Pharmacokinetic characterization of carnosol from rosemary (Salvia Rosmarinus) in male C57BL/6 mice and inhibition profile in human cytochrome P450 enzymes.

Rosemary (Salvia Rosmarinus) is a rich source of dietary diterpenes with carnosol as one of the major polyphenols used to standardize rosemary extracts approved as a food preservative, however, at present there is not any information on the murine pharmacokinetic profile of carnosol or its potential for drug interactions. The present study utilizes cell-free, cell-based, and animal-based experiments to define the pharmacokinetic profile of the food based phytochemical carnosol. Mice were administered carnosol (100 mg/kg body weight) by oral gavage and plasma levels were analyzed by LC-MS/MS to establish a detailed pharmacokinetic profile. The maximum plasma concentration exceeded 1 µM after a single administration. The results are significant as they offer insights on the potential for food-drug interactions between carnosol from rosemary and active pharmaceutical ingredients. Carnosol was observed to inhibit selected CYP450 enzymes and modulate metabolic enzymes and transporters in in vitro assays.

Pharmacokinetic Analysis of Carnosic Acid and Carnosol in Standardized Rosemary Extract and the Effect on the Disease Activity Index of DSS-Induced Colitis.

Rosemary extract (RE) is an approved food preservative in the European Union and contains dietary phytochemicals that are beneficial for gastrointestinal health. This study investigated the effects of RE on dextran sodium sulfate (DSS)-induced colitis and also determined the pharmacokinetics of dietary phytochemicals administered to mice via oral gavage. Individual components of rosemary extract were separated and identified by LC-MS/MS. The pharmacokinetics of two major diterpenes from RE, carnosic acid (CA) and carnosol (CL), administered to mice via oral gavage were determined. Then, the effect of RE pre-treatment on the disease activity index (DAI) of DSS-induced colitis in mice was investigated. The study determined that 100 mg/kg RE significantly improved DAI in DSS-induced colitis compared to negative control. Sestrin 2 protein expression, which increased with DSS exposure, was reduced with RE treatment. Intestinal barrier integrity was also shown to improve via fluorescein isothiocyanate (FITC)-dextran administration and Western blot of zonula occludens-1 (ZO-1), a tight junction protein. Rosemary extract was able to improve the DAI of DSS-induced colitis in mice at a daily dose of 100 mg/kg and showed improvement in the intestinal barrier integrity. This study suggests that RE can be an effective preventative agent against IBD.

Galactose-Modified PH-Sensitive Niosomes for Controlled Release and Hepatocellular Carcinoma Target Delivery of Tanshinone IIA.

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.

The effects of borneol on the pharmacokinetics and brain distribution of tanshinone IIA, salvianolic acid B and ginsenoside Rg1 in Fufang Danshen preparation in rats.

Fufang Danshen preparation (FDP) is consisted of Salviae Miltiorrhizar Radix et Rhizoma (Danshen), Notoginseng Radix et Rhizoma (Sanqi) and Borneolum Syntheticum (borneol). FDP is usually used to treat myocardial ischemia hypoxia, cerebral ischemia and alzheimer's disease, etc. In the treatment of cerebrovascular diseases, borneol is usually used to promote the absorption and distribution of the bioactive components to proper organs, especially to the brain. The purpose of this study is investigating the effects of borneol on the pharmacokinetics and brain distribution of tanshinone IIA (TS IIA), salvianolic acid B (SAB) and ginsenoside Rg1 in FDP. Male healthy Sprague-Dawley (SD) rats were given Danshen extracts, Sanqi extracts (Panax notoginsengsaponins) or simultaneously administered Danshenextracts, Sanqi extracts and borneol. Plasma and brain samples were collected at different points in time. The concentration of TS IIA, SAB and Rg1 was determined by UPLC-MS/MS method. The main pharmacokinetics parameters of plasma and brain tissue were calculated by using Phoenix WinNolin 6.1 software. In comparison with Danshen and Sanqi alone, there were significant differences in pharmacokinetic parameters of TS IIA, SAB and Rg1, and the brain distribution of SAB and TS IIA when Danshen, Sanqi and borneol were administrated together. Borneol statistically significant shortened tmax of TS IIA, SAB and Rg1 in plasma and brain, increased the bioavaiability of Rg1, inhibited metabolism of Rg1 and enhanced the transport of TS IIA and SAB to brain. These results indicated that borneol could affect the multiple targets components and produce synergistic effects. Through accelerating the intestinal absorption and brain distribution, borneol caused the effective ingredients of Danshen and Sanqi to play a quicker therapeutic role and improved the therapeutic effect.

