Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aß and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aß plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD.

Mechanical properties and acoustic emission characteristics of deep hard coal after segmented high-temperature treatment.

Based on engineering background that local heating of coal seam is uneven due to underground coal gasification, coal-bed gas exploitation via heat injection, spontaneous combustion of coal seam, etc., segmented heating coal sample was used to simulate coal seam under uneven heating condition, and experimental study on mechanical behaviors of coal sample after segmented heat treatment at high temperatures was conducted. Test results show that temperature at 100 °C ~ 400 °C did not reach ignition temperature of deep hard coal for the experiment and was not enough to change main ingredients of coal sample, which less affected compression strength, elastic modulus, acoustic emission behavior of coal sample. Although compaction stage-elastic stage-plastic stage-broken stage appeared in compression stress-strain curve of coal sample, height increase led to decrease of compression strength, elastic modulus of coal sample, cumulative amplitude and ringing count for acoustic emission in the form of power function. Meanwhile, it is found that final failure modes of coal sample after segmented heat were mainly shear failure and separation failure and friction mixed failure was secondary. In addition, influence of heating temperature at 100 °C ~ 400 °C on failure modes of coal sample was small. However, height increase in the heating section of coal sample made shear failure surface gradually move to the heating section and separation failure surface moved with the change of contact surface position between heating section and non-heating section. Furthermore, the integral failure degree of coal sample was more serious. Finally, based on variation behaviors of acoustic emission parameter for coal sample after segmented heating, inversion formula on acoustic emission parameter for strength of coal sample was discussed and verified via experimental result of coal sample with different segmented heat height after heating treatment at 200 °C.

Cardiac safety analysis of first-line chemotherapy drug pegylated liposomal doxorubicin in ovarian cancer.

Pegylated liposomal doxorubicin (PLD) is a nano-doxorubicin anticancer agent. It was used as early as 2014 to treat ovarian and breast cancer, multiple myeloma and Kaposi's sarcoma. The 2018 National Comprehensive Cancer Network guidelines listed PLD as first-line chemotherapy for ovarian cancer. PLD has significant anticancer efficacy and good tolerance. Although PLD significantly reduces the cardiotoxicity of conventional doxorubicin, its cumulative-dose cardiotoxicity remains a clinical concern. This study summarizes the high-risk factors for PLD-induced cardiotoxicity, clinical dose thresholds, and cardiac function testing modalities. For patients with advanced, refractory, and recurrent malignant tumors, the use of PLD is still one of the most effective strategies in the absence of evidence of high risk such as cardiac dysfunction, and the lifetime treatment dose should be unlimited. Of course, they should also be comprehensively evaluated in combination with the high-risk factors of the patients themselves and indicators of cardiac function. This review can help guide better clinical use of PLD.

The impact of Pegylated liposomal doxorubicin in recurrent ovarian cancer: an updated meta-analysis of randomized clinical trials.

BACKGROUND: Previous meta-analysis studies suggested that pegylated liposomal doxorubicin (PLD) may improve the survival rate of patients with recurrent ovarian cancer. The aim of the present meta-analysis, then, was to further update the role of PLD in the treatment of recurrent ovarian cancer. METHODS: We performed a literature search using the electronic databases Medicine, EMBASE, Web of Science, and the Cochrane Library to 27 July 2020. We only restricted the randomized clinical trials. Study-specific hazard ratios and 95% confidence interval (HR/95% CI) and risk ratios and 95% confidence interval (RR/95% CI) were pooled using a random-effects model. RESULTS: Ten studies (12 trials) were included after screening 940 articles. We categorized the eligible studies into two groups: the doublet regimens (four trials, 1767 patients) showed that PLD plus carbo provided superior progression-free survival (PFS) (HR, 0.85; 95% CI, 0.74-0.97) and similar overall survival (OS) (HR, 1.00; 95% CI, 0.88-1.14) compared to paclitaxel (PAC) plus carboplatin (carbo). PLD plus carbo was associated with significantly more anemia and thrombocytopenia, and other side effects were well tolerated. The monotherapy regimens (eight trials, 1980 patients) showed that PLD possessed a similar PFS (HR, 1.02; 95% CI, 0.90-1.16) and OS (HR, 0.88; 95% CI, 0.77-1.01) relative to other monotherapies. PLD alone was also more associated with mucositis/stomatitis and hand-foot syndrome, while other side effects were well tolerated. CONCLUSIONS: In platinum-sensitive recurrent ovarian cancer, PLD plus carbo was more effective than PAC plus carbo, while in platinum-resistant or -refractory recurrent ovarian cancer, PLD exhibited similar survival to other monotherapies. Regarding side effects, PLD plus carbo and mono chemotherapy were both well tolerated.

