Reversible renal failure associated with ibuprofen: case report and review of the literature

A report of a probable case of acute, reversible renal failure and hyperkalemia, after an increase in dose of ibuprofen, is presented. Other cases of renal dysfunction associated with various nonsteroidal antiinflammatory drugs (NSAIDs) are reviewed. The ability of NSAIDs to inhibit prostaglandin synthesis may explain the various renal consequences. Possible predisposing factors to renal deterioration include the amount of drug consumed, presence of compromised renal blood flow, underlying renal insufficiency, nephrotoxic drug combinations, and high urinary prostaglandin excretion. Generally, the renal failure with NSAIDs is acute and reversible, though analgesic nephropathy with papillary necrosis and chronic renal failure are reported. Electrolytes, blood urea nitrogen, and serum creatinine levels need to be monitored in high-risk patients with predisposing factors and for chronic, long-term use of drugs that inhibit prostaglandin synthesis.     

Rhabdomyolysis and necrotic bowel after acetaminophen and ibuprofen overdose

A 28-year-old man with schizophrenia intentionally ingested a lethal dose of acetaminophen and an unknown quantity of ibuprofen. He arrived at the hospital with acute renal and fulminant liver failure complicated by rhabdomyolysis. His creatine kinase level was 20,306 U/L on admission, which increased to 245,595 U/L by hospital day 2, and subsequently decreased to 339 U/L by day 16. The patient underwent liver transplantation on day 3; necrotic bowel was found during surgery. Rhabdomyolysis associated with acetaminophen overdose has been described only in a few case reports, but rarely in association with acetaminophen taken alone. The literature does not provide a clear association between acetaminophen and rhabdomyolysis because of other possible traumatic and nontraumatic causes. In this case, the Naranjo adverse drug reaction probability scale indicated a probable adverse reaction of rhabdomyolysis associated with acetaminophen overdose. In addition, nonsteroidal antiinflammatory agents (NSAIDs) are well known to be ulcerogenic in the upper gastrointestinal tract, but potential effects on the lower tract are less well known. Only a few NSAID-induced cases of ischemic colitis have been reported. Several mechanisms of action have been proposed, such as direct mucosal damage and inhibition of intestinal prostaglandin production. In this patient, the Naranjo scale indicated a probable adverse reaction of ischemic colitis associated with ibuprofen overdose. Patients who have taken an acetaminophen overdose should be assessed for rhabdomyolysis as a possible complication. In addition, an evaluation of ibuprofen-induced bowel necrosis in these patients may be warranted.     

Concentration of ibuprofen in cervical mucus.

Concentrations of an acidic drug, ibuprofen, in cervical mucus and serum have been measured by HPLC after oral administration in six healthy volunteers. After an 800 mg single dose of ibuprofen, the concentration reached in cervical mucus was less than 4% of that in serum. It is postulated that because ibuprofen is an acidic drug which is not subject to 'ion-trapping' in the acidic environment of cervical mucus, it is not concentrated in this secretion.     

Serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus

Aim

The aim of this study was to explore the effects of early oral ibuprofen administration on the incidence of hemodynamically significant patent ductus arteriosus (hsPDA) and define the association between serum ibuprofen levels and ductal closure.

Method

Preterm infants with a gestational age of <28 weeks and/or birth weight of <1,000 g were randomized either to the intervention (ibuprofen prophylaxis) or control group. The intervention group received oral ibuprofen 10 mg/kg within 12–24 h after birth followed by 5 mg/kg at 24 and 48 h. Serum ibuprofen levels after the treatment were analyzed in the intervention group, and the incidence of hsPDA and complication rates were compared between two groups.

Results

Nineteen infants who received one course (three doses) of prophylactic ibuprofen in the intervention group and 17 infants in the control group who underwent an echocardiographic examination on the fourth day of life were analyzed. hsPDA was observed in five (26 %) infants in the intervention group and ten (58 %) infants in the control group (p?=?0.09). In the intervention group two infants experienced gastrointestinal bleeding two infants had spontaneous intestinal perforation, and two infants developed acute kidney failure. Mean serum ibuprofen level was 28.7?±?16.9 mg/L in the intervention group, and there was no correlation between ibuprofen level obtained on the fourth day and ductal closure.

