Physiologically Based Pharmacokinetic (PBPK) Modeling of Lornoxicam: Exploration of doses for CYP2C9 Genotypes and Patients with Cirrhosis.

Lornoxicam physiologically based pharmacokinetic (PBPK) models were developed and validated on the basis of clinical pharmacokinetic results obtained by considering CYP2C9 genetic polymorphisms in healthy adult populations. PBPK models were extended to predict lornoxicam pharmacokinetics for patients with cirrhosis by quantitatively examining the pathophysiological information associated with cirrhosis. The predicted plasma exposure to lornoxicam was approximately 1.12-2.83 times higher in the CYP2C9*1/*3 and *1/*13 groups than in the CYP2C9*1/*1 group of healthy adult populations and patients with cirrhosis. The predicted plasma exposure to lornoxicam was approximately 1.28-3.61 times higher in patients with cirrhosis than in healthy adult populations. If the relationship between lornoxicam exposure in plasma and drug efficacy was proportional, then the proposed adjusted doses of lornoxicam for each group varied from 1.25 mg to 8 mg. As the severity of cirrhosis increased, or when the CYP2C9 genotype was *1 heterozygous, the dose adjustment range of lornoxicam increased. Therefore, the effect of pathophysiological factors (cirrhosis severity) on the pharmacokinetics of lornoxicam might be more important than that of CYP2C9 genetic factors. These results could be useful for broadening the scope of clinical application of lornoxicam by enabling dose selection based on CYP2C9 genotypes and liver cirrhosis degree.

A Promising Single Oral Disintegrating Tablet for Co-Delivery of Pitavastatin Calcium and Lornoxicam Using Co-Processed Excipients: Formulation, Characterization and Pharmacokinetic Study.

SIGNIFICANCE: Statins are an important class of drugs that help to control hyperlipidemia, and one of these statins recently used is pitavastatin calcium (PITA). Nevertheless, the most reported adverse effect of statins is myopathy. Therefore, combining statins with non-steroidal anti-inflammatory drugs (NSAIDs) as Lornoxicam (LORNO) can help in the management of statin-induced myopathy. PURPOSE: This study aimed to formulate and evaluate different oral disintegrating tablets (ODTs) containing PITA using different co-processed excipients. The best PITA-ODT was selected and reformulated with the addition of LORNO, forming a single ODT comprising both drugs. The pharmacokinetic parameters of PITA and LORNO in a single ODT were compared to those of the marketed products (Lipidalon® and Lornoxicam®). METHODS: Eight PITA-ODTs were prepared via direct compression. The prepared PITA-ODTs were evaluated for their weight variation, thickness, breaking force, friability, drug content, and wetting time (WT). In-vitro disintegration time (DT) and dissolution were also evaluated and taken as parameters for selection of the best formula based on the criteria of scoring the fastest DT and highest Q10 min. LORNO was added to the selected PITA-ODT, forming a single ODT (M1) comprising both drugs, which was subjected to an in-vivo pharmacokinetic study using rats as an animal model and liquid chromatography-mass spectrometry (LC-MS/MS) for analysis of both drugs in rat plasma. RESULTS: Results showed that all PITA-ODTs had acceptable physical properties in accordance with pharmacospecial standards. PITA-ODT prepared with Pharmaburst® (F2) had significantly (p<0.05) the fastest DT (6.66±1.52 s) and highest Q10 min (79.07±2.02%) and was chosen as the best formula. The in-vivo pharmacokinetic study of M1 formula showed higher percent relative bioavailability (%RB) of 286.7% and 169.73% for PITA and LORNO, respectively, compared with the marketed products. CONCLUSION: The single ODT comprising PITA and LORNO was promising for instant co-delivery of both drugs with higher %RB when compared with the marketed products.

An in vivo Caenorhabditis elegans model for therapeutic research in human prion diseases.

Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival. Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system. Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood-brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals. This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system.

Piroxicam loaded polymer hybrid microspheres based tablets with modified release kinetics: Development, characterization and in vivo evaluation.

