Biomedical subjects

W C Wong

Publications and source records attributed to W C Wong.

At least 37 records · Page 2Linked to original sources

PubMed2000

In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist.

L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(¿3-[4-(2-pyridin yl)-1-piperidinyl]propyl¿amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2000

2-amino-2-oxazolines as subtype selective alpha(2) adrenoceptor agonists.

Cyclohexylamino oxazoline 1 (AGN 190837), an analogue of 2 (Bay a6781), is a potent alpha(2) adrenoceptor agonist. On the basis of a design generated by receptor-ligand modeling, a number of cyclohexyl and norbornyl analogues were synthesized wherein the propyl group of 1 was replaced by phenylalkyl subsituents. This resulted in compound 6 being an alpha(2c) selective agonist, as well as 7 and 9 being alpha(2a)/alpha(2c) selective.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2000

An animal model for allergic penicilliosis induced by the intranasal instillation of viable Penicillium chrysogenum conidia.

BACKGROUND: A study was undertaken to determine the consequences of long term intranasal instillation of Penicillium chrysogenum propagules in a mouse model. METHODS: C57 Black/6 mice were inoculated intranasally each week for six weeks with 10(4) viable and non-viable P chrysogenum conidia. Cytokine levels and cellular responses in these animals were then measured. RESULTS: Compared with controls, mice inoculated intranasally each week for six weeks with 10(4) P chrysogenum conidia (average viability 25%) produced significantly more total serum IgE (mean difference 1823.11, lower and upper 95% confidence intervals (CI) 539.09 to 3107.13), peripheral eosinophils (mean difference 5.11, 95% CI 2.24 to 7.99), and airway eosinophilia (rank difference 11.33, 95% CI 9.0 to 20.0). With the exception of airway neutrophilia (mean difference 20.89, 95% CI 3.72 to 38.06), mice inoculated intranasally with 10(4) non-viable conidia did not show significant changes in total serum IgE, peripheral or airway eosinophils. However, when compared with controls, this group (10(4) non-viable) had a significant increase in total serum IgG(2a) (mean difference 1990.56, 95% CI 790.48 to 3190.63) and bronchoalveolar lavage (BAL) fluid levels of interferon (IFN)-gamma (mean difference 274.72, 95% CI 245.26 to 304.19). In addition, lung lavages from mice inoculated intranasally with 10(4) viable P chrysogenum conidia had significantly increased levels of interleukin (IL)-4 (mean difference 285.28, 95% CI 108.73 to 461.82) and IL-5 (mean difference 16.61, 95% CI 11.23 to 21.99). The IgG(2a)/IgE ratio and the IFN-gamma/IL-4 ratio was lower in the group of mice inoculated intranasally with 10(4) viable conidia than in the 10(4) non-viable conidia group and the controls. When proteins were extracted from P chrysogenum conidia, attached to microtitre plates and incubated with serum from the 10(4) viable group, significant increases in conidia-specific IgE and IgG(1) were observed compared with controls, while serum from the 10(4) non-viable group was similar to controls. CONCLUSIONS: These data suggest that long term inhalation of viable P chrysogenum propagules induces type 2 T helper cell mediated (Th2) inflammatory responses such as increases in total and conidia-specific serum IgE and IgG(1), together with BAL fluid levels of IL-4 and IL-5 and peripheral and airway eosinophilia, which are mediators of allergic reactions.

Administration, Intranasal↗

PubMed1999

A case-controlled MRI/MRA study of neurovascular contact in hemifacial spasm.

