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- Interconversion of ketoprofen recognition in firefly luciferase-catalyzed enantioselective thioesterification reaction using from Pylocoeria miyako (PmL) and Hotaria parvura (HpL) just by mutating two amino acid residues. [JOURNAL ARTICLE]
- J Biotechnol 2013 May 14.
We identified the critical amino acid residues for substrate recognition using two firefly luciferases from Pylocoeria miyako (PmL) and Hotaria parvura (HpL), as these two luciferase enzymes exhibit different activities toward ketoprofen. Specifically, PmL can catalyze the apparent enantioselective thioesterification reaction, while HpL cannot. By comparing the amino acid sequences around the active site, we identified two residues (I350 and M397 in PmL and F351 and S398 in HpL) that were different between the two enzymes, and the replacement of these amino acids resulted in changing the ketoprofen recognition pattern. The inactive HpL was converted to the active enzyme toward ketoprofen and vice versa for PmL. These residues also affected the enantioselectivity toward ketoprofen; however, the bioluminescent color was not affected. In addition, using molecular dynamics calculations, the replacement of these two amino acids induced changes in the state of hydrogen bonding between ketoprofen and the S349 side chain through the active site water. As S349 is not considered to influence color tuning, these changes specifically caused the differences in ketoprofen recognition in the enzyme.
- Kinsbourne syndrome: case report. [Journal Article]
- Rev Bras Anestesiol 2013 May-Jun; 63(3):287-9.
Kinsbourne syndrome is a rare neurological disorder that primarily affects children previously healthy and aged between 6 and 36 months. It is characterized by opsoclonus (rapid, irregular, horizontal and vertical eye movements) and myoclonus that may affect trunk, limbs or face, and cerebellar ataxia. It may be considered a paraneoplastic syndrome by association with neuroblastomas, hepatoblastomas and, rarely, ganglioneuromas. The aim of this paper was to present the most relevant aspects of Kinsbourne syndrome, as well as the technique used for resection of mediastinal tumor in a child with this syndrome.Child, 1 year and 5 months, with a diagnosis of posterior mediastinal tumor and Kinsbourne syndrome. Premedicated with oral midazolam. Anesthesia induced with sevofl urane, nitrous oxide, fentanyl, and rocuronium. Maintenance of anesthesia with sevofl urane, nitrous oxide, fentanyl, and rocuronium. Neuromuscular block reversal with neostigmine combined with atropine. Postoperative analgesia with the use of dipyrone, morphine, and ketoprofen. Taken to the intensive care unit extubated, with stable hemodynamic and respiratory parameters. ICU discharge four days after surgery and hospital discharged on the seventh postoperative day without complications. Anatomopathological examination revealed ganglioneuroblastoma.Kinsbourne syndrome is a rare neurological disorder. The drugs used in our patient proved safe and allowed an uneventful anesthesia. Drugs that trigger or aggravate opsoclonus and myoclonus, such as ketamine and etomidate, should be avoided in these patients.
- Ketoprofen inhibits expression of inflammatory mediators in human dental pulp cells. [Journal Article]
- J Endod 2013 Jun; 39(6):764-7.
Conventional root canal treatment is the treatment of choice for the irreversible pulpitis caused by bacterial infection. More recently, vital pulp therapy has been proposed as an alternative for management of inflamed dental pulp. Ketoprofen is an anti-inflammatory agent commonly used as a component of mouth rinse for oral lesions. Here, we examined the effect and mechanisms of action of ketoprofen on the expression of inflammatory mediators induced by the lipopolysaccharide (LPS) in dental pulp cells.Human dental pulp cells were exposed to LPS or LPS + ketoprofen, and reverse-transcription polymerase chain reaction was used to detect interleukin-1β and tumor necrosis factor α. The effect of these treatments on mitogen-activated protein kinase pathways was assessed by Western blots for extracellular signal-regulated kinase and c-Jun N-terminal kinase.LPS induced interleukin-1β and tumor necrosis factor α in dental pulp cells. Ketoprofen effectively inhibited interleukin-1β and tumor necrosis factor α production in LPS-stimulated dental pulp cells. Notably, ketoprofen inhibited phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase.Ketoprofen inhibited expression inflammatory mediators in dental pulp cells stimulated with LPS. The inhibitory effect of ketoprofen on inflammatory cytokines is associated with inhibition of the mitogen-activated protein kinase pathway.
- Photopatch testing in Asians: a 5-year experience in Singapore. [Journal Article]
- Photodermatol Photoimmunol Photomed 2013 Jun; 29(3):116-20.
