Effect of Cimetidine on Metformin Pharmacokinetics and Endogenous Metabolite Levels in Rats.

Tubular secretion is a primary mechanism along with glomerular filtration for renal elimination of drugs and toxicants into urine. Organic cation transporters (OCTs) and multidrug and toxic extrusion (MATE) transporters facilitate the active secretion of cationic substrates, including drugs such as metformin and endogenous cations. We hypothesized that administration of cimetidine, an Oct/Mate inhibitor, will result in increased plasma levels and decreased renal clearance of metformin and endogenous Oct/Mate substrates in rats. A paired rat pharmacokinetic study was carried out in which metformin (5 mg/kg, intravenous) was administered as an exogenous substrate of Oct/Mate transporters to six Sprague-Dawley rats with and without cimetidine (100 mg/kg, intraperitoneal). When co-administered with cimetidine, metformin area under the curve increased significantly by 3.2-fold, and its renal clearance reduced significantly by 73%. Untargeted metabolomics was performed to investigate the effect of cimetidine on endogenous metabolome in the blood and urine samples. Over 8,000 features (metabolites) were detected in the blood, which were shortlisted using optimized criteria, i.e., a significant increase (P value < 0.05) in metabolite peak intensity in the cimetidine-treated group, reproducible retention time, and quality of chromatogram peak. The metabolite hits were classified into three groups that can potentially distinguish inhibition of i) extra-renal uptake transport or catabolism, ii) renal Octs, and iii) renal efflux transporters or metabolite formation. The metabolomics approach identified novel putative endogenous substrates of cationic transporters that could be tested as potential biomarkers to predict Oct/Mate transporter mediated drug-drug interactions in the preclinical stages. SIGNIFICANCE STATEMENT: Endogenous substrates of renal transporters in animal models could be used as potential biomarkers to predict renal drug-drug interactions in early drug development. Here we demonstrated that cimetidine, an inhibitor of organic cation transporters (Oct/Mate), could alter the pharmacokinetics of metformin and endogenous cationic substrates in rats. Several putative endogenous metabolites of Oct/Mate transporters were identified using metabolomics approach, which could be tested as potential transporter biomarkers to predict renal drug-drug interaction of Oct/Mate substrates.

Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.

PURPOSE: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations. METHODS: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations. RESULTS: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively. CONCLUSION: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.

Online monitoring of epithelial barrier kinetics and cell detachment during cisplatin-induced toxicity of renal proximal tubule cells.

Real-time and non-invasive assessment of tissue health is crucial for maximizing the potential of microphysiological systems (MPS) for drug-induced nephrotoxicity screening. Although impedance has been widely considered as a measure of the barrier function, it has not been incorporated to detect cell detachment in MPS with top and bottom microfluidic channels separated by a porous membrane. During cell delamination from the porous membrane, the resistance between both channels decreases, while capacitance increases, allowing the detection of such detachment. Previously reported concepts have solely attributed the decrease in the resistance to the distortion of the barrier function, ignoring the resistance and capacitance changes due to cell detachment. Here, we report a two-channel MPS with integrated indium tin oxide (ITO) electrodes capable of measuring impedance in real time. The trans-epithelial electrical resistance (TEER) and tissue reactance (capacitance) were extracted from the impedance profiles. We attributed the anomalous initial increase observed in TEER, upon cisplatin administration, to the distortion of tight junctions. Cell detachment was captured by sudden jumps in capacitance. TEER profiles illuminated the effects of cisplatin and cimetidine treatments in a dose-dependent and polarity-dependent manner. The correspondence between TEER and barrier function was validated for a continuous tissue using the capacitance profiles. These results demonstrate that capacitance can be used as a real-time and non-invasive indicator of confluence and will support the accuracy of the drug-induced cytotoxicity assessed by TEER profiles in the two-channel MPS for the barrier function of a cell monolayer.

Cimetidine repurposed as a potential immunomodulatory agent against colorectal carcinoma: A systematic review.

