Absorption of effervescent paracetamol tablets relative to ordinary paracetamol tablets in healthy volunteers

Objectives: The aim of this study was to compare the rate of absorption between ordinary paracetamol tablets and effervescent paracetamol tablets. Methods: Twenty healthy volunteers participated in an open randomised crossover study and were given a 1000-mg dose of either ordinary paracetamol tablets (2 × 500 mg Panodil tablets, SmithKline Beecham) or effervescent paracetamol tablets (2 × 500 mg Pinex Brusetablett, Alpharma AS) with a 3-week washout period in between. Blood samples were collected for 3 h. Maximum serum concentration (C_max) and the time to maximum serum concentration (t_max) were recorded and the area under the concentration versus time curve (AUC) was calculated. Results: The mean t_max was significantly shorter when paracetamol effervescent tablets were taken (27 min) rather than ordinary paracetamol tablets (45 min) (P=0.004). There was no significant difference between the mean C_max of 143 μmol/l with effervescent tablets and that of 131 μmol/l with ordinary tablets. The mean AUC_0–3 h was significantly higher with paracetamol effervescent tablets (223.8 μmol · h · l⁻¹) than with ordinary tablets (198.2 μmol · h · l⁻¹; P=0.003). After 15 min, 17 (85%) subjects in the effervescent group had a serum concentration of 70 μmol/l (lower therapeutic serum concentration) or higher relative to only 2 (10%) subjects in the ordinary tablet group (P=0.001). Conclusion: Paracetamol effervescent tablets are absorbed significantly faster than ordinary paracetamol. Thus, effervescent tablets might offer significantly faster pain relief when paracetamol is used. Received: 4 October 1999 ;/ Accepted in revised form: 15 February 2000     

Oral metamizol (1 g and 2 g) versus ibuprofen and placebo in the treatment of lower third molar surgery pain: randomised double-blind multi-centre study

Objective: To assess the efficacy of metamizol 1 g and 2 g in the relief of pain after surgical extraction of the lower third molar, and to compare the therapeutic effect with that of ibuprofen 600 mg or placebo. Methods: A total of 253 patients aged between 18 years and 60 years who had undergone extraction of the lower third molar (types II–IV) under local anaesthesia, up to a maximum of 108 mg of mepivacaine, were randomly assigned to a single oral dose of a new galenic form (drinkable vials) of metamizol 1 g (n = 75), metamizol 2 g (n = 72), ibuprofen 600 mg (n = 74) or placebo (n = 32). Pain intensity was evaluated by a 100-mm visual analogue scale. To enter the study, a pain level of 50 mm or more was required. The duration of the trial was 1 h. Assessments were carried out at 15, 30 and 60 min after treatment. Results: The analgesic efficacy of metamizol 2 g was significantly better than ibuprofen and placebo with regard to all evaluated parameters. The values of the pain intensity difference at 15 min, the percentage of patients with a decrease of 50% or more on the visual analogue scale at 60 min and the sum of pain intensity differences at 60 min showed metamizol 2 g to be significantly more effective than metamizol 1 g. In general, metamizol 1 g was as effective as ibuprofen 600 mg. The analgesic efficacy of placebo was significantly lower than that of all active treatments. A lower number of patients treated with metamizol 1 g (n = 1) or metamizol 2 g (n = 1) needed rescue medication than those given ibuprofen (n = 7) or placebo (n = 5). No serious adverse effects developed and none of the patients had to leave the study for this reason. Conclusions: The model of the lower third molar, for which the analgesic outcome referred to the first hour after drug administration, demonstrated that the analgesic efficacy of oral metamizol 2 g was significantly higher than that of ibuprofen 600 mg or placebo. Metamizol 1 g and ibuprofen 600 mg showed a similar therapeutic effect. All regimens were as well tolerated as placebo. Received: 6 July 1997 / Accepted in revised form: 6 October 1997     

Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis

Objective: To estimate the analgesic effect of ibuprofen and to test whether codeine and caffeine enhance its effect on post-surgical pain. Method: Systematic overview of the literature and meta-analysis of published randomised, controlled trials. Results: Ibuprofen is effective in dental pain, episiotomy pain and other post-operative pain. There is a dose–response relationship over the range 50–400 mg. The difference in total pain-relief score relative to placebo was 19–31%. On average, patients were over three times more likely to obtain moderate to excellent pain relief with ibuprofen than with placebo (response-rate ratio = 3.45) and the number needed to treat was 2.44. Codeine 60 mg enhanced the analgesic effect of ibuprofen 400 mg by about 8% in the total pain-relief scale, but it also increased its adverse effects. The additive effect of caffeine was inconsistent. Conclusion: Ibuprofen is an effective analgesic in postoperative pain. Codeine 60 mg adds to the analgesic effect of ibuprofen 400 mg. Any additive caffeine effect requires validation. Received: 5 February 1997 / Accepted in revised form: 11 August 1997     

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC_0–3, AUC_0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C_max) 2- to 2.5-fold compared with placebo. The AUC_0–3 and the C_max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole. Received: 1 July 1996 / Accepted in revised form: 4 September 1996     

Lack of acetaminophen ceiling effect on R-III nociceptive flexion reflex

Objective: The analgesic efficacy of intravenous doses of acetaminophen (paracetamol) 0.5 g, 1 g and 2 g (administered as propacetamol) was assessed in 11 healthy subjects in a randomised, double-blind, placebo-controlled crossover study. The antinociceptive effect was assessed over 8 h by measurement of the nociceptive flexion reflex threshold (R-III) in response to selective transcutaneous electrical stimulations. Results: After acetaminophen 0.5 g, R-III increased to a mean maximum of 23% over baseline values; after 1 g to 28%, and after 2 g to 40%. The AUC_0–8 h of the analgesic effects and the AUC_0–8 h of plasma concentrations closely correlated and were dose-dependent: r _s = 0.37, for R-III and r _s = 0.94, for the plasma concentrations. Intravenous acetaminophen exerted a dose-dependent central antinociceptive effect. Received: 19 August 1996 / Accepted in revised form: 18 August 1997     

Evaluation of ibuprofen versus aspirin and paracetamol on efficacy and comfort in children with fever

Objective: We compared efficacy and impact on the comfort of ibuprofen (7.5 mg/kg per dose), aspirin (10 mg/kg/dose) and paracetamol (10 mg/kg per dose) on children with fever aged 6–24 months in an open, randomised study with three parallel groups. Methods: The main criterion for efficacy was area under the curve (AUC) of percentage temperature reduction. Comfort was assessed on scores depending on general behaviour and degree of relief. General behaviour was assessed on a verbal scale and on a visual analogue scale (VAS) and the degree of relief was assessed in relation to baseline on a verbal scale. Results: The efficacy of ibuprofen was better than that of aspirin or paracetamol. In spite of more adverse events, the comfort scores were significantly in favour of ibuprofen 6 h after the first dose of treatment. Received: 29 March 1996 / Accepted in revised form: 2 August 1996     

The negative mucosal potential: separating central and peripheral effects of NSAIDs in man

