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.

Role for Carboxylic Acid Moiety in NSAIDs: Favoring the Binding at Site II of Bovine Serum Albumin.

The molecular structures of nonsteroidal anti-inflammatory drugs (NSAIDs) vary, but most contain a carboxylic acid functional group (RCOOH). This functional group is known to be related to the mechanism of cyclooxygenase inhibition and also causes side effects, such as gastrointestinal bleeding. This study proposes a new role for RCOOH in NSAIDs: facilitating the interaction at the binding site II of serum albumins. We used bovine serum albumin (BSA) as a model to investigate the interactions with ligands at site II. Using dansyl-proline (DP) as a fluorescent site II marker, we demonstrated that only negatively charged NSAIDs such as ibuprofen (IBP), naproxen (NPX), diflunisal (DFS), and ketoprofen (KTP) can efficiently displace DP from the albumin binding site. We confirmed the importance of RCOO by neutralizing IBP and NPX through esterification, which reduced the displacement of DP. The competition was also monitored by stopped-flow experiments. While IBP and NPX displaced DP in less than 1 s, the ester derivatives were ineffective. We also observed a higher affinity of negatively charged NSAIDs using DFS as a probe and ultrafiltration experiments. Molecular docking simulations showed an essential salt bridge between the positively charged residues Arg409 and Lys413 with RCOO-, consistent with the experimental findings. We performed a ligand dissociation pathway and corresponding energy analysis by applying molecular dynamics. The dissociation of NPX showed a higher free energy barrier than its ester. Apart from BSA, we conducted some experimental studies with human serum albumin, and similar results were obtained, suggesting a general effect for other mammalian serum albumins. Our findings support that the RCOOH moiety affects not only the mechanism of action and side effects but also the pharmacokinetics of NSAIDs.

Carrageenan-xanthan nanocomposite film with improved bioadhesion and permeation profile in human skin: A cutaneous-friendly platform for ketoprofen local delivery.

Ketoprofen (KET), commonly used for inflammation in clinical settings, leads to systemic adverse effects with prolonged use, mitigated by topical administration. Nanotechnology-based cutaneous forms, like films, may enhance KET efficacy. Therefore, this study aimed to prepare and characterize films containing KET nanoemulsions (F-NK) regarding mechanical properties, chemical composition and interactions, occlusive potential, bioadhesion, drug permeation in human skin, and safety. The films were prepared using a κ-carrageenan and xanthan gum blend (2 % w/w, ratio 3: 1) plasticized with glycerol through the solvent casting method. Non-nanoemulsioned KET films (F-K) were prepared for comparative purposes. F-NK was flexible and hydrophilic, exhibited higher drug content and better uniformity (94.40 ± 3.61 %), maintained the NK droplet size (157 ± 12 nm), and was thinner and lighter than the F-K. This film also showed increased tensile strength and Young's modulus values, enhanced bioadhesion and occlusive potential, and resulted in more of the drug in the human skin layers. Data also suggested that nano-based formulations are homogeneous and more stable than F-KET. Hemolysis and chorioallantoic membrane tests suggested the formulations' safety. Thus, the nano-based film is suitable for cutaneous KET delivery, which may improve the drug's efficacy in managing inflammatory conditions.

REKOVER study protocol: a pRospective patient treatment rEgistry of tramadol and dexKetoprofen trometamol oral fixed-dose combination (SKUDEXA) in mOderate to seVere acutE pain in Real-world setting in Asia.

