Non-steroidal Anti-inflammatory Ketoprofen Research Articles

Dissolution of Ketoprofen from Poly(Ethylene Glycol) Solid Dispersions

The effect of solid dispersions (SDs) on the solubility of the nonsteroidal anti-inflammatory drug ketoprofen was determined. Ketoprofen and its SDs with poly(ethylene glycol) PEG-400, -1000, -1500, -2000, and -3000 were studied. Dissolution of ketoprofen from the SDs increased by 1.2 – 1.8 times; the dissolution rate, by 1.7 – 2.4 times. The improved release of ketoprofen from the SDs was proposed to be due to several factors such as solubilization and amorphization of the compound and formation of intermolecular H-bonds. The results could be used to develop rapidly dissolving ketoprofen solid dosage forms.

A single dose of ketoprofen in the immediate postpartum period has the potential to improve dairy calf welfare in the first 48 h of life

The welfare impact of birth on newborn calves has rarely been studied. Dystocia in particular may have significant welfare costs for calves. While analgesia is sometimes provided to calves born to difficult parturition by veterinary surgeons in practice, it is not known if this is actually beneficial. On a commercial dairy farm, we examined the behavioural time budget of 39 Holstein heifer calves born with the aid of farmer assistance and 36 calves born without assistance; half of each group were randomly allocated to receive either a single dose of the non-steroidal anti-inflammatory drug ketoprofen or a saline placebo in a two by two factorial design. The calves were group housed and their behaviour was recorded for 48 h postpartum and analysed using instantaneous focal sampling (every 5 min in alternate hours). Regardless of analgesic treatment, calves born with assistance showed behaviours consistent with experiencing a less positive welfare state (lying with their head down and in lateral recumbency, and less time playing than unassisted calves). Behavioural differences between calves treated with ketoprofen and calves treated with saline (in particular increased play) suggest that the birth experience may be painful for all calves, even if no assistance is required. Our findings suggest that a single dose of ketoprofen in the immediate postpartum period may improve calf welfare regardless of assistance status and has the potential to contribute to significant welfare gains in dairy calves.

A nanocomposite consisting of an amorphous seed and a molecularly imprinted covalent organic framework shell for extraction and HPLC determination of nonsteroidal anti-inflammatory drugs.

A novel nanocomposite consisting of an amorphous seed and a molecularly imprinted covalent organic framework shell was prepared via a heterogeneous nucleation and growth method. By using ibuprofen as the dummy template, a molecularly imprinted covalent organic framework (MICOF) with a large surface area was prepared from 1,3,5-triformylbenzene and 4,4'-diaminobiphenyl. It was placed on the surface of monodisperse amorphous seeds. Owing to strong π-interaction, the MICOF@SiO2 nanocomposite displays fast binding kinetics, large adsorption capacities and selectivity for nonsteroidal anti-inflammatory drugs (NSAIDs). Following desorption from the MICOF@SiO2 with methanol containing 1% ammonium hydroxide, the NSAIDs ketoprofen, ibuprofen, diclofenac, indomethacin, flurbiprofen and naproxen were quantified by HPLC with UV detection. Under optimized conditions, the method exhibits good linearity within the range of 0.002-1.0μgmL-1, low limits of detection (0.38-2.92μgL-1), and acceptable repeatability. The recoveries of NSAIDs at three spiking levels range from 77 to 112%, and the RSDs are <9.4%. The method was successfully applied to the analysis of NSAIDs in spiked environmental water samples. Graphical abstract A molecular imprinted covalent organic framework nanocomposite (MICOF@SiO2) was prepared by heterogeneous nucleation and growth method. It was explored as a sorbent for the solid phase extraction of nonsteroidal anti-inflammatory drugs before determination by HPLC with UV detection.

