Classification Model for Epileptic Seizure Using Simple Postictal Laboratory Indices.

Distinguishing syncope from epileptic seizures in patients with sudden loss of consciousness is important. Various blood tests have been used to indicate epileptic seizures in patients with impaired consciousness. This retrospective study aimed to predict the diagnosis of epilepsy in patients with transient loss of consciousness using the initial blood test results. A seizure classification model was constructed using logistic regression, and predictors were selected from a cohort of 260 patients using domain knowledge and statistical methods. The study defined the diagnosis of seizures and syncope based on the consistency of the diagnosis made by an emergency medicine specialist at the first visit to the emergency room and the diagnosis made by an epileptologist or cardiologist at the first outpatient visit using the International Classification of Diseases 10th revision (ICD-10) code. Univariate analysis showed higher levels of white blood cells, red blood cells, hemoglobin, hematocrit, delta neutrophil index, creatinine kinase, and ammonia levels in the seizure group. The ammonia level had the highest correlation with the diagnosis of epileptic seizures in the prediction model. Therefore, it is recommended to be included in the first examination at the emergency room.

Hair Growth Effect of DN106212 in C57BL/6 Mouse and Its Network Pharmacological Mechanism of Action.

Centipeda minima (CMX) has been widely investigated using network pharmacology and clinical studies for its effects on hair growth via the JAK/STAT signaling pathway. Human hair follicle papilla cells exhibit hair regrowth through the expression of Wnt signaling-related proteins. However, the mechanism of action of CMX in animals has not been elucidated fully. This study examined the effect of induced hair loss and its side-effects on the skin, and observed the mechanism of action of an alcoholic extract of CMX (DN106212) on C57BL/6 mice. Our results showed that DN106212 was more effective in promoting hair growth than dimethyl sulfoxide in the negative control and tofacitinib (TF) in the positive control when mice were treated with DN106212 for 16 days. We confirmed that DN106212 promotes the formation of mature hair follicles through hematoxylin and eosin staining. We also found that the expression of vascular endothelial growth factor (Vegfa), insulin-like growth factor 1 (Igf1), and transforming growth factor beta 1 (Tgfb1) is related to hair growth using PCR. DN106212-treated mice had significantly higher expression of Vegfa and Igf1 than TF-treated ones, and inhibiting the expression of Tgfb1 had similar effects as TF treatment. In conclusion, we propose that DN106212 increases the expression of hair growth factors, promotes the development of hair follicles, and promotes hair growth. Although additional experiments are needed, DN106212 may serve as an experimental basis for research on natural hair growth-promoting agents.

Characterization of Channeling Effects Applied to Extended-Release Matrix Tablets Containing Pirfenidone.

Pirfenidone (PRF) is an anti-fibrotic agent that has been approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate idiopathic pulmonary fibrosis. However, the current oral administration dosing regimen of PRF is complex and requires high doses. Patients are instructed to take PRF three times daily, with each dose consisting of up to three capsules or tablets (600 mg/d or 1.8 g/d of PRF) taken with food. To improve the dosing regimen, efforts are being made to develop an extended-release tablet with a zero-order release pattern. In this study, two types of extended-release matrix tablets were compared: non-channeled extended-release matrix tablets (NChMT) and channeled extended-release matrix tablets (ChMT). In vitro release tests, swelling and erosion index, rheology studies, and X-ray microcomputed tomography (XRCT), were conducted. The results indicated that ChMT maintained a zero-order release pattern with a constant release rate, while NChMT exhibited a decreased release rate in the latter half of the dissolution. ChMT exhibited accelerated swelling and erosion compared to other formulations, and this was made possible by the presence of channels within the tablet. These channels allowed for thorough wetting and swelling throughout the entire depth of the tablet. The formation of channels was confirmed through XRCT images. In conclusion, the presence of channels in ChMT tablets increased the rate of swelling and erosion, resulting in a zero-order release pattern. This development offers the potential to improve the dosage of PRF and reduce its associated side effects.

Iatrogenic Ankle Charcot Neuropathic Arthropathy after Spinal Surgery: A Case Report and Literature Review.

