Dextrans--potential polymeric drug carriers for suprofen.

Dextrans are clinically useful biodegradable polysaccharide macromolecules and have been utilized as carriers for suprofen. Conjugates of suprofen were synthesized by preparing their acylimidazol derivatives which were condensed in situ with dextrans of different molecular weights (40000, 60000, 110000 and 200000). The structures of the synthesized conjugates were confirmed by IR and NMR spectroscopy. The degrees of substitution obtained were between 7.5 and 9.0%. The molecular weight was determined by the Mark-Howin Sakurada viscosity equation. Hydrolysis was studied in different buffer solutions (pH 1.2, 7.4, 9.0) and 80% human plasma (pH 7.4) and followed first order kinetics. Much faster hydrolysis was observed at pH 9.0 compared to pH 7.4 buffer solution and 80% human plasma (pH 7.4). Biological evaluation for acute and chronic anti-inflammatory activity was performed and the results were found to be comparable with the parent drug. The ulcerogenic index of conjugates showed a remarkable reduction compared to the parent suprofen.

Comparative efficacy of topically applied flurbiprofen, diclofenac, tolmetin, and suprofen for the treatment of experimentally induced blood-aqueous barrier disruption in dogs.

OBJECTIVE: To compare the relative efficacies of 4 topical nonsteroidal anti-inflammatory drugs at preventing blood-aqueous barrier (BAB) disruption in dogs. DESIGN: 1 eye of each dog was treated with 1% suspensions of diclofenac, flurbiprofen, suprofen, or tolmetin, or with control solution. After 4 applications of eyedrops at 10-minute intervals, BAB disruption was induced in the treated eye by anterior chamber paracentesis. The severity of BAB disruption was measured by anterior chamber fluorophotometry. ANIMALS: 40 ocular-normal dogs. PROCEDURE: After pretreatment with eyedrops, rapid 100-microliters nonleaking anterior chamber paracentesis was performed in 1 eye of each dog to induce BAB disruption. 1 day after paracentesis, 1 ml of 10% fluorescein sodium was injected i.v.. The amount of fluorescein entering the anterior chamber of each eye was measured 30 to 60 minutes later by use of a computerized scanning fluorophotometer. The degree of BAB disruption was determined by comparing the amount of fluorescein entering the aqueous humor of the paracentesed eye with that of the nonparacentesed eye. RESULTS: At postparacentesis day 1, the order of statistically significant BAB-stabilizing efficacy among groups was: diclofenac > flurbiprofen > suprofen > tolmetin = control solution. CONCLUSIONS: Topically applied 1% suspensions of diclofenac, flurbiprofen, and suprofen are effective at preventing BAB disruption after paracentesis in dogs, indicating their potential usefulness for treatment of prostaglandin-mediated ocular disease. 1% tolmetin is no more effective than control solution.

Effects of topical suprofen and flurbiprofen on the miosis produced by anterior chamber irrigation with cholinergic agonists.

Pretreatment with topical nonsteroidal anti-inflammatory drugs is common practice to maintain maximal pupil dilation for cataract surgery. Most surgeons also inject a cholinergic agent intracamerally for miosis after intraocular lens insertion. We evaluated the effects of topical suprofen and flurbiprofen on the miosis induced by anterior chamber irrigation with either acetylcholine or carbachol. One eye of 30 pigmented rabbits was dilated with cyclopentolate HCl and phenylephrine HCl. Three groups, each composed of ten eyes, received flurbiprofen, suprofen, or a control. In each group, five eyes received acetylcholine by anterior chamber irrigation and five received carbachol. Pupil diameters were measured with calipers before and five minutes after irrigation by an observer unaware of the treatment regimen. Irides irrigated with carbachol constricted less than those irrigated with acetylcholine (P = .016). In anterior chambers irrigated with carbachol, suprofen was associated with less miosis than either tears (P = .005) or flurbiprofen (P = .009); however, if the infusion was performed with acetylcholine, no differences between the three groups were noted (P = .44).

