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Efficient and noninvasive drug delivery for glaucoma therapy necessitates prolonged retention on the ocular surface and deep penetration into the cornea. However, inherent physiological defenses such as rapid tear clearance and low cornea permeability present significant challenges that hinder the effectiveness of trans-corneal drug delivery. In this study, we demonstrate the potential of zwitterionic micelles composed of poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)-block-poly(ε-caprolactone) (OPDEA-PCL) amphiphiles as a biocompatible carrier for trans-corneal drug delivery. These micelles exhibit enhanced adhesion to ocular tissues and resistance to tear clearance due to their unique affinity for cell membranes. These characteristics facilitate adsorptive-mediated transcytosis, significantly augmenting trans-corneal transport and intraocular accumulation of the glaucoma medication brinzolamide (BRZ). As a result, OPDEA-PCL/BRZ formulations effectively normalize intraocular pressure in an open-angle glaucoma rat model, surpassing PEGylated and free BRZ formulations. This research underscores the potential utility of OPDEA-PCL micelles as a promising vehicle for noninvasive topical trans-corneal drug delivery in glaucoma therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

A hollow fiber membrane (HFM) was previously characterized as a potential permeation component of a dissolution/permeation system. Two objectives were to assess the impact of micellization on drug permeation across HFM and identify a preferred permeation model from three models: permeation from only free drug, permeation from both free drug and micelle-bound drug, and permeation with enhancement from micelle shuttling. HFM studies were conducted under unsaturated drug conditions, using griseofulvin and the more hydrophilic drug meloxicam, with and without surfactant [sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (10) lauryl ether]. Griseofulvin was micelle incorporated to a greater extent than meloxicam, such that griseofulvin flux decreased to a greater extent than for meloxicam. The griseofulvin permeation model from only free drug was rejected, since griseofulvin flux required free drug to be about 5-20 fold higher in HFM flux studies than supported by solubility studies, depending on surfactant. Permeation from both free griseofulvin and micelle-bound griseofulvin successfully accommodated observed flux, where micelle permeability was about 5-fold lower than free drug permeability for HFM with 10 KDa MWCO. Permeation with enhancement from micelle shuttling was not the preferred explanation, although the model accommodated flux data and provided aqueous boundary layer thicknesses similar to other setups., Competing Interests: Declaration of competing interest There are no conflicts of interest for these authors to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ocular drug delivery presents significant challenges due to various anatomical and physiological barriers. Ultradeformable vesicles have emerged as better vesicular systems for achieving deeper corneal penetration and enhanced ocular bioavailability. This research aims to develop a hybrid vesicular system with improved deformability and compare it to conventional vesicular carriers. The ultradeformable vesicle, termed "transniosomes," is a combination of niosomes, liposomes, and transfersomes, loaded with brinzolamide as model drug. The brinzolamide-loaded transniosomes (BRZ-TN) was formulated and compared with different vesicular systems through in vitro, ex vivo, and in vivo characterizations. The optimized BRZ-TN demonstrated a vesicle size of 112.06 ± 4.13 nm and an entrapment efficiency of 93.63 ± 0.30 %. With a deformability index of 6.405, the BRZ-TN exhibited a permeability of 86.68 ± 2.51 % over 10 h, which is approximately 1.3 times higher than other conventional vesicular systems. Additionally, the BRZ-TN showed a drug flux of 0.247 ± 0.01 mg/cm 2 /h and an apparent permeability of 0.09 ± 1.21 cm/s. Pre-clinical experiments confirmed the superiority of the optimized BRZ-TN, achieving a 37 % reduction in intraocular pressure (IOP), post 6hr of administration, indicating its prolonged therapeutic effect and improved ocular bioavailability. The findings of this study suggest that transniosomes are superior to other carriers and hold great promise as a nanocarrier for ocular drug delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nasal systemic drug delivery may provide an easy way to substitute parenteral or oral dosing, however, the excipients have an important role in nasal formulations to increase the permeability of the mucosa and prolong the residence time of the drug. In this work, we aimed to produce meloxicam potassium monohydrate (MXP) containing nasal powders by a nano spray drier with the use of a neutral, an anionic and a cationic β-cyclodextrin as permeation enhancers, and (polyvinyl)alcohol (PVA) as a water soluble polymer. The following examinations were performed in order to study the effect of the applied excipients on the nasal applicability of the formulations: laser scattering, scanning electron microscope measurement, XRPD, DSC and FTIR measurements, adhesivity, in vitro drug release and permeability tests through an artificial membrane and RPMI 2650 cells. Based on our results, spherical particles were prepared with a size of 1.89-2.21 µm in which MXP was present in an amorphous state. Secondary interactions were formed between the excipients and the drug. The charged cyclodextrin-based formulations showed significantly higher adhesive force values regardless of the presence of PVA. The drug release was fast and complete. The passive diffusion of MXP was influenced not only by the charge of the cyclodextrin, but the presence of PVA, too. The permeation of the drug was enhanced in the presence of the anionic cyclodextrin testing it on RPMI 2650 cell model., (Copyright © 2024. Published by Elsevier B.V.)

Pain management in amphibians is an emerging field of veterinary medicine with only a limited number of analgesics studied for their efficacy. The African-clawed frog, Xenopus laevis, is a popular animal model in research due to its oocyte morphology and embryonic development. We investigated analgesic effects of 2 formulations of meloxicam (standard and extended release [ER]) along with their pharmacokinetics and potential toxicity in this species. Adult female African-clawed frogs (n = 6/group) received either standard (0.2, 0.4, 1, or 5 mg/kg) or ER meloxicam (0.6, 1.2, 3, or 15 mg/kg) injected into the dorsal lymph sac. The acetic acid test (AAT) was performed at -1, 1, 6, 12, 24, 48, and 72 h postadministration to evaluate pain response. In addition, a subset of frogs (n = 2/group) were euthanized 72 h postinjection and submitted for necropsy. There were no significant differences in AAT with both formulations compared with saline control. No signs of meloxicam-induced toxicity with either formulation was present in histology. A pharmacokinetic study was conducted for both the standard and ER formulation of meloxicam at 5 and 15 mg/kg, respectively. Results were consistent with the fact that both formulations of meloxicam were readily absorbed with the standard plasma concentrations peaking at 20.40 µg/mL at 2 h and ER plasma concentration at 30.4 µg/mL at 12 h. The elimination half-life was only determinable for standard formulation (7.74 h). According to the AAT, both formulations of meloxicam did not provide effective analgesia in adult female Xenopus laevis despite reaching high plasma concentrations.

