Single and mixture toxicity of selected pharmaceuticals to the aquatic macrophyte Lemna minor.

Plants represent uncommon targets to evaluate pharmaceuticals toxicity. In this work, Lemna minor was employed as a plant model to determine the toxicity of selected pharmaceuticals, and to assay if such toxicity could be predicted by QSAR models based on green algae. Among eight compounds, measurable toxicity was determined for ketoprofen (EC50 = 11.8 ± 1.9 mg/L), fluoxetine (EC50 = 27.0 ± 8.7 mg/L) and clindamycin 2-phosphate (EC50 = 57.7 ± 1.7 mg/L). Even though a correlation of r2 = 0.87 was observed between experimental toxicity towards algae and L. minor, QSAR estimations based on algae data poorly predicted the toxicity of pharmaceuticals on the plant. More experimental data for L. minor are necessary to determine the applicability of these predictions; nonetheless, these results remark the importance of measuring experimental ecotoxicological parameters for individual taxa. The toxicity of pharmaceutical binary mixtures (ketoprofen, fluoxetine and clindamycin) revealed in some cases deviations from the concentration addition model; nonetheless these deviations were small, thus the interactions are unlikely to be of severe biological significance. Moreover, the EC50 concentrations determined for these pharmaceuticals are significantly higher than those detected in the environment, suggesting that acute effects on L. minor would not take place at ecosystem level.

Behavioral Battery for Testing Candidate Analgesics in Mice. I. Validation with Positive and Negative Controls.

This study evaluated a battery of pain-stimulated, pain-depressed, and pain-independent behaviors for preclinical pharmacological assessment of candidate analgesics in mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to produce four pain-related behaviors in male and female ICR mice: stimulation of 1) stretching, 2) facial grimace, 3) depression of rearing, and 4) depression of nesting. Additionally, nesting and locomotion in the absence of the noxious stimulus were used to assess pain-independent drug effects. These six behaviors were used to compare effects of two mechanistically distinct but clinically effective positive controls (ketoprofen and oxycodone) and two negative controls that are not clinically approved as analgesics but produce either general motor depression (diazepam) or motor stimulation (amphetamine). We predicted that analgesics would alleviate all IP acid effects at doses that did not alter pain-independent behaviors, whereas negative controls would not. Consistent with this prediction, ketoprofen (0.1-32 mg/kg) produced the expected analgesic profile, whereas oxycodone (0.32-3.2 mg/kg) alleviated all IP acid effects except depression of rearing at doses lower than those that altered pain-independent behaviors. For the negative controls, diazepam (1-10 mg/kg) failed to block IP acid-induced depression of either rearing or nesting and only decreased IP acid-stimulated behaviors at doses that also decreased pain-independent behaviors. Amphetamine (0.32-3.2 mg/kg) alleviated all IP acid effects but only at doses that also stimulated locomotion. These results support utility of this model as a framework to evaluate candidate-analgesic effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behavioral endpoints. SIGNIFICANCE STATEMENT: Preclinical assays of pain and analgesia often yield false-positive effects with candidate analgesics. This study used two positive-control analgesics (ketoprofen, oxycodone) and two active negative controls (diazepam, amphetamine) to validate a strategy for distinguishing analgesics from nonanalgesics by profiling drug effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice.

An in vitro investigation of genotoxic effects of dexketoprofen trometamol on healthy human lymphocytes.

Non-steroidal anti-inflammatory drugs are drugs with analgesic, antipyretic, and anti-inflammatory effects. This study uses in vitro methods to investigate the potential and unknown genotoxic effects of dexketoprofen trometamol, an active substance in painkillers, on healthy human lymphocytes. In this study, a cytokinesis-block micronucleus cytome assay is used to investigate potential clastogenic, aneugenic activity and to identify chromosome breakages caused by the active drug substance dexketoprofen trometamol; a comet assay is performed to identify the genotoxic damage resulting from DNA single-strand breaks; a real-time reverse transcription polymerase chain reaction panel system is used to evaluate the potential negative effects on the expression of the genes responsible for DNA damage assessment. Dexketoprofen trometamol induces toxic effects in healthy human lymphocytes at concentrations of 750-1000 µg/mL and above, and shows clastogenic, aneugenic activity by inducing micronucleus formations at exposures of 750-500 µg/mL. At concentration intervals of 1000, 500, 250, 100 µg/mL, dexketoprofen trometamol also resulted in DNA damage in the form of strand breaks, as demonstrated by highly significant increases in DNA tail length and density comet parameters when compared to spontaneous values. Human lymphocytes exposed to 750-100 µg/mL dexketoprofen trometamol were found to have significantly increased levels of expression of the XPC, XRCC6, PNKP genes in the DNA damage signaling pathway. It can be concluded that dexketoprofen trometamol may have cytotoxic, cytostatic, genotoxic effects on healthy human lymphocytes in vitro, depending on the concentration and duration of exposure. It is anticipated that this outcome will be supported by advanced studies.

