Pharmacokinetic and Pharmacodynamics of Self-Assembled Cubic Liquid Crystalline Nanoparticle Gel After Transdermal Administration.

BACKGROUND The aim of this study was to assess the pharmacokinetics after transdermal administration by a novel skin microdialysis technology in rats. The guinea pig model was established by investigating the pharmacodynamics. MATERIAL AND METHODS Three different agents were given after hair removal, and the samples were extracted by microdialysis and detected by HPLC. Subcutaneous/plasma concentration-time curves of the 3 different agents were analyzed and the pharmacokinetic parameters were calculated. The SS-04B UV light therapy instrument was used in the modeling. Changes in melanin index and histopathology were observed with HE staining. RESULTS The increment and decrement results showed that the concentration had no significant effect on drug recovery both in vivo and in vitro. After the paeonol cubic liquid crystalline nanoparticles gel (PAE-LCNPs) was administered, the maximum peak time (tmax) of paeonol skin concentration appeared at 2.42±0.20 h, the maximum skin concentration Cmax was (926±105) ng/ml, and the area under the curve AUC0-8 was (8056±954) ng/h/ml. The tmax was shortened much more than in the other groups, and the performance of PAE-LCNPs targeting was good. Pharmacodynamic results showed that PAE-LCNPs can reduce melanocytes and reduce the melanin index, proving its utility in the treatment of melanin deposition. CONCLUSIONS The skin microdialysis study indicated PAE-LCNPs have good transdermal permeability and efficacy. Pharmacological experiments based on the study found that the topical pigmentation model of guinea pigs showed a better therapeutic effect.

Cucurbitacin B Protects Against Pressure Overload Induced Cardiac Hypertrophy.

Lack of effective anti-cardiac hypertrophy drugs creates a major cause for the increasing prevalence of heart failure. In the present study, we determined the anti-hypertrophy and anti-fibrosis potential of a natural plant triterpenoid, Cucurbitacin B both in vitro and in vivo. Aortic banding (AB) was performed to induce cardiac hypertrophy. After 1 week of surgery, mice were receive cucurbitacin B treatment (Gavage, 0.2 mg/kg body weight/2 day). After 4 weeks of AB, cucurbitacin B demonstrated a strong anti-hypertrophy and -fibrosis ability as evidenced by decreased of heart weight, myocardial cell cross-sectional area and interstitial fibrosis, ameliorated of systolic and diastolic abnormalities, normalized in gene expression of hypertrophic and fibrotic markers, reserved microvascular density in pressure overload induced hypertrophic mice. Cucurbitacin B also showed significant hypertrophy inhibitory effect in phenylephrine stimulated cardiomyocytes. The Cucurbitacin B-mediated mitigated cardiac hypertrophy was attributable to the increasing level of autophagy, which was associated with the blockade of Akt/mTOR/FoxO3a signal pathway, validated by SC79, MK2206, and 3-MA, the Akt agonist, inhibitor and autophagy inhibitor in vitro. The overexpression of constitutively active Akt completely abolished the Cucurbitacin B-mediated protection of cardiac hypertrophy in human cardiomyocytes AC16. Collectively, our findings suggest that cucurbitacin B protects against cardiac hypertrophy through increasing the autophagy level in cardiomyocytes, which is associated with the inhibition of Akt/mTOR/FoxO3a signal axis. J. Cell. Biochem. 118: 3899-3910, 2017. © 2017 Wiley Periodicals, Inc.

Mechanisms contributing to cardiac remodelling.

Cardiac remodelling is classified as physiological (in response to growth, exercise and pregnancy) or pathological (in response to inflammation, ischaemia, ischaemia/reperfusion (I/R) injury, biomechanical stress, excess neurohormonal activation and excess afterload). Physiological remodelling of the heart is characterized by a fine-tuned and orchestrated process of beneficial adaptations. Pathological cardiac remodelling is the process of structural and functional changes in the left ventricle (LV) in response to internal or external cardiovascular damage or influence by pathogenic risk factors, and is a precursor of clinical heart failure (HF). Pathological remodelling is associated with fibrosis, inflammation and cellular dysfunction (e.g. abnormal cardiomyocyte/non-cardiomyocyte interactions, oxidative stress, endoplasmic reticulum (ER) stress, autophagy alterations, impairment of metabolism and signalling pathways), leading to HF. This review describes the key molecular and cellular responses involved in pathological cardiac remodelling.

Models for improved diagnosis of left ventricular hypertrophy based on conventional electrocardiographic criteria.

