Non-steroidal Anti-inflammatory Ketoprofen Research Articles

New inhibitors of 5-lipoxygenase catalytic activity based on 2-(3-methylphenyl)propanoic acid and 4-substituted morpholine derivatives.

New potential inhibitors of 5-lipoxygenase (5-LOX) based on the structure of 2-(3-benzoylphenyl)propanoic acid (an active component of the nonsteroidal antiinflammatory drug Ketoprofen) were designed using the SARD-21 program. The docking of these compounds in the active site of 5-LOX suggested that seven compounds can interact with this enzyme. Two of them can also be dual inhibitors of 5-LOX and two isoforms of cyclooxygenase.

Hidden exposure to formaldehyde in a swab caused allergic contact dermatitis

Octocrylene is an ultraviolet (UV)B and UVAII absorber that was introduced some 15 years ago, and is now widely used in sunscreen agents and skin care cosmetics. Since 2003, several studies, notably from France, Belgium, Spain, and Italy, have reported an increasing number of patients with photocontact allergy to octocrylene. This reaction is seen mainly in adult patients who have previously used topical products containing the non-steroidal anti-inflammatory drug ketoprofen. Photosensitization to ketoprofen leads, in many cases, to photocontact allergy to octocrylene; the mechanism of this reaction is unknown. Contact allergy to octocrylene also occurs, but is far less frequent, and is seen, in most cases, in children, resulting from the use of octocrylene-containing sunscreen products. In this article, (photo)contact allergy to octocrylene is fully reviewed.

Contact and photocontact allergy to octocrylene: a review

Octocrylene is an ultraviolet (UV)B and UVAII absorber that was introduced some 15 years ago, and is now widely used in sunscreen agents and skin care cosmetics. Since 2003, several studies, notably from France, Belgium, Spain, and Italy, have reported an increasing number of patients with photocontact allergy to octocrylene. This reaction is seen mainly in adult patients who have previously used topical products containing the non-steroidal anti-inflammatory drug ketoprofen. Photosensitization to ketoprofen leads, in many cases, to photocontact allergy to octocrylene; the mechanism of this reaction is unknown. Contact allergy to octocrylene also occurs, but is far less frequent, and is seen, in most cases, in children, resulting from the use of octocrylene-containing sunscreen products. In this article, (photo)contact allergy to octocrylene is fully reviewed.

Determination of 4′-isobutylacetophenone and other transformation products of anti-inflammatory drugs in water and sludge from five wastewater treatment plants in Sweden by hollow fiber liquid phase microextraction and gas chromatography–mass spectrometry

This work describes the development of a two-phase hollow fiber liquid phase microextraction method for the determination of three hydrophobic transformation products of the nonsteroidal anti-inflammatory drugs ketoprofen, ibuprofen and diclofenac: 3-acetobenzophenone, 4´-isobutylacetophenone and diclofenac amide. The optimized method involved extraction for 180min at a stirring speed of 440rpm. Hollow fibers (0.6mm i.d.) of 6cm length were employed and the acceptor phase consisted of 1-octanol. 5% Sodium chloride was added to samples to prevent loss of the solvent during extraction. Extracts were analyzed by GC–MS and method detection limits were in the range of 1.6–5.6ngL−1. The method was applied for the determination of target analytes in influent samples from five Swedish wastewater treatment plants (WWTPs). All three analytes were found in very low or non-detectable concentrations. The most abundant compound was 3-acetobenzophenone found at four of the investigated WWTPs at an average concentration of 62ngL−1. Diclofenac amide and 4′-isobutylacetophenone were only detected above LOD at one WWTP each at a concentration of 55 and 197ngL−1, respectively. Samples of water entering and exiting the activated sludge treatment as well as digested sludge were also collected from one of the WWTPs. Only diclofenac amide was detected in these samples. A higher concentration was detected in the effluent from the activated sludge treatment than the influent, thus indicating the formation of this compound during treatment. In the sludge, diclofenac amide was detected at 183ngg−1wet weight. Based on these results it can be concluded that the amounts of these compounds reaching WWTPs are very small, suggesting negligible risks to the aquatic environment. However, they also indicate the potential formation during the activated sludge process and accumulation into sludge for at least one of the compounds which is why further studies of these processes are needed.

