Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Immediate analgesic effect of acupuncture intervention within 10 min during acute migraine attacks: protocol of a randomised controlled trial.

INTRODUCTION: Migraine is a widespread neurological disorder characterised by recurrent moderate-to-severe headaches. These headaches can seriously affect patients' daily life and work, especially during acute attacks when patients often need immediate pain relief. This study aims to assess the immediate analgesic effect of acupuncture for 10 min during acute migraine attacks. METHODS AND ANALYSIS: The study will randomly divide 80 participants into either the acupuncture group or the sham acupuncture group with an allocation ratio of 1:1. Each group will receive 10 min of treatment, and the post-treatment evaluation will be performed after 0, 0-2, 4, 6, 8 and 10 min of acupuncture. The primary outcome is the pain Visual Analogue Scale (VAS) score assessed before and after treatment at 10 min. Additionally, secondary outcomes include the pain VAS score assessed at 0-2, 4, 6 and 8 min, blinding assessment and treatment effectiveness expectations scale. Data will be collected at baseline time and the end of treatment (after 10 min). Adverse events during each treatment period will be collected and recorded. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Second Affiliated Hospital of Yunnan University of Chinese Medicine (2022-008). All participants will provide written informed consent before randomisation. The results of this study will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registration Center (ChiCTR2200066976).

Stable Atropine Loaded Film As a Potential Ocular Delivery System For Treatment Of Myopia.

PURPOSE: The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia. METHODS: ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs. RESULT: After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia. CONCLUSION: The ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.

Kuntai Capsule Combined With Letrozole on Gonadal Hormone Levels and Ovarian Function in Patients With PCOS: A Systematic Review and Meta-Analysis.

Background: The efficacy of Kuntai capsule combined with letrozole (LE) in improving ovarian function of polycystic ovary syndrome (PCOS) has been evaluated before, but there is still a lack of evidence-based support for the regulation of sex hormone levels. In recent years, new randomized clinical trials (RCTs) have been reported on the effect of combined therapy on regulating sex hormone levels. Objective: We aimed to systematically evaluate the efficacy of Kuntai capsule combined with LE in the treatment of PCOS. Methods: A search across the China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang database, PubMed, Web of Science, The Cochrane Library, and Embase was conducted on Kuntai capsule combined with LE in the treatment of PCOS. The time of the self-built database was up to April 30, 2021. RCTs of LE in the control group and LE combined with Kuntai capsule in the experimental group were selected. RevMan5.3 software was used for data analysis. Results: A total of 17 studies were gathered, which included 1,684 patients. The meta-analysis results showed that the total effective rate of the combined group was 93.36% and that of the LE group was 78.15%. The improvement in the ovulation rate, pregnancy rate, number of mature follicles, endometrial thickness, cervical mucus score, and serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) in the combined group was consistent with the results of a previous meta-analysis and was better than that in the LE group (p < 0.05). In addition, the combination group was better than the LE group in regulating the levels of estradiol (E2) and testosterone (T) (p < 0.05). There were no adverse drug reactions in the two groups during treatment. Conclusion: As a type of pure traditional Chinese medicine preparation, Kuntai capsule combined with LE had a better effect than LE alone in the treatment of PCOS, with advantages mainly reflected in enhancing ovarian function and regulating the levels of sex hormones in vivo, among others, but the value of combined therapy still needs to be verified by more high-quality RCTs.

Toxicity Reduction and Efficacy Promotion of Doxorubicin in the Treatment of Breast Tumors Assisted by Enhanced Oral Absorption of Curcumin-Loaded Lipid-Polyester Mixed Nanoparticles.