Static and dynamic failure mechanisms of circular granite under the condition of water-heat cycles.

Based on the engineering environment where rocks surrounding wellbores in energy storage areas are influenced by high temperature, cool and hot water, thermal stress etc. in the exploitation of hydrothermally geothermal energy, the experimental study on mechanical properties of ring granite under the static and dynamic loads in the water-heat condition was performed. The experimental results showed that when the ring granite was influenced by the inner diameters, heating temperatures, curing temperatures and heat recovery cycle times, the impact load-strain curves were nonlinear. However, the concave stages, platform stages and cliff-like drop stages appeared in the load-strain curves under the static loads. The radical peak loads decreased exponentially with the growth of the damage factors and the dynamic peak loads were far greater than the static peak loads. By analyzing the damage cracks and broken fragments, it was found that under the static and dynamic radical loads, the cracks generated in the ring specimens were tensile cracks and the failure mode was tensile failure. However, the dynamic failure was more aggressive than the static failure. Then, the apparent deformation modulus was defined to describe the deformation characteristics of ring granite before the radical peak loads. And it is found that the variation law of dynamic apparent deformation modulus is more dispersed than the changes of static apparent deformation modulus. Finally, based on the deformation and failure characteristics of ring granite obtained from the tests, the static and dynamic failure criteria considering whether the cracks along the loading direction were generated in the inner ring wall were deduced and verified by the corresponding tests.

Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors.

Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced α-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.

Biomechanical Model Study of the Effect of Partial Facetectomy on Lumbar Stability Under Percutaneous Endoscopy.

OBJECTIVE: To investigate the effect of partial facetectomy on lumbar stability using percutaneous endoscopy. METHODS: Five male adult volunteers with no history of lumbar disease participated in the study. Based on computed tomography data, a three-dimensional model of the L3-S1 segment was created using the Mimics l5.0 and Ansys 13.0 software. The use of an 8.5-mm-diameter ring saw was simulated to cut through 5 different needle insertion points (IPs) commonly used in the clinic on the left-side facet joint (FJ) of L5 to perform facetectomy. The first to third IPs were on the apex of the superior FJ, the midpoint of the ventral side of the superior FJ, and the lowest point of the ventral side of the superior FJ. The fourth and fifth IPs represented the positions of the second and third IPs (8.5 mm/2) after the radius of the ring saw was translated to the dorsal side of the superior FJ. Physiologic load was applied to the human models. The pressure on the left and right FJ of the L5 vertebra, the pressure on the L4-5 intervertebral disc, and the range of motion of the lumbar spine were recorded when normal flexion and extension and lateral flexion and rotation of the lumbar spine model after facetectomy were simulated. RESULTS: Compared with the intact group, the second IP, maximum pressure on the L4-5 intervertebral disc after facetectomy was not significantly different under any condition (P > 0.05). The maximum pressure on the left FJ of L5 showed significant differences during right rotation of the lumbar spine (P < 0.05). The pressure on the right FJ of L5 was significantly different during left rotation of the lumbar spine (P < 0.05). The range of motion of the lumbar spine was not significantly different under any condition (P > 0.05). CONCLUSIONS: The second IP at the midpoint of the ventral side of the superior FJ showed minimal effect on lumbar spine biomechanics compared with all the other IPs during percutaneous transforaminal facetectomy. Thus, it can be considered as the most suitable IP for facetectomy.

Sub-stoichiometric reductive etherification of carbohydrate substrates and one-pot protecting group manipulation.