BACKGROUND: Electrocardiogram (ECG) is commonly used clinically due to convenience, but its accuracy is insufficient for left ventricular hypertrophy (LVH) diagnosis. In this study, we attempted to improve diagnostic accuracy of LVH by establishing models with ECG parameters. METHODS: Eighty hundred and twenty eight patients were recruited in the present study which were divided into groups according to gender, age and body mass index (BMI). The sensitivity, specificity, Youden index, positive predictive value, negative predictive value and accuracy were calculated using ultrasonic cardiogram criteria of LVH as the gold standard. Area under the curve was also calculated to assess the diagnostic accuracy of 22 conventional ECG criteria in different groups. Stepwise discriminant analyses were performed to establish models of ECG for LVH. RESULTS: The diagnostic accuracy of ECG11 (S V2 + R V5,6) and ECG12 (S V1,2 + R V5,6) was significantly higher than the other 20 criteria, while ECG15 (R V5/R V6) was lowest. The ECG12 sensitivity for males was 52.5%, for <60 years old was 44.2%, and for BMI <25 kg/m2 was 46.2%,higher than for females (27.5%), for ≧60 years old (35.7%), and for BMI ≧25 kg/m2(27.6%), respectively. The difference between genders was the most obvious. Based on these observations, the following models for males and females were established:[Formula: see text]and[Formula: see text]respectively. The sensitivities of the two new models were 71.4% and 75.8%, significantly higher than the22 conventional ECG criteria. CONCLUSION: Two models developed based on gender can be considered for use to investigate the preliminary assessment of the probability of LVH.

Folic Acid-Targeted Etoposide Cubosomes for Theranostic Application of Cancer Cell Imaging and Therapy.

BACKGROUND The aim of this study was to develop a novel Poloxamer-based drug delivery system featuring a tumor-targeting folate moiety, which was expected to provide better targeting properties and therapeutic effects compared with the traditional cubosomes (Cubs). MATERIAL AND METHODS Both folate-modified Cubs containing etoposide (ETP-Cubs-FA) and normal cubic nanoparticles loaded with etoposide (ETP-Cubs) were prepared through the fragmentation of bulk gels under the homogenization condition of 1500 bar, and a mean particle size of around 180 nm was obtained with a narrow size distribution. The cubosomes were further characterized by differential scanning calorimetry (DSC) and Polarized light microscopy (PLM). The release of ETP in vitro from these nanoparticles was found to be 82.5% at 36 h, showing a sustained release property compared with the free drug administration. RESULTS Folate-modified cubosomes exhibited best anti-proliferative activity followed by normal cubosomes and the free drug. A further cell uptake study of Rhodamine B-loaded Cubs-FA (Rh-B-Cubs-FA) showed a marked increase of cellular accumulation compared with free Rh-B and Rh-B-loaded Cubs (Rh-B-Cubs). In vivo Rh-B-based tumor imaging demonstrated that Cubs-FA specifically targeted the tumor tissue. CONCLUSIONS The folate-modified cubosomes containing ETP may be a promising drug candidate for antitumor treatment.

Characterization and Bioavailability of Wogonin by Different Administration Routes in Beagles.

BACKGROUND With the gradually accumulating research on pharmacological activity of wogonin, the in vitro analysis research on wogonin has become more and more popular, but there are very few reports about in vivo detection, and there are no solid dispersions (SDs) of Wogonin. The aim of this study was to explore the formation of solid dispersions (SDs) of wogonin. The reasons for the low bioavailability were studied through different routes of administration. MATERIAL AND METHODS SDs was formulated using the solvent evaporation method via polyvinylpyrrolidone K30 (PVP). The characterization of the drug and its carrier was detected by X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The serum concentrations of Wogonin were detected using the LC-MS/MS method. Six beagles were fed 3 different formulations of wogonin in 3 cycles. RESULTS The SDs of wogonin had a higher solubility than the physical mixtures. Based on XRD and DSC, wogonin was transformed from a crystalline morphology to an amorphous structure. The main pharmacokinetic parameters of i.g. administration (crude material and SD) and i.v. route were as follows: Cmax (2.5±1.1), (7.9±3.3), and (6838.7±1322.1) µg/L, tmax (0.7±0.3) and (0.3±0.2) h for the former, AUC0-t (7.1±2.0), (21.0±3.2) and (629.7±111.8) µg·h/L. The absolute bioavailability of native wogonin and wogonin arginine solution were (0.59±0.35)% and (3.65± 2.60)%. Further research showed that the low bioavailability of wogonin might be associated with low solubility and rapid combination with glucuronic acid in vivo. CONCLUSIONS The significantly increased solubility of SDs and the further preparation of arginine solution could significantly increase the bioavailability of wogonin.

