Effects Of Different Administration Routes Research Articles

Intranasal delivery of a recombinant adenovirus vaccine encoding the PEDV COE elicits potent mucosal and systemic antibody responses in mice.

Porcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus that causes substantial economic loss to the global pig industry. The emergence of PEDV variants has increased the need for new vaccines, as commercial vaccines confer inferior protection against currently circulating strains. It is well established that the induction of mucosal immunity is crucial for PEDV vaccines to provide better protection against PEDV infection. In this study, we constructed a recombinant adenovirus expressing the core neutralization epitope (COE) of G2b PEDV based on human adenovirus serotype 5 (Ad5). We evaluated the effects of different administration routes and doses of vaccine immunogenicity in Balb/c mice. Both intramuscular (IM) and intranasal (IN) administration elicited significant humoral responses, including COE-specific IgG in serum and mucosal secretions, along with serum-neutralizing antibodies. Moreover, IN delivery was more potent than IM in stimulating IgA in serum and mucosal samples and in dampening the immune response to the Ad5 vector. The immune response was stronger after high versus low dose IM injection, whereas no significant difference was observed between high and low IN doses. In summary, our findings provide important insights for developing novel PEDV vaccines.IMPORTANCEPorcine epidemic diarrhea (PED) is a highly contagious disease that has severe economic implications for the pork industry. Developing an effective vaccine against PEDV remains a necessity. Here, we generated a recombinant adenovirus vaccine based on Ad5 to express the COE protein of PEDV (rAd5-PEDV-COE) and systematically evaluated the immunogenicity of the adenovirus-vectored vaccine using different administration routes (intramuscular and intranasal) and doses in a mouse model. Our results show that rAd5-PEDV-COE induced potent systemic humoral response regardless of the dose or immunization route. Notably, intranasal delivery was superior to induce peripheral and mucosal IgA antibodies compared with intramuscular injection. Our data provide valuable insights into designing novel PEDV vaccines.

Anti-PEG IgM production induced by PEGylated liposomes as a function of administration route.

Modifying the surface of nanoparticles with polyethylene glycol (PEG) is a commonly used approach for improving the in vitro stability of nanoparticles such as liposomes and increasing their circulation half-lives. We have demonstrated that, in certain conditions, an intravenous (i.v.) injection of PEGylated liposomes (PEG-Lip) induced anti-PEG IgM antibodies, which led to rapid clearance of second doses in mice. SARS-CoV-2 vaccines, composed of mRNA-containing PEGylated lipid nanoparticles, have been widely administered as intramuscular (i.m.) injections, so it is important to determine if PEGylated formulations can induce anti-PEG antibodies. If the favorable properties that PEGylation imparts to therapeutic nanoparticles are to be widely applicable this should apply to various routes of administration. However, there are few reports on the effect of different administration routes on the in vivo production of anti-PEG IgM. In this study, we investigated anti-PEG IgM production in mice following i.m., intraperitoneal (i.p.) and subcutaneous (s.c.) administration of PEG-Lip. PEG-Lip appeared to induce anti-PEG IgM by all the tested routes of administration, although the lipid dose causing maximum responses varied. Splenectomy attenuated the anti-PEG IgM production for all routes of administration, suggesting that splenic immune cells may have contributed to anti-PEG IgM production. Interestingly, in vitro experiments indicated that not only splenic cells but also cells in the peritoneal cavity induced anti-PEG IgM following incubation with PEG-Lip. These observations confirm previous experiments that have shown that measurable amounts of PEG-Lip administered i.p., i.m. or s.c. are absorbed to some extent into the blood circulation, where they can be distributed to the spleen and/or peritoneal cavity, and are recognized by B cells, triggering anti-PEG IgM production. The results obtained in this study have important implications for developing efficient PEGylated nanoparticular delivery system.

Effect of Different Administration Routes of Dexmedetomidine on Postoperative Delirium in Elderly Patients Undergoing Elective Spinal Surgery: A Prospective Randomized Double-Blinded Controlled Trial.