OBJECTIVE: To determine the survival benefit and immunomodulatory effects of cimetidine pre-, peri- or post-operatively in patients with colorectal cancer (CRC). METHODS: A systematic review was conducted using PubMed and Cochrane Library to retrieve randomized control trials (RCTs) that investigated the effects of cimetidine on survival and immunomodulation via improvement in tumor infiltrating lymphocytes (TILs) and peripheral blood lymphocytes. The review was carried out in accordance with the extended Preferred Reporting Items for Systematic Reviews and Meta-analyses. RESULTS: Four studies with the total of 267 patients were included in this systematic review. Treatment duration varied from 5 days to 1 year. Two studies reported a significant TIL response in the resected specimens after administering cimetidine, while one RCT showed an escalation of CD3, CD4 and CD57 lymphocytes in peripheral blood compared to the baseline following cimetidine treatment (p < 0.01). Of the three trials that examined the effects of cimetidine on survival, only two studies revealed significant survival benefit while the remaining study only showed a trend towards survival benefit. CONCLUSION: Repurposing of existing drugs like cimetidine has a potential to offer a survival benefit by acting as an immunomodulatory agent in patients undergoing curative resection for CRC. However, the heterogeneity seen in current studies and the evolvement of adjunctive therapies for CRC warrant large-scale, well-designed prospective RCTs to establish the efficacy of cimetidine in CRC.

Incidence of dislocation and associated risk factors in patients with a femoral neck fracture operated with an uncemented hemiarthroplasty.

BACKGROUND: Several factors might be associated with risk of dislocating following uncemented hemiarthroplasty (HA) due to femoral neck fracture (FNF). Current evidence is limited with great variance in reported incidence of dislocation (1-15%). Aim of this study was to identify the cumulative incidence of first-time dislocation following HA and to identify the associated risk factors. METHOD: We performed a retrospective cohort study of patients receiving an HA (BFX Biomet stem, posterior approach) at Copenhagen University Hospital, Bispebjerg, in 2010-2016. Patients were followed until death or end of study (dec 2018). Dislocation was identified by code extraction from the Danish National Patient Registry. Variables included in the multivariate model were defined pre-analysis to include: age, sex and variables with a p-value < 0.1 in univariate analysis. A regression model was fitted for 90 days dislocation as the assumption of proportional hazard rate (HR) was not met here after. RESULTS: We identified 772 stems (some patients occurred with both right and left hip) and 58 stems suffered 90 dislocations during the observation period, resulting in a 7% (CI 5-9) incidence of dislocation 90 days after index surgery. 55 of the 58 stems (95%) experienced the first dislocation within 90 days after surgery. Only absence of dementia was identified as an independent protective factor in the cause-specific model (HR 0.46 (CI 0.23-0.89)) resulting in a 2.4-fold cumulative risk of experiencing a dislocation in case of dementia. Several other variables such as age, sex, various medical conditions, surgery delay and surgical experience were eliminated as statistical risk factors. We found a decrease in survival probability for patients who experienced a dislocation during follow-up. CONCLUSIONS: The incidence of first-time dislocation of HA (BFX Biomet stem, posterior approach) in patients with a hip fracture is found to be 7% 90 days after surgery. Due to the non-existing attribution bias, we claim it to be the true incidence. Dementia was among several variables identified as the only risk factor for dislocation. In perspective, we may consider treating patients with dementia by other methods than HA e.g., HA with cement or with a more constrained solution. Also, a surgical approach that reduce the risk of dislocation should be considered.

Cimetidine for recurrent respiratory papillomatosis in pregnancy as an alternative adjuvant treatment.

BACKGROUND: We report the first case of cimetidine as an alternative adjuvant therapy in a pregnant woman with recurrent respiratory papillomatosis (RRP). A 40 year old woman at 19 week gestation presented with progressive hoarseness and shortness of breath for 1 month. Flexible nasopharyngolaryngoscopy revealed multiple papillomatous lesions over both vocal cords and subglottic area obstructing 60% of her airway. She had previously been diagnosed with juvenile onset RRP at the age of 5 and underwent endoscopic clearance regularly every 6 months. METHOD: The patient was started on a trial of oral cimetidine at a dose of 30 mg/kg and responded well, eventually requiring endoscopic excision only after 2 years. Subsequently, she underwent in vitro fertilisation treatment and stopped taking her cimetidine. After undergoing endoscopic clearance of her papillomata under general anaesthesia, she restarted on cimetidine during her 2nd and 3rd trimester. RESULTS: Ensuing follow-up demonstrated stable minimal papillomata lesions on her right inferior surface of her vocal cord with no recurrence on her left vocal cord and subglottic area. CONCLUSION: Cimetidine is generally safe and not known to be associated with any major teratogenic risks during pregnancy. RRP is postulated to worsen in pregnant women due to the increase in oestrogen levels during pregnancy. Hence, adjuvant therapy was imperative for our patient to reduce recurrent papillomata formation during her pregnancy. Larger scale studies are warranted to assess the use of long-term high-dose cimetidine in terms of efficacy and safety in pregnancy.

