Antidepressant desipramine leads to C6 glioma cell autophagy: implication for the adjuvant therapy of cancer.

Depression is the most common psychiatric syndrome in cancer patients and adversely affects anti-cancer immune system and life quality of patients. Antidepressant desipramine (DMI) is clinically prescribed in the auxiliary treatment of cancer patients. Increasing evidences suggest that DMI has a broad spectrum of target-off biological effects, such as anticancer properties. Our previous study revealed that DMI at the clinical relevant concentrations could induce CHOP-dependent apoptotic death in C6 glioma cells. In this study, we further explored the pro-autophagic effect of DMI in C6 glioma cells and its underlying mechanism. Treatment with DMI could induce autophagic cell death characterized by the formation of autophagosome and the elevated level of autophagic protein Beclin-1 and cellular redistribution of marker LC3. Meanwhile, DMI inhibited the activation of PI3K-AKT-mTOR pathway which is considered as a negative regulator of autophagy. Furthermore, DMI activated PERK-eIF2α and ATF6 of endoplasmic reticulum (ER) stress pathway, while knockdown of PERK with the PERK-specific short interfering RNA (siRNA) could obviously attenuate the autophagy. The results strongly suggested that DMI could induce autophagy through the PERK-ER stress pathway in C6 glioma cells. Our findings provided new insights into another beneficial potential of antidepressant DMI in the adjuvant therapy of cancer.

Determination of Bis(9)-(-)-Meptazinol, a bis-ligand for Alzheimer's disease, in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study.

A rapid, simple and sensitive LC-MS/MS method was developed and validated for the determination of Bis(9)-(-)-Meptazinol (B9M) in rat plasma. Protein precipitation method was used for sample preparation, using five volumes of methanol as the precipitation agent. The analytes were separated by a Zorbax Extend-C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 9.8) (95:5, v/v), and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of IS (Bis(5)-(-)-Meptazinol) and B9M were 1.9 min and 3.3 min, respectively. The limit of detection was 0.1 ng/ml and the linear range was 1-500 ng/ml. The relative standard deviation (RSD) of intra-day and inter-day variation was 4.4-6.2% and 6.2-8.9%, respectively. The extraction recoveries of B9M in plasma were over 95%. The method proved to be applicable to the pharmacokinetic study of B9M in rat after intravenous and subcutaneous administration.

The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis.

Arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) could induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells, respectively, thus the possibility of synergism between them was raised. This meta-analysis assessed the effectiveness and safety of ATO combined with ATRA in the treatment of APL. Compared with ATO alone, induction therapy with ATO/ATRA significantly increased the complete remission (CR) rate (RR: 1.08, 95% CI: 1.00-1.17, P=0.04), shortened the time to achieve CR (WMD: -6.51, 95% CI: -11.32 to -1.70, P=0.008), and improved the molecular remission rate after consolidation therapy (RR: 1.74, 95% CI: 1.14-2.66, P=0.01) and the 1-year disease-free survival rate (RR: 1.22, 95% CI: 1.00-1.50, P=0.05). There were no statistically significant differences between two treatments in terms of early death and main adverse events. These results suggested that ATO/ATRA could synergistically improve the overall outcome of newly diagnosed and relapsed APL patients, supporting the use of ATO/ATRA as an effective treatment for all APL patients previously untreated with ATO.

Atropine in ameliorating the progression of myopia in children with mild to moderate myopia: a meta-analysis of controlled clinical trials.

