Beneficial Effects of Multi-Micronutrient Supplementation with Collagen Peptides on Global Wrinkles, Skin Elasticity and Appearance in Healthy Female Subjects.

INTRODUCTION: With ageing, collagen production slows down, leading to wrinkle appearance and loss of elasticity. Replenishing key structural molecules through oral supplementation is a promising strategy that complements the topical delivery of cosmetic products and creates a holistic skincare regimen. The present study assessed the effectiveness of a food supplement with collagen peptides, vitamins and minerals in improving the quality of the skin and general wellbeing of healthy women. METHODS: This was an open-label study of 135 women aged between 45 and 65 years. A 3-month treatment phase followed a 4-week washout phase, with visits scheduled at baseline and after each month of treatment. Subjects received three tablets of Richelet Skin Renewal daily. The primary outcome was change from baseline to month 3 in global wrinkles score by expert grader analysis. Secondary outcomes included changes in skin elasticity and other skin attributes, product assessment via self-perception questionnaires and total antioxidant status. RESULTS: A total of 116 subjects completed the study. The mean global wrinkles score indicated a statistically significant decrease from 5.9 at baseline to 5.0 at month 3 (p < 0.0001), with 83.6% of subjects showing an improvement; significant changes were reported at all intermediate visits. The increase in skin elasticity was also statistically significant (R2 score 0.74 at month 3; p < 0.0001). All subjects (100%) demonstrated significant improvements in skin texture, skin tone evenness, skin radiance and overall skin quality at the month 3 visit. CONCLUSIONS: The study product achieved statistically significant, noticeable effects on global wrinkles, skin elasticity and a range of skin attributes after 3 months of use in healthy women. These results strengthen the evidence for supplementation of collagen peptides and other micronutrients as an effective component of anti-ageing skincare.

Onset of analgesia by a topically administered flurbiprofen lozenge: a randomised controlled trial using the double stopwatch method.

BACKGROUND: The double stopwatch (DSW) method for determining the onset of analgesic activity has been implemented extensively by investigators studying orally administered drugs. OBJECTIVE: The aim of this randomised, placebo-controlled trial was to use the DSW method to determine the time to onset of analgesia of a single dose of a topically administered non-steroidal anti-inflammatory drug, flurbiprofen 8.75 mg lozenge. METHODS: Adults with acute sore throat (n = 122) were examined to confirm the presence of tonsillopharyngitis (Tonsillo-Pharyngitis Assessment) and sore throat pain of at least moderate intensity (≥6 on a 0-10 Sore Throat Scale). Lozenges containing flurbiprofen 8.75 mg or inert ingredients (identically flavoured) were administered under double-blind conditions in the clinic while patients assessed pain and pain relief over 3 hours. Onset of analgesia was determined using the DSW method and reported as the Kaplan-Meier median time to meaningful relief. The median time to first perceived relief was also documented. RESULTS: About 78% of flurbiprofen-treated patients reported meaningful pain relief compared with 48% of placebo-treated patients (p < 0.01); median time to meaningful relief for flurbiprofen-treated patients was 43 minutes (placebo-treated patients were right-censored due to non-responsivity; p = 0.01). Median time to first perceived pain relief was 11 minutes for flurbiprofen-treated patients and 19 minutes for placebo-treated patients (p = 0.03). Flurbiprofen lozenge was well tolerated, with no serious adverse events occurring and no patient discontinuing due to an adverse event. CONCLUSION: These results indicate that the DSW method can be successfully applied to the evaluation of the onset of action of a locally administered analgesic in patients with acute sore throat, demonstrating that the onset of action (time to meaningful pain relief) of flurbiprofen lozenge was <45 minutes.

Qualities of Sore Throat Index (QuaSTI): measuring descriptors of sore throat in a randomized, placebo-controlled trial.