Positron Emission Tomography-Based Pharmacokinetic Analysis To Assess Renal Transporter-Mediated Drug-Drug Interactions of Antimicrobial Drugs.

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [18F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [18F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CLrenal) of [18F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CLrenal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [18F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [18F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.

P19-derived neuronal cells express H1, H2, and H3 histamine receptors: a biopharmaceutical approach to evaluate antihistamine agents.

Histamine is a biogenic amine implicated in various biological and pathological processes. Convenient cellular models are needed to screen and develop new antihistamine agents. This report aimed to characterize the response of neurons differentiated from mouse P19 embryonal carcinoma cells to histamine treatment, and to investigate the modulation of this response by antihistamine drugs, vegetal diamine oxidase, and catalase. The exposure of P19 neurons to histamine reduced cell viability to 65% maximally. This effect involves specific histamine receptors, since it was prevented by treatment with desloratadine and cimetidine, respectively, H1 and H2 antagonists, but not by the H3 antagonist ciproxifan. RT-PCR analysis showed that P19 neurons express H1 and H2 receptors, and the H3 receptor, although it seemed not involved in the histamine effect on these cells. The H4 receptor was not expressed. H1 and H2 antagonists as well as vegetal diamine oxidase diminished the intracellular Ca2+ mobilization triggered by histamine. The treatment with vegetal diamine oxidase or catalase protected against mortality and a significant reduction of H2O2 level, generated from the cells under the histamine action, was found upon treatments with desloratadine, cimetidine, vegetal diamine oxidase, or catalase. Overall, the results indicate the expression of functional histamine receptors and open the possibility of using P19 neurons as model system to study the roles of histamine and related drugs in neuronal pathogenesis. This model is less expensive to operate and can be easily implemented by current laboratories of analysis and by Contract Research Organizations.

Analysis of Cimetidine Crystal Polymorphs by X-ray Absorption Near-Edge Spectroscopy.

Sulfur K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of the active pharmaceutical ingredients (APIs) containing sulfur atoms. Cimetidine (CIM) was used as a model API. Each crystal form of CIM has its own XANES spectrum, so we can discriminate the crystal form by its spectrum. The analysis of the crystal structure of CIM revealed that the difference in the shape of XANES spectra was ascribable to the difference in the C-S-C bond angle of CIM molecules and the intermolecular hydrogen bonds, such as C-H···S and N-H···S, and S-S interaction. It was found that the peak shape of the XANES spectrum is gentle when the C-S-C bond angle is large, while the peak shape can be steep when the C-S-C bond angle is small. Furthermore, it was found that the peak energy values varied depending on the hydrogen bonds and S-S interaction. By linear combination fitting using XANES spectra, it was possible to quantify the ratio of CIM form A crystal in mixed powders of form A and monohydrate crystals. These results indicate that XANES measurements can be a useful technique to evaluate the crystal polymorphism of APIs containing S atom in pharmaceutical formulation.

TNFα-dependent mTOR activity is required for tenotomy-induced ectopic ossification in mice.