Background: Oral dose formulations must be soluble in gastrointestinal fluids for systemic absorption. The solubility of meloxicam was determined in 16 different age-specific simulated gastric and intestinal media that mirrored the microenvironments in pediatrics and adults., Methods: The solubility of meloxicam in the 16 different age-specific simulated gastric and intestinal biorelevant media was assessed using the standard US pharmacopeial method. The molecular descriptors of meloxicam were used to assess its intestinal permeability., Results: Meloxicam exhibited low solubility in the age-specific simulated gastric media for fasted and fed states and in pediatrics and adults. Similarly, meloxicam exhibited low solubility in the age-specific simulated media that mirrored neonates fed cow milk-based formula. On the other hand, meloxicam exhibited high solubility in the rest of the age-specific pediatric and adult intestinal media that simulated the fasted and fed states. The pediatric-to-adult solubility ratios were outside the 80-125% range in 7 (58.3%) and was borderline in 1 (8.3%) out of the 12 calculated ratios. These findings indicated that the solubility of meloxicam showed clinically significant differences in 8 (66.7%) of the compared media., Conclusion: Meloxicam exhibited low solubility in the age-specific simulated gastric media and high solubility in the simulated intestinal media for adults and pediatrics. Moreover, the pediatric-to-adult solubility ratios may have clinically significant implications. These differences can be translated into a higher likelihood of failing to demonstrate bioequivalence of different formulations containing meloxicam and variabilities in the performance of these formulations., (© 2024. The Author(s).)

Background: Low-calorie sweetener (LCS) consumption is prevalent among lactating mothers, yet infants' exposure to LCS in human milk is not well-characterized., Objectives: Conduct a pharmacokinetic study of sucralose and acesulfame-potassium (ace-K) in mothers' milk and plasma over 72 h and in infants' plasma., Methods: Following baseline blood and milk collection, mothers (n = 40) consumed 20 oz of diet cranberry juice containing sucralose and ace-K. Blood samples were collected from the mother 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after beverage ingestion, and milk was expressed at 1, 2, 3, 4, 6, 8, 12, and 24 h postingestion. One blood sample was collected from each infant, the timing of which was determined using pharmacokinetics model-based simulation. Concentration-time profiles of LCS from the mother's plasma and milk were analyzed using noncompartmental methods., Results: Ace-K rapidly entered human milk with the largest observed concentration of 373.0 (coefficient of variation 69%) ng/mL first detected 4 h following diet beverage ingestion. Sucralose appeared in human milk 1-2 h after diet beverage ingestion with the largest observed concentration of 7.2 (coefficient of variation 63%) ng/mL first detected 7 h postingestion. The mean 24-h milk to plasma ratio of ace-K was 1.75 [standard deviation (SD) 1.37] with a mean relative infant dose of 1.59% (SD 1.72%). Ace-K was detected in all infants' plasma with an mean concentration of 9.2 (SD% 14.8) ng/mL ∼6 h after maternal beverage ingestion. The mean 24-h milk to plasma ratio of sucralose was 0.15 (SD 0.06) with a mean relative infant dose of 0.04% (SD 0.02%). Sucralose was detected in only 15 infants' plasma, and the mean concentration was 5.0 (SD% 7.1) ng/mL ∼5 h after diet beverage ingestion., Conclusions: Ace-K rapidly transfers from human milk into infants' circulation whereas sucralose was detected at much lower concentrations and in some but not all infants. Future research should investigate the effects of early-life sucralose and ace-K exposure via human milk on infants' health. This trial was registered at clinicaltrials.gov as NCT05379270., (Copyright © 2024 American Society for Nutrition. All rights reserved.)

This study evaluates the use of poly(vinyl alcohol), collagen, and chitosan blends for developing a microneedle patch for the delivery of meloxicam (MEL). Results confirm successful MEL encapsulation, structural integrity, and chemical stability even after ethylene oxide sterilization. Mechanical testing indicates the patch has the required properties for effective skin penetration and drug delivery, as demonstrated by load-displacement curves showing successful penetration of pig ear surfaces at 3N of normal load. In vitro imaging confirms the microneedle patch penetrates the pig's ear cadaver skin effectively and uniformly, with histological evaluation revealing the sustained presence and gradual degradation of microneedles within the skin. Additionally, in vitro drug diffusion experiments utilizing ballistic gel suggest that microneedles commence dissolution almost immediately upon insertion into the gel, steadily releasing the drug over 24 h. Furthermore, the microneedle patch demonstrates ideal drug release capabilities, achieving nearly 100% release of meloxicam content from a single patch within 18 h. Finally, in vivo studies using pigs demonstrate the successful dissolution and transdermal drug delivery efficacy of biodegradable microneedle patches delivering meloxicam in a porcine model, with over 70% of microneedles undergoing dissolution after 3 days. While low detectable meloxicam concentrations were observed in the bloodstream, high levels were detected in the ear tissue, confirming the release and diffusion of the drug from microneedles. This work highlights the potential of microneedle patches for controlled drug release in veterinary applications.

