Interactive Associations between PPARγ and PPARGC1A and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case-control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01-9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69-0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.

Machine Learning Approaches for Predicting Bisphosphonate-Related Osteonecrosis in Women with Osteoporosis Using VEGFA Gene Polymorphisms.

OBJECTIVE: This nested case-control study aimed to investigate the effects of VEGFA polymorphisms on the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in women with osteoporosis. METHODS: Eleven single nucleotide polymorphisms (SNPs) of the VEGFA were assessed in a total of 125 patients. Logistic regression was performed for multivariable analysis. Machine learning algorithms, namely, fivefold cross-validated multivariate logistic regression, elastic net, random forest, and support vector machine, were developed to predict risk factors for BRONJ occurrence. Area under the receiver-operating curve (AUROC) analysis was conducted to assess clinical performance. RESULTS: The VEGFA rs881858 was significantly associated with BRONJ development. The odds of BRONJ development were 6.45 times (95% CI, 1.69-24.65) higher among carriers of the wild-type rs881858 allele compared with variant homozygote carriers after adjusting for covariates. Additionally, variant homozygote (GG) carriers of rs10434 had higher odds than those with wild-type allele (OR, 3.16). Age ≥ 65 years (OR, 16.05) and bisphosphonate exposure ≥ 36 months (OR, 3.67) were also significant risk factors for BRONJ occurrence. AUROC values were higher than 0.78 for all machine learning methods employed in this study. CONCLUSION: Our study showed that the BRONJ occurrence was associated with VEGFA polymorphisms in osteoporotic women.

Risk factors for neutropenia and febrile neutropenia following prophylactic pegfilgrastim.

AIM: Neutropenia is a common side effect of myelosuppressive chemotherapy. Administration of granulocyte colony-stimulating factor is being used for neutropenia prophylaxis, but there are patients who develop neutropenia or febrile neutropenia despite prophylaxis. We attempted to identify potential risk factors for chemotherapy-induced neutropenia in patients with pegfilgrastim prophylaxis. METHODS: This was a single-center, retrospective, observational study of patients with breast cancer or diffuse large B-cell lymphoma. We obtained patients' data from electronic medical records, including baseline demographics and clinical characteristics regarding diseases, treatments and laboratory values. The outcome measures assessed were the incidence of neutropenia and febrile neutropenia. RESULTS: There were a total of 127 patients, including 77 patients with diffuse large B-cell lymphoma (DLBCL) and 50 patients with breast cancer, and we analyzed 722 chemotherapy cycles. We found 88 cases (12.2%) of grade 3 or 4 neutropenia and 39 cases of febrile neutropenia (5.4%). In the univariate analysis, variables associated with both grade 3 or 4 neutropenia and febrile neutropenia were age, cancer type, cancer stage, radiotherapy and platelet count. A multivariate logistic regression model revealed that age, radiotherapy and platelet count were significant factors in severe neutropenia, whereas platelet count was the only statistically significant factor in febrile neutropenia. Platelet counts of less than 150 000/mm3 increased the risk of neutropenia and febrile neutropenia approximately fourfold. In the subgroup analysis of patients with DLBCL, it was found that platelet count was a significant factor for both neutropenia and febrile neutropenia. CONCLUSION: Among cancer patients with pegfilgrastim prophylaxis, advanced age, absence of radiation therapy and low platelet count were independent predictors of neutropenia, and low platelet count was the predictor of febrile neutropenia.

Application of monodirectional Janus patch to oromucosal delivery system.

