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Comparison of the efficacy of intrauterine diclofenac and ibuprofen pellets as adjuvants to quinacrine nonsurgical female sterilization.

Bairagi NR, Mullick BC, Kessel E, Mumford SD.

Indian Rural Medical Association, West Bengal, India.

To investigate relative efficacy of intrauterine diclofenac and ibuprofen as adjuvants to intrauterine quinacrine for nonsurgical sterilization, a total of 900 women were systematically allocated to 2 monthly insertions of pellets of diclofenac (75 mg) or ibuprofen (55.5 mg) as adjuvants to intrauterine quinacrine (216 mg) in a rural private practice in West Bengal, India. All women were prescribed oral contraceptives for three months from first insertion. In the middle of the study increased care was taken to insert pellets at the fundus. There was no statistically significant difference found in cumulative life-table pregnancy failure rates at 36 months for women receiving diclofenac (2.7 +/- 0.82) or ibuprofen (3.4 +/- 0.89). Taking care to insert pellets at the fundus resulted in a decline of failures at 24 months from 4.4 +/- 0.92 to zero. Intrauterine administration of pellets of quinacrine (216 mg) plus diclofenac (75 mg) or ibuprofen (55.5 mg) with 3 months' oral contraception provides acceptable efficacy if pellets are inserted to the fundus.

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Pathological and biochemical modifications of renal function in ibuprofen-induced interstitial nephritis.

Chen CY, Pang VF, Chen CS.

Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Republic of China.

Use of ibuprofen in patients with asymptomatic renal failure is known to produce acute renal toxicity. One of the manifestations is interstitial nephritis of which the pathogenic mechanism remains unclear. In the present study, this nephrotoxic syndrome was induced in rabbits by giving a single dose of uranyl nitrate, followed by consecutive doses of ibuprofen. This animal model thus allowed the assessment of renal functional and pathological changes associated with ibuprofen use in renal insufficiency. In these rabbits, the major abnormality appeared to be confined to the tubulointerstitial compartment. Microscopic examinations of the renal necropsy specimens showed tubular necrosis and interstitial lymphocytic infiltration. The histological finding of lymphocytic aggregation suggests that this nephrotoxic effect stems from a cytotoxic immune reaction in the interstitium. Moreover, levels of renal 2-arylpropionyl-CoA epimerase, a key enzyme involved in the metabolic inversion of ibuprofen, showed a significant reduction, which may result from the massive destruction of the tubular cells in these animals. These results support the premise that renal insufficiency is a prerequisite factor for ibuprofen-induced interstitial nephritis.

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Interaction of salicylate and ibuprofen with the carboxylic acid: CoA ligases from bovine liver mitochondria.

Vessey DA, Hu J, Kelley M.

Liver Study Unit, Department of Veteran's Affairs Medical Center, San Francisco, CA 94121, USA.

Neither salicylate nor ibuprofen was a substrate or inhibitor of the long-chain fatty acid:CoA ligase. In contrast, all three xenobiotic-metabolizing medium-chain fatty acid:CoA ligases (XL-I, XL-II, and XL-III) had activity toward salicylate. The K(m) value for salicylate was similar for all three forms (2 to 3 microM), but XL-II and XL-III had higher activity at Vmax. For ibuprofen, only XL-III catalyzed its activation, and it had a K(m) for ibuprofen of 36 microM. Studies of salicylate inhibition of XL-I, XL-II, and XL-III revealed that it inhibited the benzoate activity of all three forms with K1 values of ca. 2 microM, which is in agreement with the K(m) values obtained with salicylate as substrate. Kinetic analysis revealed that salicylate conjugation by all three forms is characterized by substrate inhibition when salicylate exceeds ca. 20 microM. Substrate inhibition was more extensive with XL-I and XL-III. Previous work on the ligases employed assay concentrations of salicylate in the range of 0.1 to 1.0 mM, which are clearly inhibitory, particularly toward XL-I and XL-III. Thus, activity was not properly measured in previous studies, which accounts for the fact that salicylate conjugation was only found with one form, which is most likely XL-II since it has the highest Vmax activity and shows the least amount of substrate inhibition. Studies with ibuprofen indicated that it inhibited XL-I, XL-II, and XL-III, with KI values being in the range of 75-125 microM. The short-chain ligase was inhibited by both salicylate and ibuprofen with KI values of 93 and 84 microM, respectively. It was concluded that pharmacological doses of salicylate, but not ibuprofen, will affect the metabolism of medium-chain fatty acids and carboxylic acid xenobiotics and that the previously described mitochondrial ibuprofen:CoA ligase activity is attributable to XL-III.