BACKGROUND: Neurovascular contact (NVC) with the root exit zone (REZ) of the ipsilateral facial nerve is associated with hemifacial spasm (HFS), but unresolved issues remain. OBJECTIVES: To 1) determine the frequency of symptomatic and nonsymptomatic NVC, 2) determine the features of NVC associated with HFS, and 3) correlate severity of HFS to these features. METHODS: Two independent, blinded, prospective assessments of high-resolution MR and MR angiography (MRA) images were performed on Chinese cases (HFS: n = 44; age-matched control subjects: n = 20). RESULTS: Over 88% of 44 symptomatic sides in patients with HFS had NVC of the ipsilateral facial nerve. At least 80% of symptomatic sides involved NVC at the anterior aspect of the REZ [REZ(ant.)]. Although NVC was observed in approximately half of nonsymptomatic sides, at least 70% of them were not at REZ(ant.). NVC at the cisternal and intracanalicular portions of the facial nerve were not associated with HFS. Half of our patients with HFS had bilateral NVC, but none had bilateral symptoms. Most of our MR/MRA images showed that the size and position of the arterial branches of the vertebrobasilar system were markedly asymmetric. Of patients with bilateral NVC, over 83% had asymmetric NVC sites. The anterior inferior cerebellar artery was the most common vessel involved in NVC, but was not significantly associated with HFS. Most of the NVC involved one vessel at one contact point with no indentation. The development of HFS was significantly associated with nerve indentation in NVC. The development and severity of HFS were not associated with multiple contact points in NVC. No significant interobserver variability existed between the blinded assessments. CONCLUSIONS: MRI/MR angiography are accurate, fast, and safe in characterizing neurovascular contact (NVC) at the brainstem. The site of NVC and ipsilateral facial nerve indentation in NVC are significant determinants for the development of hemifacial spasm (HFS). The lack of bilateral NVC at the anterior aspect of the root exit zone of the facial nerve could explain in part the lack of bilateral symptoms. The development and severity of HFS are not associated with a specific blood vessel or multiple contact points in NVC.

Adult↗

PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.

Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety.

We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.

Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.

Adrenergic alpha-Antagonists↗

PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 4. Structure-activity relationship in the dihydropyrimidine series.

We have previously disclosed dihydropyridines such as 1a,b as selective alpha(1a) antagonists as a potential treatment for benign prostatic hyperplasia (BPH). The propensity of dihydropyridines toward an oxidation led us to find suitable replacements of the core unit. The accompanying papers describe the structure-activity relationship (SAR) of dihydropyrimidinones 2a,b as selective alpha(1a) antagonists. We report herein the SAR of dihydropyrimidines such as 4 and highlight the similarities and differences between the dihydropyrimidine and dihydropyrimidinone series of compounds.

Administration, Oral↗

PubMed1999

Design and synthesis of novel dihydropyridine alpha-1a antagonists.

A series of analogs of SNAP 5150 containing heteroatoms at C2 or C6 positions is described. Herein, we report that the presence of alkyl substituted heteroatoms at the C2(6)-positions of the dihydropyridine are well tolerated. In addition, 15 inhibited the phenylephrine induced contraction of dog prostate tissue with a Kb of 1.5 nM and showed a Kb (DBP, dogs, microg/kg)/Kb (IUP, dogs, microg/kg) ratio of 14.8/2.5.

Adrenergic Antagonists↗

PubMed1999

Continually measured fungal profiles in sick building syndrome.

Buildings with indoor air quality (IAQ) complaints frequently have high airborne concentrations of Penicillium species, while buildings with few IAQ complaints have an indoor air (IDA) fungal ecology similar to outdoor air (ODA), where Cladosporium species is usually the dominant microorganism. These studies compared fungal air profiles, measured continually over 6 h in a documented sick building, in IDA in a room experiencing IAQ problems with fungal profiles measured concurrently in ODA. The dominant species collected at both sites were Penicillium species, Cladosporium species, and Alternaria species. In the IDA, Penicillium species were always the dominant organisms, ranging from 150 to 567 cfu/m3 (89.8-100% of the total fungi). In the ODA, Cladosporium species were dominant in four samples (40.0-70.6%), while Penicillium species were dominant (52.7-79.6%) in two. These data demonstrate that, even though ODA fungal profiles are changing continuously, IDA fungal profiles in "sick" buildings tend to remain unchanged.

