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The present study deals with the influence of hydroxypropylmethylcellulose 4000 in the protection of Piroxicam polymorphs which could appear during the processes of formulation of extended release tablets. The physico-chemical tests and the dissolution profiles of polymorphs and tablets showed that the metolose incorporated in the tablets at a rate equivalent to 5% could possibly act doubly; initially by protecting the piroxicam polymorphism transition (form II) during compression, then modulating its in vitro release (extended release).

To clarify the clinical efficacy of a single oral 2 g dose of azithromycin extended-release for heterosexual male patients with urethritis, and the current antimicrobial sensitivity of Neisseria gonorrhoeae to azithromycin, a prospective clinical trial was conducted from 2011–2013. In patients with gonococcal urethritis, the eradication rate was 90.9% (30 of 33). The susceptibility rates of isolated Neisseria gonorrhoeae strains to ceftriaxone, spectinomycin, cefixime and azithromycin were 100%, 100%, 95.3% (41/43) and 37.2% (16/43), respectively. In the patients with nongonococcal urethritis, the eradication rate was 90.0% (45 of 50). The microbiological eradication rates for the pathogens were 90.9% (30/33) for Neisseria gonorrhoeae, 91.5% (43/47) for Chlamydia trachomatis, 71.4% (5/7) for Mycoplasma genitalium, and 100% (13/13) for Ureaplasma urealyticum. The main adverse event was diarrhea and its manifestation rate was 35.2% (32 of 120). The symptom of diarrhea was mostly temporary and resolved spontaneously. The conclusion was that the treatment regimen with a single oral 2 g dose of azithromycin extended-release would be effective for patients with urethritis. However, the antimicrobial susceptibilities of Neisseria gonorrhoeae and Mycoplasma genitalium should be carefully monitored because of possible treatment failure.

Background: The change in the reaction time of a tail or paw exposed to a thermal stimulus is a measure of nociceptive activity in laboratory animals. Tail-flick and plantar thermal sensitivity (Hargreaves) tests are non-invasive, minimize stress, and can be used to screen animals for phenotype and drug activity. Objective: Hargreaves testing has been widely used in rats. We investigated its use to measure the activity of opiate analgesia in mice. Methods: Mice were used in thermal stimulus studies at 1-5 hours and 1-5 days to test acute and extended release preparations of buprenorphine. Results: Hargreaves testing had limited value at 1-5 hours because mice can have an obtunded response to opiate therapy. Tail-flick studies with restrained mice are not affected by the initial locomotor stimulation. Discussion: The present report describes a simple restraint system for mice. The utility of the system is demonstrated by examining the efficacy of acute and extended release buprenorphine injections in Balb/c and Swiss mice. Conclusion: Standardized tail-flick testing provides a sensitive robust method to monitor opiate activity in mice.

Porous implants or implantable scaffolds used for tissue regeneration can encourage tissue growth inside the implant and provide extended drug release. Water-soluble polymers incorporated into a biodegradable or inert implant matrix may leach out upon contact with biological fluids and thereby gradually increasing the porosity of the implant and simultaneously release drug from the implant matrix. Different molecular weight grades of methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) were mixed with polylactide and extruded into model implants containing nitrofurantoin as a model drug. The effect of the leached pore formers on the implant porosity and the rheology of the implant microenvironment in vitro was investigated and it was shown that HPMC pore formers had the greatest effect on the surrounding viscosity, with higher drug release and pore forming ability as compared to the MC pore formers. The highest molecular weight HPMC led to the most significant increase in viscosity of the implant microenvironment, while the highest drug release was achieved with the lowest molecular weight HPMC. The data suggested that the microenvironmental rheology of the implant, both in the formed pores and in biological fluids in the immediate vicinity of the implant could be an important factor affecting the diffusion of the drug and other molecules in the implantation site. [ABSTRACT FROM AUTHOR]

