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J Ong

Publications and source records attributed to J Ong.

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

The (S)-enantiomer of 2-hydroxysaclofen is the active GABAB receptor antagonist in central and peripheral preparations.

In the guinea-pig isolated ileum, (RS)-(+/-)-baclofen induced a depression of cholinergic twitch contractions, reversibly and competitively antagonised by (S)-2-hydroxysaclofen (pA2 = 5.2 +/- 0.2), but not by (R)-2-hyroxysaclofen. The depression of excitatory field potentials by baclofen ( 5 mu M) in rat CA1 hippocampal slices was antagonised by (S)-2-hydroxysaclofen (100 mu m) (pA2 = 4.3), whilst in rat neocortex, (S)-2-hyroxysaclofen (50-500 mu M) antagonised the baclofen (10 mu M)-induced suppression of spontaneous discharges, the (R)-enantiomer being inactive. These results show that (S)-2-hydroxysaclofen is the active antagonist at central and peripheral GABAB receptors.

Animals↗
PubMed1995

Interactions of N-ethylmaleimide and aluminium fluoride with GABAB receptor function in rat neocortical slices.

Interactions of N-ethylmaleimide and aluminium fluoride (AlF - 4) with GABAB receptors have been examined using spontaneously discharging rat neocortical slices. The suppression of discharges by the GABAB receptor agonist baclofen (5-10 mu M) was irreversibly prevented by N-ethylmaleimide (10-50 mu M) and its analog N-phenylmaleimide (10-50 mu M), whilst superfusion of slices with NaF (10 mM) and AlCl3 (100 mu M) to form a fluoroaluminate (AlF - 4) complex markedly potentiated the action of baclofen. The lipoxygenase inhibitors, nordihydroguaiaretic acid (10-50 mu M) and eicosatetraynoic acid (10-50 mu M) or the phospholipase A2 inhibitor bromophenacylbromide (50-100 mu M) did not affect the response to baclofen. The depressant action of baclofen is evidently mediated through G-proteins, but is not dependent on arachidonic acid metabolites.

Aluminum Compounds↗
PubMed1995

GABAB receptors.

GABAB receptors are a distinct subclass of receptors for the major inhibitory transmitter 4-aminobutanoic acid (GABA) that mediate depression of synaptic transmission and contribute to the inhibition controlling neuronal excitability. The development of specific agonists and antagonists for these receptors has led to a better understanding of their physiology and pharmacology, highlighting their diverse coupling to different intracellular effectors through Gi/G(o) proteins. This review emphasises our current knowledge of the neurophysiology and neurochemistry of GABAB receptors, including their heterogeneity, as well as the therapeutic potential of drugs acting at these sites.

Baclofen↗
PubMed1995

Characterization of GABAB ligands in vivo.

1. While GABAB antagonists have been examined in vitro, very few have been tested in vivo. A range of GABAB antagonists were tested against baclofen-induced muscle relaxation and hypothermia. 2. The GABAB antagonists exhibited a range of in vivo activity profiles. 3. CGP 35348 showed clear antagonist effects, while BPBA and 4-ABPA appeared to have agonist properties. 4. Phaclofen, 2-hydroxysaclofen, 3-APPA and 9G seemed to have little effect in this system at the doses tested. 5. Differences between in vivo and in vitro activity could be explained by differences in blood-brain barrier permeability, or possible differences in affinities for the sub-classes of GABAB receptors.

Animals↗
PubMed1995

Accelerated cisplatin-based chemotherapy for advanced bladder cancer.

The toxicity and efficacy of accelerated cisplatin, vincristine and methotrexate was assessed in patients with advanced urothelial carcinoma. 30 consecutive patients were entered into a phase II trial and treated with cisplatin, vincristine and methotrexate given every 10 days (MOPq10) for four cycles, followed by two further cycles at 21 day intervals. Five complete responses and 14 partial responses were observed (overall response rate 63%; 95% confidence interval 45-78%). The median progression-free survival was 7.5 months (range 1.8-28) and the median overall survival 10.5 months (range 2.36). Toxicity was moderate with no treatment-related deaths. It is concluded that although the overall survival is still disappointing, the toxicity is less with the protocol than reported with methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) or escalated M-VAC (E-MVAC) and the time on treatment is shorter. MOPq10 provided palliative benefit to two-thirds of patients with advanced transitional cell carcinoma including those in their eighth decade.

Adult↗
PubMed1995

Secondary tumours following etoposide containing therapy for germ cell cancer.