Air Microbiology↗

PubMed1999

Emergency obstetric hysterectomies for postpartum haemorrhage.

OBJECTIVE: To review emergency obstetric hysterectomy in our unit, including the indications for and morbidity associated with the procedure. DESIGN: A retrospective cases analysis. SUBJECTS AND METHODS: Records of obstetric patients who had undergone emergency hysterectomies in between 15 October 1993 and 31 December 1997 were reviewed retrospectively. RESULTS: There were 15,474 deliveries and 7 emergency obstetric hysterectomies. All cases had total abdominal hysterectomy. The indications for hysterectomy were uterine atony and placental disorders. There were one case of urinary bladder injury and 2 cases of disseminated intravascular coagulopathy. There was no maternal mortality. CONCLUSION: Emergency obstetric hysterectomy remains a potentially life-saving procedure in unavoidable catastrophe. The 7 patients with life threatening postpartum haemorrhage underwent hysterectomy after failure of conservative measures. The morbidity is low and there was no mortality in this series.

Adult↗

PubMed1998

Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia.

We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1998

Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.

A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.

Adrenergic alpha-Agonists↗

PubMed1998

Correlation between the prevalence of certain fungi and sick building syndrome.

OBJECTIVE: To examine the role of fungi in the production of sick building syndrome. METHODS: A 22 month study in the United States of 48 schools (in which there had been concerns about health and indoor air quality (IAQ). Building indoor air and surface samples, as well as outdoor air samples were taken at all sites to look for the presence of fungi or their viable propagules. RESULTS: Five fungal genera were consistently found in the outdoor air and comprised over 95% of the outdoor fungi. These genera were Cladosporium (81.5%), Penicillium (5.2%), Chrysosporium (4.9%), Alternaria (2.8%), and Aspergillus (1.1%). At 20 schools, there were significantly more colony forming units per cubic metre (CFU/m3) (p < 0.0001) of propagules of Penicillium species in the air samples from complaint areas when compared with the outdoor air samples and the indoor air samples from noncomplaint areas. At five schools, there were more, although not significant (p = 0.10), Penicillium propagules in the air samples from complaint areas when compared with the outdoor air samples and the indoor air samples from noncomplaint areas. In 11 schools, the indoor air (complaint areas) fungal ratios were similar to that in the outdoor air. In these 11 schools Stachybotrys atra was isolated from swab samples of visible growth under wetted carpets, on wetted walls, or behind vinyl wall coverings. In the remaining 11 schools, the fungal ratios and CFU/m3 of air were not significantly different in different areas. Many of the schools took remedial action that resulted in an indoor air fungal profile that was similar to that outdoors. CONCLUSIONS: Propagules of Penicillium and Stachybotrys species may be associated with sick building syndrome.

Air Microbiology↗

PubMed1997

Enhancement of oculomotor nerve: a diagnostic criterion for ophthalmoplegic migraine?

The oculomotor nerve of a 6-year-old boy with recurrent headache and recurrent ophthalmoplegia was contrast-enhanced on a magnetic resonance imaging (MRI) scan during an episode. The boy exhibited dramatic response to steroid treatment. The clinical features of ophthalmoplegic migraine and Tolosa-Hunt syndrome overlapped in this patient. We suggest that a positive MRI finding can be included as one of the diagnostic criteria in the classification of ophthalmoplegic migraine and that a trial of steroid is worthwhile in the presence of enhancement of the oculomotor nerve since ophthalmoplegic migraine may be noninfectious but inflammatory in etiology.

Anti-Inflammatory Agents↗

PubMed1997

Electron microscopic study of sprouting dendrites in the ciliary ganglia of cat and monkey (Macaca fascicularis) following pre- and post-ganglionic axotomy.

