Risk of suicide within 1 year of cancer diagnosis.

The association of the risk of suicide with cancer at different time points after a new cancer diagnosis is unclear. This study explored the suicide hazard at different time points after a first cancer diagnosis during the 1-year period before suicide. This case-crossover study included 2,907 suicide cases from 2002 to 2012 in Taiwan and compared the odds of suicide risk at different time points during one year after any cancer diagnosis with self-matched periods. The 13th month preceding the suicide date was used as the control period, and the hazard period was the duration from the 1st to 12th month in the conditional logistic regression for case-crossover comparisons. Among major groups of cancers, group of lip, oral cavity and pharynx cancers tended to have higher risk of suicide than other groups of cancers. The first month of cancer diagnosis was associated with the highest risk of suicide compared with the 13th month before suicide. The odds ratio (OR) of suicide were significantly in the first six months after cancer diagnosis but declined afterwards. For example, the adjusted OR was 3.47 [95% confidence interval (CI) = 2.60-4.62] in the first month and 1.53 (95% CI = 1.11-2.12) in the sixth month following cancer diagnosis. These findings provide clinicians with a vital reference period during which sufficient support and necessary referral to mental health support should be provided to reduce the risk of suicide among patients with newly diagnosed cancer morbidity.

Is Heart Failure Associated With Risk of Suicide?

BACKGROUND: The high prevalence of heart failure (HF) in developed countries imposes a substantial burden on health care resources. Depression is widely recognized as a risk factor associated with HF. This study examined the relationship between suicide and HF after controlling for depression and other comorbidities. METHODS AND RESULTS: The population comprised 52,749 adult patients who died from suicide from 2000 to 2012 and 210,996 living control subjects matched by age, sex, and residence area. Data were obtained from the Health and Welfare Data Science Center, Taiwan. Multivariable models were constructed to evaluate the relationship between HF and suicide. In the case and control groups 1624 (3.08%) and 4053 (1.92%) patients had HF, respectively, indicating that HF was associated with an increased risk of suicide (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.59-1.79). The risk of suicide was highest during the initial 6 months after HF (adjusted OR 7.04, 95% CI 5.37-9.22) and subsequently declined gradually. Among psychiatric disorders, mood disorders (adjusted OR 7.42, 95% CI 7.06-7.79) yielded the highest odds of suicide. CONCLUSIONS: The risk of suicide is higher for patients with HF than for healthy individuals without HF. This risk is particularly high during the first 6 months after HF diagnosis. This study provides strong evidence that depression is a negative prognostic factor for patients with HF and increases the risk of suicide. The results suggest that early screening and treatment for depression and suicide risk should be conducted for patients with HF.

Suicide and chronic kidney disease: a case-control study.

BACKGROUND: The association of chronic kidney disease (CKD) and dialysis with suicide is not well established. The objectives of this study were to assess the association of suicide with CKD and dialysis and investigate whether differences exist between dialysis modalities or the durations of dialysis. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database. A total of 51 642 patients who died from suicide between 2000 and 2012 and 206 568 living control patients matched by age, gender and residency area were examined. Known risk factors included sociodemographic characteristics, physical comorbidities and psychiatric disorders, which were controlled for as covariates in the analysis. The crude odds ratios (ORs) and adjusted ORs (aORs) for various risk factors were obtained using conditional logistic regression. RESULTS: After potential confounders were controlled for, CKD was significantly associated with an increased risk of suicide [aOR = 1.25, 95% confidence interval (CI) = 1.17-1.34]. End-stage renal disease patients on haemodialysis (HD) had an increased risk of suicide compared with controls (aOR = 3.35, 95% CI = 3.02-3.72). Moreover, patients who initially underwent dialysis within 0-3 months had a significantly increased risk of suicide (aOR = 20.26, 95% CI = 15.99-25.67). CONCLUSIONS: CKD and HD are positively associated with suicide. Suicide is preventable; therefore, assessing mental and physical disorders is essential and recommended to all physicians, particularly those treating patients in the early phase of HD.

Cross-sectional investigation of drug-related problems among adults in a medical center outpatient clinic: application of virtual medicine records in the cloud.

