Modulation of methylation in the FMR1 promoter region after long term treatment with L-carnitine and acetyl-L-carnitine.
Explore the source record for details and available documents.
Acetylcarnitine↗
Biomedical subjects
M Calvani
Publications and source records attributed to M Calvani.
L-Acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors.
L-Acetylcarnitine (LAC, 100 mg/kg, s.c.), a drug commonly used for the treatment of painful neuropathies, substantially reduced mechanical allodynia in rats subjected to monolateral chronic constriction injury (CCI) of the sciatic nerve and also attenuated acute thermal pain in intact rats. In both cases, induction of analgesia required repeated injections of LAC, suggesting that the drug induces plastic changes within the nociceptive pathway. In both CCI- and sham-operated rats, a 24-day treatment with LAC increased the expression of metabotropic glutamate (mGlu) receptors 2 and 3 in the lumbar segment of the spinal cord, without changing the expression of mGlu1a or -5 receptors. A similar up-regulation of mGlu2/3 receptors was detected in the dorsal horns and dorsal root ganglia of intact rats treated with LAC for 5-7 days, a time sufficient for the induction of thermal analgesia. Immunohistochemical analysis showed that LAC treatment enhanced mGlu2/3 immunoreactivity in the inner part of lamina II and in laminae III and IV of the spinal cord. An increased mGlu2/3 receptor expression was also observed in the cerebral cortex but not in the hippocampus or cerebellum of LAC-treated animals. Reverse transcription-polymerase chain reaction combined with Northern blot analysis showed that repeated LAC injections selectively induced mGlu2 mRNA in the dorsal horns and cerebral cortex (but not in the hippocampus). mGlu3 mRNA levels did not change in any brain region of LAC-treated animals. To examine whether the selective up-regulation of mGlu2 receptors had any role in LAC-induced analgesia, we have used the novel compound LY 341495, which is a potent and systemically active mGlu2/3 receptor antagonist. LAC-induced analgesia was largely reduced 45 to 75 min after a single injection of LY 341495 (1 mg/kg, i.p.) in both CCI rats tested for mechanical allodynia and intact rats tested for thermal pain. We conclude that LAC produces analgesia against chronic pain produced not only by peripheral nerve injury but also by acute pain in intact animals and that LAC-induced analgesia is associated with and causally related to a selective up-regulation of mGlu2 receptors. This offers the first example of a selective induction of mGlu2 receptors and discloses a novel mechanism for drug-induced analgesia.
Acetylcarnitine↗
Fever episodes in early life and the development of atopy in children with asthma.
The hygiene hypothesis proposes that declining exposure to infections may contribute to the allergy and asthma "epidemic", but studies to identify the infections involved have so far provided conflicting data. An alternative approach could be based on an attempt to identify the mechanisms common to several different infections, which may exert an atopy "protective" effect. One of these mechanisms may be fever, which is frequently associated with infections and may stimulate the synthesis of interferon-gamma. The aim of this study was to test whether the frequency of fever episodes in the first years of life are related to the development of atopy. Asthmatic (cases, n=317) and nonasthmatic children (controls, n=304) attending the outpatients' allergy clinic were enrolled. The number of fever episodes in the first 2 yrs of life was retrospectively assessed by parental report via a questionnaire completed by interview. Atopy was determined by skin-prick tests to 10 prevalent inhalant allergens at the time of examination. Fever episodes in the first or in the second year of life were significantly more frequent among children with asthma. However, this difference was totally accounted for by a subgroup of children who started wheezing in the first 12 months of life. A significant inverse association between fever episodes in the first 12 months of life and atopy was found among cases, but not in controls. The association persisted after adjusting for age, sex, daycare attendance and family history of atopic disease and this was totally accounted for by asthmatic children who started wheezing after the first 12 months of life. No significant association was found between fever episodes in the second year of life and atopy for cases and controls. The data presented here suggests that fever episodes early in life may affect the natural history of asthma by preventing the development of atopy and highlights the need to monitor fever episodes of any kind in longitudinal studies aimed at investigating the hygiene hypothesis prospectively.