Emerging organic contaminants in coastal waters: Anthropogenic impact, environmental release and ecological risk

This study provides a first estimate of the sources, distribution, and risk presented by emerging organic contaminants (EOCs) in coastal waters off southwestern Taiwan. Ten illicit drugs, seven nonsteroidal anti-inflammatory drugs (NSAIDs), five antibiotics, two blood lipid regulators, two antiepileptic drugs, two UV filters, caffeine, atenolol, and omeprazole were analyzed by solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry (SPE–LC–MS/MS). Thirteen EOCs were detected in coastal waters, including four NSAIDs (acetaminophen, ibuprofen, ketoprofen, and codeine), three antibiotics (ampicillin, erythromycin, and cefalexin), three illicit drugs (ketamine, pseudoephedrine, and MDMA), caffeine, carbamazepine, and gemfibrozil. The median concentrations for the 13 EOCs ranged from 1.47ng/L to 156ng/L. Spatial variation in concentration of the 13 EOCs suggests discharge into coastal waters via ocean outfall pipes and rivers. Codeine and ampicillin have significant pollution risk quotients (RQ>1), indicating potentially high risk to aquatic organisms in coastal waters.

Nonsteroidal anti-inflammatory therapy: changes on renal function of healthy dogs

To evaluate the renal function in healthy dogs submitted to nonselective and preferential COX-2 nonsteroidal anti-inflammatory drug (NSAID) therapy. Twenty four healthy dogs were distributed into four groups (G) (n=6): ketoprofenG--treated with ketoprofen; nimesulideG--treated with nimesulid; meloxicanG--treated with meloxican; and etodolacG--treated with etodolaco. All the dogs received the NSAIDs for 10 days by oral route. Physical examination and renal function (urinalysis, urinary sodium and gamma-glutamyl transpeptidase (GGT), serum urea, creatinine, potassium and sodium, and endogenous creatinine clearance) were evaluated before, after five and ten days (T0, T5 and T10) of the treatment in all groups. Changes were observed in urinalysis, with a significant increase in renal cells in the urine at T5 and T10 in nimesulideG. Significant reduction in urinary sodium in nimesulideG at T5 was observed. The clearance values were lower in ketoprofenG at T10. Meloxicam and etodolac were the drugs that have proven to be safer for short-term therapy in healthy dogs in relation to renal function. NSAIDs ketoprofen and nimesulide should be used judiciously in dogs with renal dysfunction, since there are promoted changes in renal function.

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous κ-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous κ-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the μ-opioid agonist morphine) or by the κ-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and κ-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous κ-opioid systems, in mediating acute pain-related behavioral depression in rats.

Effects of post-partum administration of ketoprofen on sow health and piglet growth

The effect of the non-steroidal anti-inflammatory drug ketoprofen on the post farrowing phase of sows was studied in a randomized, blinded, placebo-controlled trial. Ketoprofen (3mg/kg) was administered intramuscularly to 20 healthy sows for 3days post-partum (p.p.). The control group (n=20) received a saline placebo. Backfat, number of days of constipation and days before feed refusal were measured. Body condition (BCS) and shoulder sores were scored for 1week p.p. Changes in BCS, backfat and shoulder sore scores were analysed with ANOVA. Blood was collected on days −1, 0, 5 and 14 with respect to medication. Aspartate aminotransferase (AST), creatinine kinase (CK), haptoglobin and serum amyloid A (SAA) were quantified and analysed with a Mann–Whitney U test.BCS and backfat decreased less following ketoprofen administration than with the placebo (−0.08±0.2 vs. −0.8±0.2, 1.0±0.8mm vs. −2.0±0.9mm, respectively; P<0.05 for both) during the first 2weeks of lactation. The shoulder sore score deterioration was milder during days 4–6 p.p. with ketoprofen than placebo (P<0.05). Duration of constipation was shorter with ketoprofen than placebo (5.5±0.3 vs. 6.4±0.3days p.p.; P<0.05). Incidences of feed refusal occurred later in the ketoprofen group than in the placebos (9.6±0.9 vs. 3.8±0.8days p.p.; P<0.05). AST and SAA values were higher after ketoprofen administration than placebo on day 5 p.p. (P<0.05). It was concluded that ketoprofen appeared to benefit sows during the first 2weeks post farrowing, but caused some tissue irritation.

