Effects of flurbiprofen enantiomers on pain-related chemo-somatosensory evoked potentials in human subjects.

1. The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjective pain ratings. 2. Healthy female volunteers (n = 16, age 23-36 years) participated in a placebo-controlled, randomised, double-blind, four-way crossover study. Single doses of (S)-flurbiprofen (50 mg), (R)-flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful CO2- stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3. The CSSERP-amplitude P2, a measure of analgesic effect, decreased after administration of both (R)- and (S)-flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05). The analgesia-related decreases in evoked potential produced by (R)-flurbiprofen were dose-dependent. Comparing similar doses of (R)- and (S)-flurbiprofen, the decrease in CSSERP-amplitudes produced by the (S)-enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4. The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)-flurbiprofen caused only little toxicity in rats as compared with the (S)-enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)-flurbiprofen in pain therapy.     

Toxicological studies on azapropazone.

The toxicity of azapropazone, a non-steroidal anti-inflammatory analgesic compound was studied in mice, rats, hamsters, guinea pigs, rabbits, cats, mongrel and beagle dogs, domestic pigs, rhesus monkeys, cynomolgus monkeys and baboons in experiments which ranged from acute, single-dose studies up to treatment periods of 1 year. The beagle dog was found to be especially sensitive to gastro-intestinal ulceration from azapropazone and this contrasted with the marked lack of gastro-intestinal hazard to other animals and particularly to the 3 primate species studied. The animal experiments did not indicate any potential risk to other body systems, and comparisons with other anti-inflammatory compounds, where these were made, suggest that azapropazone is at least as safe as other commonly-used agents. Azapropazone was not found to have teratogenic, carcinogenic or antimitotic activity and was shown not to produce local tissue damage.     

Excretion of azapropazone in human breast milk

The excretion of azapropazone in breast milk was studied in four lactating women over one dosing interval following repeated doses of 600 mg b.d. for at least three days. Plasma and milk samples were collected up to 12 hours after drug intake. An average of 0.8 mg azapropazone was calculated as being excreted in breast milk in the 12 hour period. The breast fed neonate would ingest 0.2 mg/kg during this period.     

HPLC determination of azapropazone in human plasma

Determination of Azapropazone in Human Plasma by HPLC A HPLC method is described to determine azapropazone in human plasma. Azapropazone is extracted from acidified plasma samples (pH 4) with dichloroethane and reextracted into an alkaline methanol solution. Concentrations down to 0.1 μg per milliliter plasma can be determined. The procedure is suitable for pharmacokinetic routine analyses.     

Pharmacokinetics of azapropazone in the elderly.

Plasma concentrations of azapropazone have been measured in young and elderly subjects after a single dose of 600 mg azapropazone. Maximum concentrations were higher in the elderly. Renal function was impaired in the older subjects. Mean azapropazone clearance was significantly reduced (P less than 0.001) in the old, compared to the young. Elimination half-life was prolonged but the difference did not reach statistical significance due to the wide variation of the values in the elderly. The volume of distribution of azapropazone and degree of adipose tissue did not differ between the two groups. Azapropazone clearance correlated well with creatinine clearance (P less than 0.001) when all the subjects were included and for the younger subjects only but not for the elderly patients alone. The addition of fat mass into the regression equation improved the relationship in all groups but in the older group levels of statistical significance were not achieved. Reasons for the difference between young and old are discussed. The effects of age on the pharmacokinetics of azapropazone suggest that therapeutic plasma levels may be achieved with a dose of 600 mg daily.     

The determination of azapropazone in blood plasma.

Three methods for the determination of azapropazone were studied for the analysis of blood plasma samples taken after oral administration of azapropazone. A gas chromatographic method was compared with two simple spectrophotometric assay methods and the effect of metabolites of the drug on each method is described. It is concluded that metabolites are unlikely to cause significant interference with the two simple methods and that either is suitable for determination of plasma levels of the drug. Some problems associated with a gas chromatographic method are described and the comparative results of the examination of plasma samples using these methods are given.     

Long-term use of azapropazone in rheumatoid conditions.

In an open assessment of azapropazone, 51 patients with rheumatoid disorders, mainly rheumatoid arthritis, were treated continuously for periods up to 3 years (range 2 weeks to 38 months). Treatment was interrupted or discontinued in 9 patients for various reasons. Initial dosage was 1200 mg. daily, but this was usually reduced after a few months to a maintenance level of 900 mg. daily. An overall assessment of patient response at the end of the study period indicated that only 4 (7.8%) of the 51 patients failed to obtain satisfactory relief during treatment: 28 (54.6%) showed objective signs of improvement, such as reduced joint swelling and stiffness, as well as subjective evidence of symptom relief, and a further 19 patients (37.3%) reported an equivocal analgesic effect with azapropazone. Few side-effects were reported, mainly mild gastralgia and nausea, and routine laboratory investigations throughout the long-term study revealed no abnormalities in the blood picture, liver or renal function or coagulation factors. There was also no evidence of any interaction between azapropazone and other drugs used concomitantly.     

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.     

Effects on platelet functions and pharmacokinetics of azapropazone and ketorolac tromethamine given as single parenteral doses.

The biosynthesis of thromboxane (TX) B2 and immunoreactive prostaglandin (PG) F2 alpha in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 72 h after intravenous injection of 600 mg azapropazone 2H2O and intramuscular injection of 30 mg ketorolac tromethamine in six healthy subjects. The drug doses were selected on the basis of comparable analgesic activity (maximal recommended analgesic dose). Both platelet aggregation and prostanoid biosynthesis were inhibited by racketorolac to a significantly greater extent and for a longer period of time than by azapropazone. Correlations between serum concentrations and the inhibitory effects on TXB2 biosynthesis were observed for both drugs. Using the sigmoidal Emax model the mean serum concentration of azapropazone inhibiting platelet TXB2 generation by 50% (EC50) was found to be 98.1 +/- 41.9 (s.d.) micrograms ml-1, a value 1000 times higher than that for rac-ketorolac. The moderate inhibition of platelet function by azapropazone as compared with rac-ketorolac might be an advantage with regard to its use as a post-operative analgesic.     