Purpose: Sustained release hydrogel with bupivacaine (AnestaGel™) is a novel formulation of extended release bupivacaine in a biohydrogel Matrix™. We sought to compare the analgesic effects via mechanical allodynia, the pharmacokinetic characteristics via serum blood levels, and the local tissue effects via pathology, following injection of either sustained release hydrogel with bupivacaine, liposome bupivacaine, or hydrogel only (negative control group). Materials and methods: Ninety rats (30 in each group) were randomized to receive a sciatic nerve block injection of either sustained release hydrogel with bupivacaine, liposome bupivacaine (Exparel®), or a biohydrogel matrix. The total force generated was obtained at varying time points. Pathologic analysis was undertaken on days 5 and 42 of the study. Six additional rats (two in each group) were randomized to receive a sciatic nerve block injection of either sustained release hydrogel with bupivacaine, liposome bupivacaine, or bupivacaine and pharmacokinetic data were obtained for up to 120 hours. Results: The sustained release hydrogel with bupivacaine group had significantly better response to mechanical allodynia compared to the other two groups. The pathology showed no significant adverse events at 42 days in any group. Finally, bupivacaine was present longer in the serum of sustained release hydrogel with bupivacaine group than the other two groups. Conclusion: The sustained release hydrogel with bupivacaine achieved longer lasting analgesia with no significant findings on pathology at 42 days when compared to both positive and negative controls. [ABSTRACT FROM AUTHOR]

Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practice, resulting in a greater incidence of adverse events. A prodrug of nalbuphine has been developed, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain an effective blood level of nalbuphine. An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine. Twelve healthy Taiwanese were randomized to receive an intramuscular injection of 20 mg nalbuphine HCl and 150 mg DNS sequentially with a washout period of 5 days. To prevent DNS hydrolysis during sample analysis, the effect of four esterase inhibitors was evaluated in the quantitation of DNS in human whole blood and thenoyltrifluoroacetone was chosen. The bioavailability of nalbuphine from intramuscularly injected DNS relative to that from nalbuphine HCl was 85.4%. The mean absorption time of nalbuphine from DNS was 145.2 h. It took approximately 6 days for the complete release of DNS into the blood stream where DNS was rapidly hydrolysed to nalbuphine; suggesting a single injection of 150 mg DNS in our extended-release formulation could provide long-lasting pain relief. [ABSTRACT FROM AUTHOR]

Background:VERxVE data showed non-inferior virologic efficacy with extended release nevirapine (NVP-XR) dosed 400 mg once daily (QD) versus immediate release nevirapine (NVP-IR) 200 mg twice daily in a double-blind, non-inferiority study in treatment-naïve HIV-1-positive patients. Objective:To study the pharmacokinetics (PK) of the NVP formulations and identify possible associations with demographic factors. Methods:Patients with viral load ≥1000 copies/mL and CD4+ count > 50– <400 cells/mm3(males) and >50– <250 cells/mm3(females) at screening received NVP-IR 200 mg QD during a 14-day lead-in and were then stratified by baseline viral load and randomized to NVP-XR or -IR. NVP trough concentrations at steady state (SS) (Cpre,ss,N) were measured up to week 48 for all participating patients. In a PK sub-study, SS parameters – AUC0–24,Cmax,Cmin, and peak-to-trough fluctuation were obtained and analyzed with relative bioavailability assessed at week 4 by plasma collection over 24 h. Results:Trough concentrations were stable from week 4 to week 48 for all patients (n = 1011) with both formulations, with NVP-XR/IR ratios of 0.77–0.82. Overall, 49 patients completed the PK sub-study: 24 XR and 25 IR. NVP-XR showed less peak-to-trough fluctuation (34.5%) than IR (55.2%), and lower AUC0–24,Cmin,Cmax, and trough concentrations than IR. However, no effect of SS trough concentrations was found on the virologic response proportion at least up to 1000 ng/mL. No significant association was found between NVP PK and gender, race, and viral load. Conclusion:These data suggest NVP-XR achieves lower but effective NVP exposure compared with NVP-IR. [ABSTRACT FROM AUTHOR]

