Co-administration Of Ibuprofen Research Articles

Damage-associated molecular patterns as a mechanism of sevoflurane-induced neuroinflammation in neonatal rodents.

General anesthesia is inevitable for pediatric patients undergoing surgery, though volatile anesthetic agents may cause neuroinflammation and neurodevelopmental impairment; however, the underlying pathophysiology remains unclear. We aimed to investigate the neuroinflammation mechanism in developing rat brains associated with sevoflurane exposure time, by identifying the specific damage-associated molecular patterns (DAMPs) pathway and evaluating the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in alleviating neuroinflammation. A three-step experiment was conducted to investigate neuroinflammation induced by sevoflurane. First, the exposure time required for sevoflurane to cause neuroinflammation was determined. Next, the specific pathways of DAMPs involved in neuroinflammation by sevoflurane were identified. Finally, the effects of NSAIDs on sevoflurane-induced neuroinflammation were investigated. The expression of various molecules in the rat brain were assessed using immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, western blot analysis, and enzyme-linked immunosorbent assay. In total, 112 rats (aged 7 days) were used, of which six rats expired during the experiment (mortality rate, 5.3%). Expression of CD68, HMGB-1, galectin-3, TLR4, TLR9, and phosphorylated NF-κB was significantly increased upon 6 h of sevoflurane exposure. Conversely, transcriptional levels of TNF-α and IL-6 significantly increased and IFN-γ significantly decreased after 6 h of sevoflurane exposure. Co-administration of NSAIDs with sevoflurane anesthesia significantly attenuated TNF-α and IL-6 levels and restored IFN-γ levels. In conclusion, 6 h of sevoflurane exposure induces neuroinflammation through the DAMPs pathway, HMGB-1, and galectin-3. Co-administration of ibuprofen reduced sevoflurane-induced neuroinflammation.

Coadministration of ibuprofen/caffeine on bleaching-induced tooth sensitivity: A randomized clinical trial

This clinical trial evaluated the effect of the coadministration of ibuprofen/caffeine on bleaching-induced tooth sensitivity (TS). A triple-blind, parallel-design, randomized clinical trial was conducted on 84 patients who received ibuprofen/caffeine or placebo capsules. The drugs were administered for 48 hours, starting 1 hour before the in-office bleaching. Two bleaching sessions were performed with 35% hydrogen peroxide gel with 1-week interval. TS was recorded up to 48 hours after dental bleaching with a 0-10 visual analogic scale (VAS) and a 5-point numeric rating scale (NRS). The color was evaluated with VITA Classical and VITA Bleachedguide scales (ΔSGU) and VITA Easyshade spectrophotometer (ΔE*ab and ΔE00). The absolute risk of TS in both groups was evaluated using Fischer's exact test. Comparisons of the TS intensity (NRS and VAS data) were performed by using the Mann-Whitney test and a two-way repeated measures ANOVA, respectively. The color alteration between the groups was compared with the Student's t test. The significance level was 5%. There was no statistically significant difference between the groups for the absolute risk of TS (p = 1.00) or for the intensity of TS (p > 0.05). A bleaching of approximately 7 shade guide units was observed on the Vita Classical and Vita Bleachedguide scales, with no statistical difference between the groups. It was concluded that coadministration of ibuprofen and caffeine did not reduce the absolute risk or intensity of TS and did not interfere with the efficacy of dental bleaching.

Longer-Term Omega-3 LCPUFA More Effective Adjunct Therapy for Tuberculosis Than Ibuprofen in a C3HeB/FeJ Tuberculosis Mouse Model.

Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group (p = 0.039), but was higher in the ibuprofen group than the treated control group (p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p= 0.0114 and p= 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT (p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course.

Co-Administered Low Doses Of Ibuprofen And Dexamethasone Produce Synergistic Antinociceptive Effects On Neuropathic Mechanical Allodynia In Rats.