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Non-steroidal anti-inflammatory drugs protect amyloid beta protein-induced increase in the intracellular Cl- concentration in cultured rat hippocampal neurons.

Iwata R, Kitagawa K, Zhang NY, Wu B, Inagaki C.

Department of Pharmacology, Kansai Medical University, Fumizono-cho 10-15, Moriguchi, Osaka 570-8506, Japan.

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen reportedly decrease a risk for the progression of Alzheimer's disease (AD), whose mechanisms are still controversial. We previously reported that pathophysiological concentrations (1-10 nM) of amyloid beta proteins (Abetas) increased intracellular Cl- concentration ([Cl-]i) and aggravated glutamate neurotoxicity in the rat brain neuronal culture. In this study, we examined the effects of therapeutic concentrations of ibuprofen and other drugs with cyclo-oxygenase (COX)-1 and/or COX-2 inhibiting activities on 10 nM Abeta25-35-induced changes in cultured rat hippocampal neurons. Ibuprofen (10-100 microM) dose-dependently inhibited the Abeta25-35-induced increase in [Cl-]i in pyramidal cell-like neurons. Not only ibuprofen, aspirin (100 microM), indomethacin (50 microM), and selective COX-1 or COX-2 inhibitor (10 nM ketrolac or 2 microM NS398) also blocked the Abeta-induced increase in neuronal [Cl-]i, though such effects of COX-2 preferring drugs were limited in aggregated Abeta-induced changes. Further, ibuprofen as well as selective COX-1 or COX-2 inhibitor reduced Abeta-induced aggravation of glutamate toxicity as assessed by cell viability. These findings suggest that NSAIDs protect neurons from Abeta-induced degeneration via inhibition of neuronal COX-1 as well as COX-2.

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Influence of acidic beverage (Coca-Cola) on pharmacokinetics of ibuprofen in healthy rabbits.

Kondal A, Garg SK.

Department of Pharmacology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India.

The study was aimed at determining the effect of Coca-Cola on the pharmacokinetics of ibuprofen in rabbits. In a cross-over study, ibuprofen was given orally in a dose of 56 mg/kg, prepared as 0.5% suspension in carboxymethyl cellulose (CMC) and blood samples (1 ml) were drawn at different time intervals from 0-12 hr. After a washout period of 7 days, Coca-Cola in a dose of (5 ml/kg) was administered along with ibuprofen (56 mg/kg) and blood samples were drawn from 0-12 hr. To these rabbits, 5 ml/kg Coca-Cola was administered once daily for another 7 days. On 8th day, Coca-Cola (5 ml/kg) along with ibuprofen (56 mg/kg), prepared as a suspension was administered and blood samples (1 ml each) were drawn at similar time intervals. Plasma was separated and assayed for ibuprofen by HPLC technique and various pharmacokinetic parameters were calculated. The Cmax and AUC0-alpha of ibuprofen were significantly increased after single and multiple doses of Coca-Cola, thereby indicating increased extent of absorption of ibuprofen. The results warrant the reduction of ibuprofen daily dosage, frequency when administered with Coca-Cola.

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Effect of ibuprofen on the in vitro and in vivo reactivation of latent HSV-1.

Cherrick HM, Li KK, Li SL, Park NH.

Section of Oral Biology, UCLA School of Dentistry.

Prostaglandins have been suggested to play an important role in the reactivation of latent herpes simplex virus. To further understand the role of prostaglandins in the reactivation process, we investigated the effects of ibuprofen, a nonsteroidal anti-inflammatory drug with prostaglandin synthesis inhibitory activity, on the in vitro and in vivo reactivation of latent type 1 herpes simplex virus in mouse ganglia and rabbits, respectively. Ibuprofen, at a concentration of 50 or 100 microM, did not alter the titer of reactivated virus from explanted ganglia with latent virus, but, at a concentration of 200 or 500 microM, it significantly reduced the reactivated viral titer from the ganglia. Ibuprofen also directly inhibited the replication of herpes simplex virus in trigeminal ganglia and Vero cell monolayers, which indicates that the drug reduced the recovery of reactivated viral titers from explanted ganglia with latent virus by acting on the replication process rather than on the reactivation mechanism in vitro. The systemic administration of ibuprofen failed to demonstrate any significant effect on the ocular shedding of virus after attempted reactivation by 6-hydroxydopamine iontophoresis in rabbits with latent herpes simplex virus infection. This failure in vivo could be due to the short half-life and low concentration of ibuprofen at the site of reactivation and replication of latent virus. Alternatively, in the clinical setting, it is conceivable that ibuprofen may not have an effect on in vivo reactivation of latent herpes.