Reduction in serum IL-1β, IL-6, and IL-18 levels and Beck Depression Inventory-II score by combined sertraline and ketoprofen administration in major depressive disorder: A clinical trial

BackgroundThe immunological changes in major depressive disorder (MDD) and the use of some anti-inflammatory drugs as adjuvant treatment to some antidepressants have been mentioned in many studies. The effect of nonsteroidal anti-inflammatory drug ketoprofen on depression was studied previously in animals only. Aim of the studyThe adjuvant effect of ketoprofen on the antidepressant effect of sertraline in patients with MDD was examined by a follow-up study. The effect of the drug combination on the serum level of interleukin (IL)-1ß, IL-6, and IL-18 in patients with MDD was also investigated. MethodsOut of 140 patients with MDD included in the study, 34 were followed up for 2 months of treatment combining sertraline and ketoprofen. The cytokine levels and Beck Depression Inventory-II scores of the patients with MDD were compared with those of 40 healthy controls. All cytokine levels were measured with ELISA. ResultsThe serum IL-1ß, IL-6, and IL-18 levels in patients with MDD increased and became significantly higher than those of the controls (p < 0.05). The follow-up study indicated that the MDD group treated with the drug combination exhibited lower cytokine levels and Beck score compared the group that treated with sertraline alone. ConclusionKetoprofen enhances the treatment outcome of patients with MDD and reduces the level of immunological markers by its anti-inflammatory properties. This study also further confirms the inflammatory changes in MDD and may attract attention on the use of anti-inflammatory drugs as adjuvant therapy in MDD.

Cochrane in CORR®: Topical NSAIDs for Chronic Musculoskeletal Pain in Adults.

Cochrane in CORR®: Topical NSAIDs for Chronic Musculoskeletal Pain in Adults.

European photopatch test baseline series: A 3-year experience.

In 2012, a consensus was reached regarding a baseline photopatch test series on the basis of the results of a European multicentre study. To describe experience with the European photopatch test series. A retrospective analysis of 116 patients tested with the European photopatch test series between 2014 and 2016 was performed. Fifty-five positive photopatch test reactions in 25 subjects were recorded, most commonly caused by the topical non-steroidal anti-inflammatory drugs ketoprofen, dexketoprofen, and etofenomate. Organic ultraviolet (UV) absorbers constituted the second main category of agents eliciting positive photopatch test reactions. Among UV absorbers, benozophenone-3 and octocrylene were the most frequent photoallergens. UV absorbers that have been introduced more recently rarely elicited positive photopatch test reactions. Positive patch test reactions were less commonly observed than positive photopatch test reactions, namely, 21 reactions in 14 patients. We present the largest clinical experience with the European photopatch test baseline series hitherto reported. The results are similar to those underlying the above consensus process, reaffirming the usefulness of this series.

Trends and patterns of analgesic prescribing in Malaysian public hospitals from 2010 to 2016: tramadol predominately used.

PurposeTo examine the trends of analgesic prescribing at public tertiary hospital outpatient settings and explore the patterns of their utilization in nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, and opioid patients.Patients and methodsThis cross-sectional study was conducted from 2010 to 2016 using the prescription databases of two tertiary hospitals in Malaysia. Prescriptions for nine NSAIDs (ketoprofen, diclofenac, celecoxib, etoricoxib, ibuprofen, indomethacin, meloxicam, mefenamic acid, and naproxen), tramadol, and five other opioids (morphine, fentanyl, oxycodone, dihydrocodeine, and buprenorphine) were included in this study. Annual number of patients and prescriptions were measured in repeat cross-sectional estimates. Descriptive statistics and linear trend analysis were performed using Stata version 13.ResultsA total of 192,747 analgesic prescriptions of the nine NSAIDs, tramadol, and five other opioids were given for 97,227 patients (51.8% NSAIDs patients, 46.6% tramadol patients, and 1.7% opioid patients) from 2010 to 2016. Tramadol (37.9%, n=72,999) was the most frequently prescribed analgesic, followed by ketoprofen (17.5%, n=33,793), diclofenac (16.2%, n=31,180), celecoxib (12.2%, n=23,487), and other NSAIDs (<4.5%). All the analgesics were increased over time except meloxicam, indomethacin, and mefenamic acid. Opioids, primarily morphine (2.2%, n=4,021) and oxycodone (0.5%, n=1,049), were prescribed the least, but the rate of increase was the highest.ConclusionTramadol was the most frequently prescribed analgesic in hospital outpatient settings in Malaysia. Opioids were prescribed the least, but noted the highest increase in utilization.

Acute uncomplicated cystitis: is antibiotic unavoidable?