Objective: We wanted to test whether assessment of both a central pain-related signal (chemo-somatosensory evoked potential, CSSEP) and a concomitantly recorded peripheral signal (negative mucosal potential, NMP) allows for separation of central and peripheral effects of NSAIDs. For this purpose, experimental conditions were created in which NSAIDs had previously been observed to produce effects on phasic and tonic pain by either central or peripheral mechanisms. Methods: According to a double-blind, randomised, controlled, threefold cross-over design, 18 healthy subjects (11 males, 7 females; mean age 26 years) received either placebo, 400 mg ibuprofen, or 800 mg ibuprofen. Phasic pain was applied by means of short pulses of CO₂ to the nasal mucosa (stimulus duration 500 ms, interval approximately 60 s), and tonic pain was induced in the nasal cavity by means of dry air of controlled temperature, humidity and flow rate (22 °C, 0% relative humidity, 145 ml · s⁻¹). Both CSSEPs as central and NMPs as peripheral correlates of pain were obtained in response to the CO₂ stimuli. Additionally, the subjects rated the intensity of both phasic and tonic pain by means of visual analogue scales. Results: As described earlier, administration of ibuprofen was followed by a decrease in tonic pain but – relative to placebo – an increase in correlates of phasic pain, indicating a specific effect of ibuprofen on the interaction between the pain stimuli under these special experimental conditions. Based on the similar behaviour of CSSEP and NMP, it was concluded that the pharmacological process underlying this phenomenon was localised in the periphery. By means of the simultaneous recording of interrelated peripheral and central electrophysiologic correlates of nociception, it was possible to separate central and peripheral effects of an NSAID. The major advantage of this pain model is the possibility of obtaining peripheral pain-related activity directly using a non-invasive technique in humans. Received: 19 May 1996 / Accepted in revised form: 14 November 1996     

Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen

Objective Ibuprofen, a nonsteroidal anti-inflammatory agent, is metabolised in vitro by cytochrome P450 (CYP) 2C8 and 2C9. We studied the possible effect of gemfibrozil, an in vivo inhibitor of CYP2C8, on the pharmacokinetics of ibuprofen in healthy volunteers. Methods In a randomised two-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each subject ingested 400 mg of racemic ibuprofen. Plasma concentrations of ibuprofen enantiomers and gemfibrozil were measured. Results Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC_0–∞) of R-ibuprofen by 34% (range −10 to 67%; P < 0.001). The elimination half-lives (t _1/2) of R- and S-ibuprofen were increased by 54 and 34% (range 11–162% and 16–85%; P < 0.001) respectively. The other pharmacokinetic variables of R- and S-ibuprofen were not changed significantly. The AUC_0–∞ ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil (P < 0.001). Conclusions Gemfibrozil moderately increases the AUC_0–∞ of R-ibuprofen and prolongs its t _1/2, indicating that R-ibuprofen is partially metabolised by CYP2C8. The interconversion of R- to S-ibuprofen can explain the small effect of gemfibrozil on the t _1/2 of S-ibuprofen. The gemfibrozil-ibuprofen interaction is of limited clinical significance.     

Investigation into the antinociceptive potential of remoxipride administered intrathecally in sheep

Systemic administration of remoxipride, a dopamine (D₂) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of remoxipride. Remoxipride (17.7 mg) administered intrathecally via chronically indwelling catheters produced a greatly variable but significant (p<0.05) increase in nociceptive thresholds as judged by a focused mechanical stimulus (blunt pin) applied to the forelimb of four sheep. However, this dose of remoxipride induced a marked forelimb motor impairment as judged by a subjective visual analogue scoring system. Conversely, intrathecal xylazine (100 and 200 μg), an α-adrenergic agonist with antinociceptive properties, did not produce forelimb weakness although the higher dose (200 μg) produced significant sedation. In vitro autoradiography was performed on cervical spinal cord sections taken from sheep. Remoxipride displaced [³H] YM-09151-2, a selective D₂ antagonist, from densely-labelled areas in the superficial layer of the dorsal horn, lamina X and ventral horn. Even though there are possible anatomical substrates within the spinal cord for both an antinociceptive and motor disturbance action of remoxipride, the behavioural data suggest that the spinal cord is unlikely to be the primary site of antinociceptive action for systemically-administered doses of remoxipride. Received: 29 July 1996 / Accepted: 6 December 1996     

Changes in urinary PGE<Subscript>2</Subscript> after ibuprofen treatment in preterm infants with patent ductus arteriosus