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The neutrophil respiratory burst and tissue injury in septic acute lung injury: the effect of cyclooxygenase inhibition in swine.

Carey PD, Jenkins JK, Byrne K, Walsh CJ, Fowler AA, Sugerman HJ.

Department of Surgery, Medical College of Virginia, Richmond 23229.

Cyclooxygenase inhibition has been proposed as treatment for sepsis-induced acute lung injury. However, the mechanism of protection offered by the cyclooxygenase inhibitor ibuprofen is not well understood. To elucidate this mechanism, the effects of ibuprofen on the neutrophil respiratory burst and alveolar-capillary membrane leak were studied. Anesthetized swine (15 to 25 kg) were intubated and mechanically ventilated (fraction of inspired oxygen, 0.5). Control animals (n = 5) received a sham infusion of 0.9% NaCl, animals with sepsis (n = 10) received a 1-hour infusion of live Pseudomonas aeruginosa (5 x 10(8) colony-forming units/ml at 0.3 ml/20 kg/hr), and treated animals (ibuprofen-treated control animals [n = 4] or ibuprofen-treated animals with sepsis [n = 9]) received ibuprofen (12.5 mg/kg at 0 and 120 minutes). All animals were studied for 300 minutes. Neutrophils were isolated at 0, 60, and 300 minutes. Neutrophil superoxide anion production (O2-) was assessed in a kinetic fashion (in nanomoles per minute) by superoxide dismutase-inhibitable cytochrome C reduction (phorbol myristate acetate stimulation). Bronchoalveolar lavage protein estimation (0 and 300 minutes) and extravascular lung water (double indicator dilution) were performed to assess alveolar-capillary membrane leak. Ibuprofen significantly attenuated sepsis-enhanced maximum neutrophil generation of O2- (6.0 +/- 0.5 nmol/min for animals with sepsis, 300 minutes, vs 4.1 +/- 0.5 nmol/min for ibuprofen-treated animals, with sepsis, 300 minutes; p less than 0.05), indicating an in vivo down-regulatory effect on neutrophil oxidant generation. Ibuprofen also prevented increased airspace bronchoalveolar lavage protein and extravascular lung water accumulation, suggesting a protective effect on the alveolar-capillary membrane. This protective effect of ibuprofen in acute lung injury may be through a decreased neutrophil respiratory burst.

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Ibuprofen intervention in canine septic shock: reduction of pathophysiology without decreased cytokines.

Coran AG, Drongowski RA, Paik JJ, Remick DG.

Section of Pediatric Surgery, C.S. Mott Children's Hospital, Ann Arbor, Michigan.

This study was undertaken to evaluate the effect of a cyclooxygenase inhibitor, ibuprofen, at various time intervals in a live Escherichia coli model of canine septic shock. Group I (control) animals (n = 5) received a LD100 dose of 10(9) live E. coli per kilogram were given no further treatment. Group II animals (n = 5) received a 10 mg/kg bolus of ibuprofen 10 min prior to bacterial infusion. Group III animals (n = 5) received ibuprofen 15 min after the bacterial infusion. Statistical analysis revealed the following: Group II animals had significantly higher MABP and significantly lower levels of serum fluorescent products (superoxide radical activity), plasma thromboxane B2, prostaglandin E2, and endotoxin levels compared to Group I animals (P less than 0.05). Plasma levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were significantly elevated (P less than 0.05) from baseline in all animals (Groups I, II, and III), but ibuprofen treatment failed to either increase or decrease these levels. This study demonstrates that ibuprofen treatment can significantly reverse the deleterious hemodynamic and metabolic effects commonly seen in live E. coli septic shock without depressing the endogenous production of TNF or IL-6. These data support the hypothesis that sepsis initiates a cascade of mediators with the cytokines TNF and IL-6 being proximal events which in turn stimulate the next level, with ibuprofen probably exerting its inhibitory effect distal to this point in the cascade.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1326683&dopt=Abstract ibuprofen Motrin