Pain‐related depression of the mesolimbic dopamine system in rats

Some stressors produce prodepressant behavioral effects by activating endogenous kappa opioid systems that in turn depress mesolimbic dopamine release. This study evaluated the role of this mechanism in pain‐related behavioral depression in rats. Adult male Sprague‐Dawley rats were prepared either with intracranial electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self‐stimulation; ICSS) or cannulae for microdialysis measures of nucleus accumbens dopamine (NAcc DA). Changes in ICSS and NAcc DA were examined after treatment with a chemical noxious stimulus (intraperitoneal injection of dilute acid) or an exogenous kappa agonist (U69593). Additional studies examined sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the mu opioid receptor agonist morphine) or by the kappa antagonist norbinaltorphimine (norBNI). Both acid and U69593 depressed ICSS and NAcc DA release. However, the pain‐related effects of acid were blocked by pretreatment with ketoprofen and morphine, but not by norBNI. Conversely, effects of U69593 were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. These results support a role for the mesolimbic dopamine system, but not endogenous kappa opioid systems, in mediating pain‐related depression of behavior in rats.

Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 μg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, "downstream" inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.

Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils

Non-steroidal anti-inflammatory drugs (NSAIDs) induce the shedding of L-selectin in human neutrophils through a mechanism still not well understood. In this work we studied both the functional effect of NSAIDs on the neutrophils/endothelial cells dynamic interaction, and the potential involvement of reactive oxygen species (ROS) in the NSAIDs-mediated down-regulation of L-selectin. When human neutrophils were incubated with diclofenac, a significant reduction in the number of cells that rolled on activated endothelial cells was observed. Different NSAIDs (flufenamic acid, meclofenamic acid, diclofenac, indomethacin, nimesulide, flurbiprofen, meloxicam, phenylbutazone, piroxicam, ketoprofen and aspirin) caused variable increase in neutrophil intracellular ROS concentration, which was inversely proportional to the change produced in L-selectin surface expression. Pre-incubation of neutrophils with superoxide dismutase, but not with catalase, showed both a significant protective effect on the L-selectin down-regulation induced by several NSAIDs and a diminished effect of diclofenac on neutrophil rolling. Interestingly, diclofenac and flufenamic acid but not piroxicam significantly increased the extracellular superoxide anion production by neutrophils, and inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activity with diphenyleneiodonium prevented the down-regulation of L-selectin by diclofenac. In accordance with these results, neutrophils from patients with chronic granulomatous disease, a hereditary disease in which neutrophils show a reduced capacity to form superoxide radicals, exhibited a lower down-regulation of L-selectin (IC50: 15.3μg/ml) compared to normal controls (IC50: 5.6μg/ml) in response to diclofenac. ConclusionA group of NSAIDs is capable of interfering with the ability of neutrophils to interact with endothelial cells by triggering L-selectin-shedding through the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane.

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist Δ9-tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1-10 mg/kg) and CP55940 (0.0032-0.32 mg/kg) dose-dependently blocked acid- stimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiation-related depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans.