Objectives The aim of this first-in-human study was to assess the safety and effectiveness of the Virtue sirolimus-eluting balloon in a cohort of patients with in-stent restenosis (ISR). Background Angioplasty balloons coated with the cytotoxic drug paclitaxel have been widely used for ISR treatment. The Virtue angioplasty balloon (Caliber Therapeutics, New Hope, Pennsylvania) delivers sirolimus in a nanoencapsulated liquid formulation. This clinical trial is the first to examine a sirolimus-eluting balloon for ISR. Methods In this prospective, single-arm feasibility study at 9 European centers, 50 ISR patients were treated with the Virtue balloon. Angiographic measurements at 6 months are reported, along with 12-month clinical follow-up. Results Procedural success in the intention-to-treat population was 100%. The primary safety endpoint was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) assessed at 30 days (0%, n = 50). The primary performance endpoint was in-segment late lumen loss (LLL) at 6 months (0.31 ± 0.52 mm; n = 47). Secondary 6-month endpoints include binary restenosis (19.1%), diameter stenosis (30.3 ± 19.9%), and major adverse cardiac events (MACE) (10.2%, n = 49). In the 36-patient per-protocol population (excluding major protocol violations and previously stented ISR), LLL was 0.12 ± 0.33 mm at 6 months. Clinical outcomes at 1 year for the intention-to-treat group were 12.2% TLF and 14.3% MACE and for the per-protocol population were 2.8% TLF and 2.8% MACE. Conclusions This first-in-human study showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon, 6-month LLL rates in line with current stent-free ISR treatment options, and clinical outcomes that warrant further evaluation in dedicated randomized studies. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon® 90H) as extended release excipient in matrix tablets for three model drugs with different aqueous solubility (theophylline, caffeine and diprophylline). The tablets could be prepared by direct compression because of the favorable phospholipid powder flow properties (Carr's index: 12.64 and angle of repose: 28.85) and good compactibility. Tablets of low porosity were formed already at low pressure of 40 MPa and with drug loadings up to 70% due to high plasticity of the phospholipid. Extended drug release was achieved with the drugs of different solubility and at various drug loadings. For example, the caffeine release time (t 80% ) from 8 mm tablets ranged from 1.5 h to 18 h at 70% and 10% drug loading, respectively. The drug release was governed by diffusion and could therefore be modelled by Fick's law of diffusion. Drug release profiles were thus a function of drug solubility, drug loading and tablet dimension. Matrix tablets of caffeine (20% drug loading) showed robust dissolution with regard to agitation (50–100 rpm) and ionic strength of the release media (100–600 mOsmol/kg). Caffeine release was pH-dependent with a faster drug release at acidic pH, which was attributed to a protonization of the phosphatidyl group of the matrix-former and thus a higher hydrophilicity. [ABSTRACT FROM AUTHOR]

The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index. For these reasons, it represents an agent that could benefit from modified release formulations to overcome these limitations. The objective of this review is to discuss the clinical evaluation of immediate and modified release tacrolimus formulations in renal transplant recipients. Clinical trials from early development of immediate release tacrolimus to formulation-specific post-marketing trials of modified release tacrolimus formulations are reviewed with an emphasis on key elements relating to trial design end endpoint assessment. Particular elements that can be addressed with formulation alterations, such as pharmacokinetics, pharmacogenomics, and toxicity and corresponding clinical evaluations are discussed. In addition, current knowledge gaps in the clinical evaluation of immediate and modified release tacrolimus formulations are discussed to highlight potential avenues for the future development of different tacrolimus formulations with outcomes relevant to the regulators, the transplant community, and to transplant recipients. This review shows that new formulations may alter tacrolimus bioavailability, alleviate certain adverse events while potentially enhancing patient convenience. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Ficḱs law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices. [ABSTRACT FROM AUTHOR]

We report the preparation, characterization, and drug release kinetics of a pH-responsive hydrogel film from a dendrimer megamer. The megamer (GP32) is a three-dimensional reticulated structure with a mean diameter of 71.16 nm (PDI 0.150) and was prepared by the reaction between Poly(amidoamine) generation4 (PAMAM G4) dendrimer and glutaraldehyde (G:P molar ratio 32). The crosslinking units in the megamer are provided mainly by the bicyclic dimer 2-hydroxy-3,4,4a,7,8,8a-hexahydro-2 H-chromene-6-carbaldehyde as determined by high-resolution (800 MHz) H NMR and FTIR. The hydrogel film (F[GP32]) is formed upon evaporation of a methanolic solution of the megamer and has a high degree of organization and homogeneity. Further crosslinking with glutaraldehyde (CLF[GP32]) enhanced the mechanical properties of the hydrogel film. The chemical constitution and unique megamer architecture enable the hydrogel film to carry both lipophilic and hydrophilic substances. The film did not cause any dermal irritation or clinical signs of toxicity in tests on rabbits, allowed for a sustained release of ketoprofen and played an important role in the process of drug delivery into the receptor medium. This performance taken together with the absence of toxicity makes this hydrogel film a good choice for dermal sustained drug release. [ABSTRACT FROM AUTHOR]