AIM: Patients with pharyngitis often describe various sensory, affective and evaluative pain qualities. Using an 11-word/phrase index, the Qualities of Sore Throat Index (QuaSTI), we characterized throat symptoms and evaluated changes in a randomized controlled trial (NCT01986361). MATERIALS & METHODS: Patients received a single flurbiprofen 8.75 mg (n = 101) or placebo (n = 21) lozenge and rated throat soreness at baseline and regular intervals over 3 h, and the QuaSTI at baseline, 1, 2 and 3 h post-treatment. RESULTS: The QuaSTI distinguished active drug from placebo and detected clinically important (≥2-point) changes over 3 h. Mean change from baseline over 3 h was significantly greater for flurbiprofen (154%) than placebo (p < 0.05). CONCLUSION: The QuaSTI is a sensitive instrument for measuring therapeutic effects in patients with pharyngitis.

Flurbiprofen 8.75 mg lozenges for treating sore throat symptoms: a randomized, double-blind, placebo-controlled study.

AIM: This study assessed multiple doses of flurbiprofen 8.75 mg lozenges for the relief of three prominent symptoms of acute pharyngitis: pain intensity (primary end point), difficulty swallowing and swollen throat. PATIENTS & METHODS: A total of 204 patients (102 in each group) with confirmed pharyngitis (onset ≤4 days) were randomly assigned to take up to five flurbiprofen or placebo lozenges every 3-6 h, for 7 days. Using validated rating scales (sore throat pain intensity, difficulty swallowing and swollen throat) patients rated their symptoms for the duration of the study. RESULTS: Over the first 24 h, patients treated with flurbiprofen lozenges reported significantly greater reductions in sore throat pain (47%) as well as difficulty swallowing (66%) and swollen throat (40%) compared with placebo (all p < 0.05). CONCLUSION: Multiple doses of flurbiprofen lozenges provide effective relief of sore throat pain intensity as well as difficulty swallowing and swollen throat.

Efficacy of flurbiprofen 8.75 mg lozenge in patients with a swollen and inflamed sore throat.

OBJECTIVE: Sore throat is often over-treated with antibiotics, therefore there is a need for non-antibiotic treatments that provide effective relief. From the patient's point of view, symptoms of pharyngeal inflammation such as a "swollen" and "inflamed" throat are often considered the most bothersome; so, a non-steroidal anti-inflammatory drug could be an appropriate treatment. We investigated the efficacy and safety of flurbiprofen 8.75 mg lozenge in adults with a swollen and inflamed throat. RESEARCH DESIGN AND METHODS: We enrolled adults with moderate-to-severe sore throat and evidence of tonsillo-pharyngitis into a randomized, double-blind study. Patients received flurbiprofen 8.75 mg or placebo lozenges every 3-6 hours as needed (up to five lozenges in 24 hours) and rated their symptoms (sore throat pain, difficulty swallowing and the sensation of a swollen throat) on standard linear scales regularly over 24 hours. The efficacy of flurbiprofen lozenge was determined in patients reporting a swollen and inflamed throat at baseline, as well as those with relatively severe symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01049334. MAIN OUTCOME MEASURES: The main outcome measures were the time-weighted summed differences in patient-reported sore throat pain, difficulty swallowing and swollen throat over 24 hours. RESULTS: Out of 204 patients, 124 (60.8%) described their throats as swollen and inflamed at baseline. Flurbiprofen lozenges provided greater relief than placebo over 24 hours: 79.8%, 99.6% and 69.3% (for sore throat pain, difficulty swallowing and swollen throat, respectively, all P ≤ 0.01). These outcomes were more substantial in patients with relatively severe symptoms. No serious or unexpected adverse events occurred. CONCLUSIONS: Flurbiprofen 8.75 mg lozenge appears to provide effective, well-tolerated relief of sore throat, difficulty swallowing and swollen throat in adults with a swollen and inflamed throat, as well as those with relatively severe symptoms. A limitation of these findings is that, while predetermined, these are secondary outcomes derived from a targeted sub-group of patients, not the entire study population.

Efficacy of flurbiprofen 8.75 mg spray in patients with sore throat due to an upper respiratory tract infection: A randomised controlled trial.