INTRODUCTION: Satisfactory management of acute pain remains a major medical challenge despite the availability of multiple therapeutic options including the fixed-dose combination (FDC) drugs. Tramadol and dexketoprofen trometamol (TRAM/DKP) 75/25 mg FDC was launched in 2018 in Asia and is widely used in the management of moderate to severe acute pain. There are limited data on its effectiveness and safety in Asian patients, and therefore, a need to better understand its usage patterns in clinical practice. We aim to understand the usage pattern of TRAM/DKP FDC, its effectiveness and tolerability in patients with moderate to severe acute pain in Asia. METHODS AND ANALYSIS: REKOVER is a phase-IV, multicountry, multicentre, prospective, real-world observational study. A total of 750 postsurgical and non-surgical patients (male and female, aged 18-80 years) will be recruited from 13 tertiary-care hospitals (15 sites) in Singapore, Thailand, the Philippines and Malaysia. All patients prescribed with TRAM/DKP FDC and willing to participate in the study will be enrolled. The recruitment duration for each site will be 6 months. The severity of pain will be collected using Numeric Pain Rating Scale through the treatment period from day 1 to day 5, while satisfaction with the treatment will be evaluated using Patient Global Evaluation Scale at the end of treatment. Any adverse event reported during the study duration will be recorded for safety analysis (up to day 6). The study data will be entered into the ClaimIt portal and mobile application (app) (ObvioHealth, USA). All the inpatient data will be entered into the portal by the study site and for outpatient it will be done by patients through an app. ETHICS AND DISSEMINATION: The study has been approved by the local ethics committee from each study sites in Singapore, Thailand, the Philippines and Malaysia. Findings will be disseminated through local and global conference presentations, publications in peer-reviewed scientific journals and continuing medical education.

Simultaneous Determination of Enantiomeric Purity and Organic Impurities of Dexketoprofen Using Reversed-Phase Liquid Chromatography-Enhancing Enantioselectivity through Hysteretic Behavior and Temperature-Dependent Enantiomer Elution Order Reversal on Polysaccharide Chiral Stationary Phases.

A reversed-phase high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of the potential impurities of dexketoprofen, including the distomer R-ketoprofen. After screening the separation capability of four polysaccharide columns (Lux Amylose-1, Lux Amylose-2, Lux Cellulose-1 and Lux Cellulose-2) in polar organic and in reversed-phase modes, appropriate enantioseparation was observed only on the Lux Amylose-2 column in an acidified acetonitrile/water mixture. A detailed investigation of the mobile phase composition and temperature for enantio- and chemoselectivity showed many unexpected observations. It was observed that both the resolution and the enantiomer elution order can be fine-tuned by varying the temperature and mobile phase composition. Moreover, hysteresis of the retention times and enantioselectivity was also observed in reversed-phase mode using methanol/water mixtures on amylose-type columns. This could indicate that the three-dimensional structure of the amylose column can change by transitioning from a polar organic to a reversed-phase mode, which affects the enantioseparation process. Temperature-dependent enantiomer elution order and rare enthalpic/entropic controlled enantioseparation in the operative temperature range were also observed in reversed-phase mode. To find the best methodological conditions for the determination of dexketoprofen impurities, a full factorial optimization design was performed. Using the optimized parameters (Lux Amylose-2 column with water/acetonitrile/acetic acid 50/50/0.1 (v/v/v) at a 1 mL/min flow rate at 20 °C), baseline separations were achieved between all compounds within 15 min. Our newly developed HPLC method was validated according to the current guidelines, and its application was tested on commercially available pharmaceutical formulations. According to the authors' knowledge, this is the first study to report hysteretic behavior on polysaccharide columns in reversed-phase mode.

Single-dose nonsteroidal anti-inflammatory drugs in horses have no impact on concentrations of cytokines or growth factors in autologous protein solution and platelet-rich plasma.

OBJECTIVE: To determine the effects of a single dose of the NSAIDs phenylbutazone, firocoxib, flunixin meglumine, and ketoprofen on concentrations of growth factors and cytokines in autologous protein solution (APS) and platelet-rich plasma (PRP). ANIMALS: 6 adult university-owned horses. METHODS: For the first phase, 6 horses were randomized to receive ketoprofen (1,000 mg) or flunixin meglumine (500 mg) IV. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before and 6 hours after administration of NSAIDs. Horses underwent a 2-week washout period, after which the protocol was repeated using a crossover design. For the second phase, following at least a 2-week washout period, the study protocol was repeated with phenylbutazone (1 g) or firocoxib (57 mg) administered orally. Plasma was collected 6 hours after administration for evaluation of drug concentrations, and APS and PRP were analyzed for concentrations of drug, platelets, leukocytes, and several growth factors and cytokines (PDGF, fibroblast growth factor, TGF-ß1, IL-1ß, IL-10, IL-6, IL-8, and tumor necrosis factor-α) before and 6 hours after administration of NSAIDs using immunoassays. RESULTS: There were no significant differences in concentrations of cytokines or growth factors before or after administration of any NSAID. There were significant differences in concentrations of leukocytes and platelets based on both product and time. NSAID concentrations in plasma were not significantly different from concentrations in APS and PRP. CLINICAL RELEVANCE: These results help guide clinicians on the appropriate use of these NSAIDs in conjunction with the processing of APS and PRP, which is unlikely to significantly alter the final product after single-dose administration.

