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PubMed2004

The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip.

OBJECTIVE: To compare the analgesic efficacy of single and multiple doses of ibuprofen with that of paracetamol in patients with knee or hip osteoarthritis (IPSO study). METHOD: 222 patients were randomised in a double blind, multicentre study-156 (70%) had a painful knee joint and 66 (30%) a painful hip joint. The main efficacy criterion was pain intensity assessment after a single dose (ibuprofen 400 mg, paracetamol 1000 mg). Functional disability assessment and patient global assessment were carried out over 14 days. RESULTS: The sum of the pain intensity difference over 6 hours after the first administration was significantly higher (p = 0.046) in the ibuprofen group than in the paracetamol group. Over 14 days pain intensity decreased from the first day and was significantly lower in the ibuprofen group than in the paracetamol group (p<0.05). The functional disability of the patient was assessed using the WOMAC; the ibuprofen group improved significantly over 2 weeks compared with the paracetamol group for each of the subscales: stiffness (p<0.002), pain (p<0.001), physical function (p<0.002). The drugs were equally safe. CONCLUSION: The IPSO study shows that for the treatment of osteoarthritic pain, ibuprofen 400 mg at a single and multiple dose (1200 mg/day) for 14 days is more effective than paracetamol, either as a single dose of 1000 mg or a multiple dose (3000 mg/day). Because ibuprofen and paracetamol have similar tolerability, this study indicates that the efficacy/tolerability ratio of ibuprofen is better than that of paracetamol in this indication over 14 days.

Acetaminophen↗
PubMed2003

The influence of morphine on the absorption of paracetamol from various formulations in subjects in the supine position, as assessed by TDx measurement of salivary paracetamol concentrations.

The aim of this study was to determine the influence of the type of paracetamol formulation on the rate of absorption when subjects are in the supine position, with or without taking concomitant morphine. Two groups of healthy volunteers were used, who were in the fasting state and remained in the supine position during the study. One group took 1,500 mg of paracetamol on three occasions as conventional tablets, dispersible tablets or a suspension in a randomized crossover design. Seventeen saliva samples per subject were obtained (time zero to 360 min post-dose), which were then centrifuged and kept at -20 degrees C prior to analysis. The second group repeated the study following four doses of morphine syrup (10 mg 4 hourly) in the 12 h preceding paracetamol ingestion. In this phase of the study, paracetamol absorption from suspension was not investigated. A TDx assay was used to determine salivary paracetamol concentrations. The tmax for conventional tablets when taken concomitantly with morphine was 160 (+/- 81) min compared to 51 (+/- 58) min for subjects not taking morphine. For dispersible tablets the tmax in the morphine group was 14 (+/- 9) min compared to 15 (+/- 12) min without morphine. The results suggest that patients who are confined to bed and taking morphine will have an unacceptably long delay between taking conventional paracetamol tablets and the paracetamol reaching therapeutic plasma concentrations. Conversely, there is little effect on the absorption of dispersible paracetamol under the same conditions.

Absorption↗
PubMed1985

Methionine in paracetamol tablets, a tool to reduce paracetamol toxicity.

The analgesic effect, toxicity and kinetics of oral paracetamol were compared with those of paracetamol + l-methionine (5:1). The analgesic effect of paracetamol, studied in the Randall-Selitto test in rats, was not changed by methionine: ED50 was 94.6 mg/kg without methionine and 94.1 mg/kg with it. However, methionine reduced the acute toxicity (LD50) of paracetamol by 50% (p less than 0.05) in non-fasted, fasted and phenobarbital-pretreated mice. In a randomized cross-over study in 10 human volunteers the pharmacokinetics of paracetamol (1,500 mg) was not affected by methionine (300 mg). The absorption of methionine from the combination tablets was rapid, peak concentrations occurred in plasma at 30 min and were 3-4 times higher than after paracetamol tablets not containing methionine. Methionine in products containing paracetamol should increase their safety and be the simplest way to reduce the high mortality in paracetamol overdosage.

