Single Administration Group Research Articles

Benserazide, a cystathionine beta-synthase (CBS) inhibitor, potentially enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and the HIF1-α/VEGF pathway.

Cancer targeted therapy is essential to minimize damage to normal cells and improve treatment outcomes. The elevated activity of Cystathionine beta-synthase (CBS), an enzyme responsible for producing endogenous hydrogen sulfide (H2S), plays a significant role in promoting tumor growth, invasiveness, and metastatic potential. Consequently, the selective inhibition of CBS could represent a promising therapeutic strategy for cancer. Currently, there is much interest in combining paclitaxel with other drugs for cancer treatment. This study aimed to investigate the efficacy of combining benserazide, a CBS inhibitor, with paclitaxel in treating tumors. Firstly, we demonstrated CBS is indeed involved in the progression of multiple cancers. Then it was observed that the total binding free energy between the protein and the small molecule is -98.241kJ/mol. The release of H2S in the group treated with 100μM benserazide was reduced by approximately 90% compared to the negative control, and the thermal denaturation curve of the complex protein shifted to the right, suggesting that benserazide binds to and blocks the CBS protein. Next, it was found that compared to paclitaxel monotherapy, the combination of benserazide with paclitaxel demonstrated stronger antitumor activity in KYSE450, A549, and HCT8 cells, accompanied by reduced cell viability, cell migration and invasion, as well as diminished angiogenic and lymphangiogenic capabilities. In vivo studies showed that the combined administration of benserazide and paclitaxel significantly reduced the volume and weight of axillary lymph nodes in comparison to the control group and single administration group. Further mechanistic studies revealed that the combination of benserazide and paclitaxel significantly suppressed the S-sulfhydration of SIRT1 protein, thereby inhibiting the expression of SIRT1 protein and activating SIRT1 downstream Notch1/Hes1 signaling pathway in KYSE450, A549, and HCT8 cells. Meanwhile, we observed that benserazide combined with paclitaxel induced a more significant downregulation of HIF-1α, VEGF-A, VEGF-C, and VEGF-D proteins expression levels in KYSE450, A549, and HCT8 cells compared to paclitaxel alone. These findings indicated that benserazide enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and down-regulating HIF-1α/VEGF signaling pathway. This study suggests that benserazide may have potential as a chemosensitizer in cancer treatment.

Toxicokinetics of MDMA and Its Metabolite MDA in Rats.

To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA. A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis. In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: T=10.362C-1.183, R2=0.974 6; T=7.397 3C-0.694, R2=0.961 5 (T: injection time; C: concentration ratio of MDMA to MDA in plasma). The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.

Combining Runmu fengye tang preparation with hydroxysugar glycolic acid eye drops regulates Th17/Treg balance to treat dry eyes via inhibition of JAK2/STAT3 pathway

Purpose: To determine effective therapies for the prevention and clinical treatment of dry eye.
 Methods: A scopolamine-induced dry eye rabbit model was administrated with Runmu Fengliang tang (RMFS) and hypromellose 2910, dextran 70 and glycerol eye drops (HGA). Schirmer's I test (SIt), break-up time (BUT) and histopathologic examinations (H&E) were used to assess dry eye symptoms and lacrimal gland damage. Flow cytometry was used to determine the number of apoptotic cells and percentages of Th17 and Treg, while Western blot assay was used to evaluate the expression of proteins related to JAK2/STAT3 pathway.
 Results: The combination of RMFS with HGA significantly increased tear secretion (p < 0.001), shortened tear break-up time (p < 0.001), repaired ocular surface damage and reduced apoptosis (p < 0.05) in the scopolamine-induced dry eye model in rabbits, compared with the single-administration group. In addition, it regulated the Th17/Treg-related cytokine balance and inhibited the JAK2/SATA3 pathway.
 Conclusion: The combination of RMFS and HGA alleviate dry eye symptoms by inhibiting the JAK2/SATA3 pathway in model rabbits induced by scopolamine and this treatment could be a potential therapeutic strategy for the treatment of dry eye disease. Future studies should focus on clinical data collection to investigate the efficacy and safety of the combination.