Piroxicam (PC) is a non-steroidal anti-inflammatory drug characterized by poor aqueous solubility and reported to cause and impart crucial GIT irritation, bleeding, peptic and duodenal ulcer. Engineering of PC loaded microcapsules and its surface modification using different polymers has become the popular approach to address the said issues. The purpose of the study was to develop new PC loaded gastro-protective polymer hybrid microspheres (PHM) with subsequent conversion to tablet dosage form having modified dissolution rate and improved bioavailability. The crystallinity of the PC loaded PHM were established through powder X-ray diffraction. The optimised microspheres, PC-M1 with particle size 32±3.0µm, entrapment efficiency 83.78±2.5% and in vitro drug release 87.1±2.6% were further subjected to tablets development and in vivo evaluation. The in vitro drug release study conducted for PHM at pH media 1.2 and 6.8 demonstrated retarded and enhanced drug release rates (P<0.001) respectively. Both accelerated and real time stability studies confirmed stability of the PC loaded PHM based tablets. A substantial improvement in the drug plasma concentration 12.6±2.36 (P<0.001) was observed for the produced tablets compared to the marketed formulations.

Effect of piroxicam administration in infertile women undergoing assisted reproductive technologies: A systematic review and meta-analysis.

OBJECTIVE: To evaluate piroxicam effect on different pregnancy outcomes among infertile women undergoing assisted reproductive technologies (ART). METHODS: We searched for the available randomized clinical trials (RCTs) in four different databases during January 2021 that compared piroxicam (intervention group) to placebo/no treatment (control group) in infertile women performing ART. We extracted the available data from included studies and pooled them in a meta-analysis model using RevMan software. We pooled the dichotomous data as risk ratios (RR) with the corresponding 95% confidence intervals (CI) using RevMan software. Our outcomes were rates of clinical pregnancy, ongoing pregnancy, miscarriage, and any adverse events. RESULTS: Seven RCTs met our inclusion criteria with a total number of 1226 patients. Piroxicam was linked to a significant increase in clinical pregnancy rate compared to control group (RR = 1.30, 95% CI [1.09, 1.55], p = .003). However, we did not report any significant difference between both groups in ongoing pregnancy rate (RR = 1.27, 95% CI [0.72, 2.24], p = .41). In addition, the rates of miscarriage and adverse events were not different among both groups. CONCLUSIONS: Piroxicam administration increases the clinical pregnancy rate among infertile women. However, piroxicam does not affect miscarriage and ongoing pregnancy rates.

Co-delivery of norfloxacin and tenoxicam in Ag-TiO2/poly(lactic acid) nanohybrid.

A nanohybrid formulation of silver­titanium dioxide nanoparticles/poly(lactic acid) (Ag-TiO2/PLA) was designed for Norfloxacin/Tenoxicam (NOR/TENO) targeted delivery to maximize the bioavailability and minimize the side effects of the drugs. Ag-TiO2 nanoparticles were prepared via Stober method. NOR, TENO and a mixture of NOR/TENO (NT) were loaded onto Ag-TiO2 nanoparticles and coated by PLA via solution casting. The physical interaction between the drugs and carrier was confirmed by Fourier-transform infrared (FTIR) analysis. X-ray diffraction (XRD) demonstrated that Ag-TiO2 consists of a cubic phase of Ag with two phases of TiO2 (anatase and brookite). Ag nanoparticle fine spots coated with TiO2 were collected to form spheres averaging at 100 nm in size. In-vitro release behavior of drugs was studied at different pH (5.4, 7.4) and the release of drug from NT/Ag-TiO2/PLA was faster at pH 7.4. Gram-positive and Gram-negative bacteria were used to investigate antibacterial properties of the nanohybrid. Cytotoxicity of the nanohybrid using an MTT assay was studied against different tumor and normal cell lines. It was found that NT/Ag-TiO2/PLA has an excellent cytotoxic effect against various bacterial cells and tumor cell lines. In addition, antioxidant properties of the nanohybrids were tested using ABTS method and the nanohybrid showed moderate antioxidant activity.

Presumptive Lornoxicam Intoxication in Four Dogs.