Charcot neuropathic arthropathy is a relatively rare, chronic disease that leads to joint destruction and reduced quality of life of patients. Early diagnosis of Charcot arthropathy is essential for a good outcome. However, the diagnosis is often based on the clinical course and longitudinal follow-up of patients is required. Charcot arthropathy is suspected in patients with suggestive symptoms and an underlying etiology. Failed spinal surgery is not a known cause of Charcot arthropathy. Herein we report a patient with ankle Charcot neuropathic arthropathy that developed after failed spinal surgery. A 58-year-old man presented to the emergency room due to painful swelling of the left ankle for 2 weeks that developed spontaneously. He underwent spinal surgery 8 years ago that was associated with nerve damage, which led to weakness of great toe extension and ankle dorsiflexion, and sensory loss below the knee. CT and T2-weighted sagittal MRI showed a fine erosive lesion, subluxation, sclerosis, fragmentation, and large bone defects. Based on the patient's history and radiological findings, Charcot arthropathy was diagnosed. However, the abnormal blood parameters, positive blood cultures, and severe pain despite the decreased sensation suggested a diagnosis of septic arthritis. Therefore, diagnostic arthroscopy was performed. The ankle joint exhibited continued destruction after the initial surgery. Consequently, several repeat surgeries were performed over the next 2 years. Despite the early diagnosis and treatment of Charcot arthropathy, the destruction of the ankle joint continued. Given the chronic disease course and poor prognosis of Charcot arthropathy, it is essential to consider this diagnosis in patients with neuropathy.

Development of self-microemulsifying tablets containing dutasteride for enhanced dissolution and pharmacokinetic profile.

This study aimed to develop self-microemulsifying tablets containing the hydrophobic drug dutasteride for easy administration and high in vivo absorption. The candidate lipids and surfactants were formulated into a self-microemulsifying drug delivery system (SMEDDS), and their mean droplet size upon dilution was evaluated. The SMEDDS containing Capmul® MCM, Captex® 355, and Cremophor® EL showed improved dissolution in the gastric medium when compared to the dissolution of the conventional product (Avodart®) and the raw drug. Among the various porous silicon microparticles for solidifying SMEDDS, Neusilin® US2 showed favorable properties in terms of maximum adsorption capacity, powder flow, and compaction. However, the amount of drug released from the solidified SMEDDS after the adsorption process was lower than that of liquid SMEDDS, indicating incomplete desorption. After observing the effect of the solid-to-liquid ratio and pre-filling the pores with blank SMEDDS, complete desorption was obtained when the pores were first adsorbed with polyvinylpyrrolidone. The self-microemulsifying tablets exhibited improved bioavailability (29.9% and 15.2%) compared to the conventional soft gelatin product. Therefore, the proposed system could successfully solubilize the hydrophobic drug while maintaining rapid and complete desorption from the solid carrier, resulting in enhanced in vivo performance.

A formulation development strategy for dual-release bilayer tablets: An integrated approach of quality by design and a placebo layer.

Although dual-release mechanism bilayer tablets containing one drug in both immediate- and sustained-release layers are widely used to improve therapeutic efficiency, studies quantitatively analyzing the drug amount released from each layer and the mutual effect of each layer's mechanical properties on drug product quality are limited. Here, the formulation of a dual-release bilayer tablet containing sarpogrelate HCl was optimized with a placebo layer and quality by design (QbD) approach. The placebo layer was developed to replace the active pharmaceutical ingredient and its mechanical properties were evaluated. The formulation was developed using the placebo layer to quantitatively analyze the drug released from each layer. The mixture design and Monte Carlo simulation enabled robust design space identification. The mutual effect of each layer's mechanical properties on drug product quality was confirmed by multivariate analysis using the optimal settings in the design space. The optimized formulation was characterized by comparison with a reference drug for various quality attributes and in vivo pharmacokinetic parameters, which ensured the bioequivalence of the optimized bilayer tablet with the reference drug. This study shows that the integration of QbD and a placebo layer is an effective optimization strategy for dual-release bilayer tablets containing one drug in different layers.

Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach.

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in-line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

Hair Growth Stimulation Effect of Centipeda minima Extract: Identification of Active Compounds and Anagen-Activating Signaling Pathways.

