < 0.05) was observed in patients with allergic rhinitis and indicates either a down-regulation of the capillary system or an altered effect of histamine on superficial vessels, perhaps mediated by a shift in histamine receptor type. There was an observed increase in neutrophils at the mucosal surface under baseline conditions (rhinitis median, 49.6%; normal subjects, 32.72%: p < 0.05), which suggests an important primary role in the pathogenesis of this condition for this active cell. The observed increase in secretory volume response to histamine in allergic subjects, which persisted beyond 40 minutes after a single D100 challenge, may be related to an altered sensitivity of glandular tissue. There are important changes in nasal reactivity to histamine challenge in allergic rhinitis that may have implications for its pathogenesis.

Adult↗
PubMed1993

Progress in the medicinal chemistry of dopaminergic agents.

Ergot alkaloids and their derivatives have long been recognized for their potent pharmacologic activity. A number of ergot derivatives, including the dopamine agonists bromocriptine and pergolide, are currently in clinical use for the treatment of CNS and endocrine disorders. In an effort to develop more selective dopamine agonists, studies were directed to elucidate the dopaminergic pharmacophore of the ergoline nucleus. During the course of this work, it was found that the tricyclic system containing only the B-, C-, and D-rings of the ergoline skeleton (2, X = CH) possessed D-2 dopamine agonist activity. As a result of this discovery, interest was stimulated in the preparation of other heteroareno[g]quinoline systems (3, "BCD partial ergolines") for investigation of their dopaminergic properties. Factors which we found to be particularly important in determining dopaminergic activity were: (1) the nature of the heteroaromatic B ring; (2) the orientation of that heteroaromatic ring; (3) the substituents on the heteroaromatic ring; and (4) the relative and absolute stereochemistry at the CD ring fusion. We report here the synthesis and pharmacologic activity of a series of BCD partial ergolines (3) and describe how the study of these new compounds allows for the delineation of structural features important in D2 dopamine receptor activation.

Animals↗
PubMed1993

Possible involvement of dopamine in the long-term serotonin depletion by p-chloroamphetamine and beta,beta-difluoro-p-chloroamphetamine in rats.

The role of dopamine in the long-term depletion of serotonin in rat brain by p-chloroamphetamine (PCA) and related compounds was investigated by comparing effects of beta,beta-difluoro-p-chloroamphetamine (beta,beta-difluoro-PCA) and 4-methyl-alpha-ethyl-meta-tyramine (H75/12), reported to cause only short-term serotonin depletion, with those of PCA. A single dose of beta,beta-difluoro-PCA had no long-term effects on serotonin in whole rat brain, even after pretreatment with proadifen which decreased the rate at which beta,beta-difluoro-PCA disappeared from brain. The possibility that proadifen might antagonize serotonin depletion was ruled out; proadifen did not prevent long-term serotonin depletion by PCA. Long-term depletion of brain serotonin was found after repeated injections of beta,beta-difluoro-PCA (five injections 4 hr apart) and was prevented by fluoxetine pretreatment. beta,beta-Difluoro-PCA given after the monoamine oxidase inhibitor pargyline or after carbidopa/L-dopa also caused long-term serotonin depletion, although H75/12 did not. At early times after single doses producing the same initial depletion of serotonin, PCA caused a large increase in dopamine and a large decrease in the metabolite 3,4-dihydroxyphenylacetic acid in whole brain, thereby increasing the ratio dopamine/3,4-dihydroxyphenylacetic, and the other two drugs caused smaller effects. Extracellular dopamine was increased markedly by PCA, less by beta,beta-difluoro-PCA, and not at all by H75/12. These results suggest an association between dopamine release and long-term depletion of serotonin and add to evidence that dopamine release by PCA may be essential to its neurotoxic actions on brain serotonin neurons.

Amphetamines↗
PubMed1993

Preclinical studies on LY228729: a potent and selective serotonin1A agonist.

LY228729 is a conformationally restricted tryptamine derivative with a carboxamide serving as a protophilic group to mimic the hydroxyl in serotonin (5-HT). LY228729 has high affinity for the 5-HT1A receptor, weak affinity for the 5-HT1D receptor and no significant affinity for other monoaminergic receptors studied. LY228729 was less effective than 5-carboxamidotrytamine in suppressing K(+)-evoked release of 3H-5-HT from parietal-occipital cortical slices from guinea pigs, which is in agreement with its weak 5-HT1D receptor affinity. LY228729 reduced hypothalamic 5-hydroxyindole-3-acetic acid levels and increased serum corticosterone levels in rats. LY228729 reduced hypothalamic 5-hydroxytryptophan accumulation after decarboxylase inhibition. LY228729 increased flat posture and lower lip retraction scores in rats at doses between 0.1 and 1 mg/kg s.c. (p.o. doses were 10 times higher) and these effects were blocked by (+/-) pindolol. LY228729 induced a hypothermic response in rats, which was blocked by (+/-) pindolol. These in vivo responses are characteristics of compounds with 5-HT1A agonist activity. In the preclinical efficacy models, LY228729 suppressed motion sickness responses in cats; decreased ejaculatory latency and the increased copulatory efficiency and rate in rats and increased punished responding at lower doses than it lowered unpunished responding in rats. Collectively, these results indicate that LY228729 is potent 5-HT1A agonist with bioavailability properties sufficient for clinical evaluation and with efficacy in preclinical models of anxiety, sexual disorders and motion sickness. Since the 5-HT1A agonists that have been studied previously have antidepressant activity, this indication will also be evaluated.

Animals↗
PubMed1992

Dextromethorphan antagonizes the acute depletion of brain serotonin by p-chloroamphetamine and H75/12 in rats.

A role for calcium in p-chloroamphetamine-induced neurotoxicity has been inferred previously from protective effects of dextromethorphan. We found that dextromethorphan reduces rat brain concentrations of 5-hydroxyindoleacetic acid and blocks the acute, non-neurotoxic depletion of brain serotonin by p-chloroamphetamine and by H75/12. Inhibition of the membrane transporter on brain serotonin neurons by dextromethorphan in vivo might explain its protective effect against p-chloroamphetamine neurotoxicity.

Amphetamines↗
PubMed1992

A pentahalogenated monoterpene from the red alga Portieria hornemannii produces a novel cytotoxicity profile against a diverse panel of human tumor cell lines.

A polyhalogenated acyclic monoterpene, 6(R)-bromo-3(S)-(bromomethyl)-7- methyl-2,3,7-trichloro-1-octene (1) was obtained as a major component of the organic extract of the red alga Portieria hornemannii. X-ray diffraction analysis provided the complete structure, including correct placement of the different halogen atoms and determination of the absolute stereochemistry. Detailed NMR analyses provided complete 1H and 13C assignments. Compound 1 exhibited highly differential cytotoxicity against the U.S. National Cancer Institute's new in vitro human tumor cell line screening panel; brain tumor, renal, and colon tumor cell lines were most sensitive to 1, while leukemia and melanoma lines were relatively less sensitive. A second collection of P. hornemanni yielded the novel, monocyclic 2, considerably less cytotoxic and devoid of differential activity. On the basis of its unprecedented cytotoxicity profile in the NCI primary screen, compound 1 has been selected by the NCI Decision Network Committee for preclinical drug development.

Antineoplastic Agents↗
PubMed1992

The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum.

Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1 microM and 0.4 microM, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.

Antiviral Agents↗