Conclusion

Oral ibuprofen prophylaxis reduces the rates of hsPDA even it is not statistically significant. The ductal closure rate did not correlate with serum ibuprofen levels. Due to high prevalence of adverse events observed, our data do not support the use of oral ibuprofen for prophylaxis of hsPDA.     

Ibuproxam and ibuprofen. A pharmacological comparison

The anti-inflammatory, analgesic and antipyretic effects and the tolerability of 2-(4-isobutylphenyl)-propionic acid (ibuprofen) were compared with those of its derivative 2-(4-isobutylphenyl)-propiohydroxamic acid (ibuproxam, Ibudros. Our experiments show that the interfering action of the two drugs with the reactive processes of the tibio-tarsic articulation, brought about by carrageenin, serotonin, dextrane and formalin is of the same intensity. Also, the analgesic activity is perfectly consistent with the antipyretic one. However, the tolerability of the two molecules is different; the acute toxicity is consistent in the case of the single parenteral administration and it differs in the case of a single or repeated oral treatment. When used under these conditions, ibuproxam is considerably less damaging to the gastroenteric tube than is ibuprofen. The hypothesis is put forth that the greater tolerability of ibuproxam is due to its pharmacokinetics: it is, as such, little or not toxic for the mucous membrane of the digestive apparatus, and it progressively releases ibuprofen, whose concentrations in the blood would remain below those levels that cause systemic lesions in the gastroenteric tract.     

A toxicological and pharmacological study of ibuprofen guaiacol ester (AF 2259) in the rat

Ibuprofen guaiacol ester (AF 2259) was studied in comparison with ibuprofen and guaiacol, administered together and separately. The gastrointestinal toxicity, behavioral disorders, and acute toxicity of AF 2259 are lower than those of ibuprofen. Both products, at equimolar doses, are equally active on edema and fever. At high doses guaiacol produces behavioral disorders and lethal effects, whereas at doses equimolar to ibuprofen, it is devoid of ulcerogenic and pharmacological effects. Concurrent administration of ibuprofen and guaiacol produces behavioral disorders and higher lethal effects than those produced by each of the two drugs administered separately, whereas their ulcerogenic and pharmacological activity is similar to that of ibuprofen. In discussing these results, it is stressed that ibuprofen guaiacol ester appears to be better tolerated than ibuprofen because of its peculiar pharmacokinetics which has been studied by different authors; in fact, the ester releases ibuprofen slowly, thus reducing its local and general toxicity.     

An unreported complication of intravenously administered ibuprofen: gastrointestinal bleeding

Ibuprofen is used for the closure of ductus arteriosus either intravenously or enterally. Although intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, transient renal failure, oliguria, hyponatremia and thrombocytopenia are reported complications during or after ibuprofen treatment, gastrointestinal bleeding, to our knowledge, has not been reported previously. We herein report a premature newborn, in whom ibuprofen was used intravenously for the closure of ductus arteriosus and gastrointestinal bleeding developed as a complication, and aim to discuss this rare adverse effect. In conclusion, we emphasize the importance of close follow-up of premature newborns during intravenous ibuprofen treatment considering also the other rare systemic side effects reported in the literature.     