The present paper reports the ultrastructure of dendritic sprouting and formation of associated synapses in the ciliary ganglion of cat and monkey induced by pre- and post-ganglionic axotomy. In both series of experiments, sprouting dendrites were observed mostly at 3-5 days postoperatively; such profiles were identified by their dense packing of mitochondria and glycogen-like granules. In longitudinal section, such profiles appeared as expanded extensions from the normal-looking dendritic trunks. None were observed to arise directly from the neuronal soma. After preganglionic nerve section, the cross-sectional diameters of such profiles measured 2.2 +/- 1.0 microm (range: 0.9-6.2 microm) in cat and 2.4 +/- 0.7 microm (range: 0.9-5.5 microm) in monkey. After postganglionic nerve section, the cross-sectional diameters of such profiles measured 2.1 +/- 0.7 microm (range: 0.8-4.5 microm) in cat and 2.8 +/- 1.4 microm (range: 1.1-7.0 microm) in monkey. After preganglionic axotomy, in both cat and monkey, the axon terminals began to degenerate at 3 days postoperatively and disappeared by 5 days postoperatively. However, at later postoperative survival periods, the axon terminals reappeared and were observed to make synaptic contacts with the sprouting dendrites. Some of the sprouting dendrites were observed to degenerate, some as early as 3 days postoperatively; such profiles did not appear to have any synapse on them. After postganglionic axotomy, such sprouting dendritic profiles were also observed to make synaptic contacts with axon terminals; some were only closely associated with profiles filled with synaptic vesicles. The results thus suggest that through the formation of new synapses, sprouting of dendrites may have a role to play in neuronal survival after axotomy.

Animals↗

PubMed1997

The effects of bilateral vagotomy on substance P-like immunoreactive nerves in the cardiac ganglia of the monkey (Macaca fascicularis).

The present study showed that neural degeneration occurred in the cardiac ganglia after bilateral vagotomy. At 1 week after operation, a majority of the substance P-like immunoreactive (SP-IR) nerve fibres were affected and they showed signs of degeneration. SP-IR nerve endings forming the pericellular baskets around seemingly normal neuronal cell bodies were also degenerated. By 2 weeks after operation, numerous macrophage-like cells infiltrated the cardiac ganglia and they engulfed the degenerating SP-IR cellular debris. At 3 months after operation, a few fine SP-IR nerve fibres were detected in the cardiac ganglia, together with a few small solitary SP-IR neurons. At 6-12 months after operation, numerous SP-IR nerve fibres were observed in the cardiac ganglia. Some of the SP-IR nerve endings started to form pericellular baskets around the seemingly normal neuronal cell bodies. It is concluded that there is reinnervation of the heart by SP-IR nerve fibres after surgical interruption to both vagi. However, the origin of these SP-IR nerve fibres and terminals remains unknown.

Animals↗

PubMed1996

Localization of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity in the gastrointestinal sphincters in the guinea pig.

The distribution of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), a marker for nitric oxide synthase (NOS), in the nerves of gastrointestinal sphincters in guinea pigs was investigated to throw some light on the role of nitric oxide (NO) in these sphincteric regions. The nerve fibres with NADPH-d activity were observed chiefly in the circular muscle layer of the wall of gastrointestinal sphincters. Compared with the adjacent non-sphincteric regions, the proportions of NADPH-d positive myenteric neurons in the lower esophageal sphincter (LES), pyloric sphincter (PS) and internal anal sphincter (IAS) were higher (P < 0.05). The densities of NADPH-d-positive fibres in the circular muscle of above sphincteric regions were also higher (in LES P < 0.01; in PS and IAS P < 0.05). Within the circular muscle of LES, some discrete NADPH-d-positive intrinsic nerve cell bodies, usually smaller than their outlying myenteric neurons, were also observed. The dense distribution of NADPH-d-positive fibres within the circular muscles of gastrointestinal sphincteric regions suggests that NO, as a non-adrenergic non-cholinergic (NANC) inhibitory neurotransmitter, might play an important role in the neuronal regulation of the guinea-pig gastrointestinal sphincters.

Animals↗