Centipeda minima (L.) A. Braun & Asch is a well-studied plant in Chinese medicine that is used for the treatment of several diseases. A recent study has revealed the effects of extract of Cetipeda minima (CMX) standardized by brevilin A in inducing hair growth. However, the mechanism of action of CMX in human hair follicle dermal papilla cells (HFDPCs) has not yet been identified. We aimed to investigate the molecular basis underlying the effect of CMX on hair growth in HFDPCs. CMX induced the proliferation of HFDPCs, and the transcript-level expression of Wnt family member 5a (Wnt5a), frizzled receptor (FZDR), and vascular endothelial growth factor (VEGF) was upregulated. These results correlated with an increase in the expression of growth-related factors, such as VEGF and IGF-1. Immunoblotting and immunocytochemistry further revealed that the phosphorylation of ERK and JNK was enhanced by CMX in HFDPCs, and ß-catenin accumulated significantly in a dose-dependent manner. Therefore, CMX substantially induced the expression of Wnt signaling-related proteins, such as GSK phosphorylation and ß-catenin. This study supports the hypothesis that CMX promotes hair growth and secretion of growth factors via the Wnt/ß-catenin, ERK, and JNK signaling pathways. In addition, computational predictions of drug-likeness, together with ADME property predictions, revealed the satisfactory bioavailability score of CMX compounds, exhibiting high gastrointestinal absorption. We suggest that CMX could be used as a promising treatment for hair regeneration and minimization of hair loss.

Inhaled bosentan microparticles for the treatment of monocrotaline-induced pulmonary arterial hypertension in rats.

The conventional treatment of pulmonary arterial hypertension (PAH) with oral bosentan hydrate has limitations related to the lack of pulmonary selectivity. In this study, we verified the hypothesis of the feasibility of dry powder inhalation of bosentan as an alternative to oral bosentan hydrate for the treatment of PAH. Inhalable bosentan microparticles with the capability of delivery to the peripheral region of the lungs and enhanced bioavailability have been formulated for PAH. The bosentan microparticles were prepared by the co-spray-drying method with bosentan hydrate and mannitol at different weight ratios. The bosentan microparticles were then characterized for their physicochemical properties, in vitro dissolution behavior, and in vitro aerodynamic performance. The in vivo pharmacokinetics and pathological characteristics were evaluated in a monocrotaline-induced rat model of PAH after intratracheal powder administration of bosentan microparticles, in comparison to orally administered bosentan hydrate. The highest performance bosentan microparticles, named SDBM 1:1, had irregular and porous shape. These microparticles had not only the significantly highest aerosol performance (MMAD of 1.91 µm and FPF of 51.68%) in the formulations, but also significantly increased dissolution rate, compared with the raw bosentan hydrate. This treatment to the lungs was also safe, as evidenced by the cytotoxicity assay. Intratracheally administered SDBM 1:1 elicited a significantly higher Cmax and AUC0-t that were over 10 times higher, compared with those of the raw bosentan hydrate administered orally in the same dose. It also exhibited ameliorative effects on monocrotaline-induced pulmonary arterial remodeling, and right ventricular hypertrophy. The survival rate of the group administrated SDBM1:1 intratracheally was 0.92 at the end of study (Positive control and orally administrated groups were 0.58 and 0.38, respectively). In conclusion, SDBM 1:1 showed promising in vitro and in vivo results with the dry powder inhalation. The inhaled bosentan microparticles can be considered as a potential alternative to oral bosentan hydrate for the treatment of PAH.

Anti-obesity effect with reduced adverse effect of the co-administration of mini-tablets containing orlistat and mini-tablets containing xanthan gum: In vitro and in vivo evaluation.

The purpose of this study was to develop an oral dosage form of orlistat for the treatment of obesity with reduced adverse effects, for example, fatty and oily stool that have been reported to be associated with the mechanism of action of orlistat. Based on the in vitro results obtained in this study, xanthan gum was selected as an oil-entrapping agent. Thus, the co-administration of mini-tablets containing orlistat and mini-tablets containing xanthan gum was proposed as the optimized dosage form for orlistat. The prepared mini-tablets showed an equivalent drug release profile with a similarity factor value, f2, more than 50 to that of commercially marketed orlistat immediate-release capsules, Xenical® capsules. In addition, the optimized formulation also showed the in vivo anti-obesity effects similar to those of Xenical® capsules. In particular, the analysis of feces excreted by Sprague-Dawley rats revealed that the optimized formulation resulted in significantly less oily stool, steatorrhea, than Xenical® capsules (P < 0.05). Consequently, the proposed formulation, the co-administration of mini-tablets containing orlistat and mini-tablets containing xanthan gum, may be considered as a promising anti-obesity treatment with reduced adverse effects related to orlistat.

Preparation and characterization of metformin hydrochloride controlled-release tablet using fatty acid coated granules.

