RVT-1601

Hypericin (HY) is a naphthodianthrone that naturally occurs in Hypericum perforatum L. It is a promising photosensitiser used in photodynamic therapy for and diagnosis of oncological diseases. However, its hydrophobic character is an obstacle that has prevented its efficient use. The commonly used solvent, dimethyl sulfoxide (DMSO), is a controversial constituent of HY formulations and its use has been rejected by many researchers studying HY both in vitro and in vivo. In this study, we propose the utilisation of hydrotropy to solubilise HY in an aqueous environment. Cromolyn (DSCG) is a non-toxic, well-tolerated, antiallergic drug that has been employed in clinical practice since 1970, and in aqueous solution it acts as a hydrotrope. At a molecular ratio of 1:12,000 HY to DSCG, the compound is able to solubilise HY in aqueous environment. In an HT-29 cell suspension, DSCG (1.8 mmol L^-1) considerably enhances the interaction between HY (150 nmol L^-1) and HT-29 cells, which leads to an HY fluorescence emission increase with a half-time approximately 2 min compared to 29 min for samples that lack DSCG. Studies using HT-29 adenocarcinoma cells showed that DSCG at a given concentration significantly improved accumulation of HY within cells compared to DMSO (p < 0.05) despite the relative resistance of the HT-29 cell line to HY-PDT. Though no significant difference between total reactive oxygen species production was observed for photoactivated HY dissolved in DMSO and DSCG, significant singlet oxygen generation by photoactivated HY dissolved in a DSCG-containing water solution at the studied molecular ratio was confirmed. We also clarified that DSCG does not act as a scavenger of ABTS and galvinoxyl free radicals. The results from an MTT assay showed that DSCG also significantly enhanced the cytotoxicity of photoactivated HY compared to DMSO (p < 0.05). This study has demonstrated the ability of DSCG to act as a solvent of HY and enhance the effectiveness of HY-PDT compared to the commonly used organic solvent, DMSO.

In 1960s, cromolyn sodium (CS) has been introduced as the first non-steroidal anti-inflammatory drug for the treatment of allergic and mast-cell driven diseases. Its applicability has been limited due to a poor bioavailability. Here we present pharmacokinetic data of a novel high concentration formulation of CS (PA101) delivered via a high-efficiency nebulizer (eFlow®) in healthy volunteers (HVs), allergic asthmatics and patients with indolent systemic mastocytosis (ISM). In HVs, PA101 40 mg and 80 mg (30 L) and PA101 40 mg (40 L), Intal^TM (via LC® Plus) 20 mg and Nalcrom® (oral suspension) 200 mg showed maximum measured plasma concentration (C_max) of 156, 236, 88.6, 17.8 and 5.23 ng/mL, respectively, with respective areas under the plasma time-concentration curve (AUC) of 338, 526, 212, 40.6 and 33.3 h·ng/mL. Systemic exposure (AUC) to CS with PA101 40 mg was approximately 8-fold and 11-fold higher compared to Intal^TM and Nalcrom® in HVs, respectively. PA101 via eFlow® yielded comparable PK profiles in HVs and patients. Systemic bioavailability of PA101 was approximately 25% compared to approximately 1% for Nalcrom® and approximately 10% for Intal^TM, respectively. These data warrant further research on the therapeutic potential of PA101 (via eFlow®) in allergic and mast-cell driven diseases.