PURPOSE: To analyze and characterize data regarding the prevalence and types of outpatient drug-related problems (DRPs) found by clinical pharmacists after implementation of the Virtual Medicine Record in Cloud System (VMRCS). METHODS: A cross-sectional study regarding outpatient pharmaceutical care was conducted at a medical center in Taiwan. Patients aged >20 years old with multiple chronic diseases and polypharmacy were enrolled. In Stage I (1 October-31 December 2014), patients received pharmaceutical care according to prescription data accessed online in the VMRCS. In Stage II (1 June-31 August 2015), the VMRCS were pre-download and arranged to the institute's required format, facilitated DRP detection. Clinical pharmacists then reviewed and evaluated the prescription data through pre-downloaded VMRCS. Overall, 1539 and 1600 prescriptions were evaluated in these two stages, respectively. DRPs were recorded using the Pharmaceutical Care Network Europe (PCNE)-DRP. RESULTS: DRPs were found for 50.2% of patients in Stage I and 55.2% in Stage II (p < 0.05) and were most frequently encountered for "Drugs for the cardiovascular system" and caused by "Inappropriate duplication of therapeutic group or active ingredient." In terms of problems, incidence of "Unnecessary drug treatment" was highest. Duplicate medications were most frequently seen for "Drugs for acid-related disorders." The efficiency to identify DRPs was at least 2.4 times higher with pre-downloaded prescription data than with real-time online queries. CONCLUSIONS: With VMRCS, DRPs were more easily identified whether patients received medical care in the same hospital or not. DRPs could be efficiently prevented through the use of pre-downloaded patient prescription data. Copyright © 2016 John Wiley & Sons, Ltd.

Developing school-pharmacist partnerships to enhance correct medication use and pain medication literacy in Taiwan.

OBJECTIVE: To evaluate the effectiveness of the health promoting school (HPS)-community pharmacist partnership program that promotes students' correct medication use and enhances pain medication literacy in Taiwan. DESIGN: Pre- and post-studies and intervention/comparison group comparisons. SETTING: Primary and middle schools, along with their communities, in Taiwan. PARTICIPANTS: In 2013, baseline and follow-up self-administered, online surveys were received from 5,373 students enrolled in intervention primary and middle schools and from 4,643 students enrolled in comparison primary and middle schools. MAIN OUTCOME MEASURE: The level of medication literacy, including correct medication use knowledge, self-efficacy, and skills. RESULTS: The development and implementation of the HPS-community pharmacist partnership program in primary and middle schools significantly enhanced students' knowledge, self-efficacy, and skills in correct medication use and pain medication literacy (P <0.001). CONCLUSION: The HPS-community pharmacist partnership had a positive impact on enhancing correct medication use and pain medication literacy in Taiwan.

Efficacy of simethicone and N-acetylcysteine as premedication in improving visibility during upper endoscopy.

BACKGROUND: Simethicone and N-acetylcysteine have been widely used in improving endoscopic visibility. However, the optimal dose, volume, and dosing time for the premedication regimen are still unclear. AIM: Our aim was to assess the efficacy of premedication in improving endoscopic visibility and determine the contributions of dose, volume, and premedication time. METHODS: A total of 1849 patients were prospectively treated in three groups: group A: 100-mg simethicone suspension in 5 mL water; group B: 100-mg simethicone suspension in 100 mL water; and group C: 100-mg simethicone suspension in 100 mL water containing 200 mg N-acetylcysteine. Mucosa visibility was assessed at seven sites of upper gastrointestinal tract. The sum of scores was considered as total mucosal visibility score (TMVS). RESULTS: The upper body of stomach had the worst visibility score for all groups. TMVS of groups B and C were significantly lower than those of group A. Group C had a significantly fewer patients requiring endoscopic flushing than groups A and B. The TMVS for groups B and C were significantly lower than for group A within 30 min of beginning premedication. Beyond 30 min of premedication, there was no significant difference in the TMVS among groups. CONCLUSIONS: Premedication using 100 mg simethicone in 100 mL of water improves endoscopic visibility. Addition of N-acetylcysteine to simethicone in 100 mL of water reduces the need for endoscopic flushing. For patients unable to tolerate a large fluid volume, a 5-mL simethicone suspension administered more than 30 min prior to upper endoscopy is suggested.

Pre-medication to improve esophagogastroduodenoscopic visibility: a meta-analysis and systemic review.