Acute uncomplicated cystitis in women is one of the most frequently diagnosed bacterial infections. In a pilot, open, noncomparative prospective study, 29 nonpregnant, sexually active women with acute uncomplicated cystitis were enrolled. The mean age was 28.9 ± 4.3, range 22-36 years. All patients received unique therapy: the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen, 100 mg once a day for 5 days, and Canephron, 2 dragees three times a day for 1 month. In 2 days, four patients (13.8%) had no tendency to improvement; they were considered as nonresponders and antibiotics were prescribed for them. The remaining 25 patients (86.2%) showed significant improvement and were considered as responders; they continued the therapy with ketoprofen and Canephron. In 7 days, 21 patients (72.4%) had no dysuria and leucocyturia; they were considered as fast responders to phytotherapy. In four patients (13.8%), after 7 days of therapy insignificant dysuria and leucocyturia were found; they were considered as slow responders to phytotherapy. All 25 patients continued the intake of Canephron for 1 month to prevent a relapse. When treatment finished, all patients were well. In 6 months, no relapses were diagnosed. The majority (86.2%) of young, nonpregnant women with acute uncomplicated cystitis were cured by 30 days of phytotherapy combined initially (5 days) with the NSAID ketoprofen; an antibiotic was indicated in only 13.8% of patients. Patients with acute uncomplicated cystitis may be divided into three subgroup: nonresponders to phytotherapy; slow responders to phytotherapy; fast responders to phytotherapy. Antibiotic therapy is indicated in nonresponders, but slow and fast responders may be treated without an antibiotic, by phytotherapy with an initial short course of an NSAID only.

Periparturient Behavior and Physiology: Further Insight Into the Farrowing Process for Primiparous and Multiparous Sows.

Giving birth is a critical time for many species and is often the most painful event ever experienced by females. In domestic species, like the pig, pain associated with parturition represents a potential welfare concern, and the consequences of pain can cause economic losses (e.g., by indirectly contributing to piglet mortality as pain could slow post-farrowing recovery, reduce food and water intake, reducing milk let-down). This study investigated pain assessment and its management in primiparous (gilts) and multiparous (sows) breeding pigs, including the provision of a non-steroidal anti-inflammatory drug (NSAID) post-parturition. Individuals were randomly allocated to receive the NSAID ketoprofen (3 mg/kg bodyweight) (n = 11 gilts, 16 sows) or the equivalent volume of saline (n = 13 gilts, 16 sows) by intramuscular injection 1.5 h after the birth of the last piglet. Data collected included putative behavioral indicators of pain (back leg forward, tremble, back arch), salivary cortisol concentrations pre-farrowing and up to 7 days post-injection. In addition, post-partum biomarkers of inflammation, including the acute phase protein C-reactive protein (CRP) and 3 porcine cytokines [interleukin-1 β (IL1 β), interleukin-6 (IL6), and tumor necrosis factor α (TNF α)] were measured in plasma collected 6 h following the injection. Behaviors were analyzed using generalized linear mixed models, and physiological variables with linear mixed models. No difference in putative pain behaviors, salivary cortisol, CRP, or cytokines were found between individuals treated with ketoprofen or those administered the saline control. However, there were some differences between gilts and sows, as sows exhibited more putative pain behavior than gilts, had higher salivary cortisol on the day of farrowing and had higher plasma TNF α. Conversely, gilts had higher salivary cortisol than sows on day 3 post-farrowing and had higher CRP. This indicates that, like human females, multiparous sows experience more pain from uterine activity following birth than primiparas. This study provides useful information for developing management practices relating to post-farrowing care for breeding pigs.