Dexketoprofen versus Tenoxicam in Acute Severe Pain Due to Primary Dysmenorrhea.

OBJECTIVE: To evaluate the analgaesic efficacy of tenoxicam and dexketoprofen in patients admitted to the Emergency Medicine (EM) Clinic with severe acute pain due to primary dysmenorrhea (PD). STUDY DESIGN: Randomised-controlled trial. Place and Duration of the Study: Emergency Medicine Clinic, Health Sciences University, Adana City Training and Research Hospital, Adana, Turkiye, from January to December 2022. METHODOLOGY: Patients presenting with PD, were divided into two groups of 60 each, administered 50 mg dexketoprofen and 20 mg tenoxicam intravenously. Visual analogue scale (VAS) scores were recorded at the 15th, 30th, 60th, and 120th minutes. VAS scores and ΔVAS scores were compared with the effectiveness of drugs, the need for rescue drugs and its side-effects. RESULTS: Intravenous (IV) dexketoprofen was administered to 60 of the patients and IV tenoxicam was administered to another 60. At the time of admission, mean VAS scores of the patients were 8.8 ± 0.9 for the dexketoprofen group and 8.6 ± 0.8 for the tenoxicam group. The VAS scores of the dexketoprofen group were found to be statistically significantly lower after 30 minutes with lower need for rescue analgaesics. ΔVAS scores of the dexketoprofen group were statistically significantly higher from the 30th minute. CONCLUSION: According to the VAS scoring, IV dexketoprofen was a more effective drug than IV tenoxicam in patients who were admitted to the EM clinic with severe pain due to PD. KEY WORDS: Dexketoprofen, Primary dysmenorrhea, VAS score.

Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in topical anhydrous and aqueous gels.

BACKGROUND: Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of acute and chronic pain associated with inflammatory conditions. This study aims to evaluate the in vitro percutaneous absorption of ketoprofen 10% formulated in proprietary anhydrous and aqueous gels using the Franz skin finite dose model. MATERIALS AND METHODS: The anhydrous gel was initially characterized for cytotoxicity using EpiDerm skin tissue model by cell proliferation assay and Western blot analysis. The Ultra Performance Liquid Chromatography method for measuring ketoprofen was validated and the stability of ketoprofen 10% in the anhydrous gel formulation was evaluated at 5°C and 25°C for 181 days. The percutaneous absorption of ketoprofen was determined using donated human skin. The tissue sections were mounted within Franz diffusion cells. A variable finite dose of each ketoprofen formulation in either anhydrous or aqueous gel was applied to the skin sections and receptor solutions were collected at various time points. RESULTS: Cell proliferation assay showed minimal cell death when EpiDerm skin tissue was exposed to the anhydrous gel for 24 h; the levels of protein markers of cell proliferation were not affected after 17-h exposure. Ketoprofen was stable in the anhydrous gel when stored at 5°C and 25°C. When compounded in the anhydrous and aqueous gels, ketoprofen had mean flux rate of 2.22 and 2.50 µg/cm2 /h, respectively, after 48 h. The drug was distributed to the epidermis and dermis sections of the skin. Both the anhydrous and aqueous gels facilitated the percutaneous absorption of ketoprofen without statistically significant differences. CONCLUSION: The anhydrous gel can be used as a base to facilitate the transdermal delivery of ketoprofen. Although the anhydrous and aqueous gels can deliver a similar amount of ketoprofen, the anhydrous gel (water activity below 0.6) allows for extended default beyond-use-date of compounding preparations.