Intravenous dexmedetomidine has been reported to decrease the occurrence of postoperative delirium (POD) in elderly patients. Nevertheless, some previous studies have indicated that intratracheal dexmedetomidine and intranasal dexmedetomidine are also effective and convenient. The current study aimed to compare the effect of different administration routes of dexmedetomidine on POD in elderly patients. We randomly allocated 150 patients (aged 60 years or more) scheduled for spinal surgery to receive intravenous dexmedetomidine (0.6 μg/kg), intranasal dexmedetomidine (1 μg/kg) before anesthesia induction, or intratracheal dexmedetomidine (0.6 µg/kg) after anesthesia induction. The primary outcome was the frequency of delirium during the first 3 postoperative days. The secondary outcomes were the incidence of postoperative sore throat (POST) and sleep quality. Adverse events were recorded, and routine treatment was performed. Compared with the intranasal group, the intravenous group had a significantly lower occurrence of POD within 3 days (3 of 49 [6.1%] vs 14 of 50 [28.0%]; odds ratio [OR], 0.17; 95% confidence intervals [CIs], 0.05-0.63; P < .017). Meanwhile, patients in the intratracheal group had a lower incidence of POD than those in the intranasal group (5 of 49 [10.2%] vs 14 of 50 [28.0%]; OR, 0.29; 95% CI, 0.10-0.89; P < .017). Whereas, there was no difference between the intratracheal and intravenous groups (5 of 49 [10.2%] vs 3 of 49 [6.1%]; OR, 1.74; 95% CI, 0.40-7.73; P > .017). The rate of POST was lower in the intratracheal group than that in the other 2 groups at 2 hours after surgery (7 of 49 [14.3%] vs 12 of 49 [24.5%] vs 18 of 50 [36.0%], P < .017, respectively). Intravenous dexmedetomidine had the lowest Pittsburgh Sleep Quality Index score on the second morning after surgery (median [interquartile range {IQR}]: 4 [3-5] vs 6 [4-7] vs 6 [4-7], P < .017, respectively). Compared with the intranasal group, the intravenous group had a higher rate of bradycardia and a lower incidence of postoperative nausea and vomiting (P < .017). The intranasal group was associated with the highest incidence of hypertension (P < .017). For patients aged ≥60 years undergoing spinal surgery, compared with the intranasal route of dexmedetomidine, intravenous and intratracheal dexmedetomidine reduced the incidence of early POD. Meanwhile, intravenous dexmedetomidine was associated with better sleep quality after surgery, and intratracheal dexmedetomidine resulted in a lower incidence of POST. Adverse events were mild in all 3 administration routes of dexmedetomidine.

Oral and Vaginal Hormonal Contraceptives Induce Similar Unfavorable Metabolic Effects in Women with PCOS: A Randomized Controlled Trial.

This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased (p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min (p = 0.011) and AUCglucose (p = 0.018) increased in the CVC group. Fasting insulin levels (p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride (p < 0.001) and hs-CRP (p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS.

Bacterial lipopolysaccharide with different administration routes affects intestinal mucosal morphological, immunological, and microbial barrier functions in goslings

The current study was conducted to evaluate the effects of different administration routes of bacterial lipopolysaccharide (LPS) on intestinal mucosal morphological, immunological, and microbial barrier functions in goslings. First, we compared intestinal villi morphology of goslings under intraperitoneal or oral LPS treatment through hematoxylin and eosin staining. Then, we determined the signatures of the microbiome in the ileum mucosa of goslings subjected to oral LPS treatment at 0, 2, 4, and 8 mg/kg BW by 16S sequencing, and analyzed the changes in intestinal barrier functions and permeability, levels of LPS in the ileum mucosa, plasma, and liver tissue, and the induced inflammatory response of Toll-like receptor 4 (TLR4). As a result, intraperitoneal LPS injection resulted in a thicker intestinal wall in the ileum within a short time, whereas villus height was less affected; in contrast, oral LPS treatment exerted a stronger influence on villus height but not on intestinal wall thickness. We also found that oral LPS treatment affected the structure of the intestinal microbiome, reflected by changes in the clustering of intestinal microbiota. The average abundance of Muribaculaceae showed an increasing trend with increasing LPS levels, and that of the genus Bacteroides decreased, compared with the control group. In addition, oral LPS treatment with 8 mg/kg BW affected the intestinal epithelial morphology, damage the mucosal immune barrier, downregulated the expression of tight junction proteins, increased circulating D-lactate levels, and stimulated the secretion of various inflammatory mediators and activation of the TLR4/MyD88/NFκB pathway. This study presented the injuries of intestinal mucosal barrier function induced by LPS challenges in goslings and provided a scientific model for searching the novel strategies to attenuate the immunological stress and gut injury caused by LPS.

Safety and efficacy of different tirofiban administration routes on acute ischemic stroke patients with successful recanalization: A propensity score matching analysis.

