Comparison of aceclofenac with diclofenac in the treatment of osteoarthritis.

A multicentre randomised, double-blind, parallel group, general practice study was undertaken to investigate the efficacy and safety of aceclofenac (200 patients, 100 mg twice daily and placebo once daily) in comparison with diclofenac (197 patients, 50mg three times daily) in patients with osteoarthritis of the knee. The treatment period of twelve weeks was preceded by a washout period of two weeks duration. At end point, patients in both aceclofenac and diclofenac-treated groups exhibited significant improvement in pain intensity (p = 0.0001). Although both treatment groups showed significant improvement in all investigators' clinical assessments (joint tenderness, swelling, pain on movement, functional capacity, overall assessment), there were no significant differences between the groups. There was, however, a trend towards greater improvement in complete knee movement and reduced pain on movement with aceclofenac. In patients with initial flexion deformity, aceclofenac was significantly more effective than diclofenac in improving knee flexion after 2-4 weeks treatment. Patients' subjective assessment of pain relief demonstrated significantly greater efficacy with aceclofenac. At end point, 71% of patients in the aceclofenac group reported improvement in pain intensity as compared to 59% treated with diclofenac (p = 0.005). Tolerability of aceclofenac was better than with diclofenac as fewer patients experienced gastrointestinal adverse events. In particular, the incidence of treatment related diarrhoea was less with aceclofenac (1%) than the diclofenac (6.6%). In summary, this study supports a therapeutic role for aceclofenac in arthritis and suggests that it is an alternative NSAID to diclofenac in the treatment of osteoarthritis.

Effect of electroconvulsive shock on the uptake and release of noradrenaline and 5-hydroxytryptamine in rat brain slices.

The uptake and release of [3H]noradrenaline and [3H]-5-hydroxytryptamine (5-HT) were studied in cerebral cortex slices from rats 30 min and 24 h after a single electroconvulsive shock (ECS) and 24 h after a series of five shocks given over 10 days. Both the Km and Vmax for 5-HT uptake were lower than controls 24 h after a single ECS, whereas after 5 ECS spread over 10 days both parameters remained depressed, though only the fall in Vmax was significant. Noradrenaline uptake was not altered after a single ECS, but the Vmax and Km were elevated following chronic ECS treatment. Neither ECS treatment schedule had any effect on the potassium-stimulated release of either transmitter. It is possible that the changes in monoamine uptake seen following ECS are an adaptive response to alterations in the synaptic cleft concentration of these transmitters.

Regional GABA concentration and [3H]-diazepam binding in rat brain following repeated electroconvulsive shock.

It has been confirmed that 24 hours following a series of electroconvulsive shocks (ECS) given once daily for 10 days (ECS X 10) to rats there is an increase in GABA concentration in the corpus striatum. A similar change was seen after the ECS had been given to rats anaesthetised with halothane, or when 5 ECS were given spread out over 10 days, the rats being anaesthetised during the ECS. A daily convulsion for 10 days elicited by flurothyl exposure resulted in an increased striatal GABA concentration, but also increased the GABA concentration in the hypothalamus, hippocampus and cortex. The increase in striatal GABA concentration was present 24 hours after ECS daily for 5 days or 3 days after ECS daily for 10 days. No change in [3H]-diazepam binding was seen in hippocampus, cortex or corpus striatum 24 hours after the last of 10 once daily ECS. The increase in striatal GABA concentration was therefore seen at all times when enhanced monoamine-mediated behaviours have been demonstrated following seizures.

Further evidence for a relationship between changes in GABA concentration in rat brain and enhanced monoamine-mediated behavioural responses following repeated electroconvulsive shock.