BACKGROUND/AIMS: The use of pre-medication to improve visibility in gastrointestinal endoscopy has not been well addressed and remains controversial. The aim is to evaluate the effects of current pre-medication on endoscopic visualization. METHODOLOGY: We made the overall strategies to search the different databases and assessed the quality of included studies according to the included and excluded standard. 1541 patients were treated with pre-medication. RESULT: Ten prospective studies involving 1541 patients were included. There was improved visibility in patients treated with Simethicone (weighted mean difference -4.3; 95% confidence interval (CI), -4.94 to -3.67), compared to those who did not use Simethicone. In the Simethicone based regiment, administration of Pronase was noted with significantly improved visibility in the location of antrum and fundus, compared to those who did not use; however, administration of N-acetyl-L-cysteine could not lead to significantly improved visibility. Simethicone offered better visibility than N-acetyl-L-cysteine and Pronase alone. CONCLUSIONS: There is improved visibility with pre-medication using Simethicone before esophagogastroduodenoscopy. In the Simethicone based regimen, administration of Pronase or N-acetyl-Lcysteine may be of little use in improving visibility. Based on the literature review, Simethicone dissolved in the water with the acceptably lowest ratio of 0.7 can still offer the good visibility but 30 mL of water should be avoided.

Interactions between psychiatric and physical disorders and their effects on the risks of suicide: a nested case-control study.

Previous studies, which included predominantly Caucasian populations, examined psychiatric and physical illness and associated suicide risk. We used a nationwide database to reassess the findings in an Asian population, and also analyzed the influence of different onset timing of psychiatric and physical illness and the suicide risk. We included 55,630 suicide cases aged 20-110 years. Using an incidence density sampling approach, we selected 222,520 controls matched by age, sex, and residence area from 2000 to 2012. We included most major psychiatric and physical illnesses defined by ICD-9-CM codes with anatomical classifications. By using conditional logistic regression models with adjustment of covariates, such as patients' marital status and education levels, we found that patients with psychiatric illness had higher suicide risk (adjusted IRR, 7.72; 95% CI: 7.35-8.09) compared with those with neither physical nor psychiatric illness and the risk increased substantially in patients with both psychiatric and physical illnesses (adjusted IRR, 18.35; 95% CI: 16.40-20.86). Specifically, we found the suicide risk was relatively higher (adjusted IRR, 1.28; 95% CI: 1.10-1.40) when psychiatric disorders occurred before physical illness compared with the other way around. The findings warrant attention to high suicide risk and preventive treatments in patients with both psychiatric and physical illnesses.

Development of a Nucleic Acid Lateral Flow Immunoassay for the Detection of Human Polyomavirus BK.

The BK virus (BKV) is an emerging pathogen in immunocompromised individuals and widespread in the human population. Polymerase chain reaction is a simple and highly sensitive method for detecting BKV, but it is time consuming and requires expensive instruments and expert judgment. The lateral flow assay, a rapid, low-cost, minimal-labor, and easy-to-use diagnostic method, was successfully applied for pathogen detection. In this study, we used oligonucleotide probes to develop a simple and rapid sandwich-type lateral flow immunoassay for detecting BKV DNA within 45 minutes. The detection limit for the synthetic single-stranded DNA was 5 nM. The specificity study showed no cross-reactivity with other polyomaviruses, such as JC virus and simian virus 40. For the Escherichia coli containing BKV plasmid cultured samples, the sensitivity was determined to be 107 copies/mL. The approach offers great potential for BKV detection of various target analytes in point-of-care settings.

Human single-donor composite skin substitutes based on collagen and polycaprolactone copolymer.

The development and characterization of an enhanced composite skin substitute based on collagen and poly(epsilon-caprolactone) are reported. Considering the features of excellent biocompatibility, easy-manipulated property and exempt from cross-linking related toxicity observed in the 1:20 biocomposites, skin substitutes were developed by seeding human single-donor keratinocytes and fibroblasts alone on both sides of the 1:20 biocomposite to allow for separation of two cell types and preserving cell signals transmission via micro-pores with a porosity of 28.8 +/- 16.1 microm. The bi-layered skin substitute exhibited both differentiated epidermis and fibrous dermis in vitro. Less Keratinocyte Growth Factor production was measured in the co-cultured skin model compared to fibroblast alone condition indicating a favorable microenvironment for epidermal homeostasis. Moreover, fast wound closure, epidermal differentiation, and abundant dermal collagen deposition were observed in composite skin in vivo. In summary, the beneficial characteristics of the new skin substitutes exploited the potential for pharmaceutical screening and clinical application.

Improving tenoxicam solubility and bioavailability by cosolvent system.