Purpose  To investigate changes in urinary PGE₂ after ibuprofen treatment in preterm infants with patent ductus arteriosus (PDA). Methods  Twenty preterm infants with a hemodynamically significant PDA (gestational age, 28.6 ± 2.3 weeks) and 20 controls (gestational age, 30.4 ± 1.5 weeks) were prospectively enrolled at 48–72 h of life. After enrollment, the former underwent conventional ibuprofen-lysine treatment. At 48–72 h (T₀) and 108–144 h of life (T₁), urine samples were noninvasively collected in both groups to measure urinary PGE₂ concentrations (enzyme immunoassay method), and renal function was investigated. Results  Urinary PGE₂ decreased significantly both in ibuprofen-treated patients (66.95 ± 16.78 vs. 27.15 ± 17.92 pg/mL, P < 0.001) and in controls (71.7 ± 16.2 vs. 53.2 ± 18.4 pg/mL, P < 0.001) from T₀ to T₁. However, urinary PGE₂ at T₁ was significantly lower (P < 0.001) in the ibuprofen group compared to the control group. Acute renal failure occurred in three ibuprofen-treated patients (15%). Conclusions  Ibuprofen markedly reduces (59.4%) urinary PGE₂ and may alter renal function in the newborn.     

Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage – a pilot study

Objective The pharmacokinetics of nimodipine following enteral administration in the early phase after subarachnoid haemorrhage (SAH) has not been described. If a sufficient absorption could be achieved with enterally administered nimodipine, this would be more feasible dosage form and result in a significant reduction in pharmaceutical costs given that the parenteral formulation of nimodipine currently used is tenfold more expensive than the enteral formulation. Methods This was a pilot study in which 17 patients with aneurysmal SAH were randomly assigned to receive nimodipine within 24 h after initial bleeding either as an 60 mg tablet/suspension at 4-h intervals, or as a continuous intravenous infusion of 2 mg/h. Serum nimodipine concentrations were measured during the 4 h following the first dose, and at 24 and 72 h on a validated gas chromatography mass spectrometer (GC-MS). Results Nimodipine AUC values (expressed in μg min/ml) were lower in the eight SAH patients receiving enteral nimodipine [AUC_0–4 range: 0.13–5.4 (median: 0.32); AUC_24–28 range: 0.16–6.1 (0.71); AUC_72–76 range: 0.47–20.6 (1.9)] than in the nine patients receiving a continuous intravenous infusion of nimodipine [AUC_0–4 range: 2.4–4.9 (3.4), p = 0.059; AUC_24–28 range: 4.7–10.3 (7.3), p = 0.001; AUC_72–76 range: 3.4–8.6 (6.9), p = 0.001]. In three of five good-grade SAH patients receiving nimodipine tablets the AUC values were comparable to those of the intravenous administration, but in two good-grade patients with tablets and in all three poor-grade (Hunt&Hess, grade IV) SAH patients receiving the suspension, the rate and extent of nimodipine absorption was negligible. Conclusion This pilot study indicates that the rate and extent of nimopidine absorption following enteral administration in some acute SAH patients could be negligible, and this may particularly be the case in patients with a decreased level of consciousness.     

Transplacental kinetics of lead in pregnant mini-pigs

This study examined the maternal and fetal blood kinetics of lead in pregnant, near term mini-pigs. A lead dose of 1 mg/kg was administered to the animals by i.v. injection as bolus. During the 5-h sampling period, the two-compartment maternal pharmacokinetics demonstrated a rapid phase T _1/2 of 8 min and a slower phase T_1/2 of 199 min. Lead reached the fetus with a time lag of 81 min. At 24 h after administration the ratio of fetal to maternal blood lead concentration seemed to become stable. When lead was injected directly into the fetal blood circulation, the decay of fetal blood lead fitted a one-compartment model. The disappearance half-life was 92 min. Lead can obviously accumulate in fetal liver; the lead level in fetal brain showed no detectable changes. This study confirmed that lead can also pass through the epitheliochorial placenta. Received: 1 August 1995 / Accepted: 21 August 1996     