BACKGROUND: Viral infections cause most cases of pharyngitis (sore throat); consequently, antibiotics are generally not warranted. However, a treatment targeting pain and inflammation, e.g. a topical non-steroidal anti-inflammatory spray, may be helpful for patients. OBJECTIVE: To evaluate the efficacy and safety of flurbiprofen 8.75 mg spray. METHODS: This randomised, double-blind, parallel group study was conducted at six community-based clinical research centres in Australia and two in New Zealand. Adults with sore throat due to upper respiratory tract infection (onset ≤ four days) took one dose of flurbiprofen (n = 249) or placebo spray (n = 256); after six hours, they could re-dose every three-six hours as required, for three days (max. five doses/day). The primary endpoint was the area under the change from baseline curve in throat soreness from zero-two hours (AUC0-2h). The change from baseline in other sore throat symptoms also assessed efficacy. RESULTS: The mean AUC0-2h for throat soreness was significantly greater with flurbiprofen spray (-1.82; 95% CI: -1.98 to 1.65) compared with placebo (-1.13; 95% CI: -1.27 to 0.99) (P < 0.0001). Significantly greater reductions from baseline were observed with flurbiprofen spray compared with placebo from the first time-points assessed (five minutes for throat soreness/difficulty swallowing, 20 minutes for sore throat pain intensity and 30 minutes for swollen throat) for up to six hours (P < 0.05 for all). There was no significant difference in adverse events between treatment groups during the three-day study. CONCLUSION: Flurbiprofen spray provides rapid and long-lasting relief from sore throat symptoms, and is well-tolerated over three days.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

BACKGROUND: The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. METHODS: Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). RESULTS: Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P<0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P<0.01). There were no serious adverse events. CONCLUSIONS: Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

Onset of action of a lozenge containing flurbiprofen 8.75 mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity.

A new onset-of-action model was utilized to distinguish the pharmacologic activity of flurbiprofen 8.75mg delivered in a lozenge from the demulcent effect of the lozenge base. In a randomized, double-blind, placebo-controlled trial, patients with sore throat rated pain on a Sore Throat Pain Intensity Scale before taking one flurbiprofen or placebo lozenge and at frequent (2-minute) intervals over the first hour after treatment. Further ratings of the Sore Throat Pain Intensity Scale and other patient-reported outcomes (difficulty swallowing, swollen throat, pain relief) were obtained at varying intervals over 6 hours. Onset of pharmacologic activity was defined as the median time of first perceived pain reduction if a patient reported clinically meaningful (at least moderate) relief. The conventional method of comparing mean treatment responses at each time point was also implemented. Demulcent action was detected at the first 2-minute assessment. By the new method, 102 flurbiprofen-treated patients were identified as first perceiving pain relief at 12 minutes, compared with >120 minutes by 102 patients using placebo (P<0.001). By the conventional method, mean percentage pain reduction for flurbiprofen 8.75 mg was first significantly differentiated from placebo at 26 minutes (P<0.05). Efficacy of flurbiprofen lozenge was demonstrated for 3.5-4hours on the 4 patient-reported outcomes (all P<0.05 compared with placebo). There were no serious adverse events. This patient-centered onset-of-action model identifies the initiation of pain relief in patients who are definite drug responders, here demonstrating that a flurbiprofen 8.75-mg lozenge provides early relief of sore throat.

A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain.

OBJECTIVES: To compare the efficacy and safety of single versus combination non-prescription oral analgesics in community-derived people aged 40 years and older with chronic knee pain. METHODS: A randomised, double-blind, four-arm, parallel-group, active controlled trial investigating short-term (day 10) and long-term (week 13) benefits and side-effects of four regimens, each taken three times a day: ibuprofen (400 mg); paracetamol (1000 mg); one fixed-dose combination tablet (ibuprofen 200 mg/paracetamol 500 mg); two fixed-dose combination tablets (ibuprofen 400 mg/paracetamol 1000 mg). RESULTS: There were 892 participants (mean age 60.6, range 40-84 years); 63% had radiographic knee osteoarthritis and 85% fulfilled American College of Rheumatology criteria for osteoarthritis. At day 10, two combination tablets were superior to paracetamol (p<0.01) for pain relief (determined by mean change from baseline in WOMAC pain; n=786). At 13 weeks, significantly more participants taking one or two combination tablets rated their treatment as excellent/good compared with paracetamol (p=0.015, p=0.0002, respectively; n=615). The frequency of adverse events was comparable between groups. However, by 13 weeks, decreases in haemoglobin (≥1 g/dl) were observed in some participants in all groups. Twice as many participants taking two combination tablets had this decrease compared with those on monotherapy (p<0.001; paracetamol, 20.3%; ibuprofen, 19.6%; one or two combination tablets, 24.1%, 38.4%, respectively). CONCLUSIONS: Ibuprofen/paracetamol combination analgesia, at non-prescription doses, confers modest short-term benefits for knee pain/osteoarthritis. However, in this population, paracetamol 3 g/day may cause similar degrees of blood loss as ibuprofen 1200 mg/day, and the combination of the two appears to be additive. Study no ISRCTN77199439.