Curcumin (CUR), a polyphenol derived from turmeric, exhibits anticancer and anti-inflammatory properties. However, it has poor water solubility, stability, and oral bioavailability. To overcome these limitations, lipid-polyester mixed nanoparticles (NPs) embedded in enteric polymer-EudragitL100-55(Eu) were formulated (CUR-NPs-Eu). NPs composed of mPEG-b-PCL have a hybrid core made up of middle chain triglyceride (MCT) and poly(ε-caprolactone) (PCL) for enhancing drug loading. The CUR-NPs with MCT content of 10% had a particle size of 121.2 ± 16.8 nm, ζ potential of -16.25 ± 1.38 mV, drug loading of 9.8%, and encapsulation efficiency of 87.4%. The transport of the CUR-NPs-Eu across Caco-2 monolayers is enhanced compared with CUR alone (1.98 ± 0.94 × 10-6 of curcumin versus 55.43 ± 6.06 × 10-6 cm/s of curcumin-loaded NPs) because of the non-disassociated nanostructure during absorption. The absolute bioavailability of CUR-NPs-Eu was 7.14%, which was drastically improved from 1.08% of the CUR suspension (CUR-Sus). Therefore, in the xenograft 4T1 tumor-bearing mice, increased drug accumulation in heart and tumor was noticed because of enhanced oral bioavailability of CUR. The chemosensitizing effect of CUR was attributed to its NF-κB reduction effect (148 ± 11.83 of DOX alone versus 104 ± 8.71 of combined therapy, ng/g tissue). The cardioprotective effect of CUR was associated with maintenance of cardiac antioxidant enzyme activity and down-regulation of NF-κB. This study provided a partial illustration of the mechanisms of chemosensitizing and cardioprotective effects of CUR utilizing the oral availability promotion effect brought by the NPs-Eu formulation. And these results further demonstrated that the capability of this NPs-Eu system in oral delivery of poorly soluble and poorly permeable drugs.

Melatonin Alleviates Neuroinflammation and Metabolic Disorder in DSS-Induced Depression Rats.

There is a bidirectional relationship between inflammatory bowel disease (IBD) and depression/anxiety. Emerging evidences indicate that the liver may be involved in microbiota-gut-brain axis. This experiment focused on the role of melatonin in regulating the gut microbiota and explores its mechanism on dextran sulphate sodium- (DSS-) induced neuroinflammation and liver injury. Long-term DSS-treatment increased lipopolysaccharide (LPS), proinflammation cytokines IL-1ß and TNF-α, and gut leak in rats, breaking blood-brain barrier and overactivated astrocytes and microglia. Ultimately, the rats showed depression-like behavior, including reduction of sucrose preference and central time in open field test and elevation of immobility time in a forced swimming test. Oral administration with melatonin alleviated neuroinflammation and depression-like behaviors. However, melatonin supplementation did not decrease the level of LPS but increase short-chain fatty acid (SCFA) production to protect DSS-induced neuroinflammation. Additionally, western blotting analysis suggested that signaling pathways farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF 15) in gut and apoptosis signal-regulating kinase 1 (ASK1) in the liver overactivated in DSS-treated rats, indicating liver metabolic disorder. Supplementation with melatonin markedly inhibited the activation of these two signaling pathways and its downstream p38. As for the gut microbiota, we found that immune response- and SCFA production-related microbiota, like Lactobacillus and Clostridium significantly increased, while bile salt hydrolase activity-related microbiota, like Streptococcus and Enterococcus, significantly decreased after melatonin supplementation. These altered microbiota were consistent with the alleviation of neuroinflammation and metabolic disorder. Taken together, our findings suggest melatonin contributes to reshape gut microbiota and improves inflammatory processes in the hippocampus (HPC) and metabolic disorders in the liver of DSS rats.

Pharmaceutical strategies of improving oral systemic bioavailability of curcumin for clinical application.

Curcumin (Cur), a natural compound from Curcuma longa Linn, has various of pharmacological activities such as anti-cancer, anti-inflammatory, anti-oxidant, anti-Alzheimer, anti-microbial and more. Curcumin also has nephroprotective, hepatoprotective, neuroprotective, antirheumatic and cardioprotective effects. However, its low aqueous solubility inhibits the oral bioavailability of curcumin. As well, curcumin can be metabolized rapidly by intestinal tract which can also result in low oral bioavailability. In fact, the bioavailability of curcumin is low even through intraveneous administration routes. Various of pharmaceutical strategies for oral administration including solid dispersions, nano/microparticles, polymeric micelles, nanosuspensions, lipid-based nanocarriers, cyclodextrins, conjugates, polymorphs have been developed in order to improve the oral bioavailability of curcumin. These pharmaceutical strategies can increase the solubility of curcumin, improve the intestinal stability of curcumin, change the absorption route of curcumin and allow for coadministration with other adjuvants. Here we discuss efficacy studies in vitro and in vivo of curcumin nanoformulations, as well as human clinical trials.

A Comprehensive Preclinical Evaluation of Intravenous Etoposide Lipid Emulsion.