Photopatch testing is important for diagnosing photoallergic contact dermatitis. We aimed to evaluate the use of photopatch test at the National Skin Centre, Singapore.All patients who had photopatch tests done between 2007 and 2011 at the National Skin Centre were included.Twenty-two patients were included. The mean age was 40.2. Female : male ratio was 3.4. The ethnic groups were Chinese (68%), Malay (4%), Indian (14%) and others (14%). Ten out of 22 patients (45.5%) had a positive photopatch test. There were 20 positive photopatch test reactions found in these 10 patients, and all 20 positive reactions were of current relevance. The frequencies of the positive photopatch test reactions were 2-hydroxy-4-methoxybenzophenone (oxybenzone) (n = 6), 2-hydroxymethoxymethylbenzophenone (mexenone) (n = 3), 2-ethylhexyl-4-dimethylaminobenzoate (n = 1), ketoprofen gel (n = 1) and the patient's own product (n = 9).Our study suggests that sunscreen is the most common photoallergen to date as opposed to musk ambrette, which was the most common photoallergen in our earlier study in 1991-1993. This finding is similar to the recent European Multicentre Photopatch Test Study.
- Severe water intoxication secondary to the concomitant intake of non-steroidal anti-inflammatory drugs and desmopressin: a case report and review of the literature. [Journal Article]
- Hormones (Athens) 2013 Jan; 12(1):135-41.
Most of the clinical data on the safety profile of desmopressin (DDAVP), which is an effective treatment for both polyuric conditions and bleeding disorders, originate from studies on the tailoring of drug treatment, whereas few reports exist describing severe side effects secondary to drug-drug interaction. We herein describe a case of severe hyponatremia complicated by seizure and coma due to the intake of non-steroidal anti-inflammatory drugs (NSAIDs) in a patient on DDAVP replacement therapy for central diabetes insipidus (DI). A 50-yr-old Caucasian man, with congenital central DI, developed an episode of generalized tonic-clonic seizure, resulting in coma immediately after being admitted to the Emergency Unit for weakness and emesis. Based on his medical history and clinical findings, water intoxication secondary to ketoprofen intake (200 mg/day for the last 3 days) concomitant with DDAVP replacement therapy (Minirin® 60 mcg 4 tablets a day) was hypothesized as being the cause of the severe euvolemic hypotonic hyponatremia (natremia 113 mEq/l, plasma osmolality 238 mOsm/Kg). After standard emergency procedures, appropriate gradual restoration of serum sodium levels to the normal range was achieved in 72 hours. Hydratation was maintained according to water excretion and desmopressin therapy was re-introduced. We discuss this case report in the context of the published literature. The present report first highlights the potentially life-threatening side effects associated with over-the-counter NSAIDs during DDAVP replacement therapy for central DI. Risks and benefits of co-treatment should be carefully considered and therapeutic alternatives to NSAIDs should be recommended to patients with central DI in order to improve DDAVP safety.
- Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine. [JOURNAL ARTICLE]
- Neuropharmacology 2013 May 2.
Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC-51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth.
- Solubility enhancement of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) using polypolypropylene oxide core PAMAM dendrimers. [JOURNAL ARTICLE]
- Int J Pharm 2013 Apr 28; 451(1-2):18-22.
The aim of the present study was to evaluate the aqueous solubility enhancement properties of polypropylene oxide cored PAMAM (PPO@PAMAM) dendrimers. The solubility of NSAIDs (Ketoprofen, Ibuprofen and Diflunisal) was investigated in the presence of PPO@PAMAM dendrimers at room temperature in buffer solution. The effects of dendrimer concentration, generation and core size on the solubility of NSAIDs have been investigated. The experimental results showed that the solubility of the NSAIDs was approximately proportional to dendrimer concentration and generation. In addition, the effect of core size on the solubility of NSAIDs in constant generation and concentration of PPO@PAMAM dendrimer was Ketoprofen>Diflunisal>Ibuprofen. Under optimized conditions, PPO@PAMAM dendrimers are highly effective solubility enhancer for NSAIDs due to its new polypropylene oxide core.
- Enantiomeric fraction determination of 2-arylpropionic acids in a package plant membrane bioreactor. [Journal Article]
- Chirality 2013 May; 25(5):301-7.
Enantiomeric compositions of three 2-arylpropionic acid (2-APA) drugs, ibuprofen, naproxen, and ketoprofen, were monitored in a membrane bioreactor (MBR) treating municipal effluent in a small rural town in Australia. Specific enantiomers were determined as amide diastereomers using the chiral derivatizing reagent, (R)-1-phenylethylamine (PEA), followed by gas chromatography-tandem mass spectrometry (GC-MS/MS). The six individual enantiomers were quantified by isotope dilution and the enantiomeric fractions (EFs) were determined. Over four separate sampling events, ibuprofen EF ranged from 0.88 to 0.94 (median 0.93) in the influent and 0.38 to 0.40 (median 0.39) in the effluent. However, no significant change in ketoprofen EF was observed, with influent EFs of 0.56-0.60 (median 0.58) and effluent EFs 0.54-0.68 (median 0.56). This is the first report of enantiospecific analysis of ketoprofen in municipal wastewater and it is not yet clear why such different behavior was observed compared to ibuprofen. Naproxen EF was consistently measured at 0.99 in the influent and ranged from 0.86 to 0.94 (median 0.91) in the effluent. This study demonstrates that EF is a relatively stable parameter and does not fluctuate according to concentration or other short-term variables introduced by sampling limitations. The enantiospecific analysis of chiral chemicals presents a promising approach to elucidate a more thorough understanding of biological treatment processes and a potential tool for monitoring the performance of key biological pathways. Chirality 25:301-307, 2013. © 2013 Wiley Periodicals, Inc.