This study aimed to explore the effect of different administration routes of a low dose of tirofiban on acute ischemic stroke (AIS) patients with successful recanalization after endovascular treatment (EVT). This is a cohort study that retrospectively analyzed data of patients with AIS who underwent EVT and achieved successful recanalization from a prospective registry. Eligible patients were divided into three groups according to their use of tirofiban. Propensity score matching (PSM) was used to balance baseline bias. Safety outcomes included any intracranial hemorrhage (ICH) and symptomatic ICH (sICH). Efficacy outcomes included arterial reocclusion, in-hospital mortality, 3-month mortality, and 3-month functional outcomes. We included 821 patients with 306 in the no tirofiban group, 202 in the IA + IV tirofiban group, and 313 in the IV tirofiban group. After PSM, each group included 101 patients with balanced baseline characteristics. There was no difference between the IV tirofiban group and the no tirofiban group in terms of safety and efficacy outcomes (all p > 0.05). Compared with no tirofiban, IA + IV tirofiban group did not increase ICH (30.7% vs. 37.6%, p > 0.05) and sICH (6.9% vs. 17.8%, p> 0.05) whereas reduced 3-month mortality (14.3% vs. 28.7%, p< 0.05) and improved 3-month modified Rankin Scale (median 3 vs. 4, p< 0.05). A low dose of tirofiban, regardless of their administration routes, was safe for AIS patients who achieved successful recanalization with EVT, whereas only IA + IV tirofiban improved clinical outcomes.

Effect of Serial Systemic and Intratumoral Injections of Oncolytic ZIKVBR in Mice Bearing Embryonal CNS Tumors.

The Zika virus (ZIKV) has shown a promising oncolytic effect against embryonal CNS tumors. However, studies on the effect of different administration routes and the ideal viral load in preclinical models are highly relevant aiming for treatment safety and efficiency. Here, we investigated the effect and effectiveness of different routes of administration, and the number of ZIKVBR injections on tumor tropism, destruction, and side effects. Furthermore, we designed an early-stage human brain organoid co-cultured with embryonal CNS tumors to analyze the ZIKVBR oncolytic effect. We showed that in the mice bearing subcutaneous tumors, the ZIKVBR systemically presented a tropism to the brain. When the tumor was located in the mice’s brain, serial systemic injections presented efficient tumor destruction, with no neurological or other organ injury and increased mice survival. In the human cerebral organoid model co-cultured with embryonal CNS tumor cells, ZIKVBR impaired tumor progression. The gene expression of cytokines and chemokines in both models suggested an enhancement of immune cells recruitment and tumor inflammation after the treatment. These results open new perspectives for virotherapy using the ZIKVBR systemic administration route and multiple doses of low virus load for safe and effective treatment of embryonal CNS tumors, an orphan disease that urges new effective therapies.

Clustering and Erratic Movement Patterns of Syringe-Injected versus Mosquito-Inoculated Malaria Sporozoites Underlie Decreased Infectivity.

ABSTRACTMalaria vaccine candidates based on live, attenuated sporozoites have led to high levels of protection. However, their efficacy critically depends on the sporozoites’ ability to reach and infect the host liver. Administration via mosquito inoculation is by far the most potent method for inducing immunity but highly impractical. Here, we observed that intradermal syringe-injected Plasmodium berghei sporozoites (syrSPZ) were 3-fold less efficient in migrating to and infecting mouse liver than mosquito-inoculated sporozoites (msqSPZ). This was related to a clustered dermal distribution (2-fold-decreased median distance between syrSPZ and msqSPZ) and, more importantly, a 1.4-fold (significantly)-slower and more erratic movement pattern. These erratic movement patterns were likely caused by alteration of dermal tissue morphology (>15-μm intercellular gaps) due to injection of fluid and may critically decrease sporozoite infectivity. These results suggest that novel microvolume-based administration technologies hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.IMPORTANCE Malaria still causes a major burden on global health and the economy. The efficacy of live, attenuated malaria sporozoites as vaccine candidates critically depends on their ability to migrate to and infect the host liver. This work sheds light on the effect of different administration routes on sporozoite migration. We show that the delivery of sporozoites via mosquito inoculation is more efficient than syringe injection; however, this route of administration is highly impractical for vaccine purposes. Using confocal microscopy and automated imaging software, we demonstrate that syringe-injected sporozoites do cluster, move more slowly, and display more erratic movement due to alterations in tissue morphology. These findings indicate that microneedle-based engineering solutions hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.