Improving in vitro bioaccessibility and bioactivity of carnosic acid using a lecithin-based nanoemulsion system.

As a phenolic terpenoid, carnosic acid (CA) mainly exists in rosemary, which can be effectively used for the treatment of degenerative and chronic diseases by taking advantage of its health-promoting bioactivities. However, the low solubility and dissolution of CA in aqueous solutions at ambient and body temperatures result in low stability and bioaccessibility during the digestion process, which limits its application scope in the functional foods industry. In this regard, a lecithin based nanoemulsion system (CA-NE) is employed in the present work to enhance the bioaccessibility and bioactivities of CA. It is revealed that the CA-NE under investigation exhibits high loading capacity (2.80 ± 0.15%), small particle size (172.0 ± 3.5 nm) with homogeneous particle distribution (polydispersity index (PDI) of 0.231± 0.025) and high repulsive force (zeta potential = -57.2 ± 0.24 mV). More importantly, the bioaccessibility of CA-NE is improved by 2.8-fold compared to that of CA in MCT oil. In addition, the cellular antioxidant assay (CAA) and cellular uptake study of the CA-NE in HepG2 cell models demonstrate a longer endocytosis process, suggesting the well-controlled release of CA from CA-NE. Furthermore, an improved anti-inflammatory activity was evaluated via the inhibition of the pro-inflammatory cytokines, nitric oxide (NO) and TNF-α production in LPS-stimulated RAW 264.7 macrophage cells. The results clearly demonstrated a promising application of CA-NE as a functional food.

Comparative pharmacokinetics of seven bioactive components in normal, sham-operated, and myocardial ischemia-reperfusion injury rats after oral administration of the Salvia Miltiorrhiza-Moutan Cortex herb pair.

Recently the Salvia Miltiorrhiza-Moutan Cortex (SM-MC) herb pair is considered as a promising Chinese medicinal mixture exhibiting a range of pharmacological activities, including treating cardiovascular disease due to its unique composition. In this study, we conducted the comparative pharmacokinetic analysis of seven main bioactive components of SM-MC in a different model rat. A straightforward ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) strategy that could simultaneously evaluate the levels of seven compounds was used to ensure the reliability of these pharmacokinetic analyses in rat plasma. The rat plasma samples were collected from normal, sham-operated, and myocardial ischemia-reperfusion injury (MIRI) groups at predetermined time points after the administration of SM-MC. The main pharmacokinetic parameters were detected and calculated. We successfully assessed the maximum concentration (Cmax ), time to Cmax (Tmax ), the elimination rate constant (λz ), total half-life (t1/2 ), total body clearance (CL), and the area under the concentration-time curve from 0 to last sampling time (AUC0-t ) and extrapolated to infinity (AUC0-∞ ). To sum up, an optimized UPLC-MS/MS approach that could be used to rapidly, simultaneously, and sensitively detect seven bioactive compounds derived from SM-MC extract preparations was successfully developed, which may offer a pharmacokinetic basis for preclinical and clinical studies of SM-MC herb pair for treating MIRI.

Improving the bioaccessibility and bioavailability of carnosic acid using a lecithin-based nanoemulsion: complementary in vitro and in vivo studies.