Adolescent↗
Long-term ethanol administration enhances age-dependent modulation of redox state in brain and peripheral organs of rat: protection by acetyl carnitine.
Evidence is accumulating that intermediates of oxygen reduction may be associated with the development of alcoholic disease. Free radical-induced perturbation of the oxidant/antioxidant balance in the cell is widely recognized as the main causative factor of age-related disorders. In the present study we investigated the effects of 20 months of ethanol consumption on the antioxidant defense system in different rat organs compared with normal aging in the absence and presence of treatment with L-acetyl carnitine. We demonstrate that aged rats underwent significant perturbation of the antioxidant defense system, as indicated by depletion of reduced glutathione (GSH) content, increased oxidized GSH, free radical-induced luminescence associated with increased hydroxynonenal content and decreased GSH reductase activity. These modifications, observed particularly in brain and liver compared with other organs, were enhanced by long-term alcohol exposure and, interestingly, were significantly reduced with acetyl carnitine supplements. Our results indicate that decreased GSH reductase activity and thiol depletion are important factors in effecting a pathogenic role for oxidative stress in aging and in all situations in which age-correlated and oxidant-induced changes occur, such as in alcoholism. Administration of acetyl carnitine greatly reduces these metabolic abnormalities. Our findings support its pharmacological potential in the management of alcoholic disturbances.
Acetylcarnitine↗
Long-term ethanol administration enhances age-dependent modulation of redox state in different brain regions in the rat: protection by acetyl carnitine.
Chronic alcoholism is a major public health problem and causes multiorgan diseases and toxicity. Although the majority of ethanol ingested is metabolized by the liver, it has intoxicating effects in the brain. Evidence is accumulating that intermediates of oxygen reduction may be associated with the development of alcoholic disease. Several studies have shown the capacity of carnitine and its derivatives to influence ethanol metabolism. We have previously demonstrated that preadministration of L-carnitine to rats receiving ethanol significantly reduced fatty acid ethyl esters in different organs and that the carnitine/acylcarnitine system is crucial for maintaining a functional acetyl-CoA/CoA ratio under conditions in which cellular homeostasis is exposed to the deleterious effects of accumulating organic acids. Ethanol, administered to rats for 20 months, induced significant changes in the status of glutathione, primarily in the brain regions of hippocampus and cerebellum, followed by cortex and striatum, where a decrease in reduced glutathione (GSH) and the GSH/oxidized glutathione ratio was found. The same brain regions showed a significant increase in free radical-induced luminescence and hydroxynonenal (HNE), which were associated with decreased GSH reductase activity. Long-term supplementation with acetyl carnitine significantly reduced GSH depletion, particularly in the brain regions of hippocampus, an effect associated with decreased luminescence and HNE formation. In addition, acetyl carnitine treatment increased GSH reductase and arginase activities. Our results indicate that decreased GSH reductase activities associated with thiol depletion are important factors sustaining a pathogenic role in alcohol-related pathologies. Administration of acetyl carnitine greatly reduces these metabolic abnormalities. This evidence supports the pharmacological potential of acetyl carnitine in the management of alcoholic disturbances.
Acetylcarnitine↗
Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages.
We studied the regulation of the kynurenine pathway of tryptophan metabolism in human monocyte-derived macrophages (MDM) with the aim of evaluating macrophage involvement in inflammatory neurological disorders. Cultured MDM metabolized tryptophan and released kynurenine metabolites, including the excitotoxin quinolinic acid (QUIN). Lipopolysaccharides (LPS) or the pro-inflammatory cytokines INFgamma and TNFalpha increased, while IL 4 or IL 10 inhibited the rate of tryptophan metabolism and the release of QUIN. The incubation media of INFgamma-exposed MDM caused neuronal death in primary cultures of mixed cortical cells. Glutamate receptor antagonists or poly(ADP-ribose) polymerase inhibitors significantly reduced this death, thus suggesting new possibilities for the treatment of neuronal damage in neuroinflammatory disorders.
