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The results from the present studies confirm that indoprofen is an orally effective analgesic drug. Both the 100- and 200-mg dosages of indoprofen demonstrated superior analgesic activity when compared to 600 mg aspirin.
Six patients (4 men, 2 women) with moderate/large knee effusions due to rheumatoid arthritis (RA) were studied after receiving indoprofen, 25 mg intra-articularly and then 200 mg orally 1 week later. There was significant improvement in pain (t = 3.74, P less than 0.05), morning stiffness (t = 2.91, P less than 0.05) and range of movement (t = 2.52, P less than 0.05) for at least 1 week following the intra-articular injection. The terminal phase plasma half-life after the 200 mg oral dose was 6.4 +/- 0.7 h (mean +/- SEM) and was significantly longer than the often quoted plasma half-life of 2-3 h from previous studies, but much less than the pharmacodynamic half-life. Synovial fluid concentration were not significantly different from those in plasma in the post-distribution phase. Intra-articular indoprofen may be a useful addition to the treatment of RA.
The intermediate anion derived from the vicarious nucleophilic substitution (VNS) of hydrogen reacts with a series of alkyl halides to generate the corresponding alpha-alkylated conventional VNS product in a one-pot process. This one-pot VNS-alkylation reaction offers a convenient route to a range alpha-substituted nitrobenzyl phosphine oxides, sulfones, and esters via a three-component coupling reaction. Reactions of alpha-chloroethyl phenyl sulfone (14) and ethyl 2-chloropropionate (16) with nitrobenzene followed by subsequent addition of an alkylating agent give a series of sulfones and esters bearing an alpha-aryl quaternary center. The VNS-alkylation protocol has been applied to the synthesis of derivatives of Indoprofen from nitrobenzene using readily available inexpensive starting materials. Indoprofen itself was prepared using the conventional VNS reaction in four steps and 24% overall yield from nitrobenzene.
A double-blind, placebo-controlled parallel-group study was carried out in 100 patients with postoperative pain. The analgesic activity of indoprofen given in a single dose as an i.v. bolus followed by a 2-h infusion, at total doses of 100, 200, and 400 mg was investigated. The highest dose of 400 mg was given additionally as an i.v. bolus alone. Intensity of pain was assessed before, and 30 min, 1, 2, 4, 6 and 8 h after treatment on a 0-4 point scale. An overall assessment was made at the end of treatment by the investigator and the patient using a 0-4 point scale and a visual analogue scale. Statistical analyses according to a multiple regression model on rating scale scores at fixed times and on overall assessments showed: (i) indoprofen was always more active than placebo in providing pain relief; (ii) there was a significant dose--response relationship; and (iii) there was no difference between the two schedules of administration of the largest dose.
The effects of pulmonary instillation of hydrochloric acid on solute flux from the lung (measured as the clearance of 99mTcDTPA) together with an index of oedema formation (the ratio of lung wet weight to lung dry weight) was measured in rats. There was a significant increase in 99mTcDTPA clearance (P less than 0.001) and also in lung wet:dry weight ratio (P less than 0.01) 4-5 h following acid challenge. There was no difference in the effects of challenge with acid of pH1 and pH2. In addition, intravenous injection of indoprofen (20mg/kg) a non-steroidal anti-inflammatory agent failed to produce any beneficial effect on the variables under study when given after acid (pH2) challenge. There was also histological evidence of an influx and sequestration of granulocytes into the lung. Despite this, the plasma concentration of thiobarbituric acid reactive material (used as an index of cell-derived, oxidant-free radical production) was significantly reduced in all acid-treated groups. These data show that hydrochloric acid will initiate a severe inflammatory response in the lung of the rat and that the non-steroidal anti-inflammatory agent indoprofen when given after the injury produced no evidence of a beneficial effect on this inflammatory response.