Comparison of Outcomes in Patients with Obesity Between Two Administration Routes of Omeprazole After Laparoscopic Sleeve Gastrectomy: An Open-Label Randomized Clinical Trial

BackgroundThe effect of different administration routes of omeprazole remains unclear on the recovery in patients with obesity after laparoscopic sleeve gastrectomy (LSG).MethodsWe designed a randomized clinical trial enrolling 120 patients with a BMI≥32.5 kg/m2 after LSG. They were randomized into two groups to be administered with omeprazole by rapid intravenous injection (group A) or by continuous micropump infusion (group B). The plasma concentration of omeprazole was monitored upon initiating administration. Change in intragastric pH and gastrointestinal symptoms during follow-up served as indicators for therapeutic evaluation.ResultsPatients in the two groups showed no difference in the AUC curves (P=0.25), but group A had significantly higher peak concentration (P<0.001), and shorter time to reach peak concentration after administration (P<0.001), compared to group B. Before and after the administration of omeprazole, the average change in intragastric pH was much lower in group A (0.031 ± 0.61) than in group B (0.48 ± 0.74) (P=0.004). The incidence of gastrointestinal symptoms was similar between the two groups (P=0.85); however, the average duration of remaining symptoms was longer in group A (3.97 months; 95% CI, 2.90–5.04) than in group B (2.82 months; 95% CI, 2.01–3.63) (P=0.04).ConclusionContinuous micropump infusion of omeprazole may improve the outcomes in patients with obesity after LSG.Trial registrationChina Clinical Trial Registration Center (ChiCTR), ChiCTR-IPR-17013365. Registered 13 November 2017. http://www.chictr.org.cn/showproj.aspx?proj=22892.

Effect of different administration and dosage of dexmedetomidine in the reduction of emergence agitation in children: a meta-analysis of randomized controlled trials with sequential trial analysis.

BackgroundBeneficial effects of dexmedetomidine (DEX) against emergence agitation (EA) in children remain controversial. We performed a more comprehensive meta-analysis to evaluate the protective effect of different administration routes, timing, patterns, and doses of DEX on EA in children.MethodsThe randomized controlled trials about DEX preventing EA in children were searched in PubMed, Cochrane Library, Embase, and Web of Sciences up to October 7, 2020. The traditional meta-analysis and subgroup analysis were performed to study the influence of DEX on EA in children. The sequential trial analysis (TSA) further analyzed the pooled results to evaluate meta-analyses’ robustness. Grading of recommendation, assessment, development, and evaluation (GRADE) was used to assess evidence quality.ResultsSixty-seven studies with 5,688 pediatric patients were included. DEX significantly decreased EA in children compared to placebo [RR 0.29, 95% confidence intervals (CI): 0.25–0.34] and midazolam (RR 0.34, 95% CI: 0.25–0.45), with firm evidence from TSA. Notably, using DEX significantly reduced severe EA incidence (RR 0.23, 95% CI: 0.16–0.32), with firm evidence by TSA and high quality of GRADE. Pre-specified subgroup analyses revealed firm and high-quality evidence for a reduction of EA, only if the perineural route administers DEX (RR 0.24, 95% CI: 0.14–0.41), as premedication (RR 0.27, 95% CI: 0.20–0.36), as continuous dosage (RR 0.25, 95% CI: 0.18–0.33), at high dose (RR 0.24, 95% CI: 0.18–0.31). The pooled results also showed that DEX reduced the incidence of PONV compared to placebo (RR 0.43, 95% CI: 0.33–0.55). Evidence for DEX’s influence on other secondary outcomes (emergence time, time in PACU, rescue analgesia, hypotension, and bradycardia) is insufficient to draw any conclusion.ConclusionsOur findings confirm the beneficial effects of DEX on EA, severe EA, and PONV in children. There was firm and high-quality evidence for the efficacy of DEX in preventing EA in children when perineural routes administered DEX, as premedication, as continuous dosage, and at a high dose. The best dose, route, patterns, and timing of DEX and influence on other outcomes call for further studies.