Therapeutic strategy for facial paralysis based on the combined application of Si-based agent and methylcobalamin

Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Intractable facial paralysis has a poor prognosis, and new treatments are required. Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Reactive oxygen species can inhibit peripheral nerve regeneration after injury. Therefore, the administration of an appropriate antioxidant can promote nerve regeneration. Silicon (Si)-based agents can react with water to generate antioxidant hydrogen. Oral administration of Si-based agents can effectively alleviate symptoms of disease models associated with oxidative stress. Thus, we orally administered a Si-based agent to a facial paralysis model mice to investigate whether promotion of nerve regeneration occurred. The combined administration of methylcobalamin (MeCbl) with the Si-based agent was also investigated. The Si-based agent improved the clinical score evaluation of facial paralysis. Electroneuronography and immunostaining showed that the Si-based agent promoted myelination and recovery of facial nerve function. Furthermore, in the drug-administered group, oxidative stress associated with facial nerve injury was reduced more than that in the non-administered group. The clinical score evaluation, neuroregeneration effect, and reduction of oxidative stress were improved in the combination group compared to the single administration group. The Si-based agent could rapidly improve the disappearance of facial expressions by promoting myelin sheath formation and alleviating oxidative stress. Combination therapy with a Si-based agent and MeCbl should improve the prognosis and treatment of intractable facial paralysis.

Simultaneous Determination and Pharmacokinetics Study of Three Triterpenes from Sanguisorba officinalis L. in Rats by UHPLC–MS/MS

A selective and rapid ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) method was established and validated for the determination of ziyuglycoside I, 3β,19α-dihydroxyurs-12-en-28-oic-acid 28-β-d-glucopyranosyl ester, and pomolic acid in rats after the oral administration of ziyuglycoside I, 3β,19α-dihydroxyurs-12-en-28-oic-acid 28-β-d-glucopyranosyl ester, pomolic acid, and Sanguisorba officinalis L. extract. The separation was carried out on an ACQUITY UPLC®HSS T3 column (2.1 mm × 100 mm, 1.8 μm), using methanol and 5 mmol/L ammonium acetate water as the mobile phase. The three compounds were quantified using the multiple reaction monitoring mode with the electrospray ion source in both the positive and negative mode. Liquid-liquid extraction was applied to the plasma sample preparation. Bifendate was selected as the internal standard. The intra-day and inter-day precision and the accuracy of the method were all within receivable ranges. The lower limit of quantification of ziyuglycoside I, 3β,19α-dihydroxyurs-12-en-28-oic-acid 28-β-d-glucopyranosyl ester, and pomolic acid were 6.50, 5.75, and 2.63 ng/mL, respectively. The extraction recoveries of analytes in rat plasma ranged from 83 to 94%. The three components could be rapidly absorbed into the blood (Tmax, 1.4–1.6 h) both in the single-administration group or S. officinalis extract group, but the first peak of PA occurred at 0.5 h and the second peak at 4–5 h in the S. officinalis extract. Three compounds were eliminated relatively slowly (t1/2, 7.3–11 h). The research was to establish a rapid, sensible, and sensitive UHPLC–MS/MS method using the multi-ion mode for multi-channel simultaneous mensuration pharmacokinetics parameters of three compounds in rats after oral administration of S. officinalis extract. This study found, for the first time, differences in the pharmacokinetic parameters of the three compounds in the monomer compounds and S. officinalis extract administration, which preliminarily revealed the transformation and metabolism of the three compounds in vivo.

A general toxicity and biodistribution study of human natural killer cells by single or repeated intravenous dose in severe combined immune deficient mice

Natural killer (NK) cells are a part of the innate immune system and represent the first line of defense against infections and tumors. NK cells can eliminate tumor cells without major histocompatibility restriction and are independent of the expression of tumor-associated antigens. Therefore, they are considered an emerging tool for cancer immunotherapy. However, the general toxicity and biodistribution of NK cells after transplantation remain to be understood. This study was conducted to evaluate the general toxicity and biodistribution of human NK cells after single or repeated intravenous dosing in severely combined immunodeficient (SCID) mice. There were no test item-related toxicological changes in single and repeated administration groups. The no observed adverse effect level of human NK cells was 2 × 107 cells/head for both male and female SCID mice. Results from the biodistribution study showed that human NK cells were mainly distributed in the lungs, and a small number of the cells were detected in the liver, heart, spleen, and kidney of SCID mice, in both the single and repeated dose groups. Additionally, human NK cells were completely eliminated from all organs of the mice in the single dose group on day 7, while the cells persisted in mice in the repeated dose group until day 64. In conclusion, transplantation of human NK cells in SCID mice had no toxic effects. The cells were mainly distributed in the lungs and completely disappeared from the body over time after single or repeated intravenous administration.

SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study

▪BackgroundHepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as congenital or acquired iron-loading anaemias. These conditions are a major source of morbidity and mortality. SLN124 increases hepatic hepcidin synthesis and hence plasma hepcidin by silencing its repressor, TMPRSS6. SLN124 has been shown to lower serum iron levels for at least 6 weeks after single administration in mice and has also been shown to increase haemoglobin in a mouse model of beta-thalassemia. Here we report results from a randomised, double-blind, placebo-controlled phase 1, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously (sc) administered SLN124 in healthy volunteers.ObjectivesThe primary objective was to evaluate the safety and tolerability of single ascending doses of SLN124 in healthy subjects. In addition, PK parameters of SLN124 and PD biomarkers of iron metabolism were evaluated.MethodsEach subject received a single dose of SLN124 or placebo given by sc injection into their abdomen. Dose levels of 1 mg/kg, 3 mg/kg and 4.5 mg/kg were evaluated. At each dose level, 6 subjects received SLN124 and 2 received matching placebo.ResultsThree cohorts of 8 subjects (6:2) were included in the study. The mean age of subjects was 31.3 years (SD 7.8) and 71% were male. There were no serious adverse events or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. The majority of TEAEs were mild, including transient mild injection site reactions, which resolved without intervention. No dose limiting toxicities were observed.Plasma hepcidin levels at baseline were (mean ± SD) 2.3±1.1, 2.5±1.8 and 2.7±2.0 nM in the three treatment groups, respectively. After a single administration of 1, 3 or 4.5 mg/kg of SLN124, levels were increased by 3.1±2.7, 5.8±2.6 and 7.8±2.9 nM on day 29 and by 2.6±2.6, 2.8±1.4 and 3.5±1.8 nM day 57 post dosing, respectively.Serum iron was reduced by mean (±SD) 32% (26), 40% (14) ,46% (21) on day 8 and by 42% (20), 48% (14) and 47% (26) on day 29 for single doses of 1, 3 and 4.5 mg/kg, respectively. Average percentage changes in all three treatment groups were also still reduced from baseline at day 57.The mean (±SD) percent transferrin saturation (TSAT) was reduced from baseline levels in all single dose administration groups with maximum decreases observed at day 29 but reductions still observed at day 57. (Table 1).The observed PK is consistent with the PK model based on preclinical data.Thus, whereas the effects of SLN124 on plasma hepcidin show clear increments across the dose range tested, the effect on lowering serum iron and transferrin saturation shows something of a plateau effect at the highest dose. In future studies in patients with raised baseline transferrin saturations, it will be of note to determine whether transferrin saturation continues to decrease at the highest SLN124 doses.Conclusion/summaryIn summary, SLN124, a GalNAc conjugated siRNA targeting TMPRSS6, effectively reduces serum iron levels and has the potential as a therapeutic for patients with alpha and beta-thalassemia, myelodysplastic syndromes, hereditary hemochromatosis and other related disorders. The effect on hepcidin levels at the end of study, day 57, suggest a prolonged duration of action. The encouraging efficacy signal on serum iron and transferrin saturation and the expected benign safety profile of SLN124 supports further development. The GEMINI II trial (NCT04718844) is currently recruiting and wil l evaluate single and multiple doses of SLN124 in patients withthalassemia and myelodysplastic syndromes. [Display omitted] DisclosuresPorter: bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scrimgeour: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Martinez: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. James: Silence Therapeutics: Consultancy. Aleku: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Wilson: Silence Therapeutics: Consultancy. Muckenthaler: Silence Therapeutics: Research Funding. Schaeper: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Campion: Silence Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company.

