Indoprofen, a new analgesic and anti-inflammatory drug in cancer pain.

Evaluation of the analgesic activity of indoprofen was carried out in patients with cancer pain under double-blind conditions and compared with aspirin and placebo. A randomized experimental design was followed. Single oral doses were given of the test drug (100 and 200 mg), aspirin (600 and 1,000 mg), and placebo. For measuring analgesia, 5-point pain intensity and pain relief semiquantitative scales were used. Potency ratio between drugs was calculated on SPID (sum of pain intensity differences) and TOTPAR (total pain relief) and resulted in 10.3 by combination of estimates. In a group of only 24 patients, the data supported the following conclusions: indoprofen at 100 and 200 mg single doses is effective in relieving cancer pain; it displays a dose-related analgesic effect comparable to that of aspirin with only one-tenth the dose.

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).

Inhibition of lipolysis by nicotinic acid and by acipimox.

Acipimox (5-methylpyrazinecarboxylic acid 4-oxide) is a new lipolysis inhibitor that has a distant chemical relationship with nicotinic acid (NA). The tritiated compound (100 mg) is rapidly absorbed, peak plasma radioactivity being reached after 2 hr, with an almost total elimination unchanged in urine. A comparison of th antilipolytic activity of three doses of acipimox and three doses of NA showed acipimox to be 20 times as potent as NA. There was a correlation between intensity and duration of effect for acipimox, but not for NA. Plasma acipimox levels correlated with inhibition of lipolysis. In consideration of the very good subjective tolerability of acipimox at all doses tested, this drug may be suitable for control of lipolysis in hyperlipidemias.

A study of the analgesic potency of indoprofen and pentazocine in postoperative pain.

The relative potency of intravenous indoprofen and intramuscular pentazocine in postoperative pain was evaluated. Indoprofen was administered in 200- and 400-mg single doses and pentazocine was given in 15- and 30-mg doses. Pain was assessed at different time intervals, and additional medication consumption was recorded, as well as side effects and overall evaluations. An analysis of peak pain intensity difference (PID) has shown a significant dose-effect relationship for both drugs and a potency ratio of 1:7 between indoprofen and pentazocine (mg to mg). Based on the frequency of patients requiring remedication and those reporting total pain relief in at least one instance, the potency ratio of indoprofen:pentazocine was 1:13 and 1:10, respectively. The mean peak PID of the pooled data for both doses of each drug was significantly greater for indoprofen. Intravenous indoprofen 400 mg was ranked the most effective overall.

Indoprofen in knee joint osteoarthritis: a double-blind, crossover clinical trial.

A double-blind, crossover clinical trial has been carried out in subjects with knee joint osteoarthritis to assess the activity of two nonsteroidal antiinflammatory drugs. Eighteen outpatients with a severe systemic form were given orally indoprofen (800 mg/day), indomethacin (80 mg/day), and placebo for one week without interval between treatment periods. Significant improvement was seen in subjective and objective signs and symptoms after both drugs, which gave similar results. No significant differences between drugs were noted as to patients' opinions and preferences, which were in agreement with clinical indexes. No improvement in most cases and deterioration in a few subjects followed placebo administration, probably because the majority of the sample was made up of placebo non-reactors. Consequently, the activity data of the trial might be interpreted as expression of the pure pharmacologic activity of the tested drugs. Safety was very satisfactory: patients complained only rarely of trivial and clinically unimportant side effects; no variations in laboratory tests were noted.

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.

beta-Adrenoceptor activation induces prostaglandin E2 generation in guinea-pig trachea.

Isoproterenol and salbutamol caused relaxation of guinea-pig trachea, and generation of PGE2. The phenomenon appears to be specific for beta-adrenergic agonists since the relaxant activity induced by atropine, theophylline and papaverine was not associated with generation of prostaglandin-like material from tracheal smooth muscles. Indomethacin reduced only slightly the relaxation of the tracheal tissue induced by isoproterenol and salbutamol. The possibility is discussed that the increased arachidonic acid metabolism during trachea beta-adrenergic relaxation represents a metabolic event involving phospholipid methylation and membrane fluidity.

Indoprofen, a new non-steroidal anti-inflammatory drug, in the treatment of osteoarthrosis: report on a multi-centre study in 1629 patients.