Stereoselective pharmacokinetics and inversion of suprofen enantiomers in humans.

The stereoselective pharmacokinetics of suprofen enantiomers has been studied in humans by means of stable isotope-labeled pseudoracemate-diastereomer methodology. After a single oral dose of a near equimolar mixture of unlabeled-(R)-(-)- and [2H3]-(S)-(+)-suprofen [or unlabeled-(S)- and [2H3]-(R)-suprofen] to three healthy male subjects, the plasma concentrations of drug were determined by a stereospecific gas chromatography-mass spectrometry method. Racemic [2H7]suprofen was used as an internal standard. The method involved chiral derivatization with (S)-(-)-1-(naphthyl)ethylamine to form the diastereomeric amide. The plasma concentrations were consistently higher for the (R)-isomer than the (S)-isomer. No significant difference in the elimination half-life of the enantiomers was observed. An average of 6.8% of an administered dose of the (R)-isomer was stereospecifically inverted to the (S)-isomer. There was no measurable inversion of the (S)- to (R)-isomer. The present stable isotope-labeled pseudoracemate-diastereomer methodology has made it possible to evaluate the pharmacokinetics of each enantiomer, including the estimation of chiral inversion after administration of the racemic mixture.

In vitro-in vivo correlation exemplified by sustained release formulations of suprofen.

To evaluate some prototype oral sustained release formulations of the analgesic drug suprofen (alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid, Suprol) in vitro-in vivo correlations were performed. Numerical deconvolution led to hypothetical in vivo absorption curves which were in close agreement with the in vitro dissolution profiles. Furthermore, a linear correlation was obtained between the in vivo and in vitro mean residence times calculated from the blood level data.

Effect of concurrent topical corticosteroid and NSAID therapy of experimental keratitis.

The ability of suprofen, a nonsteroidal anti-inflammatory drug, and prednisolone acetate, a corticosteroid, to suppress polymorphonuclear leukocyte invasion of the rabbit cornea during an experimental keratitis was evaluated following topical ophthalmic administration of either drug alone or both drugs concurrently. Suprofen therapy initiated immediately after induction of inflammation was ineffective. However, if suprofen therapy was begun 48 hr prior to the induction of inflammation, the drug was effective. In contrast, prednisolone acetate therapy begun after the induction of inflammation was effective; 48 hr of pretreatment with the corticosteroid produced a marked increase in its therapeutic effect. When administered according to the same regimen, concurrent therapy with suprofen and prednisolone acetate was significantly more effective than treatment with either drug alone. This result was obtained irrespective of whether concurrent therapy was initiated prior to or after the inflammatory event.

Treatment of postoperative pain with suprofen injected by the intramuscular route.

The analgesic effect and the tolerability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 200 mg/ml were compared with lysine acetylsalicylate 0.9 g/2.5 ml; the study included 60 subjects in severe to very severe pain following orthopedic surgery. The trial was performed in randomized single-blind fashion in patients who had given informed consent. The substances were injected into the upper out quadrant; maximally 4 intramuscular injections were given within 2 days. The test population was homogeneous with respect to the anamnestic data. The intensity of pain prior to treatment was comparable in both groups. Statistical analysis of the data revealed that suprofen was at the rating times (15 min to 4 h) significantly superior to the control groups. The investigator's and the patients' final appreciation indicated good to very good effect in 93% of the subjects on suprofen, and in 40 and 47%, respectively, of the patients in the control group. Here, too, suprofen was significantly superior to the reference Substance. Systemic and local tolerability of both drugs was very good. Adverse drug experience (heartburn) occurred in only 1 patient in the control group.

Clinically controlled comparative study of intravenous single doses of suprofen versus indoprofen.