Metformin hydrochloride (MFM) is often used as a controlled-release (CR) tablet to reduce dosing frequency. However, the MFM CR tablet contains significant amounts of excipients and the tablet size is also large. Dosing convenience and patient compliance can be increased by reducing the size of the CR tablets. The aim of this study was to prepare and evaluate the MFM controlled-release tablet (MFM-CRT) using two types of release modulators, inner and outer. The MFM-CRT was prepared by coating the MFM granules using a binder solution containing aluminum stearate (ALS) as the inner release-modulator, and polyethylene oxide (PEO) as the outer release-modulator. The dispersion stability of the binder solution was optimized by the dispersion analyzer. The MFM-CRT was evaluated for dissolution rate and tablet volume. Additionally, dissolution behavior and dissolution kinetics of the MFM-CRT were analyzed using micro-computed tomography (micro-CT). Although the optimal MFM-CRT showed no difference in the release rate as compared to the commercially available product of Glucophage® XR 500 mg (f2 value: 72), the length of the long axis was reduced by 6 mm and the weight was reduced by about 27%. We expect patient compliance to improve because of effective sustained release and volume reduction of MFM-CRT.

Investigation of critical factors affecting mechanical characteristics of press-coated tablets using a compaction simulator.

Press-coated tablets have become an indispensable dosage form in chronotherapeutic drug delivery. Drug release from press-coated tablets has been extensively studied, yet there is little knowledge about their mechanical characteristics. This study aimed to systematically investigate the effects of critical factors on the structure, layer adhesion, and delamination tendency of the tablets. Material elasticity was found to play an important role in determining tablet structure in that excessive elastic mismatch between core and shell materials caused tablet defects during decompression and ejection. Unlike bilayer tablets, the overall strength of press-coated tablets was more affected by binding capacity of coating materials than by the core properties. Shell/core ratio was another factor affecting tablet integrity against external stresses. To mitigate the risk of delamination, poor layer adhesion must be compensated by increasing the coating thickness or enhanced by optimizing the formulation and process (e.g., core plasticity/brittleness, initial core solid fraction, and compression speed). X-ray micro-computed tomography revealed the presence of a shell-core gap and inhomogeneous density distribution within the tablet where the side coat appeared as the least dense and weakest region. These findings will enable the improvement of tablet quality and widen the application of press coating in industrial manufacturing.

Systematic approach to elucidate compaction behavior of acyclovir using a compaction simulator.

In this research, various approaches were attempted with a compaction simulator to investigate the unidentified compaction behavior of acyclovir, a model compound. Various indicators for the compaction behavior of acyclovir were obtained and compared with those of three commonly used excipients with relatively well-known compaction behavior. From two frequently used powder compaction models, the Heckel and Walker models, curvature of plot, yield stress, D0, SRS value, and W value were acquired. In addition, compression and elastic energies were obtained during the loading and unloading phases, respectively. The ratio of the two energies was also utilized. To characterize the mechanical properties of materials during bond formation, the radial tensile strength of powder compacts was measured. For all evaluations, the effects of compaction rate and lubrication were studied simultaneously. We found that primary particles of acyclovir were compacted mainly by plastic flow, with high viscoelasticity and low particle interactions. Their bond formation was highly sensitive to strain rate and lubrication. This study showed the potential application of a compaction simulator to elucidate the compaction behavior of a material of interest.

Development of novel bilayer gastroretentive tablets based on hydrophobic polymers.

This study aimed to develop a bilayer gastroretentive (GR) tablet containing an insoluble drug and ascertain the potential of using hydrophobic polymers in GR matrix systems. Highly porous tablets were prepared using a camphor-based sublimation technique. After the screening of several commonly used polymers, two types of GR layers, a conventional hydrophilic GR layer and a hydrophobic GR layer, were designed. The optimal drug layer comprising Metolose® 90SH-100SR and dicalcium phosphate provided not only a gradual matrix erosion but also high strength after hydration. Regarding the GR layers, the hydrophobic layer based on Kollidon® SR was superior to the hydrophilic layer made of PEO 7 M in terms of wet strength, implying a higher resistance to mechanical stresses upon water absorption. Also, the excellent tableting properties of Kollidon® SR and the effects of curing in improving its matrix hardness resulted in porous tablets with better mechanical strength. Moreover, good flowability and low cohesion of Kollidon® SR formulation were advantageous in direct compression. In conclusion, novel bilayer GR tablets were successfully developed, indicating the potential for widening the application of GR systems to insoluble drugs. The results also suggested numerous advantages of incorporating Kollidon® SR into the production of GR tablets.