A multi-centre trial was carried out in 1629 patients with osteoarthrosis in 233 clinical centres to investigate the therapeutic efficacy and tolerability of indoprofen in this clinical condition. The results from assessments of both subjective and objective variables were comparable to those obtained in Phase 3 studies. Moreover, 87.2% of patients expressed a 'good' or 'very good' opinion on the product's efficacy after treatment, usually with 3 tablets (600 mg) daily for 4 weeks. The benefit/risk relationship was confirmed as very favourable on account of the marked activity of the drug and the acceptable frequency of adverse reactions, which were mainly subjective and slight and confined to the gastro-intestinal tract.

Indoprofen versus ibuprofen in osteoarthrosis: a short-term, double-blind, crossover trial.

A double-blind, crossover, short-term clinical trial was carried out in osteoarthrosis to compare the activity of two non-steroidal anti-inflammatory drugs. Twenty-four patients were given orally, in sequence, 600 mg indoprofen daily and 1200 mg ibuprofen daily, or vice-versa, for 1 week with no interval between treatment periods. Pain, quality of sleep, and overall effectiveness were recorded at the end of each week by inviting patients to express a score on a simple rating scale. Finally, patients were asked to express a preference for one treatment or the other. Significant improvement was observed in all parameters following treatment with both drugs. The distribution of score differences between indoprofen and ibuprofen was in favour of the former in all measurements; statistical analysis, however, demonstrated a significant superiority of indoprofen only for pain elicited by passive motion. The patients' preferences were also in favour of indoprofen, though not attaining statistical significance. Indoprofen was well tolerated, and no side-effects were observed. While on treatment with ibuprofen, 1 patient had to be withdrawn from the study because of gastric intolerance and 2 further patients had transient skin rashes.

Factors influencing the clinical diagnosis of pulmonary embolism: analysis of 229 postmortem cases.

Although appreciable advances have been made in understanding epidemiology, diagnosis and treatment, acute pulmonary embolism (PE) is still largely undetected and untreated. The aim of our study was to ascertain whether the rate of correct clinical diagnosis of acute PE has changed in recent years (from 1989 to 1995) and, possibly, to identify factors that might contribute to the underdiagnosis of the disease.

Intravenous indoprofen in the management of renal colic.

Recent reports imply that the prostaglandin system is involved in the pathogenesis of pain due to renal colic, and prostaglandin-synthetase inhibitors have been proposed in the management of this condition. A dose-response study has therefore been performed in patients with renal colic, using two intravenous non-steroidal antiinflammatory drugs, indoprofen and lysine acetylsalicylate (ASA). Seventy-five inpatients (15 per group) were treated with three dose levels of indoprofen (100, 200 and 400 mg) or two dose levels of ASA (500 and 1500 mg) according to a double-blind, randomized, parallel-group design. The patients scored their pain at 15, 30, 60, 120 and 180 minutes after treatment; they also assessed the overall efficacy of treatment by means of a visual analogue scale. The results showed that, in terms of mean pain score, there was a prompt analgesic response in each treatment group, higher effects being obtained with increasing dose levels of both drugs. However, the statistical prerequisites for calculating a potency ratio between the drugs under study were satisfied only for a few variables, in which cases the relative potency of indoprofen to ASA varied between 7.1 and 8.8. The analysis of the frequencies of response, on the other hand, revealed for indoprofen a significant dose-effect regression, the higher dose of this drug giving a complete or nearly complete relief of pain in the majority of patients.

Can pulmonary artery pressure be predicted without right heart catheterization in chronic obstructive lung disease?

We have investigated the dependance of observed pulmonary artery mean pressure (PAP) on body surface, age, PaO2, pH, PaCO2, hematocrit, and spirometric data (VC, FEV1/VC, RV/TLC) in 70 patients with chronic obstructive lung disease (COLD). After elimination of all variables that failed to correlate with PAP, multifactorial analysis showed that only two of nine independent variables, namely PaO2 and body surface, correlated significantly with PAP. According to our calculations, 28.9% of total PAP is predictable by PaO2, 1.5% by H+ concentration, 2.8% by RV/TLC, and 2.5% by body surface. Fully 64.2% of total variability was not accounted for by our regression analysis; thus the error of predicted PAP was so great (+/- 17 mm Hg for P = 0.05) as to invalidate the method. We also recalculated our subjects' PAP values by applying Enson's and Grassi's equations to our own lung function and biochemical data, and compared the predicted PAP values thus obtained with those measured directly in our subjects. Both equations proved imprecise and/or inaccurate in the individual case. From this we conclude that whereas available equations may be suitable for predicting the mean PAP value of a large population sample, the same equations cannot give a reliable prediction in individual cases.