In this study, we report a new reductive etherification procedure for protection of carbohydrate substrates and its application for one-pot preparation of glycosyl building blocks. The reported procedure features the use of polymethylhydrosiloxane (PMHS) as a sub-stoichiometric reducing agent, which prevents the transilylation side reaction and improves the efficiency of the reductive etherification method. Application of the PMHS reductive etherification procedure for one-pot protecting group manipulation are described.

Cytochrome P450-Mediated λ-Cyhalothrin-Resistance in a Field Strain of Helicoverpa armigera from Northeast China.

Resistance to pyrethroid and organophosphate insecticides has been a growing problem in the management of cotton bollworm Helicoverpa armigera (Hübner) populations in the Yangtze River and Yellow River valleys of China, but resistance status and mechanisms of H. armigera populations from northeast China are less documented. In this study, a field strain collected from Shenyang in northeast China (SYR) is up to 16-fold more resistant than a susceptible strain (SS) to λ-cyhalothrin, while the resistance level to phoxim remained low (2.6-fold). Synergist tests and enzymatic assays show that increased cytochrome P450 monooxygenase (P450) activity is the main mechanism for λ-cyhalothrin resistance. Eight out of 10 genes from CYP6 and CYP9 subfamilies were significantly overexpressed in the SYR strain, and CYP6AE11 was the mostly overexpressed P450 (59-fold). These results suggest that overexpression of multiple P450 enzymes contributes to λ-cyhalothrin resistance in the SYR strain of H. armigera from northeast China.

LC50 of lambda-cyhalothrin stimulates reproduction on the moth Mythimna separata (Walker).

Lambda-cyhalothrin has long been recommended as an effective insecticide to control the oriental armyworm, Mythimna separata (Walker), a notorious migratory pest of agricultural plants. Previous researches have suggested that survival, development, and reproduction of insects are influenced by sublethal concentrations of insecticides. However, the effects of sublethal concentrations of lambda-cyhalothrin on M. separata are less known. In this study, we determined the toxicity and effects of LC20 and LC50 concentration of lambda-cyhalothrin on development and reproduction of M. separata. Results indicate that LC20 of lambda-cyhalothrin tends to decrease the life traits of M. separate, with a shortening larvae period of offspring and oviposition period, whereas LC50 of lambda-cyhalothrin stimulates daily maximal fecundity and forwards the oviposition peak, suggesting a stimulation of reproduction by LC50 of lambda-cyhalothrin. The M. separata population was increased by an LC50 concentration of lambda-cyhalothrin, resulting in a net reproductive rate (R0) and intrinsic rate of increase (rm) significantly higher than that of the control. Transcripts of vitellogenin (MsVg) and vitellogenin receptor (MsVgR) genes were suppressed at day 1 after emergence of moth which developed from the larvae exposed to LC20 and LC50 of lambda-cyhalothrin, but were significant induced when the moth begin to lay eggs (day 4), with a more remarkable induction by LC50 of lambda-cyhalothrin than those of LC20 of lambda-cyhalothrin. Our results indicate that the observed stimulation of reproduction is therefore the results of up-regulation of MsVg and MsVgR by LC50 of lambda-cyhalothrin.

CpGSTd3 is a lambda-Cyhalothrin Metabolizing Glutathione S-Transferase from Cydia pomonella (L.).

Little is known about the role of specific delta GST genes in the detoxification of lambda-cyhalothrin in the global quarantine fruit pest codling moth, Cydia pomonella (L.). Real-time quantitative PCR shows that CpGSTd3 was ubiquitously expressed at all developmental stages and is most abundant in the larval stage and lowest in the egg stage; the mRNA level of CpGSTd3 is higher in the midgut and Malpighian tubules of fourth-instar larvae and abdomens of adults than in other tissues. Exposure of fourth-instar larvae to an LD10 dosage of lambda-cyhalothrin significantly induced the transcript of CpGSTd3 at 3 h, but the mRNA level was down-regulated after 12 h of treatment. Recombinant CpGSTd3 expressed in Escherichia coli was able to catalyze the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) and with an IC50 value of 0.65 mM for lambda-cyhalothrin. Metabolism assays indicate that recombinant CpGSTd3 could metabolize lambda-cyhalothrin. These results suggest that CpGSTd3 is probably a lambda-cyhalothrin metabolizing GST in C. pomonella.