Cell Death↗
Propionyl-L-carnitine as protector against adriamycin-induced cardiomyopathy.
Propionyl- l -carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of many forms of cardiomyopathies. In this study, the possible mechanisms whereby PLC could protect against adriamycin (ADR)-induced cardiomyopathy were carried out. Administration of ADR (3 mg kg(-1)i.p., every other day over a period of 2 weeks) resulted in a significant two-fold increase in serum levels of creatine phosphokinase, lactate dehydrogenase and glutamic oxaloacetic transaminase, whereas daily administration of PLC (250 mg kg(-1), i.p. for 2 weeks) induced non-significant change. Daily administration of PLC to ADR-treated rats resulted in complete reversal of ADR-induced increase in cardiac enzymes except lactate dehydrogenase which was only reversed by 66%. In cardiac tissue homogenate, ADR caused a significant 53% increase in malonedialdehyde (MDA) and a significant 50% decrease in reduced glutathione (GSH) levels, whereas PLC induced a significant 33% decrease in MDA and a significant 41% increase in GSH levels. Daily administration of PLC to ADR-treated rats completely reversed the increase in MDA and the decrease in GSH induced by ADR to the normal levels. In rat heart mitochondria isolated 24 h after the last dose, ADR induced a significant 48% and 42% decrease in(14)CO(2)released from the oxidation of [1-(14)C]palmitoyl-CoA and [1-(14)C]palmitoylcarnitine, respectively, whereas PLC resulted in a significant 66% and 54% increase in the oxidation of both substrates, respectively. Interestingly, administration of PLC to ADR-treated rats resulted in complete recovery of the ADR-induced decrease in the oxidation of both substrates. In addition, in rat heart mitochondria, the oxidation of [1-(14)C]pyruvate, [1-(14)C]pyruvate and [1-(14)C]octanoate were not affected by ADR and/or PLC treatment. Moreover, ADR caused severe histopathological lesions manifested as toxic myocarditis which is protected by PLC. Worth mentioning is that PLC had no effect on the antitumour activity of ADR in solid Ehrlich carcinoma. Results from this study suggest that: (1) in the heart, PLC therapy completely protects against ADR-induced inhibition of mitochondrial beta -oxidation of long-chain fatty acids; (2) PLC has and/or induces a powerful antioxidant defense mechanism against ADR-induced lipid peroxidation of cardiac membranes; and finally (3) PLC has no effect on the antitumour activity of ADR.
Animals↗
Latent coeliac disease in a child with epilepsy, cerebral calcifications, drug-induced systemic lupus erythematosus and intestinal folic acid malabsorption associated with impairment of folic acid transport across the blood-brain barrier.
UNLABELLED: A 15-year-old boy with epilepsy and cerebral calcifications, treated with valproic acid, ethyl phenylbarbiturate and ethosuximide, was referred for drug induced systemic lupus erythematosus. Anti-gliadin (AGA) and anti-endomysium (EMA) antibody tests were both positive (EMA titre 1:50). Endoscopic duodenal biopsy showed intense chronic inflammation without villous atrophy or crypt hyperplasia. The child was discharged with a gluten-containing diet. The follow-up showed an increase in EMA titre (1:200) and the persistence of AGA. After 15 months, a second endoscopic intestinal biopsy showed flat mucosa and villous atrophy. Three serum folic acid determinations showed 1.8, 2.4, 2.0 ng/ml (reference range 2.5-16.9 ng/ml) prior to the two intestinal biopsies, but returned to normal levels (11.8 ng/ml) after a gluten-free diet and oral supplementation together. Two years later, the frequency of epileptic seizures was unchanged despite ongoing anti-epileptic treatment and a gluten-free diet. As cerebral calcification and epilepsy are reminiscent of the findings in congenital folate malabsorption, oral loading tests with 5 mg folic acid were carried out and showed impaired intestinal absorption and a defect in the transport across the blood-brain barrier. Low CSF folate levels (13.9 and 12.6 ng/ml, reference range 15-40 ng/ml) and an alteration in the CSF/serum folate ratio (1.43 and 1.16, normal ratio 3:1) were also found as well as increased levels of cystathionine both in CSF (40 micromol/l, reference range 18-28 micromol/l) and in serum (32 micromol/l, reference value <0.10 micromol/l). CONCLUSION: Impairment of intestinal folic acid absorption with a defect in folic acid transport across the blood-brain barrier has been demonstrated in a case of epilepsy and cerebral calcifications associated with coeliac disease.