Gestational intermittent hypoxia induces neuroinflammation and impairs compensatory respiratory plasticity in adult offspring

Sleep disordered breathing during pregnancy is increasing at an alarming rate, but virtually nothing is known about long‐lasting effects on adult offspring physiology. Preliminary data suggest that microglia isolated from adult rat offspring exposed to in utero intermittent hypoxia exhibit enhanced inflammatory gene expression and primed responses to inflammatory stimuli. Since neuroinflammation abrogates some forms of respiratory plasticity, we tested the hypothesis that gestational intermittent hypoxia (GIH) impairs respiratory plasticity in adult offspring. Pregnant rat dams were exposed to chronic intermittent hypoxia (8 hrs/day, 2 min 10.5% O2 separated by 2 min of 21% O2) or intermittent normoxia from gestation days 10–21 (GIH and GNX, respectively). Respiratory plasticity was assessed by measuring the response to recurrent neural apnea in urethane‐anesthetized, mechanically ventilated male and female GNX and GIH offspring. Recurrent neural apnea was induced by briefly hyperventilating below the CO2 apneic threshold for breathing (5, ~1 min neural apnea episodes, separated by 5 min). In GNX offspring, recurrent neural apnea triggered a significant increase in phrenic burst amplitude (45±3 %baseline, n=6, p&lt;0.05), a form of plasticity known as inactivity‐induced phrenic motor facilitation (iPMF). By contrast, intermittent neural apnea did not trigger increased phrenic burst amplitude in GIH offspring (7±8 %baseline, n=10, p&gt;0.05), suggesting that in utero intermittent hypoxia impairs the capacity to elicit iPMF. Further, the phrenic response to intermittent neural apnea was significantly different in GIH and GNX rats (p&lt;0.05). A critical role for microglial neuroinflammation is suggested by preliminary data indicating that the capacity to elicit iPMF can be restored in adult GIH offspring in which microglia are depleted with Pexidartinib (PLX3397) or following administration of the non‐steroidal anti‐inflammatory drug ketoprofen. Since iPMF is hypothesized to be a compensatory form of respiratory plasticity that prevents recurrent apneas, the impact of impaired iPMF on breathing stability in adult GIH offspring during sleep is currently being investigated.Support or Funding InformationHL105511, NS085226This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inflammation Differentially Impacts Phrenic Long‐term Facilitation (pLTF) in Rats with Motor Neuron Death Induced by Intrapleural CTB‐saporin Injections

Intrapleural injection of cholera toxin B fragment conjugated to saporin (CTB‐SAP) selectively kills respiratory motor neurons, and mimics aspects of neuromuscular disorders and neurodegenerative diseases including phrenic motor neuron death, decreased phrenic motor output, and increased microglial cell number. Our previous results demonstrated unexpectedly that respiratory plasticity is not only observed 7 days (d) after CTB‐SAP delivery, but that it is actually enhanced compared to control treatments. At 28d, however, respiratory plasticity is comparable to control levels, suggesting that the underlying mechanisms of plasticity at both time points may differ. Because inflammation is a hallmark of all neurodegenerative diseases, and it is known to prevent the development of acute intermittent hypoxia‐induced phrenic long‐term facilitation (pLTF), we predicted that inflammation would impair pLTF in CTB‐SAP‐treated rats and thus, anti‐inflammatory drugs would enhance pLTF at both time points. Using anesthetized, paralyzed and ventilated CTB‐SAP‐treated adult Sprague Dawley rats, we studied acute intermittent hypoxia (AIH; 3, 5 min bouts of 10.5% O2) induced pLTF following intrathecal C4 delivery of the nonsteroidal anti‐inflammatory drug ketoprofen to rats that received bilateral, intrapleural injections of: 1) CTB‐SAP (25μg), or 2) un‐conjugated CTB and SAP (control) in rats treated 7d or 28d prior. Surprisingly, preliminary results indicate that ketoprofen attenuates pLTF in 7d CTB‐SAP‐treated rats, but enhances it in the 28d CTB‐SAP‐treated rats. These observations suggest that inflammation potentially contributes to pLTF in 7d CTB‐SAP‐treated rats, whereas it may undermine pLTF in 28d CTB‐SAP‐treated rats. Studies are underway to assess cervical spinal levels of both pro‐inflammatory and anti‐inflammatory and neurotrophic molecules at both time points, and their cellular source. Future studies will investigate the potential contributions of microglia to the mechanisms whereby inflammation differentially impacts pLTF in CTB‐SAP‐treated rats. Results from this project will increase our understanding of how inflammation and microglial activities influence respiratory plasticity following motor neuron death, and will have broad implications for therapies restoring ventilatory function in many disorders in which motor neuron death is associated.Support or Funding InformationNIH K99/R00 HL119606This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Patch and Photo-Patch Testing are Important in Patients with Idiopathic Photodermatoses