[In vitro and in vivo evaluation of total flavones of Hippophae rhamnoides self-microemulsifying drug delivery system].

The goal of the study is to evaluate the self-microemulsifying drug delivery system (SMEDDS) which enhances the oral bioavailability of the poorly water-soluble drug, total flavones of Hippophae rhamnoides (TFH). It is orally administered for the protection of human cardiovascular system. Self-microemulsifying time, particle size, polydispersity index (PDI), morphological characterization, in vitro dispersity, stability, in situ intestinal absorption and relative bioavailability were investigated in detail. The TFH-SMEDDS rapidly formed fine oil-in-water microemulsions with 0.1 mol x L(-1) hydrochloride solution, with average size of which was less than 40 nm, PDI was below 0.2, and the particles of which were observed round-shaped under transmission electron microscope. Almost 90% of TFH (expressed with quercetin) was released from SMEDDS within 20 min, which was remarkably higher than that from common capsules. The stability test showed the TFH-SMEDDS maintained stable in 6 months under accelerated condition. In situ absorption study demonstrated the absorption rate constant of TFH-SMEDDS (expressed with quercetin) was significantly higher than that of TFH in ethanolic solution (P < 0.05). The absorption of TFH from SMEDDS showed a 4.18-fold increase in relative bioavailability (expressed with quercetin) compared with that of the suspension. The results suggest that SMEDDS is a promising drug delivery system to increase the oral bioavailability of TFH.

The use of polyion complex micelles to enhance the oral delivery of salmon calcitonin and transport mechanism across the intestinal epithelial barrier.

The objective of the present study was to demonstrate the effect of polyanionic copolymer mPEG-grafted-alginic acid (mPEG-g-AA)-based polyion complex (PIC) micelles on enhancing the oral absorption of salmon calcitonin (sCT) in vivo and in vitro and identify the transepithelial transport mechanism of PIC micelles across the intestinal barrier. mPEG-g-AA was first successfully synthesized and characterized in cytotoxicity. The PIC micelles were approximately of 72 nm in diameter with a narrow distribution. The extremely significant enhancement of hypocalcemia efficacy of sCT-loaded PIC micelles in rats was evidenced by intraduodenal administration in comparison with sCT solution. The presence of mPEG-grafted-chitosan in PIC micelles had no favorable effect on this action in the referred content. In the Caco-2 transport studies, PIC micelles could significantly increase the permeability of sCT across Caco-2 monolayers without significantly affecting transepithelial electrical resistance values during the transport study. No evident alterations in the F-actin cytoskeleton were detected by confocal microscope observation following treatment of the cell monolayers with PIC micelles, which further certified the incapacity of PIC micelles to open the intercellular tight junctions. In addition, TEM observations showed that the intact PIC micelles were transported across the everted gut sac. These suggested that the transport of PIC micelles across Caco-2 cell monolayers involve a predominant transcytosis mechanism via endocytosis rather than paracellular pathway. Furthermore, PIC micelles were localized in both the cytoplasm and the nuclei observed by CLSM. Therefore, PIC micelles might be a potentially applicable tool for enhancing the oral absorption of cationic peptide and protein drugs.

Improved absorption of salmon calcitonin by ultraflexible liposomes through intranasal delivery.