A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain.

Combination analgesia is often recommended for the relief of severe pain. This was a double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single-dose study designed to compare the efficacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination, and a paracetamol/codeine combination, using the dental impaction pain model. Subjects with at least 3 impacted third molars and experiencing moderate to severe postoperative pain were randomised to receive: 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg; 2 tablets of ibuprofen 200 mg/codeine 12.8mg; 2 tablets of paracetamol 500mg/codeine 15mg; or placebo. Results for the primary endpoint, the sum of the mean scores of pain relief combined with pain intensity differences over 12hours, demonstrated that 1 and 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically significantly more efficacious than 2 tablets of placebo (P<0.0001) and paracetamol/codeine (P⩽0.0001); furthermore, 2 tablets offered significantly superior pain relief to ibuprofen/codeine (P=0.0001), and 1 tablet was found noninferior to this combination. Adverse events were uncommon during this study and treatment emergent adverse events were statistically significantly less frequent in the groups taking the ibuprofen/paracetamol combination compared with codeine combinations. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics currently indicated for strong pain. A single-tablet combination of ibuprofen 200mg/paracetamol 500mg provides highly effective analgesia, comparable or superior to other combination analgesics indicated for strong pain.

Comparison of the analgesic efficacy of concurrent ibuprofen and paracetamol with ibuprofen or paracetamol alone in the management of moderate to severe acute postoperative dental pain in adolescents and adults: a randomized, double-blind, placebo-controlled, parallel-group, single-dose, two-center, modified factorial study.

BACKGROUND: Combination analgesics may offer improved analgesic efficacy, particularly for moderate to severe pain. OBJECTIVE: This study evaluated the analgesic benefits of concurrent ibuprofen and paracetamol compared with each drug used alone in the management of acute postoperative dental pain. METHODS: Healthy patients aged 16 to 40 years undergoing surgical removal of 3 to 4 impacted molars (total impaction score > or = 9) were enrolled in this randomized, double-blind, placebo-controlled, parallel-group, single-dose, 2-center, modified factorial US study. Patients were randomly assigned in a ratio of 2:1:2:1:1 to ibuprofen 400 mg/paracetamol 1000 mg, ibuprofen 200 mg/paracetamol 500 mg, ibuprofen 400 mg, paracetamol 1000 mg, or placebo when postoperative pain reached moderate to severe intensity. The primary efficacy end point was the sum of pain relief and pain intensity differences from 0 to 8 hours (SPRID8). Several secondary end points were also measured, including total pain relief (TOTPAR), sum of pain intensity differences (SPID), and SPID on the visual analog scale (SPID VAS) at various time points. Other analgesic efficacy measures included peak effect, onset and duration of effect, and patients' overall assessment of treatment. The tolerability of study medications was assessed in terms of the frequency and nature of adverse events, which were assessed with standard questions, as well as changes from baseline in vital signs. RESULTS: A total of 234 patients were randomly assigned to treatment and included in the intent-to- treat population. The patients were predominantly female (74.4% [174/234]) and white (76.5% [179/234]); mean (SD) age was 20.8 (3.1) years and weight was 69.1 (16.5) kg. For SPRID8, the group treated with ibuprofen 400 mg/paracetamol 1000 mg had significantly better mean scores compared with ibuprofen alone (P < 0.001), paracetamol alone (P < 0.001), and ibuprofen 200 mg/paracetamol 500 mg (P = 0.02). The group taking ibuprofen 200 mg/paracetamol 500 mg achieved significantly better mean SPRID8 scores than paracetamol alone (P = 0.03), but not ibuprofen alone (P = NS). Ibuprofen 400 mg/paracetamol 1000 mg was associated with significantly better scores than was single-agent therapy for TOTPAR, SPID, and SPID VAS at all time intervals and for SPRID from 4 to 6 hours (all, P < 0.001). Pairwise comparisons found statistically significant differences in favor of all active treatments versus placebo for virtually all efficacy end points, thereby supporting assay sensitivity. Adverse events were similar across treatments; the most frequent were nausea (26.1% [61/234]), vomiting (18.8% [44/234]), headache (10.3% [24/234]), and dizziness (8.1% [19/234]). CONCLUSION: Concurrent ibuprofen and paracetamol appeared to provide significantly better analgesic efficacy compared with ibuprofen or paracetamol alone for acute postoperative dental pain in these adolescents and adults.

