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Intranasal drug delivery system is a non-invasive drug delivery route with the advantages of no first-pass effect, rapid effect and brain targeting. It is a feasible alternative to drug delivery via injection, and a potential drug delivery route for the central nervous system. However, the nasal physiological environment is complex, and the nasal delivery system requires "integration of medicine and device". Its delivery efficiency is affected by many factors such as the features and formulations of drug, delivery devices and nasal cavity physiology. Some strategies have been designed to improve the solubility, stability, membrane permeability and nasal retention time of drugs. These include the use of prodrugs, adding enzyme inhibitors and absorption enhancers to preparations, and new drug carriers, which can eventually improve the efficiency of intranasal drug delivery. This article reviews recent publications and describes the above mentioned aspects and design strategies for nasal intranasal drug delivery systems to provide insights for the development of intranasal drug delivery systems.
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Administration, Intranasal , Drug Delivery Systems , Pharmaceutical Preparations , Drug Carriers , Brain , Nasal Cavity/physiology , Nasal MucosaABSTRACT
OBJECTIVE To re-evaluate systematic review/meta-analysis of escitalopram in the treatment of depression， and to provide reference for clinical use of escitalopram. METHODS Retrieved from CNKI， Wanfang database， VIP， SinoMed， PubMed and the Cochrane Library， etc.， systematic review/meta-analysis of escitalopram in the treatment of depression were collected from the construction of the database to May 17， 2022. The literatures were screened according to the inclusion and exclusion criteria， the basic information of the included literatures was extracted， and the methodological quality， reporting quality and evidence quality of the included literatures were evaluated by using AMSTAR 2 scale， PRISMA statement， and GRADE system， respectively. RESULTS A total of 16 systematic reviews/meta-analyses were included. The results of efficacy comparison showed that escitalopram in the treatment of depression was superior to sertraline in improving the total effective rate， and was comparable to paroxetine， duloxetine and fluoxetine in improving cure rate. The results of safety comparison showed that the safety of escitalopram was higher than that of paroxetine and venlafaxine. The overall methodological quality evaluation of AMSTAR 2 scale was low， and all of them were rated as extremely low； main reason was the lack of many key items. PRISMA score was between 12 and 23 points. Among them， there were 5 literatures with scores ＞21 points， and the reports were relatively complete， 10 literatures with scores between 15 and 21 points， and the reports had certain defects， and 1 literature with scores ≤15 points， with serious information missing. The results of the grading of GRADE evidence showed that， of the 160 included outcome indicators， 69 were moderate evidence， 64 were low-level evidence， and 27 were very low-level evidence. CONCLUSIONS The total effective rate of escitalopram in improving depressive patients is not inferior to that of sertraline； compared with paroxetine， escitalopram is safer. However， the evidence level of the above conclusions is low.
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Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.
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Objective:To investigate the serum levels of soluble growth stimulation expression gene 2 protein (sST2) and inflammatory factors in patients with acute left ventricular ejection fraction reduction heart failure (HFrEF) treated with sacubitril/valsartan.Methods:Ninety six patients with acute HFrEF admitted in The Affiliated Hospital of Qingdao University from March 2020 to March 2021 were enrolled. The patients were treated with sacubitril/valsartan,the dose was gradually increased from 50 mg b.i.d to the target dose of 200 mg b.i.d according to hemodynamics. After 12 weeks, the target dose was achieved in 72 cases (compliance group), and did not achieved in 24 cases (non-compliance group). The serum levels of sST2, IL-1β, IL-6, TNF-αand IL-10 were measured and compared between the two groups. The changes in left atrial anteroposterial diameter (LA), left ventricular end-diastolic diameter (LVDd) and left ventricular ejection fraction (LVEF) values were assessed with echocardiography. The adverse reactions, readmission rate and all-cause death within 3 months after discharge were compared between the two groups.Results:A total of 96 patients with acute HFrEF completed the follow-up, including 72 patients (75.0%) in the compliance group and 24 (25.0%) in the non-compliance group; aged 50-75 (66.1±6.7) years old, and 68 (70.8%) males. After treatment, the serum levels of sST2, IL-1β, IL-6 and TNF-α were decreased, and the IL-10 level was increased in both groups ( P<0.05); while the improvement of serum indicators in the compliance group was more marked ( P<0.05). Echocardiography showed that the LA, LVDd, and LVEF were significantly increased after treatment ( P<0.05) in compliance group, while there was no significant changes before and after treatment in the non-compliance group. SST2, inflammatory factors and echocardiographic measurements of patients in the standard group had statistical significance before and after treatment ( P<0.05), and the difference showed a downward trend. No deterioration of renal function and angioedema were observed in both groups, and there was no significant difference in hyperkalemia (two in compliance group and one in non-compliance group), symptom hypotension (each in two groups) between the two groups (χ 2=0.12, 0.68; P>0.05). In the non-compliance group, 10 patients (41.7%) were readmitted due to heart failure, and 6 patients (25.0%) died; while there were no readmitted cases or fatal cases in compliance group (χ 2=33.49, 19.20; P<0.05). Conclusion:Early application of sacubitril and valsartan sodium in patients with acute HFrEF after hemodynamic stabilization can significantly improve left ventricular remodeling, for those with earlier escalation to the target dose, it is more beneficial. The changes of serum sST2 and inflammatory factor level after treatment may predict the efficacy of sacubitril/valsartan therapy.