Synthesis and characterization of a diruthenium(II,III)–ketoprofen compound and study of the in vitro effects on CRC cells in comparison to the naproxen and ibuprofen derivatives

A new diruthenium(II,III) complex, of formula [Ru2Cl(ket)4], Ruket, containing the non-steroidal anti-inflammatory drug ketoprofen was synthesized and mainly characterized by electrospray ionization mass spectrometry (ESI-MS), UV–Vis–IR electronic spectroscopy and FTIR and Raman vibrational spectroscopies. The four drug-carboxylato bridging ligands stabilize a Ru2(II,III) mixed valent core in a paddlewheel type structure as confirmed by ESI mass spectra, electronic and vibrational spectroscopies and magnetic measurements. Ruket and the analogous compounds containing ibuprofen, Ruibp, and naproxen, Runpx, were tested for the biological effects in the human colon carcinoma cells HT-29 and Caco-2 expressing high and low levels of COX-2 respectively. All compounds only weakly affected the proliferation of the colorectal cancer cells HT-29 and Caco-2, and similarly only partially inhibited the production/activity of MMP-2 and MMP-9 by HT-29 cells, suggesting that COX-2 inhibition by these drugs can only partially be involved in the pharmacological effects of these derivatives.

The removal and degradation of pharmaceutical compounds during membrane bioreactor treatment

Pharmaceutical compounds such as non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics have been detected in sewage treatment plant (STP) effluents, surface and ground water and even in drinking water all over the world, and therefore have developed as compounds of concern. Membrane bioreactor (MBR) treatment has gained significant popularity as an advanced wastewater treatment technology and might be effective for an advanced removal of these pollutants. This paper evaluates the treatment of wastewater containing three NSAIDs (acetaminophen, ketoprofen and naproxen) and three antibiotics (roxithromycin, sulfamethoxazole and trimethoprim) performed in two MBRs with sludge retention times (SRTs) of 15 (MBR-15) and 30 (MBR-30) days over a period of four weeks. It was observed that NSAIDs were removed with higher efficiencies than the antibiotics for both MBRs, and the MBR-30 presented higher removal efficiencies for all the compounds than obtained by MBR-15. Removal rates ranged from 55% (sulfamethoxazole) up to 100% (acetaminophen, ketoprofen). Besides mineralisation biological transformation products of ketoprofen and naproxen produced by wastewater biocoenosis were identified in both MBR permeates using liquid chromatography coupled with mass spectrometry (LC-MS). The results indicated the importance of investigating the environmental fate of pharmaceuticals and their transformation products reaching the environment.

Synthesis, anti-HBV activity and renal cell toxicity evaluation of mixed phosphonate prodrugs of adefovir

A series of phosphonate ester prodrugs of adefovir incorporating l-amino (thio)acid and non-steroidal anti-inflammatory drug (NSAID) moieties were synthesized and their anti-HBV activity and renal cell toxicity were evaluated in HepG2 2.2.15 and HK-2 cells respectively. Bioactivity evaluation results revealed that this kind of adefovir prodrug have lower renal cell toxicity than adefovir dipivoxil. Compounds 8a and 8b, incorporating the NSAID ketoprofen and the l-amino acid (Val or Ile) structural fragments, exhibited more potent anti-HBV activity than adefovir dipivoxil with IC50 = 0.51 and 0.73 μM, SI = 1697.64 and 881.92 respectively. In vitro stability studies showed that the synthesized prodrugs have higher chemical and plasma stability than the positive control adefovir dipivoxil.

Modifications in prolactin binding capacity in the rat liver induced by non-steroidal anti-inflammatory drugs.

Modifications in prolactin specific binding in the rat liver induced by different non-steroidal anti-inflammatory drugs (indomethacin, piroxicam, ketoprofen, phenylbutazone, mefenamic acid and acetylsalicylic acid) have been studied. All caused a dose-dependent inhibition of prolactin binding capacity whereas no change was found in dissociation constant values. The inhibitory effect is reversible and highly specific, since insulin binding to the same membrane preparation is not affected. The degree of inhibitory activity on prolactin binding is related to the anti-inflammatory activity of each drug, which supports the hypothesis of an involvement of prostaglandin synthesis.

