Jennifer Ong’s research while affiliated with The University of Adelaide and other places

GABAB autoreceptors inhibit release of γ-aminobutyric acid (GABA) from GABAergic nerve terminals. Agonists of these receptors (baclofen) inhibit, whereas antagonists [(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid] (Sch 50911) enhance release of the transmitter. The actions of thymol (2-isopropyl-5-methylphenol) and a structurally related compound (2-tert-butyl-4-methylphenol, 4MP) on release of [3H]GABA were examined in rat neocortical slices where the GABAergic nerves had been preloaded with [3H]GABA and subsequently stimulated electrically on two occasions. Test agents, baclofen and Sch 50911 were added to the superfusion medium prior to the second period of stimulation. Overflows of [3H]GABA as a consequence of these stimulations (SIO1 and SIO2) were calculated and the effects of agents determined by comparing the SIO2/SIO1 ratio in the presence of each agent with that in control tissue. Thymol potentiated the release of [3H]GABA (EC50 170 μM), an action reversed by baclofen (2μM). Baclofen alone had little effect on GABA release. 4MP inhibited the release of [3H]GABA (IC50 3μM) and this effect was blocked by Sch 50911 (10μM). Sch 50911 alone potentiated the release of GABA markedly. These results imply that 4MP is an agonist of GABAB autoreceptors, however further studies are needed to confirm that thymol is indeed an antagonist. Of interest are structural differences in these agents. Thymol has a propyl group in the ortho position relative to the phenolic hydroxyl whereas in 4MP this is a butyl group and the methyl group moves from position 5 to 4. Whether one or both of these changes was responsible for the above actions is unknown.This article is protected by copyright. All rights reserved.

Tramadol is an atypical centrally acting analgesic agent available as both oral and parenteral preparations. For patients who are unable to take tramadol orally, the subcutaneous route of administration offers an easy alternative to intravenous or intramuscular routes. This study aimed to characterise the absorption pharmacokinetics of a single subcutaneous dose of tramadol in severely ill patients and in healthy subjects. Blood samples (5 ml) taken at intervals from 2 minutes to 24 hours after a subcutaneous dose of tramadol (50 mg) in 15 patients (13 male, two female) and eight healthy male subjects were assayed using high performance liquid chromatography. Pharmacokinetic parameters were derived using a non-compartmental approach. There were no statistically significant differences between the two groups in the following parameters (mean ± SD): maximum venous concentration 0.44 ± 0.18 (patients) vs. 0.47 ± 0.13 (healthy volunteers) mcg/ml (p = 0.67); area under the plasma concentration-time curve 177 ± 109 (patients) vs. 175 ± 75 (healthy volunteers) mcg/ml*min (p = 0.96); time to maximum venous concentration 23.3 ± 2 (patients) vs. 20.6 ± 18.8 (healthy volunteers) minutes (p = 0.73) and mean residence time 463 ± 233 (patients) vs. 466 ± 224 (healthy volunteers) minutes (p = 0.97). The similar time to maximum venous concentration and mean residence time suggest similar absorption rates between the two groups. These results indicate that the same dosing regimens for subcutaneous tramadol administration may therefore be used in both healthy subjects and severely ill patients. Trial registration ACTRN12611001018909