The aim of this work to study the feasibility of using phospholipid free vesicles with positive charge inducer in a slowly dissolving polymer ocular insert to successfully control intraocular pressure (IOP) for an extended period. Brinzolamide (BRNZ) was chosen as a model drug and a full factorial design was assembled to investigate the drug loading effect, ratio of cholesterol to fatty moiety and the type of the fatty moiety used on the vesicle size and entrapment efficiency. Linear regression models were constructed, and optimization of the formulation compositions yielded two formulae with palmitic acid as a negatively charged vesicles and cetrimide positively charged vesicles. Both formulae were studied in term of permeation efficiency through bovine corneal membranes. Positively charged vesicles although it didn't achieve the highest flux and cumulative amount permeated per unit surface area in the experiment time course, it achieved the highest retention of drug inside the corneal tissue, so it was chosen to be incorporated in a slowly dissolving polymer ocular insert. The insert was evaluated in term content, physical evaluation, and release properties. In vivo evaluation of the casted ocular inserts was conducted in male albino rabbits against market eye drop product and IOP readings were collected for 48 hours. The positively charged sterosomes containing BRNZ and formulated in polymer ocular inserts achieved extended control of IOP of the test animals compared to the market product., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The goal of the present study was to prepare meloxicam (MX) entrapped hybrid particles (HPs) to enhance intestinal permeation and anti-inflammatory activity. MX-HPs were prepared by nanoprecipitation method using lipid, chitosan, poloxamer, and TPGS. The formulations (MX-HPs1, MX-HPs2, MX-HPs3) were evaluated for particle size, entrapment efficiency, and drug release to select the optimized composition and further evaluated for permeation study, stability study, morphology, interaction study, and anti-inflammatory activity by carrageenan-induced rat paw edema test. The prepared MX-HPs showed nano sized particles (198.5 ± 3.7 to 223.8 ± 2.1 nm) and PDI (<0.3), zeta potential (16.5 ± 2.7 to 29.1 ± 3.6 mV), and high entrapment efficiency (75.1 ± 4.7 to 88.5 ± 3.9%). The surface morphology was assessed by transmission electron microscopy and showed non-aggregated particles. Infra-red (IR) spectroscopy of pure MX as well as formulation revealed no drug-polymer interaction and X-ray diffraction confirmed the conversion of crystalline MX into amorphous form. The release study data revealed prolonged MX release for 24 h. The selected optimized hybrid particles (MX-HPs2) revealed a 2.3-fold improved enhancement ratio than free MX. The storage stability and gastrointestinal stability data demonstrated a stable formulation in SIF as well as SGF. The anti-inflammatory activity showed better therapeutic action than pure MX dispersion. From the study, it can be concluded that the prepared MX-HPs may be a promising delivery system for MX in treating inflammatory disorders., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Meloxicam is routinely used for pain alleviation in pre-ruminant calves during husbandry procedures. The pharmacokinetics of a single dose (0.5 mg/kg) of meloxicam was investigated after intravenous (IV), subcutaneous (SC), and oral (PO) administration in 30 pre-ruminant calves. Each group included 10 calves. Oral meloxicam was administered at least 1 h after feeding. Plasma samples were collected for up to 168 h, and the meloxicam concentration was analysed with liquid chromatography and mass spectrometry, followed by a noncompartmental pharmacokinetic analysis. The maximum meloxicam concentrations in plasma were 1.91 ± 0.27 μg/mL and 1.77 ± 0.16 μg/mL after SC and PO routes, respectively. The time of maximum concentration was 7.6 ± 2.8 h after SC and 10.0 ± 5.7 h after PO administration. The approximate bioavailability of meloxicam was 97% for SC and PO routes. The elimination half-lives were 79.2 ± 12.4, 84.6 ± 24.8, and 84.8 ± 22.3 h after IV, SC, and PO routes, respectively. The results suggest that the therapeutic meloxicam concentrations in plasma that are required for pain relief in other species, such as horses, may be maintained for several days following a single dose (0.5 mg/kg) administered IV, SC, or PO in calves., (© 2023 The Authors. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

The pharmacokinetics of meloxicam was studied in 1-, 6-, and 12-month-old sheep following a single intravenous (i.v.) dose of 1 mg/kg. The experiments were carried out when the Romanov sheep were 1 month old (7.93 ± 0.91 kg), 6 months old (27.47 ± 4.91 kg), and 12 months old (37.10 ± 3.64 kg). Meloxicam concentration in plasma was determined by high-performance liquid chromatography and the data collected were evaluated by non-compartmental kinetic analysis. Meloxicam was detected in the plasma up to 72 h following i.v. administration in all age groups. The volume of distribution at steady state (V dss ) and total body clearance (Cl T ) were significantly higher in 1-month-old (304.87 mL/kg and 16.57 mL/h/kg) than in 12-month-old (193.43 mL/kg and 10.50 mL/h/kg) sheep. The area under the concentration-time curve from 0 to 72 h value of meloxicam was lower in 1-month-old (58.51 h*μg/mL) compared to 12-month-old (92.59 h*μg/mL) sheep. There was no difference in t 1/2ʎz value in different age groups. The body extraction ratio values for meloxicam ranged from 0.0186 to 0.0719 after i.v. administration in all age groups. Meloxicam showed an increase in plasma concentration and a decrease in V dss and Cl T in 12-month-old compared to 1-month-old sheep. Compared to 1-month-old and 12-month-old sheep, there was no difference in these parameters in 6-month-old sheep. Because the age of sheep has an influence on the pharmacokinetics of meloxicam, dosage apparently may need to be adjusted for age., (© 2023 John Wiley & Sons Ltd.)

This study aimed to determine the pharmacokinetics of meloxicam in pigeons. Twenty-four 7-wk-old meat pigeons (Columba livia) were randomly divided into 3 groups (PO, IM, and IV) and given a single dose of 1 mg/kg body weight of meloxicam. Plasma samples were taken at predetermined times, which were then analyzed using a validated high-performance liquid chromatography (HPLC) method and subjected to noncompartmental analysis using Phoenix software. Results indicated that meloxicam was absorbed effectively and quickly after PO and IM dosing. Peak concentrations (0.83 ± 0.21 and 1.59 ± 0.49 μg/mL) were achieved at 2 and 0.26 h, respectively, with mean absorption times of 2.56 ± 1.50 and 1.47 ± 0.89 h. Bioavailability was high at 86.31 ± 43.45% and 81.57 ± 52.58%, respectively, and the area under the concentration-time curve (AUC 0-∞ ) was 5.33 ± 2.68 and 5.03 ± 3.26 h·µg/mL. After IV administration, the elimination was faster with a total body clearance (CL) of 188.75 ± 83.23 mL/h/kg, an elimination half-life (t 1/2 λz ) of 1.76 ± 0.56 h, and a volume of distribution at steady-state (V SS ) of 427.50 ± 188.43 mL/kg. Considering the lack of a precise analgesic threshold of meloxicam in pigeons and the notable differences in its analgesic threshold among various animal species, formulating a dosing regimen in pigeons presented a significant challenge. Based on the previous analgesic threshold (3.5 μg/mL) in parrots, a higher dose (e.g., 2 mg/kg) or shorter dosing interval (e.g., every 6 h) is recommended for treating pain in pigeons. Nonetheless, further pharmacodynamic research is required to verify these recommendations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fish species are important for various purposes including aquaculture stock and display animals, but there are significant gaps in the medical knowledge regarding pharmacological parameters and effective pain management. Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that has been studied in few teleost species and with several administration routes. However, these species were typically freshwater or euryhaline fish, and evaluation in marine species is lacking. The pharmacokinetic properties of meloxicam were determined in nine adult China rockfish ( Sebastes nebulosus ), presumed healthy based on physical examination and benign medical histories. Based on a pilot study, China rockfish were given 1 mg/kg meloxicam via IM injection in the epaxial musculature, and, after a 48-h washout period, 1 mg/kg meloxicam was given by PO gavage. Blood samples were collected from the caudal vein at baseline and at nine time intervals over a 48-h time period following administration of meloxicam. Plasma meloxicam concentrations were determined by reverse phase high-performance liquid chromatography, and noncompartmental analysis was performed. The mean peak plasma concentration after IM injection was 4.9 µg/ml, and the mean terminal half-life was 5.0 h. The mean peak plasma concentration after PO administration was 0.07 µg/ml. Based on these findings, IM injected meloxicam reaches plasma levels consistent with therapeutic concentrations in select mammals, and peak levels were maintained for ≤12 h. Single-dose PO administration failed to achieve similar concentrations, and clinical practicality is unknown. Further studies evaluating NSAID multidose regimes and their pharmacodynamic effects may provide additional dosing information.