Ketoprofen-Based Ionic Liquids: Synthesis and Interactions with Bovine Serum Albumin.

The development of ionic liquids based on active pharmaceutical ingredients (API-ILs) is a possible solution to some of the problems of solid and/or hydrophobic drugs such as low solubility and bioavailability, polymorphism and an alternative route of administration could be suggested as compared to the classical drug. Here, we report for the first time the synthesis and detailed characterization of a series of ILs containing a cation amino acid esters and anion ketoprofen (KETO-ILs). The affinity and the binding mode of the KETO-ILs to bovine serum albumin (BSA) were assessed using fluorescence spectroscopy. All compounds bind in a distance not longer than 6.14 nm to the BSA fluorophores. The estimated binding constants (KA) are in order of 105 L mol-1, which is indicative of strong drug or IL-BSA interactions. With respect to the ketoprofen-BSA system, a stronger affinity of the ILs containing l-LeuOEt, l-ValOBu, and l-ValOEt cation towards BSA is clearly seen. Fourier transformed infrared spectroscopy experiments have shown that all studied compounds induced a rearrangement of the protein molecule upon binding, which is consistent with the suggested static mechanism of BSA fluorescence quenching and formation of complexes between BSA and the drugs. All tested compounds were safe for macrophages.

Differential protein modulation by ketoprofen and ibuprofen underlines different cellular response by gastric epithelium.

Ketoprofen L-lysine salt (KLS), is widely used due to its analgesic efficacy and tolerability, and L-lysine was reported to increase the solubility and the gastric tolerance of ketoprofen. In a recent report, L-lysine salification has been shown to exert a gastroprotective effect due to its specific ability to counteract the NSAIDs-induced oxidative stress and up-regulate gastroprotective proteins. In order to derive further insights into the safety and efficacy profile of KLS, in this study we additionally compared the effect of lysine and arginine, another amino acid counterion commonly used for NSAIDs salification, in control and in ethanol challenged human gastric mucosa model. KLS is widely used for the control of post-surgical pain and for the management of pain and fever in inflammatory conditions in children and adults. It is generally well tolerated in pediatric patients, and data from three studies in >900 children indicate that oral administration is well tolerated when administered for up to 3 weeks after surgery. Since only few studies have so far investigated the effect of ketoprofen on gastric mucosa maintenance and adaptive mechanisms, in the second part of the study we applied the cMap approach to compare ketoprofen-induced and ibuprofen-induced gene expression profiles in order to explore compound-specific targeted biological pathways. Among the several genes exclusively modulated by ketoprofen, our attention was particularly focused on genes involved in the maintenance of gastric mucosa barrier integrity (cell junctions, morphology, and viability). The hypothesis was further validated by Real-time PCR.

Protective effects of combined ß-caryophyllene and silymarin against ketoprofen-induced hepatotoxicity in rats.

