Ketoprofen a nonsteroidal anti-inflammatory drug (NSAID) is widely used in over-the-counter to treat pain, swelling and inflammation. Due to extensive application these drugs has been detected in ...surface waters which may create a risk to aquatic organisms. The aim of the present study is to assess the ecotoxicity of ketoprofen at different concentrations (1, 10 and 100 μg/ml) on embryos and adult zebrafish (1, 10 and 100 μg L−1) under laboratory conditions. In embryos, concentration dependent developmental changes such as edema, spinal curvature, slow heartbeat, delayed hatching, and mortality rate were observed. In adult zebrafish, biochemical enzymes such as AST, ALT and LDH activities were significantly (P < 0.05) increased whereas a decrease in Na+/K+-ATPase activity was noticed in all the tested concentrations of the drug ketoprofen. Similarly, exposure of ketoprofen caused a significant decrease in antioxidant levels in liver tissue (SOD, CAT, GSH, GPx, and GST). However, lipid peroxidation (LPO) level in liver tissue was found to be increased. The histopathological studies further evidenced the impact of ketoprofen in the liver tissue of zebrafish. The present result concludes that ketoprofen could have an impact on the development and biological endpoints of the zebra fish at above concentrations. The malformation in the development of the embryo and changes in the biological end points may provide integrated evaluation of the toxic effect of ketoprofen on zebrafish in a new perspective.
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•Ketoprofen toxicity was evaluated in embryonic and adult zebrafish at different concentrations.•Ketoprofen causes developmental abnormalities in zebrafish embryos.•Long term study reveals that ketoprofen exposure alters biochemical and antioxidant responses of adult fish.•A concentration dependent toxicity on above parameters were observed.
Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple ...analgesics for the treatment of episodic tension-type headache (ETTH) in adults.
We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554.
We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity
between the studies was low.
Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).
The aim of this study was to evaluate skin delivery of ketoprofen when covalently tethered to mildly cationic (2+ or 4+) peptide dendrimers prepared wholly by solid phase peptide synthesis. The amino ...acids glycine, arginine and lysine formed the dendrimer with ketoprofen tethered either to the lysine side-arm (Nε) or periphery of dendrimeric branches. Passive diffusion, sonophoresis- and iontophoresis-assisted permeation of each peptide dendrimer-drug conjugate (D1–D4) was studied across mouse skin, both in vitro and in vivo. In addition, skin toxicity of dendrimeric conjugates when trialed with iontophoresis or sonophoresis was also evaluated. All dendrimeric conjugates improved aqueous solubility at least 5-fold, compared to ketoprofen alone, while also exhibiting appreciable lipophilicity. In vitro passive diffusion studies revealed that ketoprofen in its native form was delivered to a greater extent, compared with a dendrimer-conjugated form at the end of 24h (Q24h (μg/cm2): ketoprofen (68.06±3.62)>D2 (49.62±2.92)>D4 (19.20±0.89)>D1 (6.45±0.40)>D3 (2.21±0.19). However, sonophoresis substantially increased the skin permeation of ketoprofen-dendrimer conjugates in 30min (Q30min (μg/cm2): D4 (122.19±7.14)>D2 (66.74±3.86)>D1 (52.10±3.22)>D3 (41.66±3.22)) although ketoprofen alone again proved superior (Q30min: 167.99±9.11μg/cm2). Next, application of iontophoresis was trialed and shown to considerably increase permeation of dendrimeric ketoprofen in 6h (Q6h (μg/cm2): D2 (711.49±39.14)>D4 (341.23±16.43)>D3 (89.50±4.99)>D1 (50.91±2.98), with a Q6h value of 96.60±5.12μg/cm2 for ketoprofen alone). In vivo studies indicated that therapeutically relevant concentrations of ketoprofen could be delivered transdermally when iontophoresis was paired with D2 (985.49±43.25ng/mL). Further, histopathological analysis showed that the dendrimeric approach was a safe mode as ketoprofen alone. The present study successfully demonstrates that peptide dendrimer conjugates of ketoprofen, when combined with non-invasive modalities, such as iontophoresis can enhance skin permeation with clinically relevant concentrations achieved transdermally.
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Abstract Introduction Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are ...considered therapeutic candidates. As a biomarker of neuroinflammatory processes,11 C-labeled ketoprofen methyl ester (11 CKTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that 11 CKTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. 11 CKTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study. Methods 11 CKTP-Me was synthesized by rapid C -11 Cmethylation of 11 CCH3 I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of > 99% and specific activity of > 25 GBq/μmol at injection. Six young healthy male humans were injected with 11 CKTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis. Results No adverse effects were observed during PET scanning after 11 CKTP-Me injection. 11 CKTP-Me was rapidly metabolized to11 C-labeled ketoprofen (11 CKTP) within 2–3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41μGy/MBq, respectively). The mean effective dose was 4.7 μSv/MBq, which was comparable to other11 C-labeled radiopharmaceuticals. Conclusion 11 CKTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. 11 CKTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.