Self-Assembled Cubic Liquid Crystalline Nanoparticles for Transdermal Delivery of Paeonol.

BACKGROUND: The aim of this study was to optimize the preparation method for self-assembled glyceryl monoolein-based cubosomes containing paeonol and to characterize the properties of this transdermal delivery system to improve the drug penetration ability in the skin. MATERIAL AND METHODS: In this study, the cubic liquid crystalline nanoparticles loaded with paeonol were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel by high-pressure homogenization. We evaluated the Zeta potential of these promising skin-targeting drug-delivery systems using the Malvern Zeta sizer examination, and various microscopies and differential scanning calorimetry were also used for property investigation. Stimulating studies were evaluated based on the skin irritation reaction score standard and the skin stimulus intensity evaluation standard for paeonol cubosomes when compared with commercial paeonol ointment. In vitro tests were performed on excised rat skins in an improved Franz diffusion apparatus. The amount of paeonol over time in the in vitro penetration and retention experiments both was determined quantitatively by HPLC. RESULTS: Stimulating studies were compared with the commercial ointment which indicated that the paeonol cubic liquid crystalline nanoparticles could reduce the irritation in the skin stimulating test. Thus, based on the attractive characteristics of the cubic crystal system of paeonol, we will further exploit the cosmetic features in the future studies. CONCLUSIONS: The transdermal delivery system of paeonol with low-irritation based on the self-assembled cubic liquid crystalline nanoparticles prepared in this study might be a promising system of good tropical preparation for skin application.

[Predictive analysis on Shenmai injection-induced adverse reactions with Logistic model and ROC curve].

To study relevant risk factors of Shenmai injection induced adverse reactions by using Logistic model and ROC curve, and made the prediction for the occurrence of relevant adverse reactions/events. Case data of patients treated with Shenmai injection were collected by using the prospective, multi-center, large-sample, nested-case control method, in order to analyze the risk factors of Shenmai injection-induced adverse reactions/events, establish the logistic model and draw the receiver operating characteristic (ROC) curve for risk factors. During the study, 7632 patients (including 3 477 males and 4 155 females) were included, and eight of them suffered adverse reactions/events. Based on a multi-factor Logistic model analysis, the age (> or = 50 years) (OR = 5.061, 95% CI: 2.197-7.924; P = 0.001), the total number of medication days (OR = -1.020, 95% CI: -l.652 - 0.388; P = 0.002) and the single dose (OR = 0.245, 95% CI: 0.127-0.364; P = 0.000) were significant independent risk factors for Shenmai injection-induced adverse reactions/events. According to the results, ROC curves were drawn with age (> or = 50 years), the total number of days of inedication and single dose; The area under ROC curves the joint predictor (0.9753, 95% CI: 0.9443-1.000, P < 0.005) was larger than that of the other three single indexes, with a higher risk prediction value. The independent risk factors for Shenmai injection-induced adverse reactions/events included the age (> or = 50 years), the total number of days of medication and single dose. In clinical practice, the age (> or = 50 years), the total number of days of medication and the medication dose can be substituted in the joint predictor calculation formula (P = 1 / [1 + e(-(-21.58 + 5.061 x Xage - 1.020 x Xd + 0.245 x X(mL)] to predict the potential adverse reactions of patients and adjust the dosage regimen.

A 6-year retrospective study of adverse drug reactions due to drug-drug interactions between nervous system drugs.

OBJECTIVE: The primary objective of this study was to determine the frequency and characteristics of adverse drug reactions (ADRs) due to drug-drug interactions (DDIs) between nervous system drugs recorded for hospitalized patients in China. The secondary objective was to identify and record the possible mechanisms underlying these DDIs. METHODS: In this retrospective study performed from January 2007 to December 2012, we detected and analyzed ADRs caused by potential or actual DDIs between nervous system drugs, by using the Center of Adverse Drug Reaction Monitoring, Bengbu Food and Drug Administration (CADRMBFDA) database. RESULTS: The CADRMBFDA database contained 1,207 reports of ADRs due to nervous system drugs, involving 1,079 hospitalized patients. Of the ADRs reported, 131 (12.14%) were associated with potential and actual DDIs. There were 259 (21.46% of the total ADR reports) reports on potential and actual DDIs. The proportion of serious ADRs (6 out of 131) was significantly higher among actual DDI reports (p < 0.001) than among the remaining reports (6 out of 942). CONCLUSIONS: The results of our study confirmed that the CADRMBFDA database was a valuable resource for detecting actual DDIs. Moreover, the database helps identify drugs that can cause serious ADRs, thus indicating focus areas for healthcare education.