Purpose: Molecular imaging of tumor HER2 expression may allow patient selection for HER2-targeted therapies. Our aim was to introduce hexahistidine (His 6 ) peptides into pertuzumab Fab to enable labeling with the [ 99m Tc(CO) 3 (H 2 O) 3 ] + complex and study these radioimmunoconjugates for microSPECT/CT imaging of HER2-positive tumor xenografts in mice., Procedures: Fab were produced by papain digestion of pertuzumab and reacted with sulfo-SMCC for conjugation to His 6 -containing peptides (CGYGGHHHHHH). His 6 -peptide conjugation was measured by a radiometric assay. His 6 -pertuzumab Fab were labeled at 0.4-1.0 MBq/μg with [ 99m Tc(CO) 3 (H 2 O) 3 ] + for 1 h at 37 °C. HER2 immunoreactivity was assessed in a direct (saturation) binding assay using HER2-overexpressing SK-BR-3 human breast cancer (BC) cells. MicroSPECT/CT and biodistribution studies were performed in NOD/SCID mice with HER2-positive s.c. SK-OV-3 human ovarian cancer, or MDA-MB-361 or MDA-MB-231 human BC xenografts at 4 or 24 h post i.v. injection of [ 99m Tc]His 6 -pertuzumab Fab (29-49 MBq, 70 μg). The specificity of tumor uptake was assessed by comparison to irrelevant [ 99m Tc]Fab 3913 in SK-OV-3 tumor-bearing mice., Results: SDS-PAGE analysis demonstrated cleavage of pertuzumab to produce Fab, which eluted as a single peak with a retention time of 13.8 min on SE-HPLC. Fab were conjugated to 2.1 ± 0.5 His 6 peptides and labeled with [ 99m Tc(CO) 3 (H 2 O) 3 ] + to a radiochemical purity of 92-97 % at 0.4-0.8 MBq/μg. [ 99m Tc]His 6 -pertuzumab Fab exhibited saturable and specific binding to SK-BR-3 cells with a K D  = 51.3 ± 5.2 × 10 -9  M and B max  = 3.5 ± 0.1 × 10 6 receptors/cell. SK-OV-3 tumors were imaged at 4 and 24 h p.i [ 99m Tc]His 6 -pertuzumab Fab. Tumor uptake at 24 h p.i. was 4.1 ± 0.6 %ID/g, which was 13-fold significantly greater than [ 99m Tc]Fab 3913 (0.3 ± 0.0 %ID/g; P < 0.01). MicroSPECT/CT imaged HER2-overexpressing MDA-MB-361 tumors but not MDA-MB-231 tumors with low HER2 expression. Tumor uptake was 5.2-fold significantly greater at 24 h p.i. in MDA-MB-361 than MDA-MB-231 tumors (3.2 ± 0.1 %ID/g vs. 0.8 ± 0.1 %ID/g; P < 0.05)., Conclusions: MicroSPECT/CT with [ 99m Tc]His 6 -pertuzumab Fab imaged tumors in NOD/SCID mice that exhibited intermediate or high HER2 expression, but not tumors with low HER2. [ 99m Tc]His 6 -pertuzumab Fab is promising for SPECT imaging of tumor HER2 expression., (© 2021. World Molecular Imaging Society.)

Starting from lead compound 4 , the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF 3 group delivered an excellent pharmacological profile with a p K a of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N -(3-((3 R ,6 R )-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2 H -1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 ( NB-360 ), able to reduce significantly A β levels in mice, rats, and dogs in acute and chronic treatment regimens.

Sulthiame is an old antiepileptic medicine with controversial history, whose effectiveness and safety in use have been stated in some current studies. However, there is still a need for further clinical examinations for confirmation of its usefulness and tolerability in monotherapy and add-on therapy for epilepsy of various etiologies. A fully validated RP HPLC-UV method for determination of sulthiame in serum/plasma samples using desethylatrazine as the internal standard was developed. The biological fluid was prepared for analysis by a simple precipitation method with acetonitrile. The following validation parameters of the method were determined: selectivity/specificity, linearity range (0.2-50.0 μl/ml, R 2  > 0.9999), limits of detection (0.19 μl/ml) and quantification (0.58 μl/ml), precision (intra-day CV 1.06% and inter-day CV 1.25%), extraction recovery (~100%), accuracy (bias, -4.61-0.80%), carryover and ruggedness. Moreover, the stability of the medicine in plasma samples under different storage conditions was also tested. The usability of the method for clinical examinations was checked by analysis of serum samples originating from 19 patients treated with sulthiame. The proposed method is appropriate for determination of sulthiame in serum/plasma samples for drug monitoring purposes, as well as for pharmacokinetic studies., (© 2020 John Wiley & Sons, Ltd.)

Aim: The aim of this study was to compare the ocular and systemic absorption of brimonidine (BMD) and brinzolamide (BZM) in rabbits after the topical administration of a fixed-combination ophthalmic suspension of 0.1% BMD tartrate and 1% BZM (FCBB) with that after the administration of the respective single-drug formulations., Materials and Methods: Ocular and systemic drug absorption was estimated by determining BMD and BZM concentrations in the aqueous humor, retina/choroid, vitreous body, and blood/plasma by liquid chromatography/tandem mass spectrometry after the administration of FCBB, 0.1% BMD tartrate ophthalmic solution (0.1% BMD), or 1% BZM ophthalmic suspension (1% BZM) to rabbits., Results: In concomitant administration, instilling 0.1% BMD and 1% BZM successively without interval lowered aqueous humor concentrations of both drugs compared to those observed with a 5-min interval. After FCBB administration, BMD and BZM concentrations in the aqueous humor were comparable with those observed after the administration of 0.1% BMD and 1% BZM, whereas BMD concentrations in posterior ocular tissues were equal to or higher than those observed after 0.1% BMD. Plasma BMD concentrations following the administration of FCBB were 0.8-fold lower than those after 0.1% BMD; no remarkable differences were observed in blood BZM concentrations for both formulations., Conclusions: FCBB achieved drug distribution in the aqueous humor and systemic exposure that were comparable to those for the single-drug formulations. The viscosity of FCBB may increase BMD distribution in the retina/choroid. The administration interval affects ocular drug absorption with the concomitant administration of 0.1% BMD and 1% BZM, which can be overcome by using the fixed-combination of both drugs.

Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aβ reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

Co-delivery nanoparticles with characteristics of intracellular precision release drug have been generally accepted as an effective therapeutic strategy for eye diseases. In this study, we designed a new co-delivery system (miRNA/NP-BRZ) as a lasting therapeutic approach to prevent the neuro-destructive after the long-term treatment of glaucoma. Neuroprotective and intraocular pressure (IOP) response were assessed in in vivo and in vitro models of glaucoma. At the meaning time, we describe the preparation of miRNA/NP-BRZ, drug release characteristics, intraocular tracing, pharmacokinetic and pharmacodynamics study and toxicity test. We found that miRNA/NP-BRZ could remarkably decrease IOP and significantly prevent retinal ganglion cell (RGC) damages. The new formula of miRNA-124 encapsulated in PEG-PSA-BRZ nanoparticles exhibits high encapsulation efficiency (EE), drug-loading capacity (DC), and stable controlled-release efficacy (EC). Moreover, we also verified that the miRNA/NP-BRZ system is significantly neuroprotective and nontoxic as well as lowering IOP. This study shows our co-delivery drug system would have a wide potential on social and economic benefits for glaucoma.

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20 , a molecule with biochemical IC 50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ 40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.

A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot ® 50, 100, and 200 mg) were administered in open-label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed-effect modeling. The plasma maximal concentrations (C max ) showed striking nonlinear disposition of sultiame, with a 10-fold increase while doses were doubled. Conversely, whole blood C max increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two-compartment model with first-order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Objective: To investigate the effects of topical dorzolamide 2% q8h and brinzolamide 1% q8h, administered either alone (A and B, respectively) or in combination with topical timolol 0.5% q12h (C and D, respectively), on the circadian pattern of intraocular pressure (IOP), the pupil size, and heart rate in healthy cats., Methods: In this prospective, randomized, double-blinded study, 10 healthy, adult cats were randomly assigned to one of four groups and the eye to be medicated was randomly assigned. IOP, pupil diameter, and heart rate were measured at 3-hour intervals. A 5 days' adjustment period was followed by a 5 days' placebo (baseline) period. Then, all groups of cats received all four treatments (A-D) according to a Latin square-based rotating schedule. Five days' medication periods were alternated with 3 days' washout periods., Results: Mean baseline IOP was 13.6 ± 2.7 mm Hg. All treatments resulted in a statistically significant decrease in mean IOP in the treated eye: A: -2.33 mm Hg (95% CI: -2.71, -1.94), B: -1.91 mm Hg (95% CI: -2.30, -1.53), C: -2.36 mm Hg (95% CI: -2.74, -1.97), and D: -2.37 mm Hg (95% CI: -2.76, -1.98) and the nontreated eye: A: -0.19 mm Hg (95% CI: -0.28, -0.11), B: -0.18 mm Hg (95% CI: -0.27, -0.10), C -0.31 mm Hg (95% CI: -0.40, -0.23), and D: -0.24 mm Hg (95% CI: -0.32, -0.15). Timolol resulted in an additional, significant decrease in IOP of 4% and 5%, respectively, compared to A and B, and in mild bradycardia and miosis., Conclusions: Topical administration of dorzolamide 2% and brinzolamide 1% q8h significantly decreased IOP in healthy cats. Supplemental timolol 0.5% eye drops q12h resulted in an additional, statistically significant reduction of IOP., (© 2019 The Authors. Veterinary Ophthalmology published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Ophthalmologists.)

A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037 μg/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to investigate the corneal penetration of brinzolamide (BZ) nanoemulsions (NEs) and evaluate their in vitro and ex vivo irritancy potential. Twelve BZ NEs were prepared by the spontaneous emulsification method and ex vivo permeability studies were conducted using excised bovine corneas fixed onto Franz diffusion cells. To confirm the safety of the formulations for ophthalmic use, preparations were examined for potential ocular irritancy using a cell viability assay on retinal cells, the Hen's Egg Test-Chorio-Allantoic Membrane (HET-CAM) and the bovine corneal opacity-permeability (BCOP) test. Seven BZ NEs exhibited superior penetration across isolated bovine cornea compared to the marketed BZ suspension. The half maximal inhibitory concentration (IC 50 ) values of various surfactants and oils determined using the sulforhodamine B cell viability assay on retinal cells showed that Transcutol P, Cremophor RH40 and Triacetin were the least toxic excipients and may be safely used in the eye at various concentrations. HET-CAM and BCOP tests revealed that NE6B and NE4C did not result in any irritation and were thus considered safe for ocular use. Our finding suggests that optimized NEs can be a safe and effective vehicle for ocular delivery of BZ.

Widely recognized as a promising approach to degrading recalcitrant pollutants, Advanced Oxidation Processes (AOPs) have drawn much attention for their effectiveness and efficiency. Among all the AOPs, the Fenton system has been widely applied for oxidation and mineralization of micropollutants due to its ease of implementation and high catalytic efficiency. However, the necessity of preceding acidification, together with rapid consumption and slow regeneration of Fe(II) resulting in deterioration of reactivity, has reduced its competitiveness as a practical option for water treatment. Acknowledging the above drawbacks, this study investigates the potential viable option to enhance the Fenton system. Acesulfame was chosen as the model compound due to its ubiquitous occurrence and persistence in the environment. UV-assisted photo-Fenton treatment was found to remove the parent compound effectively; the transformation profile of acesulfame was identified and elucidated with the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Prolonged UV photo-Fenton treatment was effective for mineralization of the majority of the transformation products, without increasing the overall toxicity as indicated by Vibrio fischeri bioluminescence assay. The positive effects of the addition of redox mediators to Fenton systems at neutral pH were confirmed in this study. The results could be the basis for further development of homogeneous catalytic degradation techniques for the oxidation of environmental contaminants at circumneutral pHs to neutral pHs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-β (Aβ) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aβ peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aβ1-40 and Aβ1-42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development.