Clinical pharmacokinetics of ibuprofen arginine

Currently, several ibuprofen compounds are available on the market, mainly differing in terms of pharmaceutical composition that influence the pharmacokinetic profile and eventually the onset of drug action. This review will mainly deal with the clinical pharmacokinetics of ibuprofen arginine, an alternative formulation specifically designed to improve the absorption of ibuprofen. Indeed, available data from studies in healthy volunteers have consistently shown that the formulation of ibuprofen arginine is characterized by prompt absorption of ibuprofen as compared to the conventional formulation at all tested doses with higher peak plasma concentration and lower Tmax values. This trend has been confirmed also in studies dealing with chiral ibuprofen pharmacokinetics. Most importantly, the shortening in the absorption time observed either with racemic mixture or with the S(+)-enantiomer of ibuprofen arginine did not imply a faster drug elimination eventually leading to inadequate daily drug exposure, as documented by T1/2 and AUC values being comparable to those measured with the free acid form. Taken together, the pharmacokinetic/dynamic characteristics of ibuprofen arginine can be considered particularly favorable for several clinical conditions, such as moderate/severe pain, in which a rapid pharmacologic effect is required.     

The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus

The aim of this study was to examine the diffusion of commonly administered analgesics, ibuprofen and paracetamol, through gastric mucus. As ibuprofen and paracetamol are often formulated with alkalising excipients, or are commonly co-administered with antacids that have been demonstrated to alter their absorption, diffusion was also studied in the presence of a range of soluble and insoluble antacids or buffering agents. The effect of pH, which has been demonstrated to modify the properties of mucus, was also studied. Mucus was a significant barrier to diffusion for both drugs, compared to an unstirred aqueous layer with diffusion rates significantly lower in the presence of a mucus barrier for both drugs; ibuprofen diffusion also demonstrated a significant increase in the lag time. Paracetamol diffusion was not significantly affected by addition of any antacid, whereas ibuprofen rates were affected and the diffusion lag time for ibuprofen was significantly reduced in all cases. Isolated increases in pH increased the rate and reduced the lag time for ibuprofen diffusion. It was shown that mucus acts as a passive barrier in the case of paracetamol diffusion, and an interactive barrier to ibuprofen diffusion. Changes in mucus viscosity at different pH values may be responsible for the observed changes in ibuprofen diffusion rate.     

Effects of ibuprofen on chemotactic peptide-receptor binding and granulocyte response

Inhibition of complement-mediated granulocyte aggregation has been proposed recently as a mechanism of action of high-dose corticosteroids and ibuprofen in shock states. Such inhibition by corticosteroids may be effected through alteration of receptor function, and we have therefore examined the effect of ibuprofen on the extent and kinetics of binding of the synthetic chemotactic peptide formylmethionine-leucine-phenylalanine (FMLP) to its specific receptor on the granulocyte surface. Dose-dependent inhibition of binding was observed at ibuprofen concentrations paralleling plasma levels achieved with 30 mg/kg intravenous bolus therapy, and also at concentrations achieved with oral therapy. Ibuprofen did not affect the receptor number, but did decrease the association rate constant for the FMLP-receptor interaction (30% of normal for 0.125 mg/ml ibuprofen), leading to a decrease in receptor affinity for ligand. Dissociation kinetics, as determined by cold chase experiments, were unaltered by ibuprofen. We conclude that ibuprofen, like corticosteroids, can slow the rate of association of FMLP with its receptor on the granulocyte surface while allowing dissociation to proceed; altered kinetics of receptor-FMLP interaction may explain the inhibition of granulocyte aggregation. Blockade of granulocyte surface receptors for inflammatory stimuli may be important in the clinical effects of very high-dose corticosteroids and ibuprofen such as are administered in shock; such effects are seen at blood levels of ibuprofen that occur with oral therapy. Similar observations may hold for other physiologic stimuli.     