Ketoprofen (Ket), widely utilized in treatment of many inflammatory disorders, is found to induce liver toxicity especially with overdose. This study aimed to evaluate the possible protective effects of concomitant ß-caryophyllene (Cary) and silymarin (Sily) against Ket-induced hepatotoxicity in rats. Forty adult male albino rats were divided into 5 groups (each n = 8): the control group received distilled water for 6 weeks; the Ket-treated group received distilled water for 5 weeks and Ket in a dose of 8 mg·kg(-1)·day(-1) p.o. for the 6th week; the Cary + Ket treated group received Cary in a dose of 200 mg·kg(-1)·day(-1) orally for 6 weeks and Ket for the 6th week; the Sily + Ket treated group received Sily in the dose of 150 mg·kg(-1)·day(-1) for 6 weeks and Ket for the 6th week; and the Cary + Sily + Ket treated group received Sily and Cary for 6 weeks and Ket for the 6th week. At end of the experiment, serum ALT, AST, and albumin and liver total antioxidant capacity (t.TAC) and malondialdehyde (t.MDA) were measured in all rats. Ket increased serum ALT and AST and t.MDA and decreased t.TAC. Cary and Sily improved these changes. Combined Cary and Sily restored these liver changes to nearly normal. Combined Cary and Sily is hepatoprotective, with the ability to scavenge oxidants against Ket-induced hepatotoxicity in rats.

Assessment of in vitro antiovulatory activities of nonsteroidal anti-inflammatory drugs and comparison with in vivo reproductive toxicities of medaka (Oryzias latipes).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used therapeutic agents; however, their pharmacological actions raise concerns about potential risks to the reproductive health of aquatic vertebrates. In the present study, a medaka ovulation assay was applied as an in vitro model to evaluate NSAID-induced antiovulatory activity. We first tested five NSAIDs, including diclofenac sodium (DCF), ketoprofen (KP), salicylic acid (SA), mefenamic acid (MA), and acetylsalicylic acid (ASA) for their antiovulatory activities toward the follicles isolated from the ovaries of spawning females. Of all the chemicals tested, DCF had the highest antiovulatory activity, with the concentration that caused 50% inhibition (IC50) (101 µM). MA was the second most potent inhibitor following DCF, but KP, SA, or ASA had little inhibitory effect on the ovulation of the follicles. The in vitro antiovulatory activity of five NSAIDs showed good correlation with data published on the inhibitory activity on human COX-2. Second, we selected DCF and SA as the most and least potent NSAIDs, respectively, and examined the effects on reproduction of intact fish in order to evaluate whether the ovulation assay was a reasonable predictor of potential reproductive effects in fish. Females exposed to DCF showed a concentration-dependent decrease in the number of spawned eggs and an increment in the gonadosomatic index (GSI), possibly due to an anovulation in the females. In contrast, neither fecundity nor the GSI of females decreased at up to 20 mg/L of SA, at which acute lethality to medaka was induced. In conclusion, the medaka ovulation assay reflected the potency of NSAID-induced antiovulatory activity and may thus serve as an in vitro model for the prediction of NSAID-induced reproductive toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1710-1719, 2016.

Parental (F0) exposure to Cadmium and Ketoprofen induces developmental deformities in offspring (F1): A transgenerational toxicity assessment in zebrafish model.

In the aquatic environment, the primary pollutants of heavy metals and pharmaceuticals always occur in coexisting forms, and the research about combined impacts remains unclear, especially transgenerational effects. Cadmium (Cd) is a heavy metal that can damage the endocrine reproduction systems and cause thyroid dysfunction in fish. Meanwhile, ketoprofen (KPF) is a nonsteroidal anti-inflammatory drug (NSAID) that can cause neurobehavioral damage and physiological impairment. However, to our knowledge, the combined exposure of Cd and KPF in transgenerational studies has not been reported. In this investigation, sexually mature zebrafish were subjected to isolated exposure and combined exposure to Cd (10 µg/L) and KPF (10 and 100 µg/L) at environmentally relevant concentrations for 42 days. In this background, breeding capacity, chemical accumulation rate in gonads, and tissue morphologies are investigated in parental fish. This is followed by examining the malformation rate, inflammation rate, and gene transcription in the F1 offspring. Our results indicate that combined exposure of Cd and KPF to the parental fish could increase the chemical accumulation rate and tissue damage in the gonads of fish and significantly reduce the breeding ability. Furthermore, these negative impacts were transmitted to its produced F1 embryos, reflected by hatching rate, body deformities, and thyroid axis-related gene transcription. These findings provide further insights into the harm posed by Cd in the presence of KPF to the aquatic ecosystems.

Ecotoxicological effects of ketoprofen and fluoxetine and their mixture in an aquatic microcosm.