The results are reported of an open multicentre trial in 228 rheumatic patients with flare-ups. Fourteen centres adopting the same investigational protocol collaborated in the study. Indoprofen was administered for 1 week at a daily dosage of 1000 mg according to a treatment schedule used with success in acute gouty arthritis: a 400 mg i.v. bolus was followed by 200 mg (1 tablet) t.i.d. Subjective (pain) and objective variables were used for reliable assessment of activity. Marked reduction of pain intensity was already noticeable on day 1 of treatment and was followed by progressive improvement in subjective and objective variables for all the diagnoses considered. According to the patients' own overall assessments, results were good or very good in more than 50% of cases. The best outcomes were obtained in low back pain, acute gout and psoriatic arthritis. At the end of treatment only 7.4% of patients experienced no change or deterioration of symptoms. Adverse reactions, consisting mostly of mild and reversible gastrointestinal disturbances, were reported by 9.2% of patients, but only in 1.8% was treatment discontinued. Indoprofen administered according to the above schedule is an appropriate treatment for acute episodes of rheumatic diseases.
In a triple-blind controlled study, significant pain alleviation (p less than 0.01) was registered in patients with osteoarthrosis (OA) of the hip in the first 24 h after hip joint distension. There was no significant difference between treatment with indoprofen (a new non-steroidal anti-inflammatory drug for intra-articular use) and placebo. Pain relief lasted for at least 12 weeks in approximately half of the patients, in whom a significant increase in joint mobility was registered. Intra-articular indoprofen was not superior to placebo as regards pain relief or increased joint mobility. These findings indicate that the effect of a single hip joint distension in OA is due to a mechanical distension of the joint capsule, perhaps involving disruption of local agglutinations, and not due to suppression of inflammation.
Indoprofen at 10-12 mg/kg body weight was compared with aloxiprin at 80 mg/kg body weight in children suffering from juvenile chronic arthritis. Indoprofen was significantly superior to aloxiprin in reducing soft tissue swelling and joint limitation and was effective in relieving pain and morning slowness and improving grip strength. The drug was well tolerated and is a satisfactory agent for the treatment of chronic arthritis in children.
A double-blind crossover trial was carried out in 60 patients with osteoarthritis of large joints. Patients received both indoprofen 600 mg daily and diclofenac 100 mg daily for one week without any interval between treatments. The variables investigated were: pain at rest, pain on active motion under load, quality of sleep, articular flexion and patient's preference. The assessments were made before and at the end of each treatment period. Significant improvements were found for all variables with both drugs. No significant differences were detected between the two drugs. Ten patients (6 on indoprofen and 4 on diclofenac) reported adverse reactions i.e. slight gastralgia in most cases. No withdrawals of treatment were observed.
The inhibiting effects of indoprofen were compared with those of indomethacin on prostaglandin-synthetase activity in rat hypothalamus. A dose-dependent inhibition of PG-synthetase activity was obtained after intramuscular administration of both antiphlogistic agents; however, indoprofen was found more powerful. In conclusion, the present experiments provide additional evidence against the idea that pyrogen fever is due to the release of PG's of the E type within the hypothalamus since when comparing results obtained with the two antiphlogistic drugs used, no correlation exists between potency in inhibiting PG's synthesis and antipyretic activity.
This double-blind, parallel-design study used postsurgical dental outpatients as subjects. The patients self-administered a single dose of one of the study medications when they estimated their pain to be of moderate or severe intensity. The study medications were 200 mg of indoprofen, 650 mg of acetaminophen, 650 of acetaminophen with 60 mg of codeine, 650 mg of acetaminophen with 100 mg of d-propoxyphene N, and a placebo. On a report form, data were recorded on baseline pain and then hourly for four hours, intensity of pain, relief of pain, and side effects were reported. Also, an overall evaluation was recorded. Data were analyzed with the use of analysis of variance and Duncan's Multiple Range test. All four active treatments were statistically superior to placebo for sum pain intensity difference, total relief of pain, and overall evaluation parameters. Both opioid-analgesic combinations showed small additive effects over acetaminophen alone, and indoprofen was superior to both combination treatments and acetaminophen alone.
A comparison was made between indoprofen (800 mg/day), naproxen (500 mg/day) and placebo in 30 patients with well defined osteoarthritis of the hip. Treatments were given for 10 days each, according to a double-blind, cross-over design. Objective and subjective criteria were adopted for evaluation of effectiveness. Special attention was paid to side effects. There was a marked difference between the active drugs and placebo. Indoprofen was significantly better than naproxen on many variables, and was, in most cases, preferred to the latter, by patients and investigator.