Investigation on selenium and mercury interactions and the distribution patterns in mice organs with LA-ICP-MS imaging

It is the first time to investigate local distribution patterns of mercury (Hg) in mice organs after Hg and Se exposure with detection of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Two batch of adult mice were employed to be exposed to inorganic mercury (iHg) and methylmercury (MeHg) with or without Se at the dose of 55 μmol kg−1. Tissue sections of brain, kidney, liver, and spleen from one batch mice were prepared to get local imaging of Hg by LA-ICP-MS. Tissues from another batch mice were used to quantify Hg and Se in tissues with ICP-MS after acid digestion. The results indicated that, for mice exposed to iHg, Hg mainly distributed in kidney, a little in liver, and hardly in brain and spleen; for mice exposed to MeHg, lower amount of Hg was found in kidney, liver and spleen, and almost no Hg was found in brain. It was interesting that for Hg and Se co-administration groups, higher level of Hg was observed in kidney, liver, spleen and even in brain than single Hg administration groups. In addition, Se level in organ tissues increased obviously not only in Se exposure group but also in MeHg exposure group, while the phenomenon was not observed in iHg exposure group. HepG2 cells were employed to investigate Se and Hg interactions in single cell level, similar bioaccumulation behavior of Hg was found between cells and mice organs. Higher level of Hg was observed in cells cultured with Se and Hg medium than cells cultured with single Hg medium. The results are expected to provide new insight to investigate Hg and Se interactions in animal bodies and in-vitro cells.

Pharmacovigilance of herb-drug interactions: A pharmacokinetic study on the combination administration of herbal Kang’ai injection and chemotherapy irinotecan hydrochloride injection by LC–MS/MS

Chinese herbal drugs are often combined with chemotherapy drugs for the treatment of cancers. However, the combination administrations often do not have scientifically sound bases established on full preclinical and clinical investigations. A commonly used anti-colon-cancer herb-drug pair, irinotecan (CPT-11) hydrochloride injection and Kang’ai (KA) injection was taken as an example to investigate the possible pharmacokinetic interactions between Chinese herbal drugs and chemotherapy injections to determine the potential adverse drug reactions (ADRs). Rats were randomly divided into three groups and received 20 mg/kg CPT-11 injection 15 min after administration of 4 mL/kg saline for the CPT-11 single administration group and 4 mL/kg KA injection for the separated co-administration group, respectively. In the pre-mixed co-administration group, rats received a mixture of 20 mg/kg CPT-11 injection and 4 mL/kg KA injection. Blood samples were collected at 10 pre-determined time points between 0 and 24 h. The tissue samples were collected at 5 and 8 min after the injections, respectively. A reliable LC–MS/MS method was established for the simultaneous determination of CPT-11 and its metabolites, SN-38, SN-38 G and APC in the rat plasma and tissue samples, after full confirmation of two injections chemical and stability compatibilities. Compared to the C0 (5129 ± 757 ng/mL) and AUC0-t (7858 ± 1307 ng h/mL) of CPT-11 in the CPT-11 single administration group, the C0 (4574 ± 371 ng/mL) and AUC0-t (8779 ± 601 ng h/mL) after the separated co-administration remained unchanged, but the pre-mixed co-administration resulted with a significant increased C0 (29,454 ± 12,080 ng/mL) and AUC0-t (15,539 ± 5165 ng h/mL) (p < 0.05). Since the exposures of CPT-11 in most tissues in the pre-mixed co-administration group were dramatically lower than the separated co-administration group, the increased CPT-11 plasma concentration may be produced by the delayed tissue distribution because of the encapsulation by the components contained in KA injection, such as polysaccharides. Similar differences were also found in its metabolite, SN-38 G. There are obvious herb-drug interactions between CPT-11 injection and KA injection after the pre-mixed co-administration. The resulting excessive CPT-11 in the plasma may lead to many serious ADRs. Therefore, the full evaluation of herb-drug interactions is necessary and inappropriate combinations should be avoided.

Effect of intra-articular administration of autologous PRP and activated PRP on inflammatory mediators in dogs with osteoarthritis