A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: a multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study.

BACKGROUND: The combination of ibuprofen and paracetamol may confer analgesic benefits over monotherapy with either agent. In a previous study, an ibuprofen/paracetamol combination provided significantly better analgesic efficacy than comparable doses of ibuprofen or paracetamol alone in patients experiencing moderate to severe acute postoperative pain after extraction of impacted third molars. OBJECTIVE: This study compared the efficacy and tolerability of 3 doses of a single-tablet fixed-dose combination (FDC) of ibuprofen and paracetamol (ibuprofen/paracetamol doses of 100 mg/250 mg, 200 mg/500 mg, and 400 mg/1000 mg) with comparable doses of ibuprofen (200 or 400 mg) monotherapy, paracetamol (500 or 1000 mg) monotherapy, and placebo in the 8 hours after surgical removal of 3 to 4 impacted third molars (stage 1) and with placebo over the next 72 hours (stage 2). METHODS: This was a multicenter, 2-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study. Male or female outpatients were eligible for the study if they were aged >or=16 years, were referred for surgical removal of at least 3 impacted third molars (2 of which had to be mandibular impacted molars), and gave written informed consent. In stage 1, patients were randomly assigned to ibuprofen 200 mg, ibuprofen 400 mg, paracetamol 500 mg, paracetamol 1000 mg, FDC ibuprofen 100 mg/paracetamol 250 mg, FDC ibuprofen 200 mg/paracetamol 500 mg, FDC ibuprofen 400 mg/paracetamol 1000 mg, or placebo. In stage 2, patients who had been taking FDC therapy or placebo continued the same treatment, whereas those taking monotherapy received FDC therapy, incorporating the same dose of active monotherapy from stage 1. First-line rescue medication (hydrocodone 7.5 mg and paracetamol 500 mg) was available at any time after dosing; however, in stage 1, any patient who required rescue medication within 60 minutes of receipt of study medication was considered a "dropout" from therapy, and, in stage 2, patients who required >2 doses of first-line rescue medication in a 24-hour period were considered treatment failures. In stage 1, the primary efficacy end points were the sum of pain relief and pain intensity differences over an 8-hour follow-up period (SPRID8) and the pain relief and pain intensity difference scores at each time point (15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, and 480 minutes after dosing). Several secondary variables were also measured, including the patient's global assessment of the study medication. The 2-stopwatch method was used for measures of perceptible and meaningful pain relief. In stage 2, the primary efficacy end point was the number of completed 24-hour periods (as 0, 1, 2, or 3) in which the patient required no more than one dose of rescue medication and rated the treatment as "good," "very good," or "excellent." The tolerability of study medications was assessed in relation to the frequency, nature, and severity of adverse events (AEs), as well as their relationship to study medication; vital signs were also measured. AEs were assessed at 8 hours after dosing in stage 1, at 72 hours after dosing in stage 2, and at the follow-up visit (7-10 days after surgery); in addition, patients were instructed to report any AE that occurred between scheduled assessments. RESULTS: Of 735 patients randomly assigned in stage 1, a total of 715 (97.3%) entered and 678 (92.2%) completed stage 2. Most patients were female (62.6% [460/735]) and white (91.3% [671/735]); the mean (SD) age was 20.3 (3.5) years and the mean weight was 69.7 (15.7) kg. The mean total impaction score was 11.1 (1.4), and the mean baseline pain score on the visual analog scale was 76.9 (12.0). Overall, 422 of 735 patients (57.4%) reported severe pain at baseline and 313 of 735 (42.6%) reported moderate pain. For the primary efficacy end point (SPRID8), FDC ibuprofen 400 mg/paracetamol 1000 mg was significantly more effective than ibuprofen 400 mg (P = 0.02) and paracetamol 1000 mg (P < 0.001) in the immediate postoperative period (stage 1), and FDC ibuprofen 200 mg/paracetamol 500 mg was significantly more effective than ibuprofen 200 mg (P < 0.001) and paracetamol 500 mg (P < 0.001). The FDC ibuprofen 200 mg/paracetamol 500 mg was also significantly more effective than paracetamol 1000 mg (P < 0.001), but failed to reach statistical significance in comparison with ibuprofen 400 mg. Continued postoperative therapy with all 3 FDCs on an as-needed basis was significantly more effective than placebo during the subsequent 72 hours (all, P < 0.001). During stage 1, rescue medication was required by 53 of 73 (72.6%), 29 of 75 (38.7%), 21 of 74 (28.4%), 56 of 76 (73.7%), and 51 of 74 (68.9%) patients in the placebo group and the ibuprofen 200-mg, ibuprofen 400-mg, paracetamol 500-mg, and paracetamol 1000-mg treatment groups, respectively. In the FDC treatment groups, the need for rescue medication included 27 of 71 (38.0%), 40 of 143 (28.0%), and 32 of 149 (21.5%) patients in the ibuprofen 100-mg/paracetamol 250-mg, ibuprofen 200-mg/paracetamol 500-mg, and ibuprofen 400-mg/paracetamol 1000-mg groups, respectively. The rates of treatment-related AEs between the first and second doses of study medication were significantly lower for FDC ibuprofen 400 mg/paracetamol 1000 mg (8/149 patients [5.4%]) than for placebo (14/73 [19.2%]; P < 0.01) and paracetamol 1000 mg (10/74 [13.5%]; P < 0.05); and also lower for FDC ibuprofen 200 mg/paracetamol 500 mg (9/143 [6.3%]) compared with ibuprofen 200 mg (12/75 [16.0%]; P < 0.05) and paracetamol 500 mg (17/76 [22.4%]; P < 0.001). CONCLUSION: FDC ibuprofen 200 mg/paracetamol 500 mg and ibuprofen 400 mg/paracetamol 1000 mg were significantly more effective in this population than were comparable doses of ibuprofen or paracetamol alone in moderate to severe acute dental pain and were significantly more effective than placebo in providing sustained pain relief.

