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Biomedical subjects

A Naylor

Publications and source records attributed to A Naylor.

At least 19 recordsLinked to original sources
PubMed2001

Autoradiographic localisation and contractile properties of prostatic endothelin receptors in patients with bladder outlet obstruction.

OBJECTIVES: Previous studies have used endothelin (ET) receptor agonists and antagonists to localise ET receptor subtypes in prostatic tissue. We have utilised high affinity ET(A) ([(125)I]PD151242) and ET(B) ([(125)I]BQ3020) receptor-specific radioligands to determine the density and distribution of ET receptor subtypes in prostatic tissues obtained from patients with symptomatic benign prostatic hyperplasia (BPH). The contractile properties of the ET receptor subtypes as well as the effect of ET-1 on alpha(1)-adrenergic receptor-mediated prostatic smooth muscle contraction were assessed. PATIENTS AND METHODS: Saturation binding and quantitative autoradiographic studies were performed using specific radioligands for ET(A) and ET(B) receptors on prostate sections obtained from patients with bladder outflow obstruction secondary to BPH. In vitro isometric tension studies were carried out to characterise the ET receptor subtypes in prostatic smooth muscle strips from the same group of patients. In addition, the effect of ET-1 on alpha(1)-adrenergic receptor-induced prostatic smooth muscle contraction was also investigated. RESULTS: There were dense ET(A) and ET(B) receptor-binding sites in the prostatic stroma. ET(A) receptor-binding sites were also prominent on the prostatic epithelium. ET-1 and sarafotoxin 6 c (ET(B) receptor agonist) elicited prostatic smooth muscle contraction (-log EC(50) 8.31+/-0.15 and 8.22+/-0.22 M, respectively). Both BQ123 (ET(A) antagonist) and BQ788 (ET(B) antagonist) significantly inhibited ET-1- and S6c-mediated prostatic smooth muscle contractile responses, respectively. ET-1 at sub-threshold concentrations significantly enhanced alpha(1)-adrenergic receptor-mediated prostatic smooth muscle contractile responses. CONCLUSIONS: ET(A) receptor-binding sites are prominent in both prostatic stroma and epithelium, whereas ET(B) receptor-binding sites were predominantly seen in the prostatic stroma in symptomatic BPH. Both ET(A) and ET(B) receptors mediate prostatic smooth muscle contraction. ET-1 enhances alpha(1)-adrenergic receptor-mediated contractile responses, suggesting that ET may play a pathophysiological role in bladder outlet obstruction associated with BPH.

Aged↗
PubMed1998

The insulin-like growth factor type I receptor stimulates growth and suppresses apoptosis in prostatic stromal cells.

Stromal cells derived from benign prostatic hyperplasia synthesize and secrete measurable levels of insulin-like growth factor (IGF). Seventy-two-hour conditioned medium obtained from these cells contains IGF-II at levels ranging from 125-177 ng/mL.10(6) cells. IGF-I is almost undetectable. RT-PCR analysis has demonstrated that the genes for both the type I IGF receptor (IGF-IR) and the type II IGF receptor (IGF-IIR) are expressed by benign stromal cells in vitro. Competition binding analysis for IGF-I and IGF-II confirmed the existence of binding sites for both ligands with respective Kd and binding capacities of 4.9 x 10(-9) mol/L and 6.6 x 10(5) sites/cell and 4.7 x 10(-9) mol/L and 3.8 x 10(6) sites/cell. Under serum-free conditions, IGF-I and IGF-II at 500 ng/mL induce 80% and 113% increases in stromal cell density, respectively, over a 96-h period. Incubation with the IGF-IR-neutralizing antibody alpha IR3 (50 micrograms/mL) reduces the rate of stromal cell proliferation by approximately 60-80% even in the presence of stimulatory concentrations of IGFs. Camptothecin-induced apoptosis is inhibited by the addition of IGF-I and -II (500 ng/mL). alpha IR3 suppresses these survival signals and itself induces cell death in the prostatic stroma. The data suggest that IGF-IR is a pivotal molecule in prostatic stromal cell maintenance, and that specific antagonism may offer a novel means of controlling the fibromuscular expansion characteristic of benign prostatic hyperplasia.