The aim of this study is to investigate the potential of D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) modified nanoliposomes as an ophthalmic delivery system of brinzolamide (Brz) for glaucoma treatment. The Brz loaded nanoliposomes containing TPGS (T-LPs/Brz) were firstly developed by a thin-film dispersion method. The average particle size was 96.87 ± 4.43 nm. The entrapment efficiency of the Brz was 95.41 ± 3.03% and the drug loading was 4.00 ± 0.13%. T-LPs/Brz exhibited obvious sustained release of Brz; in stark contrast to the normal liposomes of Brz (LPs/Brz) and the commercial formulation AZOPT® (Brz ophthalmic suspension, Brz-Sus). Enhanced trans-corneal transport of Brz was achieved with T-LPs/Brz. Compared with both Brz-Sus and LPs/Brz, the apparent permeability coefficient (P app ) of T-LPs/Brz was 10.2 folds and 1.38 folds higher, respectively. Moreover, T-LPs/Brz extended the cornea residence of Brz. White New Zealand rabbits treated with T-LPs/Brz had 3.18 folds and 1.57 folds Brz concentration 2 h after treatment than Brz-Sus and LPs/Brz, respectively. Further pharmacodynamic studies showed that T-LPs/Brz maintained an effective intraocular pressure (IOP) reduction from 3 h to 11 h after administration, while Brz-Sus and LPs/Brz presented effective IOP decreases from 3 h to 6 h and 3 h to 8 h respectively. The preliminary safety evaluation demonstrated that T-LPs/Brz had no significant side effects; specifically, no cornea damage and eye irritation. All the results indicated that TPGS modified nanoliposomes were a promising ocular delivery carriers for Brz to treat glaucoma. As such, T-LPs/Brz might be worthy of further translational study., (Copyright © 2018. Published by Elsevier B.V.)

Background: The objective of this study was to develop a more bio-available and safe nanosuspension of meloxicam (MX), which could dramatically improve inflammation targeting., Methods and Results: MX-loaded bovine serum albumin (BSA) nanosuspensions were prepared using acid-base neutralization in aqueous solution and the prepared nanosuspensions were characterized. The results obtained showed that the prepared nanosuspensions had a narrow size distribution with a mean particle size of 78.67±0.22 nm, a polydispersity index of 0.133±0.01, and a zeta potential of -11.87±0.91 mV. The prepared MX nanosuspensions were spherically wrapped by BSA with a smooth surface as shown by transmission electron microscopy. Stability studies showed that the nanosuspensions were physically stable at 4°C with a shelf life of at least 6 months. In the in vitro dissolution test, the MX-loaded BSA nanosuspension (MX-BSA-NS) exhibited sustained release. In addition, an in vivo pharmacokinetic study in rats following intravenous injection showed that the half-life ( t 1/2 ), mean residence time (MRT), and area under the concentration-time curve (AUC 0-∞ ) of MX-BSA-NS was increased by 169.83%, 150.13%, and 148.80%, respectively, in comparison with MX conventional solution (MX solution). Furthermore, results from inflammation targeting studies showed that the concentration of MX increased significantly in inflamed tissues but was reduced in normal tissues compared with the MX solution group after injection of MX-BSA-NS., Conclusion: The prepared MX-BSA-NS significantly increased the inflammation-targeting properties and bioavailability of MX, suggesting its potential as a promising formulation for the targeted drug delivery of MX in future clinical applications., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nonclinical assays with JNJ-54861911, a β-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (C max ) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; C max , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation., (© 2018, The American College of Clinical Pharmacology.)

A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine meloxicam in beagle dog plasma. Sample pretreatment involved a one-step protein precipitation with methanol of 0.1 mL plasma. Analysis was performed on a Venusil ASB-C 18 column with mobile phase consisting of methanol-water (containing 0.1% formic acid) (75:25, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization source. Each plasma sample was chromatographed within 4.1 min. The linear calibration curves for meloxicam was obtained in the concentration range of 10.3-4.12 × 10 3  ng/mL (r ≥ 0.99). The intra- and inter-day precisions (relative standard deviation) were ≤ 15%, and accuracy (relative error) was within ±7.3%. The method herein described was fully validated and successfully applied to the pharmacokinetic study of meloxicam tablets in beagle dog., (Copyright © 2018 John Wiley & Sons, Ltd.)

The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid-lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid-lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post-treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post-treatment, except for the 16-hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome., (© 2018 John Wiley & Sons Ltd.)

This work deals with fast-dissolving drug delivery systems of meloxicam (MX) derived from electrospun polyvinylpyrrolidone (PVP)/2-hydroxypropyl-β-cyclodextrin (HPβCD) nanofiber mats. Electrospinning of solutions with different solvent systems [dimethylformamide (DMF) and ethyl alcohol (EtOH)] was performed. Prepared films were evaluated for morphology, physical, and mechanical properties. MX content, dissolving time, MX release, and cytotoxicity of films were investigated. In vivo studies were also performed in healthy human volunteers. The results showed that MX/HPβCD complexes improved the solubility of MX. PVP also increased MX solubility and the stability of MX/HPβCD complexes. Films were successfully prepared by two solvent systems with fiber in the nanometer range. MX was well incorporated into the films (100% efficiency). The X-ray patterns and DSC experiment indicated an amorphous form of MX. A fast disintegration time and burst release of MX was obtained from EtOH system. Cytotoxicity testing of the films produced by EtOH system proved safer than the DMF system. In vivo studies revealed that films rapidly dissolved in the mouth and had a less bitter taste than MX. These results suggest that electospun films from EtOH system may be a good candidate for fast-dissolving drug delivery systems to increase palatability of dosage forms.

Due to a lack of reference blood concentrations in the literature, the forensic evaluation of prothipendyl findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested prothipendyl amounts were often vague. To describe a concentration range in clinical samples, prothipendyl and prothipendyl sulfoxide concentrations were determined in serum samples of 50 psychiatric patients receiving 40 mg, 80 mg, or 160 mg doses of prothipendyl. The analyses of prothipendyl and prothipendyl sulfoxide were carried out using validated methods of high performance liquid chromatography coupled to triple quadrupole mass spectrometry (LC-QQQ-MS), respectively. 40 mg doses caused average prothipendyl serum concentrations of 18.0 ng/mL (1 hour after intake) and 7.9 ng/mL (10.5 hours after intake), while 80 mg doses caused averages of 42.6 ng/mL and 15.2 ng/mL at the mentioned times of sampling. Irrespective of the given dose, prothipendyl concentrations below 30 ng/mL were observed in 80% of the patient samples taken 1 hour after ingestion as well as in 90% of the samples collected 10.5 hours after administration. Serum concentrations of the Phase I metabolite prothipendyl sulfoxide averaged 4.3 ng/mL (1 hour after intake) and 3.6 ng/mL (10.5 hours after intake). Possible drug-drug interactions regarding absorption and metabolism of prothipendyl are discussed. Results of the herein presented study are useful for the interpretation of analytical prothipendyl findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing two death cases involving prothipendyl findings., (Copyright © 2017 John Wiley & Sons, Ltd.)