BackgroundThe traditional analgesics used to treat neuropathic pain such as anticonvulsants, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs) lack efficacy and/or carry unpleasant side effects. The present study aimed to investigate the synergistic antinociceptive effects of co-administered low doses of ibuprofen and dexamethasone in rats with trigeminal neuropathic pain.Materials and methodsA Sprague-Dawley rat model for trigeminal neuropathic pain was produced using mal-positioned dental implants. The left mandibular second molar was extracted under anesthesia and replaced with a miniature dental implant to induce injury to the inferior alveolar nerve.ResultsMonotherapy with intraperitoneal injection of high-dose ibuprofen (30 mg/kg) or dexamethasone (10 mg/kg) but not low-dose ibuprofen (1, 5, 10 mg/kg) or dexamethasone (0.01, 1 mg/kg) attenuated the neuropathic mechanical allodynia in the rats with inferior alveolar nerve injury. We examined the synergistic antinociceptive effects of co-administered ibuprofen (5 mg/kg) and dexamethasone (0.01, 0.1, 1 mg/kg). The early co-administration of ibuprofen (5 mg/kg) with dexamethasone (0.1, 1 mg/kg) on postoperative days (POD) 1–3 significantly inhibited mechanical allodynia before the pain had been established. We also observed the synergistic antinociceptive effects of the same doses the combined treatment on mechanical allodynia on POD 7–9, when the pain had already been established. The attenuation of c-fos immuno-positive cells in the ipsilateral trigeminal subnucleus caudalis after the intraperitoneal co-administration of ibuprofen (5 mg/kg) with dexamethasone (1 mg/kg) confirmed these synergistic antinociceptive effects. Moreover, the magnitude of the effects of this co-administration was comparable with that of gabapentin both before and after the pain had been established.ConclusionThese results suggest that a combination of ibuprofen and dexamethasone at low doses is an alternative therapeutic strategy for neuropathic pain and provide a rationale for the use of such drug combinations in patients who are unable to tolerate high-dose monotherapy.

Combined Biological Effects of N-Bromotaurine Analogs and Ibuprofen. Part II: Influence on a Local Defense System.

The stable N-bromotaurine analogs (N-dibromo-dimethyl taurine, N-monobromo-dimethyl taurine), and bromamine T (BAT) show anti-inflammatory and microbicidal properties. These bromamines are good candidates for a treatment of skin infectious/inflammatory diseases as local antiseptics. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is commonly used in various infectious/inflammatory diseases due to its analgesic and antipyretic therapeutic effects. However, systemic administration of ibuprofen may also result in adverse side effects. It has been reported that ibuprofen enhances serum levels of TNF-α and worsens secondary skin infections caused by invasive streptococci (S. pyogenes). Recently we have demonstrated that bromamines inhibit the stimulatory effect of ibuprofen on the production of inflammatory cytokines (TNF-α, IL-6). The aim of this study was to examine the combined antibacterial actions of ibuprofen and bromamines against S. pyogenes and their joint effect on the generation of reactive oxygen species (ROS) by activated neutrophils and macrophages. We have shown that the microbicidal activity of bromamines against S. pyogenes was not altered by ibuprofen. On the other hand, co-administration of ibuprofen and bromamines markedly decreased the generation of ROS by activated neutrophils and macrophages. Finally, we discuss how the antioxidant combined effect of bromamines and ibuprofen may affect a local defense system.

Influence of nonsteroidal anti-inflammatory drugs on aspirin\u2019s antiplatelet effects and suggestion of the most suitable time for administration of both agents without resulting in interaction