The aim of this study was to investigate the effects of the intra-articular use of platelet rich plasma (PRP) and bio-physically activated PRP (BPRP) on the inflammatory mediators for the treatment of osteoarthritis in dogs. The animals included in this study were 36 mix breed dogs diagnosed with osteoarthritis in the stifle as a result of the clinical and radiological examinations. The dogs were randomly divided into three groups: PRP (platelet-rich plasma), BPRP (biophysically activated platelet-rich plasma) and control (given 0.9% isotonic saline). These three main groups were each further divided into two groups as single and double according to the number of intraarticular administrations. Joint fluid analyses, a clinical examination (Hudson Visual Analog Scale and Canine Brief Pain Inventory Tests) radiographic and ultrasonographic examinations were performed on days 1, 15, 30, 60, and 90 for each group. Genesis System 2 branded and BPRP preparation kits were used in this study. An ELISA method was used to measure the cytokines in charge of the inflammatory mediation (IL-1β, IL-6, IL-10, TNF-α) in the synovial fluid samples. The records obtained from the walking and pain rating tests were subjected to a statistical analysis program and a Mann-Whitney U test was performed. The results of the ELISA were evaluated by a Tukey test. There was a significant difference between the single and double groups of the PRP administration on days 60 and 90 (P &amp;lt; 0.05) in the walking and pain scores. The double groups of the PRP had better results than the single groups. There was a significant difference between the single groups of the PRP and BPRP for the IL-10 on the 30&lt;sup&gt;th&lt;/sup&gt; day (P &amp;lt; 0.05). In the single application groups, the BPRP was better than the PRP on day 30 in the IL-10 measurements. In the comparison of the single and double administration groups, there was significant difference between the single and double groups of the BPRP on day 90 (P &amp;lt; 0.05). The double groups of the BPRP had better results than the single groups. In addition, the biophysically activated PRP was found to be superior to the PRP for the IL-10 content. In conclusion, the efficacy of the PRP and BPRP was related to the degree of the osteoarthritis (OA). Especially the success rate in the acute OA patients was higher due to the anti-inflammatory activity of the BPRP. Moreover, the double administration groups gave more positive results than the single administration groups.

Herb-Drug Interaction: Application of a UPLC-MS/MS Method to Determine the Effect of Polygonum capitatum Extract on the Tissue Distribution and Excretion of Levofloxacin in Rats.

Polygonum capitatum has unique curative effects on the urinary system. In fact, many Polygonum capitatum-based preparations are currently used in the clinic. In China, the combination of levofloxacin (LVFX) with a Chinese herbal preparation derived from Polygonum capitatum has been used for the clinical treatment of urinary system diseases, which can improve the curative effects and reduce the side effects of LVFX. However, the herb-drug interaction (HDI) between these drugs has not been reported and the effect of Polygonum capitatum on the in vivo process of LVFX is unclear. In this article, a sensitive ultraperformance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) method was developed to evaluate the effects of the combined application of LVFX and the Polygonum capitatum extract on tissue distribution and excretion. Thereafter, the method was validated for selectivity, accuracy, precision, linearity, lower limit of quantification (LLOQ), dilution integrity, recovery, and matrix effect. Based on tissue distribution, LVFX could diffuse into all of the tested tissues, with significant differences in the content of each tissue between the coadministration group and single administration group. At 48 h after the combination was orally administered, the urinary cumulative excretion of LVFX decreased from 20.69% to 11.84% while its fecal cumulative excretion decreased from 26.08% to 13.28%. Our results suggest that a drug interaction exists between the two drugs in the process of distribution and excretion. This study provides important experimental evidence for further studies on the clinical efficacy and mechanism of the Polygonum capitatum extract and LVFX.

Comparative pharmacokinetics of tedizolid in rat plasma and cerebrospinal fluid

To investigate the possibility of tedizolid phosphate's application in the treatment of intracranial infection, a preclinical comparative pharmacokinetic study was designed. Based on the assumption that the classic efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may participate in the transportation of TDZ, two groups of rats were intravenously administered 6 mg/kg tedizolid phosphate alone or 6 mg/kg tedizolid phosphate combined with 1 mg/kg elacridar which was an inhibitor of P-gp and BCRP. Plasma and cerebrospinal fluid samples were collected according to a pharmacokinetic schedule. All the plasma and cerebrospinal fluid samples were assessed with a validated LC-MS/MS method. The penetration ratio of tedizolid from the blood to cerebrospinal fluid was calculated, and a comparison of the penetration ratios between the two groups was made. The mean Cmax of tedizolid in the CSF in the tedizolid phosphate group and the tedizolid phosphate combined with elacridar group was 154 ng/mL and 300 ng/mL, respectively, and the mean penetration ratio of tedizolid in the tedizolid phosphate group and the tedizolid phosphate combined with elacridar group was 2.16% and 3.53%, respectively. The relatively high Cmax in the CSF proved the possibility of tedizolid phosphate's application in the treatment of intracranial infection, and the higher penetration ratios, Cmax, csf and AUCcsf of the rats in co-administered elacridar group than those in the single-administration group indicated that the transporters P-gp and BCRP might be involved in the transportation of tedizolid.