INTRODUCTION: Ectopic ossifications often occur in skeletal muscles or tendons following local trauma or internal hemorrhage, and occasionally cause severe pain that limits activities of daily living. However, mechanisms underlying their development remain unknown. MATERIALS AND METHODS: The right Achilles tendon in 8-week-old female or male mice was dissected. Some mice were injected intraperitoneally either with phosphate-buffered saline, dimethyl sulfoxide, cimetidine, rapamycin, celecoxib or loxoprofen for 10 weeks. One week after surgery, immunohistochemical analysis was performed for mTOR, TNFα or F4/80. Ten weeks after surgery, ectopic ossification at the tenotomy site was detected by 3D micro-CT. RESULTS: Ectopic ossification was seen at dissection sites in all wild-type mice by dissection of the Achilles tendon. mTOR activation was detected at dissection sites, and development of ectopic ossification was significantly inhibited by administration of rapamycin, an mTOR inhibitor, to wild-type mice. Moreover, administration of the histamine 2 blocker cimetidine, which reportedly inhibits ectopic ossification in tendons, was not effective in inhibiting ectopic ossification in our models. TNFα-expressing F4/80-positive macrophages accumulate at dissection sites and that ectopic ossification of the Achilles tendon dissection was significantly inhibited in TNFα-deficient mice in vivo. Ectopic ossification is significantly inhibited by administration of either celecoxib or loxoprofen, both anti-inflammatory agents, in wild-type mice. mTOR activation by Achilles tendon tenotomy is inhibited in TNFα-deficient mice. CONCLUSION: The TNFα-mTOR axis could be targeted therapeutically to prevent trauma-induced ectopic ossification in tendons.

Renal tubular transporter-mediated interactions between mirogabalin and cimetidine in rats.

Cimetidine at a clinical dosage decreased the renal clearance (CLr) of mirogabalin in humans by inhibition of renal secretion. Mirogabalin is a substrate of human OAT1/3, OCT2, MATE1 and/or MATE2-K. To clarify the mechanism behind the above interaction, it was investigated whether cimetidine inhibits the process of mirogabalin uptake at the basolateral side or the process of its efflux at the apical side in rat kidney in vivo.Cimetidine was administered to rats by a constant infusion to achieve an unbound plasma concentration of 7.0 µM and examine its effect on the renal disposition of [14C]metformin, [3H]p-aminohippuric acid (PAH), and [14C]mirogabalin.Cimetidine significantly induced the intrarenal accumulation of radioactivity (Kp, kidney) and decreased the renal clearance (CLr) of [14C]mirogabalin. These effects resulted in significantly decreased total clearance (CLt). Kp, kidney, and CLr of [14C]metformin, except CLt, were also affected, but no parameters of [3H]PAH were affected by cimetidine.These findings clarified that an unbound plasma concentration of cimetidine of 7.0 µM inhibited the apical efflux not the basolateral uptake of [14C]mirogabalin in rat kidney, suggesting that mirogabalin/cimetidine interaction was caused by inhibiting the apical efflux transporter, human MATE1 and/or MATE2-K, not the basolateral uptake transporter, human OCT2, in the kidney.

The Clinical Application and Progress of Mirogabalin on Neuropathic Pain as a Novel Selective Gabapentinoids.

Background: Neuropathic pain is a complex sort of pain that is detrimental to individuals' health, both physically and mentally, but merely a small portion of them could witness pain alleviation. Mirogabalin, by distinctive binding characteristics of voltage-gated calcium channels, has won approval from the Japanese authority as a third member of gabapentinoids in Japan. Our review was aimed at encompassing the bulk of clinical research on mirogabalin, which included clinical trials, special considerations, coadministration studies, case reports, and cost-effectiveness studies. Methods: A review was carried out on a series of platforms, such as PubMed, MEDLINE, and Scopus, up to December 2021 using the keywords as follows: "mirogabalin OR mirogabalin besylate OR Tarlige OR DS-5565" AND "neuropathic pain OR Neuropathy." Results: Mirogabalin demonstrated analgesic activity and manageable adverse reactions and provides a new alternative for individuals with PHN or DPNP in 3 phase II and 4 III trials. Mirogabalin alleviated pain markedly in comparison with placebo. Administration of mirogabalin on a long-term basis is a flexible dosage regimen for patients with PHN. It is noteworthy that mirogabalin should be administrated cautiously when combined with probenecid and cimetidine on account of a slight increase in pharmacodynamics effects of mirogabalin. Conclusion: The development of mirogabalin allows further optimization of individual treatment strategies so as to provide more therapeutic choices in this medical domain.