A novel dissolution apparatus has been proposed as an alternative apparatus for dissolution testing. In this study, we evaluated the performance of the new intestine model for simulating the peristaltic action (IMSPA), generating the movement that closely mimics peristaltic contractions of the small intestine. Two polyethylene oxide matrix tablet formulations, containing a model drug belonging to class III of the Biopharmaceutics Classification System, were tested. Dissolution was also performed in the USP2 apparatus. The release profiles were further compared to the in vivo data to evaluate the in vivo relevance of the new apparatus. The results demonstrated that the novel apparatus showed good discriminatory power between different polyethylene oxide formulations. Moreover, a better relation to the in vivo data was established by the IMSPA as compared to the USP2 apparatus. In conclusion, the model parameters were efficiently controlled to ensure the dissolution conditions crucial for evaluating the in vivo release performance of the tested formulations. [ABSTRACT FROM AUTHOR]

Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time-weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0-12 hours and -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8-12 hours (all P < .001 vs placebo). In study 2 (n = 106), mean (SD) time-weighted sum of pain relief and pain intensity difference scores were 18.2 (20.0) versus 41.5 (21.0) at 0-12 hours and 10.3 (12.0) versus 18.4 (12.1) at 8-12 hours for placebo versus ibuprofen IR/ER, respectively ( P < .001 for both); efficacy was sustained over each of the four 12-hour dosing intervals with ibuprofen. Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses. [ABSTRACT FROM AUTHOR]

Objective. To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods. This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results. Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P=0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact (P< 0.0001) or manipulated (P50.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions. Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products. [ABSTRACT FROM AUTHOR]

Background: Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. Methods: Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol®), Glyceryl palmitostearate (Precirol®), Glyceryl behenate (Compritol®) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5-1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. Results: Sphericity indicated by shape factor (eR) varied with type and concentration of lipids: Geleol® (eR = 0.891-0.997), Precirol® (eR = 0.611-0.743), Compritol® (eR = 0.665-0.729) and Carnauba wax (eR = 0.499-0.551). Highly spherical pellets were obtained with Geleol® (Aspect ratio = 1.005-1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153-1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol® and Compritol®, (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax. Scanning electron microscopy of Compritol® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol® and Compritol® pellets, explained by Korsmeyer-Peppas (R2 = 0.978-0.993) indicated non-Fickian diffusion (n = 0.519-0.597). Combinations of (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax pellets followed Zero-order (R2 = 0.991-0.995). Similarity test was performed using combination of Geleol® and Compritol® (i) as a reference. Conclusions: Matrices for the extended release of Meclizine HCl from extruded-spheronized pellets were successfully formed by using three lipids (Geleol®, Compritol® and Carnauba wax) in different combinations. The encapsulated pellets of Meclizine HCl can be effectively used for treatment of motion sickness, nausea and vertigo for extended period of time. [ABSTRACT FROM AUTHOR]

The main objective of this work was to explore the potential of coupling fused deposition modeling in three-dimensional (3D) printing with hot-melt extrusion (HME) technology to facilitate additive manufacturing, in order to fabricate tablets with enhanced extended release properties. Acetaminophen was used as the model drug and different grades and ratios of polymers were used to formulate tablets. Three-point bending and hardness tests were performed to determine the mechanical properties of the filaments and tablets. 3D-printed tablets, directly compressed mill-extruded tablets, and tablets prepared from a physical mixture were evaluated for drug release rates using a USP-II dissolution apparatus. The surface and cross-sectional morphology of the 3D-printed tablets were assessed by scanning electron microscopy. Differential scanning calorimetry and thermogravimetric analysis were used to characterize the crystal states and thermal properties of materials, respectively. The 3D-printed tablets had smooth surfaces and tight structures; therefore, they showed better extended drug release rates than the directly compressed tablets did. Further, this study clearly demonstrated the feasibility of coupling HME with 3D printing technology, which allows for the formulation of drug delivery systems using different grades and ratios of pharmaceutical polymers. In addition, formulations can be made based on the personal needs of patients. [ABSTRACT FROM AUTHOR]