Carnosic acid (CA) represents one of the most effective antioxidants that can be applied for the prevention of degenerative and chronic diseases. However, the intrinsic hydrophobic nature of CA results in low solubility and poor dissolution in the gastrointestinal (GI) tract, which limits its applications in a variety of functional food systems. In order to address these issues, we encapsulated CA in a lecithin-based nanoemulsion (CA-NE) to improve its bioaccessibility and bioavailability which are evaluated using in vitro and in vivo digestion models. The CA-NE demonstrated a loading capacity of 2.6-3.0%, an average particle size of 165 nm, a ζ-potential value of -57.2 mV, and good stability during 4-weeks of storage at 4, 25, and 37 °C. The in vitro static pH-stat lipolysis model and dynamic TNO gastrointestinal (TIM-1) model demonstrated a 12.6 and 5.6 fold increase in the total bioaccessibility of CA encapsulated in nanoemulsion, respectively, as opposed to CA in suspension form. Moreover, the in vivo pharmacokinetics study on a rat model (Male Sprague Dawley) confirmed that the bioavailability of CA in nanoemulsion showed a 2.2 fold increase, as compared to that of CA in suspension form. In conclusion, the bioaccessibility and bioavailability of CA were remarkably improved by encapsulation of CA in a lecithin-based nanoemulsion. Moreover, the combined in vitro and in vivo study could serve as a useful approach for the comprehensive evaluation of oral lipid-based delivery systems.

Pharmacological properties of tanshinones, the natural products from Salvia miltiorrhiza.

Danshen (Cai, et al. 2016) is the dry root and rhizome of the herbaceous plant Salvia miltiorrhiza Bge. of family labiatae, a perennial plant that is native to China and Japan. The primary modern clinical applications of Danshen are for heart disease, chronic hepatitis, early cirrhosis, cerebral ischemia and pulmonary heart disease. Emerging evidence from cellular, animal, and clinical studies has begun to illuminate the pharmacological attributes of the primary lipophilic tanshinones from Danshen, which include tanshinone I, tanshinone II, cryptotanshinone and dihydrotanshinone, etc. Tanshinones offer the properties of anti-oxidation, anti-inflammation, antitumor, phytoestrogenic activity, vasodilation, neuroprotection, regulate metabolic function and other pharmacological advances. This chapter will review the discovery of the pharmacodynamic mechanism and pharmacokinetic studies of tanshinones and Danshen for further clinical applications.

Comparative pharmacokinetics and tissue distribution of cryptotanshinone, tanshinone IIA, dihydrotanshinone I, and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats.

Salvia miltiorrhiza is one of the most commonly used traditional Chinese medicines in the treatment of cardiovascular and cerebrovascular diseases. Cryptotanshinone (CTS), tanshinone IIA (Tan IIA), dihydrotanshinone I (diTan I), and tanshinone I (Tan I) are the main active compounds in the liposoluble extract of Salvia miltiorrhiza. The differences in the pharmacokinetic and tissue distribution behaviors of the four tanshinones after oral administration of the liposoluble extract of Salvia miltiorrhiza and pure compounds are not clear. This study aims to compare the pharmacokinetics and tissue distribution of the four tanshinones after oral administration of pure tanshinone monomers and the liposoluble extract of Salvia miltiorrhiza. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis method was developed for the determination of the four tanshinones. The results showed that the AUC and Cmax of tanshinones in rats receiving the extract of Salvia miltiorrhiza were significantly increased compared with those receiving the pure tanshinones. In the tissue distribution experiments, the AUC of the four tanshinones in the extract was much greater than the AUC of the monomers in the lung, heart, kidney, liver, and brain, and the coexisting constituents particularly promoted the distribution of tanshinones into tissues that the drug cannot sufficiently penetrate. These findings suggested that the coexisting constituents in the liposoluble extract of Salvia miltiorrhiza play an important role in the alteration of plasma concentration and tissue distribution of the four tanshinones. Understanding these differences could be of significance for the development and application of Salvia miltiorrhiza extract and tanshinone components.

Effects of sulfotanshinone sodium injection on the pharmacokinetics and pharmacodynamics of warfarin in rats in vivo.