Can pulmonary hypertension be predicted by non-invasive approach? Echocardiographic and haemodynamic study.

41 patients suffering from Chronic Obstructive Lung Disease (COLD) and 44 with Sarcoidosis were studied. Said patients underwent respiratory function tests, echocardiography (M.mode) to assess the right ventricular index ( RVI = diameter of the right ventricular cavity corrected by body surface) and the thickness of the right ventricular anterior wall ( RVAWT ); patients also underwent right heart haemodynamics (Swan-Ganz catheter). These data were further statistically studied by means of multiple regression in order to assess the eventuality of a non-invasive prediction of pulmonary artery mean pressure (PAP): variables taken into consideration were: age, body surface (BS), RVI , RVAWT , arterial oxygen pressure (PaO2), arterial carbon dioxide pressure (PaCO2) and PAP dependence according to each case group and the interaction of each group itself on the variables. RVI appeared to be the most reliable, in fact, when PaCO2 is also available, the standard error of estimation (SEE) was only 3.84 mmHg and the coefficient of determination was equal to 85.5% with a notable improvement when compared to results seen in previous studies. This behaviour was observed both in patients with early sarcoidosis and in COLD patients with mild pulmonary hypertension. This might be due to the fact that we took the right ventricle into consideration which inevitably feels the increase in pulmonary hypertension.

[The cardiologist facing pulmonary embolism. The experience of 160 cases of acute cor pulmonale]. / Il cardiologo di fronte all'embolia polmonare. Esperienza su 160 casi di cuore polmonare acuto.

BACKGROUND: The results of recent multicenter studies dealing with pulmonary embolism often reveal remarkable discrepancies in terms of diagnosis, prognosis and treatment, partly due to the heterogeneity of study patients and of evaluation criteria. Our prospective study focused exclusively on patients affected by pulmonary embolism with a hemodynamic pattern of acute cor pulmonale, investigated at a single center. Particular attention was paid to in-hospital mortality, embolic recurrences, major bleeding and underlying pathologies. METHODS: This study includes 160 cases (103 women with a median age of 71 years and 57 men with a median age of 65 years) in whom the clinical and echocardiographic findings suggestive of acute pulmonary embolism were confirmed by lung perfusion scan, pulmonary angiography, techniques for the detection of deep vein thrombosis and/or autopsy. RESULTS: The most common clinical manifestations were: dyspnea (92% of cases), tachycardia (80%), syncope (44%), cardiac arrest (22%), and shock (20%). Thoracic pain was present in only 27% of patients. None of the patients showed a normal ECG; a right bundle branch block was found in 47% of cases. T-wave inversion in the precordial leads (32%) was not related to the severity and outcome of pulmonary embolism. Present or previous deep vein thrombosis was found in 53 and 26% of cases, respectively. Only in 2 patients pulmonary embolism was secondary to a deep vein thrombosis of the upper limbs. Intravenous heparin alone was used in 36% of cases, whereas 56% were treated with thrombolytic agents + heparin. Major bleeding occurred in 9% of patients treated with heparin alone, and in 16% of those who received heparin + thrombolytic drugs. Death occurred in 17% of the former, and in 27% of the latter patients. The in-hospital mortality rate was related not only to the presence of cardiac arrest and--to a lower degree--of shock, but also to the recurrence of pulmonary embolism and to the underlying heart disease. No relationship was found between mortality and age, intracardiac thrombi or malignancy. Prognosis was quite different depending on clinical presentation, with a death rate ranging from 11% in the absence of systemic hypertension, and 77% in the presence of cardiac arrest. CONCLUSIONS: Even the "massive" pulmonary embolism that is observed in a cardiac department represents a true "spectrum" of pathological conditions, a spectrum that should be taken into account not only in order to evaluate prognosis and treatment in a particular case, but also when meta-analyses are performed.