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- Characterization of combined cross-linked enzyme aggregates from laccase, versatile peroxidase and glucose oxidase, and their utilization for the elimination of pharmaceuticals. [JOURNAL ARTICLE]
- Sci Total Environ 2014 Feb 28.:90-99.
In order to transform a wide range of pharmaceutically active compounds (PhACs), the three oxidative enzymes laccase (Lac) from Trametes versicolor, versatile peroxidase (VP) from Bjerkandera adusta and glucose oxidase (GOD) from Aspergillus niger were concomitantly cross-linked after aggregation, thus, making a combined cross-linked enzyme aggregate (combi-CLEA) that was versatile and involved in an enzymatic cascade reaction. From the initial enzymes about 30% of initial laccase activity was recovered along with 40% for each of VP and GOD. The combi-CLEA showed good results in conditions close to those of real wastewater (neutral pH and medium temperature) as well as a good ability to resist to denaturing conditions such as high temperature (60°C) and low pH (3). Batch experiments were realized to test the free enzyme's ability to degrade, a PhACs cocktail, mainly in a synthetic wastewater containing acetaminophen, naproxen, mefenamic acid, indometacin, diclofenac, ketoprofen, caffeine, diazepam, ciprofloxacin, trimethoprim, fenofibrate and bezafibrate, carbamazepine and its by-product 10-11 epoxy-carbamazepine. High removal was achieved (more than 80%) for the five first compounds. Then, the elimination ability of the combi-CLEA with or without hydrogen peroxide, glucose or manganese sulfate was determined. Globally, our results demonstrated that VP has a wider removal spectrum than Lac. These removal features are enhanced under more specific conditions, whereas the combi-CLEA combined advantages of both VP and laccase. Finally, the elimination of PhACs in a municipal wastewater treatment plant effluent using the combi-CLEA was marginally investigated. Concentrations of most of the selected PhACs were below the limit of quantification (lower than 20ng/L) except for acetaminophen. Its combi-CLEA-mediated removal reached up to 25%.
- Ilioinguinal-iliohypogastric nerve block with intravenous dexketoprofen improves postoperative analgesia in abdominal hysterectomies. [Journal Article]
- Braz J Anesthesiol 2013 Jul-Aug; 63(4):334-9.
In this study, our aim was to evaluate the effects of intravenous dexketoprofen trometamol with ilioinguinal and iliohypogastric nerve block on analgesic quality and morphine consumption after total abdominal hysterectomy operations.We conducted this randomized controlled clinical study on 61 patients. The study was conducted in the operation room, post-anesthesia care unit, and inpatient clinic. We randomly grouped the 61 patients into control group (group C), block group (group B) and dexketoprofen-block group (group DB). Before the skin incision performed after anesthesia induction, we performed ilioinguinal iliohypogastric block (group C given saline and group P and DB given levobupivacaine). In contrast to group C and B, group DB was given dexketoprofen. We administered morphine analgesia to all patients by patient-controlled analgesia (PCA) during the postoperative 24hours. We recorded Visual Analogue Scale (VAS), satisfaction scores, morphine consumption and side effects during postoperative 24hours.We found the DB group's VAS scores to be lower than the control group and block group's (p < 0.05) values at postoperative 1(st), 2(nd), 6(th) and 12(th) hours. VAS scores of group C were higher than of group B at postoperative ﬁrst 2hours. Time to ﬁrst PCA demand was longer, morphine consumption values were lower and satisfaction scores were higher in group DB than in the other two groups (p < 0.05).Ilioinguinal-iliohypogastric nerve block with IV dexketoprofen increases patient satisfaction by decreasing opioid consumption, increasing patient satisfaction, which suggests that dexketoprofen trometamol is an effective non-steroidal anti-inﬂammatory analgesic in postoperative analgesia.
- Kinsbourne syndrome: case report. [Journal Article]
- Braz J Anesthesiol 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 sevoﬂurane, nitrous oxide, fentanyl, and rocuronium. Maintenance of anesthesia with sevoﬂurane, 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.
- Considerations for a Pediatric Biopharmaceutics Classification System (BCS): Application to Five Drugs. [JOURNAL ARTICLE]
- AAPS PharmSciTech 2014 Feb 21.
It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.
- Topical therapies in the management of chronic pain. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Postgrad Med 2013 Jul; 125(4 Suppl 1):25-33.
Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting > 25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, infections, and systemic side effects. Several types of topical agents have been shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who have pre-existing gastrointestinal risk or are aged ≥ 75 years. Topical NSAIDs have been shown to provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain who have cancer, although clinical trial results have not been consistent. Data suggest that topical therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain.
- Options in topical therapies in the management of patients with acute pain. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Postgrad Med 2013 Jul; 125(4 Suppl 1):19-24.
The traditional cornerstones of analgesic therapy for patients with acute pain have been oral therapies; however, all oral agents exhibit a variety of potentially dose-limiting or intolerable adverse effects in patients. Elderly patients and those with concomitant conditions already being managed with multiple systemic drugs may be particularly susceptible to systemic toxicities with oral analgesic therapies. Topical agents offer an alternative to oral modalities and can effectively treat patients with acute pain while offering lower systemic absorption and conferring little risk of systemic toxicity. The objective of this article is to review the therapeutic usefulness of available topical therapies in their most thoroughly investigated applications, the treatment of patients with acute musculoskeletal and herpetic pain. For example, although heating pads/wraps and cold packs are widely used to alleviate pain associated with sprains, strains, and contusions, evidence of the effectiveness of these methods is lacking. However, there are sufficient data supporting the use of various topical formulations of nonsteroidal anti-inflammatory drugs (NSAIDs) for these indications (ketoprofen gel or patch, ibuprofen gel or cream, and diclofenac gel or patch), and demonstrating markedly less patient risk of systemic toxicity than is associated with oral NSAID therapy. A ketoprofen patch was shown to be effective and well tolerated in the treatment of patients with tendinopathies. In the treatment of acute neck or low back pain, cold and heat therapies have demonstrated limited effectiveness for patients, and the efficacy of topical NSAIDs has not been established. Use of topical NSAID therapy has been useful in reducing acute-phase herpes zoster pain, and the lidocaine 5% patch has been shown to reduce acute herpetic pain intensity once lesions have healed (the patch cannot be applied to open skin lesions). Topical analgesics represent an alternative treatment modality for patients experiencing acute pain who cannot or choose not to take oral therapies.
- Elimination of ketoprofen from the stratum corneum after topical administration with ketoprofen formulations in human subjects. [JOURNAL ARTICLE]
- Int J Pharm 2014 Feb 12.
To assess the drug concentrations and elimination rate of ketoprofen in the stratum corneum following topical administration of two different formulations in human subjects for reference in the risk management of photocontact dermatitis caused by topical ketoprofen.Ketoprofen tape and gel were used as test formulations. The stratum corneum at the application sites was removed by tape-stripping at scheduled times after removal of the formulations. The ketoprofen concentration in the stratum corneum was determined by liquid chromatography with tandem mass spectrometry.The ketoprofen concentration in the stratum corneum decreased and the elimination half-life in the stratum corneum was comparable between tape and gel after removal of the test formulations. The ketoprofen concentration in the stratum corneum decreased more rapidly after the subjects took a shower. Ketoprofen was not detected in the stratum corneum adjacent to the tape application sites.Ketoprofen in the stratum corneum appears to reach the lower limit of quantitation (0.005μg) 12-16 days after removal of tape or gel. This period is similar to that recommended for avoiding ultraviolet light after removal of topical ketoprofen formulations in the Summary of Product Characteristics for topical ketoprofen in the European Union.
- Evaluation of the effects of dexketoprofen trometamol on knee joınt: an in vivo & in vitro study. [Journal Article]
- Indian J Med Res 2013 Dec; 138(6):912-8.
Background & objectives: Intra-articular (ia) injections of local anaesthetics and non-steroidal anti-inflammatory drugs (NSAID's) are simple and efficient to ensure post-operative analgesia but some of these have toxic effects on the synovium and cartilage. Dexketoprofen is recently introduced S-enantiomer of ketoprofen with a better analgesic and side effect profile. This study was done to evaluate the possible toxic effects of dexketoprofen trometamol on knee joint cartilage and symovium in vitro and in vivo.