This study was to explore the effects of sulfotanshinone sodium injection (SSI) on the pharmacokinetics and pharmacodynamics of warfarin in rats.The studies of single dose and multiple dose of warfarin were designed to assess the interaction between warfarin and SSI. Rats were divided into different groups randomly and administered with warfarin in the absence or presence of SSI. Prothrombin time (PT) and activated partial thromboplastin time (APTT) values were detected by blood coagulation analyzer, and international normalized ratio (INR) values were calculated. Plasma concentrations of warfarin enantiomers were determined by UPLC-MS/MS method, pharmacokinetic parameters were calculated.The single-dose study demonstrated that the repeated doses of SSI alone had no effect on PT, APTT and INR values, but had a significant effect on PT and INR values produced by a single dose of warfarin, APTT values were unaffected. The Cmax, AUC of R-warfarin and S-warfarin were reduced, t1/2 were shortened. The multiple-dose study showed that PT, APTT, INR values, and the Cmax and AUC of R-warfarin and S-warfarin decreased significantly after administration of SSI.The finding implied that SSI could accelerate warfarin metabolism and weaken its anticoagulation. However, human SSI-warfarin interaction studies need to be conducted to confirm this finding.

Preparation, preliminary pharmacokinetics and brain tissue distribution of Tanshinone IIA and Tetramethylpyrazine composite nanoemulsions.

Objective: Tanshinone IIA (TSN) and Tetramethylpyrazine (TMP) were combined in a composite, oil-in-water nanoemulsions (TSN/TMP O/W NEs) was prepared to prolong in vitro and vivo circulation time, and enhance the bioavailability of TSN. Material and methods: Physicochemical characterization of TSN/TMP O/W NEs was characterized systematically. The in vitro dissolution and in vivo pharmacokinetic experiments of TSN/TMP O/W NEs were also evaluated. Result: A formulation was optimized, yielding a 32.5 nm average particle size, an encapsulation efficiency of over 95 %, and were spherical in shape as shown by TEM. TSN/TMP O/W NEs were shown to extend the release and availability in vitro compared to raw compounds. In pharmacokinetic study, the AUC0→∞ and t1/2 of the TSN/TMP O/W NEs were 481.50 mg/L*min and 346.39 min higher than TSN solution, respectively. Brain tissue concentration of TSN was enhanced with TSN/TMP O/W NEs over raw TSN and even TSN O/W NEs. Conclusions: Therefore, nanoemulsions are an effective carrier to increase encapsulation efficiency of drugs, improve bioavailability and brain penetration for TSN - which is further enhanced by pairing with the co-delivery of TMP, providing a promising drug delivery.

Rapid Identification of Tanshinone IIA Metabolites in an Amyloid-ß1-42 Induced Alzherimer's Disease Rat Model using UHPLC-Q-Exactive Qrbitrap Mass Spectrometry.

Alzheimer's disease (AD) is a neurodegenerative disorder that damages health and welfare of the elderly, and there has been no effective therapy for AD until now. It has been proved that tanshinone IIA (tan IIA) could alleviate pathological symptoms of AD via improving non-amyloidogenic cleavage of amyloid precursor protein, decreasing the accumulations of p-tau and amyloid-ß1-42 (Aß1-42), and so forth. However, the further biochemical mechanisms of tan IIA are not clear. The experiment was undertaken to explore metabolites of tan IIA in AD rats induced by microinjecting Aß1-42 in the CA1 region of hippocampus. AD rats were orally administrated with tan IIA at 100 mg/kg weight, and plasma, urine, faeces, kidney, liver and brain were then collected for metabolites analysis by UHPLC-Q-Exactive Qrbitrap mass spectrometry. Consequently, a total of 37 metabolites were positively or putatively identified on the basis of mass fragmentation behavior, accurate mass measurements and retention times. As a result, methylation, hydroxylation, dehydration, decarbonylation, reduction reaction, glucuronidation, glycine linking and their composite reactions were characterized to illuminate metabolic pathways of tan IIA in vivo. Several metabolites presented differences in the distribution of tan IIA between the sham control and the AD model group. Overall, these results provided valuable references for research on metabolites of tan IIA in vivo and its probable active structure for exerting neuroprotection.