Comparison of the Impact of Different Administration Routes on the Efficacy of a Thermoresistant Newcastle Disease Vaccine in Chickens

Route of vaccine administration has a great impact on immunization and protection outcomes in chickens. This study was conducted to compare the effect of different administration routes on the efficacy of a thermoresistant Newcastle disease (ND) vaccine (ND.TR.IR) in chickens. A total of 100 one-day-old specific pathogen-free chicks were divided into five groups (n = 20 chicks per group) and vaccinated through different routes at 10 and 20 days of age. Treatments included no vaccination (control [C]), 1 dose inoculation through eye drop (ED), 1 dose inoculation through drinking water (DW), 1 dose inoculation through feed (FV1), and 10 doses inoculation through feed (FV10). At 20 and 34 days of age, antibody titers were measured against ND virus (NDV) in all the chickens by hemagglutination inhibition (HI) test. Chicks immunized with ND.TR.IR vaccine through different routes of administration also were intramuscularly challenged with a local virulent NDV (vNDV) (Ck/ir/Beh/2011) 14 days after booster vaccination (at 34 days of age). Our results showed that in comparison with the FVs groups, the immunized chicks through ED induced a higher HI antibody titers at 20 days of age (p < 0.05). Meanwhile, vaccination through ED induced higher HI antibody titers at day 34 of age compared with all other groups (p > 0.05). The percentages of the protective HI antibody titers (≥log23) detected in ED and DW groups at 20 days of age were higher than those detected in the FV1 group (p < 0.05). However, routes of vaccination had no significant effect on the rate of protective titers at day 34 of age (100%, 90%, 75%, and 85% for ED, DW, FV1, and FV10, respectively). The percentage of post-NDV challenge survived chickens was not affected by the route of vaccination (p > 0.05), but immunization of chicks with ND.TR.IR in FV1 group provided relatively poorer protection when compared with the other groups (90% vs. 100%, respectively). Altogether, immunization of chicks with ND.TR.IR vaccine through different routes of administration induced protective NDV antibody HI titers, and provided protection against vNDV. However, when the vaccine was administrated through feed, a higher dose of vaccine is recommended.

Comparison of different immunization routes on the immune responses induced by Mycobacterium tuberculosis ESAT-6/CFP-10 recombinant protein

According to some difficulties against tuberculosis (TB) vaccination, development of new TB vaccines has been noted in recent years. Selection of proper route for vaccination is one of the most important factors for induction of good immune responses. Hence, in this study, the effects of different administration routes, including intranasal (I.N), subcutaneous (S.C) and intramuscular (I.M) on immune responses against Mycobacterium tuberculosis ESAT-6/CFP-10 recombinant protein has been considered.Recombinant ESAT-6/CFP-10 protein with or without adjuvant (MF59 or cholera toxin B (CTB)) was administered by three routes of I.M, I.N and S.C to mice for three times. Then, the levels of specific antibodies, lymphocyte proliferation and IFN-γ/IL-5 cytokine profile have been carried out to evaluate the humoral and cellular responses.The results showed that the titers of specific antibodies were quickly elevated in S.C and I.M groups after first immunization. Otherwise, the raise of antibody has delay in the I.N immunized animals. The levels of IFN-γ and lymphocyte proliferation have been increased in all of vaccinated groups. However, the I.N immunized mice have lower levels of IL-5 production.Based on our finding, the ESAT-6/CFP-10 recombinant protein is a potent stimulator of immune responses in all of three immunization strategies. However intranasal administration of this antigen has tended to reinforcement of cellular immune responses.

Blockade of programmed death-ligand 1 attenuates indirect acute lung injury in mice through targeting endothelial cells but not epithelial cells