Influence of Topography and Composition of Commercial Titanium Dental Implants on Cell Adhesion of Human Gingiva-Derived Mesenchymal Stem Cells: An In Vitro Study.

The topography and composition of dental implant surfaces directly impact mesenchymal cell adhesion, proliferation, and differentiation, crucial aspects of achieving osseointegration. However, cell adhesion to biomaterials is considered a key step that drives cell proliferation and differentiation. The aim of this study was to characterize characterize the topography and composition of commercial titanium dental implants manufactured with different surface treatments (two sandblasted/acid-etched (SLA) (INNO Implants, Busan, Republic of Korea; BioHorizonsTM, Oceanside, CA, USA) and two calcium phosphate (CaP) treated (Biounite®, Berazategui, Argentina; Zimmer Biomet, Inc., Warsaw, IN, USA)) and to investigate their influence on the process of cell adhesion in vitro. A smooth surface implant (Zimmer Biomet, Inc.) was used as a control. For that, high-resolution methodologies such as scanning electron microscopy (SEM), X-ray dispersive spectroscopy (EDX), laser scanning confocal microscopy (LSCM), and atomic force microscopy (AFM) were employed. Protein adsorption and retromolar gingival mesenchymal stem cells (GMSCs) adhesion to the implant surfaces were evaluated after 48 h. The adherent cells were examined by SEM and LSCM for morphologic and quantitative analyses. ANOVA and Tukey tests (α = 0.05) were employed to determine statistical significance. SEM revealed that INNO, BioHorizonsTM, and Zimmer implants have an irregular surface, whereas Biounite® has a regular topography consisting of an ordered pattern. EDX confirmed a calcium and phosphate layer on the Biounite® and Zimmer surfaces, and AFM exhibited different roughness parameters. Protein adsorption and cell adhesion were detected on all the implant surfaces studied. However, the Biounite® implant with CaP and regular topography showed the highest protein adsorption capacity and density of adherent GMSCs. Although the Zimmer implant also had a CaP treatment, protein and cell adhesion levels were lower than those observed with Biounite®. Our findings indicated that the surface regularity of the implants is a more determinant factor in the cell adhesion process than the CaP treatment. A regular, nanostructured, hydrophilic, and moderately rough topography generates a higher protein adsorption capacity and thus promotes more efficient cell adhesion.

The Use of a Coded Healing Abutment in the Restoration of a Single, Immediately Placed Implant in the Esthetic Zone: A Clinical Case Report.

For several years, the implant-level impression procedure started by removal of the healing abutment, followed by connection of the impression coping to the implant. Encode Complete (Encode, Biomet 3i, Biomet 3i, Palm Beach Gardens, FL) was introduced to eliminate implant-level impressions by offering a healing abutment-level impression protocol. This report illustrated the treatment of a single tooth in the anterior esthetic zone using Encode Complete. A 23-year-old female patient reported to the prosthodontics clinic complaining of a fractured maxillary anterior tooth that was deemed nonrestorable. After immediate implant placement, soft tissue preservation and temporization of the implant, healing abutment level impression was made. The codes embedded on the occlusal surface communicated the implant depth, hex-orientation, platform diameter, and interface. The definitive Encode gold-plated titanium abutment was anatomically designed virtually with customized margin, contour, taper, and emergence profile. The milling process was initiated, and the virtual design data were sent to the Robocast Center for analog placement in the original Encode master cast. The definitive abutment was placed on the master cast using Robocast technology, followed by the fabrication of the final porcelain fused to zirconia cement-retained all ceramic crown. The abutment was secured to the implant with a Gold-Tite abutment screw, followed by the final cement-retained implant crown placement. Recall visits were obtained at 1 week, 1 month, 3 months, and 1 year after final prosthesis insertion.

Comparative outcomes between a new robotically assisted and a manual technique for total knee arthroplasty in patients with osteoarthritis: a prospective matched comparative cohort study.