Lornoxicam is a nonsteroidal anti-inflammatory drug extensively used in human medicine, which is not approved for canine use. Lornoxicam intoxication has been rarely reported in dogs. Four dogs of various breeds, aged 7 months to 10 years, were admitted with a recent history of melena, anorexia and depression, occurring 1-4 days after the ingestion of lornoxicam (dose range: 0.53-2.7 [median 1.17] mg/kg). No clinically relevant comorbidities were documented, but low doses of prednisolone had been given in 3 of the dogs, in close temporal association with lornoxicam. Major clinical and clinicopathologic findings on admission included mucosal pallor, melena, depression, severe anemia, neutrophilic leucocytosis, and panhypoproteinemia. Perforated pyloric and duodenal ulcers were documented in 3 dogs by exploratory celiotomy or postmortem. Prolonged hospitalization (5-20 days) with extensive supportive care and multiple blood transfusions was required in 3 of the 4 dogs who survived to discharge. Lornoxicam ingestion may cause protracted and severe gastrointestinal tract injury and bleeding, blood loss anemia, panhypoproteinemia, and perforated gastrointestinal ulcers, associated with significant morbidity and mortality in dogs.

A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.

BACKGROUND & AIMS: p21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/ß-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice. METHODS: IL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT. RESULTS: When compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased ß-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation. CONCLUSIONS: PAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.

Management of recurrent aphthous ulcers exploiting polymer-based Muco-adhesive sponges: in-vitro and in-vivo evaluation.

Recurrent aphthous ulcer (RAU) is a well-known painful, inflammatory disease with uncertain etiology for which local symptomatic therapy is only available. The aim of this study was to formulate and characterize muco-adhesive sponges containing a mixture of tenoxicam and miconazole nitrate to manage pain, inflammation and avoid candida infection that may accompany RAU due to poor oral hygiene. Two polymers at different concentrations were used to prepare sponges applying simple freeze-drying. Medicated chitosan (2%) sponges (mC2) showed acceptable physical appearance, surface pH (6.3 ± 0.042), porosity (25.7% ± 1.8), swelling index (5.7 ± 0.11), in-vivo and ex-vivo muco-adhesion time (115 min.±0.813 and 155 min.±1.537, respectively), ex-vivo muco-adhesion force (0.09 N ± 0.002) and scanning electron microscope (SEM) images. For concurrent clear-cut determination of tenoxicam and miconazole nitrate from mC2, a new UPLC method was developed and validated. mC2 sponges exhibited superior in-vitro drug release profiles where ∼100% of tenoxicam released within 5 min for fast pain relief with a more prolonged miconazole nitrate release. Furthermore, in-vivo animal study revealed that mC2 caused a significant decrease in the acetic acid-induced ulcer size in rats after 6 days of treatment (p < .0001) compared to negative and positive controls. Additionally, histopathological examination showed faster healing with complete restoration of the normal oral histology in rats. The present study concludes that chitosan sponge loaded with a combination of tenoxicam and miconazole nitrate could improve healing of RAU cases.

Coacervate Thermoresponsive Polysaccharide Nanoparticles as Delivery System for Piroxicam.

Low water solubility frequently compromises the therapeutic efficacy of drugs and other biologically active molecules. Here, we report on coacervate polysaccharide nanoparticles (CPNs) that can transport and release a model hydrophobic drug, piroxicam, to the cells in response to changes in temperature. The proposed, temperature-responsive drug delivery system is based on ionic derivatives of natural polysaccharides-curdlan and hydroxypropyl cellulose. Curdlan was modified with trimethylammonium groups, while the anionic derivative of hydroxypropyl cellulose was obtained by the introduction of styrenesulfonate groups. Thermally responsive nanoparticles of spherical shape and average hydrodynamic diameter in the range of 250-300 nm were spontaneously formed in water from the obtained ionic polysaccharides as a result of the coacervation process. Their morphology was visualized using SEM and AFM. The size and the surface charge of the obtained objects could be tailored by adjusting the polycation/polyanion ratio. Piroxicam (PIX) was effectively entrapped inside the nanoparticles. The release profile of the drug from the CPNs-PIX was found to be temperature-dependent in the range relevant for biomedical applications.

Bilosomes as Promising Nanovesicular Carriers for Improved Transdermal Delivery: Construction, in vitro Optimization, ex vivo Permeation and in vivo Evaluation.