This study aimed to characterise and compare the absorption pharmacokinetics of a single subcutaneous dose of oxycodone in critically ill patients and healthy subjects. Blood samples taken at intervals from two minutes to eight hours after a subcutaneous dose of oxycodone in patients (5 mg) and healthy volunteers (10 mg) were assayed using high performance liquid chromatography. Data were analysed using a non-compartmental approach and presented as mean (SD). Parameters were corrected for dose differences between the groups assuming linear kinetics. Ten patients (eight male, two female) and seven healthy male subjects were included. Maximum venous concentration and area under the concentration curve were approximately two-fold lower in the patient group for an equivalent dose, suggesting either reduced bioavailability or increased clearance: maximum venous concentration 0.14 ± 0.06 vs 0.05 ± 0.02 µg/ml (P <0.0001); area under the concentration curve 19.50 ± 9.15 vs 9.72 ± 2.71 µg/ml/minute (P <0.001) respectively. However, time to maximum venous concentration and mean residence time were not different, suggesting similar absorption rates: time to maximum venous concentration 22.10 ± 18.0 vs 20.50 ± 16.10 minutes (P=0.81); mean residence time 353 ± 191 vs 291 ± 80 minutes (P=0.26). Kinetic parameters were less variable in patients than in volunteers. The patients therefore had reduced exposure to subcutaneous oxycodone. This warrants further model-based analysis and experimentation. Dose regimens for subcutaneous oxycodone developed in healthy volunteers cannot be directly translated to critically ill patients.

1. GABA B autoreceptors are a subclass of GABA B receptors that inhibit the release of [ ³ H]GABA from GABAergic nerve terminals. Baclofen is an agonist that reduces [ ³ H]GABA, whilst the antagonist (+)‐(S)‐5,5‐dimethylmorpholinyl‐2‐acetic acid (Sch 50911) enhances [ ³ H]GABA release in electrically‐stimulated rat neocortical brain slices preloaded with [ ³ H]GABA. Here, the pharmacological actions of a series of compounds derived from the positive allosteric modulator, 2,6‐di‐tert‐butyl‐4‐(3‐hydroxy‐2,2‐dimethyl‐propyl)‐phenol (CGP7930), were examined on GABA B autoreceptors. 2. The compound, 3‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐2,2‐dimethyl‐1‐oximinopropane (compound 2), at 10 μmol/L had little effect on the stimulation‐induced overflow of [ ³ H]GABA when superfused alone, but when superfused in the presence of baclofen (2 μmol/L) inhibited the overflow of [ ³ H]GABA. These effects were reversed by Sch 50911 (10 μmol/L). Although compounds 1‐(4‐chlorophenyl)‐3‐(4‐hydroxy‐3,5‐di iso propylphenyl)‐2‐methyl‐1‐oximinopropane (compound 1), 1‐[(3,5‐di t butyl‐4‐hydroxyphenyl)methyl]‐1‐oximinomethylcyclohexane (compound 3), 3‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐1,2‐diphenyl‐1‐oximinopropane (compound 4) and 4‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐3‐methyl‐2‐oximinobutane (compound 5) (each at 10 μmol/L) tended to reduce the stimulation‐induced overflow in the presence of baclofen, an effect reversed by Sch 50911, their status as modulators is not confirmed in the present study. 3. Another derivative, 3‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐1‐(4‐chlorophenyl)‐2‐methyl‐1‐oximinopropane (compound 6) (10 μmol/L), acted as an agonist as it inhibited the release of [ ³ H]GABA by 32% (EC 50 of 3.3 μmol/L), an effect reversed by Sch 50911 (10 μmol/L). The other compounds, 1‐[(3,5‐di t butyl‐4‐hydroxyphenyl)methyl]‐1‐methyl‐2‐oximinocyclohexane (compound 7), 4‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐3,3‐dimethyl‐2‐oximinobutane (compound 8) and 4‐(4‐hydroxy‐3,5‐di iso propylphenyl)‐3,3‐dimethyl‐2‐oximinobutane (compound 9) (each at 10 μmol/L), were inactive. 4. These findings indicate that this series of compounds show different modes of activity at GABA B autoreceptors.