PURPOSE: Etoposide is one of the principal chemotherapeutic agents used for the treatment of small cell lung cancer (SCLC). There are some disadvantages of currently available etoposide injections (EI) such as low LD50, necessary dilution before clinical application, thus, etoposide lipid emulsion (ELE) was developed and expected to have a comparable or better effect on SCLC. METHODS: ELE was prepared through high-pressure homogenization method, and a series of evaluations such as encapsulation efficiency (EE%), in vitro release, stability studies, pharmacokinetics study, safety assessment and pharmacodynamic study were systematically performed. RESULTS: ELE had high EE% and good stability. Pharmacokinetics study revealed ELE had a longer T1/2 F compared with EI, which is in agreement with in vitro release in which ELE released slower than EI (EI released over 80% within 12 h, while ELE released 50%). Safety tests showed there was no hematology or significant tendency of accumulated toxicity, and LD50 of ELE was higher than EI. Furthermore, percentage of tumor inhibition (TI%) of ELE was comparable with EI in the same dose. CONCLUSIONS: Unlike EI, ELE could further increase the dose, which endowed etoposide with a greater potential for cytotoxic agent. LE is a promising delivery system for etoposide.

Using a trait-based approach to optimize mixotrophic growth of the red microalga Porphyridium purpureum towards fatty acid production.

BACKGROUND: Organic carbon sources have been reported to simultaneously increase the growth and lipid accumulation in microalgae. However, there have been no studies of the mixotrophic growth of Porphyridium purpureum in organic carbon media. In this study, three organic carbon sources, glucose, sodium acetate, and glycerol were used as substrates for the mixotrophic growth of P. purpureum. Moreover, a novel trait-based approach combined with Generalized Additive Modeling was conducted to determine the dosage of each organic carbon source that optimized the concentration of cell biomass or fatty acid. RESULTS: A 0.50% (w/v) dosage of glucose was optimum for the enhancement of the cell growth of P. purpureum, whereas sodium acetate performed well in enhancing cell growth, arachidonic acid (ARA) and eicosapentaenoic acid (EPA) content, and glycerol was characterized by its best performance in promoting both cell growth and ARA/EPA ratio. The optimum dosages of sodium acetate and glycerol for the ARA concentration were 0.25% (w/v) and 0.38% (v/v), respectively. An ARA concentration of 211.47 mg L-1 was obtained at the optimum dosage of glycerol, which is the highest ever reported. CONCLUSIONS: The results suggested that a comprehensive consider of several traits offers an effective strategy to select an optimum dosage for economic and safe microalgae cultivation. This study represents the first attempt of mixotrophic growth of P. purpureum and proved that both biomass and ARA accumulation could be enhanced under supplements of organic carbon sources, which brightens the commercial cultivation of microalgae for ARA production.

Biopharmaceutical characters and bioavailability improving strategies of ginsenosides.

Deglycosylation is the most important gastrointestinal metabolism in which ginsenosides are split off from glycosyl moieties by the enzymes secreted from intestinal microflora, and two possible metabolic pathways of protopanaxdiol-type ginsenosides (PPD-type ginsenosides) and protopanaxtriol-type ginsenosides (PPT-type ginsenosides) have been concluded. The former is deglycosylated at C-3 and/or C-20, and transformed to protopanaxdiol (PPD). By comparison, the latter is deglycosylated at C-6 and/or C-20, and eventually transformed to protopanaxtriol (PPT) instead. The pharmacokinetic behavior of PPD-type ginsenosides and PPT-type ginsenosides is different, mainly in a faster absorption and elimination rate of PPT-type ginsenosides, but almost all of ginsenosides have a low oral bioavailability, which is relevant to the properties, the stability in the gastrointestinal tract, membrane permeability and the intestinal and hepatic first-pass effect of ginsenosides. Fortunately, its bioavailability can be improved by means of pharmaceutical strategies, including nanoparticles, liposomes, emulsions, micelles, etc. These drug delivery systems can significantly increase the bioavailability of ginsenosides, as well as controlling or targeting drug release. Ginsenosides are widely used in the treatment of various diseases, the most famous one is the Shen Yi capsule, which is the world's first clinical application of tumor neovascularization inhibitors. Hence, this article aims to draw people's attention on ocotillol-type ginsenosides, which have prominent anti-Alzheimer's disease activity, but have been overlooked previously, such as its representative compound-Pseudoginsenoside F11(PF11), and then provide a reference for the druggability and further developments of ocotillol-type ginsenosides by utilizing the homogeneous structure between dammarane-type ginsenosides and ocotillol-type ginsenosides.

Ontogenetic establishment of order-specific nuclear organization in the mammalian thalamus.