BackgroundLow-dose aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1) and suppresses platelet aggregation. It is effective for secondary prevention of cardiovascular events. Because nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly bind with COX-1, the antiplatelet effects of aspirin may be suppressed when NSAIDs are co-administered. This interaction could be avoided by avoiding simultaneous administration; however, the minimum interval that should separate the administration of aspirin and loxoprofen is not well known. In this study, we investigated how to avoid the influence of NSAIDs on the antiplatelet effects of aspirin. An in vitro experiment was performed to investigate the influence of ibuprofen and loxoprofen at various concentrations on aspirin’s antiplatelet action.MethodsPlatelet aggregation and thromboxane B2 (TXB2) levels were measured after addition of aspirin only and NSAIDs plus aspirin to platelet-rich plasma. NSAIDs were used at their maximum plasma concentrations, the assumed concentration after 6 h (for loxoprofen only), and the assumed concentration after 12 h of taking one clinical dose. Platelet aggregation threshold index (PATI), defined as the putative stimulus concentration giving 50% aggregation, was calculated as an index of aggregation activity.ResultsPATI decreased in ibuprofen plus aspirin group compared to that in the aspirin only group, regardless of ibuprofen concentration. Furthermore, PATI significantly decreased when aspirin was added after loxoprofen-trans-OH addition at the maximum concentration (4.1 ± 0.1 μg/mL), compared to that in aspirin only group (5.9 ± 0.1 μg/mL). PATI showed no significant difference after addition of loxoprofen at the assumed concentration after 6 h (aspirin only group, 5.0 ± 0.5 μg/mL; loxoprofen-trans-OH plus aspirin group, 4.9 ± 0.4 μg/mL).In addition, TXB2 concentration tended to decrease with increasing PATI.ConclusionsIt is desirable to avoid ibuprofen co-administration with the usual once-daily low-dose aspirin therapy; however, a 6-h interval between loxoprofen and aspirin could avoid this potential interaction when loxoprofen is taken before aspirin.

Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice.

Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.

Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences.

Evaluation of pharmacokinetic and pharmacodynamic interactions of sodium oxybate with ibuprofen: A randomized, double-blind, placebo-controlled, crossover study

Sodium oxybate (SXB) is the sodium salt of gamma hydroxybutyrate (GHB), a substrate for the monocarboxylate transporter (MCT) that may be inhibited by nonsteroidal anti-inflammatory drugs. This study evaluated potential drug–drug interactions of SXB and ibuprofen with regard to pharmacokinetics (PK), pharmacodynamics (PD), and safety. Healthy volunteers were randomized to SXB + ibuprofen placebo, SXB + ibuprofen, or SXB placebo + ibuprofen in a three-period, double-blind, crossover design with a 2-day washout between periods. Ibuprofen/placebo (4x200mg capsules) was given qid every 4 h on days 1 and 2, and 1 h before and 3 h after the first SXB dose on day 3; SXB/placebo was given as two 3 g doses 4 h apart on day 3. Blood and urine samples were taken at predefined times for noncompartmental PK analysis. PD testing, performed during each treatment period, included the Karolinska Sleepiness Scale (KSS), and a selection of automated tests from CDR System (www.bracketglobal.com) including the Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Tracking, and Numeric Working Memory tasks. Safety was assessed at specified time points, and throughout the study. 21 subjects enrolled and completed the study (95% male; 57% white; mean age 34.4 ± 8.4 years). Although mean plasma SXB concentrations were approximately 5% lower with ibuprofen co-administration ( P < 0.05), the 90% CIs of the geometric LS means for SXB PK parameters with and without ibuprofen were within the 80–125% equivalence range. Urinary excretion of SXB increased ∼2-fold with ibuprofen (mean renal clearance = 874.2 mL/h for SXB + ibuprofen and 463.6 mL/h for SXB alone; P < 0.0001), and the percent mean ratio of the geometric LS means was 194% (90% CI 172%, 219%) exceeding the equivalence range. Cognitive function impairments and increased sleepiness were observed with SXB with and without ibuprofen, but no PD interactions were observed. The most common adverse events (AEs) were consistent with the drug profiles. AEs in ⩾2 subjects with SXB + ibuprofen were somnolence ( n = 15), euphoric mood ( n = 10), dizziness ( n = 5), headache ( n = 3), and nausea ( n = 2), and reflect a combined effect of both drugs. Although renal excretion of SXB increased, likely as a result of MCT inhibition by ibuprofen, plasma PK ratios were within the equivalence range, suggesting the interaction was not clinically significant. No PD interactions were observed, and AEs were consistent with the drug profiles. This study was sponsored by Jazz Pharmaceuticals, Inc.