The objective of this work was to explore the potential of ultraflexible liposomes as carriers for improving the absorption of salmon calcitonin (sCT) through intranasal administration. The average diameters of positively charged ultraflexible liposomes ranged from about 73 to 99 nm, while those of negatively charged ones were 114 and 157.6 nm, respectively. The content of sodium deoxycholate in liposomes markedly affected the size and encapsulated efficiency of liposomes. The absorption of sCT through intranasal administration was evaluated by hypocalcemic efficacy in rats. The total Ca decrease D% of sCT-loaded ultraflexible liposomes with positive and negative charges were significantly bigger than that of sCT solution, while there was no significant difference in the hypocalcemic efficacy between plain liposome and sCT solution. Unexpectedly, the hypocalcemic efficacy of sCT-loaded ultraflexible liposomes with positive charges was not significantly better than those with negative charges. The decrease rate and extent of the serum calcium level for subcutaneous injection of sCT solution were almost equivalent to those for intranasal administration of negatively and positively charged ultraflexible liposomes within the first 2h, indicating that the ultraflexible liposomes could quickly enhance the penetration of the drug during their residence in the nasal cavity. The results of the toxicity of sCT-loaded ultraflexible liposomes to nasal mucosa demonstrated that the ultraflexible liposomes exerted slight toxicity on the nasal mucosa. On an overall evaluation, the ultraflexible liposomes may be a useful vehicle for intranasal delivery of sCT.

Novel polyion complex micelles for liver-targeted delivery of diammonium glycyrrhizinate: in vitro and in vivo characterization.

Polyion complex micelles (PIC micelles) based on methoxy poly(ethylene glycol)-grafted-chitosan (mPEG-g-Chitosan) and lactose-conjugated PEG-grafted-chitosan (Lac-PEG-g-Chitosan) were designed as carriers for anionic drugs. Diammonium glycyrrhizinate (DG)-loaded conventional PIC micelles (mPIC micelles) and lactose-modified PIC micelles (Lac-PIC micelles) were prepared successfully with encapsulation efficiency of 97.4% and 96.7%, respectively. These micelles were uniform spherical particles with a mean size of 21.6 and 26.4 nm by transmission electron microscopy, respectively. No significant size change of these micelles in three months indicated their good physical stability. The in vitro drug release behavior of mPIC micelles in different media as well as the changes of size and zeta potential demonstrated that the drug was released mainly through swelling and diffusion induced by ion exchange. The pharmacokinetic experiments showed that the area under the curve of DG plasma concentration-time profile in rats for mPIC micelles and Lac-PIC micelles were 1.2 times and 0.4 times higher than that for DG injection, respectively. The liver targeting ability of both mPIC micelles and Lac-PIC micelles was evaluated in rats, revealing that Lac-PIC micelles could deliver more DG to liver than mPIC micelles. Therefore, the Lac-PIC micelles prepared in this study were promising liver-targeted nanocarriers for DG.

[Preparation of brain targeted immunoliposomes].

To prepare a kind of effective non-viral transduction vector, which can deliver exogenous gene into the brain, this vector can be injected through vein system and has the ability to penetrate blood brain barrier. Several groups of materials proportion, type of oil phase, water-oil ratio, phosphatides-cholesterol ratio, temperature of steaming, ultrasonic temperature and time were compared for optimization. Well-constructed immunoliposomes encapsuling LacZ gene were infused into rats through tail vein. 48 h after injection, expression product beta-galactosidase of LacZ gene was detected by histochemistry staining to convince the validity of immunoliposomes as non-viral vectors. The best proportion of synthesis immunoliposomes is as following: phosphatides-cholesterol ratio is 1:1, lipids/drug is 100:1, the type of oil phrase is dichloromethane, oil-water ratio is 4:1, temperature of steaming is 30 degrees C, ultrasonic temperature and time is 10 degrees C and 5 min. At last, 10% trehalose was added as a stabilizer. The entrapment rate is 87.24% and antibody coupling rate is 69%. When immunoliposomes were infused into rats, the expression of LacZ gene could be observed in the brain and periphery organs. Through the best proportion of materials, gene delivering immunoliposomes had been synthesized successfully. This non-viral vector can deliver exogenous gene penetrating blood brain barrier and express in the brain, and will be well-used in the field of gene therapy of cerebral diseases.

Amphotericin B-loaded poly(ethylene glycol)-poly(lactide) micelles: preparation, freeze-drying, and in vitro release.