The thalamus connects the cortex with other brain regions and supports sensory perception, movement, and cognitive function via numerous distinct nuclei. However, the mechanisms underlying the development and organization of diverse thalamic nuclei remain largely unknown. Here we report an intricate ontogenetic logic of mouse thalamic structures. Individual radial glial progenitors in the developing thalamus actively divide and produce a cohort of neuronal progeny that shows striking spatial configuration and nuclear occupation related to functionality. Whereas the anterior clonal cluster displays relatively more tangential dispersion and contributes predominantly to nuclei with cognitive functions, the medial ventral posterior clonal cluster forms prominent radial arrays and contributes mostly to nuclei with sensory- or motor-related activities. Moreover, the first-order and higher-order sensory and motor nuclei across different modalities are largely segregated clonally. Notably, sonic hedgehog signaling activity influences clonal spatial distribution. Our study reveals lineage relationship to be a critical regulator of nonlaminated thalamus development and organization.

Evaluating the safety of phytosterols removed perilla seed oil-based lipid emulsion.

OBJECTIVES: The aim of this study was to ascertain the potential toxicity of perilla seed oil-based lipid emulsion (POLE) caused by phytosterols and confirm the efficacy of the technique for removing phytosterols from perilla seed oil, and evaluate the safety of a low phytosterol POLE in a long-term tolerance study in dogs. METHODS: A comparison between a soybean oil lipid emulsion (Intralipid group A) and POLE with high (group B) versus low (group C) levels of phytosterols was made with regard to their effects on the general condition, hematological and biochemical parameters, urinalysis and histopathological changes in nine dogs receiving daily infusions for four weeks at dosage levels of 6, 6, 9 g fat /kg. RESULTS: Dogs in group A and group C remained in good condition and gained weight during the infusion period and no diarrhea or gastrointestinal bleeding occurred. Only a moderate degree of anemia was observed, the biochemical parameters changed only slightly and returned to normal after treatment had ceased. However, the dogs in group B exhibited significant symptoms of 'fat overload syndrome'. Vomiting, diarrhoea and blood in the faeces were observed. Moreover, triglyceridemia, cholesteremia, and dark urine as well as microscopic signs of liver and gastrointestinal tract damage and generalized jaundice were clearly seen. CONCLUSIONS: Phytosterols promote 'fat overload syndrome' in long-term tolerance studies of POLE in dogs by producing cholestatic liver injury and interfering with fat metabolism. And the toxicity of POLE was reduced by removing phytosterols.

TMDB: a literature-curated database for small molecular compounds found from tea.

BACKGROUND: Tea is one of the most consumed beverages worldwide. The healthy effects of tea are attributed to a wealthy of different chemical components from tea. Thousands of studies on the chemical constituents of tea had been reported. However, data from these individual reports have not been collected into a single database. The lack of a curated database of related information limits research in this field, and thus a cohesive database system should necessarily be constructed for data deposit and further application. DESCRIPTION: The Tea Metabolome database (TMDB), a manually curated and web-accessible database, was developed to provide detailed, searchable descriptions of small molecular compounds found in Camellia spp. esp. in the plant Camellia sinensis and compounds in its manufactured products (different kinds of tea infusion). TMDB is currently the most complete and comprehensive curated collection of tea compounds data in the world. It contains records for more than 1393 constituents found in tea with information gathered from 364 published books, journal articles, and electronic databases. It also contains experimental 1H NMR and 13C NMR data collected from the purified reference compounds or collected from other database resources such as HMDB. TMDB interface allows users to retrieve tea compounds entries by keyword search using compound name, formula, occurrence, and CAS register number. Each entry in the TMDB contains an average of 24 separate data fields including its original plant species, compound structure, formula, molecular weight, name, CAS registry number, compound types, compound uses including healthy benefits, reference literatures, NMR, MS data, and the corresponding ID from databases such as HMDB and Pubmed. Users can also contribute novel regulatory entries by using a web-based submission page. The TMDB database is freely accessible from the URL of http://pcsb.ahau.edu.cn:8080/TCDB/index.jsp. The TMDB is designed to address the broad needs of tea biochemists, natural products chemists, nutritionists, and members of tea related research community. CONCLUSION: The TMDB database provides a solid platform for collection, standardization, and searching of compounds information found in tea. As such this database will be a comprehensive repository for tea biochemistry and tea health research community.

Parenteral formulation of larotaxel lipid microsphere tackling poor solubility and chemical instability.