Pharmacists promote rational use of antibiotic prophylaxis in Type I incision operations via application of drug use evaluation.

OBJECTIVE: Drug use evaluation (DUE) criteria were established to assess the rational use of antibiotic prophylaxis (RUAP) in Type I incision operations (TOIO) during peri-operation period and to enhance pharmacists' responsibilities for antibiotic stewardship. METHODS: The criteria were set with a threshold based on a literature review and discussions with multidisciplinary experts. Patients who received TOIO from July 2008 to June 2012 were enrolled in the study. The percentage of prescriptions adhering to all items of criteria was 10% at baseline. RESULTS: According to DUEs and interviews by pharmacists, the percentages of prescriptions adhering to all items of criteria of DUE-1, DUE-3, DUE-5, and DUE-8 were 13.3, 20.0, 50.0 and 66.7%, respectively. The study showed that the most common inappropriate therapies were no indications for prophylaxis antibiotic use and inappropriate choices of antibiotics. Pharmacists finally disseminated DUE criteria and reports to prescribe and improve RUAP in TOIO at the hospital through the Drug and Therapeutics Committee (DTC). CONCLUSION: The study demonstrated that application of pharmacist- directed DUE is a useful strategy to detect, supervise and help correct challenges encountered during antibiotic prophylaxis in TOIO.

Electrochemically Mediated Carboxylative Cyclization of Allylic/Homoallylic Amines with CO2 at Ambient Pressure.

CO2 is an important C1 resource. We report a method for the synthesis of pharmacologically active 2-oxazolidinones by reacting CO2 with allylic amines. As opposed to previous addition reactions, the unsaturated double bonds are preserved. Thus, the product is more plastic and easier to use for subsequent structural modification. Furthermore, this method can also be applied to the synthesis of six-membered heterocycles (1,3-oxazinan-2-ones) and the participation of a low concentration of CO2, indicating it has certain practicability.

Corrigendum to "Myricetin Possesses Potential Protective Effects on Diabetic Cardiomyopathy through Inhibiting IκBα/NFκB and Enhancing Nrf2/HO-1".

[This corrects the article DOI: 10.1155/2017/8370593.].

Rosmarinic acid alleviates cardiomyocyte apoptosis via cardiac fibroblast in doxorubicin-induced cardiotoxicity.

Cardiomyocyte apoptosis is a key event in the process of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that rosmarinic acid (RA) could attenuate pressure overload-induced cardiac dysfunction via cardiac fibroblasts (CFs), however its effect in DOX-induced cardiotoxicity remains unknown. In the present study, mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to generate DOX-induced cardiotoxicity. Histological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. Neonatal rat cardiomyocytes (CMs) and CFs were used to verify the protective effect of RA in vitro. Conditioned medium derived from RA-treated CFs were prepared to illustrate the effect of RA on paracrine interplay between CFs and CMs. We found that RA significantly alleviated DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in vivo, which, however, had almost negligible beneficial effect on DOX directly induced cardiomyocyte apoptosis in vitro. Mechanistically, CFs-derived Fas L was responsible for DOX-induced cardiomyocyte apoptosis, and RA treatment could decrease Fas L expression in CFs and its release to the conditioned medium by suppressing nuclear factor of activated T cells (NFAT) activation and metalloproteinase 7 (MMP7) expression, and exerted the anti-apoptotic effect on CMs via CFs. Ionomycin, and activator of NFAT, abrogated RA-mediated protective effect on cardiomyocyte apoptosis and cardiac dysfunction. In summary, RA alleviated cardiomyocyte apoptosis by inhibiting the expression and release of Fas L in CFs via a paracrine manner, moreover, NFAT as well as MMP7 inhibition were responsible for the suppression of Fas L. RA could be a powerful new therapeutic agent to mitigate cardiomyocyte apoptosis, thereby improving DOX-induced cardiotoxicity.

Geniposide Alleviates Isoproterenol-Induced Cardiac Fibrosis Partially via SIRT1 Activation in vivo and in vitro.