This number of the Revista da Sociedade Portuguesa de Dermatologia e Venereologia contains two articles dedicated to idiopathic photodermatoses, for which autoimmune reactions to an unknown endogenous chromophore are suspected to be involved – polymorphous light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, and solar urticarial.1,2 Many of these and other photodermatoses have a very clear clinical presentation, while others may mimic allergic contact dermatitis (ACD) or photo-allergic contact dermatitis (PhACD), a classical T cell-mediated or delayed type IV hypersensitivity reaction to an exogenous chromophore applied on the skin in the presence of, or followed by exposure to ultraviolet (UV) or visible light.3,4 Allergic contact reactions can be followed by persistent photosensitivity and chronic actinic dermatitis, such as in cases of chronic ACD from certain plants, e.g., Compositae that are rich in sesquiterpene lactones,5 fragrances, lichens, and colophony,4 or in PhACD or photo-aggravated ACD from drugs like ketoprofen, etofenamate, and chlorproethazine, or even other contact allergens, such as tosylamide/formaldehyde resin, fragrances, and thiourea derivatives.4The long persistence of these chemicals in the epidermis (for up to at least 17 days in the case of ketoprofen),6 or the formation of endogenous photosensitizers might perhaps explain the progression to chronic actinic dermatitis.4In patients with idiopathic photodermatoses the use of sunscreens is mandatory, however, the sensitization risk from these chemicals may be enhanced by the previous skin inflammation and the need for repeated application for long periods.7 UV filters, which are chromophores that capture UV light, are among the most frequent causes of PhACD,8-11 namely benzophenones, dibenzoylmethane derivatives, octocrylene, and cinammates.9,10,12-14 Although more recent UV filters seem to be more photostable and less prone to induce PhACD,3 a few cases have been described,9 for example, from polysilicone-15 (Parsol®SLX).15 With regard to methylene bis-benzotriazolyl tetramethylbutylphenol (syn. bisoctrizole or Tinosorb® M), ACD from it is due to the surfactant decyl glucoside, in particular, which is added in order to stabilize the sunscreen molecule.16,17Topical drugs, such as the non-steroidal anti-inflammatory ketoprofen, piketoprofen, suprofen, etofenamate, piroxicam, and benzydamine,18 as well as phenothiazine derivatives, i.e., promethazine or chlorproethazine, and isothipendyl chlorhydrate19 are frequent causes of ACD/PhACD, either by direct application or by transfer from other individuals in close contact (consort or connubial dermatitis). Moreover, some of these chemicals, particularly ketoprofen, exhibit cross-reactions with UV filters, i.e., benzophenone(s) and octocrylene, the latter containing benzophenone residues. Also fenofibrate, a systemic drug, shares the benzophenone ring and can cross react with ketoprofen and related molecules.3,20 Furthermore, patients with PhACD from ketoprofen present with concomitant reactions to the perfume ingredient cinnamic alcohol, reactions that at present are difficult to explain by cross-reactivity.21Therefore, patch and photo-patch testing are highly recommended in patients with idiopathic and autoimmune photodermatoses, as well as in all other diseases aggravated by sunlight, in order to detect and avoid exposure to possible aggravating factors, and particularly to UV filters. Recently, recommendations for diagnostic patch testing have been issued by the European Society of Contact Dermatitis (ESCD),22 and in a cooperative effort of the ESCD and European Society of Photodermatology (ESPD), an agreement was not only reached regarding standardized protocols for photo-patch testing,23 but also on the list of 20 allergens to be included in the European baseline photo-patch tests series and an additional extended series including certain classical photo-allergens.24 Last but not least, photo-patch tests with all the patient’s own topical products and systemic photosensitizers to which the patients is exposed are strongly recommended as well, since the outcome may further contribute to the relevance of positive reactions observed, or avoid “false”- negative reactions obtained by testing standardized allergens only.24

Study comparison analgesic, antipyretic and anti-inflammatory activity of aqueous and alcoholic leaves extract of Lawsonia inermis L. (Henna) with ketoprofen in male albino rats