The effects of fluoxetine (antidepressant) and ketoprofen (analgesic) on aquatic ecosystems are largely unknown, particularly as a mixture. This work aimed at determining the effect of sublethal concentrations of both compounds individually (0.050 mg/L) and their mixture (0.025 mg/L each) on aquatic communities at a microcosm scale for a period of 14 d. Several physicochemical parameters were monitored to estimate functional alterations in the ecosystem, while model organisms (Daphnia magna, Lemna sp., Raphidocelis subcapitata) and the sequencing of 16S/18S rRNA genes permitted to determine effects on specific populations and changes in community composition, respectively. Disturbances were more clearly observed after 14 d, and overall, the microcosms containing fluoxetine (alone or in combination with ketoprofen) produced larger alterations on most physicochemical and biological variables, compared to the microcosm containing only ketoprofen, which suffered less severe changes. Differences in nitrogen species suggest alterations in the N-cycle due to the presence of fluoxetine; similarly, all pharmaceutical-containing systems decreased the brood rate of D. magna, while individual compounds inhibited the growth of Lemna sp. No clear trends were observed regarding R. subcapitata, as indirectly determined by chlorophyll quantification. The structure of micro-eukaryotic communities was altered in the fluoxetine-containing systems, whereas the structure of bacterial communities was affected to a greater extent by the mixture. The disruptions to the equilibrium of the microcosm demonstrate the ecological risk these compounds pose to aquatic ecosystems.

Growth inhibition, oxidative stress and characterisation of mortality in green algae under the influence of beta-blockers and non-steroidal anti-inflammatory drugs.

Bisoprolol and ketoprofen are widely used pharmaceuticals in medical treatment hence these substances are occurring in wastewaters and in water environment. This research investigated the toxic effects of bisoprolol and ketoprofen on two microalgae taxa, Chlorella vulgaris and Desmodesmus armatus. The results showed that both drugs inhibited the growth of the species tested and induced a decrease in chlorophyll a content compared to controls. Ketoprofen turned out to be harmful to algae as the half maximal effective concentration (EC50) values (14 days) were 37.69 mg L-1 for C. vulgaris and 40.93 mg L-1 for D. armatus. On the other hand, for bisoprolol, the EC50 values were greater than the established NOEC, 100 mg L-1. Bisoprolol and ketoprofen induced oxidative stress in the tested microorganisms, as indicated by changes in the activities of antioxidant enzymes. Exposure to 100 mg L-1 of drugs significantly increased the activity of catalase, peroxidase and superoxide dismutase. Fluorescence microscopy showed that both medicaments changed the cells' morphology. There was atrophy of chlorophyll in the cells, moreover, dying multinuclear cells and cells without nuclei were observed. In addition, there were atrophic cells, namely cells that lacked nuclei and chlorophyll. Profile area analyses showed that bisoprolol and ketoprofen treated C. vulgaris cells were approximately 4 and 2 times greater compared to control ones. Our experimental findings highlight the ecotoxicological threats for aquatic primary producers from bisoprolol and ketoprofen and provide insight into the characteristics of their death.

An initial safety assessment of hepatotoxic and nephrotoxic potential of intramuscular ketoprofen at single repetitive dose level in broiler chickens.

A study was undertaken to assess the hepatotoxic and nephrotoxic potential of ketoprofen in comparison with diclofenac upon short-term intramuscular (i.m.) administration in broiler chickens. Eighteen broiler chickens were randomly divided into 3 groups of 6 birds each. Group I served as the control and received normal saline (0.1 mL, i.m.), group II was the positive control and received diclofenac sodium (2.5 mg/kg, i.m.), and group III received ketoprofen (3 mg/kg, i.m.) daily at 24-h intervals for 5 consecutive days. Diclofenac sodium-treated birds showed severe clinical signs of toxicity with high mortality, a significant increase (P < 0.01) in serum concentrations of creatinine, uric acid, alanine aminotransferase, and aspartate aminotransferase, and these changes correlated well with gross and microscopic examination findings of kidney and liver. In contrast, ketoprofen-treated birds did not show any adverse clinical signs and no significant increase in concentration of creatinine, uric acid, alanine aminotransferase, and aspartate aminotransferase when compared with birds in group I. Gross and microscopic examination of kidney and liver showed normal organ architecture. Thus, based on the present findings, it was concluded that ketoprofen at the dose of 3 mg/kg administered intramuscularly daily for 5 d was nontoxic to broiler chickens.