Swellable and porous bilayer tablet for gastroretentive drug delivery: Preparation and in vitro-in vivo evaluation.

The purpose of this study was to develop a novel gastroretentive drug delivery system with immediate buoyancy and high wet strength. The proposed bilayer tablet was composed of a drug layer and a highly porous and swellable gastroretentive (GR) layer. The highly porous GR layer was prepared by sublimating the volatile materials after compaction with swellable polymers. This pore-forming process decreased the density of the GR layer and enabled the tablet to float immediately on the dissolution media. The GR layer formulation was optimized by comparing the swelling, erosion, and mechanical properties of candidate swellable polymers. The release rates were conveniently controlled by changing the polymer content in the drug layer, while the swelling and floating properties were provided by the GR layer. The application of percolation theory revealed that the polymer content above the estimated threshold was required for a reliable drug release profile. In vivo study in fed beagle dogs confirmed the enhanced gastric retention time of the tablets compared to that of conventional single layer tablets. Taken together, our data suggest that the proposed system can be a promising platform technology with superior GR properties and a convenient formulation process.

Physicochemical properties and drug-release mechanisms of dual-release bilayer tablet containing mirabegron and fesoterodine fumarate.

Introduction: In this study, a dual release bi-layer tablet containing Fesoterodine fumarate (Fst) 5 mg and Mirabegron (Mrb) 50 mg was prepared to investigate the different release behavior of each drug in bilayer tablet. The bilayer tablet was prepared based on monolayer-tablet formulation of each drug. Methods: The optimized bi-layer tablet showed an in vitro dissolution profile similar to commercial reference tablets Toviaz and Betmiga, based on a satisfactory similarity factor. Drug-release kinetics of each drug in the bilayer tablet were evaluated based on dissolution profiles. Drug-release behavior was evaluated by observing the surface of each layer by scanning electron microscopy and measuring the changes in weight and volume of the tablet during dissolution. Drug transfer between each layer was also investigated by Fourier -transform infrared spectroscopic imaging by observing the cross-section of the bilayer tablet cut vertically during dissolution. Results: The release of Fst was well suited for the Higuchi model, and the release of Mrb was well suited for the Hixson-crowell model. Compared with dissolution rate of each monolayer tablet, that of Fst in the bilayer tablet was slightly reduced (5%), but the dissolution rate of Mrb in bilayer tablet was dramatically decreased (20%). Also, a drug-release study confirmed that polymer swelling was dominant in Fst layer compared with polymer erosion, and degradation was dominant in MRB layer. Fourier-transform infrared imaging and 3-D image reconstruction showed that drug transfer in the bilayer tablet correlates with the results of drug-release behavior. Conclusion: These findings are expected to provide scientific insights in the development of a dual-release bilayer drug-delivery system for Fst and Mrb.

Preparation, Characterization, and Stability Evaluation of Taste-Masking Lacosamide Microparticles.

Lacosamide (LCM) is a third-generation antiepileptic drug. Selective action of the drug on voltage-gated sodium channels reduces side effects. Oral administration of LCM shows good pharmacokinetic profile. However, the bitter taste of LCM is a barrier to the development of oral formulations. In this study, we aimed to prepare encapsulated LCM microparticles (MPs) for masking its bitter taste. Encapsulated LCM MPs were prepared with Eudragit® E100 (E100), a pH-dependent polymer, by spray drying. Three formulations comprising different ratios of LCM and E100 (3:1, 1:1, and 1:3) were prepared. Physicochemical tests showed that LCM was in an amorphous state in the prepared formulations, and they were not miscible. LCM-E100 (1:3) had a rough surface due to surface enrichment of LCM. Increased E100 ratio in LCM-E100 MPs resulted in better taste-making effectiveness: LCM-E100 (1:1) and LCM-E100 (1:3) showed good taste-masking effectiveness, while LCM-E100 (3:1) could not mask the bitter taste of LCM. Dissolution results of the prepared formulations showed good correlation with taste-masking effectiveness. Nevertheless, high E100 ratio reduced the stability of the prepared formulations. Especially the difference in initial dissolution profile observed for LCM-E100 (1:3) indicated rapid reduction in taste-masking effectiveness and surface recrystallization. Therefore, LCM-E100 formulation in the ratio of 1:1 was selected as the best formulation with good taste-masking effectiveness and stability.

Use of roller compaction and fines recycling process in the preparation of erlotinib hydrochloride tablets.