Metabolomic study of polyamines in rat urine following intraperitoneal injection of γ-hydroxybutyric acid.

Recently, illegal abuse of γ-hydroxybutyric acid (GHB) has increased in drug-facilitated crimes, but the determination of GHB exposure and intoxication is difficult due to rapid metabolism of GHB. Its biochemical mechanism has not been completely investigated. And a metabolomic study by polyamine profile and pattern analyses was not performed in rat urine following intraperitoneal injection with GHB. Urinary polyamine (PA) profiling by gas chromatography-tandem mass spectrometry was performed to monitor an altered PA according to GHB administration. Polyamine profiling analysis by gas chromatography-mass spectrometry combined with star pattern recognition analysis was performed in this study. The multivariate statistical analysis was used to evaluate discrimination among control and GHB administration groups. Six polyamines were determined in control, single and multiple GHB administration groups. Star pattern showed distorted hexagonal shapes with characteristic and readily distinguishable patterns for each group. N1-Acetylspermine (p < 0.001), putrescine (p < 0.006), N1-acetylspermidine (p < 0.009), and spermine (p < 0.027) were significantly increased in single administration group but were significantly lower in the multiple administration group than in the control group. N1-Acetylspermine was the main polyamine for discrimination among control, single and multiple administration groups. Spermine showed similar levels in single and multiple administration groups. The polyamine metabolic pattern was monitored in GHB administration groups. N1-Acetylspermine and spermine were evaluated as potential biomarkers of GHB exposure and addiction.

Biopolymer-delivered vascular endothelial growth factor improves renal outcomes following revascularization.

Renal angioplasty and stenting (PTRAs) resolves renal artery stenosis, but inconsistently improves renal function, possibly due to persistent parenchymal damage. We developed a bioengineered fusion of a drug delivery vector (elastin-like polypeptide, ELP) with vascular endothelial growth factor (VEGF), and showed its therapeutic efficacy. We tested the hypothesis that combined ELP-VEGF therapy with PTRAs improves renal recovery more efficiently than PTRAs alone, by protecting the stenotic renal parenchyma. Unilateral renovascular disease (RVD) was induced by renal artery stenosis in 14 pigs. Six weeks later, stenotic kidney blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo using multidetector CT. Blood and urine were collected during in vivo studies. All pigs underwent PTRAs and then were randomized into single intrarenal ELP-VEGF administration or placebo (n = 7 each) groups. Pigs were observed for four additional weeks, in vivo CT studies were repeated, and then pigs were euthanized for ex vivo studies to quantify renal microvascular (MV) density, angiogenic factor expression, and morphometric analysis. Renal hemodynamics were similarly blunted in all RVD pigs. PTRAs resolved stenosis but modestly improved RBF and GFR. However, combined PTRAs+ ELP-VEGF improved RBF, GFR, regional perfusion, plasma creatinine, asymmetric dimethlyarginine (ADMA), and albuminuria compared with PTRAs alone, accompanied by improved angiogenic signaling, MV density, and renal fibrosis. Greater improvement of renal function via coadjuvant ELP-VEGF therapy may be driven by enhanced MV proliferation and repair, which ameliorates MV rarefaction and fibrogenic activity that PTRAs alone cannot offset. Thus, our study supports a novel strategy to boost renal recovery in RVD after PTRAs.

Induction of parturition by double administration of prostaglandin F2α in sows reduces the variation of gestation length without affecting the colostrum yield and piglet performance.