Transcriptomic response of HepG2 cells exposed to three common anti-inflammatory drugs: Ketoprofen, mefenamic acid, and diclofenac in domestic wastewater effluents.

The biological impacts of residual pharmaceuticals in the complex wastewater effluents have not been fully understood. Here, we investigated changes in the transcriptomic responses of hepatobrastoma (HepG2) cells exposed to a single or partially combined three common non-steroidal anti-inflammatory drugs (NSAIDs); ketoprofen (KPF), mefenamic acid (MFA) and diclofenac (DCF), in domestic wastewater effluents. After 48 h sub-lethal exposure to single compounds, the DNA microarray analysis identified 57-184 differently expressed genes (DEGs). The hierarchical clustering analysis and GO enrichment of the DEGs showed that gene expression profiles of the NSAIDs were distinct from each other although they are classified into the same therapeutic category. Four maker genes (i.e., EGR1, AQP3, SQSTM1, and NAG1) were further selected from the common DEGs, and their expressions were quantified by qPCR assay in a dose-dependent manner (ranging from µg/L to mg/L). The results revealed the insignificant induction of the marker genes at 1 µg/L of KPF, MFA, and DCF, suggesting negligible biological impacts of the NSAIDs on gene expression (early cellular responses) of HepG2 at typical concentration levels found in the actual wastewater effluents. Based on the quantitative expression analysis of the selected marker genes, the present study indicated that the presence of wastewater effluent matrix may mitigate the potentially adverse cellular impacts of the NSAIDs.

Physical characteristics, pharmacological properties and clinical efficacy of the ketoprofen patch: a new patch formulation.

OBJECTIVE: The mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs), to which ketoprofen belongs, is based on their cyclo-oxigenase (COX) inhibiting action, concerning both subtype COX-1 constitutive isoform and COX-2 inducible isoform. Ketoprofen administration may be carried out by oral and parenteral routes as well as by topical application, which includes transdermic patch use. Following a synthetic description of the results obtained by several investigators on ketoprofen use, the Authors present a new formulation of the ketoprofen patch obtained by the so called DermaLight Technology. MATERIALS AND METHODS: According to such a technique, the active principle is dissolved in oil components and dispersed inside an anhydrous polymeric matrix made up of styrene-isoprene-styrene (SIS), which is an elastic and flexible material that provides a gentle adhesion to the skin, maintains an elevated ketoprofen concentration and induces a strong thrust that favours the crossing of the skin by the drug; in addition, the patch is fit to be applied to the various areas of the body, including the joints. RESULTS: Patch adhesiveness reduces skin irritation due to multiple applications and to long-term use, as the DermaLight Technology minimises keratinocytes exfoliation. In pharmacokinetic studies carried out on pigs ketoprofen has been demonstrated to reach deep tissues, where the drug was detected in much higher concentrations, with respect to plasma levels, 12 hours following its application. Experimental studies carried out on rats have shown that ketoprofen patch significantly reduces the edema induced by chronic inflammation. The ulcerogenic effect of ketoprofen patch is then compared with that shown by oral administration of the drug. UD50 values of ketoprofen patch were 49.9 mg/kg and 48.9 mg/kg for the stomach and the small intestine, respectively, whereas UD50 values of oral ketoprofen were 3.6 mg/kg and 3.7 mg/kg, respectively. CONCLUSIONS: The Authors conclude by stating that ketoprofen patch is both a good alternative and a safe modality of administration, with special reference to patients who are prone to gastrointestinal disorders.

Comparison of acute toxicity of ketoprofen to juvenile and embryonic stages of Danio rerio.