Drug delivery through mucosae has received huge research attention owing to its advantageous characteristics such as accurate dose control and the avoidance of premature metabolism of vulnerable drugs by oral administration. However, body fluid in mucosae may dissolve the drug, releasing it to unwanted directions. Here, a Janus drug delivery patch with monodirectional diffusion property is devised to deliver drugs efficiently and to overcome the issue of unwanted drug release. A polyester fabric is coated with a hydrophobic polymer, poly(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-heptadecafluorodecyl methacrylate), via initiated chemical vapor deposition. Subsequently, hydrophilicity is rendered selectively on one surface by base-catalyzed hydrolysis to obtain a Janus substrate with both hydrophobic and hydrophilic surfaces. The hydrophilic surface of the Janus substrate is further coated with resveratrol-loaded hydrogel to produce a Janus drug delivery patch. The fabricated patch efficiently blocks fluid penetration from one side to the other in mucous environment. Delivery of resveratrol through hairless mouse skin and reconstructed human mucosae using Janus patch shows higher permeation flux compared to bare control patch. The Janus drug delivery patch shown in this study can be a useful tool for efficient transmucosal delivery of various kinds of drugs.

A cross-sectional study of factors related to gastrointestinal drug use in Korean adolescents.

Adolescence is critical in the habituation of diverse lifestyles and is a base for future physical well-being. Although gastrointestinal disorders are frequently reported in adolescents, studies related to GI drug use or related factors in Korean adolescents are rare. Thus, this study examined Korean adolescents for the use of GI drugs for abdominal symptoms and analyzed the associated factors. This cross-sectional study was done with a total of 2,416 students who completed a given questionnaire. The health-related questions included GI medication intake, smoking, alcohol, caffeine, regular exercise, self-cognitive health level, GI symptom, non-steroidal anti-inflammatory drugs (NSAIDs) intake, and sleep problems. In questions about GI medication intake, drugs included digestives and antacids. And the intake of GI drugs more than once during the past 1 month was regarded as taking GI drugs. The sociodemographic questions included age, gender, grade, number of close friends, extracurricular activities, and school performance. The overall prevalence for taking GI drugs, including antacids and digestives, was 17.4 %. When students taking GI drugs were compared with those not taking GI drugs, the former group showed higher rates of girls (P < 0.001) and participants in extracurricular activities (P < 0.05) than the latter group. Factors including alcohol, caffeine, self-cognitive health levels, and GI symptoms showed statistical significance with the rate of GI drug intake. The rate of GI drug intake in NSAID users was 2.7 times higher than that in non-users (P < 0.001). The prevalence rate of every sleep problem was higher in students taking GI medications except snoring, witnessed apnea, and teeth grinding. From the multiple regression, it was found that gender (female), extracurricular activities, alcohol intake, self-cognitive health levels, NSAIDs intake, and nightmares were related factors to GI drug intake. Based on the results, it was conclude that encouragement to build healthy lifestyle habits in adolescents is very important for their academic performances and health status in adulthood.

Comparison of budesonide and dexamethasone for local treatment of oral chronic graft-versus-host disease.

PURPOSE: The results of a prospective study of topical budesonide versus topical dexamethasone therapy for oral manifestations of chronic graft-versus-host disease (cGVHD) are presented. METHODS: In a prospective single-center investigation, a cohort of patients who developed oral symptoms of cGVHD after allogeneic stem cell transplantation were assigned to topical treatment with 0.03% budesonide rinse (group A, n = 26) or 0.01% dexamethasone rinse (group B, n = 24). Diagnosis of oral cGVHD symptoms, clinical staging, and treatment response scoring were performed at baseline and one month later according to current National Institutes of Health consensus criteria. RESULTS: At one-month follow-up, there was a significant decrease in the median oral cGVHD examination score in both groups (p < 0.001); the decrease in the median examination score was greater with budesonide versus dexamethasone therapy (2.5 points versus 1.0 point, p = 0.045). The rates of overall treatment response, including complete and partial responses, were 53.8% and 29.2% in groups A and B, respectively (p = 0.093). In addition, there was a significant decrease from baseline in the median self-rated oral pain severity score in group A (p < 0.001). CONCLUSION: Patients who received topical budesonide or dexamethasone rinse to treat oral manifestations of cGVHD had decreased cGVHD severity and pain scores after 30 days compared with baseline scores, though no statistical differences were seen between groups.