Pain management after total hip arthroplasty: comparative study of analgesic efficacy and tolerability between oral tramadol/dexketoprofen and injectable paracetamol + tramadol.

BACKGROUND: Multimodal analgesia for total hip arthroplasty (THA) is increasingly employed to reduce early postoperative pain and promote fast patient discharge. The aim of this study was to compare the efficacy and tolerability of tramadol/dexketoprofen (TRAM/DKP, Group A) versus paracetamol + tramadol (PARA+TRAM, Group B) in patients undergoing THA using minimally invasive direct anterior approach (DAA). METHODS: A single-centre, randomised, single-blind, parallel, interventional study conducted in 323 patients undergoing primary THA with DAA was performed. Group A consisted of 188 patients and Group B of 135. The primary endpoints were the change from baseline (measured 2 hours postoperatively) in pain intensity (PI) during the treatment period (48 hours), assessed by visual analogue scale (VAS) at pre-specified postoperative time-points (2, 8, 24, 48 hours) and the total rescue medication (RM) use during the first 24 hours postoperatively. RESULTS: As early as 2 hours after baseline, Group A showed a greater PI reduction from baseline compared to Group B (-26.24% vs. -6.87%; p < 0.001). A lower mean PI (VAS) score was consistently found over the entire observation period following treatment with TRAM/DKP than with PARA+TRAM as well as more than 2-fold higher proportion of responders at the end of treatment period. More patients in Group B required RM in comparison to those in Group A (15.6% vs. 3.7%, p < 0.001). Both treatments were well tolerated. CONCLUSIONS: After THA, oral TRAM/DKP provides faster and greater pain relief when compared to intravenous PARA+TRAM with limited consumption of RM and favourable tolerability profile. Our study expands the use of TRAM/DKP in the setting of major orthopaedic surgeries. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT04178109).

A comparison of the mixed and sequential use of acetaminophen and dexketoprofen in painful vaso-occlusive crises.

PURPOSE: Opioids are widely used to treat painful vaso-occlusive crises (VOC) in sickle cell disease (SCD). However, due to opioids' significant adverse effect profiles, the search for alternative therapies continues from the past to the present. The study aimed to investigate the efficacy of acetaminophen and dexketoprofen in the treatment of painful VOC. METHODS: This study is a single-center, prospective, non-randomized, single-blinded, controlled study. The study comprised two groups: the first administered acetaminophen and dexketoprofen mixed group, while the second received them sequential group. Opioids were used in patients with persistent pain despite these analgesics. Demographic and laboratory information, pain scores, opioid requirement, dose amount, side effects, and length of hospital stay of the patients were recorded. RESULTS: The study comprised 56 (100%) patients with painful VOC, 29 (51.8%) from the mixed group, and 27 (48.2%) from the sequential group. Opioid use was seen in 16 (55.2%) patients in the mixed group and 21 (77.8%) patients in the sequential group (p = 0.074). The median amount of opioid used was significantly lower in the mixed group than in the sequential group (p < 0.001). Also, the median length of hospital stay was significantly lower in the mixed group than in the sequential group (p < 0.001). CONCLUSION: Our study suggests that administering acetaminophen and dexketoprofen in the mix for the treatment of painful VOC in patients with SCD may be a more efficient approach compared to sequential administration. This approach appears to reduce opioid usage and shorten hospital stays.

Ketoprofen attenuates Las/Rhl quorum-sensing (QS) systems of Pseudomonas aeruginosa: molecular and docking studies.