PURPOSE: The goal of this research was to enhance the transdermal delivery of lornoxicam (LX), using nanovesicular carriers composed of the bile salt sodium deoxycholate (SDC), soybean phosphatidyl choline (SPC) and a permeation enhancer limonene. METHODS: Thin-film hydration was the technique employed for the fabrication using a Box-Behnken design with three central points. The investigated factors were SPC molar concentration, SDC amount in mg and limonene percentage (%). The studied responses were percent entrapment efficiency (%EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro drug release (after 2, 10 h). In order to obtain the optimum formula, numerical optimization by Design-Expert® software was used. Electing the optimized bilosomal formula was based on boosting %EE, ZP (as absolute value) and in vitro drug release, taking in consideration diminishing PS and PDI. Further assessment of the selected formula was achieved by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), stability testing, ex vivo skin permeation and deposition. The in vivo pharmacodynamics activities of the optimized formula were examined on male rats and mice and compared to that of the oral market product. RESULTS: The optimized bilosomal formula demonstrated to be nonirritant, with noticeably enhanced anti-inflammatory and antinociceptive activities. Superior in vivo permeation was proved by confocal laser scanning microscopy (CLSM). CONCLUSION: The outcomes demonstrated that bilosomes could improve transdermal delivery of lornoxicam.

Comparison of ibuprofen and piroxicam gel in the treatment of trauma pain: A randomized double-blind trial of geriatric population.

OBJECTIVE: This study aimed to compare the analgesic efficacy of topical ibuprofen and topical piroxicam for acute musculoskeletal injuries. METHODS: In this prospective, randomized, controlled, double-blinded study, geriatric patients were assigned to groups to receive either topical ibuprofen (n = 70) or topical piroxicam (n = 69). The first dose of gel was applied in the emergency department and the remaining doses were self-administered at home by the patients thrice daily for 72 h. For each patient, the initial baseline visual analog scale (VAS) score (V 0) was compared with the VAS scores at the 60 min (V1), 120 min (V2), 24 h (V3) and 72 h (V4) time points. The decreases in VAS scores, clinical effectiveness of the treatments, and incidence of adverse events were evaluated. RESULTS: In the topical ibuprofen group, the VAS scores were significantly lower at each measurement time point compared to baseline (p < .001). The results were as follows: V0 -V: 1.08, 95% CI: 0.56-1.61; V0 -V2: 1.09, 95% CI: 0.49-1.69; V0 -V3: 1.44, 95% CI: 0.81-2.07; V0 -V4: 1.59, 95% CI: 0.91-2.26. The mean percentage decrease in the VAS scores in the topical ibuprofen group was significantly higher than that in the topical piroxicam group (p < .001). The clinical effect of treatment was found to be significantly higher for the ibuprofen gel group (p < .001). There was no substantial difference in treatment-related adverse events between the groups (p > .05). CONCLUSION: Ibuprofen gel, which is a safe treatment option for geriatric patients, is more clinically effective than piroxicam gel. Response to Reviewers.

Effect of nanostructured lipid carriers on transdermal delivery of tenoxicam in irradiated rats.

Transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) is an effective route of drug administration, as it directs the drug to the inflamed site with reduced incidence of systemic adverse effects such as gastric hemorrhage and ulcers. Tenoxicam (TNX) is a member of NSAIDs that are marketed only as oral tablets due to very poor absorption through the skin. The current study intended to formulate and characterize a hydrogel loaded with nanostructured lipid carriers (NLCs) to enhance the transdermal delivery of TNX. Six formulations of TNX were formulated by slight modifications of high shear homogenization and ultrasonication method. The selected formula was characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo skin permeation studies. Moreover, the effectiveness of the developed formula was studied in-vivo using carrageenan-induced paw edema and hyperalgesia model in irradiated rats. Formula F4 was chosen from six formulations, as the average diameter was 679.4 ± 51.3 nm, PDI value of about 0.02, zeta potential of -4.24 mV, EE of 92.36%, globules nanoparticles without aggregations and absence of interactions in the developed formula. Additionally, the in-vivo study showed the efficacy of formula F4 (TNX-NLCs hydrogel) equivalent to oral TNX in reducing the exaggerated inflammatory response induced by carrageenan after irradiation. In conclusion, the present findings suggest that TNX-NLCs hydrogel could be a potential transdermal drug delivery system alternative to the oral formulation for the treatment of various inflammatory conditions.

Comparison of topical capsaicin and topical piroxicam in the treatment of acute trauma-induced pain: A randomized double-blind trial.