Administration of bicuculline (3.5 mg/kg i.p.) or pentylenetetrazol (30 mg/kg i.p.) 3 min before each of a series of 5 electroconvulsive shocks (ECS), given over 10 days (1, 3, 5, 8 and 10), prevented the enhanced behavioural responses to the dopamine agonist apomorphine and the 5-hydroxytryptamine agonist quipazine 24 hr after the last application of ECS. Pretreatment with these antagonists of gamma-aminobutyric acid (GABA) also abolished the rise in the concentration of GABA in the corpus striatum, normally seen after repeated ECS. Taken with data showing that the change in GABA concentration occurred at times when enhanced monoamine-mediated behavioural responses were seen, these results suggest that the enhanced behavioural responses following repeated ECS might be associated with changes in GABA function. Daily injection for 8 days with pentylenetetrazol (30 mg/kg) resulted in enhanced apomorphine-mediated behaviour. However, there was no change in the concentration of striatal GABA at this time.

Regional rat brain benzodiazepine receptor number and gamma-aminobutyric acid concentration following a convulsion.

1 Following administration to rats of an electroconvulsive shock (ECS) which resulted in a major tonic-clonic seizure, no changes in [3H]-diazepam binding characteristics were observed in cortex or hippocampus with either a well washed membrane preparation or a crude synaptosomal preparation. 2 No changes were observed in [3H]-diazepam binding in any other brain region examined 30 min after an ECS. 3 Thirty min following an ECS, regional brain gamma-aminobutyric acid (GABA) concentrations increased in hippocampus, cortex and hypothalamus. Only in the hippocampus did the increase occur within 5 min of the seizure. 4 Similar increases in GABA concentration were seen after a bicuculline-induced seizure but not after seizure induced by flurothyl; both treatments produced a tonic-clonic seizure. 5 Pretreatment of the rats with (+)-propranolol 5 min before the ECS abolished the tonic extension and prevented the brain GABA concentration changes that occur 30 min after the seizure. 6 No increase in GABA concentration was seen in hippocampus, cortex and hypothalamus 30 min after the final ECS of a course of 10 ECS given once daily for 10 days. In contrast a marked increase in striatal GABA concentration was observed. 7 These changes in GABA biochemistry following a seizure are discussed in relation to the post-ictal rise in seizure threshold that is occurring at the same time.

Repeated electroconvulsive shock attenuates clonidine-induced hypoactivity in rodents.

Clonidine administration at low dose produces hypoactivity in both rats and mice, probably by stimulation of presynaptic alpha 2-adrenoceptors in the brain. This behaviour is antagonised by yohimbine pretreatment but is unaffected by pretreatment with prazosin. An electroconvulsive shock (ECS) given once daily for 10 days markedly attenuated the hypoactivity in both species when tested 24 h after the final shock. The attenuation in mice was not found after either a single ECS or 10 subconvulsive shocks. Ten ECS did not alter the hypoactivity response produced by (+/-)-propranolol in mice. Clonidine administration decreased rat brain MOPEG-SO4 concentrations. A single ECS given daily for 10 days abolished this decrease. These results suggest that repeated ECS causes a subsensitivity of alpha 2-adrenoceptors in the brain and that these receptors may be located presynaptically.

Brain and serum calcium concentrations following electroconvulsive shock or bicuculline-induced convulsions in rats.

1 A single electroconvulsive shock (ECS; 125 V, 1 s, 50 Hz) given to rats anaesthetized with halothane produced little change in either serum or regional brain calcium concentrations, compared to rats anaesthetized with halothane, either 5 min or 24 h after the convulsion. Both anaesthetic and ECS-treated rats showed an elevated serum concentration 5 min after the ECS. 2 When 5 ECS were given spread out over 10 days there were no significant calcium concentration changes in either serum or brain except for an increase in the pons/medulla. 3 A single convulsion produced by bicuculline (0.375 mg/kg i.v.) resulted in a marked increase in the calcium concentration in serum, but not brain, 5 min later. Diazepam pretreatment (10 mg/kg i.v.) prevented both the convulsion and the serum calcium change. 4 Results are discussed in relation to clinical data on calcium changes following electroconvulsive therapy (ECT) and the enhanced monoamine-mediated behaviours which follow ECS administration to rats.