BACKGROUND: Quorum sensing (QS) is the leading cause of persistent infections and recalcitrance to antibiotic treatment of Pseudomonas aeruginosa. Hence, QS inhibitors are promising agents for the potential treatment of P. aeruginosa infections. METHODS AND RESULTS: Herein, the reducing effect of ketoprofen on virulence factors production including protease, hemolysin, pyocyanin, hydrogen cyanide, biofilm, and motility of P. aeruginosa strains was investigated. Furthermore, the quorum quenching activity of ketoprofen at the molecular level was examined by real-time PCR assessment. Our results showed that ketoprofen significantly attenuates virulence factors and biofilm formation in P. aeruginosa strains. Moreover, ketoprofen down-regulated the expression of lasI, lasR, rhlI, and rhlR genes, by 35-47, 22-48, 34-67, and 43-56%, respectively. As well, molecular docking simulation showed a high binding affinity of ketoprofen with QS regulatory proteins. CONCLUSIONS: Consequently, this study confirmed the quorum quenching activity of ketoprofen, which could be employed as a useful agent for the treatment of P. aeruginosa infections.

Discovery of novel NSAID hybrids as cPLA2/COX-2 dual inhibitors alleviating rheumatoid arthritis via inhibiting p38 MAPK pathway.

A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 ± 0.25 µΜ) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA2, and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA2 and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA2/COX-2/PGE2 pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA2 and COX-2 play a role in their etiology.

Ketoprofen products induced photosensitization of sulfonamide antibiotics: The cocktail effects of pharmaceutical mixtures on their photodegradation.

Indirect photolysis induced by naturally occurring sensitizers constitutes an important pathway accounting for the transformation and fate of many recalcitrant micropollutants in sunlit surface waters. However, the photochemical transformation of micropollutants by photosensitizing pharmaceuticals has been less investigated. In this study, we demonstrated that the non-steroidal anti-inflammatory drug ketoprofen (KTF) and its photoproducts, 3-acetylbenzophenone (AcBP) and 3-ethylbenzophenone (EtBP), could sensitize the photodegradation of coexisting sulfonamide antibiotics, e.g., sulfamethoxazole (SMX), under artificial 365 nm ultraviolet (UV) and sunlight irradiation. Key reactive species including triplet excited state and singlet oxygen (1O2) responsible for photosensitization were identified by laser flash photolysis (LFP) and electron paramagnetic resonance (EPR) techniques, respectively. High-resolution mass spectrometry (HRMS) and structure-related reactivity analyses revealed that the sensitized photolysis of SMX occurred mainly through single electron transfer. The rate constants of sulfonamides sensitized by AcBP photolysis followed the order of sulfisoxazole (SIX)＞sulfathiazole (STZ)＞SMX＞sulfamethizole (SMT). Exposure to sunlight also enhanced the photolysis of SMX in the presence of KTF or AcBP, and water matrix had limited impact on such process. Overall, our results reveal the feasibility and mechanistic aspects of photosensitization of coexisting contaminants by pharmaceuticals (or their photoproducts) and provide new insights into the cocktail effects of pharmaceutical mixtures on their photochemical behaviors in aqueous environment.

Ketoprofen in horses: Metabolism, pharmacokinetics, and effects on inflammatory biomarkers.

Ketoprofen is an anti-inflammatory drug that is commonly administered to racehorses for the alleviation of musculoskeletal pain and inflammation. This study represents a comprehensive examination of the metabolism (in vivo and in vitro), pharmacokinetics and ex vivo pharmacodynamics, of ketoprofen in horses. The in vitro metabolism as well as specific enzymes responsible for metabolism was determined by incubating liver microsomes and recombinant CYP450 and UGT enzymes with ketoprofen. For the in vivo portion, 15 horses were administered a single intravenous dose of 2.2-mg/kg ketoprofen. Blood and urine samples were collected prior to and up to 120 h post-drug administration. Additional blood samples were collected at select time points and were stimulated with calcium ionophore or lipopolysaccharide, ex vivo, to induce eicosanoid production. Drug, metabolite, and eicosanoid concentrations were determined using LC-MS/MS. Incubation of ketoprofen with equine liver microsomes generated 3-hydroxy ketoprofen, an unidentified hydroxylated metabolite, and ketoprofen glucuronide. Recombinant equine CYP2C23 produced the greatest amount of hydroxylated ketoprofen and recombinant equine UGT1A2 generated ketoprofen glucuronide. Dihydro, 3-hydroxy, and glucuronide metabolites were identified in blood and urine samples. The Vdss was 0.280, 0.385, and 0.319 L/kg for total ketoprofen, S (+) ketoprofen, and R (-) ketoprofen, respectively. The mean half-life was 6.01 h for total ketoprofen, 2.22 h for S (+) ketoprofen, and 1.72 h for R (-) ketoprofen. Stimulation of ketoprofen-treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of TXB2 , PGE2 , PGF2alpha , LTB4 , and 15(s)-HETE production for up to 120 h post-drug administration.