Ibuprofen plus isosorbide dinitrate treatment in the mdx mice ameliorates dystrophic heart structure

Background: Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. Aims: To evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice. Methods: Three groups of mice were studied: mdx mice treated with IBU (50mgkg−1)+ISDN (30mgkg−1) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged-matched mice. Animals were analysed after 10–11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area. Results: Treatment for 10–11 months with IBU+ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice. Conclusions: Treatment for 10–11 months with IBU+ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation.

Maturation of the Glomerular Filtration Rate in Neonates, as Reflected by Amikacin Clearance

During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin. Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally. Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived. Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates.

Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans.

Current therapies for muscular dystrophy are based on corticosteroids. Significant side effects associated with these therapies have prompted several studies aimed at identifying possible alternative strategies. As inflammation and defects of nitric oxide (NO) generation are key pathogenic events in muscular dystrophies, we have studied the effects of combining the NO donor isosorbide dinitrate (ISDN) and the non-steroidal anti-inflammatory drug ibuprofen. alpha-Sarcoglycan-null mice were treated for up to 8 months with ISDN (30 mg.kg(-1)) plus ibuprofen (50 mg.kg(-1)) administered daily in the diet. Effects of ISDN and ibuprofen alone were assessed in parallel. Drug effects on animal motility and muscle function, muscle damage, inflammatory infiltrates and cytokine levels, as well as muscle regeneration including assessment of endogenous stem cell pool, were measured at selected time points. Combination of ibuprofen and ISDN stimulated regeneration capacity, of myogenic precursor cells, reduced muscle necrotic damage and inflammation. Muscle function in terms of free voluntary movement and resistance to exercise was maintained throughout the time window analysed. The effects of ISDN and ibuprofen administered separately were transient and significantly lower than those induced by their combination. Co-administration of NO and ibuprofen provided synergistic beneficial effects in a mouse model of muscular dystrophy, leading to an effective therapy. Our results open the possibility of immediate clinical testing of a combination of ISDN and ibuprofen in dystrophic patients, as both components are approved for use in humans, with a good safety profile.

The impact of ibuprofen or indomethacin on renal drug clearance in neonates

Introduction. Administration of ibuprofen or indomethacin in neonates is associated with a reduction of glomerular filtration, reflected in a reduction in the elimination of drugs dependent on renal function for clearance. However, the magnitude of these effects and potential differences between ibuprofen or indomethacin remain unclear.Methods. Observations collected in two population pharmacokinetic studies in preterm neonates investigating amikacin and vancomycin disposition were used to estimate (i) the impact of ibuprofen administration and (ii) the difference between ibuprofen and indomethacin on renal drug clearance.Results. Amikacin clearance was reduced by 21% and vancomcyin was reduced by 18% during co-administration of ibuprofen. In a vancomycin pooled pharmacokinetic study, it was documented that the impact of indomethacin was significantly higher compared to ibuprofen (46 and 28%, respectively).Conclusions. Both ibuprofen and indomethacin have a quantifiable impact on renal drug clearance. Compared to ibuprofen, the impact of indomethacin is more pronounced. Population modelling with covariate analysis can be a tool to disentangle the impact of various covariates, including ibuprofen or indomethacin, on renal drug clearance.

Rationale for ibuprofen co-administration with antacids: Potential interaction mechanisms affecting drug absorption

Ibuprofen is a widely used NSAID which is often co-administered with antacids because of its gastro-irritant effects. Literature data suggest that antacid interactions may increase or decrease the drug’s absorption rate and onset of action and that the interaction may be formulation specific. In the present study, literature data on ibuprofen absorption were evaluated in order to gain insight into the nature of the in vivo effect. Solubility determinations in reactive media containing magnesium or aluminium and dissolution studies in the presence of antacid suspension were performed in an attempt to simulate in vitro the effects observed in vivo. The results obtained indicate that magnesium hydroxide enhances ibuprofen solubility, dissolution and bioavailability, while aluminium hydroxide has a retarding effect. Solubility studies indicated formation of a soluble solid ibuprofen phase in the presence of Mg 2+, in contrast, an insoluble ibuprofen salt was formed with Al 3+. The introduction of magnesium based antacid suspension into the dissolution media resulted in a formulation specific increase in drug dissolution rate with the most pronounced effect observed for the slowest release tablet formulation. The results obtained indicate the potential for in vitro studies to predict physicochemical interactions that are likely to influence drug absorption rate in vivo.

Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats

It has been observed that caffeine improves antinociceptive efficacy of some non-steroidal antiinflammatory drugs (NSAIDs) in several experimental models, however, these effects have been questioned in humans. Controversy in clinical studies may be due to the use of different protocols as well as to high interindividual variability in patient response. In addition, the antinociceptive interaction of ibuprofen + caffeine has not been studied. To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ibuprofen, and caffeine administered either separately or in combinations were determined in a model of arthritic pain: “Pain-induced functional impairment in the rat (PIFIR model). The antinociceptive efficacies were evaluated using several dose–response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine or acetylsalicylic acid alone. The animals were administered with 0.05 ml intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received either acetylsalicylic acid, morphine, ibuprofen or caffeine, or a combination ibuprofen + caffeine (18 combinations). We report here that caffeine (17.8 and 31.6 mg/kg) is able to potentiate the antinociceptive effect of ibuprofen. This investigation showed that six combinations presented effects of potentiation and twelve combinations only showed antinociceptive effects not different from that of ibuprofen alone. The maximum antinociceptive effect was 270.7 ± 12.7 area units (au), produced by ibuprofen 100 mg/kg + caffeine 17.8 mg/kg; this effect was greater than the maximum produced by morphine 17.8 mg/kg (244.7 ± 22.9 au) in these experimental conditions. The maximum potentiation was 197 % produced with the combination of ibuprofen 17.8 mg/kg + caffeine 17.8 mg/kg. These results suggest that the antinociceptive effect of ibuprofen was significantly potentiated by doses of caffeine that by themselves are ineffective in this model.

Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients. In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) > or =60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m(2)) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B(12). Aspirin (325 mg) or ibuprofen (400 mg; 2 x 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1 and 2. Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in V(ss) compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration. Pemetrexed (500 mg/m(2)) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl > or =60 mL/min) or ibuprofen (in patients with CrCl > or =80 mL/min).

Impact of ibuprofen administration on renal drug clearance in the first weeks of life

The administration of ibuprofen or any other nonselective cyclooxygenase (COX) inhibitor drug in early neonatal life is associated with a reduction of glomerular filtration, which reduces the elimination of drugs dependent on renal function for clearance. However, the relationship between COX inhibitor drug indication (prophylactic or therapeutic) and the magnitude of this effect remains unclear. Observations collected in two population pharmacokinetic studies, in preterm neonates, investigating amikacin and vancomycin were used to estimate: i) the impact of ibuprofen administration on the clearance of these drugs; and ii) the difference between prophylactic and therapeutic administration of ibuprofen on this clearance. Prophylactic administration of ibuprofen to preterm neonates on the first day of life to enhance closure of an asymptomatic patent ductus arteriosus (PDA) reduced amikacin clearance by 21% while coadministration of ibuprofen to induce closure of a symptomatic PDA resulted in an 18% reduction in vancomycin clearance in the first month of postnatal life. A significant and clinically relevant reduction in drug clearance is observed when ibuprofen is coadministered independent of indication, postmenstrual or postnatal age. Population modeling with covariate analyses can provide us with the tools to further disentangle the impact of nonselective COX-inhibitors on renal drug clearance.