Assessment of the efficacy and safety of paracetamol, ibuprofen and nimesulide in children with upper respiratory tract infections

Objective: The aim of this study was to assess and compare the efficacy and tolerability of paracetamol, ibuprofen and nimesulide in children with upper respiratory tract infections (URTIs). Methods: Ninety children with acute URTIs and fever were enrolled to the study. The patients were allocated to three groups. The first group was treated with paracetamol 10 mg/kg thrice daily; the second group with ibuprofen 10 mg/kg thrice daily; and the third group received nimesulide 2.5 mg/kg twice daily for 5 days. Results: The anti-pyretic activity of nimesulide was greater and more rapid than either paracetamol or ibuprofen. The number of patients with normal temperature was significantly greater in the first 2 days for the nimesulide group. The improvement in cough for the paracetamol group was better than the others. Conclusion: The results of this study demonstrated that the anti-pyretic effectiveness of nimesulide is better than paracetamol and ibuprofen in febrile children with URTIs. However, new studies in larger paediatric populations are required to explore the anti-inflammatory effect of nimesulide. Received: 20 April 1999 / Accepted in revised form: 13 August 1999     

Effect of omeprazole and cimetidine on plasma aldosterone response to angiotensin II

Objective: The Effect of omeprazole, a proton pump inhibitor, and cimetidine, an H₂-receptor antagonist, on plasma aldosterone (PA) response to angiotensin II (AII) were evaluated. Methods: Furosemide (a loop diuretic agent, 20 mg) was given intravenously to eight healthy subjects during a control period, and after pretreatment with omeprazole (20 mg daily) or cimetidine (800 mg daily) for 6 days. Blood samples for determination of plasma renin activity (PRA), AII, PA, adrenotorticotropic hormone (ACTH) and potassium were obtained just before, and 30, 60 min and 120 min after furosemide administration. Results: PRA, AII and PA increased significantly after furosemide administration whereas ACTH and potassium did not. Significant correlations between plasma AII and PA were obtained in the control and omeprazole trial, but not in the cimetidine trial. The slope of the regression lines of the control and omeprazole trials did not differ significantly. Conclusion: These results suggest that, in contrast to cimetidine, the inhibitory effect of omeprazole on AII-stimulated aldosterone production following dosing with furosemide is negligible. Received: 30 September 1997 / Accepted in revised form: 18 February 1998     

Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men

Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and C_max by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in C_max. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism. Received: 24 April 1996 / Accepted in revised form: 25 November 1996     

The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice

Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice. Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC), maximum terfenadine concentration (C_max) and the time to maximum concentration (t_max) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram. Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml⁻¹ · h), as was the C_max (median values 7.2 vs 2.1 ng · ml⁻¹). The t_max was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels. The 95% confidence interval for the difference in the change in QTc interval at C_max was −13 to +38 ms. Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of time. Received: 14 October 1996 / Accepted in revised form: 10 December 1996     

Effect of nifedipine on superior mesenteric artery impedance in humans

Objective: In a randomized, double-blind placebo-controlled study the acute effect of sublingual nifedipine (10 mg) on the superior mesenteric artery pulsatility index (PI) was studied over 60 min in 12 healthy subjects (Age 43 y). Methods: PI was considered as a parameter of vascular resistance and was calculated as the peak-to-peak amplitude of the waveform divided by the mean amplitude. PI measurements were performed with the subject resting and fasting and were made 5, 10, 15, 30, 45 and 60 min for 1 hour after nifedipine (10 mg) or placebo. Arterial blood pressure and heart rate were measured at the same times. Results: Placebo administration failed to change arterial blood pressure, heart rate or PI. 5 min after 10 mg sublingual nifedipine, PI had significantly decreased from 5.0 to 3.8, with a nonsignificant decrease in arterial blood pressure and an increase in heart rate. By 15 min after nifedipine administration PI had further decreased to 3.1, and there was a concomitant significant decrease in mean arterial blood pressure and increase in heart rate. Sixty minutes after drug intake PI and arterial blood pressure were still below baseline not significant but the heart rate remained significantly increased. Conclusion: Our data indicate that in healthy subjects sublingual administration of nifedipine had a vasodilator effect (decrease in PI) on the superior mesenteric vascular bed. Received: 1 August 1995/Accepted in revised form: 2 March 1996     