Patients suffering from osteoarthritis of the large joints or spine randomly allocated to either of two dose levels of indoprofen (IP, 300 or 600 mg/day) or indomethacin (IM, 75 mg/day). 147 patients were admitted to the trial. Drugs were given for one to three months. Controls for effectiveness and safety were carried out weekly during the first month and thereafter at monthly intervals. All three treatments gave significant improvement in the variables considered for effectiveness, and relief was generally evident from the first month. No significant differences were observed between the two doses of indoprofen and indomethacin. Adverse reactions, considered drug related, were reported by 11.6% of patients in the IP 300 group, 12.5% in the IP 600 group, and 18.7% of patients given indomethacin.
Forty-one patients suffering from classical or definite rheumatoid arthritis were randomly allocated to either indoprofen (800 mg/day) or indomethacin (100 mg/day) treatment in a double-blind, comparative long-term study (6 months). Both drugs reduced the symptoms of rheumatoid arthritis. A marked improvement was generally achieved within the first month and was maintained thereafter. Indoprofen was somewhat better tolerated than indomethacin.
Possible interactions between indoprofen (IP) and Warfarin Na (W) were studied in 18 patients under chronic anticoagulant treatment, according to a cross-over, double-blind design, comparing 600 mg daily of IP with placebo (PL). In all subjects the dosage of W was kept constant throughout the study (21 days). No significant differences were found between IP and PL either on coagulation parameters or on platelet count and platelet adhesiveness. Afte IP a significant decrease in platelet aggregation (induced by ADP and adrenaline) was observed. The results suggest that indoprofen can be administered to patients under anticoagulant treatment, although frequent checks of the coagulation parameters are advisable in these cases.
Eighty patients suffering from osteoarthritis of the large joints were admitted to the study and randomly allocated to a 4-treatment sequence, according to a multiple replication of a 4 x 4 Latin square design, with proper balancing of treatments, of periods and of the residual effects of drugs. Each treatment (indoprofen 300 or 600 mg/day, ASA 1500 + diazepam 6 mg/day, and matching placebo) was administered for 7 days. Examinations were carried out on admission, after a 3-4 day wash-out period, and then repeated at the end of each treatment period. Treatment with active drugs was significantly better than placebo in relieving overall pain, and in patient's and investigator's opinion on effectiveness. Treatment with indoprofen, at both dosages, was preferred more frequently than others. The incidence of adverse events during each period did not seem to depend either on the treatment being given during that period or on the previous one.
The results of a multicentre, double-blind trial are reported, where the effectiveness and safety of indoprofen (IP) were compared with indomethacin (IM) and placebo (PL), in patients with rheumatoid arthritis. After an initial "wash-out" period (3 days), each patient was given each of the three treatments for one week, in randomized sequence. The total dose of indoprofen (tablets) was 800 mg/die and that of indomethacin (capsules) 200 mg/die, in 4 daily doses after the main meals. The evaluation of effectiveness on a cumulative group of 102 cases from 18 centres showed statistically significant differences in favour of both active drugs compared to placebo, based on a series of objectives and subjective criteria. There was no significant difference between IP and IM, but on factorial analysis of correspondences, IP showed a greater difference from placebo. The patient's judgments also suggested that IP (800 mg/die) was slightly more effective than IM (100 mg/die). Adverse reactions were observed in 8.9% of the patients on IM treatment, 3.9% on IP and in 39% on PL. Laboratory variables showed no significant changes in the course of treatment.
Thirty in-patients suffering from classical or definite R.A. were given indoprofen 200 mg q.i.d., indomethacin 25 mg q.i.d. and placebo, according to a 6-line completely balanced block design. Each patient received the three treatments for ten days each. Patients were examined at baseline and after each treatment cycle. Both active drugs were significantly better than placebo on relief of pain, Ritchie index, and number of active, painful and swollen joints, morning stiffness; only indoprofen significantly improved grip strength. No significant differences were found between the two active drugs. The three treatments were well tolerated.