Acetaminophen↗
PubMed1991

Lack of effect of paracetamol on the pharmacokinetics of indomethacin and paracetamol in humans.

Paracetamol is an analgetic drug with additive effect if combined with indomethacin. In rat experiments, paracetamol has been shown to be gastro-protective, and in animal experiments, indomethacin blood levels decreased during combined treatment with paracetamol. The kinetic effect of paracetamol on indomethacin has been investigated in ten healthy volunteers. The mean area under the indomethacin plasma concentration curve AUC 0-alpha was 10.4 +/- 4.21 micrograms/mL x hr and did not change during combined paracetamol treatment (11.0 +/- 3.24 micrograms/mL x hr NS). Paracetamol levels were unchanged. In this study, no evidence was found that paracetamol can alter the pharmacokinetics of indomethacin in humans.

Acetaminophen↗
PubMed1986

Efficacy of paracetamol-esterified methionine versus cysteine or methionine on paracetamol-induced hepatic GSH depletion and plasma ALAT level in mice.

The effect of paracetamol-N-acetyl-DL-methionate (PAM) in preventing paracetamol-induced hepatic glutathione (GSH) depletion and hepatic cell damage assessed by plasma ALAT level, was compared to those of concomitantly administered paracetamol and N-acetyl-L-cysteine (NAC) or N-acetyl-DL-methionine (NAM) and paracetamol 400 mg/kg (P) alone. PAM, NAM and NAC reduced hepatic GSH depletion compared to P. The concomitant administration of GSH precursors in either form apparently maintained hepatic cell integrity as evaluated by plasma ALAT compared to predose and 16 hr control measurements. No statistically significant difference between PAM, NAM and NAC was observed. In group P a statistically significant, but transitory, rise in plasma ALAT level following dosage was seen. NAC was more effective than PAM and NAM in the prevention of GSH depletion 1 hr after dosing but was less effective in promoting de novo GSH synthesis towards 16 hr. There was no statistically significant difference between PAM and NAM with respect to effect on GSH depletion or hepatic cell integrity. PAM and NAM increased the GSH level significantly above control level 16 hr after dosing. PAM is rapidly cleaved to paracetamol and methionine following dosage as shown by the observed plasma paracetamol level. PAM compares favourably in hepatoprophylactic effect, to concomitant administration of equimolar doses of free N-acetyl-DL-methionine added to the paracetamol formulation.

Acetaminophen↗
PubMed1995

Cell injury and protection in long-term incubation of liver slices after in vivo initiation with paracetamol: cell injury after in vivo initiation with paracetamol.

Short-term in vitro methods (2-6 h) for study of cell injury by paracetamol are often used but, in vivo, injury is not apparent until 12 h or later. Many agents which protect in the short-term in vitro systems, such as fructose and glycerol which are effective, even in the late phase, after paracetamol has initiated injury, do not provide any protection in vivo. We have extended the in vitro liver slice system to a more realistic 18 h. Secondly, we have initiated injury with paracetamol in vivo, then followed the progression of injury in an in vitro system. Control liver slices incubated in a HEPES Ringer solution with antibiotics over 18 h show little sign of injury as demonstrated by leakage of lactate dehydrogenase (LDH) into the medium or loss of potassium. Liver slices exposed to 10 mM paracetamol for 2 h in vitro show extensive LDH leak at 6 h which is even more severe at 18 h. Liver slices from animals treated with paracetamol (1 g/kg i.p.) in vivo for 3 h show little LDH leakage at 6 h in vitro but by 18 h injury is very apparent. Fructose and glycerol which protect against paracetamol injury in the short-term (6-h) in vitro system, do not do so when observations are extended to 18 h. They also fail to provide any protection to the slice from animals pre-treated in vivo with paracetamol. Other agents show similar affects. There is no convincing evidence that these short-term protective agents afford any protection in vivo and we show that ibuprofen and dexamethasone do not protect in vivo. It is clear that short-term assays for cell protection have only a limited explanatory value.

