Characterization and pharmacokinetics of a novel pirarubicin liposome powder.

BACKGROUND: Pirarubicin (THP), an analogue of doxorubicin, has exhibited promising activities against acute leukemia, malignant lymphoma, and several solid tumors. However, the cumulative cardiotoxicity limits its wide application in chemotherapy. METHOD: To provide an alternative strategy for reducing the cardiotoxicity, a novel THP liposome powder (L-THP), comprising distearoylphosphatidylcholine, distearoylphosphatidylglycerol, cholesterol, and lactose was appropriately prepared based on the physicochemical properties of THP. And L-THP was characterized and evaluated. Comparative studies on pharmacokinetic and biodistribution behaviors between L-THP and commercialized THP injection were performed in normal mice through intravenous administration. RESULTS: When L-THP was reconstituted in a proper amount of normal saline for injection, it had a mean diameter of around 220.0 nm, a zeta potential of about -33.0 mV, and a high THP entrapment efficiency of more than 93.1%. Pharmacokinetics study showed that heart accumulation of THP could be reduced by 81.2% for L-THP. CONCLUSION: These results suggest that our L-THP might greatly reduce the cardiotoxicity, thus improving the therapeutic index of THP. Meanwhile, further preclinical studies are warranted to define the cardiotoxicity and the therapeutic efficacy of L-THP.

Identification of fukinolic acid from Cimicifuga heracleifolia and its derivatives as novel antiviral compounds against enterovirus A71 infection.

Human enterovirus 71 (EV-A71) infections cause a wide array of diseases ranging from diarrhoea and rashes to hand-foot-and-mouth disease and, in rare cases, severe neurological disorders. No specific antiviral drug therapy is currently available. Extracts from 75 Chinese medicinal plants selected for antiviral activity based on the Chinese pharmacopeia and advice from traditional Chinese medicine clinicians were tested for activity against EV-A71. The aqueous extract of the rhizome of Cimicifuga heracleifolia (Sheng Ma) and Arnebia euchroma (Zi Cao) showed potent antiviral activity. The active fractions were isolated by bioassay-guided purification, and identified by a combination of high-resolution mass spectrometry and nuclear magnetic resonance. Fukinolic acid and cimicifugic acid A and J, were identified as active anti-EV-A71 compounds for C. heracleifolia, whereas for A. euchroma, two caffeic acid derivatives were tentatively deduced. Commercially available fukinolic acid analogues such as L-chicoric acid and D-chicoric also showed in vitro micromolar activity against EV-A71 lab-strain and clinical isolates.

Solid dispersion tablets of breviscapine with polyvinylpyrrolidone K30 for improved dissolution and bioavailability to commercial breviscapine tablets in beagle dogs.

Breviscapine, one of cardiovascular drugs extracted from a Chinese herb Erigeron breviscapinus, has been frequently used to treat cardiovascular diseases such as hypertension, angina pectoris, coronary heart disease and stroke. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. To overcome these drawbacks, breviscapine solid dispersion tablets consisting of breviscapine, polyvinylpyrrolidone K30 (PVP K30), microcrystalline cellulose and crospovidone were appropriately prepared. In vitro dissolution profiles showed that breviscapine released percentage of solid dispersion tablets reached 90 %, whereas it was only 40 % for commercial breviscapine tablets. Comparative pharmacokinetic study between solid dispersion tablets and commercial products was investigated on the normal beagle dogs after oral administration. Results showed that the bioavailability of breviscapine was greatly increased by 3.45-fold for solid dispersion tablets. The greatly improved dissolution rate and bioavailability might be attributed to intermolecular hydrogen bonding reactions between PVP K30 and scutellarin. These findings suggest that our solid dispersion tablets can greatly improve the bioavailability as well as the dissolution rate of breviscapine.

Metabonomic study on the cumulative cardiotoxicity of a pirarubicin liposome powder.

Pirarubicin (THP) is an anthracycline frequently used in the chemotherapy against acute leukemia, malignant lymphoma and several solid tumors. However, its clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that results in irreversible congestive heart failure. To provide a strategy for constraining or minimizing the cumulative cardiotoxicity of THP, a pirarubicin liposome powder (L-THP) was appropriately prepared, and the cumulative cardiotoxicity of L-THP and free THP (F-THP) were investigated on Sprague-Dawley rats after 3 successive doses. Urinary samples for metabonomic study, serum samples for biochemical assay, and heart samples for histopathology test were collected. As a result, the metabonomics-based findings such as PLS-DA plotting showed minimal metabolic alterations in L-THP as compared to F-THP, and correlated with the changes of serum biochemical assay and cardiac histopathology as measurements of damage to heart tissue. Our results confirm that when encapsulated into liposomes, the cumulative cardiotoxicity of THP can be greatly ameliorated. Lipophilic aglycone metabolites of THP associated with redox cycling are cardiotoxic for the possibility of reactive oxygen species (ROS) formation. Also, metabonomic analysis shows that the successive doses of THP will lead to severe metabolic pathways disturbances in the cell energy production. Further, the preliminary efficacy study of L-THP on lung cancer was evaluated in the approach of in vitro cytotoxicity on A549 cells by high content screening (HCS) analysis, and L-THP was found to exhibit better therapeutic index against lung cancer than THP.