1H MRS brain measures and acute lorazepam administration in healthy human subjects.

The effects of acute lorazepam administration on 1H magnetic resonance spectroscopy (MRS) in vivo brain spectra were examined in the left dorsolateral prefrontal cortex (L-DLPFC) of healthy human subjects. We wanted to examine whether lorazepam administration would result in significant changes in the levels of 1H-MRS metabolites in this brain region. Ten healthy controls underwent a short echo-time 1H-MRS session immediately before, and a second one 1 h after lorazepam administration (2mg/orally). The measured 1H-metabolites included N-acetyl-aspartate, phosphocreatine+creatine, trimethylamines, myo-inositol, glutamate, and glutamine, which were expressed as absolute values and ratios. No significant differences were found after lorazepam administration for any of the measured metabolite levels or ratios (paired t-tests, p >.05). This study demonstrated that lorazepam can potentially be utilized to acutely sedate psychiatric subjects during in vivo 1H-MRS sessions, as it does not appear to produce significant changes in the 1H-MRS spectra in this specific brain region.     

Effects of nicotine and amphetamine on latent inhibition in human subjects

Latent inhibition (LI) is a phenomenon in which repeated non-reinforced exposure to a stimulus retards subsequent conditioning to that stimulus; it reflects a process whereby irrelevant stimuli become ignored, and has been the subject of study concerning attentional abnormalities in schizophrenia. Low doses of the indirect dopamine (DA) agonists, amphetamine and nicotine, disrupt LI in the rat. These drugs are believed to disrupt LI via DA release in the nucleus accumbens; LI in amphetamine- and nicotine-treated rats is reinstated by administration of the DA antagonist haloperidol. In human subjects, low doses of amphetamine abolish LI, and more recently haloperidol has been shown to potentiate LI. The present study investigated the effects of nicotine on LI in human subjects, and also attempted to replicate the abolition of LI by amphetamine. Nicotine failed to affect LI when administered either subcutaneously or by cigarette smoking. LI was, however, abolished in a group of subjects given 5 mg amphetamine 90 min before testing. Supplementary analyses of the data pooled from all three experiments showed that, in contrast to an earlier report, LI was no weaker in smokers than in non-smokers.     

Effects of zolpidem versus diazepam and placebo on breathing control parameters in healthy human subjects.

The following study explores the possibility that zolpidem, a new hypnotic agent derived from imidopyridine, may induce changes in ventilatory function in normal subjects. The study, conducted double-blind on 16 subjects (eight men and eight women, aged 21 to 33 years) was undertaken in two successive phases: phase A with a cross-over, intended to compare the ventilatory effects of 10 mg oral dose of diazepam with a placebo, and then phase B, with a Latin square design, intended to compare the effects of 10 and 20 mg oral doses of zolpidem with 10 mg oral doses of diazepam and a placebo. Central inspiratory drive was assessed by occlusion pressure (P0.1) and breathing pattern in air and during carbon dioxide rebreathing. Measurements were performed one and three hours after each drug or placebo administration. Zolpidem did not affect tidal volume (Vt), slopes S1, S2 or P0.1, but decreased the duration of the phases of the respiratory cycle ti by 14% (p less than 0.01) and ttot by 15% (p = 0.03) after three hours post dosing without any change in ventilation, Vt/ti or ti/ttot. Nevertheless, these timing changes, although statistically significant, seem to have no clinical relevance to overall ventilation regulation in normal subjects. On the other hand, diazepam slightly changed S2 at three hours post dosing (0.14 +/- 0.07 versus 0.17 +/- 0.10 after the placebo; p = 0.06) without modifying the other parameters.     

Effects of organophosphates on bioelectrical activity of the brain

Effects on electroencephalogram of acute and chronic exposure of two main groups of organophosphates: classic anticholinesterases (OP) and new bicyclic organophosphates (PTBO) are described. The role of muscarinic receptors of the midbrain reticular formation in the mechanism of action of OP and the possible mechanism of action of PTBO as blockers of a chloride ionophore of the GABA receptor complex are presented. The mechanism of convulsive activity of both groups are also discussed.     

Dose-related effects of ibuprofen on pain-related potentials.

1. The aim of this study was to investigate the dose-related effects of ibuprofen (placebo, 400 and 800 mg rac-ibuprofen [Aktren], administered orally) on experimentally-induced tonic and phasic pain. 2. Eighteen volunteers participated in this randomized, double-blind, three-fold cross-over study. Measurements were obtained before and 90 min after administration of the drugs. Phasic pain was produced by CO2 pulses of two concentrations applied to the right nostril. The left nostril was stimulated with a constant stream of dry air which produced a tonic painful sensation described as dull and burning. Subjects rated the intensity of the painful stimuli by means of visual analogue scales. In addition, chemo-somatosensory event-related potentials (CSSERP) were also recorded in response to phasic painful CO2 stimuli. 3. While mean intensity estimates of both tonic and phasic painful stimuli showed a non-significant dose-related decrease, a statistically significant dose-related decrease was observed for CSSERP amplitudes. 4. In conclusion, in order to investigate analgesic drug effects, CSSERP appear to be a more sensitive measure compared with psychophysically obtained responses.