The analgesic effects of single intravenous doses of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 200 mg/ml and alpha-4-(2-isoindolinyl-2-one)-phenylpropionic acid (indoprofen) 200 mg were compared within the scope of a randomized single-blind study. The test population consisted of 87 patients for whom analgesic treatment was indicated as soon as severe to major pain set in following meniscectomy or disease of a ligament. The treatment groups were homogeneous with respect to demographic data and intensity of pain prior to treatment. In the pain models chosen both drugs resulted in rapid pain relief within 15 min following their application. As to decreased intensity of pain (SPID) and pain relief (TOTPAR), the results obtained 2 h after the test were with indoprofen statistically significantly superior to those obtained with suprofen. The investigator's global appreciation of effectiveness revealed no intergroup differences. Therapeutic results were seen in 95.5% of the subjects on suprofen and in 97.6% of those on indoprofen. The tolerability of suprofen was very good in 95.3% of the cases on suprofen and in 97.3% of those on indoprofen. Four patients in the suprofen group experienced adverse reactions that were, however, not drug related.

Controlled single-blind clinical study of suprofen syrup versus metamizole syrup.

The analgesic effect and the tolerability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) syrup 200 mg and metamizole syrup 500 mg were compared in a randomized single-blind study including hospitalized patients with severe to moderate chronic pain. The 2 treatment groups consisted of 30 subjects each and were homogeneous as to the demographic data. Pain intensity was appreciated by the investigator prior to the treatment and on days 2, 3, and 5 of the study; pain relief was assessed on days 2, 3, and 5 of the therapy. Although pain intensity was on treatment with suprofen more markedly reduced than with metamizole, there was no statistically significant difference between the 2 treatment groups (chi 2-test). The Mann-Whitney test revealed that on days 3 and 5 pain relief with suprofen was significantly superior to that with metamizole. According to the investigator's final global evaluation, suprofen syrup 200 mg had very good to good effect in 70% of the cases, whereas the effectiveness of metamizole was rated good to very good in 44%. Side-effects manifesting themselves as gastric irritation and nausea were recorded for 3 patients on suprofen and 2 subjects on metamizole.

Double-blind placebo-controlled study of the efficacy and tolerability of suprofen suppositories in patients with osteoarthritic pain.

In a placebo-controlled double-blind trial analgesic effectiveness and tolerability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 300 mg suppositories were evaluated for 45 informed patients suffering from chronic pain due to osteoarthritis; the subjects were treated rectally, t.i.d., for 10 days. Suprofen proved to be statistically significantly superior to placebo in all the variables considered for evaluation of the analgesic effect, i.e., pain intensity and relief scores, sum of pain intensity differences (SPID), total pain relief (TOTPAR), global assessments by investigator and patient. In particular, the efficacy of suprofen was judged by the physician good or very good in 86.3% of the patients. Similar frequencies of rectal side-effects were observed in both treatment groups, with slightly but not significantly higher incidence in the group treated with suprofen. Haematologic and clinical chemistry laboratory tests showed no statistically significant alterations due to the treatment.

Open clinical study with suprofen drops in the treatment of postoperative and posttraumatic pain.

Analgesic effect and tolerability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) drops were tested in an open study including 51 informed outpatients with moderate to severe postoperative and posttraumatic pain. Suprofen drops were administered for 7 days, at doses of 33 drops (= 200 mg of suprofen) t.i.d. or q.i.d. The pain intensity was recorded prior to the treatment and after 2, 4 and 7 days; pain relief was assessed on days 2, 4 and 7. Effectiveness and tolerability were by the investigator and by the patients globally evaluated upon completion of the trial. The intensity of pain dropped within the 7-day treatment period from initially severe pain to mild. Pain relief was seen in 92% of the subjects after day 2, in 98% after day 4, and in 100% after day 7 of treatment. Investigator's and patients' final evaluation of the therapeutic effect indicated good analgesic activity in 86% of the population, and very good analgesic effect in 84%. Moderate effect was seen in 12 and 14%, respectively. The tolerability of suprofen drops was by investigator and patients considered good to very good in 82% of the cases, moderate in 16%, and poor in 1 case.