BACKGROUND: Reports have implied etoposide as the cause of secondary leukaemia in patients treated for germ cell cancer. PATIENTS AND METHODS: Between 1979 and 1992, 679 male patients with germ cell cancer received etoposide containing chemotherapy. RESULTS: Six of 679 patients developed acute myeloid leukaemia (relative risk 150; CI: 55-326). None of these patients had a primary mediastinal germ cell tumour and only 1 patient received previous radiotherapy. The median interval between the onset of cytotoxic treatment and the development of leukaemia was 27 months. The FAB M4 morphology was seen in 4 of 6 cases. CONCLUSION: The benefit of etoposide containing protocols outweigh the risk of leukaemia in patients with intermediate or high risk disease, however in patients with good risk disease non-etoposide containing protocols should be explored.

Acute Disease↗
PubMed1994

Differing actions of nitropropane analogs of GABA and baclofen in central and peripheral preparations.

In the guinea-pig isolated ileum, both baclofen (5-100 microM) and gamma-aminobutyric acid (GABA; 5-100 microM) induced a bicuculline-insensitive depression of cholinergic twitch contractions which was reversibly and competitively antagonised by 3-amino-1-nitropropane (50-250 microM). 3-Amino-1-nitropropane (pA2 = 5.0 +/- 0.1) was twice as potent as 2-hydroxysaclofen (pA2 = 4.5 +/- 0.1), but was equipotent with 3-aminopropyl(P-diethoxymethyl)phosphinic acid (CGP 35348) (pA2 = 4.9 +/- 0.2), and did not show any partial agonist activity at these peripheral GABAA or GABAB receptor sites. In rat neocortical slices, 3-amino-1-nitropropane did not activate GABAB receptor sites or affect baclofen-induced suppression of spontaneous discharges. In the cat spinal cord, however, under in vivo conditions, the corresponding nitro analog of baclofen 3-amino-2-(4-chloro)-nitropropane was an agonist at GABAB receptor sites, although more than 60 times weaker than baclofen in depressing monosynaptic excitatory field potentials, whereas 3-amino-1-nitropropane was an extremely weak agonist at bicuculline-sensitive GABAA sites. The differing actions of 3-amino-1-nitropropane at peripheral and central GABAB receptor sites suggest heterogeneity among these receptors.

Animals↗
PubMed1994

Gamma-guanidinobaclofen is a peripheral GABAB receptor agonist.

In the guinea-pig isolated ileum, both baclofen and gamma-guanidinobaclofen elicited dose-dependent depression of cholinergic twitch contractions, sensitive to the GABAB receptor antagonists phaclofen and 2-hydroxysaclofen. gamma-Guanidinobaclofen was 5 times less potent than R,S-(+/-)-baclofen in depressing the contractions. The corresponding GABA analogs, guanidinoacetic acid, beta-guanidinopropionic acid and gamma-guanidinobutanoic acid were inactive. In rat neocortical slices maintained in Mg(2+)-free medium, baclofen (1-50 microM) reduced the amplitude and rate, whilst gamma-guanidinobaclofen (1 mM) has a very weak GABAB receptor agonist action, 100 times weaker than baclofen. gamma-Guanidinobaclofen is therefore a GABAB receptor agonist, more potent at peripheral than central GABAB receptors.

Animals↗
PubMed1994

Suppression of GABAB receptor function in rat neocortical slices by amiloride.

Interactions of amiloride with GABAB receptors have been examined using spontaneously discharging rat neocortical slices. These discharges were suppressed by the GABAB receptor agonist baclofen (10 microM), and were prevented by amiloride and its analogs 5-(N,N-dimethyl)-amiloride, 5-(N-methyl-N-isobutyl)-amiloride and benzamil, but not by triamterene (100-500 microM). Each of these also increased the spontaneous discharge rate and reduced the discharge amplitude. The action of amiloride and its analogs in preventing the action of baclofen, may involve allosteric modification of the receptor binding sites via guanine nucleotide-binding proteins, or an indirect effect through antagonism of co-activated adenosine A1 receptors.

Amiloride↗
PubMed1994

Rapid antenatal diagnosis of beta-thalassemia in Chinese caused by the common 4-bp deletion in codons 41/42 using high-resolution agarose gel electrophoresis and heteroduplex detection.

The 4-bp deletion in codons 41/42 (-TTCT) in the beta-globin gene is a common mutation that causes beta-thalassemia in Chinese. A simple method, which involved PCR amplification of the relevant region, was used for the antenatal diagnosis of a fetus at risk for this mutation. The fetal PCR product showed a single fragment of normal size on MetaPhor gel. The homozygous normal status was further confirmed by the generation of heteroduplexes only after addition of homozygous mutant DNA.