Apoptosis↗
PubMed1998

Increasing breastfeeding rates to reduce infant illness at the community level.

OBJECTIVE: Although breastfeeding is associated with lower rates of a variety of infant illnesses, skeptics have suggested that much of the association is attributable to confounding, even after appropriate statistical adjustment. This article utilizes a novel design to investigate changes in infant illness at the community level after a successful breastfeeding promotion program. METHODS: In this population-based cohort study, the medical records of all infants born in one Navajo community the year before a breastfeeding promotion program (n = 977) and the year during the intervention (n = 858) were reviewed. Outcomes assessed include changes after the intervention in: proportion breastfeeding and/or breastfeeding exclusively; incidence of common infant illnesses in the first year of life; and feeding-group specific incidence of illness. RESULTS: The proportion of women breastfeeding exclusively for any period of time increased from 16.4% to 54.6% after the intervention. The percent of children having pneumonia and gastroenteritis declined 32. 2% and 14.6%, respectively, after the intervention. Feeding-group specific rates of these illnesses were unchanged, indicating that the decline observed was attributable to the increased proportion of infants breastfeeding. In contrast, rates of croup and bronchiolitis increased after the intervention among those fed formula from birth, suggesting a viral epidemic which was limited to those never exclusively breastfed. Finally, sepsis declined in both formula-fed and breastfed infants after the intervention, suggesting that other factors affected this illness outcome after the intervention. CONCLUSIONS: Increasing the proportion of exclusively breastfed infants seems to be an effective means of reducing infant illness at the community level. The experimental design suggests that the increased incidence of illness among minimally breastfed infants is causally related to lack of breast milk, rather than being attributable to confounding.

Breast Feeding↗
PubMed1998

Novel C-2 substituted carbapenem derivatives. Part IV. Synthesis and biological activity of five membered heteroaromatic derivatives.

The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.

Carbapenems↗
PubMed1997

Effect of single point mutations of the human tachykinin NK1 receptor on antagonist affinity.

Molecular modelling and site-directed mutagenesis were used to identify eleven amino acid residues which may be involved in antagonist binding of the human tachykinin NK1 receptor. Recombinant receptors were expressed in mammalian cells using the Semliki Forest virus system. Wild type and mutant receptors showed similar expression levels in BHK and CHO cells, verified by metabolic labelling. Binding affinities were determined for a variety of tachykinin NK1 receptor antagonists in SFV-infected CHO cells. The binding affinity for GR203040, CP 99,994 and CP 96,345 was significantly reduced by mutant Q165A. The mutant F268A significantly reduced the affinity for GR203040 and CP 99,994 and the mutant H197A had reduced affinity for CP 96,345. All antagonists seemed to bind in a similar region of the receptor, but do not all rely on the same binding site interactions. Functional coupling to G-proteins was assayed by intracellular Ca2+ release in SFV-infected CHO cells. The wild type receptor and all mutants except A162L and F268A responded to substance P stimulation.

Animals↗
PubMed1997

Using cultural knowledge in health promotion: breastfeeding among the Navajo.

Although many attempts have been made to promote breastfeeding in a variety of contexts, few programs have explicitly incorporated cultural beliefs in these efforts. This article describes a breastfeeding promotion program conducted on the Navajo reservation. This program was designed to be culturally appropriate. Background information regarding beliefs and factors affecting infant feeding practices in this setting is provided, followed by a description of the intervention. The intervention, which incorporated both social marketing and community participation techniques, consisted of three components: an intervention in the health care system, a community intervention, and an individual intervention. Based on medical records review of feeding practices of all the infants born the year before (n = 988) and the year after (n = 870) the intervention, the program was extremely successful. This combination of techniques, including qualitative and quantitative research into local definitions of the problem, collaboration with local institutions and individuals, reinforcement of traditional understandings about infant feeding, and institutional change in the health care system, is an effective way of facilitating behavioral change.

