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1.  Effectiveness and tolerability of once-daily nimesulide versus ibuprofen in pain management after surgical extraction of an impacted third molar: A 24-hour, double-blind, randomized, double-dummy, parallel-group study 
Nimesulide is a nonsteroidal, anti-inflammatory drug that hasbeen used for a wide range of acute and chronic pain. A once-daily formulation of nimesulide is now commercially available, but its effectiveness in pain management after dental surgery has not been assessed.
The aim of this study was to assess the analgesic effectiveness and tolerability of oral treatment with once-daily nimesulide versus ibuprofen q6h over 24 hours in patients with postoperative pain associated with surgical extraction of an impacted third molar.
This 24-hour, double-blind, randomized, double-dummy, parallel-groupstudy was conducted at a private practice in Caracas, Venezuela. Patients aged between 12 and 60 years with moderate to severe pain after extraction of an impacted third molar were enrolled. Patients were randomized to receive a single dose of nimesulide (300-mg tablet) or ibuprofen (400-mg tablets) q6h for 24 hours. For double-dummy design, patients in the nimesulide group also received ibuprofen placebo tablets, to be taken q6h for 24 hours, and patients in the ibuprofen group received a nimesulide placebo tablet. The primary end points were pain intensity (PI) and pain relief scores over 24 hours. Secondary end points included total pain relief, PI difference (PID), sum of PID (SPID), time to first measurable change in PI (ie, PID ≥ 10 mm), and use of rescue medication (acetaminophen). Patients also rated the treatment's effectiveness as very poor to very good on questioning by the study investigator. Spontaneously reported adverse effects (AEs) were recorded.
Eighty-six patients were enrolled (56 females, 30 males), with 43 patientsper treatment group (mean age: nimesulide group, 25.2 years; ibuprofen group, 24.2 years). The baseline characteristics were statistically similar between the 2 groups. Compared with baseline, mean PI scores were significantly lower in both treatment groups at all time points throughout the study (P < 0.001). Mean PI scores were significantly lower in the nimesulide group compared with the ibuprofen group at 15 and 45 minutes and 1 hour after study drug administration (P ≤ 0.049). Time to first measurable change in PI was within the first 15 minutes in 22 patients (52%) in the nimesulide group and in 14 patients (33%) in the ibuprofen group (P = 0.03). Analgesia lasted 24 hours with nimesulide and ibuprofen (PI scores at 24 hours, 9.4 and 3.6, respectively). The mean PR score was significantly lower in the nimesulide group compared with the ibuprofen group at 1 hour after study drug administration (P = 0.049). Compared with baseline, PID and SPID were significantly higher in both treatment groups throughout the study (P < 0.001). Significantly more patients in the nimesulide group than in the ibuprofen group reported that treatment provided effective pain relief (82% vs 73%; P = 0.013). No AEs were reported in either treatment group throughout the study. Use of rescue medication was statistically similar between the nimesulide and ibuprofen groups (38% and 31%, respectively).
In this study of patients with moderate to severe pain afterextraction of impacted third molars, nimesulide and ibuprofen provided effective 24-hour relief. However, the results suggest that the analgesic effect of nimesulide had a faster onset (<15 minutes) and was stronger (based on patient opinion) than that of ibuprofen. Both study drugs were well tolerated.
PMCID: PMC3964531  PMID: 24672121
nimesulide; ibuprofen; dental pain; programmed liberation
2.  Pain-mediated altered absorption and metabolism of ibuprofen: an explanation for decreased serum enantiomer concentration after dental surgery 
Rapid onset of analgesia is essential in the treatment of acute pain. There is evidence that conditions of stress cause delayed and decreased pain relief from oral analgesic products through impaired absorption. The aim was to determine the effect of surgery for removal of wisdom teeth on the plasma concentration-time profile of ibuprofen enantiomers.
Racemic ibuprofen, 200 mg in one group (n=7) and 600 mg in another group (n=7) was administered 1 week before (control) and again after (test) surgical removal of wisdom teeth. Serum concentrations of ibuprofen enantiomers were measured for 6 h.
During the control phase, S- and R-ibuprofen concentrations were within the suggested therapeutic range. Surgery resulted in a 2 h delay in the mean time to peak concentration, significant decreases in serum ibuprofen concentration following both doses, and a fall to sub-optimal serum concentrations following the 200 mg dose. During the first 2 h after the 200 mg dose, dental extraction resulted in a significant reduction of the area under serum drug concentration (AUC (0, 2 h) mg l−1 h) from 5.6±2.9 to 1.6±1.8 (P<0.01) and from 5.5±3.0 to 2.1±2.0 (P<0.05) for S and R-ibuprofen, respectively. Similar observations were made following the 600 mg dose for AUC (0, 2 h) of S-ibuprofen (from 14.2±6.1 to 7.2±5.5 mg l−1 h, P<0.05) with no significant difference for R-ibuprofen (from 14.4±9.5 to 5.8±7.1). AUC (0, 6 h) was also significantly reduced by surgery. The pattern of stereoselectivity in serum ibuprofen concentration was reversed by surgery such that the S enantiomer was predominant in the control phase but not in the post-surgery phase, which is suggestive of reduced metabolic chiral inversion.
Surgery for wisdom tooth removal resulted in substantial decreases in the serum concentration of ibuprofen enantiomers and a prolongation in the time to peak concentration. Reduced absorption and altered metabolism are the likely cause of these changes. Thus, dental patients may experience a delayed response and possible treatment failure when taking ibuprofen for pain relief after surgery. Our observation may have implications for the treatment of other diseases.
PMCID: PMC2014238  PMID: 10233203
pain relief; dental surgery; onset of analgesia; ibuprofen enantiomers; chiral inversion
3.  The Analgesic Efficacy of Preoperative Oral Ibuprofen and Acetaminophen in Children Undergoing Adenotonsillectomy: A Randomized Clinical Trial 
Adenotonsillectomy is one of the most common surgical procedures in children. Several complications and morbidities are common after nasal surgeries and the most common is pain. Several techniques have been employed to reduce the severity of postoperative pain. One of the preoperative techniques is pre-emptive analgesia through preventive central hypersensitization. This technique is performed by applying analgesic methods before the onset of nociceptive stimuli, consequently decreasing postoperative analgesics requirements.
Preoperative oral drug administration for pain analgesia is performed in several methods. The aim of this study was to compare the analgesic effects of preoperatively administration of oral acetaminophen and ibuprofen.
Patients and Methods:
In a double-blinded, randomized placebo-controlled study, sixty 4-12 years old ASA I or II children scheduled for elective adenotonsillectomy, were assigned to receive either acetaminophen 15 mg/kg, ibuprofen 10 mg/kg or placebo 30 minutes before the operation. Postoperative pain was assessed using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), upon arrival to the post anesthetic care unit (PACU) and ward. Findings were analyzed by SPSS version 17 using variance analysis and Tukey’s test.
The average pain intensities were significantly lower in acetaminophen group based on the CHEOPS in both PACU and ward compared to ibuprofen or placebo groups; but there was no difference in pain intensity between the ibuprofen and placebo groups. Pain intensity in PACU in Acetaminophen group was 7.05 ± 0.64 vs. 8.38 ± 1.20 in placebo group and 8.14 ± 0.85 in ibuprofen group, pain intensity in ward in the acetaminophen group was 6.0.87 ± 0.85in the acetaminophen group, vs. 8.04 ± 1.02 in placebo group, and 7.78 ± 0.78 in ibuprofen group.
This study showed that administration of oral acetaminophen 30 minutes preoperatively, resulted in significantly lower pain intensity in children undergoing adenotonsillectomy in PACU and ward, compared to ibuprofen and placebo.
PMCID: PMC3961035  PMID: 24660156
Acetaminophen; Ibuprofen; Pain, Postoperative
4.  Tramadol and acetaminophen tablets for dental pain. 
Anesthesia Progress  2001;48(3):79-81.
The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 400 mg, or placebo. Active control with ibuprofen was used to determine model sensitivity. Pain relief (scale, 0-4) and pain intensity (scale, 0-3) were reported at 30 minutes after the dose and then hourly for 8 hours. Total pain relief over 8 hours (TOTPAR8) and the sum of pain intensity differences (SPID8) were calculated from the hourly scores. Time to onset of pain relief was determined by the double-stopwatch technique, and patients were advised to wait at least 2 hours before taking supplemental analgesia. Patients assessed overall efficacy (scale, 1-5) upon completion. In all, 1197 patients (age range, 16-46 years) were evaluable for efficacy; treatment groups in each study were similar at baseline. Pain relief was superior to placebo (P < or = .0001) for all treatments. Pain relief provided by tramadol/ APAP was superior to that of tramadol or APAP alone, as shown by mean TOT-PAR8 (12.1 vs 6.7 and 8.6, respectively, P < or = .0001) and SPID8 (4.7 vs 0.9 and 2.7, respectively, P < or = .0001). Estimated onset of pain relief was 17 minutes (95% CI, 15-20 minutes) for tramadol/APAP compared with 51 minutes (95% CI, 40-70 minutes) for tramadol, 18 minutes (95% CI, 16-21 minutes) for APAP, and 34 minutes (95% CI, 28-44 minutes) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (P < .05) for the tramadol/APAP group (302 minutes and 3.0, respectively) than for the tramadol (122 minutes and 2.0) or APAP (183 minutes and 2.7) monotherapy groups. A new combination analgesic, tramadol/APAP, is superior to tramadol or APAP alone with respect to pain relief and duration of action. It is also superior to tramadol alone with respect to time to onset.
PMCID: PMC2007376  PMID: 11724223
5.  Prospective, randomized, open-label, pilot clinical trial comparing the effects of dexamethasone coadministered with diclofenac potassium or acetaminophen and diclofenac potassium monotherapy after third-molar extraction in adults 
Patients who experience pain, swelling, and trismus after third-molar extraction are reported to experience a 3-fold higher rate of adverse effects (AEs) on quality of life compared with those who are asymptomatic after this surgery. Therefore, investigators emphasize the necessity for better control of this triad of sequelae. Steroids can reduce the risk for physiologic processes of inflammation, thereby suppressing the development of inflammation.
The aim of this study was to compare the effects of dexamethasone 8 mg IM and diclofenac potassium (K) 50 mg PO, dexamethasone 8 mg IM and acetaminophen 1000 mg PO, and monotherapy with diclofenac K 50 mg PO on postoperative pain, swelling, and trismus after surgical removal of third molars.
This prospective, randomized, open-label pilot study was conducted at the Department of Oral and Maxillofacial Surgery, Lagos University Teaching Hospital, Lagos, Nigeria. Patients were randomly allocated to 1 of 3 treatment groups: concomitant treatment with dexamethasone 8 mg IM and diclofenac K 50 mg PO or acetaminophen 1000 mg PO, or monotherapy with diclofenac K 50 mg PO. Overall analgesic efficacy of the drug combinations was assessed for 7 days postoperatively using a 4-point categorical pain-intensity rating scale (0 = no pain; 1 = mild pain; 2 = moderate pain; and 3 = severe pain). Facial swelling was measured in 1 dimension on days 1, 2, and 7 after surgery using a tape measure placed from the tip of the tragus, to gonion, to the tip of the contralateral tragus, and trismus was assessed using interincisal mouth-opening ability, measured using a vernier-calibrated caliper on postoperative days 1, 2, and 7. Tolerability was assessed using direct questioning of the patients at follow-up visits.
A total of 150 patients (50 per treatment group) were included in the analysis (76 women, 74 men; mean [SD] age, 26.8 [5.04] years [range, 18–45 years]; 100% Nigerian). The proportion of patients reporting no pain on the pain-intensity rating scale was significantly higher in the group receiving dexamethasone and diclofenac K compared with that in the groups receiving dexamethasone and acetaminophen or diclofenac K monotherapy (44% vs 22% and 24%, respectively; both, P < 0.05). Facial swelling was significantly less with dexamethasone and diclofenac K or dexamethasone and acetaminophen compared with diclofenac K alone (day 1: P = 0.013 and P = 0.011, respectively; day 2: P = 0.002 and P = 0.004, respectively). However, trismus relief was statistically similar between the 3 treatment groups on postoperative days 1 and 2. No AEs or complications were recorded.
In this open-label pilot study, concomitant treatment with dexamethasone and diclofenac K provided significant relief of postsurgical pain and swelling compared with dexamethasone and acetaminophen or monotherapy with diclofenac K after third-molar extraction in these patients.
PMCID: PMC3965982  PMID: 24678099
dexamethasone; diclofenac potassium; acetaminophen; third-molar extraction
6.  Ibuprofen with or without an antiemetic for acute migraine headaches in adults 
Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers do not seek professional help, relying instead on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce symptoms commonly associated with migraine headaches.
To determine efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.
Search methods
We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 22 April 2010.
Selection criteria
We included randomised, double-blind, placebo- or active-controlled studies using self-administered ibuprofen to treat a migraine headache episode, with at least 10 participants per treatment arm.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and number needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment.
Main results
Nine studies (4373 participants, 5223 attacks) compared ibuprofen with placebo or other active comparators; none combined ibuprofen with a self-administered antiemetic. All studies treated attacks with single doses of medication. For ibuprofen 400 mg versus placebo, NNTs for 2-hour pain-free (26% versus 12% with placebo), 2-hour headache relief (57% versus 25%) and 24-hour sustained headache relief (45% versus 19%) were 7.2, 3.2 and 4.0, respectively. For ibuprofen 200 mg versus placebo, NNTs for 2-hour pain-free (20% versus 10%) and 2-hour headache relief (52% versus 37%) were 9.7 and 6.3, respectively. The higher dose was significantly better for 2-hour headache relief than the lower dose. Soluble formulations of ibuprofen 400 mg were better than standard tablets for 1-hour, but not 2-hour headache relief.
Associated symptoms of nausea, vomiting, photophobia and phonophobia and functional disability were reduced within 2 hours, and fewer participants used rescue medication with ibuprofen compared with placebo. Similar numbers of participants experienced adverse events, which were mostly mild and transient.
Ibuprofen 400 mg did not differ from rofecoxib 25 mg for 2-hour headache relief, 24-hour headache relief or use of rescue medication.
Authors’ conclusions
Ibuprofen is an effective treatment for acute migraine headaches, providing pain relief in about half of sufferers, but complete relief from pain and associated symptoms for only a minority. NNTs for all efficacy outcomes were better with 400 mg than 200 mg in comparisons with placebo, and soluble formulations provided more rapid relief. Adverse events were mostly mild and transient, occurring at the same rate as with placebo.
PMCID: PMC4161114  PMID: 20927770
Administration, Oral; Analgesics, Non-Narcotic [* therapeutic use]; Antiemetics [* therapeutic use]; Drug Therapy, Combination [methods]; Ibuprofen [* therapeutic use]; Migraine Disorders [* drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
7.  Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial 
Objective To investigate whether paracetamol (acetaminophen) plus ibuprofen are superior to either drug alone for increasing time without fever and the relief of fever associated discomfort in febrile children managed at home.
Design Individually randomised, blinded, three arm trial.
Setting Primary care and households in England.
Participants Children aged between 6 months and 6 years with axillary temperatures of at least 37.8°C and up to 41.0°C.
Intervention Advice on physical measures to reduce temperature and the provision of, and advice to give, paracetamol plus ibuprofen, paracetamol alone, or ibuprofen alone.
Main outcome measures Primary outcomes were the time without fever (<37.2°C) in the first four hours after the first dose was given and the proportion of children reported as being normal on the discomfort scale at 48 hours. Secondary outcomes were time to first occurrence of normal temperature (fever clearance), time without fever over 24 hours, fever associated symptoms, and adverse effects.
Results On an intention to treat basis, paracetamol plus ibuprofen were superior to paracetamol for less time with fever in the first four hours (adjusted difference 55 minutes, 95% confidence interval 33 to 77; P<0.001) and may have been as good as ibuprofen (16 minutes, −7 to 39; P=0.2). For less time with fever over 24 hours, paracetamol plus ibuprofen were superior to paracetamol (4.4 hours, 2.4 to 6.3; P<0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P=0.008). Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone but no faster than ibuprofen alone (−3 minutes, 18 to −24; P=0.8). No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.
Conclusion Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours.
Trial registration Current Controlled Trials ISRCTN26362730.
PMCID: PMC2528896  PMID: 18765450
8.  The Potential Role of an Extended-Release, Abuse-Deterrent Oxycodone/Acetaminophen Fixed-Dose Combination Product for the Treatment of Acute Pain 
Advances in Therapy  2015;32(6):485-495.
Acute pain, prevalent as part of postoperative and traumatic pain, is often sub-optimally or inadequately treated. Fixed-dose combination analgesic products that combine a reduced amount of opioid with a nonopioid analgesic such as acetaminophen (paracetamol) in a single tablet offer potential pharmacodynamic and/or pharmacokinetic benefits, and may also result in an opioid-sparing effect. A new analgesic product (XARTEMIS™ XR, Mallinckrodt Brand Pharmaceuticals, Dublin, Ireland) combines oxycodone (7.5 mg) with acetaminophen (325 mg) in an immediate-release/extended-release (ER) formulation that is indicated for the treatment of acute pain. The ER formulation of this product provides stable serum drug concentrations that in this case lasts 12 h. Oxycodone/acetaminophen is a drug combination that offers safe and effective pain relief in a variety of acute pain syndromes such as postoperative pain. The combination formulation allows a smaller amount of oxycodone per tablet and the biphasic-layered matrix of the pill for ER may present obstacles to potential abusers. No opioid is totally abuse resistant, but the lower opioid content and tamper-resistant formulation of this product might discourage abuse. Clinicians must still be mindful of the acetaminophen part of this product in the patient’s overall daily intake (in light of acetaminophen hepatotoxicity). The new product appears to provide an important new choice in the armamentarium against acute pain.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-015-0213-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4487354  PMID: 26026272
Acute pain control; Extended-release analgesics; Fixed-dose combination products; Oxycodone/acetaminophen (paracetamol); Postoperative pain; Xartemis® XR
9.  Use of ibuprofen and risk of Parkinson disease 
Neurology  2011;76(10):863-869.
Neuroinflammation may contribute to the pathogenesis of Parkinson disease (PD). Use of nonsteroidal anti-inflammatory drugs (NSAID) in general, and possibly ibuprofen in particular, has been shown to be related to lower PD risk in previous epidemiologic studies.
We prospectively examined whether use of ibuprofen or other NSAIDs is associated with lower PD risk among 136,197 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) free of PD at baseline (1998 for NHS and 2000 for HPFS). NSAIDs use was assessed via questionnaire. Results were combined in a meta-analysis with those of published prospective investigations.
We identified 291 incident PD cases during 6 years of follow-up. Users of ibuprofen had a significantly lower PD risk than nonusers (relative risk [RR], adjusted for age, smoking, caffeine, and other covariates = 0.62; 95% confidence interval [CI] 0.42–0.93; p = 0.02). There was a dose–response relationship between tablets of ibuprofen taken per week and PD risk (p trend = 0.01). In contrast, PD risk was not significantly related to use of aspirin (RR = 0.99; 95% CI 0.78–1.26), other NSAIDs (RR = 1.26; 95% CI 0.86–1.84), or acetaminophen (RR = 0.86; 95% CI 0.62–1.18). Similar results were obtained in the meta-analyses: the pooled RR was 0.73 (95% CI 0.63–0.85; p < 0.0001) for ibuprofen use, whereas use of other types of analgesics was not associated with lower PD risk.
The association between use of ibuprofen and lower PD risks, not shared by other NSAIDs or acetaminophen, suggests ibuprofen should be further investigated as a potential neuroprotective agent against PD.
PMCID: PMC3059148  PMID: 21368281
10.  An evaluation of different ibuprofen preparations in the control of postoperative pain after third molar surgery. 
1. Two separate placebo-controlled studies of parallel design were carried out to evaluate the efficacy of single doses (400 mg) of soluble ibuprofen, ibuprofen liquid in a gelatin capsule and ibuprofen tablets (Nurofen), in patients with postoperative pain after third molar surgery. 2. All ibuprofen preparations provided significant pain relief (P less than 0.05) over a 6 h investigation period. 3. Mean pain scores after ibuprofen tablets and ibuprofen liquid in a gelatin capsule were similar. 4. Soluble ibuprofen 400 mg provided an earlier onset of pain relief (20 min) than ibuprofen tablets (30 min). 5. No unwanted effects were reported in the various ibuprofen treatment groups. 6. The ibuprofen preparations evaluated in this study are effective up to 4 h for controlling postoperative pain after third molar surgery. The soluble form is more efficacious with regard to onset of action.
PMCID: PMC1368416  PMID: 2015175
11.  Efficacy and Safety of a Fixed Combination of Tramadol and Paracetamol (Acetaminophen) as Pain Therapy Within Palliative Medicine 
Materia Socio-Medica  2015;27(1):42-47.
The goal of the research was to determine the efficacy of a fixed combination of tramadol and paracetamol (acetaminophen) in the treatment of pain of patients with the advanced stage of cancer.
Material and methods:
A prospective study was conducted at the Center for Palliative Care, University Clinical Center Tuzla, Bosnia and Herzegovina, from January 1st to December 31st 2013. A total of 353 patients who were treated with a fixed combination of tramadol and acetaminophen (37.5 mg and 325 mg) at the initial dosage 3x1 tablet (112.5 mg tramadol and 975 mg acetaminophen) for pain intensity 4, up to 4x2 tablets (300 mg of tramadol and 2600 mg paracetamol) for pain intensity 7 and 8. If the patient during previous day has two or more pain episodes that required a “rescue dose” of tramadol, increased was the dose of fixed combination tramadol and acetaminophen to a maximum of 8 tablets daily (300 mg of tramadol and 2600 mg paracetamol). Statistical analysis was performed by biomedical software MedCalc for Windows version The difference was considered significant for P<0.05.
The average duration of treatment with a fixed combination tramadol and acetaminophen was 57 days (13-330 days). Already after 24 hours of treatment the average pain score was significantly lower (p<0.0001) compared to the admission day [5.00 (4:00 to 8:00) during the first days versus 2.00 (1:00 to 7:00) during the second day of treatment]. The average dose of the fixed combination tramadol and acetaminophen tablets was 4.8 ± 1.8 (180 mg of tramadol and 1560 mg paracetamol). Side effects, in the treatment of pain with a fixed combination tramadol and acetaminophen, were found in 29.18% of patients, with a predominance of nausea and vomiting.
Fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain, with frequent dose evaluation and mild side effects.
PMCID: PMC4384875  PMID: 25870531
carcinoma pain; fixed combination tramadol and paracetamol; side effects
12.  The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol 
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.
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.
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 μg.mL-1 and 16.81 μg.mL-1, respectively, for ibuprofen from the combination, compared with 0.58 μg.mL-1 and 9.00 μg.mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 μg.mL-1 and 14.54 μg.mL-1, respectively, for the combination compared with 0.33 μg.mL-1 and 9.19 μg.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.