The pain considered is an important signs for many medical condition which is reduced by using analgesic drugs, that act either locally or systemically via central nervous system, that may have many harmful side effects. This study was carried out to evaluate the analgesic, antipyretic and anti-inflammatory effect of both aqueous and alcoholic extract of Lawsonia inermis L. and comparing with one of non-steroidal anti-inflammatory drugs (NSAID) Ketoprofen by using hot plate test, tail immersion method, and study ability of aqueous and alcoholic extract to reduce writhing induced by acetic acid injection. Also, study the antipyretic and anti-inflammatory activity of henna extract in formalin-induced paw edema . Twenty four Wister rats were used which divided randomly into four equal groups, first group served as control negative treated with distal water, second, control positive, injected with ketoprofen (8 mg/kg B.W.) third group treated with aqueous extract and fourth group treated with methanolic extract (200 mg/kg B.W.) in addition to the ketoprofen. At the end of experiment, the results clarified that alcoholic extract of henna has similar effect of ketoprofen via significant increase (P&lt;0.05) in reaction time to hot plate and tail withdrawal from hot water. Moreover, the results explained significant decrease (P&lt;0.05) in the writhes count( abdominal constriction). As well as, the ability of alcoholic extract to significant (P&lt;0.05 ) reduce body temperature comparing with control group. Likewise, the result revealed that alcoholic extract of Lawsonia inermis has anti-inflammatory activity by significant (P&lt;0.05 ) reduction in edema size induced by formalin injection in paw skin, and Tumor necrosis factor alpha. (TNF-α). Thus, the results of current study illustrated that methanolic extract of Lawsonia inermis has central and peripheral analgesic, antipyretic and anti-inflammatory activity comparing with control group.

Correlation between glucuronidation and covalent adducts formation with proteins of nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause idiosyncratic liver injury. Mechanisms involved in NSAID-induced liver injury are complex. Previous studies have suggested that acyl glucuronide of NSAIDs (NSAIDs-Glu) plays an important role in the development of liver injury via covalently binds to proteins and the resultant adduct induces immunological toxicity. As only some NSAIDs-Glu are commercially available, the evaluation of covalent protein adduct formation using ready-made NSAIDs-Glu is difficult and inconvenient. Moreover, glucuronidation potency varies with the NSAID, including stereoisomers. Therefore, in this study, we simultaneously examined the glucuronidation and covalent adduct formation using enantiomers of parent NSAIDs (ibuprofen, naproxen, pranoprofen, ketoprofen, and flurbiprofen) in rat liver microsomes. Glucuronides and covalent adducts were quantified by HPLC. The amount of covalent adduct increased with NSAIDs-Glu formation in the rat liver microsomes in a time-dependent manner. A significant positive correlation was observed between the AUC of NSAIDs-Glu and that of covalent adduct, except ketoprofen. Although ketoprofen exhibited the highest glucuronidation rate among the NSAIDs investigated, the amount of covalent adduct was similar to that for pranoprofen, which had the lowest glucuronidation rate. Thus, it may be difficult for ketoprofen glucuronide to covalently bind with proteins in the rat liver microsomes. Our results suggested that the amount of glucuronide formed is a key factor in predicting covalent bond formation with protein in NSAIDs, in addition to degradability and bindability with proteins of NSAIDs-Glu. Further studies are required to confirm the relationship between the tendency of glucuronidation and the formation of covalent adducts of NSAIDs.

Multifunctionalized mesoporous silica as an efficient reversed-phase/anion exchange mixed-mode sorbent for solid-phase extraction of four acidic nonsteroidal anti-inflammatory drugs in environmental water samples