Investigation on the possibility of biowaivers for ibuprofen

The aim of the study was to investigate the ability of in vitro dissolution to ensure bioequivalence of ibuprofen products. Ibuprofen is a Biopharmaceutics Classification System (BCS) class II drug with low solubility at pH 1.2 and 4.5 and high solubility at pH 6.8. The possibility of extending the "BCS biowaivers" to weak acidic compounds has been suggested. Three ibuprofen formulations were compared in vitro and in vivo with the reference. Dissolution profiles in several pH buffers showed similarity at 75 and 50 rpm. However, the bioequivalence studies showed that two formulations were not equivalent in C(max) because of a statistically significant difference. Conversely, another formulation was bioequivalent both in AUC and C(max) in a pilot study (n = 10) and a final study (n = 18), demonstrating that the previous failures were not due to lack of statistical power, but due to a different absorption rate that cannot be detected in vitro. In conclusion, "biowaivers" for this type of class II drugs are not feasible because the dissolution tests do not detect differences in absorption rate. Differences in absorption rate cannot be neglected, not only because absorption rate has clinical relevance but also because the clinical importance of the differences cannot be assessed if they are not quantified.     

Inhibition of human polymorphonuclear leukocyte functions by ibuprofen

We have found that pretreatment of human neutrophils with ibuprofen (0.10-1.0 mg/ml) results in an irreversible, concentration-dependent inhibition of superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme) stimulated by the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, and to a lesser extent by serum opsonized zymosan. Inhibition of granule exocytosis and oxygen radical generation at ibuprofen concentrations less than 5 mg/ml was not due to drug cytotoxicity since release of the cytoplasmic enzyme lactate dehydrogenase was not affected by ibuprofen. In contrast to neutrophil responses mediated by C5a or FMLP, ibuprofen did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate. Ibuprofen did not function as an oxygen radical scavenger in a cell-free system in which superoxide anion was generated by the aerobic action of xanthine oxidase on hypoxanthine. Ibuprofen also inhibited in a concentration-dependent fashion both directed migration (chemotaxis) and stimulated random migration (chemokinesis) of neutrophils exposed to either FMLP or C5a. Inhibition of neutrophil adherence to plastic surfaces and bovine pulmonary artery endothelial cells was equally effective when the neutrophils were treated with ibuprofen before stimulation with FMLP or phorbol myristate acetate. The inhibitory effects of ibuprofen pretreatment of neutrophils could not be overcome by addition of prostaglandins E1 or E2 (0.3-300 nM). These results demonstrate that ibuprofen is capable of suppressing many functions thought to be important in neutrophil-mediated acute pulmonary inflammatory processes. Results of these experiments further suggest that ibuprofen may inhibit neutrophil functions by acting on cellular components separate from membrane receptors or by blockade of cyclo-oxygenase products which may be involved in these neutrophil functions.     

The effect of ibuprofen on serum digoxin concentrations

This study was undertaken to determine the effects of ibuprofen (Motrin), in daily doses of at least 1600 mg, on steady-state digoxin concentrations. A total of 12 ambulatory patients (10, female; 2, male), with a mean age of 66 years (38-81 yr), completed the study. An initial baseline serum digoxin level was obtained, with follow-up levels at 7 days and, whenever possible, 28 days after ibuprofen initiation. Serum creatinine concentrations were not significantly different from baseline to 7 or 28 days of ibuprofen therapy. Results show a statistically significant (p less than 0.05) increase in digoxin levels after seven days of ibuprofen. The mean increase was 59 percent (range, 10.7-325.4 percent), with 10 of the 12 patients displaying increased seven-day levels. Digoxin levels drawn 28 days after ibuprofen initiation were not statistically different from baseline or seven-day digoxin levels.     

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children.

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUCO----infinity) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlag was less than ibuprofen, Ka was more than ibuprofen, and beta was less than ibuprofen. The ibuprofen beta was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUCO-----infinity was higher in the older (greater than or equal to 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUCO----infinity and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.     