NSAIDs are often used in horses with colic syndrome during the postoperative period, due to their ability to contrast endotoxemia and to promote an analgesic and anti-inflammatory effect. As the pharmacokinetics of a drug are often modified in unhealthy animals compared to healthy subjects, the aim of this study was to evaluate the pharmacokinetic profile of meloxicam after i.v. administration in horses undergoing laparotomy for colic syndrome. Eight horses received 0.6 mg/kg of meloxicam i.v. towards the end of surgery. Blood samples were taken at scheduled time points during the following 24 hr. The serum concentration of the drug was determined by HPLC. Terminal half-life (6.88 ± 2.96 hr), volume of distribution at steady-state (186.53 ± 61.20 ml/Kg) and clearance (27.91 ± 5.72 ml kg -1  hr -1 ) were similar to those reported in literature for healthy horses. This result suggests that no adjustment of the approved dose should be necessary when meloxicam is used to treat horses in the immediate postoperative period after surgery for colic syndrome., (© 2017 John Wiley & Sons Ltd.)

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Alzheimer's disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in the brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling. Further evaluation in an LC-MS/MS "cold tracer" study in rodents revealed high specific binding to BACE1 in brain. Upon radiolabeling, [ 18 F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans.

Dissolving microneedles (MNs) offered a simple, minimally invasive method for meloxicam (MX) delivery to the skin. However, the fabrication of dissolving MNs still faced some challenges, such as significant time consumption, loss of drug activity, and difficulty in regulating MN drug loading. To address these issues, we developed the tip-dissolving (TD) MNs. Several kinds of drugs were encapsulated successfully, and the quantity of MX ranged from 37.23 ± 8.40 to 332.53 ± 13.37 μg was precisely controlled. The effects of fabrication process on biomacromolecules stability were studied, and it was found that tyrosinase kept 90.4% activity during the fabrication process. The whole process for the fabrication of MNs only takes approximately 1 h. In order to further evaluate the potential of the TD MNs, MX TD MNs were prepared for in vitro release experiments, in vivo release experiments, safety evaluation, pharmacokinetic studies, and pharmacodynamic studies. The results demonstrated that MX TD MNs offered several advantages, including rapid release of the encapsulated drug (91.72% within 30 min), efficient drug delivery to skin (79.18%), no obvious skin irritation, decent relative bioavailability (122.3%), and strong anti-inflammatory and analgesic effects. Based on these results, we envisage that the TD MNs have promising potential for transdermal drug delivery of MX.

The aim of this article was to study the trans-epithelial absorption to reach the blood and to target the brain by axonal transport using nasal formulations with nanonized meloxicam (nano MEL spray) and its salt form known as meloxicam potassium monohydrate (MELP spray). The physicochemical properties and the mucoadhesivity of nasal formulations were controlled. In vitro and in vivo studies were carried out. These forms were first investigated in "nose-to-brain" relation. It was found that the in vitro study and in vivo study did not show any significant correlation. In vitro experiments demonstrated faster dissolution rate and higher diffusion of MELP from the spray compared with the nano MEL spray. The administration of the nano MEL spray resulted in faster absorption and constant plasma concentration of the drug after five minutes of administration as compared to MELP. The axonal transport of the drug was justified. MEL appeared in the brain tissues after the first five minutes of administration in the case of both spray forms, but its amount was too small in comparison with the total plasma concentration. The application of the nano MEL spray resulted in the same AUC in the brain as the intravenous injection. The "nose-to-blood" results predicted the nasal applicability of MEL and MELP in pain management. The "nose-to-brain" pathway requires further study.

Objective: The aim of this study was to determine sucralose and acesulfame-potassium (ace-K) pharmacokinetics in breast milk following maternal ingestion of a diet soda., Methods: Thirty-four exclusively breast-feeding women (14 normal-weight, 20 obese) consumed 12 ounces of Diet Rite Cola, sweetened with 68-mg sucralose and 41-mg ace-K, before a standardized breakfast meal. Habitual non-nutritional sweeteners intake was assessed via a diet questionnaire. Breast milk was collected from the same breast before beverage ingestion and hourly for 6 hours., Results: Owing to one mother having extremely high concentrations, peak sucralose and acesulfame-potassium concentrations following ingestion of diet soda ranged from 4.0 to 7387.9 ng/mL (median peak 8.1 ng/mL) and 299.0 to 4764.2 ng/mL (median peak 945.3 ng/mL), respectively., Conclusions: Ace-K and sucralose transfer into breast milk following ingestion of a diet soda. Future research should measure concentrations after repeated exposure and determine whether chronic ingestion of sucralose and acesulfame-potassium via the breast milk has clinically relevant health consequences.

We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The aim of the study was to develop a novel drug-in-adhesive patch for transdermal delivery of meloxicam (MLX). The formulation involved a strategy to combine a chemical enhancer with an ion-pair agent. Diethylamine (DETA) was selected as the counter ion to form the ion-pair agent MLX-DETA. MLX-DETA was characterized by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The ion-pair lifetime (T life ) of MLX-DETA was 164.1 μs. The water solubility of MLX-DETA was increased nearly 9.3-fold, compared with that of MLX. Oleic acid (OA) was selected as the chemical enhancer, and the optimized formulation consisted of 5% (w/w) MLX-DETA, 5% (w/w) oleic acid, and DURO-TAK® 87-4098 adhesive as the pressure-sensitive adhesive matrix. The permeation study in vitro showed that both the counter ion and chemical enhancer were effective in improving the skin permeation of MLX. Tissue distribution studies demonstrated that higher accumulation of MLX following application of the MLX-DETA patch to the skin could be obtained in rats compared with the MLX-patch group. In conclusion, to increase the skin absorption and obtain a sustained release for the transdermal delivery of MLX, preparation of a drug-in-adhesive patch by combining an ion pair (MLX-DETA) with a permeation enhancer (OA) is a suitable strategy.