The purpose of this study was to develop a parenteral larotaxel lipid microsphere (LTX-LM) and evaluate its stability. The preformulation study showed that LTX possessed poor solubility (0.057 µg/mL in aqueous phase) and chemical instability. LM was selected as the drug carrier due to its higher drug-loading capacities, higher physicochemical stability and reduced irritation and toxicity. High speed shear mixing and high-pressure homogenization were employed to prepare the LTX-LM. Particle size distribution (PSD), zeta-potential, drug content and entrapment efficiency (EE) were taken as indexes to optimize formulations. The dissolution studies were performed using a ZRS-8G dissolution apparatus according to the paddle method. Degradation kinetics test, freezing and thawing test and long term stability test were combined to evaluate the physicochemical stability of LTX-LM. From the degradation kinetics results, the shelf lives (T90%) of LTX in LM at 25 and 4°C (165, 555 days) were about 20 times as long as those in aqueous phase (200, 676 h), which were dramatically prolonged. The activation energies in aqueous solution and in LM calculated from the slopes were 41.93 and 42.25 kJ/mol. And its frequency factors (A) were 4.9 × 10(3)/s and 2.3 × 10(2)/s, respectively. Freezing and thawing test showed the PSD of LTX-LM became larger and wider increasing from 166.9 ± 53.2 nm to 257.4 ± 85.5 nm with more freeze-thaw cycles. From the long term stability test results, all the parameters changes were in qualified range.

Improving cabazitaxel chemical stability in parenteral lipid emulsions using cholesterol.

Intravenous lipid emulsions of cabazitaxel (CLEs) with a high stability were prepared by adding cholesterol (CH) to provide a new and more suitable delivery system for its administration. The factors affecting CLEs, such as the solubility of cabazitaxel in various oils, different kinds of lecithin, pH, different types of oil phases, and different concentrations of lipoid E80®, CH and poloxamer 188 were investigated systematically. The degradation of cabazitaxel in aqueous solution and lipid emulsion both followed pseudo first-order kinetics. A degradation mechanism was suggested by the U-shaped pH-rate profile of cabazitaxel. A formulation containing 0.5% (w/v) CH and another formulation without CH were made to investigate the protective influence of CH on the chemical stability of CLEs. The activation energy of the two formulations was calculated to be 65.74±6.88 and 54.24±1.43 kJ/mol (n=3), respectively. Compared with the untreated CH, the shelf-life of cabazitaxel with added CH was longer, namely 134.0±23.4 days versus 831.4±204.4 days (n=3) at 4 °C. This indicates that the addition of CH significantly improved the lifetime of cabazitaxel in intravenous lipid emulsions. The hydrogen bonding that takes place between cabazitaxel and CH accounts for the protective effect of CH on the chemical stability of CLEs in two ways: preventing cabazitaxel from leaking and hydrolyzing in aqueous solution and hindering hydrolysis in the oil phase. Finally, the hypothesis was confirmed by LC/TOFMS and Fourier-transform infrared-spectroscopy. As a result, CLEs were obtained successfully by the addition of CH and were stable enough to allow further research.

Lipid emulsions in parenteral nutrition: current applications and future developments.

INTRODUCTION: A parenteral lipid emulsion (LE), used as a key source of energy, essential fatty acids (FAs), and fat-soluble vitamins, is an integral part of a parenteral nutrition (PN) regimen. The conventional LEs, such as soybean oil (SO)-based emulsions, have caused concerns about the potential adverse effects involving oxidative stress, inflammation, and immune response probably because of undesirable FA composition. AREAS COVERED: Recently, alternative LEs, optimizing the FA composition with partial substitution of SO with medium-chain triglyceride (MCT), olive oil (OO), and fish oil (FO), have been developed and applied in clinical practice. This review summarizes the characteristics and beneficial clinical effects of alternative parenteral LEs in critically ill, pediatric, and long-term PN patients. EXPERT OPINION: More clinical data from sufficiently high-powered studies are required to characterize the integral biological properties of alternative LEs for further selection to fit individual needs and disease characteristics. Simultaneously, potential lipid sources with desirable FA compositions and biological properties should be selected to develop new therapeutic LEs. As supplements to current parenteral lipids, the new LEs with different therapeutic effects are expected to fit specified subpopulations of patients with different diseases. Great efforts should be devoted to the development of parenteral LEs.