对乙酰氨基酚和布洛芬均引起儿童急性荨麻疹不良反应1例

目的 探讨退热药物对乙酰氨基酚和布洛芬引起儿童急性荨麻疹的不良反应的发生及有效治疗方法。方法 临床药师全程开展药学服务,分析1例3岁患儿使用对乙酰氨基酚和布洛芬退热治疗后均出现急性荨麻疹的临床案例,并进行相关讨论。结果 患儿出现急性荨麻疹后,口服地氯雷他定干混悬剂抗过敏、地塞米松抗炎抗过敏和抗病毒药物治疗,最终患儿症状好转。结论 乙酰氨基酚和布洛芬同致急性荨麻疹的不良反应报道较为少见但仍存在,患儿用药后需密切观察,出现急性荨麻疹时可予抗过敏治疗。临床药师进行药物相关性不良反应的评分和分析,旨在为临床合理用药提供参考。     

Time dependent influence of diazepam on the pharmacokinetics of ibuprofen in man

Circadian variation in the disease activity of rheumatoid arthritis has been established. Several nonsteroidal anti-inflammatory drugs have been studied for their chronokinetic behaviour. Time dependent influence of diazepam on the pharmacokinetics of diclofenac and naproxen has been reported. We report the time dependent influence of diazepam on the pharmacokinetics of ibuprofen in healthy subjects. Either ibuprofen or ibuprofen with diazepam was administered at 10.00 or 22.00 hours to eight healthy volunteers in a randomized crossover study. Serum ibuprofen levels were estimated by high performance liquid chromatography. There was a significant (p < 0.05) increase in mean elimination half life (2.39 +/- 0.42 to 3.59 +/- 0.35 h) following ibuprofen and diazepam administration compared to ibuprofen alone administered at 22.00 hours. The mean clearance of ibuprofen was therefore lowered from 62.7 +/- 8.9 to 41.7 +/- 2.6 ml/h/kg under the influence of diazepam during the night. Such a time dependent influence of diazepam on the pharmacokinetics of ibuprofen may be due to circadian variation in the pattern of protein production in the liver and/or competitive protein binding of the two drugs during the dark period.     

A report of two deaths from massive ibuprofen ingestion

Introduction

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion.

Case 1

A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 μg/mL: the therapeutic range is 10–50 μg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired.

Case 2

A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 μg/mL and serum valproate concentration was 560 μg/mL: the therapeutic range is 50–100 μg/mL. In spite of supportive care and hemodialysis, he expired.

Discussion

We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.     

Pharmacokinetics of intravenous ibuprofen: implications of time of infusion in the treatment of pain and fever

Intravenous NSAIDs are playing an increasingly large role in analgesia, anti-inflammation and antipyresis in the hospitalized setting. For many years, ketorolac was the only intravenous NSAID available in the US, but in 2009 intravenous ibuprofen was approved by the US FDA for the treatment of pain and fever in adults. In developing intravenous ibuprofen, a range of times of infusion and dosing levels have been utilized and compared with the oral route of administration. The earliest studies utilized a 60-minute infusion, and later a 30-minute infusion was used for the pivotal/registration studies demonstrating efficacy and safety. Another recent trial in healthy volunteers demonstrated a safe and tolerable rapid infusion (5-7 minute) of intravenous ibuprofen. The pharmacokinetic data from all of the clinical trials on 400 and 800?mg doses of intravenous ibuprofen were compiled, and pharmacokinetic modelling was utilized to simulate any data not acquired in the clinical studies. The pharmacokinetic profile of the following doses was modelled: 30-minute infusion of 800?mg intravenous ibuprofen, 5- to 7-minute infusion of 400?mg intravenous ibuprofen and 400?mg ibuprofen oral tablet. These pharmacokinetic analyses revealed that, in general, maximum plasma concentration (C(max)) decreases considerably as the length of the infusion increases and that an oral dose is not able to achieve the C(max) level of any intravenous dose. For the rapid infusion, C(max) was twice that of the oral dose and, as expected, time to C(max) (t(max)) was much more rapid than with the oral dose. However, the oral dose still maintained virtually 100% oral bioavailability. The efficacy of intravenous ibuprofen in terms of pain and fever has also been studied and this review found the drug to be efficacious for both indications. Future areas of study should include assessment of the analgesic and antipyretic efficacy of a rapid (5- to 10-minute) infusion and further assessment of pre-emptive administration of intravenous ibuprofen as part of a multimodal analgesic approach in the surgical setting.