Clinical experience and results of treatment with suprofen in pediatrics. 5th communication: a single-blind study on antipyretic effect and tolerability of suprofen syrup versus metamizole drops in pediatric patients.

In a single-blind study, 60 children in two age groups (30 patients: 6 months to 3 years; 30 patients: 3 years to 12 years), were orally treated with either alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol), syrup 10 mg/ml or metamizole drops 50% for a maximum period of 4 days, up to 4 times a day. The children presented with high fever due to bacterial or virus infections. Body temperature, pulse rate, and respiratory rate were evaluated at the beginning and then 30 min, 1, 1 1/2, 2, 3, 4, 5, and 6 h after the first administration of the respective drug. Significant differences between the drugs were found for all variables; this demonstrated that with suprofen the antipyretic effect set in more rapidly than with the reference drug. No side-effects were observed in children treated with suprofen syrup. Two patients showed adverse effects, i.e. sweating and hypotension, during the treatment with metamizole. Due to its good antipyretic effect and good tolerability, suprofen appears to be particularly useful for symptomatic treatment of pediatric patients with fever caused by bacterial or virus infections.

Suprofen sustained release kinetics in healthy male volunteers. 1st communication: a single dose open crossover bioavailability study of suprofen sustained release tablets versus capsules.

An open crossover study was performed in 12 healthy male volunteers to compare the bioavailability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 600 mg sustained release tablets versus the suprofen capsule (2 X 200 mg). The pharmacokinetic profiles in plasma and urine were determined by a HPLC assay. In the dose range studied, the two suprofen formulations were not associated with any clinically significant effects on the blood pressure, heart rate or ECG. The results of the physical and neurological examinations showed no abnormal results. The results of haematology, clinical chemistry and urinalysis also showed no significant modifications. However, increased serum creatinine values were observed in some volunteers following suprofen administration. A drug relationship to this finding cannot be excluded with certainty. Two volunteers complained of nausea and vomiting following administration of two suprofen capsules. For this reason, volunteer no. 9 was withdrawn by the investigator from the study and replaced by an eligible substitute. In general, single doses of the two suprofen formulations investigated, were subjectively and objectively well tolerated. From the suprofen plasma-concentration time profiles, it was apparent that, whilst the elimination of suprofen was similar for both formulations, there was a marked delay in absorption of the tablet formulation. This formulation resulted in statistically significantly later maximum plasma levels and longer mean residence time (p less than 0.001). In comparison to the reference capsule formulation, the tablet had statistically significantly lower (75%) bioavailability. Measurement of suprofen concentrations in the urine indicated that less than 1% of the administered dose was excreted by this route.

Suprofen sustained release kinetics in healthy male volunteers. 2nd communication: a multiple dose steady-state kinetics of suprofen sustained release tablets during 6 days in healthy male volunteers.

To 12 healthy male volunteers, who had given their consent, 11 administrations of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) sustained release tablets 600 mg were given twice a day with a dosage interval of 12 h. It could be demonstrated that suprofen given as multiple dose application of sustained release tablets was well tolerated. Effective mean plasma levels were reached after the second dosage. There was no indication of accumulation nor accelerated elimination during the 6-day period. There was no statistically significant difference between the mean plasma curve after the last administration of the 6-day period and the mean plasma curve after the 3rd application. Also the AUC's in the respective intervals turned out not to be statistically significantly different from each other. Clinical and laboratory tests showed no clinically relevant deviations from the normal range. No adverse reactions whatsoever were observed.

Double-dummy comparison of suprofen and indometacin sustained release formulations.