Avaliação clínica de Rattus norvegicus após terapia antiinflamatória com e sem inibidor seletivo para COX-2

Nonsteroidal antiinflammatory drugs (NSAIDs) are the most often prescribed drugs throughout the world. They are divided into non-selective inhibitors for COX-1 and 2, which reduce the production of all PGs, constituents or not, and selective for COX-2, which inhibit only the deleterious PGs, which act on the inflammatory reaction. The hepatic function of Rattus norvegicus after the use of the nonselective NSAIDs ketoprofen and the selective NSAIDs valdecoxib, was studied. The doses administered to the animals were calculated according to the allometric scale. The serum values of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were measured, and the liver and kidney were also evaluated macroscopically and microscopically on different periods after the last administration of the drugs, according to the group to which the animal belonged. Among other observations, it can be stated that ketoprofen can cause death in rats, according to allometry, on the second day of drug administration, and that valdecoxib does not produce the noteworthy macroscopic and microscopicalterations in organs like the liver and kidney of Rattus norvegicus.

Simultaneous determination of non-steroidal anti-inflammatory drugs in river water samples by liquid chromatography–tandem mass spectrometry using molecularly imprinted polymers as a pretreatment column

A restricted access media-molecularly imprinted polymer (RAM-MIP) for flufenamic acid has been developed for the simultaneous determination of non-steroidal anti-inflammatory drugs (NSAIDs) in river water samples. The RAM-MIP was prepared using 4-vinylpyridine and ethylene glycol dimethacrylate as a functional monomer and cross-linker, respectively, by a multi-step swelling and polymerization method followed by a surface modification technique. The RAM-MIP for flufenamic acid showed excellent molecular recognition abilities for flufenamic acid and mefenamic acid, and moderate molecular recognition abilities for indomethacin, etodolac and ketoprofen. The simultaneous determination of NSAIDs (mefenamic acid, indomethacin, etodolac and ketoprofen) in river water samples was carried out by LC–MS/MS using the RAM-MIP for flufenamic acid as a pretreatment column. The concentrations of mefenamic acid, indomethacin and etodolac in river water samples were determined to be 0.4, 0.7 and 0.3 ng/L, respectively, while ketoprofen was below the limit of quantitation.

Automated Methods to Detect Lameness, the Effects of Analgesic Drug Treatment, and the Effects of Hoof Trimming in Dairy Cows

Lameness in dairy cows is a commonly occurring condition that causes decreased productivity and diminished well-being. Lameness has been shown to affect gait, weight distribution, and amount of time spent lying down in dairy cows. Automated methods of measuring weight distribution and standing, walking, and lying behaviors were used, in conjunction with evaluation of gait, to measure the effects of hoof trimming and systemic treatment with the non-steroidal anti-inflammatory drugs ketoprofen and flunixin meglumine in dairy cows.

Trimethylsilyldiazomethane (TMSD) as a new derivatization reagent for trace analysis of selected non-steroidal anti-inflammatory drugs (NSAIDs) by gas chromatography methods

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common groups of pharmaceuticals detected in environmental matrices. Although several derivatization procedures have been employed in the gas chromatographic analysis of NSAIDs, the application of trimethylsilyldiazomethane has never yet been reported. This work has studied the derivatization of widely used NSAIDs (ibuprofen, ketoprofen and naproxen) by trimethylsilyldiazomethane. Special emphasis was placed on the influence of temperature and reaction time on the reaction yield, and on the determination of the instrumental detection limit. The results are compared with those obtained by methylation using boron trifluoride methanol solution, and by silylation with a mixture of N,O-bis(trimethylsilyl)trifluoroacetamide and trimethylchlorosilane (99:1, v/v) and with N-methyl-N-[tert-butyldimethylsilyl]trifluoroacetamide. The derivatization of ibuprofen, ketoprofen and naproxen by trimethylsilyldiazomethane was shown to be simple, fast, efficient, and suitable for trace analysis (the respective instrumental detection limits for ibuprofen naproxen, and ketoprofen were 2, 4, and 4 ng). Trimethylsilyldiazomethane can be used as an alternative reagent for determining acidic drugs in environmental matrices.