Adolescent↗
Effects of acetyl-L-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat.
Increasing evidence suggests that Fatty acid ethyl esters (FAEE) play a central role in ethanol induced organ damage. In the current study we measured FAEE formation in rats after short-term oral administration of ethanol, in the presence and absence of pre-treatment with acetyl-L-carnitine. Ethanol treatment caused a significant increase in the levels of FAEE, particularly in the brain and heart, but also in the kidney and liver. Increases in FAEE were associated with a significant increase in FAEE synthase activity, GSH transferase activity, and lipid hydroperoxide levels. Pretreatment with acetyl-L-carnitine resulted in a significant reduction of FAEE accumulation, decrease in FAEE synthase and GSH transferase activities, and lipid hydroperoxide levels. Administration of acetyl-L-carnitine greatly reduced the metabolic abnormalities due to non-oxidative ethanol metabolism, through an increment in lipid metabolism/turnover and by the modulation of the activities of enzymes associated with FAEE synthesis. These results suggest a potentially important pharmacological role for acetyl-L-carnitine in the prevention of alcohol-induced cellular damage.
Acetylcarnitine↗
Carnitine protects the molecular chaperone activity of lens alpha-crystallin and decreases the post-translational protein modifications induced by oxidative stress.
Explore the source record for details and available documents.
Acetylcarnitine↗
Effects of propyonil-l-carnitine topical irrigation in distal ulcerative colitis: a preliminary report.
Explore the source record for details and available documents.
Administration, Topical↗
[L-acetylcarnitine treatment on fragile X patients hyperactive behaviour].
Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome (FXS), the most common inherited disease causing mental retardation. Therapeutical approaches are actually based on Central Nervous System (CNS) stimulants lacking a well defined rationale and efficacy while they further decrease the patient's limited attention span. A pilot study on 17 fragile X male treated with L-acetylcarnitine (LAC) over one year, showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Questionnaire. LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity. LAC is a small, hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters. Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis. The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS. The exogenous administration of LAC may affect brain activity in FXS by: I) modulation of fuel partitioning for energy production, which at the mithocondrial level is associated with the Kreb's cycle metabolic role in neurotransmitter synthesis; II) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids; III) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS. Based on the above premises an explorative, double-blind, placebo controlled, multicenter study is ongoing. A total population of 160 children from nine European centers will be enrolled. The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Questionnaire.
Acetylcarnitine↗
A 1-year controlled trial of acetyl-l-carnitine in early-onset AD.
OBJECTIVE: To determine the efficacy of acetyl-l-carnitine (ALCAR) on the rate of decline in early-onset AD patients. METHODS: A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Subjects were 45 to 65 years old, with a diagnosis of probable AD according to National Institute of Neurological Communicative Disorders-Alzheimer's Disease and Related Disorders Association criteria and had a Mini-Mental State Examination (MMSE) score between 12 and 26. They were treated with ALCAR (1 g tid) or placebo. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive Component and the Clinical Dementia Rating Scale. Secondary measures included the ADAS Non-Cognitive Subscale, the MMSE, an Activities of Daily Living Scale (ADL), and a Clinician-Based Impression of Change (CIBIC). RESULTS: Two-hundred twenty-nine patients were enrolled and randomized to drug treatment, with 117 taking placebo and 112 taking ALCAR. There were no significant differences between the two groups at baseline. For the primary outcome measures, there were no significant differences between the treatment groups on the change from baseline to endpoint in the intent-to-treat analysis. In the completer sample only, there was less deterioration in the MMSE for the ALCAR-treated subjects. There was no difference in rate of decline on the CIBIC and the ADL scale. There were no significant differences in the incidence of adverse events by treatment arm. CONCLUSION: Overall, in a prospectively performed study in young-onset AD patients, ALCAR failed to slow decline. Less decline was seen on the MMSE in the completer sample only, with the difference being mediated by reducing decline in attention. A combination of ALCAR and a cholinesterase inhibitor should be tested for additivity.