To examine the expression profile of programmed death-ligand 1 (PD-L1) on lung endothelial or epithelial cells, and to determine the specific role of PD-L1 in mouse model of indirect acute lung injury (i-ALI). Eighty male C57BL/6 mice were randomly divided into two parts (both n = 40). The effects of different administration routes on the expression of PD-L1 were observed. The mice in each part were randomly divided into sham, i-ALI, i-ALI+small interfering RNA (siRNA) random sequence control, and i-ALI+PD-L1 siRNA which could specifically inhibit PD-L1 expression groups, with 10 mice in each group. i-ALI was reproduced in a mouse model of hemorrhagic shock in combination with a subsequent cecal ligation and puncture (CLP). In sham group, only bilateral femoral arteries were ligated without catheterization or bleeding, and only cecum was separated but perforation was not ligated. Intravenous or intratracheal delivery of PD-L1 siRNA was performed 2 hours following the resuscitation to suppress the expression of PD-L1 on lung endothelial or epithelial cells. The mice in i-ALI+siRNA random sequence control group were given siRNA random sequence without inhibition effect on PD-L1 expression, and those in sham group and i-ALI group were given 100 μL phosphate buffered saline (PBS). The mice were sacrificed at 24 hours after CLP, and samples of blood, lung tissue and bronchoalveolar lavage fluid (BALF) were harvested. Expressions of PD-L1 were determined with flow cytometry. Cytokines and chemokines in plasma, lung tissue and BALF were determined by enzyme linked immunosorbent assay (ELISA). The protein concentration in plasma and BALF and the activity of myeloperoxidase (MPO) in lung tissue were quantitatively measured. The pathological changes in lung tissue were observed under light microscope. (1) Compared with sham group, PD-L1 expression on lung endothelial or epithelial cells were significantly elevated in i-ALI group [endothelial cells: (27.88±1.53)% vs. (19.64±1.03)%, epithelial cells: (58.70±8.21)% vs. (29.23±3.94)%, both P < 0.05]. (2) Mice received intravenous delivery of liposomal-encapsulated siRNA had significantly lower expression of PD-L1 on lung endothelial cells as compared with that of i-ALI group [(21.37±0.76)% vs. (27.88±1.53)%, P < 0.05]. Intratracheal delivery of naked PD-L1 siRNA mainly inhibited the PD-L1 expression on epithelial cell as compared with that of i-ALI group [(31.23±4.71) % vs. (58.70±8.21) %, P < 0.05]. The expression of PD-L1 in pulmonary microvascular endothelial cells or pulmonary epithelial cells of i-ALI mice was not affected by siRNA random sequence. (3) PD-L1 silencing on pulmonary endothelial cells induced by intravenous delivery of PD-L1 siRNA led to a lower protein ratio of BALF/plasma [(4.48±0.35)×10-3 vs. (6.11±0.56)×10-3, P < 0.05] and a decreased MPO activity in lung tissue (U×μg-1×min-1: 2.48±0.47 vs. 4.56±0.52, P < 0.05) as compared with that of i-ALI group. Moreover, inflammatory mediator levels such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) in lung tissue or plasma were significantly reduced following PD-L1 suppression on endothelial cells as compared with those of i-ALI group [IL-6 (ng/g): 177.4±23.2 vs. 287.9±57.3, MCP-1 (ng/g): 839.6±91.7 vs. 1 395.7±211.9, MIP-2 (ng/g): 923.7±107.3 vs. 1 700.9±240.2 in lung tissue; IL-6 (ng/L): 950.2±192.7 vs. 1 828.2±243.6, TNF-α (ng/L): 258.7±29.1 vs. 443.0±58.1, MCP-1 (ng/L): 2 583.8±302.3 vs. 4 328.1±416.4, MIP-2 (ng/L): 1 512.9±165.6 vs. 2 005.9±85.7 in plasma, all P < 0.05], however, there was no significant change in the levels of inflammatory factors in BALF. It was shown in lung tissue histology that PD-L1 silencing on pulmonary endothelial cells induced by intravenous delivery of PD-L1 siRNA led to lessened pulmonary edema and reduced immune cells emigration. Intratracheal delivery of PD-L1 siRNA for PD-L1 suppression on epithelial cells had minimal effects on protein ratio of BALF/plasma, MPO activity, inflammatory mediator expressions in lung tissue, plasma, and BALF as well as lung tissue histology. PD-L1 silencing on endothelial cells but not epithelial cells protected mice against hemorrhagic shock-sepsis induced i-ALI.

Preliminary analysis of the effect of different administration routes of tranexamic acid on blood loss after total hip arthroplasty for female femur neck fractures

