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- Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals. [REVIEW]
- Philos Trans R Soc Lond B Biol Sci 2014 Nov 19; 369(1656)
Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human-fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment.
- Celecoxib Inhibits Prion Protein 90-231-Mediated Pro-inflammatory Responses in Microglial Cells. [JOURNAL ARTICLE]
- Mol Neurobiol 2014 Nov 18.
Activation of microglia is a central event in the atypical inflammatory response occurring during prion encephalopathies. We report that the prion protein fragment encompassing amino acids 90-231 (PrP90-231), a model of the neurotoxic activity of the pathogenic prion protein (PrP(Sc)), causes activation of both primary microglia cultures and N9 microglial cells in vitro. This effect was characterized by cell proliferation arrest and induction of a secretory phenotype, releasing prostaglandin E2 (PGE2) and nitric oxide (NO). Conditioned medium from PrP90-231-treated microglia induced in vitro cytotoxicity of A1 mesencephalic neurons, supporting the notion that soluble mediators released by activated microglia contributes to the neurodegeneration during prion diseases. The neuroinflammatory role of COX activity, and its potential targeting for anti-prion therapies, was tested measuring the effects of ketoprofen and celecoxib (preferential inhibitors of COX1 and COX2, respectively) on PrP90-231-induced microglial activation. Celecoxib, but not ketoprofen significantly reverted the growth arrest as well as NO and PGE2 secretion induced by PrP90-231, indicating that PrP90-231 pro-inflammatory response in microglia is mainly dependent on COX2 activation. Taken together, these data outline the importance of microglia in the neurotoxicity occurring during prion diseases and highlight the potentiality of COX2-selective inhibitors to revert microglia as adjunctive pharmacological approach to contrast the neuroinflammation-dependent neurotoxicity.
- Evaluation of the photolysis of pharmaceuticals within a river by 2 year field observations and toxicity changes by sunlight. [JOURNAL ARTICLE]
- Environ Sci Process Impacts 2014 Nov 11.
To improve the risk assessment of pharmaceuticals, it is helpful to know how rapidly they are removed from river water. Direct photolysis by sunlight could be an important process, but so far few studies have attempted to compare modeled with actual losses in a river. Therefore, we quantified natural attenuation by monitoring 56 pharmaceuticals and personal care products over 2 full years in a 2.6 km stretch of an urban river. In addition, to screen photoproducts, we used the Microtox test with Vibrio fischeri to evaluate changes in the toxicity of two photolabile pharmaceuticals, ketoprofen and diclofenac, under sunlight. During transport along the river stretch, ketoprofen and the photolabile pharmaceutical furosemide were attenuated by median values of 77% and 39%. The observed attenuation showed good agreement with photochemical attenuation estimated by an existing method at each sampling, suggesting that the method appeared to be effective for estimating the direct photolysis of the pharmaceuticals during river transport. The toxicity of diclofenac decreased under sunlight, while that of ketoprofen increased immediately after exposure (around 12 times in EC20) and remained high, indicating the existence of toxic and photostable photoproducts of ketoprofen. Therefore, ecological risks of photolabile pharmaceuticals may increase during river transport in some cases, indicating the necessity to incorporate their photoproducts into the estimation method.
- Beers criteria-based assessment of medication use in hospitalized elderly patients in southern Brazil. [Journal Article]
- J Family Med Prim Care 2014 Jul; 3(3):260-5.
Population aging has evolved gradually. Polypharmacy to control disease associated with age-related physiological changes increases the risk of adverse drug reactions, including drug interactions among the elderly population.This study was intended to assess the medications used by the elderly population, aiming at identifying the potentially inappropriate medications according to the Beers Criteria.We conducted a cross-sectional study on medical records to assess the use of medications by elderly patients admitted to the Hospital Nossa Senhora da Conceição in 2011. The variables included gender, age, reasons for admission, comorbidities, and medications used by the elderly patients.In total, we reviewed 440 medical records. Patients were predominantly male (51.6%). The total number of medications used was 5904, with an average of 13.4 per person. The three most commonly used drugs were dipyrone, omeprazole, and metoclopramide. The most frequently used drugs according to the Anatomical Therapeutic Chemical Classification (ATC) system were those of the alimentary tract and metabolism, nervous system, and cardiovascular system. Of the 255 types of drugs used, 42 (16.4%) were included in the Beers list, and the three most often used were metoclopramide, ketoprofen, and aspirin.The number of medications used per patient was substantial, and potentially inappropriate medications according to the Beers Criteria were significant as well.
