Preclinical Analysis of Resistance and Cross-Resistance to Low-Dose Metronomic Chemotherapy.
Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy.
Invest New Drugs. 2013 Jun 2;
Chow A, Wong A, Francia G, Man S, Kerbel RS, Emmenegger U
Low-dose metronomic chemotherapy is an emerging form of chemotherapy with distinct mechanisms of action from conventional chemotherapy (e.g., antiangiogenesis). Although developed to overcome resistance to conventional chemotherapy, metronomic chemotherapy is subject to resistance on its own. However, there is a paucity of information on mechanisms of resistance, on cross-resistance between metronomic regimens using different cytotoxic drugs, and on cross-resistance between metronomic versus conventional chemotherapy, or versus targeted antiangiogenic therapy. Herein we show that PC-3 human prostate cancer xenografts were sensitive to both metronomic cyclophosphamide and metronomic docetaxel, but resistant to metronomic topotecan. Conventional docetaxel was only moderately active in parental PC-3 and in metronomic cyclophosphamide resistant PC-3 tumors. However, in metronomic cyclophosphamide resistant PC-3 tumors combining conventional docetaxel or bolus cyclophosphamide therapy with continued metronomic cyclophosphamide was superior to each treatment alone. Furthermore, bevacizumab had single-agent activity against metronomic cyclophosphamide resistant PC-3 tumors. Microarray analyses identified altered regulation of protein translation as a potential mechanism of resistance to metronomic cyclophosphamide. Our results suggest that sensitivity to metronomic chemotherapy regimens using different cytotoxic drugs not only depends on shared mechanisms of action such as antiangiogenesis, but also on as yet unknown additional antitumor effects that appear to be drug-specific. As clinically observed with targeted antiangiogenic agents, the continued use of metronomic chemotherapy beyond progression may amplify the effects of added second-line therapies or vice versa. However, metronomic chemotherapy is no different from other systemic therapies in that predictive biomarkers will be essential to fully exploit this novel use of conventional chemotherapeutics. HubMed – drug
Adapalene microemulsion for transfollicular drug delivery.
J Pharm Sci. 2013 May 31;
Bhatia G, Zhou Y, Banga AK
The aim of this study was to develop a microemulsion formulation of adapalene for transfollicular delivery. A pseudoternary phase diagram was developed for microemulsion consisting of oleic acid as oil phase, tween 20 as surfactant, Transcutol® as cosurfactant, and deionized water. Differential tape stripping and confocal laser scanning microscopy were performed to determine the penetration of microemulsion through hair follicles. Transmission electron microscopy, dynamic light scattering, polarizing light microscopy, and differential scanning calorimetry were performed to characterize the microstructures of microemulsion. The pH and viscosity of the microemulsions were also determined. Permeation studies were carried out in vitro on porcine ear skin over a period of 24 h using Franz diffusion cells. The drug penetration in the hair follicles increased from 0.109 ± 0.03 to 0.292 ± 0.094 ?g, as the microstructure of microemulsion shifted from oil-in-water to bi-continuous, with increase in water content of microemulsion. Confocal laser scanning microscopy images suggested that hair follicles provided the path for transfollicular permeation of adapalene microemulsion. These results suggest that microemulsion penetrated through hair follicles and are promising for transfollicular drug delivery. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. HubMed – drug
Dose-Dependent Effect of Landiolol, a New Ultra-Short-Acting ?1-Blocker, on Supraventricular Tachyarrhythmias in Postoperative Patients.
Clin Drug Investig. 2013 Jun 1;
Taenaka N, Kikawa S
BACKGROUND: ?-Adrenoceptor antagonists (?-blockers) have been reported to be effective for regulation of heart rate (HR) and restoring sinus rhythm in postoperative atrial fibrillation and atrial flutter, as well as in the prevention of those arrhythmias after open-heart surgery. OBJECTIVES: The objectives of this study were to evaluate the dose-dependent effects of landiolol, an ultra-short-acting ?1-blocker, as well as the effectiveness and safety of the drug in suppressing supraventricular tachyarrhythmias (SVT) in postoperative patients. METHODS: Landiolol was administered as a four-dose titration regimen (LL, L, M, and H doses) to postoperative patients who developed SVT. The titration sequence began with a 1-min loading infusion at a rate of 0.015 mg/kg/min, followed by a 10-min continuous infusion at 0.005 mg/kg/min (the LL dose). Infusions at progressively higher doses followed in sequence until 20 % reduction in HR was achieved. The L dose was a 1-min loading infusion at 0.03 mg/kg/min, followed by a 10-min continuous infusion at 0.01 mg/kg/min. The M dose was a 1-min loading infusion at 0.06 mg/kg/min, followed by a 10-min continuous infusion at 0.02 mg/kg/min. The H dose was a 1-min loading infusion at 0.125 mg/kg/min, followed by a 10-min continuous infusion at 0.04 mg/kg/min. The patient was then observed for 30 min to determine the cardiovascular responses to withdrawal of the medication. After completion of this follow-up period, additional maintenance infusion for up to 6 h was permitted if considered necessary by the investigator. RESULTS: A total of 108 patients were enrolled in this study. The cumulative improvement rates (percentage of patients obtaining ?20 % reduction in HR) were 11.4, 32.4, 63.1, and 87.3 % at the LL, L, M, and H doses, respectively, demonstrating the dose-dependent effectiveness of landiolol. Additional infusion for up to 6 h was conducted in 16 patients. HR was maintained between 95.5 and 116.8 beats/min during the maintenance period (mean 259.8 min). Landiolol was generally well tolerated, although one patient with sick sinus syndrome developed an approximately 5-s cardiac arrest. CONCLUSIONS: The overall results, including those pertaining to patient safety, demonstrate that landiolol is effective and useful for the treatment of postoperative SVT. HubMed – drug
Evaluation of Hippocampal Injury and Cognitive Function Induced by Embolization in the Rat Brain.
Anat Rec (Hoboken). 2013 Jun 1;
Zhang HA, Gao M, Chen B, Shi L, Wang Q, Yu X, Xuan Z, Gao L, Du G
Embolism is responsible for at least 20% of all stroke and half of cerebral infarctions. A number of animal models have been developed to mimic thromboembolic stroke. However, little aimed directly at hippocampal damage and cognitive function. In the present study, three sizes of emboli (150-178 ?m, 74-124 ?m, and 48-74 ?m) were employed to induce thromboembolic stroke model in rats. Results showed that the diameter of the particle was critical for animal behavioral and histopathological consequences. Hematoxylin-eosin (HE) staining revealed that CA1 and CA2-3, which are two of the main hippocampal subdivisions were injured seriously, especially induced by emboli(48-74 ?m) . At 24 hr, the neurological deficit scores showed that emboli injection could cause significant neurological deficit, and the increase of neurological deficit scores correlated well to the diameter of emboli. At 60 days, emboli(150-178 ?m) and emboli(48-74 ?m) lead to obvious cognitive impairment, which correlated well to the hippocampal CA1 injury. Our research might be helpful to choose suitable size of emboli to induce animal model to research subcortical ischemia and vascular dementia. However, cognitive alterations and cerebral injury following different sizes of emboli injection in rats remains a topic for future investigation. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc. HubMed – drug