(R,S)-4-Amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid (7-MBFG), a new benzofuran analogue of the GABA(B) receptor agonist baclofen, has been evaluated for pharmacological activity on GABA(B) receptors in the guinea-pig isolated ileum and rat neocortical slices. 7-MBFG (300 and 500 microM) reversibly antagonized the (R,S)-baclofen induced depression of cholinergic twitch contractions in the guinea-pig ileum and shifted the concentration-response curve for baclofen to the right, in a parallel manner, giving an apparent pA2 value of 3.7+/-0.3. Likewise, 7-MBFG (300 and 500 microM) reversibly blocked the baclofen-induced suppression of spontaneous discharges, in rat neocortical slices maintained in Mg2+ -free Krebs medium, and caused a rightward, parallel shift of the baclofen concentration-response curve, giving an apparent pA2 value of 4.1+/-0.1. The compound 7-MBFG belongs to a novel, new class of antagonist at central and peripheral GABA(B) receptors, in which the antagonist properties reside in the pseudo-aromatic character of their 3-benzo[b]furan-2-yl substituents, and might provide useful leads for further development of GABA(B) receptor ligands.

Pain relief using intermittent subcutaneous injections of an opioid (e.g. morphine) avoids the need for venous access and does not require complex or expensive pumps and devices. Although data on the pharmacokinetics of subcutaneous morphine exist, there are no comparable data for fentanyl in healthy volunteers. Therefore, the aim of this study was to characterize the pharmacokinetics of 200 microg fentanyl administered as a single bolus dose via the subcutaneous route in healthy opioid-naive volunteers. Nine healthy male volunteers were given 200 microg of subcutaneous fentanyl for more than 30 s. Opioid effects were blocked by administration of naltrexone. Venous blood samples taken at intervals from 5 min to 10 h after the dose were assayed using a liquid chromatography-mass spectrometry method. Pharmacokinetic data were analysed using a noncompartmental analysis approach. After subcutaneous bolus dose administration, the median maximum concentration of fentanyl was 0.55 ng ml(-1) (range 0.28-0.87 ng ml(-1)), reached at a median time of 15 min (range 10-30 min). The terminal half-life was 10.00 h (range 5.48-16.37 h). Absorption of subcutaneous fentanyl was relatively rapid and similar to the rate of absorption previously reported for subcutaneous morphine; the terminal half-life for fentanyl was substantially longer (10 h) than that of morphine (2.1 h), and blood concentrations were no more variable than that after administration by other nonintravenous routes.

The pharmacological actions of 2,6‐di‐ tert ‐butyl‐4‐(3‐hydroxy‐2‐spiropentylpropyl)‐phenol (BSPP), a putative presynaptic GABA B receptor modulator, were examined in electrically stimulated rat neocortical brain slices preloaded with [ ³ H]‐GABA or [ ³ H]‐glutamic acid. At 10 mmol/L, BSPP inhibited the release of [ ³ H]‐GABA in the presence of baclofen, but not that of [ ³ H]‐glutamic acid. This effect was sensitive to the GABA B receptor antagonist (+)‐( S )‐5,5‐dimethylmorpholinyl‐2‐acetic acid (Sch 50911). Alone, BSPP had no effect on the release of [ ³ H]‐GABA or [ ³ H]‐glutamic acid. It is concluded that BSPP selectively potentiates the action of baclofen at GABA B autoreceptors, but not heteroreceptors and may be a useful ligand to discriminate between presynaptic GABA B receptor subtypes.

After an initial clinical investigation of the effectiveness of an alfentanil–morphine mixture (AM) for the treatment of postoperative pain in the recovery setting, an audit was conducted to look at the effectiveness, safety and incidence of adverse opioid-related side effects of this mixture compared with morphine (M) alone. Assessment of effectiveness included the time and dose required to achieve patient comfort, the time to discharge from the postanaesthesia care unit (PACU) and pain scores; assessment of safety and side effects included measurement of sedation scores, oxygen saturation and respiratory rate as well as incidence of nausea and vomiting, and pruritus.

A series of six 2,2-disubstituted 3-[3,5-di-iso-propyl-4-hydroxyphenyl]propan-1-ol derivatives have been prepared for evaluation as allosteric modulators of GABAB receptors. The activity (EC50 30 µM) was greatest for the dimethyl analogue, but the isopropylphenyl compounds were generally weaker than the corresponding t-butyl compounds. Methylation of the phenolic group led to loss of activity.