OBJECTIVES: Myopia is the most common ocular disorder associated with increasing risk for chorioretinal degeneration, retinal detachment, and other vision-threatening abnormalities worldwide. Recently, atropine has been becoming a focus of attention due to its role in ameliorating the myopia progression in children. This meta-analysis was conducted to address the efficacy and safety of atropine on myopia in children and the dose-response relationship between atropine and annual rate of myopia progression. METHODS: Controlled clinical trials were retrospectively analyzed to compare atropine and placebo for the treatment of myopia. The primary outcome measure was annual rate of myopia progression after daily atropine application over 1 year. Data were extracted from 6 randomized clinical trials and analyzed using standard meta-analysis and meta-regression methods. RESULTS: Comparing with placebo, the effect size of atropine for retarding myopia progression was 0.773 diopters (D)/year [95% confidence interval (CI): 0.699-0.848]. Regression model, -0.728+1.281log (dose+1), revealed the dose-response relationship between atropine and myopia progression. The estimate of effect for 0.05%, 0.1%, and 0.25% atropine was -0.665 (95% CI: -1.070 to -0.260), -0.606 (95% CI: -0.967 to -0.245), and -0.442 (95% CI: -0.701 to -0.183) D/year respectively, whereas that for 0.5% and 1% was -0.208 (95% CI: -0.435-0.018) and 0.160 (95% CI: -0.293-0.613), respectively, suggesting that myopia might deteriorate at low dose of atropine but not at 0.5% atropine and 1% atropine within the duration of 6-24 months. No serious adverse event was reported during the period of treatment. The major adverse reactions associated with 0.5% and 1% atropine were photophobia, glare, and recurrent allergic blepharitis. Photochromatic lenses or sunglasses with ultraviolet protection could be used to minimize the glare and photophobia. CONCLUSION: In summary, 0.5% and 1% atropine was demonstrated to be effective and safe to ameliorate myopia progression in childhood with low-to-moderate myopia.

Is acupuncture beneficial in depression: a meta-analysis of 8 randomized controlled trials?

BACKGROUND: Depression is one of the most common mental health disorders. Acupuncture is a popular complementary and alternative medicine intervention suggested in the treatment of depression, but its effectiveness is uncertain. This updated meta-analysis was conducted to more precisely assess the beneficial effect of acupuncture in depression therapy. METHODS: The following databases were searched: MEDLINE, EMBASE, BIOSIS, Cochrane Central Register of Controlled Trials, and Chinese Scientific Journal Database. The following terms were used: acupuncture, acupressure, depression, depressive disorder, clinical trial, and randomized controlled trial. RESULTS: Eight small-randomized controlled trials comparing 477 subjects were included in the meta-analysis. Our results confirmed that acupuncture could significantly reduce the severity of depression, which was indicated by decreased scores of Hamilton rating scale for depression (HAMD) or Beck Depression Inventory (BDI). The pooled standardized mean difference of the 'Improvement of depression' was -0.65 (95% CI -1.18, -0.11; P=0.02) by random effect model. However, no significant effect of active acupuncture was found on the response rate (RR 1.32, 95% CI 0.83 to 2.10; P=0.25) and remission rate (RR 1.30, 95% CI 0.57 to 2.95; P=0.53). CONCLUSION: Although this meta-analysis might be discounted due to the low quality of individual trials, it supported that acupuncture was an effective treatment that could significantly reduce the severity of disease in the patients with depression. More full-scale randomized clinical trials with reliable designs are recommended to further warrant the effectiveness of acupuncture.

Preparation and evaluation of a novel delayed-onset sustained-release system of propranolol hydrochloride.

The objective of this work was to prepare and evaluate a new delayed-onset sustained-release system, comprising a sustained-release core tablet with hydroxypropyl methylcellulose as polymer matrix and an ethylcellulose/Eudragit L coating capable of delaying the drug release. The sustained core containing propranolol hydrochloride as the model drug was prepared by granulate tableting and the polymer coating was applied in a computer-controlled coating pan. The dissolution tests demonstrated that the in-vitro drug release was pH-dependent with sufficient gastric resistance, and the lag time (t(10%)) could be controlled by adjusting the coating level. Three dosage forms including commercial tablet, sustained-release tablet and the delayed-onset sustained-release tablet were administrated to six beagle dogs and the plasma levels of propranolol hydrochloride were measured with high-performance liquid chromatography. The delayed-onset sustained-release tablet had a lag time of 3.0 h in-vitro and 3.5 h in-vivo, and a t(max) of 7.0 h. The relative bioavailability for delayed-onset sustained-release tablet was 96.98% compared with commercial tablets. The results indicate that the new propranolol delayed-onset sustained-release system could achieve a relatively constant drug release followed by a programmed lag time, and this may provide a promising drug delivery form for chronopharmacotherapy of certain cardiovascular diseases.