The objective of the present study was to investigate whether double intra-vulvo submucosal administration of prostaglandin F2α (PGF2α) could improve farrowing synchronization compared to single administration, and the effects of the induction of farrowing on colostrum yield and piglet performances. In total, 91 sows were randomly assigned to one of three groups: i) treatment with a single or ii) double administration of PGF2α or iii) control group without any treatment. A synthetic analogue of PGF2α was administrated via the intra-vulvo submucosal route on day 114 of gestation, at 0800 hr (single administration) or at 0800 and 1400 hr (double administration). The animals were monitored during the farrowing process. The time interval from the first administration of PGF2α to the onset of parturition was compared between groups. The proportion of sows that farrowed within 32 hr of induced parturition was higher in the double administration group than in the single administration group (100 vs. 84.4%, P=0.046). The duration of farrowing was higher in single administration sows than in control (241.1 vs. 169.5 min, P=0.004) and tended to be higher than in double administration sows (241.1 vs. 190.3 min, P=0.088). Birth interval of piglets born after double administration of PGF2α was shorter than those born after a single administration (14.6 and 20.1 min, P=0.024). In sows, the induction of parturition using a double administration of PGF2α reduces variation in gestation length and significantly increases the proportion of sows with an early response to PGF2α.

Influence of postoperative intravenous infusion of tranexamic acid on perioperative blood loss in elderly patients with femoral intertrochanteric fractures treated with proximal femoral nail antirotation

Objective To evaluate the effect and safety of postoperative intravenous infusion of tranexamic acid on the perioperative blood loss in elderly patients with femoral intertrochanteric fractures treated with proximal femoral nail antirotation. Methods A retrospective case-control study was conducted on 60 aged patients with unilateral intertrochanteric fracture who were treated with proximate femoral nail annotation from January 2015 to March 2017. Patients were divided into two groups according to method of administration, with 30 cases in each group. Patients in the single administration group were given 15 mg per kilogram of tranexamic acid 20 minutes before surgery by intravenous drip (Group A), whereas patients in the twice administration group were given 15 mg per kilogram 20 minutes before surgery and 1 g 7 hours later by intravenous drip (Group B). There were 11 males and 19 females in Group A, with the age of (78.57±7.60)years. Group B included 12 males and 18 females, and the age was (76.80±7.90)years. Perioperative data including operation time, intraoperative blood loss, total blood loss, recessive blood loss, postoperative drainage volume, mean blood transfusion volume, blood transfusion rate, maximum hemoglobin drop after surgery, and postoperative hospitalization time as well as complications including deep vein thrombosis, pulmonary embolism, wound infection, intermuscular venous thrombosis, exudate, hematoma, fat liquefaction were compared between the two groups. Results The operation time was (85.00±19.17)minutes in Group A and (81.10±19.23)minutes in Group B (P>0.05). The intraoperative blood loss was (113.33±56.77)ml in Group A and (129.33±93.70)ml in Group B (P>0.05). The total blood loss was (748.47±246.71)ml in Group A and (477.83±213.78)ml in Group B(P 0.05). Conclusion Compared with the single administration of tranexamic acid, the twice administration is more effective in controlling perioperative blood loss, which is worthy of clinical application. Key words: Aged; Femoral fractures; Tranexamic acid; Blood loss, surgical

Comparative pharmacokinetics study of anastrozole after single administration and combination with celecoxib

1. There are numerous investigations demonstrating that the cyclooxygenase-2 (COX-2) inhibitors might enhance the efficiency of anastrozole in breast cancer. Hence, this study was conducted to investigate the comparative pharmacokinetics of anastrozole after single administration and combination with celecoxib.2. A simple protein precipitation procedure was adopted for the sample preparation with satisfactory extraction recovery for both anastrozole and the internal standard, and then anastrozole was separated and analysed on an ACQUITY BEH UPLC C18 column (50 × 2.0 mm, 1.7 μm, Waters) within 2 min. The calibration curves showed good linarites (r = 0.994). Intra- and inter-day precision were within 4.93 and 13.83%, respectively. The mean extraction recoveries across QC levels were within 91.4%, and the matrix effects were within 94.5%.3. Results showed that the method was reliable to determine anastrozole in rat plasma. Compared with rats in single administration group, no significant difference was found in the combination group. It is workable to use celecoxib combined with anastrozole in clinical therapy.