To study curative effect of different administration routes of tranexamic acid (TXA) on blood loss of elderly female patients with femoral neck fracture in total hip arthroplasty. From December 2015 to January 2018, 77 elderly women with femoral neck fractures undergoing total hip replacement were divided into four groups: group A, group B, group C, and group D. The group A (intravenous medication group) included 21 patients with an average age of (77.10±7.02) years old. The patients in group A received 15 mg/kg TXA intravenously 5 minutes before skin incision and intraoperative infusion of saline into the joint cavity. The group B(local medication group) included 18 cases, with an average age of (73.83±6.56) years old. The patients in group B received saline intravenously 5 minutes before skin incision and intraoperative infusion of 3 g TXA into the joint cavity. The group C (combined medication group) included 19 cases, with an average age of (74.26±6.04) year old. The patients in group C received 15 mg/kg TXA intravenously before operation and intraoperative infusion of 1.5 g TXA into the joint cavity. The group D (control group) included 19 cases, with an average age of (76.69±9.27) years old. The patients in group D received saline intravenously 5 minutes before skin incision and intraoperative infusion of saline into the joint cavity. The postoperative wound drainage volume, hemoglobin value, and the total blood loss calculated according to the height and weight and the hematocrit (HCT) before and after operation were observed and compared. In group A, the postoperative drainage was(111.91±35.02)ml; the change of hemoglobin was(26.86±12.99) g/L; and total blood loss was(628.60±306.78) ml. In group B, postoperative drainage was(108.89±36.61) ml; change of hemoglobin was(26.28±8.59) g/L; and the total blood loss was (584.41±250.86) ml. In group C, postoperative drainage was(102.63±47.36) ml; change of hemoglobin was (26.89±12.47) g/L; and total blood loss was(634.78±384.89) ml. In group D, postoperative drainage was(107.37±40.53) ml; change of hemoglobin was(40.95±12.48) g/L; and total blood loss was(1 005.24±483.37) ml. There were no significant differences among 4 groups in postoperative drainage volume (P>0.05). The hemoglobin and total blood loss in group A, B, and C were less than those in the group D(P<0.05), however, there were no significant differences among three groups(P>0.05). Application of TXA can effectively reduce blood loss during perioperative period of total hip arthroplasty for elderly women with femoral neck fracture. The best administration route and dosage should be further studied.

Effects of different administration routes of lipid emulsion on bupivacaine-induced cardiotoxicity in rats

Objective To evaluate the effects of different administration routes of lipid emulsion on bupivacaine-induced cardiotoxicity in rats. Methods Forty-eight clean healthy adult male Sprague-Dawley rats, weighing 300-350 g, were divided into 6 groups (n=8 each) using a random number table: IV infusion of normal saline (NS) group (group VN), IV infusion of lipid emulsion group (group VL), duodenal infusion of NS group (group DN), duodenal infusion of lipid emulsion group (group DL), intraperitoneal infusion of NS group (group PN) and intraperitoneal infusion of lipid emulsion group (group PL). In VN and VL groups, preheated NS and 20% lipid emulsion 3 ml·kg-1·min-1 were infused via the femoral vein for 5 min, respectively, and then 0.75% bupivacaine was infused at the rate of 2 mg·kg-1·min-1 until cardiac arrest happened.Preheated NS and 20% lipid emulsion 15 ml/kg were infused via the duodenum (over 1 min, at a constant rate) in DN and DL groups, respectively, and were intraperitoneally infused in PN and PL groups, respectively, followed by an infusion of 0.2 ml/min for 15 min in DN, DL, PN and PL groups.Then 0.75% bupivacaine was infused via the left femoral vein at a rate of 2 mg·kg-1·min-1 until cardiac arrest happened.The time to ventricular arrhythmia, mean arterial pressure (MAP) decreasing to 50% of the baseline and cardiac arrest was recorded.The amount of bupivacaine consumed was calculated immediately after ventricular arrhythmia occurred (T0), immediately after MAP decreased to 50% of the baseline (T1) and immediately after occurrence of cardiac arrest (T2). Arterial blood samples were collected at T0-2 for determination of the concentration of bupivacaine in plasma by high-performance liquid chromatography. Results Compared with group VN, the time to ventricular arrhythmia, MAP decreasing to 50% of the baseline and cardiac arrest was significantly prolonged, and the amount of bupivacaine consumed was increased at T0-2 in group VL (P 0.05). Compared with group VL, the time to ventricular arrhythmia, MAP decreasing to 50% of the baseline and cardiac arrest was significantly shortened, and the amount of bupivacaine consumed was decreased at T0-2 in DL and PL groups (P 0.05). Conclusion IV infusion of lipid emulsion can decrease bupivacaine-induced cardiotoxicity when compared with duodenal and intraperitoneal infusion in rats. Key words: Lipid emulsions, intravenous; Bupivacaine; Drug toxicity

Comparison of Efficacy and Side Effects of Different Administration Routes of Misoprostol (Oral, Vaginal, and Sublingual) for Second-Trimester Abortion

