The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood-brain barrier (BBB). Borneol is a naturally occurring compound in a class of 'orificeopening' agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the 'orifice-opening' effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol's chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose-and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery. ARTICLE HISTORY

(+)-Catechin (C) and (-)-epicatechin (EC), as the basic monomer units of flavanols, can be widely found in natural products or medicinal herbs. Recent pharmacological studies have revealed that C and EC exhibit good neuroprotective effects. However, there is little information about pharmacokinetic profiles in the brain and in vivo BBB penetration of C and EC. In this paper, an ultrasensitive method using high-performance liquid chromatography (HPLC) with chemiluminescence (CL) detection was developed for the analysis of microdialysis samples. The detection limits for C and EC in Ringer's solution were 1.0 and 1.2 ng/mL, respectively. The intraday and interday accuracies for C and EC in Ringer's solution ranged from -3.0 to 4.4%, and the intraday and interday precisions were below 5.2%. The mean in vivo recoveries of C and EC in microdialysis probes were 33.7% and 26.5% in blood while 38.3% and 29.1% in brain. Pharmacokinetic parameters were estimated using the statistical moment method after iv administration (C and EC, 20 mg/kg of body weight) in rats. Brain-to-blood (AUC(brain)/AUC(blood)) distribution ratios were 0.0726 ± 0.0376 for C and 0.1065 ± 0.0531 for EC, indicating that C and EC could pass through the BBB, which is further evidence of their neuroprotective effects.

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The efficacy of anti-VEGF agents probably lies on VEGF-dependency. Apatinib, a specific tyrosine kinase inhibitor that targets VEGF receptor 2, was assessed in patients with advanced breast cancer (ABC) (ClinicalTrials.gov NCT01176669 and NCT01653561). This substudy was to explore the potential biomarkers for VEGF-dependency in apatinib-treated breast cancer. Eighty pretreated patients received apatinib 750 or 500 mg/day orally in 4-week cycles. Circulating biomarkers were measured using a multiplex assay, and tissue biomarkers were identified with immunostaining. Baseline characteristics and adverse events (AEs) were included in the analysis. Statistical confirmation of independent predictive factors for anti-tumor efficacy was performed using Cox and Logistic regression models. Median progression-free survival (PFS) was 3.8 months, and overall survival (OS) was 10.6 months, with 17.5 % of objective response rate. Prominent AEs (≥60 %) were hypertension, hand-foot skin reaction (HFSR), and proteinuria. Higher tumor phosphorylated VEGFR2 (p-VEGFR2) expressions (P = 0.001), higher baseline serum soluble VEGFR2 (P = 0.031), hypertension (P = 0.011), and HFSR (P = 0.018) were significantly related to longer PFS, whereas hypertension (P = 0.002) and HFSR (P = 0.001) were also related to OS. Based on multivariate analysis, only p-VEGFR2 (adjusted HR, 0.40; P = 0.013) and hypertension (adjusted HR, 0.58; P = 0.038) were independent predictive factors for both PFS and clinical benefit rate. Apatinib had substantial antitumor activity in ABC and manageable toxicity. p-VEGFR2 and hypertension may be surrogate predictors of VEGF-dependency of breast cancer, which may identify an anti-angiogenesis sensitive population.

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