OBJECTIVES: Ketoprofen is a common human medicine from a class of non-steroidal anti-inflammatory drugs (NSAIDs), which is provably detected in surface waters in concentrations ordinarily in µg.L-1. The aim of this study was to compare the acute toxicity of ketoprofen to embryonic and juvenile stages of aquarium fish - zebrafish (Danio rerio). METHODS: Tests were performed according to the methods of the Organisation for Economic Co-operation and Development (OECD) No. 203 (Fish, acute toxicity test) and OECD No. 212 (Fish, short-term toxicity test on embryo and sac-fry stages). RESULTS: The results showed (mean ± SD) LC50 value of ketoprofen to be 632.30 ± 10.10 mg.L-1 in juvenile zebrafish and 6.44 ± 2.22 mg.L-1 in embryonic stages of zebrafish. The results revealed statistically significantly higher sensitivity (p<0.01) of the embryonic stages of zebrafish to ketoprofen compared to its juveniles. The susceptibility of embryos depends on many factors, especially yet improperly developed enzymatic system in embryos, different ways of the absorption of the substance into the organism or differences in metabolism pathways. CONCLUSIONS: The acute toxicity of ketoprofen for juvenile stages of zebrafish is low, but the substance seems to be toxic for embryonic stages.

The effect of ketoprofen lysine salt on mucosa of rat stomach after ethyl alcohol intoxication.

INTRODUCTION: Ketoprofen is a commonly used nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Side effects of ketoprofen occur mainly from the gastrointestinal tract due to the inhibition of cyclooxygenaze-1. Binge drinking at least once a week is reported by 80 million Europeans. On the day after many of them use NSAIDs. This increases the risk for damage of gastric mucosa. AIM: The aim of the study was to check if use of ketoprofen lysine salt (KLS) has any gastroprotective effect on mucosa of rat stomach after ethyl alcohol intoxication. MATERIALS AND METHODS: There were 6 groups of 6 male rats which received: RESULTS: In groups 1, 2 and 3 the histopathologic examination of the stomachs revealed normal picture, without signs of inflammation. In the group 4, 5 and 6 within the mucosa and submucosa there were visible numerous infiltrates of inflammatory cells, consisting mainly of lymphocytes, plasmocytes and eosinophilia. Total leukocyte count was elevated in group 3, 4, 6. There was a significant decrease of blood urea concentration in group 6 vs 2 and significant decrease of serum albumin in group 6 vs 1 and 2, and total protein vs group 1. CONCLUSION: Side effects of ketoprofen occur mainly from the gastrointestinal tract. KLS has no gastroprotective effect after ethanol-gastric injury and does not protect gastric mucosa from damage produced by binge drinking. Therefore it should not be used after drinking distilled spirits.

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism.

In a safety study, Cape Griffon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of ~1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUC(inf), V(z) and Cl being 10.42 µg/ml h, 0.37 l/kg and 0.10 l/h kg, respectively. Toxicity occurred in the 5 mg/kg group, with 7 of the 11 birds dying. Clinical signs of toxicity included depression, loss of appetite and apparent coma. Animals died within 48 h of dosing. The AUC(inf), V(z) and Cl in the birds that survived were 52.26 µg/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUC(inf), V(z) and Cl in the birds those died were 207.90 µg/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUC(inf) and C(max) in the birds that died, we surmise that toxicity resulted from saturation of the metabolic process. While the exact metabolic pathway remains unknown in these vultures, we believe that toxicity may be due to pharmacogenomic differences in the cytochrome P450 pathway.

Effects of ketoprofen on rice seedlings: Insights from photosynthesis, antioxidative stress, gene expression patterns, and integrated biomarker response analysis.