BACKGROUND: This study aimed to compare the analgesic efficacy of topical capsaicin and topical piroxicam in acute musculoskeletal injuries. METHODS: This is a prospective, randomized, controlled, double-blinded study. The data for the 67 patients in the piroxicam group and the 69 in the capsaicin group were examined. The initial visual analog scale (VAS) scores were compared with the 60th and 120th minute as well as the 24th and 72nd hour values. Differences between the VAS scores, clinical effectiveness of the treatment and side effects were evaluated. RESULTS: In the capsaicin group, the mean difference in the delta VAS scores was significantly higher at each measurement time. The mean of the percentage of reduction in the VAS scores of the topical capsaicin group was significantly higher than that in the topical piroxicam group. The highest difference in terms of both outcomes was determined at the 72nd hour VAS change. Mean differences were 1.53 (95% CI: 0.85-2.221) and 19.7 (95% CI: 12.4-27.2) respectively (p < 0.001). In the capsaicin group, the clinical effect of the treatment was found significantly higher (p < 0.01). The difference between the clinical effectiveness of the groups regarding the treatment outcomes was also statistically significant (p < 0.001). There was no significant difference between the patient groups regarding the presence of side effects. CONCLUSION: Topical capsaicin can be used as an alternative to topical piroxicam initially and at follow-up in patients presenting to the emergency department with acute pain as there were no observable differences in side-effects between the two groups.

In-vitro effects of taurolidine alone and in combination with mitoxantrone and/or piroxicam on canine transitional cell carcinoma.

The objective of this in-vitro study was to evaluate taurolidine as a therapy for transitional cell carcinomas in canine patients. Transitional cell carcinoma (TCC) is the most common cancer of the urinary bladder in dogs and accounts for approximately 2% of reported malignancies in this species. There is no cure for this neoplasm and most dogs are lost from complications associated with progression of the local disease. Taurolidine has been shown to have anti-tumor and antiangiogenic effects against a variety of neoplasms in human and animal models. Four canine TCC cell lines were treated with various concentrations of taurolidine, mitoxantrone, and piroxicam alone. In addition, combinations of taurolidine/mitoxantrone, taurolidine/piroxicam, mitoxantrone/piroxicam, and taurolidine/mitoxantrone/piroxicam were assessed. Susceptibility of the TCC cell lines was based on a 72-hour growth inhibition assay using resazurin with absorbance measured at λ530/590. The ability of taurolidine to induce apoptosis was evaluated on 2 of the cell lines with an Annexin-V/propidium iodide assay. All cell lines were susceptible to treatment with taurolidine, mitoxantrone, and piroxicam alone. The results of the combination therapies of the 3 drugs were dependent on cell line and concentration and revealed no change in cell growth inhibition, a subadditive relationship, or a synergistic relationship. Taurolidine induced apoptosis in a concentration- and time-dependent fashion. Taurolidine alone showed significant effects on cell viability in vitro in canine TCC cell lines and these effects can be potentially enhanced with the addition of mitoxantrone and/or piroxicam.

Le carcinome à cellules transitionnelles est le cancer le plus fréquent de la vessie urinaire du chien et compte pour approximativement 2 % des tumeurs malignes rapportées chez cette espèce. Il n'existe présentement pas de cure pour cette tumeur et la plupart des chiens succombent des complications associées à la progression de la tumeur au niveau de la vessie. La taurolidine est une substance avec des propriétés anticancéreuses et anti-angiogéniques contre plusieurs cancers chez l'humain et différents modèles animaux. Cette étude in vitro a évalué la taurolidine comme thérapie pour le carcinome à cellules transitionnelles chez le chien. Quatre lignées cellulaires de carcinome à cellules transitionnelles canins ont été traitées avec différentes concentrations de taurolidine, mitoxantrone, et piroxicam, seul et en combinaisons (taurolidine-mitoxantrone, taurolidine-piroxicam, mitoxantrone-piroxicam et taurolidine-mitoxantrone-piroxicam). La susceptibilité des lignées cellulaires a été déterminée par l'inhibition de croissance en 72 heures et la viabilité cellulaire a été évaluée par l'absorbance de la résazurine mesurée à λ530/590. La capacité de la taurolidine à induire l'apoptose a été évaluée avec l'essai à l'Annexin-V/Iodate de Propidium. Toutes les lignées cellulaires étaient sensibles au traitements avec la taurolidine, le mitoxantrone, et le piroxicam seul. Les résultats des traitements de combinaisons de médicaments étaient dépendants des lignées cellulaires et des concentrations des médicaments. Les combinaisons avaient soit aucun effect comparé au médicaments seuls, ou un effet sous-additif ou synergique. La taurolidine a induite l'apoptose de façon dépendante à sa concentration et temps d'exposition. La taurolidine seule a démontré des effets significatifs sur la viabilité in vitro chez chacune des quatre lignées cellulaires de carcinome à cellules transitionnelles canins. Ces effets peuvent potentiellement être améliorés par l'ajout du mitoxantrone ou piroxicam.(Traduit par les auteurs).