[Effect of exogenous Ca2+ on protective infection of Pinellia ternata and accumulation of major components under high temperature stress].

OBJECTIVE: To study the effect of exogenous Ca2+ on protective infection of Pinellia ternata and accumulation of major components under high temperature stress. METHOD: The soilless cultivation experiment was applied, stress resistance index of P. ternata leaves, statistics the rate of lodge P. ternata,the content of oxalate in different places in the plant, the content of total alkaloids, total organic acids and glucosine in P. ternata tubers were measured based on different concentrations of exogenous Ca2+. RESULT: The test results showed that, at lower concentrations of Ca2+ treatments, the rate of lodge P. ternata was higher than that of the others. With Ca2+ concentration increasing, activities of SOD and POD initially increased and then decreased, however, proline level tended to be down then up. Soluble oxalic acid content was lower than the content of unhandled treatment in P. ternata leaves and tubers; with Ca2+ concentration increasing, soluble oxalic acidl content and yield showed a tendency of decrease after increase in the leaves and tubers. Compared with other treatments, spraying 400 mg x L(-1) Ca2+ significantly enhanced the accumulation of total alkaloid and guanosine in P. ternata tubers. At Lower concentrations of Ca2+, the content of total free organic acid was higher in the tuber. CONCLUSION: With the treatment of Ca2+ the capacity of heat resistance was improved in P. ternata plants, the rate of lodge P. ternata was postponed, growing period was extended and corresponding production has increased by spraying exogenous Ca2+.

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

OBJECTIVES: The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). RESEARCH DESIGN AND METHODS: Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). RESULTS: The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. CONCLUSIONS: These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Pharmacokinetic comparisons of single herb extract of Fufang Danshen preparation with different combinations of its constituent herbs in rats.

Salvianolic acid B (SAB), tanshinone IIA (TS), ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1) and notoginsenoside R1 (R1) are major active ingredients of Fufang Danshen preparation (FDP) for its protective effects on myocardial ischemia. This study investigated the pharmacokinetics of marker compounds after oral administration of single herb extract and different combinations of constitutional herbs in FDP, and explored potential herb-herb interactions among the ingredients in the multi-herb medicine. The pharmacokinetics study on the target compounds in rat plasma was performed using an optimal ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) coupled with protein precipitation method. There were no statistically significant differences in pharmacokinetic parameters of SAB, TS, Rb1, Rg1 and R1 between single Radix Salvia miltiorrhiza (S. miltiorrhiza) or Radix Panax notoginsen (P. notoginseng) extract and combination treatment. While, in comparison with oral administration of P. notoginseng extract alone, the pharmacokinetic parameters (C(max), AUC(0-72 h), AUC(0-∞), Cl, V), particularly for Rb1 and Rg1, were significantly different after oral administration P. notoginseng extract with addition of borneol (p<0.05). The AUC(0-72 h) values of Rb1 and Rg1 were significantly increased 1.3-fold and 1.6-fold, respectively, after P. Notoginsen extract co-administered with borneol. The results showed that herb-herb interactions may be accounting for the different pharmacokinetic behaviors of active constituents administered in compound prescriptions versus in single-herb extracts, however, which were not significant in most cases.

Evaluation of submicron emulsion as vehicles for rapid-onset intranasal delivery and improvement in brain targeting of zolmitriptan.

This study was to evaluate submicron emulsion as a drug carrier for intranasal delivery of zolmitriptan (ZT). Since the drug distribution in submicron emulsion might influence the nasal absorption, two different formulations separately incorporating the drug in oily phase (ZTSE-1) and aqueous phase (ZTSE-2) were assessed. To find the better formulation for rapid-onset intranasal delivery and improvement in brain targeting of ZT, the in vivo nasal absorption of these two formulations was evaluated. The blood and cerebrospinalfluid (CSF) pharmacokinetics of ZTSE-1, ZTSE-2 and ZT solution (ZTS) were evaluated after intranasal administered to anesthetized Wistar rats. The results demonstrated that ZT from ZTSE-1 and ZTSE-2 had better brain targeting efficiency than the ZTS. In plasma and CSF, the ZTSE-2 reached peak concentration much faster than ZTSE-1 and ZTS. The ZTSE-2 also presented significantly higher initial ZT levels in CSF compared with the ZTSE-1 and ZTS. The results indicated that incorporation of ZT in the aqueous phase of submicron emulsion was effective for rapid intranasal delivery of drug to blood and brain, which would offer patients the benefits of rapid relief from migraine.