- Comparison of NSAID Patch Given as Monotherapy and NSAID Patch in Combination with Transcutaneous Electric Nerve Stimulation, a Heating Pad, or Topical Capsaicin in the Treatment of Patients with Myofascial Pain Syndrome of the Upper Trapezius: A Pilot Study. [JOURNAL ARTICLE]
- Pain Med 2014 Nov 5.
This study compared the therapeutic effect of monotherapy with a nonsteroidal anti-inflammatory drug (NSAID) patch vs an NSAID patch combined with transcutaneous electric nerve stimulation (TENS), a heating pad, or topical capsaicin in the treatment of patients with myofascial pain syndrome (MPS) of the upper trapezius.A randomized, single-blind, controlled study of combination therapy for patients with MPS was performed.Ninety-nine patients were randomly assigned to one of four different self-management methods for treatment: NSAID patch (N = 25), NSAID patch + TENS (N = 24), NSAID patch + heating pad (N = 25), and NSAID patch + topical capsaicin (N = 25). The NSAID patch used in this study was a ketoprofen patch. All treatment groups were observed for 2 weeks, and the numeric rating scale (NRS) pain score, cervical active range of motion, pressure pain threshold, and Neck Disability Index were assessed.There was no significant difference between the NSAID patch alone group and the three combination therapy groups with respect to decrease in NRS score from baseline (day 0) to each period of observation. In covariate analysis, although there was no difference among the groups in most of the periods, the data at day 14 indicated a trend (P = 0.057). There were no significant differences in the other variables.We did not observe a statistical difference in improvements to the clinical variables among the four different methods. However, further studies regarding the effectiveness of a mixture of topical capsaicin and ketoprofen in patients with MPS should be considered.
- Effects of Solution Chemistry on Adsorption of Selected Pharmaceuticals and Personal Care Products (PPCPs) by Graphenes and Carbon Nanotubes. [Journal Article]
- Environ Sci Technol 2014 Nov 18; 48(22):13197-206.
Adsorption of three selected pharmaceuticals and personal care products (PPCPs) (ketoprofen (KEP), carbamazepine (CBZ), and bisphenol A (BPA)) by two reduced graphene oxides (rGO1 and rGO2) and one commercial graphene was examined under different solution conditions. Single-walled carbon nanotubes (SWCNTs), multiwalled carbon nanotubes (MWCNTs), and powdered graphite were also investigated for comparison. All adsorption isotherms followed the order of SWCNTs > rGO1 > rGO2 > MWCNTs > graphene > graphite, consistent with the orders of their surface areas and micropore volumes. After surface area normalization, adsorption affinities of the three PPCPs onto graphenes were lower than onto graphite, suggesting incomplete occupation for adsorption sites because of the aggregation of graphene sheets and the presence of oxygen-containing functional groups. The observed pH effects on adsorption correlated well with the pH-regulated distribution of the protonated neutral species of the three PPCPs. Increasing ionic strength from 0 to 20 mM increased KEP adsorption due to the electrostatic screening by Na(+) and Ca(2+). Both humic acid (HA) and sodium dodecylbenzenesulfonate (SDBS) suppressed PPCPs adsorption to all adsorbents, but their impacts onto graphenes were lower than those onto CNTs because of their lower adsorption by graphenes. More severe HA (or SDBS) effect was found on negatively charged KEP at the tested solution pH 6.50 due to the electrostatic repulsion between the same charged KEP and HA (or SDBS). The findings of the present study may have significant implications for the environmental fate assessment of PPCPs and graphene.
- Occurrence of selected pharmaceuticals in the principal sewage treatment plants in Rome (Italy) and in the receiving surface waters. [JOURNAL ARTICLE]
- Environ Sci Pollut Res Int 2014 Oct 29.
This paper provides data on the occurrence of selected human pharmaceuticals (carbamazepine, clofibric acid, diclofenac, fenofibrate, fenoprofen, gemfibrozil, ibuprofen, ketoprofen, and naproxen) including steroid hormones (17β-estradiol, 17α-ethinylestradiol, and estrone) in influents/effluents to/from the four principal wastewater treatment plants (WWTPs) serving the city of Rome (Italy), in two different sampling campaigns. Target compounds were also analyzed in the receiving River Tiber and River Aniene. Analytical determination was carried out by LC-MS/MS after sample cleanup and concentration by off-line solid-phase extraction (SPE). The aim of the study was to increase the information currently available on the presence and persistence of pharmaceuticals in Italian urban wastewaters and to evaluate the environmental impact of the pharmaceutical residues discharged through effluents into the receiving rivers. Results indicated that after the treatment processes, most of pharmaceuticals were not completely eliminated, as average removal efficiencies were in the 14-100 % wide range during both sampling periods, with higher yields in spring than in winter. Levels detected in overall samples ranged from 5 to 2,230 ng/L in influents and from 5 to 1,424 ng/L in effluents. Carbamazepine, diclofenac, ibuprofen, and gemfibrozil showed the highest persistence to removal. Concentrations in the receiving waters were about one order of magnitude lower than in effluents, with a tendency to increase progressively through the urban tract of the river. Finally, an environmental risk analysis showed that carbamazepine, gemfibrozil, and estrone can pose a high risk at the concentrations detected in effluents and a medium risk in rivers, highlighting their potential hazard for the health of the aquatic ecosystem.