PURPOSE: Studies comparing clinical outcomes between manual (mTKA) and robotic-assisted TKA (raTKA) are limited. This prospective comparative cohort study aimed to compare early postoperative outcomes, satisfaction, and patient-reported outcome measures (PROMS) between patients undergoing mTKA and ROSA raTKA (Zimmer Biomet, Warsaw, IN) performed by one surgeon. METHODS: Thirty ROSA raTKAs and 30 mTKAs performed by one surgeon during 2020-2021 were prospectively evaluated. Groups were matched for age, sex, and body mass index. All procedures were primary unilateral TKAs using the same posterior-stabilized prosthesis (Nexgen Legacy, Zimmer Biomet, Warsaw, IN). Length of hospital stay (LOS) and blood transfusion rate were recorded. Complications, visual analogue scale score (VAS), and Oxford Knee Score (OKS) were assessed preoperatively and for six postoperative months. The Forgotten Joint Score (FJS) and patient satisfaction were evaluated 6 months postoperatively. RESULTS: No complications and similar blood transfusion rate were recorded between groups (p = 0.228). The LOS was non-significantly shorter in raTKA than in the mTKA group (p = 0.120). Mean preoperative and third-month OKS and VAS scores were comparable between groups. However, the mean 6-month OKS (p = 0.006) and VAS score (p = 0.025) were significantly better for the raTKA group. The 6-month FJS was significantly greater for raTKA than the mTKA group (p < 0.001). One patient was unhappy in raTKA, and three in the mTKA group (p = 0.301). Significantly more raTKA patients answered that they would undergo surgery again (p = 0.038). CONCLUSION: raTKA was associated with the same complication risk, less pain level, better patient satisfaction, and PROMs on 6-month follow-up than the mTKA group.

Low-Frequency Raman Spectroscopy as an Avenue to Determine the Transition Temperature of ß- and γ-Relaxation in Pharmaceutical Glasses.

In an earlier investigation, low-frequency Raman (LFR) spectroscopy was shown to detect the transition temperature of the ß-relaxation (Tß) in both amorphous celecoxib and various celecoxib amorphous solid dispersions [Be̅rzins, K. Mol. Pharmaceutics 2021, 18(10), 3882-3893]. In this study, we further investigated the application of this technique to determine Tß, an important parameter for estimating crystallization potency of amorphous drugs. Alongside commercially available amorphous drugs (zafirlukast and valsartan disodium salt), differently melt-quenched samples of cimetidine were also analyzed. Overall, the variable-temperature LFR measurements allowed for an easy access to the desired information, including the even lesser transition of the tertiary relaxation motions (Tγ). Thus, the obtained results not only highlighted the sensitivity, but also the practical usefulness of this technique to elucidate (subtle) changes in molecular dynamics within amorphous pharmaceutical systems.

Pigmented Villonodular Synovitis of the Temporomandibular Joint: Case Report and Literature Review.

Pigmented villonodular synovitis is a benign soft-tissue lesion that can affect the synovium of joint spaces, bursae, or tendon sheaths. It is a rare condition and even rarer when it originates in the temporomandibular joint. The purpose of this study is to review the literature and report an additional case of pigmented villonodular synovitis arising from the temporomandibular joint and describe the surgical approach involving a Zimmer Biomet custom-fitted total joint prosthesis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome: Clinical characteristics and treatment outcomes - a single center study in Japan.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease occurring in children. Although PFAPA is the most common periodic fever syndrome found in children, there are only a few studies defining the clinical characteristics and the efficacy of treatment strategies among Japanese children. This study aimed to clarify the demographic characteristics and clinical features of patients with PFAPA syndrome and to evaluate treatment efficacy. METHODS: We retrospectively reviewed the clinical features of children with PFAPA who visited Saitama Children's Medical Center between January and December 2019. We also evaluated treatment strategies and their efficacy; abortive treatment with corticosteroids, prophylaxis with cimetidine or colchicine, and surgical management with tonsillectomy. RESULTS: A total of 100 Japanese children (61% male) with PFAPA were included. Median age of onset was 3 years, median duration of fever episodes was 5 days, and median interval between episodes was 4 weeks. The symptoms (frequencies) were pharyngitis (89%), exudate on tonsils (71%), cervical adenitis (50%), and aphthous stomatitis (49%). Approximately 37% of patients took prednisolone for aborting fever attacks, showing a 100% response; 93% were treated with cimetidine, showing an 79.6% response, and 18% were treated with colchicine, showing a 66.7% response. Only one patient underwent tonsillectomy. CONCLUSIONS: Among Japanese children with PFAPA, 28% of them were ≥5 years with a male predominance. Pharyngitis is the most frequent symptom associated with fever. Cimetidine is suitable for initial therapy because of its safety and efficacy.