Acetylcarnitine↗
Carnitine: an osmolyte that plays a metabolic role.
Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely present in all cells from prokaryotic to eukaryotic ones. It is the sole source of carbon and nitrogen in some bacteria; it serves as osmoprotectant in others. It is a carrier of acyl moieties, and exclusively of long-chain fatty acids for mitochondrial beta-oxidation in mammals. The conspicuously similar composition of the intracellular milieu among widely different species in relation to organic osmolyte systems involves the methylamine family to which carnitine belongs. This prompted us to examine the osmolytic properties of carnitine in an attempt to clarify the metabolic functions carnitine has acquired during evolution. An understanding of the metabolic functions of this organic compatible solute impinge on research involving this compound.
Animals↗
Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system.
An efficient regulation of fuel metabolism in response to internal and environmental stimuli is a vital task that requires an intact carnitine system. The carnitine system, comprehensive of carnitine, its derivatives, and proteins involved in its transformation and transport, is indispensable for glucose and lipid metabolism in cells. Two major functions have been identified for the carnitine system: (1) to facilitate entry of long-chain fatty acids into mitochondria for their utilization in energy-generating processes; (2) to facilitate removal from mitochondria of short-chain and medium-chain fatty acids that accumulate as a result of normal and abnormal metabolism. In cancer patients, abnormalities of tumor tissue as well as nontumor tissue metabolism have been observed. Such abnormalities are supposed to contribute to deterioration of clinical status of patients, or might induce cancerogenesis by themselves. The carnitine system appears abnormally expressed both in tumor tissue, in such a way as to greatly reduce fatty acid beta-oxidation, and in nontumor tissue. In this view, the study of the carnitine system represents a tool to understand the molecular basis underlying the metabolism in normal and cancer cells. Some important anticancer drugs contribute to dysfunction of the carnitine system in nontumor tissues, which is reversed by carnitine treatment, without affecting anticancer therapeutic efficacy. In conclusion, a more complex approach to mechanisms that underlie tumor growth, which takes into account the altered metabolic pathways in cancer disease, could represent a challenge for the future of cancer research.
Antineoplastic Agents↗
Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions.
This review focuses on the regulation of myocardial fatty acids and glucose metabolism in physiological and pathological conditions, and the role of L-carnitine and of its derivative, propionyl-L-carnitine. Fatty acids are the major oxidation fuel for the heart, while glucose and lactate provide the remaining need. Fatty acids in cytoplasm are transformed to long-chain acyl-CoA and transferred into the mitochondrial matrix by the action of three carnitine dependent enzymes to produce acetyl-CoA through the beta-oxidation pathway. Another source of mitochondrial acetyl-CoA is from the oxidation of carbohydrates. The pyruvate dehydrogenase (PDH) complex, the key irreversible rate limiting step in carbohydrate oxidation, is modulated by the intra-mitochondrial ratio acetyl-CoA/CoA. An increased ratio results in the inhibition of PDH activity. A decreased ratio can relieve the inhibition of PDH as shown by the transfer of acetyl groups from acetyl-CoA to carnitine, forming acetylcarnitine, a reaction catalyzed by carnitine acetyl-transferase. This activity of L-carnitine in the modulation of the intramitochondrial acetyl-CoA/CoA ratio affects glucose oxidation. Myocardial substrate metabolism during ischemia is dependent upon the severity of ischemia. A very severe reduction of blood flow causes a decrease of substrate flux through PDH. When perfusion is only partially reduced there is an increase in the rate of glycolysis and a switch from lactate uptake to lactate production. Tissue levels of acyl-CoA and long-chain acylcarnitine increase with important functional consequences on cell membranes. During reperfusion fatty acid oxidation quickly recovers as the prevailing source of energy, while pyruvate oxidation is inhibited. A considerable body of experimental evidence suggests that L-carnitine exert a protective effect in in vitro and in vivo models of heart ischemia and hypertrophy. Clinical trials confirm these beneficial effects although controversial results are observed. The actions of L-carnitine and propionyl-L-carnitine cannot be explained as exclusively dependent on the stimulation of fatty acid oxidation but rather on a marked increase in glucose oxidation, via a relief of PDH inhibition caused by the elevated acetyl-CoA/CoA ratio. Enhanced pyruvate flux through PDH is beneficial for the cardiac cells since less pyruvate is converted to lactate, a metabolic step resulting in the acidification of the intracellular compartment. In addition, L-carnitine decreases tissue levels of acyl moieties, a mechanism particularly important in the ischemic phase.