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Objective: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. Methods: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined␣with positron emission tomography (PET) with [¹¹C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of binding of [¹¹C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. Conclusion: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals. Received: 21 August 1996 / Accepted in revised form: 22 November 1996     

Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain

Objective: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled- release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain. Methods: In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration–time curve (AUC)_0–12 h, peak plasma concentration (C_max), time to reach C_max (t_max), and C0 and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0–10 scale, while side effects and rescue medication were recorded. Results: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC_0–12 h, t_max and C_max of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC_0–12 h and C_max of M6G, and AUC_0–12 h, C_max, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the t_max of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P=0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed. Conclusion: The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain. Received: 3 September 1999 / Accepted: 15 March 2000     

Loop diuretics enhance the secretion of prostacyclin in vitro, in healthy persons, and in patients with chronic heart failure

Background: Previous studies suggest that the acute haemodynamic effects of loop diuretics are due to a direct dilation of blood vessels and are not related to diuretic properties, but possibly to prostaglandin secretion. Objectives: We investigated whether in vitro human endothelial and renal epithelial cells responded to torasemide or furosemide with enhanced secretion of the vasodilator prostaglandin prostacyclin (PGI₂). We also investigated the effects of loop diuretics on plasma concentrations of PGI₂ and its physiological antagonist thromboxane after 25 min of administration of drugs in 44 patients with congestive heart failure (CHF) and 44 healthy volunteers. Methods: The PGI₂ levels were measured after extraction in ethyl acetate by RIA as levels of 6-KetoPGF_1α, a stable metabolite from a non-enzymatic degradation. TxB2 concentration, the stable hydrolysis product of TxA2, was also measured by RIA. Results: In human endothelial and renal epithelial cells, both loop diuretics induced an increase of 6-KetoPGF_1α secretion that reached a peak after about 5 min and remained stable for 30 min of exposure to the drugs. The magnitude of the phenomenon was lesser in epithelial than in endothelial cells. Moreover, in both cell lines, there was a significantly higher secretion of 6-KetoPGF_1α to torasemide than furosemide (P < 0.05). Concentrations of 6-KetoPGF_1α at baseline were similar between the groups of CHF patients receiving the two different drugs. After 25 min of both drugs, 6-Keto-PGF_1α significantly increased (P < 0.01), and this was significantly higher in patients treated with 10 mg of torasemide (P < 0.05 vs furosemide). Levels of PGI₂ at baseline were lower in healthy controls than those reached by CHF patients and similar between groups. After 25 min of both drugs, PGI₂ plasma levels were significantly increased (P < 0.01). Baseline values of TxB2 were significantly higher in CHF patients compared with controls (P < 0.01 vs respective groups), and, more importantly, furosemide but not torasemide increased TxB2 levels in patients and controls (P < 0.05 vs baseline). Conclusions: Our study is the first demonstration in human tissue of increased secretion of PGI₂ both in vitro and in vivo, after torasemide or furosemide administration. This phenomenon, which may explain in part the vasodilatory effects of these drugs, was more evident with torasemide and was reached at lower concentrations of the drug. Accordingly, we also found that furosemide but not torasemide stimulated the release of the PGI₂ physiological antagonist thromboxane in CHF patients and healthy controls. Received: 8 May 1998 / Accepted in revised form: 14 August 1998