Base Sequence↗
PubMed1994

The effects of GABAB ligands on alcohol withdrawal in mice.

Recent research suggests that the GABAB receptor may mediate some of the acute effects of alcohol, but little is known of its involvement in alcohol withdrawal. Mice made dependent on alcohol exhibited tremor and tail arch when consumption ceased. Diazepam dose-dependently attenuated both tremor and tail arch, whereas baclofen had no effect on either of these two withdrawal symptoms. However, baclofen dose-dependently induced convulsant behaviour in the withdrawing mice, and this was significantly attenuated by the GABAB antagonists phaclofen (50 mg/kg) and CGP 35348 (300 mg/kg), but not BPBA (50 mg/kg). Phaclofen, BPBA, and CGP 35348, when administered alone and in combination with a single dose of baclofen, did have an effect on tremor, although the magnitude was small in comparison to that seen with diazepam. It appears that the GABAB receptor may play a role in mediating convulsions during alcohol withdrawal, and that in this system baclofen is proconvulsant.

Animals↗
PubMed1994

Difference between long-term contact-lens wearers and nonwearers in amplitude of the return-sweep velocity of eye movements during reading.

A Beckman Type RM Dynograph was used to record eye movements of 31 college students, 23 of whom had never worn contact lenses and 8 who had worn contact lenses for at least five years and 12 hours a day, while reading equivalent print at a distance of 33 cm. Analysis showed that the deviation indexes of .28 and .26 were comparable, meaning that these two groups showed similar return-sweep velocity amplitudes. A difference of 1.73 mm/.1 sec. between these two group means, 6.79 vs 5.06, respectively, was significant, implying that, while wearing contact lenses improved visual efficiency, it adversely affected reading speed. Further, other tasks involving rapid scanning such as scanning the roadway ahead while driving might similarly be affected.

Adult↗
PubMed1993

3-amino-2-(4-chlorophenyl)-nitropropane is a new GABAB receptor agonist, more active peripherally.

The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 +/- 1.3 microM; N-BAC = 9.2 +/- 0.3 microM) and vas deferens (IC50s for baclofen = 30 microM; N-BAC = 100 microM), competitively antagonised by phaclofen, 2-hydroxysaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 +/- 0.2) and N-BAC (4.6 +/- 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.

Animals↗
PubMed1993

R-(-)-beta-phenyl-GABA is a full agonist at GABAB receptors in brain slices but a partial agonist in the ileum.

R-(-)-beta-phenyl-GABA has been compared at GABAB receptors using cortical and ileal preparations. R-(-)-beta-phenyl-GABA (EC50 = 25 microM) was a less potent full agonist than R,S-(+/-)-baclofen (EC50 = 2.5 microM), in depressing CA1 population spikes of rat hippocampal slices, and 5 times less potent in attenuating the spontaneous discharges of rat neocortex. However, R-(-)-beta-phenyl-GABA (100-400 microM) was only a weak partial agonist in the ileum. All these actions were sensitive to CGP 35348 (3-aminopropyl-(P-diethoxymethyl)-phosphinic acid) and therefore mediated by GABAB receptors.

Animals↗
PubMed1993

The role of GABAB receptors in mediating the stimulatory effects of ethanol in mice.

Recently, the GABAB receptor antagonist phaclofen has been shown to attenuate the stimulation of locomotor activity induced by ethanol (Allan and Harris 1989). In the present study, the effects of a range of recently developed GABAB receptor antagonists (phaclofen, 2-hydroxysaclofen, beta-phenyl-beta-alanine, CGP 35348) and the GABAB receptor agonist baclofen, were studied for their ability to block the locomotor stimulation induced by a low dose of ethanol administered IP to mice (1.75 g/kg). Results showed that phaclofen, 2-hydroxysaclofen, BPBA and baclofen all dose-dependently decreased ethanol-induced locomotor activity, and, of these, baclofen and BPBA did so at doses which did not attenuate locomotor activity when administered alone. CGP 35348 had no effect on the activity produced by ethanol. The action of baclofen on ethanol-induced activity appeared to be GABAB receptor mediated, as the effects were stereospecific and were reversed by the antagonist, CGP 35348. However phaclofen, 2-hydroxysaclofen and BPBA failed to reverse the effects of baclofen. These results suggest that the GABAB receptor may modulate locomotor stimulation induced by low doses of ethanol, and furthermore, that agonist, rather than antagonist activity at the GABAB receptor is responsible for this reduction. The GABAB receptor subtype responsible for modulating the effects of ethanol may have properties different from those GABAB receptors characterised to date.

Animals↗