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Trousseau′s syndrome(TS) is a complication of cancer-associated thrombosis caused by hypercoagulability. A 58-years female patient admitted to the Affiliated Hospital of Qingdao University on October 2020 and diagnosed with Trousseau′s syndrome was reported. This was a patient with pancreatic malignant tumor. On the second day of admission, the mouth angle was distorted and the speech was vague. Craniocerebral MR showed multiple DWI high signals in the brain parenchyma, and brain MR enhancement showed no abnormal enhancement in the brain parenchyma. The patient was considered to be Trousseau′s syndrome. Using "Trousseau′s syndrome" and "cerebral infarction" as key words, the relevant literature was searched in CNKI, Wanfang and PubMed databases from January 2011 to June 2021, total of 76 cases of Trousseau′s syndrome complicated with cerebral infarction were reported in the literature. Among 77 cases (including one in this study) 36 were males and 41 were females, with a median age of 63 years old. The most common tumor type was lung adenocarcinoma (24 cases, 31.2 %). The mean D-dimer level was (17.3±12.8) mg/L, Craniocerebral CT or MRI showed that 57 cases (74.0 %) had bilateral multiple lesions; and 56 cases received anticoagulant therapy. A total of 68 patients were followed up, with a median survival time of 90 days, and one year overall survival rate was 32.6 %. The study indicates that for cerebral infarction with significantly elevated D-dimer level and multiple vascular involvement, malignant tumors should be considered.
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An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values ( = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.
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OBJECTIVE:To prepare Ibuprofen lysine sustained-release liquid suppository,and conduct the evaluation in vivo and in vitro. METHODS:Ibuprofen lysine sustained-release liquid suppository was prepared by using Poloxamer solution as main matrix,carbomer as bioadhesive agent,laurocapram as penetrant. The ratios of poloxamer 407(P407)-poloxamer 188(P188)and carbomer content were screened by using gel temperature,gel intensity,biological adhesion and release rate in vitro as indexes, and the concentration-time curves and pharmacokinetic parameters of prepared liquid suppository and common solid suppository af-ter rectal administration in Beagle dogs in vivo were compared. RESULTS:When the P407-P188 ratio was 1:1.2,the gel tempera-ture of sustained-release liquid suppository was 30.4-38.1 ℃,which was the nearest to the rectal temperature;when the content of carbomer was 0.8%,the in vitro release of sustained-release liquid suppository was in zero-order model,with favorable correlation (R2=0.996). The tmax of common solid suppository was 3.206 h,then plasma concentration decreased significantly,release time did not exceed 12 h,AUC0-∞ was 501.826 mg·h/L;tmax of sustained-release liquid suppository was 8.814 h,then plasma concentration decreased,release time exceeded 24 h,AUC0-∞ was 715.489 mg·h/L. CONCLUSIONS:Ibuprofen lysine sustained-release liquid suppository is successfully prepared,which shows better sustained-release effect and excellent correlation in vivo and in vitro than common solid suppository.
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Objective To evaluate the effect of enhanced recovery after surgery (ERAS) on immune function and clinical signs in patients with acute abdomen.Methods From March 2016 to March 2017,patients with acute abdominal admitted in the Emergency Care Center of the First Affiliated Hospital of Zhengzhou University were collected and randomized into ERAS group and conventional peri-operative management group (CPM group).In addition to clinical signs (the time of bowel movemtn recovery,the time of first postoperative ingestion and ambulation,hospital stay,complication rates),the celluar immunity (CD4 +,CD8 +,CD4 +/CD8 +) were determined during peri-operation period.Results A cohort of 240 patients were in ERAS group and 192 patients in CPM group.There was no significant difference in general condition between the two groups (P ＞ O.05).On the first day after operation,the levels of CD4 +,CD4 + /CD8 + decreased in both groups (P ＜ 0.05),but the CPM group had lower levels of CD4 +,CD4 +/CD8 +than the ERAS groups.On the 3rd and 7th days after surgery,the ERAS groups had higer levels of CD4+,CD4+/CD8+ than the CPM groups,(the levels of CD4+,CD4+/CD8+ recovery on the 3rd and 7th day after operation,and the ERAS group was significantly better than the CPM group) (P ＜ 0.05).Compared with CPM group,the recovery of bowel movement appeared earlier after operation in ERAS group with sooner resuming ingestion and ambulation after operation,shorter hospital stay,and lower WHO pain rating scale and complication rates (P ＜ O.05).Conclusions ERAS for patients with acute abdomen can alleviate postoperative suppression of immunity,preserving immune function intact and accelerating postoperative rehabilitation.