Acetaminophen↗
PubMed2003

Analgesic effect of i.v. paracetamol: possible ceiling effect of paracetamol in postoperative pain.

BACKGROUND: Despite the widespread use of paracetamol for many years, the analgesic serum concentrations of paracetamol are unknown. Therefore the correlation between serum paracetamol concentrations and the analgesic effect was studied. METHODS: Sixty-four women undergoing laparoscopic sterilization were included in a double-blind, placebo-controlled, randomized study. Patients were given i.v. propacetamol 40 mg kg(-1) (group H), 20 mg kg(-1) (group I), 10 mg kg(-1) (group L) or placebo after surgery. Alfentanil was available via patient-controlled analgesia (PCA) during the 4-h postoperative study period. The patients' self-reported pain was registered on the visual analog scale (VAS). A pharmacokinetic model was fitted to the paracetamol data. RESULTS: One to 3 h after injection of propacetamol the alfentanil consumption was significantly (P = 0.01-0.04) higher in the placebo group compared with groups H, I, and L receiving propacetamol. There were no significant differences between the amounts of alfentanil consumed in groups H, I, and L. Initial VAS-scores were moderate (5.4-6.2), and declined significantly (P < 0.0001) over time, with no difference between groups. Paracetamol followed an open two-compartment model with i.v. administration and first order elimination. The estimated concentrations immediately (t = 0) after injection were 56 mg l(-1) (H), 28 mg l(-1) (I) and 14 mg l(-1) (L). CONCLUSION: We showed a significant opioid-sparing effect of paracetamol in the immediate postoperative period. Pharmacokinetic data were in accordance with other studies. Our results suggest that a ceiling effect of paracetamol may be present at i.v. doses of 5 mg kg(-1), i.e. a serum concentration of 14 mg l(-1), which is a lower dose than previously suggested.

Absorption↗
PubMedDate not supplied

A simple HPLC assay for urinary paracetamol metabolites and its use to characterize the C3H mouse as a model for paracetamol metabolism studies.

A high performance liquid chromatographic (HPLC) assay for unchanged paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the urine of man, mouse and rat is described. The method is simple, rapid and reproducible. The metabolite assay has been used to characterize the male C3H mouse, which shows sensitivity to paracetamol toxicity similar to man, as a model for paracetamol metabolism studies. In male C3H mice there was no evidence to suggest saturability of the glucuronidation pathway on increasing the paracetamol dose from 50 to 300 mg/kg. By contrast, the metabolic ratio and fractional excretion of both the sulphate and glutathione-derived conjugates decreased with increasing paracetamol dose. For animals administered a 200 mg/kg dose of paracetamol, pretreatment with phenobarbitone or 3-methylcholanthrene increased the fractional excretion and metabolic ratio of the glutathione-derived and glucuronic acid conjugates. Piperonyl butoxide pretreatment of animals administered the same dose of paracetamol inhibited glutathione and glucuronic acid conjugation.

Acetaminophen↗
PubMed1979

Effects of tolmetin, paracetamol, and of two combinations of tolmetin and paracetamol as compared to placebo on experimentally induced pain. A double blind study.