Salts of linogliride with reduced solubilities were prepared and evaluated as potential candidates for extended-release oral dosage forms. A once-daily dose of 300–800 mg was intended. Seven acids were selected: p-acetamidobenzoic, benzoic, p-hydroxybenzoic, 3-hydroxy-2-naphthoic, 1-napsylic, pamoic, and p-toluenesulfonic acids but only four salts were able to be prepared in suitable quantities for evaluation: linogliride pamoate, p-hydroxybenzoate, 3-hydroxy-2-naphthoate, and 1-napsylate. The pH-solubility profiles of the four new salts, free base, and fumarate salt were compared over the pH 1.43–8.3 range and the intrinsic dissolution rates of the four new salts and the free base were determined at pH 1.43, 4.4, and 7.5. The range of the pH-solubility profile and intrinsic dissolution rates of the p-hydroxybenzoate salt were less than the free base and fumarate and higher than the other three new salts. The pH-solubilities and intrinsic dissolution rates of the 1-napsylate salt were pH-independent. The solubilities and intrinsic dissolution rates of the pamoate and 3-hydroxy-2-naphthoate were higher at pH 1.4–3.4 than at higher pH. At pH 4.4 and higher, the solubilities were essentially the same, in the 1–2 mg/mL range. The intrinsic dissolution rates were also very low and not very different. Dissolution studies with capsules containing 800 mg doses of the pamoate, 1-napsylate, free base, and fumarate performed in a dissolution medium of pH beginning at 2.2 and ending at 6.8 demonstrated that the pamoate and 1-napsylate salt forms dissolved slower and could be useful as extended-release forms. [ABSTRACT FROM PUBLISHER]

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), transdermal fentanyl patches, and transmucosal buprenorphine are probably the most commonly used options for providing post-operative analgesia in the early at-home period. However, these require daily administration or are associated with abuse concerns. One of the significant unmet needs in veterinary surgery and pain management is for longer acting opioids for cats to effectively bridge the gap between the in-hospital and at-home recovery periods. A proof of concept study of an extended release formulation of buprenorphine HCL (ER-Bup) was conducted using objective kinetic measures and a unilateral onychectomy model. Using a blinded, randomized, two period crossover design, four cats were allocated to control (saline) or ER-Bup (0.6 mg/kg, subcutaneously [SC]) treatment groups. All animals underwent a unilateral forelimb onychectomy per period with a washout/recovery period in between. Observational pain scores and kinetic data (using a pressure sensitive walkway [PSW]) were collected prior to (baseline) and at intervals for 72 h following surgery. Symmetry indices were derived for kinetic variables (peak vertical force [PVF]; vertical impulse [VI]) of each forelimb for landing following a jump and for walking. A rescue analgesic protocol was in place. Effect of surgery and treatment were evaluated using a mixed model statistical approach. Results: No cats required rescue analgesics based on subjective pain score. ER-Bup had a positive influence on subjective pain scores during the 72 h postsurgery (p = 0.0473). PVF and VI of the operated limb were significantly decreased for both landing (p < 0.0001 and p < 0.0001) and walking (p < 0.0001 and p < 0.0001 respectively) compared to control. ER-Bup resulted in significantly decreased asymmetry in limb use during landing (PVF, p < 0.0001; VI, p < 0.0001) and walking (PVF, p = 0.0002, VI, p < 0.0001). The novel use of data collected following a jump from an elevated platform appeared to provide all desired information and was easier to collect than walking data. Conclusion: This study demonstrates that SC administration of ER-Bup may be an effective analgesic for a 72 h period postoperatively. Furthermore, landing onto a PSW from an elevated perch may be a useful and efficient way to assess analgesics in cats using a unilateral model of limb pain. [ABSTRACT FROM AUTHOR]

Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebocontrolled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was "at the moment" drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for "at themoment" drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P< 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentrationtime profile for each treatment mimicked its respective "at the moment" drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated. [ABSTRACT FROM AUTHOR]