A network pharmacology integrated pharmacokinetics strategy for uncovering pharmacological mechanism of compounds absorbed into the blood of Dan-Lou tablet on coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Dan-Lou tablet (DLT) is developed from the traditional Chinese medicine (TCM) formula Gualou Xiebai Baijiu Tang which has been used for at least 2000 years in China. DLT has been widely used in clinical practice to treat cardiovascular diseases. AIM OF THE STUDY: This study aimed to uncover the pharmacological mechanism of the compounds absorbed into the blood of Dan-Lou tablet (DLT) on coronary heart disease (CHD) using a network pharmacology integrated pharmacokinetics strategy. MATERIALS AND METHODS: A rapid and sensitive method was developed for the simultaneous determination of the six compounds (puerarin, formononetin, calycosin, paeoniflorin, cryptotanshinone and tanshinone IIA) in rat plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS). Then, the pharmacology network was established based on the relationship between five compounds absorbed into the blood targets (puerarin, formononetin, calycosin, cryptotanshinone and tanshinone IIA) and CHD targets. RESULTS: The intra-and inter-day precision were less than 11% and the accuracy ranged from 88.2% to 112%, which demonstrated that the LC-MS/MS method could be used to evaluate the pharmacokinetic feature of the six compounds in rats after oral administration of DLT. The pathway enrichment analysis revealed that the significant bioprocess networks of DLT on CHD were positive regulation of estradiol secretion, negative regulation of transcription from RNA polymerase II promoter, lipopolysaccharide-mediated signaling pathway and cytokine activity. CONCLUSION: The proposed network pharmacology integrated pharmacokinetics strategy provides a combination method to explore the therapeutic mechanism of the compounds absorbed into the blood of multi-component drugs on a systematic level.

Segmented scan modes and polarity-based LC-MS for pharmacokinetic interaction study between Fufang Danshen Dripping Pill and Clopidogrel Bisulfate Tablet.

Fufang Danshen Dripping Pill (FDDP) and Clopidogrel Bisulfate Tablet (CBT) are usually combined for treatment of coronary artery diseases in clinical. To investigate the pharmacokinetic interaction between FDDP and CBT after oral administration of FDDP, CBT and their combination in rats, a novel LC-MS method with segmented scan modes (multiple reaction monitoring and selected ion monitoring) and polarity (positive and negative ionization) was developed. Clopidogrel and the main active ingredients of FDDP, with different chemical and ionization properties, were simultaneously quantified in plasma in a single run. The method was validated in terms of specificity, linearity, precision, accuracy, recovery, matrix effect and stability. As a result, co-administration of FDDP and CBT significantly altered the pharmacokinetic parameters of danshensu, ginsenoside Rb1, dihydrotanshinone I, tanshinone I and tanshinone IIA of FDDP, as well as clopidogrel. Mechanism studies suggested that induction of liver cytochrome P450 isozymes CYP2C11 and CYP3A1 by co-administration, as well as inhibition of carboxyl esterase 1, was partly responsible for FDDP-CBT pharmacokinetic interactions. The developed LC-MS method could be used to simultaneously quantify different types of in vivo analytes in a single run, and the results could be used for clinical medication guidance of FDDP and CBT.

Development of sustained-release pellets to modulate the in vivo processes of the main active components of Danshen: A pharmacokinetic and pharmacodynamic evaluation.