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.
PMCID: PMC2906415  PMID: 20602760
13.  Comparison of the effects of ibuprofen and acetaminophen on PGE2 levels in the GCF during orthodontic tooth movement: a human study 
Progress in Orthodontics  2013;14(1):6.
Pain is among the most cited negative effects of orthodontic treatment. Non-steroidal anti-inflammatory drugs seem to be an effective option for minimizing this but can have adverse effects on tooth movement owing to their ability to block prostaglandin synthesis. Acetaminophen has been suggested as the analgesic of choice during orthodontic treatment as it showed no effect on orthodontic tooth movement in previous animal studies. The purpose of this study was to compare the effects of ibuprofen and acetaminophen on the prostaglandin E2 (PGE2) levels of the gingival crevicular fluid (GCF) during orthodontic tooth movement in human subjects.
A total of 42 patients (mean age 18 ± 4.5 years) were randomly divided into three equal groups: ibuprofen, acetaminophen, and control groups. Maxillary canines were distalized with 150 g of force delivered by NiTi coil springs. GCF samples were obtained before (baseline) and after spring activation at 24, 48, and 168 h. The PGE2 content of the GCF was determined using enzyme-linked immunosorbent assay.
PGE2 levels in all groups increased significantly by 24 and 48 h of force application and decreased to baseline levels by 168 h. No significant difference was found between the acetaminophen and control groups at any time point. There was a significant decrease in PGE2 levels in the ibuprofen group at 24 and 48 h when compared to the other two groups.
Acetaminophen showed no significant effect on prostaglandin synthesis and may be the safe choice compared to ibuprofen for relieving pain associated with orthodontic tooth movement.
PMCID: PMC3847847  PMID: 24325834
14.  Efficacy of Standard Doses of Ibuprofen Alone, Alternating, and Combined With Acetaminophen for the Treatment of Febrile Children 
Clinical therapeutics  2010;32(14):2433-2440.
Many pediatricians recommend, and many parents administer, alternating or combined doses of ibuprofen and acetaminophen for fever. Limited data support this practice with standard US doses.
This study compared the antipyretic effect of 3 different treatment regimens in children, using either ibuprofen alone, ibuprofen combined with acetaminophen, or ibuprofen followed by acetaminophen over a single 6-hour observation period.
Febrile episodes from children aged 6 to 84 months were randomized into the 3 treatment groups: a single dose of ibuprofen at the beginning of the observation period; a single dose of ibuprofen plus a single dose of acetaminophen at the beginning of the observation period; or ibuprofen followed by acetaminophen 3 hours later. Ibuprofen was administered at 10 mg/kg; acetaminophen at 15 mg/kg. Temperatures were measured hourly for 6 hours using a temporal artery thermometer. The primary outcome was temperature difference between treatment groups. Adverse-event data were not collected in this single treatment period study.
Sixty febrile episodes in 46 children were assessed. The mean (SD) age of the children was 3.4 (2.2) years, and 31 (51.7%) were girls. Differences among temperature curves were significant (P < 0.001; the combined and alternating arms had significantly better antipyresis compared with the ibuprofen-alone group at hours 4 to 6 (hour 4, P < 0.005; hours 5 and 6, P < 0.001). All but one of the children in the combined and alternating groups were afebrile at hours 4, 5, and 6. In contrast, for those receiving ibuprofen alone, 30%, 40%, and 50% had temperatures >38.0°C at hours 4, 5, and 6, respectively (hour 4, P < 0.002; hours 5 and 6, P < 0.001).
During a single 6-hour observation period for these participating children, combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than ibuprofen alone at 4 to 6 hours.
PMCID: PMC3614072  PMID: 21353111
fever; antipyretic; acetaminophen; ibuprofen
15.  Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(−)-Ibuprofen 
Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (Cmax) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean Cmax was 116% of the control value (P < 0.05). The mean t1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.
PMCID: PMC1479148  PMID: 16723553
16.  DUEXIS® (ibuprofen 800 mg, famotidine 26.6 mg): a new approach to gastroprotection for patients with chronic pain and inflammation who require treatment with a nonsteroidal anti-inflammatory drug 
Chronic pain conditions affect at least 116 million US adults and more than one-third of adults worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively for the treatment of chronic pain due to their efficacy as anti-inflammatory and analgesic agents. Gastrointestinal toxicity is the most well known adverse effect of NSAID therapy and it may manifest as dyspepsia, ulcers, or bleeding. Current guidelines for the management of patients who require NSAIDs for chronic pain and inflammation recognize the potential toxicity associated with these drugs and the need for gastroprotection. DUEXIS® (ibuprofen 800 mg, famotidine 26.6 mg) is a proprietary combination, immediate release tablet containing 800 mg of ibuprofen and 26.6 mg of famotidine. The efficacy of DUEXIS® taken three times daily has been demonstrated in two large-scale controlled clinical trials (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies (REDUCE) and REDUCE-2) which showed that this new formulation significantly reduced the risk of endoscopic upper gastrointestinal ulcers compared with ibuprofen alone (REDUCE-1, p < 0.0001, REDUCE-2, p <0.05). DUEXIS® was also superior to ibuprofen in decreasing the risk for gastric ulcers (REDUCE-1, p < 0.001, REDUCE-2, p < 0.05) as well as duodenal ulcers (REDUCE-1, p < 0.05, REDUCE-2, p < 0.05). Safety results from these two studies indicated that treatment-emergent adverse events occurred in 55% of patients treated with DUEXIS® versus 58.7% for ibuprofen, and serious adverse events were recorded for 3.2% of patients treated with DUEXIS® versus 3.3% of those on ibuprofen. Adverse events leading to discontinuation occurred in 6.7% of patients treated with DUEXIS® and 7.6% for ibuprofen. The combination of ibuprofen and famotidine in a single tablet has the potential to improve adherence to gastroprotective therapy in patients who require NSAID treatment and the use of a histamine type 2 receptor antagonist rather than a proton-pump inhibitor may decrease the risk for clinically significant drug interactions and adverse events (e.g. interaction with clopidogrel, fracture, pneumonia, Clostridium difficile infection).
PMCID: PMC3458616  PMID: 23024710
chronic pain; famotidine; gastrointestinal; ibuprofen; proton-pump inhibitor; ulcer
17.  Double-Blind Randomized Trials of Single-Tablet Ibuprofen/High-Dose Famotidine vs. Ibuprofen Alone for Reduction of Gastric and Duodenal Ulcers 
We performed two 24-week double-blind trials (REDUCE-1 and -2 (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies)) to assess whether double-dose famotidine given in a single-tablet combination with ibuprofen (HZT-501) significantly reduces gastric and duodenal ulcers as compared with ibuprofen.
Patients (40–80 years) requiring daily non-steroidal anti-inflammatory drugs (NSAIDs) for ≥6 months with no prior ulcer complications, negative H. pylori stool test, and baseline endoscopy showing no ulcers and <5 erosions were randomly assigned in a 2:1 ratio to HZT-501 or identical-appearing ibuprofen 800 mg tablets thrice daily. Study endoscopies were done at 8, 16, and 24 weeks. After unblinding and initial analyses, 12 patients were found to be misclassified as having gastric ulcers based on the adjudication of endoscopy reports, and analyses were re-run.
In REDUCE-1, the primary end point analysis of gastric ulcers at 24 weeks with HZT-501 vs. ibuprofen was 12.7% vs. 22.9% (P=0.0044) in the post-adjudication analysis. In REDUCE-2, the primary end point analysis of upper gastrointestinal (GI) ulcers was 13.0% vs. 20.5% (P=0.0587) in the post-adjudication analysis. Prespecified pooled analyses showed significantly fewer gastric (12.5% vs. 20.7%) and duodenal ulcers (1.1% vs. 5.1%) with HZT-501 vs. ibuprofen. Proportional hazards analysis of multiple potential risk factors showed the risk ratio of upper GI ulcers with HZT-501 vs. ibuprofen was 0.46, 95% confidence interval was 0.34–0.61.
Combined results of the REDUCE studies indicate that double-dose famotidine plus ibuprofen, given as a combination tablet, decreases endoscopic upper GI ulcers as compared with ibuprofen alone.
PMCID: PMC3321505  PMID: 22186979
18.  Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery 
Paediatric anaesthesia  2010;20(11):1028-1035.
The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen.
To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T).
Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe.
A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 mg·kg−1 rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 mcg·kg−1 of intranasal fentanyl, and group 3 received acetaminophen and 1 mg·kg−1 of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined.
There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported.
We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups.
PMCID: PMC4005868  PMID: 20964769
ear tube surgery; children; postoperative analgesia; emergence agitation; intranasal fentanyl; intramuscular ketorolac
19.  Mechanism of Action of N-Acetylcysteine in the Protection Against the Hepatotoxicity of Acetaminophen in Rats In Vivo 
Journal of Clinical Investigation  1983;71(4):980-991.
N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as reduction of the quinoneimine might be responsible for the clinical efficacy of N-acetylcysteine. After the administration to rats of acetaminophen (1 g/kg) intraduodenally (i.d.) and of [35S]-N-acetylcysteine (1.2 g/kg i.d.), the specific activity of the N-acetylcysteine adduct of acetaminophen (mercapturic acid) isolated from urine and assayed by high pressure liquid chromatography averaged 76±6% of the specific activity of the glutathione-acetaminophen adduct excreted in bile, indicating that virtually all N-acetylcysteine-acetaminophen originated from the metabolism of the glutathione-acetaminophen adduct rather than from a direct reaction with the toxic metabolite. N-Acetylcysteine promptly reversed the acetaminophen-induced depletion of glutathione by increasing glutathione synthesis from 0.54 to 2.69 μmol/g per h. Exogenous N-acetylcysteine did not increase the formation of the N-acetylcysteine and glutathione adducts of acetaminophen in fed rats. However, when rats were fasted before the administration of acetaminophen, thereby increasing the stress on the glutathione pool, exogenous N-acetylcysteine significantly increased the formation of the acetaminophen-glutathione adduct from 57 to 105 nmol/min per 100 g. Although the excretion of acetaminophen sulfate increased from 85±15 to 211±17 μmol/100 g per 24 h after N-acetylcysteine, kinetic simulations showed that increased sulfation does not significantly decrease formation of the toxic metabolite. Reduction of the benzoquinoneimine by N-acetylcysteine should result in the formation of N-acetylcysteine disulfides and glutathione disulfide via thiol-disulfide exchange. Acetaminophen alone depleted intracellular glutathione, and led to a progressive decrease in the biliary excretion of glutathione and glutathione disulfide. N-Acetylcysteine alone did not affect the biliary excretion of glutathione disulfide. However, when administered after acetaminophen. N-acetylcysteine produced a marked increase in the biliary excretion of glutathione disulfide from 1.2±0.3 nmol/min per 100 g in control animals to 5.7±0.8 nmol/min per 100 g. Animals treated with acetaminophen and N-acetylcysteine excreted 2.7±0.8 nmol/min per 100 g of N-acetylcysteine disulfides (measured by high performance liquid chromatography) compared to 0.4±0.1 nmol/min per 100 g in rats treated with N-acetylcysteine alone. In conclusion, exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of acetaminophen in the rat in vivo but increases glutathione synthesis, thus providing more substrate for the detoxification of the reactive metabolite in the early phase of an acetaminophen intoxication when the critical reaction with vital macromolecules occurs.