The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol.

BACKGROUND: Ibuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet. METHODS: Both studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study. RESULTS: Pharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 microg x mL(-1) and 16.81 microg x mL(-1), respectively, for ibuprofen from the combination, compared with 0.58 microg x mL(-1) and 9.00 microg x mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 microg x mL(-1) and 14.54 microg x mL(-, respectively, for the combination compared with 0.33 microg x mL(-1) and 9.19 microg x mL(-1), respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily. CONCLUSIONS: Administration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.

Effects on serotonin in rat hypothalamus of D-fenfluramine, aminorex, phentermine and fluoxetine.

Hypothalamic 5-HT (serotonin) regulates food intake, energy expenditure and bodyweight. Using in vivo microdialysis, we determined the effects of various anorectic drugs on hypothalamic extracellular 5-HT levels during the dark phase when rats predominantly feed. Phentermine and aminorex, which were originally considered to be catecholaminergic drugs, markedly increased 5-HT efflux in rat hypothalamus. Their actions were less profound than D-fenfluramine, but considerably greater than that of the selective 5-HT reuptake inhibitor, fluoxetine. This suggests that enhanced hypothalamic 5-HT function could be involved in their anorectic actions. Pharmacological characterization revealed that D-fenfluramine, aminorex and probably also phentermine potentiate synaptic 5-HT function predominantly by release, whereas fluoxetine acts exclusively by reuptake inhibition. The results also revealed that the combined actions of phentermine and D-fenfluramine on hypothalamic extracellular 5-HT levels were additive, but not synergistic. In contrast, there was a significant negative cooperative effect on extraneuronal 5-HT of combining phentermine with fluoxetine.