Objective: Geniposide (GE) is a major component in the fruit of Gardenia jasminoides Ellis. Oxidative stress, endoplasmic reticulum (ER) stress, and canonical Smad3 pathway are implicated in the pathogenesis of cardiac fibrosis. We aim to investigate the protective roles of GE in isoproterenol (ISO)-induced cardiac fibrosis. Methods: ISO was used to induce cardiac fibrosis in male C57BL/6 mice. GE and the EX-527 were given for 2 weeks to detect the effects of GE on cardiac fibrosis. Levels of oxidative stress, ER stress, and Smad3 were evaluated by real time-PCR, Western blots, immunohistochemistry staining, immunofluorescence staining, and assay kits. Results: GE treatment alleviated cardiac dysfunction, fibrosis, and hypertrophy in mice response to ISO. Additionally, GE also suppressed the transformation of cardiac fibroblasts to myofibroblasts stimulated by transforming growth factor-ß (TGF-ß) in vitro. Mechanistically, GE inhibited the oxidative stress, ER stress, as well as Smad3 pathway activated by ISO or TGF-ß. A selective antagonist of sirtuin 1 deacetylase (SIRT1), EX-527, partially counteracted the anti-fibrotic effect and weakened the inhibitory effect on the transformation of cardiac fibroblasts to myofibroblasts after the treatment of GE. Acetylated Smad3 (ac-Smad3), oxidative stress, as well as ER stress pathway were significantly enhanced after SIRT1 was blocked while phosphorylated Smad3 (P-Smad3) was not affected. Conclusion: GE could combat cardiac fibrosis in vivo and in vitro by inhibiting oxidative stress, ER stress, and ac-Smad3 in a SIRT1-dependent manner and suppressing P-Samd3 pathway independent of SIRT1 activation. GE is expected to be a promising agent against cardiac fibrosis.

Myricetin Possesses Potential Protective Effects on Diabetic Cardiomyopathy through Inhibiting IκBα/NFκB and Enhancing Nrf2/HO-1.

Diabetic cardiomyopathy (DCM) is associated with a greater risk of mortality in patients with diabetes mellitus. Currently, no specific treatment has been suggested for DCM treatment. This study demonstrated that myricetin (M) attenuated DCM-associated cardiac injury in mice subjected to streptozotocin (SZT) and in neonatal rat cardiomyocytes (NRCM) challenged with high glucose. In vivo investigation demonstrated 6 months of M treatment (200 mg/kg/d) significantly alleviated cardiac hypertrophy, apoptosis, and interstitial fibrosis. Mechanically, M treatment significantly increased the activity of Nrf2/HO-1 pathway, strengthening antioxidative stress capacity evidenced by reversed activities of GPx and SOD, and decreased MDA production. M treatment also inhibited IκBα/NF-κB pathway, resulting in reduced secretion of inflammation cytokines including IL-1ß, TNF-α, and IL-6. Besides, the TGFß/Smad3 signaling was also blunted in DCM mice treated with M. These beneficial effects of M treatment protected cardiomyocytes from apoptosis as shown by decreased TUNEL-positive nucleus, c-caspase 3, and Bax. Similar effects of M treatment could be reproduced in NRCM treated with high glucose. Furthermore, through silencing Nrf2 in NRCM, we found that the regulation of IκBα/NFκB by M was independent on its function on Nrf2. Thus, we concluded that M possesses potential protective effects on DCM through inhibiting IκBα/NFκB and enhancing Nrf2/HO-1.

Preparation and brain delivery of nasal solid lipid nanoparticles of quetiapine fumarate in situ gel in rat model of schizophrenia.

To investigate the brain delivery in rat by nasal Quetiapine fumarate (QF) loaded with solid lipid nanoparticles in situ gel (QF-SLN-gel). QF-SLN-gel was prepared through micro-emulsion technique. The rat model of schizophrenia was established by intraperitoneal injection of (+)-MK-801, evaluated by stereotypic behavior, Mori's Water Maze (MWM) test and hematoxylin and eosin (HE) staining of hippocampus. The animals were administrated with QF via oral, nasal or tail vein approach and the concentration of QF in blood and brain was determined using high performance liquid chromatography (HPLC). The QF-SLN-gel was even and transparent, having size of 117.8±2.67 d.nm, potential of 57.2±0.24 mV and EF of 97.6±0.58%. After administration of QF-SLN-gel, the concentration of QF in blood and brain of rats in nasal QF-SLN-gel group was similar with that of rats in tail vein QF group, but significantly higher than that of rats in oral QF group. The hippocampal morphology changes induced by (+)-MK-801 were ameliorated by QF, with advantage of nasal QF-SLN-gel over tail vein QF. The nasal QF-SLN-gel had stable and good brain delivery and could ameliorate the damages in rat model of schizophrenia induced by (+)-MK-801.