The formulation study of tenoxicam, a poorly water-soluble drug, was developed by use of a ternary cosolvent system and has significantly enhanced the solubility. Additionally, the relative bioavailability of testing formulation was also evaluated by New Zealand rabbit with a single i.m. injection. The three-phase diagram for dimethylsulfoxide (DMSO)/propylene glycol/water, DMSO/ethanol/water, and DMSO/polyethoxylated castor oil/ethanol system was developed. The volume ratio of 5:4:1 in the DMSO/polyethoxylated castor oil/ethanol system resulted in a more suitable vehicle than other systems, with a high solubility (20.73 mg/ml) and low viscosity (10.0 Cp). A pharmacokinetic study of bioequivalence (F (rel) = 0.89) was also obtained. The present study not only provides a novel strategy improving tenoxicam solubility but also helps further scientific knowledge for the development of parenteral formulations.

Drug-related problems among hospitalized patients with COPD in mainland China.

Background Data are lacking about the extent of drug-related problems in hospitalized patients with COPD in China. Objective Identify types and causes of drug-related problems and assess interventions performed by pharmacists. Setting Study was conducted in an academic teaching hospital in Shanghai, China. Method Between June 2017 and July 2018, 393 patients admitted to hospital for acute exacerbation of COPD hospitalized were enrolled. Patient demographics and clinical characteristics were collected. The drug-related problems and interventions were recorded and analyzed based on the Pharmaceutical Care Network Europe (PCNE)-DRP V 8.02 classification. Main outcome measures The number, types, causes, interventions, and outcomes of the problems were analyzed. Results A total of 640 DRPs, with 763 corresponding causes, were identified for 393 patients. "Treatment safety P2" was the most common type of problem (54.2%; 347/640), and the most common causes were "drug selection C1" (24.2%; 185/763), "dose selection C3" (21.5%; 164/763) and "treatment duration C4" (17.7%; 135/763). Antibiotics, corticosteroids, and proton pump inhibitors were the three primary medication classes associated with DRPs. Patients, hospitalized for more than eight days, taking ten or more drugs or having renal dysfunctions were more likely to have drug-related problems. Pharmacists totally proposed 1557 interventions to address the problems. Most interventions (91.0%; 1418/1557) were accepted, and 91.6% of the problems were solved. Conclusion The prevalence of drug-related problems among the studied COPD patients was high. Pharmacists can have an important role in addressing the problems and optimizing the safety and effectiveness of therapies for hospitalized COPD patients.

Healthcare utilisation for eating disorders among patients with depression: a cross-sectional study in Taiwan.

OBJECTIVES: Although depressed patients may have a comorbid eating disorder (ED), to date, no study has focused on healthcare utilisation among this population. This study was designed to investigate the characteristics of healthcare service utilisation among depressed patients with ED. DESIGN: A cross-sectional study. SETTING: This population-based study used claims data from Taiwan's National Health Insurance Research database between 2001 and 2012. PARTICIPANTS: The study involved 1270 participants. These included 254 depressed individuals with ED and 1016 propensity score-matched depressed individuals without ED. OUTCOME MEASURES: We tracked each patient for a 1 year period to evaluate their healthcare service utilisation, including outpatient visits, inpatient days, and costs for psychiatry and non-psychiatry services. We performed a Mann-Whitney U test to compare outcome variables in healthcare service utilisation between the two groups. RESULTS: Patients with both depression and ED had significantly more outpatient visits (32.2 vs 28.9, p=0.023), outpatient costs (US$1089 vs US$877, p<0.001) and total costs (US$1356 vs US$1296, p<0.001) than comparison patients. For psychiatric services, patients with depression and ED had more outpatient visits (11.0 vs 6.8, p<0.001), outpatient costs (US$584 vs US$320, p<0.001) and total costs (US$657 vs US$568, p<0.001) than those without ED. For non-psychiatric services, there was no significant difference for all utilisation. This indicates that the total costs were about 1.0-fold greater for depression patient with ED than those without ED. CONCLUSION: Depression patients with ED had more outpatient visits, outpatient costs and total costs of healthcare services than those without ED.

Erythropoiesis-stimulating protein delivery in providing erythropoiesis and neuroprotection.

Erythropoietin (EPO), a glycoprotein, plays an important role in erythropoiesis and neuroprotection. EPO therapies for anemia or neurodegenerative diseases require frequent injections or high-dose systemic administration which may cause unwanted side effects. Various strategies for EPO delivery have been investigated for increasing EPO bioavailability and decreasing side effects, including nano/micro particles, PEGylation of EPO and transport-mediated delivery systems. Nano/micro particles provide EPO with long-term effect and protect EPO against proteolytic cleavage. PEGylated EPO prolong circulating time and reduce injection frequency of anemia treatment. A transport-mediated delivery system enables protein to cross biological barriers. Presently, there is no report about an effective delivery system of EPO for neuroprotection. This review focuses on EPO delivery systems for erythropoiesis or neuroprotection with prolonged duration and enhanced bioavailability.