- Nonsterodial Anti-inflammatory Drugs Reduce the Production of Quorum Sensing Regulated Virulence Factors and Swarming Motility in Human Pathogen Pseudomonas aeruginosa. [JOURNAL ARTICLE]
- Drug Res (Stuttg) 2013 Apr 18.
Antibiotics are commonly used for the treatment of microbial infections. With the widespread appearance of multi antibiotic-resistant bacteria, it is becoming increasingly more difficult to treat bacterial infections with conventional antibiotics. Thus, there is an increasing need for new strategies to cope with infectious diseases. The discovery that many pathogenic bacteria employ quorum sensing (QS) to regulate their pathogenicity and virulence factor production makes the QS system an attractive target for antimicrobial therapy. It has been suggested that inactivating the QS system of a pathogen can result in a significant decrease in virulence factor production. In this study, a variety of NSAIDs, such as diclofenac, ibufen, ketoprofen, naproxen, piroxicam were screened for their capacity to reduce the production of QS-regulated virulence factors and swarming motility in the human pathogen P. aeruginosa. Ketoprofen, diclofenac, ibufen, naproxen and piroxicam reduced the elastase production by 28-47% compared to the untreated cultures. Pyocyanin production was also inhibited by these compounds but to a lesser extent. In swarming assay plates, ketoprofen and diclofenac treated PA01 strain displayed significant reductions in swarming motility (81% and 84% respectively). These findings suggest that especially, ketoprofen and diclofenac, may prevent bacterial colonization, and thereby reducing biofilm formation, by interfering with QS-controlled swarming motility of P. aeruginosa and combinatory chemotherapy with both conventional antibiotics and tested NSAIDs could be used for the treatment of chronic infections caused by P. aeruginosa and other clinically important pathogens which regulate their pathogenicity via QS.
- Ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction coupled with liquid chromatography-quadrupole-linear ion trap-mass spectrometry for simultaneous analysis of pharmaceuticals in wastewaters. [Journal Article]
- J Chromatogr A 2013 May 24.:19-26.
A simple, rapid, low environmental toxicity and sensitive ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction (US-IL-DLLME) procedure was developed for the extraction of nine pharmaceuticals (paracetamol, metoprolol, bisoprolol, betaxolol, ketoprofen, naproxen, ibuprofen, flufenamic acid and tolfenamic acid) in wastewater, and their determination using high-performance liquid chromatography with a hybrid triple quadrupole-linear ion trap-mass spectrometer (LC-QqLIT-MS). The IL 1-octyl-3-methylimidazolium hexafluorophosphate ([C8MIM][PF6]) and acetonitrile (ACN) were used as extraction and disperser solvent, respectively, for the DLLME procedure, instead of using toxic chlorinated solvent. The factors affecting the extraction efficiency, such as the type and volume of ionic liquid, type and volume of disperser solvent, cooling in ice-water, sonication time, centrifuging time, sample pH and ionic strength, were optimized. The ultrasound-assisted process was applied to accelerate the formation of the fine cloudy solution using a small volume of disperser solvent (0.5mL of acetonitrile), which increased the extraction efficiency and reduced the equilibrium time. A slight increase in the recoveries of pharmaceuticals was observed when an ice-water bath extraction step was included in the analytical procedure. In this way, enrichment factors between 255 and 340 were obtained. Data acquisition in selected reaction monitoring mode (SRM), allowed the simultaneous identification and quantification of the analytes using two transitions (SRM1 and SRM2). Additionally, the information dependent acquisition (IDA) scan was performed to carry out the identification of those analytes whose second transition was absent or was present at low intensity, also providing extra confirmation for the other analytes. The optimized US-IL-DLLME-LC-QqLIT-MS method showed a good precision level, with relative standard deviation values between 1.1% and 11.3%. Limits of detection and quantification were in the range 0.2-60ngL(-1) and 1.0-142ngL(-1), respectively. Good enrichment factors (255-340) and recoveries (88-111%) were obtained for the extraction of the target analytes in wastewater samples. This method has been successfully applied to analyze effluent wastewater samples from a municipal wastewater treatment plant located in Almería (Spain) and the results indicated the presence of flufenamic acid and metoprolol in concentration levels of 0.1 and 1.3μgL(-1), respectively.