Polymeric micelles prepared from a series of poly(ethylene glycol)-poly(lactide) (PEG-PLA) diblock copolymers with various PLA chain lengths were designed as drug carriers for water insoluble drug amphotericin B (AmB). Physicochemical properties of AmB-loaded micelles were evaluated. Micelles were freeze-dried to obtain long-time stable formulations. The redispersibility of the freeze-dried samples was poor when the weight ratio of PLA block was bigger than the PEG block of the copolymer. Various types of lyoprotectants including saccharides and PEGs with different molecular weight were tested to improve the redispersion performance of the freeze-dried samples. PEG was proved to be more effective than saccharides on stabilizing the micelles during lyophilization when the weight ratio of PLA block was bigger than PEG block. The sustained release in vitro of AmB was evidenced. About 80% of AmB was released in 80 h. The in vitro release behavior could be best described by the first-order equation. The release rate was reduced as enhancing PLA chain length due to the stronger interaction between poorly water-soluble AmB and longer hydrophobic chain length of PLA.

[The hypocalcemia effect of salmon calcitonin ultra-flexible liposomes after intranasal administration in rats].

This article describes the preparation of salmon calcitonin ultra-flexible liposomes and their hypocalcemia effect after intranasal administration in rats. Both the conventional liposomes and ultra-flexible liposomes were prepared by rotary evaporation-sonication and extrusion. The morphology of ultra-flexible liposomes was observed with transmission electronic microscope. The size and size distribution and their zeta potential were determined by dynamic light scattering. The mean size of ultra-flexible liposomes with DC-Chol was no more than 120 nm, while the mean size of the conventional liposomes was 256.5 nm. The results showed the content of sodium deoxycholate have significant effect on the mean particle size of liposomes. The ultra-flexible liposomes were intranasal administrated at the dose of 5.0 microg x kg(-1); the concentration of serum calcium was determined by OCPC method. The results showed that the salmon calcitonin solution only slightly lowered serum calcium levels and the conventional liposomes could improve the effect of decreased serum calcium level (D%), and the ultra-flexible liposomes had the best effect on the decreased serum calcium level, and the hypocalcemia effect was correlated with the content of sodium deoxycholate which was present in the liposomes. Moreover the ciliotoxicity of ultra-flexible nanoliposomes on nasal mucocilia was investigated with the electron microscope scanning. The results showed that the ultra-flexible liposomes markedly reduced the ciliotoxicity of sodium deoxycholate on nasal mucous. Thereby the ultra-flexible liposomes significantly enhanced the hypocalcemia effect of serum calcium after intranasal administration in rats. The ultra-flexible liposomes could be an effective carrier for intranasal delivery of the peptide and protein drugs.

[In vitro and in vivo pharmaceutical behaviors of lycopene microcapsules].

AIM: To evaluate in vitro release of lycopene microcapsules. Pharmacokinetic parameters of lycopene microcapsule and lycopene powder as reference were estimated after a single dose of oral administration to dogs. The relationship between in vitro dissolution and in vivo absorption was investigated. METHODS: The content of lycopene in the release medium was determined by UV spectroscopy method. Health hybrid male dogs were used as experiment subjects and lycopene powder used as standard to estimate the pharmacokinetics of lycopene microcapsules. HPLC method was used to assay the concentration of lycopene in dog plasma. Pharmacokinetics parameters were estimated by 3P87 program. The drug release percentage in stimulated intestinal fluid was compared with the absorption at a given time point. RESULTS: The release profiles of lycopene from microcapsule showed that the lycopene gelatin microcapsule exhibited enteric property. The pharmacokinetics parameters estimated after oral administration of lycopene powder and lycopene microcapsule in a single dose of 2.5 mg x kg(-1) body weight to dogs were 7.30 h, 15.06 h for T1/2alpha; 28.10 h, 46.76 h for T1/2beta; 22.32 h, 41.03 h for T(max); 1.67 microg x h x L(-1), 2.08 microg x h x L(-1) for AUC(0-infinity), respectively. The concentration-time curves could be fitted to a two-compartment model for both the lycopene powder and the lycopene microcapsule analyzed by 3P87 program. The relationship between in vitro dissolution and in vivo absorption was found to have good correlation (r = 0. 981 9) was found. CONCLUSION: It could be concluded that lycopene microcapsule was a sustained release dosage form. The result of release in vitro could be used to predict the absorption in vivo.