Magnetic carbon nanotubes (CNTs) with encapsulated Co nanoparticles (Co@CNTs), was synthesized by exploiting the one-step pyrolysis strategy using ZIF-67 as template. The as-synthesized Co@CNTs is ...provided with the nanopores, a large specific surface area, and strong magnetic response. The obtained Co@CNTs was used as magnetic solid-phase extraction adsorbents to extract two profens including flurbiprofen and ketoprofen. The parameters of extraction efficiency, involving extraction time, sample solution volume, ionic strength, pH and the conditions of desorption efficiency, were optimized in detail. After determined by high-performance liquid chromatography-ultraviolet (HPLC-UV), the results evinced that Co@CNTs showed a high extraction efficiency with high enrichment factors of 832 and 672. The good linear range of both flurbiprofen and ketoprofen were all 5.0–1000 ng L−1, with the limit of detection were 0.60 ng L−1 and 0.70 ng L−1, respectively. Furthermore, a valid method for the extraction of flurbiprofen and ketoprofen from human serum was established. The spiking recoveries of two profens were between 86.74% and 97.22%, and the relative standard deviation was less than 6.55%. Co@CNTs can be repeatedly used at least 10 times, indicating its excellent regeneration and reusability. The results demonstrated that the Co@CNTs materials exhibits high enrichment ability and extraction efficiency, playing great promise in MSPE.
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•The facile one-step pyrolysis strategy was utilized to synthesize core-shell magnetic Co@CNTs.•The prepared Co@CNTs exhibited nanopores, high BET surface area and strong magnetic response.•High enrichment factor for profens using the Co@CNTs as MSPE adsorbent was obtained.•The developed method can be applied to enrich and detect trace profens in human serum.
Background
Use of topical nonsteroidal anti‐inflammatory drugs (NSAIDs) to treat chronic musculoskeletal conditions has become widely accepted because they can provide pain relief without associated ...systemic adverse events. This review is an update of 'Topical NSAIDs for chronic musculoskeletal pain in adults', originally published in Issue 9, 2012.
Objectives
To review the evidence from randomised, double‐blind, controlled trials on the efficacy and safety of topically applied NSAIDs for chronic musculoskeletal pain in adults.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and our own in‐house database; the date of the last search was February 2016. We also searched the references lists of included studies and reviews, and sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' web sites.
Selection criteria
We included randomised, double‐blind, active or inert carrier (placebo) controlled trials in which treatments were administered to adults with chronic musculoskeletal pain of moderate or severe intensity. Studies had to meet stringent quality criteria and there had to be at least 10 participants in each treatment arm, with application of treatment at least once daily.
Data collection and analysis
Two review authors independently assessed studies for inclusion and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat (NNT) or harm (NNH) compared to carrier or other active treatment. We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. The primary outcome was 'clinical success', defined as at least a 50% reduction in pain, or an equivalent measure such as a 'very good' or 'excellent' global assessment of treatment, or 'none' or 'slight' pain on rest or movement, measured on a categorical scale.
Main results
We identified five new studies for this update, which now has information from 10,857 participants in 39 studies, a 41% increase in participants from the earlier review; 32 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size.
In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2353 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis.
There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence).
Clinical success with carrier occurred commonly ‐ in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo.
A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed.
Authors' conclusions
Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that.
Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate‐release (IR) solid oral dosage forms containing ...ketoprofen are reviewed. Ketoprofen's solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA)/dissolution data were taken into consideration. The available data suggest that according to the current Biopharmaceutics Classification System (BCS) and all current guidances, ketoprofen is a weak acid that would be assigned to BCS Class II. The extent of ketoprofen absorption seems not to depend on formulation or excipients, so the risk of bioinequivalence in terms of area under the curve is very low, but the rate of absorption (i.e., BE in terms of peak plasma concentration, Cmax) can be altered by formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, such differences in absorption rate are acceptable for ketoprofen with respect to patient risks. As ketoprofen products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR ketoprofen solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients present also in IR solid oral drug products containing ketoprofen, which are approved in International Conference on Harmonisation or associated countries, for instance, as presented in this paper; (b) both the test drug product and the comparator dissolve 85% in 30 min or less in pH 6.8 buffer; and (c) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When one or more of these conditions are not fulfilled, BE should be established in vivo.
We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles ...(KETnano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KETnano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83 nm. In the in vitro skin penetration experiment, the penetration rate (Jc) and penetration coefficient through the skin (Kp) values of the KETnano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KETmicro gel ointment; mean particle size 7.7 µm). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (ka) and the areas under the KET concentration–time curve values in the skin of rats receiving the KETnano gel ointment were significantly higher than those of rats receiving the KETmicro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KETnano gel ointment were also significantly higher than those of rats receiving the KETmicro gel ointment. In addition, the application of the KETnano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KETmicro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET.
Dexketoprofen is an enantiomer of ketoprofen (S+) that belongs to nonsteroidal anti-inflammatory drugs and has analgesic, anti-inflammatory, and antipyretic properties. Dexketoprofen has a stronger ...effect than ketoprofen, which makes it a readily used preparation. The review aims to find in recent original publications data about dexketoprofen and its comparison with other painkilling medications. The systematic literature review was conducted in November 2021 (2018 onwards). We selected 12 articles from PubMed, Google Scholar, Medline Complete databases. In the last 4 years, there have been many publications that shed a new light on dexketoprofen. The article is a comparative analysis of dexketoprofen’s action vs other nonsteroidal anti-inflammatory drugs and the combination of dexketoprofen with tramadol vs paracetamol with tramadol. The findings of the review confirm that dexketoprofen is a very good pain reliever more potent than paracetamol. Dexketoprofen produces similar effects to lidocaine and dexmedetomidine. Complex preparations containing dexketoprofen and tramadol are very effective painkilling tandem and are more effective than tramadol and paracetamol therapy in the treatment of acute pain.
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•Dexketoprofen is an effective drug in the treatment of pain.•Dexketoprofen has a better analgesic effect than paracetamol.•Dexketoprofen with tramadol is more effective than paracetamol with tramadol.•Dexketoprofen has similar analgesic effect as lidocaine and dexmedetomidine.•Dexketoprofen with metoclopramide has better analgesic effect.
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