Breast Feeding↗
PubMed1996

Micturition in conscious rats with and without bladder outlet obstruction: role of spinal alpha 1-adrenoceptors.

1. In normal rats and rats with bladder hypertrophy secondary to outflow obstruction, undergoing continuous cytometry, we examined the responses to the selective alpha 1-adrenoceptor antagonist doxazosin given intrathecally (i.t.) and intra-arterially (i.a.). In addition, we investigated the effects of the drug on L-dopa-induced bladder hyperactivity in normal, unobstructed rats. 2. Doxazosin 50 nmol (approximately 60 micrograms kg-1), given i.t., decreased micturition pressure in normal rats and in animals with post-obstruction bladder hypertrophy. The effect was much more pronounced in the animals with hypertrophied/overactive bladders. Doxazosin did not markedly affect the frequency or amplitude of the unstable contractions observed in obstructed rats. In contrast, however, doxazosin reduced L-dopa-induced bladder overactivity. When tested, the enantiomers of doxazosin produced qualitatively similar effects to doxazosin, but there was no evidence of stereoselectivity. 3. The results suggest that in addition to the well documented action on prostatic and lower urinary tract smooth muscle, and an effect on the sympathetic outflow to the bladder, bladder neck, prostate, and external urethral sphincter, doxazosin may have an action at the level of the spinal cord and ganglia, thereby reducing activity in the parasympathetic nerves to the bladder. This effect is more pronounced in rats with bladder hypertrophy than in normal rats.

Adrenergic alpha-Antagonists↗
PubMed1996

Novel C-2 substituted carbapenem derivatives. Part I. Synthesis and biological activity of non-aromatic heterocyclic derivatives.

A new series of carbapenems, having a saturated or partially unsaturated heterocycle at C-2, has been synthesised. The in vitro antibacterial activity of these compounds and their stability to human dehydropeptidase-1 (DHP-1) are described. The stereochemistry of the C-2 side-chain and the presence of a double bond in the heterocycle were shown to have significant effects on the stabilities of the compounds to DHP-1.

Bacteria↗
PubMed1996

Novel C-2 substituted carbapenem derivatives. Part II. Synthesis and structure-activity relationships of isoxazolin-2-yl, isoxazolidin-2-yl and 2-pyrazolin-2-yl carbapenems generated using 1,3-dipolar cycloaddition chemistry.

A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem. The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1). Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity. The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.

Carbapenems↗
PubMed1994

4-[(Alkylamino)methyl]furo[3,2-c]pyridines: a new series of selective kappa-receptor agonists.

The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (mu-specific and delta-specific tissues, respectively), 17 showed only weak antagonist activity (pKB > 5.5), underlining its selectivity for the kappa-opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).

Analgesics↗
PubMed1993

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.

Analgesics↗
PubMed1992

New kappa-receptor agonists based upon a 2-[(alkylamino)methyl]piperidine nucleus.

The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

Analgesics↗
PubMed1992

GR94839, a kappa-opioid agonist with limited access to the central nervous system, has antinociceptive activity.