Methods:Forty one Sprague-Dawley rats were anaesthetized by ketamine. Dexketoprofen trometamol (0.25 ml) was injected into the right knee joint of the 35 rats and 0.25 ml serum physiologic into the left knee joint of the same animals. Six rats were sham operated. Thirty five animals were randomly divided into five equal groups. Seven animals were sacrified at 24 th , 48 th hours and 7 th , 14 th , and 21 st days of the injections. Haematoxylin eosin stained sections from the knee joints were evaluated for the signs of inflammation according to five point scale. Primary chondrocytes were isolated from the articular cartilages of rats for in vitro studies. Cells were exposed to 0.25 ml dexketoprofen trometamol or 0.25 ml dexketoprofen medium mixture at 1:1 ratio for 15, 30, 45 and 60 min. Cell viability was determined by 3-(4, 5- dimethylthiazole-2-yl)-2.5-diphenyl tetrazolium bromide (MTT) assay, 24, 48 and 72 h after drug treatment.
Results:No significant histopathologic differences were found between dexketoprofen trometamol and physiologic serum (control) applied joints at all time intervals in in vivo study. Cell proliferation in dexketoprofen trometamol treated chondrocytes was inhibited for all time intervals compared to control. In dexketoprofen-medium mixture groups significant differences were only seen 24 h after the 30 and 45 min application of medium: drug mixture. Interpretation & conclusions: Intra-articular application of dexketoprofen trometamol into the rat knee joints did not cause significant histopathological changes, but its in vitro application in primary chondrocyte culture caused significant cytotoxicity. The effects of dexketoprofen at different concentrations need to be further investigated in culture of rat and human chondrocytes.
- Removal of pharmaceuticals and personal care products during water recycling: microbial community structure and effects of substrate concentration. [JOURNAL ARTICLE]
- Appl Environ Microbiol 2014 Feb 7.
Many pharmaceuticals and personal care products (PPCPs) have been shown to be biotransformed in water treatment systems. However, little research exists on the effect of initial PPCP concentration on PPCP biotransformation or on the microbial communities treating impacted water. In this study, biological PPCP removal at varying concentrations was assessed using laboratory columns inoculated with wastewater treatment plant effluent. Pyrosequencing was used to examine microbial communities in the columns and in soil from a soil aquifer treatment site (SAT; a method of water treatment prior to reuse). Laboratory columns were supplied with different concentrations (0.25, 10, 100, or 1000 μg L(-1)) of each of 15 PPCPs. Five PPCPs (biosol, p-chloro-m-xylenol, gemfibrozil, ketoprofen, and phenytoin) were not removed at any tested concentrations. Two PPCPs (naproxen and triclosan) exhibited removals independent of PPCP concentration. PPCP removal efficiencies were dependent on initial concentrations for biphenylol, p-chloro-m-cresol, chlorophene, diclofenac, 5-fluorouracil, ibuprofen, and valproic acid, showing that PPCP concentration can affect biotransformation. Biofilms from sand samples collected from the 0.25 and 10 μg L(-1) PPCP columns were pyrosequenced along with SAT soil samples collected on three consecutive days of a wetting and drying cycle to enable comparison of these two communities exposed to PPCPs. SAT communities were similar in taxonomy and phylotype composition to column communities, and both were found to contain close relatives of known PPCP-degraders. The efficiency of biological removal of PPCPs was found to be dependent on the concentration at which the contamination occurs for some, but not all, PPCPs.
- Pharmaceutical salts and cocrystals involving amino acids: A brief structural overview of the state-of-art. [Journal Article]
- Eur J Med Chem 2014 Mar 3.:411-26.
Salification of new drug substances in order to improve physico-chemical or solid-state properties (e.g. dissolution rate or solubility, appropriate workup process, storage for further industrial and marketing development) is a well-accepted procedure. Amino acids, like aspartic acid, lysine or arginine take a great part in this process and are implicated in several different formulations of therapeutic agent families, including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class), NSAIDs (ketoprofen, ibuprofen and naproxen from profen family, acetylsalicylic acid) or antiarrhythmic agents (e.g. ajmaline). Even if more than a half of known pharmaceutical molecules possess a salifiable moiety, what can be done for new potential drug entity that cannot be improved by transformation into a salt? In this context, after a brief review of pharmaceutical salts on the market and the implication of amino acids in these formulations, we focus on the advantage of using amino acids even when the target compound is not salifiable by exploiting their zwitterionic potentialities for cocrystal edification. We summarize here a series of new examples coming from literature to support the advantages of broadening the application of amino acids in formulation for new drug substances improvement research for non-salifiable molecules.