Comparison of the effect of different administration methods of carboprost tromethamine for the treatment of scar uterus with cesarean resection

Objective To compare the clinical effect of different administration methods of carboprost tromethamine for the treatment of scar uterus with cesarean resection. Methods 120 cases of puerpera with uterine scar uterus and postpartum hemorrhage tendency were selected, and the history of cesarean section was once and more than once.According to the digital table, they were randomly divided into observation group(60 cases) and control group(60 cases), the observation group was divided into single carboprost tromethamine administration group(30 cases) and sub carboprost tromethamine administration group(30 cases). The clinical efficacy of the three groups were compared. Results In the observation group, the incidence rates of postpartum hemorrhage(13.33%, 10.00%) were significantly lower than 28.33% in the control group(χ2=10.844, 6.822, all P 0.05).24h postpartum hemorrhage in the observation group[(263.11±137.04)mL, (359.98±212.35)mL]were significantly lower than those of the control group[(461.52±127.67)mL](t=5.795, 2.247, all P 0.05). Conclusion Carboprost tromethamine can significantly reduce the bleeding rate of uterine scar again after cesarean section, sub carboprost tromethamine administration can significantly reduce the amount of bleeding in postoperative 24h, it is worth popularizing in clinical. Key words: Cesarean section; Carboprost Tromethamine; Scar; Uterus; Postpartum hemorrhage

The effect of metilpheniydate, risperidone and combination therapy on ECG in children with attention-deficit hyperactivity disorder

IntroductionThis study is to investigate ventricular repolarization on electrocardiogram (ECG) in a pediatric population receiving methylphenidate (MPH), risperidone (RIS) and combined therapy. MethodsA total of 215 patients between 6 and 12years with ADHD/conduct disorder receiving methylphenidate, risperidone and combined therapy for minimum 3months and an untreated ADHD group (n=76) was consecutively included in the study. Twelve lead ECG parameters including mean QT, QTc, T-peak to T-end (TpTe) intervals, TpTe dispersion and TpTe/QT ratio were compared. ResultsQT interval, and QTc, TpTe interval, TpTe dispersion and TpTe/QTc ratio values for groups receiving RIS, MPH and combined therapy were found to be significantly higher than other groups. Moreover, in the combined therapy group TpTe and TpTe/QTc values were higher than the single drug administration groups (p<0.05). TpTe and TpTe/QT ratio was significantly higher in the RIS group compared to that of the MPH group. ConclusionThese results suggested that combined therapy of these drugs had a more prominent impact on the T wave and RIS could be strongly associated with it.

Metabolomic analysis of urinary organic acids following intraperitoneal injection with γ-hydroxybutyric acid in rats

γ-Hydroxybutyricacid (GHB) has been used as a prescription medicine for the treatment of narcolepsy and alcohol dependence. Quantification of GHB in biological fluids from GHB intoxication cases is not clear for verifying exposure to GHB due to the presence of endogenous GHB, which is rapidly metabolized, via GABA and/or succinic semialdehyde, to succinic acid which enters the tricarboxylic acid (TCA) cycle. However, their exact mechanism was not fully understood. In this study, comprehensive organic acid (OA) profiling analysis including OAs related to TCA cycle, GHB and 2-hydroxyglutaric acid (2-HG) as a prominent metabolite was performed by gas chromatography–mass spectrometry (GC–MS) in scan mode to understand the biochemical events and monitor altered OA metabolism in rat urine samples following treatment with GHB. OA profiling as methoxime/tert-butyldimethylsilyl derivatives by GC–MS combined with star pattern analyses were performed in rat urine samples following intraperitoneal administration of GHB once per day for one (single) and ten consecutive days (multiple). In the GC–MS with selected ion monitoring (SIM) mode, GHB was massively increased in urine samples of treated groups, while it showed as trace levels in control group. In all groups, α-ketoglutaric acid was most abundant, followed by citric, and isocitric acids among 18 quantified OAs. In analysis of variance (ANOVA) test for three groups, 15 OAs including 2-HG as a prominent metabolite of GHB were significantly different (p < 0.05). All the 18 OAs in the single administration group were increased compared with the multiple administration groups, which indicates that the OA metabolic disturbance following single administration is much larger than that by multiple administration. Their values were normalized to the corresponding mean values of the control group and then plotted into star symbol patterns, which were characteristic and readily distinguishable for each group from distorted octadecagonal shapes. In particular, 2-HG was 920 and 810% higher than that of control group in single and multiple administration groups, respectively. The elevation of GHB and 2-HG is explained by administration of GHB. In principle component analysis, isocitric, citric and cis-aconitic acids were monitored as contributing factors for discrimination of the three groups, which may explain for altered metabolism of OAs related with TCA cycle by administration and intoxication of GHB. Altered organic acid metabolism following treatment with γ-hydroxybutyric acid.