BACKGROUND: Danshen is a first-line traditional Chinese medicine derived from Salvia miltiorrhiza Bunge consisting mainly of tanshinone IIA, tanshinol, protocatechuic aldehyde, and salvianolic acid B, it is widely used to treat cardiovascular diseases based on the synergistic effect of its multiple active components. Recent studies have indicated that the overall effect of traditional Chinese medicine is closely related to the in vivo coexistence of a variety of active components. HYPOTHESIS: The prolongation of the coexistence of the four active components in Danshen in vivo by regulating their pharmacokinetic processes may contribute to better efficiency. METHODS/STUDY DESIGNS: Individual sustained-release pellets of the four main active components in Danshen were respectively prepared according to the optimised formulations developed in our previous studies to modulate their in vivo processes, in which the desired release profiles of each kind of sustained-release pellets for formulation optimisation were calculated based on the point-area deconvolution and circadian rhythm of variant angina. The four kinds of sustained-release pellets were filled into capsules on the basis of the original weight ratio of the four active components in purified Salvia miltiorrhiza extract for further in vitro release and pharmacokinetic and pharmacodynamic investigations. RESULTS: The release behaviours of the combined Danshen capsules composed of the four kinds of sustained-release pellets were evaluated in three media with different pH levels (pH 1.2, 6.8, and pure water). The release profiles of each kind of sustained-release pellets in pH 6.8 PBS and pH 1.2 HCl were similar to the release profile of those in pure water (similarity factors f2 > 50). Pharmacokinetic studies revealed that the four kinds of sustained-release pellets in the combined Danshen capsules possessed the same Tmax and similar and extended MRT. Moreover, pharmacodynamic studies indicated that the combined Danshen capsules had much better anti-angina effects than commercial Danshen capsules according to comprehensive evaluations via electrocardiogram, serum index (CK-MB, cTn-I, ET, and NO), myocardial oxidative damage, and myocardial pathologic biopsy. CONCLUSION: Sustained-release preparations can markedly prolong the in vivo coexistence of multiple components in Danshen to enhance their overall effects, which provides a potent strategy for developing the combination therapy of traditional Chinese medicine.

Metabolic characteristics of Tanshinone I in human liver microsomes and S9 subcellular fractions.

Tanshinone I (TSI) is a lipophilic diterpene in Salvia miltiorrhiza with versatile pharmacological activities. However, metabolic pathway of TSI in human is unknown. In this study, we determined major metabolites of TSI using a preparation of human liver microsomes (HLMs) by HPLC-UV and Q-Trap mass spectrometer. A total of 6 metabolites were detected, which indicated the presence of hydroxylation, reduction as well as glucuronidation. Selective chemical inhibition and purified cytochrome P450 (CYP450) isoform screening experiments revealed that CYP2A6 was primarily responsible for TSI Phase I metabolism. Part of generated hydroxylated TSI was glucuronidated via several glucuronosyltransferase (UGT) isoforms including UGT1A1, UGT1A3, UGT1A7, UGT1A9, as well as extrahepatic expressed isoforms UGT1A8 and UGT1A10. TSI could be reduced to a relatively unstable hydroquinone intermediate by NAD(P)H: quinone oxidoreductase 1 (NQO1), and then immediately conjugated with glucuronic acid by a panel of UGTs, especially UGT1A9, UGT1A1 and UGT1A8. Additionally, NQO1 could also reduce hydroxylated TSI to a hydroquinone intermediate, which was immediately glucuronidated by UGT1A1. The study demonstrated that hydroxylation, reduction as well as glucuronidation were the major pathways for TSI biotransformation, and six metabolites generated by CYPs, NQO1 and UGTs were found in HLMs and S9 subcellular fractions.

Comparative in vivo constituents and pharmacokinetic study in rats after oral administration of ultrafine granular powder and traditional decoction slices of Chinese Salvia.