A mesoporous silica Santa Barbara Amorphous-15 (SBA-15) has been first functionalized with 3-[2-(2-aminoethylamino)ethylamino]propyl-trimethoxysilane (a silane with three amines) and then reacted with an excess of phenyl glycidyl ether to generate a mixed-mode anion-exchanger containing both anion-exchange (three amines) and reversed-phase (multiple ether-linked phenyls) functionalities in a single branched ligand. The resulting material has been characterized by scanning electron microscopy, transmission electron microscopy, nitrogen adsorption-desorption measurements, Fourier-transform infrared spectroscopy, and elemental analysis. The results obtained indicated a BET specific surface area (SBET) of 362.5m2g−1, a pore volume of 0.70cm3g−1 with a narrow pore size distribution centered at 6.6nm, and carbon and nitrogen contents of 28.30% and 2.84%, respectively. The dimensions of these particles (∼5μm diameter, ∼60μm length), their large surface areas, their high-density functionalities and anion-exchange mixed-mode characteristics make them very attractive for highly effective solid phase extraction (SPE) of acidic nonsteroidal anti-inflammatory drugs (NSAIDs). The important parameters on extraction efficiency including sample pH, breakthrough volume, type and volume of eluent were optimized. A simple and sensitive analytical method based on mixed-mode SPE coupled to high-performance liquid chromatography with ultraviolet detection (HPLC-UV) was developed and successfully applied to the analysis of four NSAIDs (ketoprofen, naproxen, diclofenac, and ibuprofen) in spiked real water samples with satisfactory recoveries (80.6–110.9%) and repeatability (relative standard deviation <11.3%, n=3). The limit of detections of four NSAIDs were 0.006–0.070μgL−1 for tap water, and 0.014–0.16μgL−1 for river water and wastewater, with the enrichment factors of 806–1109-fold.

Cobra Venom Factor and Ketoprofen Abolish the Antitumor Effect of Nerve Growth Factor from Cobra Venom.

We showed recently that nerve growth factor (NGF) from cobra venom inhibited the growth of Ehrlich ascites carcinoma (EAC) inoculated subcutaneously in mice. Here, we studied the influence of anti-complementary cobra venom factor (CVF) and the non-steroidal anti-inflammatory drug ketoprofen on the antitumor NGF effect, as well as on NGF-induced changes in EAC histological patterns, the activity of lactate and succinate dehydrogenases in tumor cells and the serum level of some cytokines. NGF, CVF and ketoprofen reduced the tumor volume by approximately 72%, 68% and 30%, respectively. The antitumor effect of NGF was accompanied by an increase in the lymphocytic infiltration of the tumor tissue, the level of interleukin 1β and tumor necrosis factor α in the serum, as well as the activity of lactate and succinate dehydrogenases in tumor cells. Simultaneous administration of NGF with either CVF or ketoprofen abolished the antitumor effect and reduced all other effects of NGF, whereas NGF itself significantly decreased the antitumor action of both CVF and ketoprofen. Thus, the antitumor effect of NGF critically depended on the status of the immune system and was abolished by the disturbance of the complement system; the disturbance of the inflammatory response canceled the antitumor effect as well.

The effect of post-farrowing ketoprofen on sow feed intake, nursing behaviour and piglet performance

Farrowing is a critical time for sows and piglets. Poor post-farrowing sow recovery, and piglet mortality represent a welfare concern, as well as an economic loss to the pig industry. Providing a non-steroidal anti-inflammatory drug (NSAID) to the sow post-farrowing may improve sow welfare and productivity and thereby improve health status and welfare of the piglets, which would be of economic benefit to pig producers. This study investigated the production effects of providing the NSAID ketoprofen post-farrowing, to 24 primiparous (gilts) and 32 multiparous (sows) breeding pigs, in a randomised, blinded, placebo-controlled trial. Gilts and sows were allocated to receive ketoprofen (treated) or the equivalent volume of saline (control) by intramuscular injection 1.5h after the last piglet birth. Data collected included sow feed intake, immune transfer (colostrum and piglet serum immunoglobulin-G (IgG)), nursing behaviour and piglet weight, and mortality. An additional factor in this study was that 13 individuals required additional treatment in the days after farrowing for post-farrowing illness. Therefore, data were analysed using mixed models, including treatment (treated or control), parity group (gilt or sow), and additional treatment (yes or no) as fixed factors. Stepwise binomial logistic regression was used to analyse the association between the experimental factors (treatment, additional treatment, gilt or sow), along with other gilt/sow, litter, and piglet-based measures, with piglet death before weaning. Few treatment effects were seen, with parameters being more affected by whether gilts and sows were treated for illness, or between gilts and sows. The only variable to differ by treatment was suckle grunt duration, which was greater for control compared with treated dams (P = 0.05). Feed consumption was greater for sows compared with gilts on days 6 and 7 post-farrowing, and serum IgG was greater in piglets from sows than gilts (P < 0.05). Feed consumption was reduced in dams needing additional treatment, from days 2–7 post-farrowing, and those developing illness consumed less feed overall (P = 0.004). The best regression model for predicting the odds of a piglet dying before weaning included number born alive (P = 0.03), requiring additional treatment (P = 0.006), being male (P = 0.0005), and pre-farrowing gilt/sow back-fat (P < 0.0001), which increased the log-odds of death, whereas, piglet body weight decreased the log-odds of death (P < 0.0001). This study did not demonstrate clear benefits to ketoprofen, however, high individual variation in piglet mortality, indicates potential for targeted NSAID use.

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.

Improved Monitoring of Aqueous Samples by the Concentration of Active Pharmaceutical Ingredients using Ionic-Liquid-based Systems.

Fluoroquinolones (FQs) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are two classes of Active Pharmaceutical Ingredients (APIs), widespreadly used in human healthcare and as veterinary drugs, and that have been found throughout the water cycle in the past years. These two classes of APIs are commonly present in aqueous streams in concentrations ranging from ng.L-1 to µg.L-1. Despite such low concentrations, these contaminants tend to bioaccumulate, leading to serious environmental and health issues after chronic exposure. The low concentrations of FQs and NSAIDs in aqueous media also render their difficult identification and quantification, wich may result in an unefficient evaluation of their environmental impact and persistence. Therefore, the development of alternative pre-treatment techniques for their extraction and concentration from aqueous samples is a crucial requirement. In this work, liquid-liquid systems, namely ionic-liquid-based aqueous biphasic systems (IL-based ABS), were tested as simultaneous extraction and concentration platforms of FQs and NSAIDs. ABS composed of imidazolium-, ammonium- and phosphonium-based ILs and a citrate-based salt (C6H5K3O7) were evaluated for the single-step extraction and concentration of three FQs (ciprofloxacin, enrofloxacin and norfloxacin) and three NSAIDs (diclofenac, naproxen and ketoprofen) from aqueous samples. Outstanding one-step extraction efficiencies of APIs close to 100% were obtained. Furthermore, concentration factors of both FQs and NSAIDs were optimized by an appropriate manipulation of the phase-forming components compositions to tailor the volumes of the coexisting phases. Concentration factors of 1000-fold of both FQS and NSAIDs were obtained in a single-step, without reaching the saturation of the IL-rich phase. The concentration of APIs up to the mg.L-1 allowed their easy and straightforward identification and quantification by High-Performance Liquid Chromatography (HPLC) coupled to an UV detector, as shown either with model aqueous samples or real wastewater effluent samples.

Non-steroidal anti-inflammatory drugs in the watercourses of Elbe basin in Czech Republic

Non-steroidal anti-inflammatory drugs (NSAIDs) belong to most used pharmaceuticals in the human and veterinary medicine. The widespread consumption of NSAIDs has led to their ubiquitous occurrence in water environment including large river systems. In the present study, concentrations of the five most frequently used NSAIDs (ibuprofen, diclofenac, naproxen, ketoprofen and indomethacin) were determined in the watercourses of the river Elbe basin in Czech Republic. The presence of the pharmaceuticals was measured at 29 sampling sites including urban and rural areas, small creeks and main tributaries of the Elbe monthly from April to December of 2011. For the NSAIDs quantitation, the comprehensive analytical method combing pentafluorobenzyl bromide (PFBBr) derivatization with highly sensitive two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOFMS) was developed. Although the content of all NSAIDs varied at the particular sampling points significantly, total amount of particular compounds was relatively stable during all monitored periods with only non-significant increase in the spring and autumnal months. Ibuprofen was found to be the most abundant drug with maximum concentration of 3210 ng/L, followed by naproxen, diclofenac and ketoprofen (1423.8 ng/L, 1080 ng/L and 929.8 ng/L, respectively). Indomethacin was found only at several sampling sites (maximum concentration of 69.3 ng/L). Concentrations of all compounds except ibuprofen were significantly higher at sampling sites with low flow rates (creeks), followed by the biggest watercourses.