Animals↗
Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence syndrome in rats.
The effect of acetyl-L-carnitine on alcohol consumption and its possible ability to alleviate all symptomatology of ethanol withdrawal syndrome has been investigated in rats. Alcohol-dependence was induced in animals (9-15 g/kg ethanol solution at 20% for a period of 4 days) in order to measure the effects of acetyl-L-carnitine on ethanol abstinence syndrome. The ethanol dependence phase was characterized by the onset of signs and responses of progressive severity: hyperactivity, tremors, spastic rigidity and spontaneous convulsive seizures. After 4 days, 8 h after the last ethanol administration, two groups of animals received acetyl-L-carnitine (125 mg/kg and 250 mg/kg intraperitoneally, respectively) and the intensity of the withdrawal syndrome was assessed on the basis of the appearance of tremors. The effect of acetyl-L-carnitine on voluntary alcohol consumption was investigated in a rat line selected for innate ethanol preference. For 15 days the animals could freely choose both water and/or a hydroalcoholic solution (10% p:v). Acetyl-L-carnitine was given intraperitoneally at a dose of 200 mg/kg twice daily. The water and the hydroalcoholic solution levels were checked at the same time daily. Acetyl-L-carnitine treatment significantly reduced the onset of tremors in ethanol withdrawal syndrome as well as the level of ethanol intake in alcohol-preferring rats. These results suggest a possible pharmacological role of acetyl-L-carnitine in the treatment of alcohol dependence.
Acetylcarnitine↗
[Reye's syndrome: the death of a syndrome? (Or death by a syndrome?)].
Reye syndrome is characterized by acute encephalopathy and fatty degeneration of the liver almost exclusively in children. The onset is heralded by profuse vomiting and varying neurologic impairment from irritability to coma, decerebration and death. The encephalopathy must be associated with a greater increase in the levels of ammonia, or alanine amino-transferase and aspartate amino-transferase in serum; and with a fatty metamorphosis of the liver diagnosed by biopsy or at autopsy. The only characteristic universally accepted as diagnostic are the specific mithocondrial changes in the liver-biopsy specimen. Larger studies confirmed the association of aspirin with RS. The CDC of Atlanta cautioned physician and parents and a dramatic decline in case began at that time. Classic Reye syndrome is now so rare in the USA that when an apparent case is encountered in a child who has not taken aspirin, other diagnoses should be considered. After a brief survey of RS relative lack of specificity of case definition and of the polyhedric etiopathogenetic moments, the A. on the personal experience, point: a) the biological unicity of the man and the necessary coexistence of "constitutional" factors (metabolic and/or endocrine, and/or immunitary factors, the later almost never investigated), toxic, and infectious factors for the syndrome's deflagration; b) some aspects of the continued existence of therapeutic and diagnostic problems: the aspirin and/or salicilate use and the pharmacogenetic; the continued existence of other, generally similar conditions, such the drug and other known and unknown toxic mithocondrial factors that provoke this unusual response to common infections; and the inborn errors of metabolism; c) some practical aspects of diagnostic and therapeutic approach.
Anti-Inflammatory Agents, Non-Steroidal↗