Previous studies in animals suggested that a coadministration of the anti-rheumatic/anti-inflammatory agent tolmetin (Tolectin) and of paracetamol potentiates the effects of these two drugs. The present study was carried out to assess whether or not the dosis of tolmetin necessary to obtain an analgesic effect can be reduced when paracetamol is coadministered in a model with experimentally induced pain in healthy human subjects. The effects of tolmetin 200 mg (T 200), paracetamol 400 mg (P 400), tolmetin 150 mg plus paracetamol 300 mg (T 150 + P 300), and of tolmetin 100 mg plus paracetamol 400 mg (T 100 + P 400) on pain threshold to electrical and thermal stimuli and on pain tolerance to electrical stimuli were compared to the effects of placebo under double blind conditions. Each of 20 healthy volunteers received all of the 5 treatments randomised according to four 5 X 5 Latin squares. The results showed that the combination T 100 + P 400 had better analgesic effects than the double dose of tolmetin, T 200, alone, while the effects of P 400 could not be discrminated from placebo. In a sequential t-test the effects of T 100 + P 400 could be discriminated from placebo already after 14 Ss. The effects of T 200, T 150 + P 300, and T 100 + P 400 respectively could not be differentiated, indicating that the dose of tolmetin can be reduced markedly by simultaneous administration of paracetamol without a loss in analgesic potency. Coadministration of tolmetin and paracetamol permits a marked reduction of the dose of tolmetin without any loss of analgesic potency as measured in a model with experimentally induced pain in healthy subjects.

Acetaminophen↗
PubMed1985

The effectiveness of antioxidants in reducing paracetamol-induced damage subsequent to paracetamol activation.

Paracetamol toxicity was studied in isolated mouse hepatocytes. This drug produced a concentration- and time-dependent loss of cell viability. Exposure to 5 mM paracetamol produced a rapid fall in intracellular reduced glutathione (GSH) followed by a decrease in plasma membrane integrity. The antioxidant, diphenyl-p-phenylenediamine (DPPD) had no effect on either the loss of GSH, the binding of 14C-paracetamol metabolites to protein or the loss of plasma membrane integrity when hepatocytes were incubated in 5 mM paracetamol. When hepatocytes were exposed to paracetamol for 1 hr they showed a loss of plasma membrane integrity during the subsequent 7 hr incubation. DPPD, alpha-tocopherol and promethazine reduced this effect when added after the paracetamol exposure. It appears that paracetamol exposure initiates toxic events subsequent to the generation of the reactive metabolite but prior to cell death and that the progression of these events can be interrupted by compounds with antioxidant properties.

Acetaminophen↗
PubMed1993

Liver damage and plasma concentrations of paracetamol and its metabolites after paracetamol overdosage in mice.

The effects of single oral and intraperitoneal (i.p.) overdoses of paracetamol (500 mg/kg) were studied in mice. The correlation between hepatocellular damage and plasma levels of paracetamol metabolites derived from the oxidative pathway were also investigated. Animals were killed at different intervals (1, 2.5 and 6 h) after drug administration. Plasma concentrations of paracetamol and its sulphate, glucuronide, cysteine and mercapturate conjugates were determined by HPLC. Paracetamol plasma levels were significantly higher at 1 and 2.5 h after i.p. administration as compared to oral administration (p = 0.01 and p = 0.02, respectively). Plasma levels of mercapturic acid conjugate were significantly higher at 6 h after i.p. administration (p = 0.04). After 6 h, animals given oral paracetamol showed significantly less necrosis than animals given i.p. paracetamol (p = 0.03). Plasma levels of mercapturate conjugate at 6 h showed a significant correlation with the severity of liver necrosis (r = 0.64; p = 0.02). The results suggest that i.p. paracetamol seems to be more adequate for hepatotoxicity studies in mice.

Acetaminophen↗
PubMed1996

[Analgesic effect and clinical tolerability of the combination of paracetamol 500 mg and caffeine 50 mg versus paracetamol 400 mg and dextropropoxyphene 30 mg in back pain].

