Double-blind study of the analgesic effect of indoprofen (K 4277).

In a double-blind study, indoprofen was superior to placebo in decreasing pain in patients with primary and metastatic cancer and with neuralgia. A single oral dose of 200 mg was more active than a 100-mg dose. The preferences of patients proved to be a more sensitive parameter in this study than scores of pain intensity, pain relief, and other related measurements (SPID, TOTPAR, and Peak PID).

Intravenous catheter-associated Malassezia furfur fungemia.

Malassezia furfur, a lipophilic yeast that is the etiologic agent of tinea versicolor, has not been considered as a cause of serious illness in adults in the past. Two adults are described in whom Malassezia furfur fungemia developed while receiving total parenteral nutrition supplemented with lipids. The organism was identified in blood cultures from both patients only after isolation media were supplemented with a source of fatty acids. Because M. furfur will grow only in media supplemented with fatty acids, clinicians should alert the laboratory whenever a lipophilic organism is suspected to be present in blood cultures.

Application of nonparametric procedure for bioassay data to the evaluation of analgesics in man.

Parametric tests for bioassay data are commonly applied to scores of pain intensity and relief for the assessment of potency ratios of analgesic drugs. It has been demonstrated, however, that scores derived from semiquantitative scales often deviate from normal distribution. In addition, when scores decrease as a consequence of analgesic treatment, the variances may be nonhomogenous. Both parametric and nonparametric procedures have been employed in this study for the evaluation of results of a double-blind multicenter trial of the analgesic effect of indoprofen and ASA (both drugs at three dose levels) and placebo in episiotomy pain. There was a good agreement between potency ratios obtained with the two assays. Peak PID appeared a less efficient means of estimating potency ratio than other measurements such as SPID and TOTPAR. The nonparametric test for quantitative bioassay appears to be a valid statistical procedure for evaluating results of clinical trials, and it does not imply any assumptions as to the type of distribution of the data.

Gastro-intestinal blood loss during administration of indoprofen, aspirin and ibuprofen.

The acute effect of three non-steroidal anti-inflammatory drugs, ibuprofen, acetylsalicylic acid (ASA) and indoprofen, on faecal blood loss was investigated in 15 subjects by means of 51Cr-labelled erythrocytes. Ibuprofen (900 mg/day for 5 days) and indoprofen capsules and tablets (300 mg and 600 mg/day for 5 days, respectively) slightly increased the amount of blood eliminated in faeces. The increase was of the same order of magnitude for both doses of indoprofen. ASA (1,500 mg/day for 5 days) caused about a 6-fold increase in blood loss. Four days after withdrawal of ASA, faecal blood was still about twice as high as in faeces of subjects given ibuprofen and indoprofen. The method appears sensitive and reliable for comparison of the immediate effect of anti-inflammatory drugs on gastro-intestinal mucosa.

Inhibition of platelet aggregation in man by indobufen (K 3920).

A complete crossover trial was undertaken in six healthy volunteers to gain information on dose-effect responses to indobufen by assessing the intensity and duration of the effect of 3 single oral doses of the drug on platelet aggregation induced by threshold concentration of ADP and by 3 added doses of collagen. The results of the study confirm that the activity is dose-related and is reversible since 24 hours after administration it has practically disappeared. The effect of the same dose of indobufen differed significantly according to the amount of collagen added to plasma, whereas increasing doses of indobufen provoked a significantly more marked effect when the amount of inducer employed was the same.

Pharmacokinetic, bioavailability and pharmacodynamic study of indobufen (K 3920), an inhibitor of platelet aggregation, after a single dose in man.

Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7--8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.

Indobufen (K 3920), a new inhibitor of platelet aggregation: effect of food on bioavailability, pharmacokinetic and pharmacodynamic study during repeated oral administration to man.

The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.

Effect of food on absorption of indoprofen administered orally to man in two dosage forms.

The influence of food on the bioavailability of two oral dosage forms (100-mg capsules and 200-mg tablets) of indoprofen, a new propionic acid derivative with marked anti-inflammatory and analgesic properties, has been investigated. Plasma levels and urinary excretion of indoprofen were determined both in the fasting state and after a standard meal in healthy volunteers after administration of two 100-mg capsules (4 subjects) and of one 200-mg tablet (6 subjects). Indoprofen in biological fluids was determined by gas-liquid chromatography. The extent of absorption from tablets was not affected by food as indicated from the values of the total area under plasma level curves and urinary excretion of the drug. The rate of absorption was faster after meal than in the fasting state. The opposite was found for capsules, which showed a slightly delayed absorption after food. The results suggest that food may differently influence the absorption pattern of different pharmaceutical forms of the same drug.

Pharmacokinetic studies of indoprofen in healthy volunteers and in patients.

The pharmacokinetics of indoprofen in healthy subjects after single oral and i.v. administrations is reviewed. During repeated administration of indoprofen to 6 normal subjects (200-mg tablet every 8 hours for 6 days) no variations in the disposition of the drug were found in comparison with single dose administration. In 6 inpatients, with rheumatoid arthritis, the pharmacokinetics of indoprofen was studied after single oral (tablet) and i.m. administration. As for oral doses, no difference in main kinetic parameters was detected between the patients and normal subjects except for a higher volume of distribution in the former population. The bioavailability of the drug given by i.m. injection was not significantly different from that observed after oral administration.