Effect of Ultrasound Intensity and Mode on Piroxicam Transport Across Three-Dimensional Skin Equivalent Epiderm™.

BACKGROUND: Transdermal drug delivery has many advantages compared to other routes. However, the barrier function of the stratum corneum limits the use of the skin as an administrative route for medications. Different methods were investigated to alter the barrier function of the stratum corneum and it was found that applying different ultrasound waves could enhance the skin's permeability. OBJECTIVE: The aim of this work is to study the effect of ultrasonic waves on the alteration of skin natural barrier function, to improve the permeability of the skin to Piroxicam using three-dimension skin (EpiDermTM) as a skin model for the investigation. METHOD: The effect of ultrasound at 1 MHz and 20 kHz on the permeation of Piroxicam across the three-dimensional skin equivalent using a Franz diffusion cell, was evaluated and the concentration of Piroxicam in the receiving compartment was determined using liquid chromatography method. RESULTS: The permeation of Piroxicam enhanced by 199% when therapeutic ultrasound at 1 MHz frequency was used. Significant permeation enhancement was also found upon utilizing low frequency sonophoresis at 20 kHz (427%) with no apparent damage to the membrane. CONCLUSION: Sonophoresis has a positive effect on enhancing skin permeability. The enhancement level was largely dependent on the sonication factors; frequency, intensity and length of treatment. Multiple mechanisms of action might be involved in permeation improvement of the piroxicam molecule. Those mechanisms are largely dependent on the ultrasonic conditions.

Preparation and characterization of novel anti-inflammatory biological agents based on piroxicam-loaded poly-ε-caprolactone nano-particles for sustained NSAID delivery.

Piroxicam (PX), a main member of non-steroidal anti-inflammatory drugs (NSAIDs), is mainly used orally, which causes side effects of the gastrointestinal tract. It also has systemic effects when administered intramuscularly. Intra-articular (IA) delivery and encapsulation of PX in biodegradable poly-ε-caprolactone (PCL) nanoparticles (NPs) offer potential advantages over conventional oral delivery. The purpose of this study is the development of a new type of anti-inflammatory bio-agents containing collagen and PX-loaded NPs, as an example for an oral formulation replacement, for the prolonged release of PX. In this study, the PX was encapsulated in PCL NPs (size 102.7 ± 19.37 nm, encapsulation efficiency 92.83 ± 0.4410) by oil-in-water (o/w) emulsion solvent evaporation method. Nanoparticles were then characterized for entrapment efficiency, percent yield, particle size analysis, morphological characteristics, and in vitro drug release profiles. Eventually, the NPs synthesized with collagen were conjugated so that the NPs were trapped in the collagen sponges using a cross-linker. Finally, biocompatibility tests showed that the anti-inflammatory agents made in this study had no toxic effect on the cells. Based on the results, it appears that PX-loaded PCL NPs along with collagen (PPCLnp-Coll) can be promising for IA administration based on particulate drug delivery for the treatment of arthritis.

Effectiveness of Phonophoresis Treatment in Carpal Tunnel Syndrome: A Randomized Double-blind, Controlled Trial.