OBJECTIVES: A double-blind randomized multicentric study was performed to test the hypothesis that the analgesic effect of paracetamol-cafeine is equivalent to that of paracetamol-dextropropoxyphen in patients suffering from pain due to osteoarthritis of the spine. METHODS: Rhumatologists included 124 patients who were randomized into two groups of 62 each. Pain was measured daily during the seven-day treatment Huskisson's Analog Visual Scales; 112 were per protocol and evaluable. RESULTS: The two treatment groups were statistically similar for demographics, vital signs, medical and treatment history. A majority of them had pain located at the lumbar spine only; the other patients had either pain at the cervical or dorsal spine or at several sites. At the end of the week there was a major reduction in pain level: 51.2% in patients given paracetamol-cafeine and 47.0% in those given paracetamol-dextropropoxyphen. The main criteria of efficacy--the percentage of success (decrease of pain > 50%)--was similar in the two groups as well in the intention-to-treat population (p = 0.01) as the per protocol population (p = 0.028). Kinetics of pain decrease during the first day of treatment were assessed with an hourly evaluation during the six first hours and at the 12th hour. There was no difference between the two groups. There was no serious adverse event and the frequency and intensity of the adverse events were similar in the two groups. CONCLUSION: The potentializing action of cafeine on paracetamol-induced pain relief enables a degree of pain relief equivalent to that of a combination using an analgesic with a peripheral action, paracetamol, and another with a central action, dextropoxyphen. The fact that the paracetamol-cafeine combination does not have a central action avoids secondary effects induced by central analgesics (drowsiness, constipation) in patients with osteoarthritis back pain.

Acetaminophen↗
PubMed1999

In vitro cleavage of paracetamol glucuronide by human liver and kidney beta-glucuronidase: determination of paracetamol by capillary electrophoresis.

A capillary electrophoresis (CE) method was developed using paracetamol glucuronide as a novel probe for human beta-glucuronidase activity. Using UV detection without prior sample clean-up procedures, fast and reliable quantitation of the released paracetamol was possible. The method showed good precision, accuracy and sensitivity with a limit of detection of 0.25 microM (38 ng/ml) and a limit of quantitation of 1 microM (151 ng/ml). The suitability of the method has been shown for enzyme kinetic studies using different liver and kidney homogenates, respectively. Our data clearly demonstrate that paracetamol glucuronide is cleaved by human beta-glucuronidase thereby releasing paracetamol. The CE method presented is not only a valuable tool for measuring human beta-glucuronidase activity, but also allows investigation of the contribution of deglucuronidation of paracetamol glucuronide to the disposition of paracetamol.

Acetaminophen↗
PubMed1992

The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics.

1. The effects of pirenzepine on gastric emptying, salivary flow and saliva paracetamol concentrations were investigated in healthy volunteers. 2. Pirenzepine significantly reduced the area under the saliva flow-time curves (7.29 +/- 3.30 g min-1 h without pirenzepine; 4.19 +/- 2.59 g min-1 h with pirenzepine, P less than 0.01). Pirenzepine had no significant effect on plasma paracetamol Cmax (17.5 +/- 7.8 micrograms ml-1 without pirenzepine; 12.6 +/- 7.7 micrograms ml-1 with pirenzepine), plasma tmax (0.2 h (0.2-0.8 h) without pirenzepine; (0.2 h 0.2-0.8 h) with pirenzepine) and plasma AUC(0.6 h) (32.3 +/- 7.2 micrograms ml-1 h without pirenzepine; 30.3 +/- 6.5 micrograms ml-1 h with pirenzepine). 3. Mean ratios of saliva:plasma paracetamol AUC (1.06 +/- 0.24 without pirenzepine; 1.84 +/- 0.48 with pirenzepine, P less than 0.001) and saliva:plasma paracetamol Cmax (1.7 +/- 1.0 without pirenzepine; 6.5 +/- 2.7 with pirenzepine, P less than 0.01) were significantly increased by pirenzepine pretreatment, but there was a poor correlation between the percentage change in the area under the saliva flow-time curve and the percentage change in saliva paracetamol AUC (r = 0.47, P = 0.21). 4. The findings suggest that a) pirenzepine is a more selective antagonist of the muscarinic receptors in salivary glands than those in gastric smooth muscle and b) caution is required when using saliva paracetamol concentrations to determine the pharmacokinetics of the drug in the presence of other agents which may influence salivary flow rate.