Alterations in cefalosporin levels in the serum and mandible of hyperlipaedemic rats after co-administration of ibuprofen

Several interactions between antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) have been described in the literature, and it has been reported that hyperlipidaemia induces significant changes in cefalosporin levels. The aim of this study was to determine the changes in the levels of several cefalosporins in the serum and mandible after ibuprofen co-administration in hyperlipaedemic rats. One hundred and forty male Wistar rats were used and divided in 4 groups (A-D), each of which was further divided into 5 subgroups (1-5), either with placebo or with various treatment regimes. The co-administration of NSAIDs led to increased cefalosporin levels in both control and hyperlipidaemic animals. Hyperlipidaemia was also found to augment cefalosporin levels. These observed increases might be due to the displacement of the cephalosporins from their binding sites in serum albumin and tissue proteins in the presence of ibuprofen. NSAIDs showed a greater binding affinity for tissue proteins compared to the cephalosporins, and probably play an antagonistic role in protein binding, resulting in higher concentrations of antibiotics.

Combined Treatment Potentiates the Developmental Toxicity of Ibuprofen and Acetazolamide in Rats

Aspirin (ASA), an irreversible cyclooxygenase (COX) inhibitor, induces ventricular septal defect (VSD) and diaphragmatic hernia (DH) in rat fetuses when administered on gestation days (GDs) 9–10, a critical period for cardiovascular (CV) and midline development. Evaluation of a spectrum of nonsteroidal antiinflammatory drugs (NSAIDs; reversible COX inhibitors) showed that while some NSAIDs induced VSD in rats, none of the NSAIDs evaluated produced DH. In addition to inhibiting COX, ASA also inhibits carbonic anhydrase. The purpose of this study was to determine whether concurrent inhibition of COX and carbonic anhydrase would produce a teratogenic profile that includes both VSD and DH. To inhibit both COX and carbonic anhydrase, ibuprofen (COX inhibitor) and acetazolamide (carbonic anhydrase inhibitor) were coadministered on GDs 9–10. Groups of 20 female Crl:CD(SD)IGS BR rats were given either 300 mg kg− 1 day− 1 ibuprofen, 1000 mg kg− 1 day− 1 acetazolamide, or both (combination of ibuprofen and acetazolamide). Fetuses were evaluated on GD 21 for external and visceral development. Ibuprofen induced VSD in 3.7% of fetuses per litter; no defects in appendicular skeletal development were noted. Acetazolamide induced VSD in 5.9% of the fetuses per litter and appendicular defects in 41% of the fetuses per litter. Coadministration of ibuprofen and acetazolamide produced VSD in 18.7% of the fetuses per litter and appendicular defects in 77% of the fetuses per litter; however, there were no DH. Therefore, while concurrent inhibition of COX and carbonic anhydrase did not produce DH, potentiation was noted for the induction of VSD and appendicular anomalies.

Effect of misoprostol on ibuprofen-induced renal dysfunction in patients with decompensated cirrhosis: results of a double-blind placebo-controlled parallel group study

OBJECTIVES: Patients with cirrhosis are prone to develop renal failure upon administration of nonsteroidal anti-inflammatory drugs. The aim of the present study was to determine the safety and efficacy of misoprostol (400 μg) in two repeated doses for the prevention of ibuprofen-induced decrements in renal function in decompensated cirrhotics. METHODS: Patients were given ibuprofen (800 mg) with either misoprostol (n = 9) or a placebo (n = 10). Sixty minutes later another dose of misoprostol or the placebo was administered. Renal function tests were assessed by clearance techniques. RESULTS: Administration of ibuprofen with a placebo caused significant decreases in urinary output, inulin clearance, sodium excretion, osmolar clearance, free water clearance, and urinary prostaglandin E 2 excretion. Coadministration of ibuprofen and the first misoprostol dose maintained urinary output and sodium excretion, and caused an increase in free water clearance. These changes were maintained only for 1 h. Administration of the second dose of misoprostol temporarily improved inulin and creatinine clearances. Half the patients who received misoprostol suffered from episodes of chills, fever, and diarrhea. CONCLUSION: Ibuprofen causes renal dysfunction in decompensated cirrhotics, whereas misoprostol may have some protective renal effects, which are, however, short lived and clinically insignificant. Because of side effects, misoprostol should be used with caution in these patients.