Association of cortactin and fascin-1 expression in gastric adenocarcinoma: correlation with clinicopathological parameters.

Cortactin and fascin-1 are important factors in tumor progression. We tested the hypothesis that cortactin and fascin-1 expression correlates with clinicopathological parameters of gastric adenocarcinoma. Immunohistochemical analysis of cortactin and fascin-1 was done using tissue microarrays of 100 surgical specimens, including 20 well-differentiated, 20 moderately differentiated, and 60 poorly differentiated gastric adenocarcinomas. Among the 20 well-differentiated gastric adenocarcinomas, 15 cases (75%) showed negative or weak staining (1+); 5 cases (25%) had moderate (2+) or strong (3+) cortactin expression. Among the 60 poorly differentiated gastric adenocarcinomas, more than three-quarters of the cases (76.7%) had moderate or strong cortactin expression; 14 cases (23.3%) had weak staining. Of 20 well-differentiated gastric adenocarcinoma cases, 14 (70%) showed negative or weak staining of fascin-1, whereas nearly one-third (30%) had moderate or strong expression. Among the 60 poorly differentiated gastric adenocarcinomas, 32 (53.3%) exhibited moderate or strong fascin-1 expression; fewer than half of the cases showed negative or weak staining. Higher intensity of cortactin and fascin-1 staining correlated directly with more-advanced cancer stages (TNM) and inversely with survival rates. Our findings suggest the possibility that pharmacological inhibitors of cortactin and fascin-1 activity may slow down tumor progression and prolong survival time in patients with gastric adenocarcinomas.

Cell Therapy Regulation in Taiwan.

Cell therapy is not only a novel medical practice but also a medicinal product [cell therapy product (CTP)]. More and more CTPs are being approved for marketing globally because of the rapid development of biomedicine in cell culture, preservation, and preparation. However, regulation is the most important criterion for the development of CTPs. Regulations must be flexible to expedite the process of marketing for new CTPs. Recently, the Taiwan Food and Drug Administration (TFDA) updated the related regulations such as regulation of development, current regulatory framework and process, and the application and evaluation processes. When the quality of CTPs has been improved significantly, their safety and efficacy are further ensured. The treatment protocol, a new design for adaptive licensing to current clinical practice, is a rapid process for patients with life-threatening diseases or serious conditions for which there are no suitable drugs, medical devices, or other therapeutic methods available. The hospital can submit the treatment protocol to apply for cell therapy as a medical practice, which may result in easier and faster cell therapy development, and personalized treatment for individual patients will evolve quickly.

Evaluating the effectiveness of a novel atomized liquid needle-free transdermal delivery system.

Needle-free jet injections constitute a crucial method for drug delivery. A novel liquid drug delivery system has been proposed recently, in which pressure atomizes liquid before delivering that atomized liquid to the patient's body; however, the mechanism and efficiency of the system are unclear. This study explored the shot delivery pressure, penetration depth, and cumulative amount of permeation of this system. This system was used to deliver 0.5% (w/v) methylene blue to agarose phantoms at various shot delivery pressures. Shots of methylene blue were also delivered to porcine skin samples at different shot delivery frequencies for light microscopy evaluation. A commercial microneedle array was used for comparing the effectiveness of the skin penetration depths. The array was gently stamped against porcine skin; methylene blue was subsequently applied to the area for different time points, followed by microscopic observations. In vitro skin penetration was tested using static Franz diffusion cells over 8 h. Finally, the feasibility of the system's clinical application was evaluated by analyzing the local analgesic effect in a heat nociceptive animal model. The penetration depths created using 100 shots at 100 psi were similar to those created using the commercial microneedle array for 2 h. Thermal stimulation responses showed that 15 min after diclofenac sodium was delivered by the system, heat nociception was significantly attenuated for 60 min. Our study presents a novel delivery system that may be useful for future clinical applications.

Inappropriate self-medication among adolescents and its association with lower medication literacy and substance use.