Acetaminophen↗
PubMedDate not supplied

Evaluation of ketorolac, ibuprofen-paracetamol, and dextropropoxyphene-paracetamol in postoperative pain.

STUDY OBJECTIVE: To compare the analgesic efficacy of ketorolac, ibuprofen-paracetamol (acetaminophen), and dextropropoxyphene-paracetamol in postoperative pain. DESIGN: Randomized, double-blind, parallel, single-dose study. SETTING: Multicenter, with five centers participating. PATIENTS: One hundred sixty patients with moderate to severe postoperative pain requiring oral analgesics were enrolled. Seventeen patients were excluded from final analysis due to deviation from protocol. INTERVENTIONS: Ketorolac tromethamine 10 mg, a combination of ibuprofen 400 mg plus paracetamol 325 mg, or a combination of dextropropoxyphene 65 mg plus paracetamol 400 mg was given orally to patients with moderate to severe baseline pain. MEASUREMENTS AND MAIN RESULTS: Pain intensity and pain relief scores were rated at baseline, at 30 minutes, and hourly to 6 hours. Until the end of first hour, analgesia was similar for all three regimens. Ketorolac had a significantly higher analgesic effect than the two combinations between hours 2 and 6. Analgesia was similar for the two combinations. For all three test drugs the frequency of adverse effects was similar. CONCLUSIONS: Ketorolac 10 mg is a superior analgesic to ibuprofen-paracetamol or dextropropoxyphene-paracetamol in the treatment of postoperative pain.

Acetaminophen↗
PubMed2000

Antipyretic effects of nimesulide, paracetamol and ibuprofen-paracetamol.

The antipyretic effect of nimesulide has not been adequately compared with paracetamol and ibuprofen-paracetamol combination in children. Hence, a randomized, double blind, and parallel groups' design and multicenter study was conducted on children with respiratory tract infections. Eighty-nine patients with temperatures above 38.5 degrees C were randomly administered nimesulide (1.5 mg/kg/dose), paracetamol (10.0 mg/kg/dose), or ibuprofen-patients combination (10.0 mg/kg/dose), thrice daily for five days. The axillary temperature was recorded at the baseline and at different time intervals post administration of drugs. The hematological and biochemical investigations were performed at the basal level and at the end of the treatment period. The adverse drug reactions were monitored during the trial. All the drugs produced a significant fall in temperature as compared to their respective basal values (p < 0.001). However, on looking at the change in temperatures at different time intervals from the respective basal levels, no significant difference was found among all the drugs. Surprisingly, nimesulide had a tendency to raise serum glutamate pyruvate transaminase and serum glutamate oxaloacetate transaminase levels as compared to its baseline values. There was no marked adverse effect of the drugs on other hematological and biochemical parameters investigated. No other serious adverse reaction occurred in the study. Ibuprofen-paracetamol combination, nimesulide, and paracetamol had almost similar antipyretic effects in children.

Acetaminophen↗
PubMed1981

An oral buprenorphine and paracetamol combination compared with paracetamol alone: a single dose double-blind postoperative study.

1 An oral combination of buprenorphine and paracetamol was compared with paracetamol alone in a single dose, double-blind postoperative study. One hundred and twenty patients undergoing elective minor orthopaedic operations were allocated to four groups of 30 patients. The four treatments were 1,1.5 or 2 mg of buprenorphine with paracetamol 1,000 mg or paracetamol 1,000 mg alone. 2 There were no significant differences between the groups in analgesia measured by the observer over the 6 h period of direct observations. The oral opiate produced a significant increase in duration of analgesia beyond the 6 h study period. A significant increase in side-effects was seen only at the highest buprenorphine dose compared with paracetamol. 3 The problems of trial design for analgesic combinations are considered. Drug mixtures create additional complexities which decrease the certainty of the conclusion that no real benefits result from such mixtures.

Acetaminophen↗