A Fast HPLC/UV Method for Determination of Ketoprofen in Cellular Media.

A simple, sensitive and quick HPLC method was developed for the determination of ketoprofen in cell culture media (EMEM, DMEM, RPMI). Separation was performed using a gradient on the C18 column with a mobile phase of acetonitrile and miliQ water acidified by 0.1 % (v/v) formic acid. The method was validated for parameters including linearity, accuracy, precision, limit of quantitation and limit of detection, as well as robustness. The response was found linear over the range of 3-100 µg/mL as demonstrated by the acquired value of correlation coefficient R2=0.9997. The described method is applicable for determination of various pharmacokinetic aspects of ketoprofen in vitro.

Probing the mechanism of release process from metal coordination-based acrylic pressure-sensitive adhesives: Synergistic effect of coordination and hydrogen bonding for controlled drug release.

Hydrogen bonding, ionic interactions, and dipole-dipole interactions have been extensively studied to control drug release from patches. However, metal coordination bonding has not been fully explored for the control of transdermal drug release. In this study, metal coordination-based acrylic pressure-sensitive adhesives (PSAs) were designed and synthesized in order to systemically elucidate the effect of metal coordination on drug release from acrylic PSAs. Ketoprofen (KET) and donepezil (DNP) were selected as model drugs. Results showed that the burst release rate of KET was controlled by N-[tris(hydroxymethyl)methyl]acrylamide (NAT) and Fe3+, while the DNP release rate had no significant changes. It was found that the PSA-drug interaction, rather than the molecular mobility of PSA, played a dominant role in the controlled release process of KET. The hydrogen bond interaction between NAT and KET controlled the release process, while the coordination bond interaction between Fe3+ and KET further slowed down the release of KET. In conclusion, it was found that the controlled release of KET was achieved by the synergistic effect of coordination bonding and hydrogen bonding, which opens up a facile but powerful avenue for the design of brand-new controlled release systems and new opportunities for their application in transdermal drug delivery.

The effect of the addition of nefopam to intraoperative ketoprofen and acetaminophen on postoperative morphine requirements after laparoscopic cholecystectomy: a randomized controlled trial.

BACKGROUND: Few studies investigated the use of nefopam for pain control after laparoscopic cholecystectomy in the context of multimodal analgesia. The aim of this study was to evaluate the effect of adding nefopam to ketoprofen and acetaminophen given before the end of laparoscopic cholecystectomy. METHODS: In this double-blind, controlled study, 90 patients undergoing laparoscopic cholecystectomy during sevoflurane-dexmedetomidine-based anesthesia were randomized to receive either ketoprofen and acetaminophen or nefopam, ketoprofen, and acetaminophen for postoperative pain control before the end of surgery. The primary outcome was total morphine consumption in the Postanesthesia Care Unit (PACU). RESULTS: PACU morphine consumption was significantly lower in the experimental group compared to the control group (0.9±1.8 mg vs. 2.3±2.4 mg, respectively; P=0.004, Cohen's d=0.63). In the experimental group, a smaller proportion of patients received morphine in PACU (24% vs. 60%, respectively; P=0.001), morphine during the first 24 hours after surgery (47% vs. 77%, respectively; P=0.004), and acetaminophen on the floor (76% vs. 93%, respectively; P=0.039) compared with the control group. The average pain score during PACU stay was also significantly lower in the experimental group (1.7±2.0 vs. 2.7±2.0, P=0.01). Median time to first morphine requirement (44.0 minutes, 95% CI [(31.96 to, 52.21)] was shorter in the control group than in the experimental group (higher than the 90 minutes-last time point taken in PACU). CONCLUSIONS: Adding nefopam to ketoprofen and acetaminophen before the end of laparoscopic cholecystectomy provides a reduction in morphine consumption with superior analgesia in PACU.