BACKGROUND: While self-medication is common, inappropriate self-medication has potential risks. This study assesses inappropriate self-medication among adolescents and examines the relationships among medication literacy, substance use, and inappropriate self-medication. METHOD: In 2016, a national representative sample of 6,226 students from 99 primary, middle, and high schools completed an online self-administered questionnaire. Multiple logistic regression analysis was used to examine factors related to inappropriate self-medication. RESULTS: The prevalence of self-medication in the past year among the adolescents surveyed was 45.8%, and the most frequently reported drugs for self-medication included nonsteroidal anti-inflammatory drugs or pain relievers (prevalence = 31.1%), cold or cough medicines (prevalence = 21.6%), analgesics (prevalence = 19.3%), and antacids (prevalence = 17.3%). Of the participants who practiced self-medication, the prevalence of inappropriate self-medication behaviors included not reading drug labels or instructions (10.1%), using excessive dosages (21.6%), and using prescription and nonprescription medicine simultaneously without advice from a health provider (polypharmacy) (30.3%). The results of multiple logistic regression analysis showed that after controlling for school level, gender, and chronic diseases, the participants with lower medication knowledge, lower self-efficacy, lower medication literacy, and who consumed tobacco or alcohol were more likely to engage in inappropriate self-medication. CONCLUSION: Lower medication literacy and substance use were associated with inappropriate self-medication among adolescents.

Efficacy of Combined Ultrasound-and-Microbubbles-Mediated Diclofenac Gel Delivery to Enhance Transdermal Permeation in Adjuvant-Induced Rheumatoid Arthritis in the Rat.

A previous study that investigated the effect of ultrasound (US) on the transdermal permeation of the non-steroidal anti-inflammatory drug diclofenac found that therapeutic US can increase circulation in an inflamed joint and decrease arthritic pain. Transdermal drug delivery has recently been demonstrated by US combined with microbubbles (MB) contrast agent (henceforth referred to as "US-MB"). The present study evaluated the efficacy of US-MB-mediated diclofenac delivery for treating adjuvant-induced rheumatoid arthritis (RA) in rats. RA was induced by injecting 100 µL of complete Freund's adjuvant into the ankle joint of male Sprague-Dawley rats (250-300 g) that were randomly divided into five treatment groups: (i) carbopol gel alone (the control [group C]), (ii) diclofenac-carbopol gel (group D), (iii) US plus carbopol gel (group U), (iv) US plus diclofenac-carbopol gel (group DU) and (v) US-MB plus diclofenac-carbopol gel (group DUB). The ankle width was measured over 10 d using high-frequency (40-MHz) US B-mode and color Doppler-mode imaging, covering the period before and after treatment. Longitudinal US images of the induced RA showed synovitis and neovascularity. Only a small amount of neovascularity was observed after treatment. The recovery rate on day 10 was significantly higher in group DUB (97.7% ± 2.7%, mean ± standard deviation [SD]) than in groups C (1.0% ± 2.7%), D (37.5% ± 4.6%), U (75.5% ± 4.2%) and DU (87.3% ± 5.2%) (p < 0.05). The results obtained indicate that combining US and MB can increase the skin permeability and thereby enhance the delivery of diclofenac sodium gel and thereby inhibit inflammation of the tissues surrounding the arthritic ankle. Color Doppler-mode imaging revealed that US-MB treatment induced a rapid reduction in synovial neoangiogenesis in the arthritic area.

Penetration depth, concentration and efficiency of transdermal α-arbutin delivery after ultrasound treatment with albumin-shelled microbubbles in mice.

Recently, the feasibility and effects of using microbubbles (MBs) as an ultrasound (US) contrast agent for enhancing the penetration in transdermal delivery in vivo have been demonstrated, but the mechanism and efficiency are unclear. This study demonstrates the penetration depth, concentration and efficiency of transdermal α-arbutin delivery during 4 weeks after US treatment with MBs in mice. Experimental animals were randomly divided into the following four groups (n = 5 animals per group): (1) penetrating α-arbutin alone (C), (2) US combined with penetrating α-arbutin, (3) US combined with MBs and penetrating α-arbutin, and (4) US combined with diluted MBs and penetrating α-arbutin (UBD). The penetration depths in agarose phantoms and pigskin were 47 and 84% greater for group UBD, respectively, than for group C. The in vitro skin penetration by 2% α-arbutin after 3 h was 83% greater in group UBD than in group C. The degree of in vivo skin whitening (quantified as the luminosity index) in group UBD significantly increased by 25% after 1 week, 34% after 2 weeks, and then stabilized after 3 weeks at 37% in C57BL/6J mice over a 4-week experimental period. Our results indicate that combined treatment with optimal US and MBs can increase skin permeability so as to enhance α-arbutin delivery to inhibit melanogenesis without damaging the skin in mice.