Background The current study was designed to compare the effectiveness and side effects of oral, vaginal, and sublingual misoprostol in termination of second-trimester pregnancy. Materials and Methods: In this clinical trial (2014 to 2015), 85 pregnant women in the second trimester of pregnancy were included in Imam Reza hospital, Kermanshah, Iran. They were randomly divided into three groups as follows: oral misoprostol (n=28), vaginal misoprostol (n=30), and sublingual misoprostol (n=27). Misoprostol was administered orally (oral misoprostol group), vaginally (vaginal misoprostol group), or sublingually (sublingual misoprostol group). The dosage was similar in three groups (400 micrograms every four hours up to a maximum of five doses). The mothers were followed and induction-abortion interval time, number of dosages required, and misoprostol side effects were documented. The data were analyzed by SPSS version 20.0 software. Results: The mean (standard deviation) age of the sample was 28.27 (±4.97) years. Mean gestational age was 16.58 weeks and mean gravidity was 1.99. Mean number of administered misoprostol doses was 3.89 and most patients responded to three doses of misoprostol. Mean abortion time was 20.08 hours. No side effects were reported in 60% of the subjects. Others experienced side effects such as nausea (16.5%), fever and chills (12.9%), and vaginal bleeding (9.4%). The abortion duration in 35.3% of the subjects was within 18 hours. The most successful method was oral route (82.1%), followed by vaginal route (80%), and sublingual route (70.4%). The abortion duration was statistically different between the three groups (P= 0.001). Conclusion: Finding of the presented study showed that misoprostol is a safe medication to be used for medical abortion in the second trimester of pregnancy. Oral route of administration was superior to vaginal or rectal use of misoprostol.

Impact of Bacillus Calmette–Guérin Moreau vaccine on lung remodeling in experimental asthma

We analyzed the effects of different administration routes and application times of the BCG-Moreau strain on airway and lung inflammation and remodeling in a murine model of allergic asthma. BALB/c mice (n=168) were divided into two groups. The first group received BCG-Moreau strain while the second group received saline using the same protocol. BCG or saline were intradermally or intranasally injected one or two months before the induction of asthma. Mice were further sensitized and challenged with ovalbumin or received saline. Twenty-four hours after the last challenge, BCG prevented the triggering of pro-inflammatory cytokines, probably by increasing Foxp3 and interleukin (IL)-10, modulating eosinophil infiltration and collagen fiber deposition, thus reducing airway hyperresponsiveness. In conclusion, BCG-Moreau prevented lung remodeling in the present model of allergic asthma, regardless of administration route and time of vaccination. These beneficial effects may be related to the increase in regulatory T cells and to IL-10 production in tandem with decreased Th2 cytokines (IL-4, IL-5, and IL-13).

AS-245: Effects of Differing Administration of Low-Molecular-Weight Heparin on Platelet Activation and Aspirin Intervention

To investigate the effects of different administration routes of low-molecular-weight heparin (LMWH) on platelet activation and the roles of conventional aspirin dose (100 mg/d) in the prevention of LMWH-induced platelet activation.

Intrathecal opioids, potency and lipophilicity

To determine the relationship between potency and lipophilicity for intrathecal opioids, morphine, normorphine, pethidine and methadone were studied in an electrophysiological model in the rat. Dose-response curves were constructed for the opioid effects on C fibre evoked activity of dorsal horn nociceptive neurones following intrathecal application of each opioid, and the ED 50 values were correlated with lipid solubility. A significant inverse correlation was found ( P = 0.002; r = 0.998) so that the most lipid soluble drugs were the least potent. The possible mechanism of this relationship, the implications for spinal opioid use and the effect of different administration routes on the relationship between lipid solubility and potency are considered.

Effects of administration routes on the uptake of uridine and 5-fluorouridine into an adenocarcinoma transplanted to rat liver.

In a model of secondary liver cancer in Wistar rats, the effect of different administration routes on the uptake of 3H-uridine into tumor and several normal tissues was studied. The rats were inoculated with a tumor cell suspension in the central liver lobe. Ten days later, they were distributed into four groups with a catheter placed in the gastroduodenal artery, the portal vein, one of the femoral veins, or in the peritoneal cavity. 3H-uridine was injected 46 h later and after an additional 90 minutes the animals were anesthetised and pieces of liver tumor and normal tissues were removed and frozen. The incorporation into the acid-soluble fraction and RNA was analyzed. In a separate experiment, 3H-fluorouridine was administered by the gastroduodenal artery and a comparison was made with the uptake of 3H-uridine. A significantly higher amount of uridine was incorporated into the tumor by the arterial route. The intraportal and intraperitoneal routes were comparable, while a somewhat higher incorporation was found by the systemic route. The consequences of using the different routes upon the incorporation into RNA of tumor and dose-limiting organs are demonstrated. With the aid of this experimental model, it is possible to evaluate further the effect by different manipulations on different drugs regarding the administration route.