Objectives: The aim of the study was to assess the impact of the differences in dissolution profiles of meloxicam tablets on the in-vivo bioavailability parameters after oral administration., Methods: Compare in-vitro dissolution testing in the recommended media to evaluate in-vivo bioequivalence outcomes for the Biopharmaceutics Classification System Class II weak acidic drugs. Nine Beagle dogs received a single oral administration of each formulation (7.5 mg) in a three-way crossover design., Key Findings: The dissolution of meloxicam from both test products showed marked differences with that from the reference tablet in pH 1.0, 4.5 and 6.8 media at 50 or 75 rpm. Both formulations exhibiting slow or fast dissolution were then compared with the reference product for in-vivo bioequivalence study. Both products were bioequivalent with the reference tablet in either extent or rate of oral absorption. It indicated that the dissolution profiles which discriminated between the formulations in vitro did not accurately predict the in-vivo bioequivalence outcomes., Conclusions: Comparative dissolution profiles using similarity factor (f 2 ) in the recommended media should be relaxed to fulfil the requirements for the development, scale-up and postapproval changes to immediate release oral solid dosage forms of meloxicam., (© 2017 Royal Pharmaceutical Society.)

In this study, we compared the plasma concentrations of meloxicam in pediatric rat pups (ages: 7, 14, 21, and 28 d) with those of young adult rats. Adult rats received 1.34 mg/kg SC meloxicam to determine the target peak plasma concentration (Cmax) for comparison with the pediatric animals. Pediatric rats received 1.34 mg/kg SC meloxicam, and in all age groups, Cmax met or exceeded that in adults (11.5 ±2.7 μg/mL). Plasma concentrations were similar between male and female pups within age groups, and peak plasma concentration was achieved more rapidly in rat pups than adults. The analgesic efficacy of this dose was not evaluated in this study.

The aims of the investigation were to establish for the first time (i) clinical efficacy and (ii) pharmacokinetic profile of meloxicam intravenously (IV) administered in male Mediterranean buffalo calves after surgical orchiectomy. The study was performed on 10 healthy buffalo calves, between 4 and 5 months old and between 127 and 135 kg of body weight (b.w.). An IV injection of 0.5 mg/kg b.w. of meloxicam was administered in six calves (treated group, TG) immediately after surgery; the other four animals were used as untreated control group (CG). The clinical efficacy of meloxicam was evaluated pre- and post-surgery by monitoring respiratory rate (RR), heart rate (HR), rectal temperature (T°C), serum cortisol levels (SCL) and pain score (PS). Significant inter-groups differences were detected at sampling times (T): 4 hour (h) for RR (P<0.05), at T1-4-6-8 h for PS (P<0.05) and at T4-6-8 h for SCL (P < 0.0001). Regarding the mean intra-group values observed pre (T0) and post-surgery (from T15 min to T72 h), significant difference between the groups were found for RR (P<0.01), PS and SCL (P<0.05). The pharmacokinetic profile was best fitted by a two-compartmental model and characterized by a fast distribution half-life and slow elimination half-life (0.09 ± 0.06 h and 21.51 ± 6.4 h, respectively) and meloxicam mean concentrations at 96 h was of 0.18 ± 0.14 μg/mL. The volume of distribution and clearance values were quite low, but reasonably homogenous among individuals (Vdss 142.31 ± 55.08 mL/kg and ClB 4.38 ± 0.95 mL/kg/h, respectively). The IV administration of meloxicam in buffalo calves shows encouraging effects represented by significant and prolonged analgesic effects, significant reduction of SCL as well as similar pharmacokinetic profile to bovine calves.

This study evaluated the pharmacokinetic profile of a single dose of meloxicam (1.0 mg/kg) administered subcutaneously (n = 6) or intravenously (n = 2) to black-tailed prairie dogs (Cynomys ludovicianus). Blood was collected immediately before (time 0) and at 0.5, 1, 2, 4, 8, 12 and 24 h after drug administration. Plasma meloxicam concentrations were quantified with HPLC-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. The peak plasma concentrations, time to peak plasma concentration, and terminal half-life of meloxicam after subcutaneous administration (median [minimum-maximum]) were 4.30 (3.00-4.89) μg/mL, 2.00 (0.62-4.00) h, and 11.88 (7.35-18.64) h, respectively. Plasma concentrations of meloxicam for prairie dogs in the present study showed high absorption and slow elimination after drug administration. The results of this study suggest that a 1.0-mg/kg SC dose of meloxicam administered every 24 h might be excessive for prairie dogs, although the ideal therapeutic dose in terms of safety and efficacy is unknown in this species.

The aim of the presented work was to design, formulate and evaluate the properties of low-acyl gellan macro beads with the potential application as carriers for oral delivery of meloxicam (MLX) in the prophylaxis of colorectal cancer. The beads were obtained by means of ionotropic gelation technique. Calcium chloride (1.0%, 9.0 × 10 -2  M) was used as the cross-linking agent. Nine different polymer, drug and surfactant (Tween ® 80) mixtures were used for production of the beads. The quantitative compositions of the mixtures were generated with the application of the Design of Experiments (DoE) modulus from the STATISTICA Software. The prepared formulations revealed 7.2-27.0% of drug loading and 29.2-50.7% drug encapsulation efficiency. It turned out that 0.5% amount of gellan gum in the mixtures was not sufficient to obtain spherical beads. The morphology and surface of the dried beads were analyzed by SEM. Raman spectra confirmed that MLX did not undergo structural changes during production of the beads. The swelling behavior and degradation of the beads were evaluated in three simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8). The MLX in vitro release studies were conducted on USP apparatus IV, working in the open loop mode. The obtained results showed that MLX release from the dried beads was pH-dependent. The formulations obtained from mixtures containing 1.0 and 1.5% of gellan may be considered as oral dosage forms for MLX, intended to omit the stomach and release the drug in the distal parts of the gastrointestinal tract.

OBJECTIVE To determine the pharmacokinetics of meloxicam in domestic hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg). ANIMALS 8 healthy adult White Leghorn hens. PROCEDURES Hens were administered 1 mg of meloxicam/kg PO once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma, egg whites (albumen), and egg yolks were analyzed by high-performance liquid chromatography. RESULTS The half-life, maximum concentration, and time to maximum concentration of meloxicam in plasma samples were 2.8 hours, 7.21 μg/mL, and 2 hours, respectively. Following meloxicam administration, the drug was not detected after 4 days in egg whites and after 8 days in egg yolks. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that meloxicam administered at a dose of 1 mg/kg PO in chickens appears to maintain plasma concentrations equivalent to those reported to be therapeutic for humans for 12 hours. The egg residue data may be used to aid establishment of appropriate drug withdrawal time recommendations.