- Selective and simultaneous determination of NSAIDs in equine plasma by HPLC with molecularly imprinted solid-phase extraction. [Journal Article]
- Bioanalysis 2014 Aug; 6(16):2147-58.
Detection of nonsteroidal anti-inflammatory drugs (NSAIDs) in equine plasma is a significant analytical problem in veterinary anti-doping controls.A new HPLC method coupled to selective extraction with molecularly imprinted polymers was developed for the simultaneous determination in equine plasma of the NSAIDs phenylbutazone, flunixin, oxyphenbutazone, ketoprofen and naproxen. The analytical performances of the method have been evaluated both in standard solutions and equine plasma samples. Recovery: Molecularly imprinted polymers solid-phase extraction for all NSAIDs was >94% with intra-day values below 15.0% and inter-day values below 20%. Method quantification limit was 0.01 μg/ml.The developed method could be considered as a useful alternative to existing screening methods for the determination of NSAIDs in the context of studies of pharmacokinetics and anti-doping controls.
- Experimental model of tympanic colic (acute abdomen) in chinchillas (Chinchilla lanigera). [Journal Article]
- Lab Anim Res 2014 Sep; 30(3):136-41.
Digestive disorders caused by sudden changes in diet or inappropriate diet are among the most common disorders of the digestive system. Cecal or intestinal tympany, one consequence of inappropriate diet, is characterized by the accumulation of gases, marked distension of the cecum and colon and the induction of inflammatory processes. To know the effects of intestinal tympany on the enteric plexuses, we developed a method of experimental tympanic colic (TC) in the Chinchilla lanigera. This species was used in view of its susceptibility to TC. TC was induced with a diet rich in alfalfa associated with grain overload for two weeks. Physical and clinical examination including the von Frey test confirmed the diagnosis. The chinchillas with acute abdomen were treated with 1% ketoprofen and resumption of a balanced diet. Necropsy and histopathological analysis showed tympany-induced alterations mainly in the cecum and colon. After treatment, the control conditions were restored. The TC protocol is proposed as an experimental approach designed to aid the study of the effects of acute intestinal inflammation and obstruction caused by an inappropriate diet.
- Analgesia after Epidural Dexamethasone is Further Enhanced by IV Dipyrone, but Not IV Parecoxibe Following Minor Orthopedic Surgery. [Journal Article]
- Korean J Pain 2014 Oct; 27(4):345-52.
Epidural administration of dexamethasone has been suggested for pain control after minor orthopedic surgery. This study was conducted to assess its efficacy after such surgery, combined or not to IV dipyrone, IV parecoxibe or their combination.91 patients were randomly assigned to seven groups. Patients were submitted to spinal bupivacaine anesthesia combined to epidural administration of either 10 ml saline or 10 mg dexamethasone diluted to 10-ml volume. Patients also received 10 ml IV saline or 1 gr dipyrone and/or 40 mg parecoxibe diluted to 10 ml with saline. Control group (CG) received epidural and IV saline. Dexamethasone group (DexG) received epidural dexamethasone and IV saline. Dipyrone group (DipG) received epidural saline and IV dipyrone. Dex-Dip G received epidural dexamethasone and IV dipyrone. Parecoxibe group (ParG) received epidural saline and IV parecoxibe. Dex-ParG received epidural dexamethasone and IV parecoxibe. Finally, Dex-Dip-ParG received epidural dexamethasone and IV dipyrone plus IV parecoxibe.The CG expressed 4h of analgesia and sooner requested pain killer. DexG was similar to DipG or ParG or Dex-ParG (7-hours), and they requested less ketoprofen compared to the CG (P < 0.05). However, the Dex-DipG and the Dex-Dip-ParG resulted in longer time to demand pain killer (17-hours) and less ketoprofen consumption in 24-hours (P < 0.002). Adverse effects were similar among groups.The analgesia secondary to epidural dexamethasone was enhanced by IV dipyrone, while no effects were observed by the addition of IV parecoxibe.