Contact allergy to oxidised geraniol may be over-represented in individuals with photocontact allergy to ketoprofen.

BACKGROUND: Simultaneous overrepresentations of contact allergies and photocontact allergies are common in individuals with photocontact allergy to ketoprofen. AIMS: To investigate whether contact allergy to oxidised (ox.) geraniol, geraniol, geranial, neral and citral is overrepresented in individuals with photocontact allergy to ketoprofen. METHODS: The contact allergy rates to ox. geraniol, geraniol, geranial, neral and citral in routinely patch tested dermatitis patients were compared with the corresponding rates in individuals with photocontact allergy to ketoprofen. RESULTS: Allergic patch test reactions were noted to ox. geraniol 11% (n = 39, 5.8%), ox. geraniol 6% (n = 12, 1.8%), geraniol 6% (n = 2, 0.3%), geranial (n = 18, 2.7%), neral (n = 7, 1.0%) and citral (n = 15, 2.2%). In those four patients who were diagnosed with photocontact allergy to ketoprofen during the test period, a significant overrepresentation (p = 0.020) of simultaneous contact allergy to ox. geraniol 11% was demonstrated. Overrepresentation of simultaneous contact allergy to various combinations of ox. geraniol, ox. limonene and ox. linalool was also noted in ketoprofen-photoallergic patients. CONCLUSIONS: Contact allergy to ox. geraniol, geranial and citral is common in routinely tested dermatitis patients. There is an overrepresentation of simultaneous contact allergy to ox. geraniol, ox. limonene and ox. linalool in patients with photocontact allergy to ketoprofen.

Clinical use of ketoprofen lysine salt: a reappraisal in adolescents with acute respiratory infections.

Upper respiratory infections are widespread, and they are mainly of viral etiology. It has to be remarked that every infection is always associated with an inflammatory response. Inflammation implicates a cascade of bothersome symptoms, including fever, pain (headache, myalgia, and arthralgia), malaise, and respiratory complaints. As a result, anti-inflammatory medications could be beneficial as they act on different pathogenetic pathways. The ketoprofen lysine salt (KLS) has a potent anti-inflammatory activity associated with effective analgesic and antipyretic effects and has a valuable safety profile. However, adolescents present peculiar psychological characteristics that determine their difficulty to be managed. In this regard, an adolescent with a respiratory infection requires a prompt and adequate cure. KLS, thanks to its pharmacologic profile, could be favorably used in this regard. A recent primary-care experience outlined its effectiveness in this issue.

Eutectic phase transition during tablet manufacture: effect of melting point of eutectic forming drug.

The aim was to investigate eutectic transition during tableting and storage. Mixtures of lidocaine and series of NSAIDs with increasing melting point were used as model systems to guide formulators to scaleup eutectic forming materials gaining enhanced dissolution while avoiding deleterious physical changes. Physical mixtures of NSAIDs with lidocaine were prepared at eutectic forming ratio. These were directly compressed, dry co-ground before compression, or compressed after wet granulation. Dissolution of tablets was compared to corresponding dry co-ground mixture. Thermograms of direct compressed tablet were compared to co-ground mixture and pure compound. Stability of direct compressed tablets was assessed. Tableting initiated eutexia which enhanced dissolution of NSAIDs. Eutexia was associated with tablet softening in case of low melting point ketoprofen and aceclofenac. Wet granulation hastened eutexia developing unacceptable tablet in case ketoprofen and aceclofenac. Tablets prepared by direct compression of physical mixtures underwent gradual eutectic transition upon storage with the magnitude of eutectic transition reducing with increased melting point of NSAIDs. Ketoprofen was physically unstable but aceclofenac degraded chemically as well. Tenoxicam and meloxicam tablets were physically and chemically stable. Direct compression after physical mixing is the best tableting technique, but low melting point drugs should consider different strategy before compression.