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Dry powder inhalers (DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance. The purpose of this review is to summarize and illuminate how these factors affect drug-carrier interaction and influence the performance of DPIs.
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Objective To discuss the clinical methods and curative effect of minimally invasive percutaneous plate osteosynthesis ( MIPPO) technique applied in the treatment of humeral shaft fractures. Methods A retrospective analysis was applied on 14 patients with humeral fracture underwent the MIPPO operation in our department from April 2012 to March 2013. There were 8 males and 6 females, with their ages ranging from 28 to 64 years. Results Fourteen cases were followed up for 2 months to 12 months (an average of 6 months) . Their incisions got primary healing. The fracture segments got satisfactory reduction with good apposition and alignment radiologically, and the radial never function recovered well. UCLA score concluded as excellent in 13 cases and good in 1 case. Conclusion MIPPO is a safe and effective treatment for the humeral fracture with the benefits of less invasion, fewer complications and higher union rate.
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BACKGROUND: Typically antiepileptic drugs, such as phenobarbital, fenitoina sodica and diazepam, can inhibit amygdala kindling effect in rats. However, whether midazolam has the same effect is still unclear.OBJECTIVE: To investigate the inhibitory effect of midazolam on amygdala kindling onset in rats and maximal electroshock seizure (MES) in mice and effeots of antiepileptic drugs.DESIGN: This study was divided into three subexperiments, including the effects of midazolam on amygdala kindling onset, independent activities and incidence convulsion. All the three subexperiments were completely randomized,infra-group control or self-control studies.SETTING: Medical College of Qingdao University.MATERIALS: The experiment was carried out in the Comprehensive Experimental Room, Affiliated Hospital of Medical College of Qingdao University from August 2004 to March 2005. Nine Wistar rats weighing (250±10) g and 120 Kunming mice weighing (20±5) g and either gender were provided by Animal Center of Qingdao Institute of Drug Control.Midazolam (5 g/L) was provided by Xuzhou Enhua Drugs Co., Ltd. (batch number: 20030706).METHODS: ① Establishment of amygdala kindling models: Nine kindled rats were randomly selected and intraperitoneally injected with 0.25, 0.5 and 1 mg/kg midazolam, respectively. Quadri-pathway biological signal processing system (SMUP-PC) was used to measure discharge duration (ADD) and Racine's stage. ② Sixty mice were randomly divided into 5 groups, including saline group, 40 mg/kg phenobarbital group, 0.5, 1.0 and 1.5 mg/kg midazolam groups with 12 mice in each group. And then, numbers of activities in a unit time (times per 5 minutes) were determined by XZC-4A mini-animals independent activity instrument. ③ MES models were established to calculate incidence of convulsion.MATN OUTCOME MEASURES: Effects of midazolam on ADD, Racine's stage, numbers of independent activities and incidence of convulsion.RESULTS: All the 9 rats and the 120 mice were involved in the final analysis. ① Effect of midazolam on amygdala kindling onset: After intraperitoneal injection of 0.5 and 1.0 mg/kg midazolam, ADD and Racine's stage were obviously lower than those before administration (P ＜ 0.05-0.01). After intraperitoneal injection of 0.25 mg/kg midazolam, ADD was obviously lower than that before administration (P ＜ 0.05), but there was no significant difference in Racine's stage. ②Effect of midazolam on independent activities of mice: Numbers of independent activities were lower in the phenobarbital group and 0.5, 1.0 and 1.5 mg/kg midazolam groups than those in the saline group (P ＜ 0.01), while numbers of independent activities were higher in 0.5 mg/kg midazolam group than those in the phenobarbital group (P ＜ 0.05). ③Effect of midazolam on maximal electroshock seizure: Incidence of convulsion was lower in the phenobarbital group and 0.5, 1.0 and 1.5 mg/kg midazolam groups than that in the saline group (P ＜ 0.05-0.01), while Incidence of convulsion was higher in 0.5 mg/kg midazolam group than that in the phenobarbital group (P＜ 0.05).CONCLUSION: Midazolam can significantly inhibit amygdala kindling onset, reduce numbers of independent activities,and antagonist MES in mice.
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Objective To investigate the effects of atorvastatin on cardiovascular remodeling in renovascular hypertensive rats. Methods The 2-kindey,1-clip hypertensive rats(2K1C,Goldblatt) were prepared with Sprague-Dawley rat.SD rats were randomly divided into three groups: normal control rats,hypertensive rats and hypertensive rats treated with atorvastatin(2 mg?kg~(-1)?d~(-1)).After 6 weeks treatment,systolic blood pressure(SBP) was measured using the tail-cuff method.The plasma concentration of angiotensin Ⅱ and renin activity were determined by radioimmunoassay.The heart weight,the ratio of left ventricular weight to body weight were calculated.Results The plasma concentration of angiotensin Ⅱ((106.4?7.8)ng/L) and renin activity((20.6?2.4) ng/L)were significantly increaed in hypertensive rats compared with normal rats((72.3?5.4) ng/L and(12.5?3.7) ng/L)(P