Pharmacologically active compounds found in reclaimed wastewater irrigation or animal manure fertilizers pose potential risks for agriculture. The mechanism underlying the effects of ketoprofen on rice (Oryza sativa L.) seedlings was investigated. The results showed that low concentrations (0.5 mg L-1) of ketoprofen slightly stimulate growth of rice seedlings, while high concentrations can significantly inhibit growth by reducing biomass and causing damage to roots. Ketoprofen affects photosynthetic pigment content (Chla, Chlb, and carotenoids) and chlorophyll synthesis gene (HEMA, HEMG, CHLD, CHLG, CHLM, and CAO) expression. Fluorescence parameters such as minimum fluorescence (F0), maximum fluorescence (Fm), variable fluorescence (Fv), potential photosynthetic capacity (Fv/F0), maximum quantum efficiency of PSII photochemistry (Fv/Fm), electron transfer rate (ETR), and Y(II), Y(NPQ), Y(NO) values were affected, showing photosynthetic electron transfer was blocked. Active oxygen radical (O2•-and H2O2), malondialdehyde and proline content increased. Superoxide dismutase, catalase and ascorbate peroxidase activities, glutathione content and antioxidant-related gene (FSD1, MSD1, CSD1, CSD2, CAT1, CAT2, CAT3, APX1, APX2) expression were induced. Higher integrated biomarker response values of eight oxidative stress response indexes were obtained at higher ketoprofen concentrations. Ultrastructure observation showed that ketoprofen causes cell structure damage, chloroplast swelling, increase in starch granules, and reduction in organelles. This study provides some suggested toxicological mechanisms and biological response indicators in rice due to stress from pharmacologically active compounds.

Evaluation of histophysiological alterations associated with ketoprofen administration in albino NMRI mice.

The aim of this study was to investigate the changes caused by the administration of ketoprofen to albino NMRI mice on some hematological, biochemical, and structural parameters. For this purpose, the mice were divided into two lots: a control batch and an experimental batch to which ketoprofen was administered subcutaneously at a dose of 10 mg/kg body weight per day for 7 days. A decrease in erythrocyte number and hemoglobin was observed altogether with the increase in white blood cells. Blood biochemistry indicates increased blood glucose, cholesterol, and triglyceride levels. Enzyme values (AST, ALT, and ALP) show a significant increase. Hepatic pathology reveals the enlargement of sinusoidal capillaries, the presence of leukocyte infiltrates associated with necrosis zones.

Cytotoxicity evaluation of ketoprofen found in pharmaceutical wastewater on HEK 293 cell growth and metabolism.

Inefficient ketoprofen removal from pharmaceutical wastewater may negatively impact the ecosystem and cause detrimental risks to human health. This study was conducted to determine the cytotoxicity effects of ketoprofen on HEK 293 cell growth and metabolism, including cyclooxygenase-1 (COX-1) expression, at environmentally relevant concentrations. The cytotoxic effects were evaluated through the trypan blue test, DNS assay, MTT assay, and the expression ratio of the COX-1 gene. The results of this study show insignificant (p > 0.05) cytotoxic effects of ketoprofen on cell viability and cell metabolism. However, high glucose consumption rates among the treated cells cause an imitation of the Warburg effect, which is likely linked to the development of cancer cells. Apart from that, the upregulation of COX-1 expression among the treated cells indicates remote possibility of inflammation. Although no significant cytotoxic effects of ketoprofen were detected throughout this study, the effects of prolonged exposure of residual ketoprofen need to be evaluated in the future.

Novel organ-specific effects of Ketoprofen and its enantiomer, dexketoprofen on toxicological response transcripts and their functional products in salmon.

Racemic ketoprofen (RS-KP) and its enantiomer, dexketoprofen (S(+)-KP) are widely used non-steroidal anti-inflammatory drugs (NSAIDs), and commonly detected in the aquatic environment. The present study has evaluated the toxicological effects of RS-KP and S(+)-KP on biotransformation and oxidative stress responses in gills and liver of Atlantic salmon. Fish were exposed for 10 days using different concentrations of RS-KP (1, 10 and 100 µg/L) and S(+)-KP (0.5, 5 and 50 µg/L). Biotransformation and oxidative stress responses were analysed at both transcript and functional levels. In the gills, significant inhibitory effect at transcriptional and enzymatic levels were observed for biotransformation and oxidative stress responses. On the contrary, biotransformation responses were significantly increased at transcriptional and translational levels in the liver, while the associated enzymatic activities did not parallel this trend and were inhibited and further demonstrated by principal component analysis (PCA). Our findings showed that both compounds produced comparable toxicological effects, by producing organ-specific effect differences. RS-KP and S(+)-KP did not bioaccumulate in fish muscle, either due to rapid metabolism or excretion as a result of their hydrophobic properties. Interestingly, the inhibitory effects observed in the gills suggest that these drugs may not undergo first pass metabolism, that might result to downstream differences in toxicological outcomes.