In a randomized double-dummy study a new dosage form of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol), i.e., suprofen sustained release 600 mg tablets, was compared with indometacin sustained release 75 mg capsules. The test population included 60 hospitalized subjects in severe chronic pain requiring analgesic treatment. The treatment groups were homogeneous as to their anamnestic data. Treatment was given for 3 weeks; the drugs were uniformly administered in the morning and in the evening. The intensity of pain was assessed using a visual analog scale (VAS) prior to administration of the first dose on day 1 of the therapy, and then for up to 10 h. Further assessments of pain intensity and pain relief were obtained after 1, 2, and 3 weeks of therapy. Comparison of the mean pain intensity (VAS) at the individual rating times revealed statistically significant better pain relief with suprofen than with indometacin already 1 h after the administration (p less than 0.05, multivariate analysis of variance). This statistically significant difference as compared with indometacin was confirmed at all subsequent time points. The weekly assessments of pain intensity showed that the results obtained with suprofen were superior to those with indometacin, although they were not statistically significant. However, pain relief after 2 weeks' treatment with suprofen was significantly superior (p = 0.0061, exact test) to the result observed with indometacin. The results obtained with suprofen in weeks 1 and 3 were superior to those with indometacin, but they were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of pupillary constriction during cataract surgery using suprofen.

The efficacy of a new nonsteroidal anti-inflammatory agent, suprofen, for reducing pupillary constriction during cataract surgery was ascertained in a double-masked, multicenter, clinical study. Prior to surgery 1.0% suprofen or a placebo was instilled; the surgeon's normal regimen of mydriatics and cycloplegics was used. Suprofen (209 patients) was far more effective than the placebo (203 patients) in maintaining a dilated pupil prior to intraocular lens (IOL) implantation (or instillation of a miotic). The mean pupillary area prior to IOL implantation was 6.3 sq mm larger (20% larger) in patients treated with suprofen than in patients receiving the placebo. The investigators' subjective evaluations of the adequacy of pupil size for IOL implantation and of the difficulty of IOL implantation favored patients treated with suprofen over those receiving the placebo.

Suprofen. A review of its pharmacodynamic and pharmacokinetic properties, and analgesic efficacy.

Suprofen (sutoprofen) is a non-steroidal anti-inflammatory analgesic, closely related structurally to drugs such as ibuprofen, ketoprofen and naproxen. In patients with acute pain, single oral doses of suprofen are at least as effective as: usual therapeutic doses of aspirin; codeine alone or combined with aspirin; dextropropoxyphene alone or in various combinations; oxycodone combined with aspirin; dipyrone; pentazocine; paracetamol (acetaminophen); diflunisal; ibuprofen; indomethacin; or mefenamic acid. In chronic pain due to osteoarthritis, suprofen is as effective as usual dosages of aspirin or dextropropoxyphene during long term therapy, and as effective as diclofenac, ibuprofen, indomethacin and naproxen during short term treatment. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects, although discontinuation due to gastrointestinal effects may be necessary less frequently with suprofen than with aspirin, dextropropoxyphene or combinations of the two. Suprofen appears to be a useful alternative to mild analgesics, analgesic combinations or the older more established non-steroidal anti-inflammatory drugs in the treatment of patients with acute or chronic pain. However, further definition of its efficacy and tolerability is required, especially in comparison with newer non-steroidal anti-inflammatory analgesics.

Effect of suprofen on corneal wound healing.

We studied the effect of suprofen, a new ophthalmic nonsteroidal anti-inflammatory agent, on corneal wound healing. Nine-millimeter, central, perforating corneal wounds were made in albino rabbits and sutured with 10-0 nylon. The animals were randomly treated with balanced salt solution, suprofen vehicle, 1% suprofen, or 0.1% dexamethasone sodium phosphate administered topically for six days. On the seventh postoperative day, the sutures were removed and, in situ, the intraocular pressure was increased in a controlled manner until the wound burst. Dexamethasone applied four times a day significantly inhibited corneal wound healing, whereas suprofen given as often as hourly did not. Pretreatment with hourly administered suprofen for two days prior to surgery, in addition to the same postoperative hourly therapy, also did not significantly decrease stromal wound strength.