1. The pharmacological profile of GR94839, a kappa-opioid agonist with limited access to the central nervous system, has been investigated. Its antinociceptive activity has been compared with that of GR103545, a centrally-penetrating kappa-agonist and ICI204448, the previously described peripherally-selective kappa-agonist. 2. GR94839 was a potent agonist in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50: 1.4 +/- 0.3 nM; n = 6), but had limited activity at mu- or delta-opioid receptors. 3. In the mouse abdominal constriction test, GR94839 was 238 fold more potent when given i.c.v. (ED50: 0.008 (0.004-0.029) mg kg-1; n = 18) than when s.c. (ED50: 1.9 (0.7-3.1) mg kg-1; n = 30). In comparison, GR103545 was equipotent when given i.c.v. or s.c. 4. After intravenous administration, the maximum plasma to brain concentration-ratio attained by GR94839 was 18 compared with 2 for GR85571, a structurally-related kappa-agonist that is centrally-penetrating. 5. GR94839 inhibited the 2nd phase of the rat formalin response at doses 7 fold lower than those required to inhibit the 1st phase (ED50 vs 1st phase: 10.2 (6.7-17.1) mg kg-1, s.c.; ED50 vs 2nd phase: 1.4 (1.0-1.8) mg kg-1, s.c.; n = 18). GR103545 was equipotent against the two phases. 6. Intraplantar administration of the opioid antagonists, norbinaltorphimine (100 micrograms) or naltrexone (1 microgram), reversed the antinociceptive effect of systemic GR94839 (3 mg kg-1, s.c.) against the 2nd phase of the formalin response and intraplantar injection of GR94839 (30-100 micrograms) selectively inhibited the 2nd phase.7. GR94839 and IC1204448 reversed the hyperalgesia in the zymosan-inflamed rat paw at doses (ED50 GR94839: 2.0 (1.1-3.2) mg kg-', s.c.; ED50 IC1204448: 1.2 (0.8-1.7) mg kg-', s.c.), lower than those required to raise the noxious pressure threshold in the non-inflamed paw (EDSO GR94839: 16.4 (8.6-46.7) mg kg', s.c.; ED50 IC1204448: 68.0 (22.1-32000) mg kg', s.c.). GR103545 raised the noxious presure threshold in the inflamed and non-inflamed paws at the same doses.8. GR94839 was sedative in the rat rotarod test (ED50: 35 (12-245) mg kg-', s.c.) at doses higher than those required to inhibit the 2nd phase of the formalin response or reverse hyperalgesia in the zymosan-inflamed rat paw. The doses were comparable to those that inhibited the 1st phase of the formalin response and raised the noxious pressure threshold in the non-inflamed paw.9. The results suggest that GR94839 is a selective kappa-agonist which has antinociceptive activity against inflammatory pain at doses that produce limited central effects. These antinociceptive effects are probably mediated at peripheral opioid receptors.

Analgesics↗
PubMed1991

Neuroprotective actions of GR89696, a highly potent and selective kappa-opioid receptor agonist.

1. The effect of a novel, highly potent and selective kappa-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2. In the Mongolian gerbil model, administration of GR89696 (3 to 30 micrograms kg-1, s.c.), immediately before and at 4 h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other kappa-agonists, GR86014 (1 mgkg-1, s.c.) and GR91272 (1 mgkg-1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mgkg-1, s.c. Repeated post-treatment with GR89696 (100 micrograms kg-1, s.c.) or GR44821 (10 mgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3. In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 micrograms kg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 micrograms kg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4. The results indicate that the potent kappa-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

Animals↗
PubMed1990

A series of novel, highly potent and selective agonists for the kappa-opioid receptor.

1. This paper describes the opioid receptor pharmacology and in vivo activity of several novel benzene-acetamidopiperidine and benzeneacetamidopiperazine analogues. 2. These compounds all showed potent, naloxone-reversible, full agonist activity in the field-stimulated rabbit vas deferens, indicating that they are kappa-opioid agonists; but showed very little activity in the rat or hamster vas deferens, indicating good selectivity with regard to mu- and delta-opioid receptors. 3. They were all potent antinociceptive agents, the most potent compound, GR 103545, having an ED50 value in the mouse abdominal constriction test of 0.25 micrograms kg-1 s.c. The compounds also produced sedation and diuresis, but had little effect on respiration rate or gastrointestinal motility. 4. It is concluded that the seven novel compounds described are all potent and selective agonists for the kappa-opioid receptor.

Abdomen↗