PMCID: PMC436956  PMID: 6833497
20.  Prophylactic Use of Oral Acetaminophen or IV Dexamethasone and Combination of them on Prevention Emergence Agitation in Pediatric after Adenotonsillectomy 
The present study was aimed to evaluate the efficacy of acetaminophen plus dexamethasone on post-operative emergence agitation in pediatric adenotonsillectomy.
A total of 128 patients were randomized and assigned among four groups as: Intravenous (IV) dexamethasone, oral acetaminophen, IV dexamethasone plus oral acetaminophen, placebo. Group 1 received 0.2 mg/kg dexamethasone plus 0.25 mg/kg strawberry syrup 2 h before surgery. Group 2 received 20 mg/kg oral acetaminophen (0.25 ml/kg) with 0.05 ml/kg IV normal saline. Group 3 received 20 mg/kg acetaminophen and 0.2 mg/kg dexamethasone intravenously. Group 4 received 0.25 ml/kg strawberry syrup and 0.05 ml/kg normal saline. Agitation was measured according to Richmond agitation sedation score in the post anesthetic care unit (PACU) after admission, 10, 20 and 30 min after extubation. Pain score was measured with FACE scale. Nurse satisfaction was measured with verbal analog scale. If agitation scale was 3 ≥ or pain scale was 4 ≥ meperidine was prescribed. If symptoms did not control wit in 15 min midazolam was prescribed. Patients were discharged from PACU according Modified Alderet Score. Data were analyzed with ANOVA, Chi-square, and Kruskal-Wallis among four groups. P < 0.05 was considered statistically significant.
A total of 140 patients were recruited in the study, which 12 of them were excluded. Thus, 128 patients were randomized and assigned among four groups. The four treatment groups were generally matched at baseline data. Median of pain score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001, 0.003 respectively). Also median of agitation score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001). Incidence of pain and incidence of agitation after extubation were not statistically identical among groups (P < 0.001 and P = 0.002 respectively). Mean of recovery time, duration of agitation and 1st time to agitation appearance, meperidine and midazolam consumption, nurse satisfaction and complication frequency were not statistically identical among groups (P < 0.001).
Acetaminophen, dexamethasone and combination of them are superior to placebo for prevention of agitation after adenotonsillectomy in children. Furthermore combinations of both drugs are superior to acetaminophen or dexamethasone separately.
PMCID: PMC4085924  PMID: 25013691
Acetaminophen; adenotonsillectomy; dexamethasone; postoperative agitation
21.  Comparison of preemptive analgesic effects of a single dose of nonopioid analgesics for pain management after ambulatory surgery: A prospective, randomized, single-blind studyin Turkish patients 
Preemptive analgesia used for postsurgical pain management has been shown to reduce the requirements of postoperative analgesics.
The aim of this study was to compare the preemptive analgesic effects of diflunisal, naproxen sodium, meloxicam, acetaminophen, and rofecoxin (no longer available in some markets) in patients undergoing ambulatory dental surgery and the need for postoperative pain management in these patients.
This prospective, randomized, single-blind study was conducted at the Departments of Anesthesiology and Reanimation and Oral and Maxillofacial Surgery, Baskent University, Adana Teaching and Medical Research Center, Adana, Turkey. Turkish outpatients aged ≥ 16 years with American Society of Anesthesiologists physical status 1 (ie, healthy) and scheduled to undergo surgical extraction of an impacted third molar were enrolled. Patients were randomly assigned to receive diflunisal 500 mg, naproxen sodium 550 mg, meloxicam 7.5 mg, acetaminophen 500 mg, or rofecoxib 12.5 mg. All medications were administered orally 1 hour before surgery as preemptive analgesia and after surgery if needed, up to the maximum recommended dose. Surgery was performed with the patient under local anesthesia (articaine hydrochloride). Pain intensity was assessed using a 100-mm visual analog scale (VAS) (0 = none to 100 = worst possible pain) at 2, 4, 6, and 12 hours after ambulatory surgery. The use of additional analgesics was recorded for 24 hours using patient diaries. Postoperative adverse events were recorded using the diaries.
One hundred fifty patients (108 women, 42 men; mean [SE] age, 26.8 [0.6] years; 30 patients per group) had data available for analysis. Demographic data were similar between the 5 groups. No significant differences in mean VAS scores were found between the 5 groups at any time point. All mean VAS scores indicated minor pain. The rate of additional postoperative analgesics required was significantly lower in the diflunisal group compared with groups receiving naproxen sodium, meloxicam, acetaminophen, and rofecoxib (3 [10%] patients vs 11 [37%], 15 [50%], 15 [50%], and 14 [47%] patients, respectively; all, P < 0.05). Bleeding at the surgical site was reported in 2 patients each in the diflunisal, naproxen sodium, meloxicam, and acetaminophen groups, and in 1 patient in the rofecoxib group; the between-group differences were not significant. No significant differences in the prevalences of other adverse effects (eg, nausea, vomiting, allergy, gastrointestinal symptoms) were found between the 5 treatment groups.
In the present study in patients undergoing third molar extraction, adequate preemptive analgesia, based on VAS scores, was found with all of the nonopioid analgesic agents used. Fewer patients required rescue medication with diflunisal. All 5 study drugs were similarly well tolerated.
PMCID: PMC3966011  PMID: 24678075
preemptive analgesia; ambulatory surgery; NSAIDs
22.  Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies: evidence from Phase I studies in healthy volunteers 
We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs’ efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug’s pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0–t, and AUC0–∞). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5–1 hour – a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone.
PMCID: PMC4018313  PMID: 24851040
coadministration; pharmacokinetic profile; adverse events; ibuprofen; isosorbide dinitrate
23.  Bioavailability of ibuprofen following oral administration of standard ibuprofen, sodium ibuprofen or ibuprofen acid incorporating poloxamer in healthy volunteers 
The aim of this study was to compare the pharmacokinetic properties of sodium ibuprofen and ibuprofen acid incorporating poloxamer with standard ibuprofen acid tablets.