Pharmacokinetic characteristics of capsaicin-loaded nanoemulsions fabricated with alginate and chitosan.

Nanotechnologies are being employed to enhance the stability and oral bioavailability of lipophilic substances, such as capsaicin. This study aimed to examine the pharmacokinetic properties of the formulated capsaicin-loaded nanoemulsions. A pharmacokinetic study was carried out using double-layer nanoemulsions fabricated with alginate and chitosan polymers and triple-layer nanoemulsions fabricated with chitosan/alginate polymers. Capsaicin nanoemulsions and capsaicin control (oleoresin capsicum) were administered to the rat at a dose of 10 mg/kg. A statistically significant difference was found in the area under the curve from time zero to time infinity (AUCinf) among formulations (p < 0.01). In comparison to the control group, the relative bioavailability of formulated nanoemulsions was up to 131.7. The AUCinf increased in a nano-size-dependent manner; as nano size decreased, AUCinf increased. IN comparison to the double-layer nanoemulsions, the triple-layer nanoemulsion showed a significantly increased volume of distribution, resulting in the increased clearance and decreased AUCinf. It was concluded that the formulated nanoemulsions could significantly enhance the bioavailabilty of capsaicin.

The effects of terpenes on the permeation of lidocaine and ofloxacin from moisture-activated patches.

The effects of terpenes on the release and permeation of ofloxacin and lidocaine from moisture-activated composite patches were investigated. Ofloxacin without enhancers showed very low permeation rate (0.58 microg/cm(2)/hr), and the addition of cineole enhanced the permeation flux 14.1-times; /-menthol and d-limonene increased it 4.7- and 3.5-times, respectively. The highest permeation flux (77.7 +/- 25.3 microg/cm(2)/hr) of lidocaine from the composite patches was also achieved when cineole at the concentration of 0.33% in the gel base was added. /-Menthol also revealed enhancing effect on the permeation of lidocaine; however, d-limonene failed to increase the permeation rate of lidocaine. In conclusion, for effective moisture- activated patches containing lidocaine and ofloxacin, cineole could be used as an effective and safe enhancer.

Liposome composition is important for retention of liposomal rhodamine in P-glycoprotein-overexpressing cancer cells.

Multidrug resistance (MDR) caused by high expression of P-glycoprotein (Pgp) in cancer patients remains one of the major obstacles to successful therapy of cancer. Earlier studies have shown that the incorporation of Pgp-substrate drugs in liposomes may provide a strategy to circumvent Pgp-mediated drug efflux. The present study investigated the impact of liposome composition on the efflux of Pgp-substrate incorporated in liposomes. Liposomes with varying compositions were loaded with rhodamine 123, a fluorescent probe frequently used as a Pgp-substrate, and the retention of rhodamine was compared in two breast cancer cell lines: wild-type cells with no detectable Pgp expression (MCF-7/WT) and Pgp-expressing cells resulting from stable transfection of the MDR1 gene (MCF-7/Pgp). Pgp-expression decreased the rhodamine retention in MCF-7 cells, suggesting that Pgp is functional. Liposome loading increased rhodamine retention in MCF-7/Pgp cells, but not in MCF-7/WT cells. Surface charge of liposomes did not affect the rhodamine retention, whereas the incorporation of cholesterol and polyethyleneglycol-attached lipids was effective in further increasing the rhodamine retention in MCF-7/Pgp cells. Since further study demonstrated that the rate of rhodamine release from liposomes tended to be inversely correlated with rhodamine retention by cells, it seems likely that more rigid liposomes are able to sequester rhodamine more efficiently, thereby inhibiting direct interactions of rhodamine with Pgp proteins. Taken together, these findings suggest that Pgp-mediated MDR in cancer cells may be more effectively modulated by optimizing the composition of liposomes for loading Pgp-substrate anti-cancer drugs.