Clinical study on the influence of a fixed-dose combination of famotidine with calcium carbonate and magnesium hydroxide on the bioavailability of famotidine.

The potential interaction of the H2-receptor antagonist famotidine (CAS 76824-35-6) with calcium carbonate (CAS 471-34-1) and magnesium hydroxide (CAS 1309-42-8) during administration of the famotidine fixed dose combination (FDC) formulation was investigated. A randomized, open-label, two-period, crossover study was carried out on 12 healthy Chinese volunteers. Plasma concentration-time profiles of famotidine were similar with the FDC formulation and common formulation. Confidence interval (90% CI) for maximal concentration (C(max)) and area under the curve (AUC(o-t)) of famoti-dine were 94.8-112.2% and 94.2-112.3%, respectively. These findings suggest that calcium carbonate/magnesium hydroxide antacids have no significant effects on famotidine pharmacokinetics when they are administered together with famotidine as an FDC formulation.

Synergistically enhanced transdermal permeation and topical analgesia of tetracaine gel containing menthol and ethanol in experimental and clinical studies.

The aim of this study is to observe the synergistically enhanced percutaneous penetration and skin analgesia of tetracaine gel containing menthol and ethanol through experimental and clinical studies. Four anesthetic gels containing 4% tetracaine in carbomer vehicle named T-gel (containing no menthol or ethanol), 5%M/T-gel (containing 5% menthol), 70%E/T-gel (containing 70% ethanol, an optimal concentration for antiseptic), and 5%M+70%E/T-gel (containing both 5% menthol and 70% ethanol), respectively, were fabricated. The in vitro mouse skin permeation was investigated using a Franz diffusion cell. The mouse skin morphology was examined by a scanning electron microscope. The in vivo skin analgesic effect in mice was evaluated using the von Frey tests. To determine the efficacy of tetracaine gels for managing the pain in human volunteers, a paralleled, double-blinded, placebo-controlled, randomized controlled trial design combined with verbal pain scores (VPS) was performed. The combination of menthol and ethanol (5%M+70%E/T-gel) conferred significantly higher tetracaine diffusion across full-thickness mouse skin than 5%M/T-gel, 70%E/T-gel, and T-gel. The ultra structure changes of mouse skin stratum corneum treated with 5%M+70%E/T-gel were more marked compared with those of any other tetracaine gel. von Frey tests in mice showed a synergistically enhanced effect of menthol and ethanol on the analgesia of tetracaine gel. The mean VPS were significantly lower for volunteers treated with 5%M+70%E/T-gel than those receiving other gels or the EMLA cream. 5%M+70%E/T-gel possessed the shortest anesthesia onset time, the longest anesthesia duration and the strongest anesthesia efficacy. Seventy percent ethanol in 5%M+70%E/T-gel not only improved the analgesic efficacy of the tetracaine gel through synergistically enhanced percutaneous permeation with menthol but also served as an antiseptic agent keeping drug application site from infection. 5%M+70%E/T-gel is a potential topical anesthesia preparation for clinical use.

Pharmacokinetics of sibutramine hydrochloride in Chinese healthy volunteers.

AIM: To evaluate the pharmacokinetic profiles of the pharmacologically active primary amine metabolite of sibutramine, N-di-desmethyl sibutramine (BTS 54505) in Chinese origin. METHODS: According to a randomized cross-over design, a single oral dose of 20 mg of sibutramine hydrochloride capsule was given to 20 healthy Chinese young volunteers. After dosing, serial blood samples were collected for a period of 72 h. BTS 54505 concentration in plasma was analyzed by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: Various pharmacokinetic parameters including AUC0-t, AUC0-infinity, Cmax, Tmax, T1/2, Kelm and MRT were determined for both test and reference capsules and found to be in good agreement with literature values. CONCLUSION: The test and reference sibutramine capsules were bioequivalent.