Twenty-two healthy volunteers were enrolled into this randomised, single-dose, 3-way crossover, open-label, single-centre, pharmacokinetic study. After 14 hours' fasting, participants received a single dose of 2 × 200 mg ibuprofen acid tablets (standard ibuprofen), 2 × 256 mg ibuprofen sodium dihydrate tablets (sodium ibuprofen; each equivalent to 200 mg ibuprofen acid) and 2 × 200 mg ibuprofen acid incorporating 60 mg poloxamer 407 (ibuprofen/poloxamer). A washout period of 2-7 days separated consecutive dosing days. On each of the 3 treatment days, blood samples were collected post dose for pharmacokinetic analyses and any adverse events recorded. Plasma concentration of ibuprofen was assessed using a liquid chromatographic-mass spectrometry procedure in negative ion mode. A standard statistical ANOVA model, appropriate for bioequivalence studies, was used and ratios of 90% confidence intervals (CIs) were calculated.
Tmax for sodium ibuprofen was less than half that of standard ibuprofen (median 35 min vs 90 min, respectively; P = 0.0002) and Cmax was significantly higher (41.47 μg/mL vs 31.88 μg/mL; ratio test/reference = 130.06%, 90% CI 118.86-142.32%). Ibuprofen/poloxamer was bioequivalent to the standard ibuprofen formulation, despite its Tmax being on average 20 minutes shorter than standard ibuprofen (median 75 mins vs 90 mins, respectively; P = 0.1913), as the ratio of test/reference = 110.48% (CI 100.96-120.89%), which fell within the 80-125% limit of the CPMP and FDA guidelines for bioequivalence. The overall extent of absorption was similar for the three formulations, which were all well tolerated.
In terms of Tmax, ibuprofen formulated as a sodium salt was absorbed twice as quickly as from standard ibuprofen acid. The addition of poloxamer to ibuprofen acid did not significantly affect absorption.
PMCID: PMC2796637  PMID: 19961574
24.  Direct Protection Against Acetaminophen Hepatotoxicity by Propylthiouracil 
Journal of Clinical Investigation  1981;67(3):688-695.
Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [3H]acetaminophen, liver microsomes from phenobarbital-pretreated rats, and an NADPH-generating system, we found that PTU had a dose-dependent additive effect with GSH on inhibition of acetaminophen covalent binding. PTU administration also resulted in a dose-dependent decrease in both GSH depletion and covalent binding in vivo in acetaminophen-treated mice. To examine the possible mechanisms by which PTU exerts its protective effect, we studied the action of PTU on both acetaminophen conjugation and metabolic activation. PTU had no effect upon acetaminophen pharmacokinetics in phenobarbital-pretreated rats, as examined by measuring acetaminophen concentration in bile, urine, and blood after an intraperitoneal dose, nor did it alter the total amount of polar conjugates formed. Microsomes from PTU-treated rats were unaltered in cytochrome P-450 concentrations and p-nitroanisole-O-demethylase, benzo-α-pyrene hydroxylase, and cytochrome c-reductase activities. Furthermore PTU did not decrease acetaminophen-GSH adduct formation in vitro, suggesting that there was no reduction in drug activation. However, in bile from [35S]PTU and [3H]acetaminophen treated rats, as well as in incubates of the two drugs with liver microsomes, a new 35S- and 3H-containing product could be identified. By both thin layer chromatography and high pressure liquid chromatography this new product, which co-eluted with [3H]acetaminophen, was separated from unreacted [35S]PTU. The formation of this product in vitro was a function of PTU concentration and reached a maximum of 0.06 μmol/min per mg protein at 0.5 mM PTU. In vivo, the total biliary excretion of this product over 4 h (116 nmol) equaled the net reduction in acetaminophen metabolite covalent binding in the liver of phenobarbital-pretreated rats (108 nmol). We conclude that PTU, independent of its antithyroid effect, diminishes hepatic macromolecular covalent binding of acetaminophen reactive metabolite both in vivo and in vitro, and it does so by detoxifying the reactive metabolite through direct chemical interaction in a manner similar to GSH. These observations may define the mechanism by which PTU is protective against liver injury caused by acetaminophen.
PMCID: PMC370618  PMID: 7204554
25.  A Comparative Study of the Effect of Prednisolone and Celecoxib on MMO (Maximum Mouth Opening) and Pain Following Removal of Impacted Mandibular Third Molars 
The purpose of this study was to compare the effects of prednisolone and celecoxib on pain and maximum mouth opening (MMO) after surgical removal of mandibular third molars.
Methods and Materials
This double-blind clinical study was conducted upon 60 subjects. These patients received 4 tablets of either 100 mg celecocxib or 5 mg prednisolone: one tablet before surgery and the rest for every 8 h post-operation. The subjects were asked to take acetaminophen codeine as rescue dose. Interincisal distance of upper and lower central teeth and pain measurements (according to Visual Analogue Scale) were taken before surgery, 24 h, 48 h and 7 days after surgery.
Average pain intensity in 24 h after surgery in patients receiving celecoxib was 3.6 ± 2.5 with significant difference to the other group (p = 0.041), but in subsequent evaluations prednisolone group reported less pain intensity, but the differences were not significant. MMO in 48 h after surgery was lower in prednisolone group (p = 0.640) and in further evaluations the groups were almost similar. Analyzing the data revealed no significant difference between groups in MMO.
According to this study there is no significant difference in the effects of prednisolone or celecoxib upon MMO, while celecoxib had better results for pain relief in 24 h after surgery in comparison to prednisolone.
PMCID: PMC3682002  PMID: 24431837
Celecoxib; Prednisolone; Pain; Maximum mouth opening; Third molar surgery

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