This study focuses on improving the manufacturing process for a generic immediate-release tablet containing erlotinib hydrochloride by adding a fines recycling process during roller compaction. Due to the large fraction of small-sized API particles, the starting powder mixture was inconsistently fed into the roller compactor. Consequently, poorly flowing granules with a high ratio of fines were produced. A fines recycling step was, therefore, added to the existing roller compaction process to minimize the risks caused by the poor granule flow. A laboratory scale roller compactor and a tablet simulator were used to prepare granules at various process conditions. The effect of dry granulation parameters on size distribution, API distribution, powder flow, compaction properties, and dissolution profile was evaluated. The granule batch after fines recycling had markedly improved size distribution and flowability while maintaining acceptable tablet tensile strength and rapid dissolution profile. The application of the fines recycling process at commercial scale resulted in reliable dissolution performance and batch-to-batch consistency, which were further confirmed by bioequivalence to the reference product. Understanding how granule properties are impacted by the fines recycling process may enable fine-tuning of the dry granulation process for optimal product quality.

Mid-term follow-up results of calcaneal reconstruction for calcaneal malunion.

BACKGROUND: We hypothesized that calcaneal reconstruction can relieve chronic pain due to calcaneal malunion. We report the mid-term follow-up results of calcaneal reconstruction for calcaneal malunion. METHODS: We reviewed the records of 10 male patients (10 ft) who underwent calcaneal reconstruction for calcaneal malunion between January 2009 and July 2014 at the mid-term follow-up. Talocalcaneal height and angle, calcaneal pitch, calcaneal width, Böhler angle, Stephens classification, and Zwipp classification were evaluated by three orthopedic doctors at each visit (pre-reconstruction, post-reconstruction, and at the last follow-up). RESULTS: The mean follow-up period was 67.1 months (range, 48-101 months). The sites of pain before reconstruction were lateral aspect (4 patients), plantar aspect (3 patients), diffuse pain (2 patients), and anterior aspect (1 patient). There was a significant difference in talocalcaneal height, talocalcaneal angle, calcaneal pitch, calcaneal width, and Böhler angle before and after reconstruction (p < 0.05). There was no significant difference between reconstruction and the last follow-up. Radiological measurement agreement was calculated to be moderate to strong (intraclass correlation coefficient: 0.659-0.988). Mean American Orthopedic Foot & Ankle Society Ankle and Hindfoot score improved from 66.50 ± 9.37 pre-reconstruction to 80.30 ± 8.52 at the last follow-up (p < 0.05). The mean visual analog scale score improved from 8.60 ± 1.43 before reconstruction to 3.40 ± 0.84 at the last follow-up (p < 0.05). Most patients were satisfied with the outcome postoperatively. CONCLUSIONS: Our results showed substantial improvement in the clinical and radiological outcomes after calcaneal reconstruction of calcaneal malunion. This outcome was maintained until the mid-term follow-up. Therefore, calcaneal reconstruction may be a good option for the treatment of chronic pain caused by the malunion of a calcaneal fracture without severe subtalar arthritis. Further prospective studies are needed to test this theory. LEVEL OF EVIDENCE: Level IV, Retrospective Case Series.

Formulation and evaluation of carrier-free dry powder inhaler containing sildenafil.

Pulmonary delivery of sildenafil for the treatment of pulmonary arterial hypertension could overcome the limitations of intravenous and oral administration routes, such as poor patient compliance and systemic side effects. In this study, a carrier-free dry powder inhaler (DPI) formulation was developed, using spray drying technique and L-leucine as a dispersibility enhancer. Sildenafil citrate salt and sildenafil free base were evaluated for drug transport using a Calu-3 cell model, and their suitability for DPI production by spray drying was tested. Characteristics of the resultant carrier-free DPI powders were examined, namely crystallinity, morphology, size distribution, density, zeta potential, and aerodynamic performance. A Box-Behnken design was adopted to optimize the formulation and process conditions, including leucine amount, fraction of methanol in spraying solvent, and inlet temperature. While both sildenafil forms exhibited sufficient permeability for lung absorption, only sildenafil base resulted in DPI powders which were stable for 6 months. The introduction of leucine into the formulations effectively enhanced aerodynamic performance of the powders and particles with favorable size, shape, and density were produced. The optimal DPI formulation determined from experimental design possesses excellent aerodynamic performance with 89.39% emitted dose and 80.08% fine particle fraction, indicating the possibility of incorporating sildenafil into carrier-free DPIs for pulmonary delivery.