OBJECTIVE: To determine the effects of phonophoresis of piroxicam (PH-P) and phonophoresis of dexamethasone sodium phosphate (PH-Dex) on mild to moderate carpal tunnel syndrome (CTS), and to compare each of them with the control group of nondrug ultrasound (US) therapy. DESIGN: A randomized, double-blind controlled trial. SETTING: Department of rehabilitation medicine, university hospital. PARTICIPANTS: Patients with clinical signs and symptoms of CTS underwent an electrophysiological study to confirm the diagnosis of CTS and severity grading. Thirty-three patients, 50 hands (52% of the patients had bilateral CTS, n = 17) with mild to moderate CTS were randomly allocated into three study groups: PH-P, PH-Dex, or US. INTERVENTION: All three groups received 10 sessions of 1-MHz frequency, 1.0 w/cm2 intensity ultrasound wave with stroking technique, continuous mode, at the palm side of the hand over the carpal tunnel area-10 minutes per session, two to three times per week for 4 weeks, for a total of 10 sessions. During each session, the patients received 15 cm3 of study gel according to the study groups. The PH-P group received 0.5% piroxicam gel mixture (equivalence of 20 mg of piroxicam). The PH-Dex group received 0.4% dexamethasone sodium phosphate gel mixture (equivalence 60 mg of dexamethasone). The US group received nondrug gel. MAIN OUTCOME MEASUREMENTS: Boston Carpal Tunnel Questionnaire for symptom severity (BCTQ SYMPT), Boston Carpal Tunnel Questionnaire for functional status (BCTQ FUNCT) and electrophysiological parameters of the median nerve including distal sensory latency (DSL) and distal motor latency (DML) were evaluated before the first treatment and after the last treatment. RESULTS: After treatment, all treatment groups (PH-P, PH-Dex, and US) showed significant improvements of the BCTQ SYMPT (P < .001, -0.74 ± 0.73 [-1.12, -0.37], -0.91 ± 0.96 [-1.41, -0.42], and - 0.68 ± 0.71 [-1.05, -0.30], respectively) and the BCTQ FUNCT (P < .001, -0.68 ± 0.89 [-1.14, -0.22], -0.74 ± 0.84 [-1.17, -0.30], and - 0.80 ± 0.80 [-1.22, -0.37], respectively). For the BCTQ SYMPT, only the PH-Dex showed an improvement score above MCID at 0.8 level [-0.91 ± 0.96]. The improvement of BCTQ FUNCT score of all groups was above Minimal Clincally Important Difference (MCID) at 0.5 level (-0.68 ± 0.89, -0.74 ± 0.84 and - 0.80 ± 0.80, respectively).The DSL was decreased in all groups but the changes were not statistically significant (P = .70, -0.11 ± 0.34 [-0.28, 0.06], -0.09 ± 0.32 [-0.26, 0.07], and - 0.14 ± 0.29 [-0.29, 0.02], respectively). The DML showed decrease only in PH-DEX and the US group but it was not statistically significant (P = .68, 0.05 ± 0.44 [-0.17, 0.27], -0.09 ± 0.51[-0.34, 0.17], and - 0.27 ± 0.49 [-0.53, 0.01], respectively). All measured outcomes were not statistically different in between-group-comparison of BCTQ SYMPT, BCTQ FUNCT, DSL, and DML (P = .58, P = .79, P = .20 and P = .39, respectively). However, there was a clinically significant difference of the improvement of BCTQ SYMPT in between-group comparison; only the PH-DEX was above the MCID level, while the PH-P and US were not. CONCLUSIONS: Neither nondrug US nor phonophoresis treatments (PH-P and PH-Dex) were effective to improve the DSL and DML in mild to moderate CTS. All three groups showed significant improvements in clinical symptoms (BCTQ SYMPT) and functional status (BCTQ FUNCT). At 1 MHz frequency and 1.0 w/cm2 intensity of ultrasound wave, there is no statistically significant difference between phonophoresis and the nondrug US. LEVEL OF EVIDENCE: I.

Anisotropic nanocellulose gel-membranes for drug delivery: Tailoring structure and interface by sequential periodate-chlorite oxidation.

This study investigates periodate-chlorite oxidation as a pretreatment to tailor the surface charge density of cellulose nanofibers employed in open-porous anisotropic hydrogel membranes for transdermal drug delivery. The obtained materials feature high specific surface (≤500 m2 g-1, BET), small average pore size (ca. 40 nm) and tunable surface charge, which are key properties for adsorption and slow release of charged drug molecules. Loading of the non-steroidal anti-inflammatory drug (NSAID) piroxicam (PRX) into the membranes confirmed that the extent of loading is governed by surface charge density and carboxylate group content, respectively, which can be controlled by the oxidation procedure within the range of 0.74-2.00 mmol g-1. Prolonged release of PRX over several hours was observed upon exposure of the loaded membranes to simulated human skin fluid demonstrating the applicability as drug delivery patches.