Recommendations for Defining and Reporting Adherence Measured by Biometric Monitoring Technologies: Systematic Review.

BACKGROUND: Suboptimal adherence to data collection procedures or a study intervention is often the cause of a failed clinical trial. Data from connected sensors, including wearables, referred to here as biometric monitoring technologies (BioMeTs), are capable of capturing adherence to both digital therapeutics and digital data collection procedures, thereby providing the opportunity to identify the determinants of adherence and thereafter, methods to maximize adherence. OBJECTIVE: We aim to describe the methods and definitions by which adherence has been captured and reported using BioMeTs in recent years. Identifying key gaps allowed us to make recommendations regarding minimum reporting requirements and consistency of definitions for BioMeT-based adherence data. METHODS: We conducted a systematic review of studies published between 2014 and 2019, which deployed a BioMeT outside the clinical or laboratory setting for which a quantitative, nonsurrogate, sensor-based measurement of adherence was reported. After systematically screening the manuscripts for eligibility, we extracted details regarding study design, participants, the BioMeT or BioMeTs used, and the definition and units of adherence. The primary definitions of adherence were categorized as a continuous variable based on duration (highest resolution), a continuous variable based on the number of measurements completed, or a categorical variable (lowest resolution). RESULTS: Our PubMed search terms identified 940 manuscripts; 100 (10.6%) met our eligibility criteria and contained descriptions of 110 BioMeTs. During literature screening, we found that 30% (53/177) of the studies that used a BioMeT outside of the clinical or laboratory setting failed to report a sensor-based, nonsurrogate, quantitative measurement of adherence. We identified 37 unique definitions of adherence reported for the 110 BioMeTs and observed that uniformity of adherence definitions was associated with the resolution of the data reported. When adherence was reported as a continuous time-based variable, the same definition of adherence was adopted for 92% (46/50) of the tools. However, when adherence data were simplified to a categorical variable, we observed 25 unique definitions of adherence reported for 37 tools. CONCLUSIONS: We recommend that quantitative, nonsurrogate, sensor-based adherence data be reported for all BioMeTs when feasible; a clear description of the sensor or sensors used to capture adherence data, the algorithm or algorithms that convert sample-level measurements to a metric of adherence, and the analytic validation data demonstrating that BioMeT-generated adherence is an accurate and reliable measurement of actual use be provided when available; and primary adherence data be reported as a continuous variable followed by categorical definitions if needed, and that the categories adopted are supported by clinical validation data and/or consistent with previous reports.

Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk.

Many mothers need to take some medications during breastfeeding, which may carry a risk to breastfed infants. Thus, determining the amount of a drug transferred into breast milk is critical for risk-benefit analysis of breastfeeding. Breast cancer resistance protein (BCRP), an efflux transporter which usually protects the body from environmental and dietary toxins, was reported to be highly expressed in lactating mammary glands. In this study, we developed a mechanistic lactation physiologically based pharmacokinetic (PBPK) modeling approach incorporating BCRP mediated transport kinetics to simulate the concentration-time profiles of five BCRP drug substrates (acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin) in nursing women's plasma and milk. Due to the lack of certain physiological parameters and scaling factors in nursing women, we combine the bottom up and top down PBPK modeling approaches together with literature reported data to optimize and determine a set of parameters that are applicable for all five drugs. The predictive performance of the PBPK models was assessed by comparing predicted pharmacokinetic profiles and the milk-to-plasma (M/P) ratio with clinically reported data. The predicted M/P ratios for acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin were 2.48, 3.70, 3.55, 1.21, and 5.78, which were all within 1.5-fold of the observed values. These PBPK models are useful to predict the PK profiles of those five drugs in the milk for different dosing regimens. Furthermore, the approach proposed in this study will be applicable to predict pharmacokinetics of other transporter substrates in the milk.