Salvia miltiorrhiza, one of the most well-known herbal medicines, is commonly used for the treatment of coronary heart diseases in China. Besides traditional decoction slices (TDS), another relatively new product of S. miltiorrhiza, ultrafine granular powder (UGP; D90 < 45 µm), is also increasingly being used. In this paper, a UHPLC-LTQ-Orbitrap MS technique was developed for a metabolite profile study after oral administration of UGP and TDS of S. miltiorrhiza. The results showed that the number of in vivo absorbed compounds from UGP was much greater than that from TDS, and different types of products from S. miltiorrhiza will have different metabolic processes in vivo. Furthermore, a UHPLC-Q-Trap MS/MS method for simultaneously determining four tanshinones (tanshinone IIA, dihydrotanshinone I, tanshinone I and cryptotanshinone) was established and applied to assess the pharmacokinetics of the two types of products. All of the analytes displayed significant higher area under the concentration-time curve and peak concentration after oral administration of UGP than after TDS, indicating that ultrafine powder product could improve the bioavailability and absorption of cryptotanshinon,tanshinone II A,dihydrotanshinonE I and tanshinone I in vivo. The present study provides scientific information for further exploration of the pharmacology of these two types of S. miltiorrhiza and offers a reference for clinical administration of S. miltiorrhiza.

Triphenylphosphonium and D-α-tocopheryl polyethylene glycol 1000 succinate-modified, tanshinone IIA-loaded lipid-polymeric nanocarriers for the targeted therapy of myocardial infarction.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide. Currently, the best treatment options for myocardial infarction focus on the restoration of blood flow as soon as possible, which include reperfusion therapy, percutaneous coronary intervention, and therapeutic thrombolytic drugs. MATERIALS AND METHODS: In the present study, we report the development of lipid-polymeric nanocarriers (LPNs) for mitochondria-targeted delivery of tanshinone IIA (TN). D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was linked to the triphenylphosphonium (TPP) cation. The LPNs were fabricated by nanoprecipitation method. LPNs were evaluated in vitro and in vivo in comparison with free drugs and other similar nanocarriers. RESULTS: The mean diameter of TN/nanoparticles (NPs) was 89.6 nm, while that of TN/LPNs was 121.3 nm. The zeta potential of TN/NPs and TN/LPNs was -33.6 and -22.3 mV, respectively. Compared with free TN and TN/NPs, TN/LPNs exhibited significantly improved compatibility and therapeutic efficiency. In addition, the in vivo pharmacokinetics, biodistribution, and infarct therapy studies in Sprague Dawley rats showed that TPP-TPGS/TN/LPNs had better efficiency than their nonmodified TN/LPNs counterparts in all respects. CONCLUSION: These results indicated that the TPP-TPGS/TN/LPNs were promising nanocarriers for efficient delivery of cardiovascular drugs and other therapeutic agents for the treatment of CVDs.

Bioaccessibility and inhibitory effects on digestive enzymes of carnosic acid in sage and rosemary.

In this study, the aim was to determine the bioaccessibilities of carnosic acid in sage and rosemary and in vitro inhibitory effects of these samples on lipid and starch digestive enzymes by evaluating the lipase, α-amylase and α-glucosidase enzyme inhibition activities. The content of carnosic acid in rosemary (18.72 ±â€¯0.33 mg/g) was found to be higher than that content of that in sage (3.76 ±â€¯0.13 mg/g) (p < 0.05). The carnosic acid bioaccessibilities were found as 45.10 ±â€¯1.88% and 38.32 ±â€¯0.21% in sage and rosemary, respectively. The tested sage and rosemary showed inhibitory activity against α-glucosidase (Concentration of inhibitor required to produce a 50% inhibition of the initial rate of reaction - IC50 88.49 ±â€¯2.35, 76.80 ±â€¯1.68 µg/mL, respectively), α-amylase (IC50 107.65 ±â€¯12.64, 95.65 ±â€¯2.73 µg/mL, respectively) and lipase (IC50 6.20 ±â€¯0.63, 4.31 ±â€¯0.62 µg/mL, respectively). Furthermore, to the best of our knowledge, this is the first work that carnosic acid standard equivalent inhibition capacities (CAEIC50) for these food samples were determined and these values were in agreement with the IC50 values. These results show that sage and rosemary are potent inhibitors of lipase, α-amylase and α-glucosidase digestive enzymes.

Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties.

The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice.