BACKGROUND Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy.Long-acting injectable(LAI)antipsychotics have been widely used to improve adherence and prevent...BACKGROUND Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy.Long-acting injectable(LAI)antipsychotics have been widely used to improve adherence and prevent relapse in patients with various severe psychotic disorders,but there is a lack of high-quality data from previous research on the safety of LAI antipsychotics during pregnancy.AIM To summarize relevant data on maternal,pregnancy,neonatal,and developmental outcomes from published cases of LAI antipsychotic use in pregnancy.METHODS A literature search was performed through November 11,2023,using three online databases:PubMed/MEDLINE,Scopus,and Web of Science.Case reports or case series that reported information about the outcomes of pregnancy in women who used LAI antipsychotics at any point in pregnancy,with available full texts,were included.Descriptive statistics,narrative summation,and tabulation of the extracted data were performed.RESULTS A total of 19 publications satisfied the inclusion criteria:3 case series,15 case reports,and 1 conference abstract.They reported the outcomes of LAI antipsychotic use in 74 women and 77 pregnancies.The use of secondgeneration LAI antipsychotics was reported in the majority(n=47;61.0%)of pregnancies.First-generation LAI antipsychotics were administered during 30 pregnancies(39.0%).Most of the women(approximately 64%)had either satisfactory control of symptoms or no information about relapse,while approximately 12%of them had developed gestational diabetes mellitus.A minority of cases reported adverse outcomes such as stillbirth,spontaneous abortion,preterm birth,low birth weight,congenital anomalies,and neurological manifestations in newborns.However,there were no reports of negative long-term developmental outcomes.CONCLUSION Currently available data seem reassuring,but further well-designed studies are required to properly evaluate the risks and benefits of LAI antipsychotic use during pregnancy.展开更多
The objectives of e-STAR Romania (NCT00283517) were to collect clinical outcome data of Romania schizophrenia or schizo-affective disorder patients;prospectively to assess the reasons of treatment initiation, medicati...The objectives of e-STAR Romania (NCT00283517) were to collect clinical outcome data of Romania schizophrenia or schizo-affective disorder patients;prospectively to assess the reasons of treatment initiation, medication usage patterns;to document (long-term) clinical efficacy;and to collect safety data, as well as recording 2-year corresponding retrospective data. In total, 378 eligible subjects were enrolled who were initiated either on risperidone long-acting injectable (RLAI) (290) or on an oral antipsychotic (OA) (88) at baseline as required by the local Summary of the Product Characteristics. Data were collected from per patient both retrospectively and prospectively over a 24-month period at 3-month intervals after starting treatment. The results indicated that subjects suffering from schizophrenia or schizo-affective disorder initiated on RLAI were less likely to be hospitalized within the first 24 months after the initiation of treatment. Moreover, subjects treated with RLAI experienced significant improvements in their illness severity and functioning. Discontinuation rates for RLAI were low and doses were stable throughout the 24 months following the initiation of treatment. In addition, the necessity for supplementary concomitant medication was reduced. Adverse events were reported in 20.3% (RLAI) and 11.4% (OA) of the subjects. In general, patients initiated on RLAI and OA at baseline both clinically improved on all assessed parameters but a larger improvement was observed for patients on RLAI. Incidences of reported AEs during the use of RLAI in a naturalistic setting are comparable with those described in clinical studies;however, the incidence of extrapyramidal signs and weight gain was lower than expected.展开更多
Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) for the treatment of opioid-dependent patients. Design, Setting, and Participan...Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) for the treatment of opioid-dependent patients. Design, Setting, and Participants: A 12 weeks, open-label, randomised controlled trial conducted between June 2009-July 2011, at 14 Hospital-based drug clinics, in the 12 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder. Of the 3200 individuals screened, 3000 (93.7%) adults were randomized 1500 participants to receive injections of Long-acting depot formulations ofNalmefene (Nalmefene Consta 393.1 mg) given intramuscularly once in 12 weeks and 1500participants to receive extended-release Naltrexone (Vivitrol 380 mg), administered intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Opioid abstinence (percentage i.e. the number of patients who achieved complete abstinence during week 12). Confirmed abstinence or “opioid-free” was defined as a negative urine drug test for opioids and no self-reported opioid use. Weeks 1 - 4 were omitted from this endpoint to allow for stabilization of abstinence. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of mu-opioid receptor occupancy following single doses of Nalmefene extended-release injection (Nalmefene Consta 393.1 mg) as well as the plasma concentration of Nalmefene and Nalmefene-3-O-glucuronide. Safety was assessed by adverse event reporting. Results: Of 3000 participants, mean (SD) age was 27.1 (±4.8) years and 831 (27.7%) were women. 1500 individuals were randomized to receive injections of Long-acting depot formulations of Nalmefene (Nalmefene Consta 393.1 mg) and 1500 to receive injections of extended-release Naltrexone (Vivitrol 380 mg);2088 participants (69.6.0%) completed the trial. Primary endpoints: Confirmed Opioid Abstinence: Complete abstinence was sustained by 86% (n = 1290) of Nalmefene patients (patients treated with Nalmefene Consta 393.1 mg, long-acting depot formulations) compared with 43% (n = 645) of patients treated with extended-release Naltrexone 380 mg (Vivitrol), during weeks 5 - 12 (χ2 = 672.34, P Secondary Endpoint: Craving: A statistically and clinically significant reduction in opioid craving was observed with Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot formulations) vs. Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) by week 4 (P =0.0048), which persisted every week through 12 (P < 0.0001). Patients given Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot formulations) had a 75% decrease in craving from baseline to week 12. Patients given a Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) had a 3% increase in craving from baseline to week 12 (Mean change in self-reporting craving). Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) helped significantly more patients complete 12 weeks treatment (n = 1245, 83%) compared with extended-release Naltrexone (Vivitrol 380 mg) (n = 570, 38%) (χ2 = 635.53, P < 0.0001). Patients on long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) had longer treatment retention than patients on extended-release Naltrexone (Vivitrol 380 mg). Concentrations of Nalmefene and Nalmefene-3-O-Glucuronide in Plasma: Analyses were made of 275 study sample. There was no statistically significant difference for plasma nalmefene concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Nalmefene were 20.3 and 28.5 ng/ml and concentrations of nalmefene-3-O-glucuronide were 2.1 and 4.1 ng/ml, respectively. Plasma levels of Nalmefene remained above 20 ng/ml for approximately 12 weeks after administration of Nalmefene, long-acting depot formulations (Nalmefene Consta 393.1 mg). PET Assessments: Very high mu-opioid receptor occupancy by Nalmefene was detected 1 day after treatments at which time point the occupancy was 100.0% after Nalmefene injection (Nalmefene Consta 393.1 mg). Nalmefene Consta 393.1 mg injection (long-acting intramuscular formulation of Nalmefene) led to a very high occupancy ofmu-opioid receptors in all brain areas examined;the thalamus, caudate nucleus, and frontal cortex. Depending on the brain area mu-opioid receptor occupancy varied between 83.0% and 85.8% 84 days after dosing. Adverse Reactions: Adverse events were similar in opioid-dependent patients treated with long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) vs. patients treated with extended-release Naltrexone (Vivitrol 380 mg). Conclusions and Relevance: Long-acting depot formulations of Nalmefene (Nalmefene Consta 393.1 mg) was more effective then extended-release Naltrexone (Vivitrol 380 mg) in maintaining short-term abstinence from heroin and should be considered as a treatment option for opioid-dependent individuals.展开更多
Risperidone long-acting injectable (RLAI) is approved for the treatment of schizophrenia in many countries. The suggested site is the gluteal muscle with a needle length of two inches (50 mm) in Japan, which is longer...Risperidone long-acting injectable (RLAI) is approved for the treatment of schizophrenia in many countries. The suggested site is the gluteal muscle with a needle length of two inches (50 mm) in Japan, which is longer than the ordinarily used needle for intramuscular injections. The aim of this study was to determine the optimal needle insertion length for accurate delivery of RLAI procedure among subjects who have normal body mass index (BMI: 18 to 25) and high BMI (>25). Thirty-seven patients with schizophrenia were administered RLAI intramuscularly into the dorsogluteal muscle. The standard procedure required inserting 80% of the two inch needle. By using data collected by ultrasonography, the findings confirmed that the median needle insertion lengths for subjects with normal and high BMI were 39.0 and 45.5 mm, respectively. To deliver RLAI effectively and safely, the authors strongly recommend that a specialized needle be used that is “marked” at the 40 mm point from the tip of the needle to the base. In this way regardless of subcutaneous fat content, the RLAI can be safely delivered into the muscle without causing untoward or side effects.展开更多
In some cases, if the insertion depth is shallower than expected, intramuscular (IM) injection of risperidone long-acting injectable (RLAI) may not penetrate the muscle fascia. However, if needle insertion depth is de...In some cases, if the insertion depth is shallower than expected, intramuscular (IM) injection of risperidone long-acting injectable (RLAI) may not penetrate the muscle fascia. However, if needle insertion depth is deeper than anticipated, needle penetration may cause damage to nerves, arteries and veins. Few clinical studies were done to evaluate the depth of needle length insertion reaching the intended gluteal muscle. The aim of this study was to evaluate the suitable depth of injecting RLAI. Twenty-six patients with schizophrenia were treated with RLAI, and randomly divided into two groups: 50 mm needle inserted group (Group-D, deep insertion, n = 13) and 20 mm needle insertion group (Group-S, shallow insertion, n = 13). For Group-S, the needle length was marked with a spacer at exactly 20 mm. Injections were performed by the psychiatrist or nurse, alternating between the two gluteal sites by double-cross method every two weeks. Clinical psychotic symptoms and injection site reactions were recorded throughout the study period. Experienced psychologists who were blinded from the needle-length experimental variable evaluated patients’ psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS) every two weeks. The plasma 9-hydroxyrisperidone (9-OH-RIS) concentrations were measured every two weeks;comparison data were determined on the 8th week and the 14th week. No significant difference was observed in 9-OH-RIS concentrations, psychotic symptoms, injection site skin reactions of subjects in both groups. However, in Group-D, injection site adverse reactions were confirmed in two subjects (15%). In Group-S, injection site reactions were confirmed in six subjects (46%). Although effective 9-OH-RIS concentrations were obtained with the insertion using both depth, it was concluded that the 50 mm insertion length was more suitable for dorsogluteal IM injections in adult patients with schizophrenia as demonstrated by the incidence of local adverse skin reactions.展开更多
Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participant...Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participants: A 12-week, A multicenter, randomized, placebo-controlled trial conducted between June 2009-July 2011, at 17 Hospital-based drug clinics, in the 15 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 cocaine use disorder. Of the 2800 patients who were assessed between March 10, 2009 to August 10, 2010, 2600 (93%) were eligible and willing to take part in the trial and were enrolled: 1300 were randomly assigned to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks and 1300 to receive Placebo injections, given intramuscularly once in 12 weeks. Only 100 of 2800 patients (3.6%) did not meet the inclusion criteria. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Cocaine abstinence (percentage i.e. the number of patients who achieved complete abstinence during 12 weeks). Confirmed abstinence or “cocaine-free” was defined as a negative urine drug test for cocaines and no self-reported cocaine use. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of Central Dopamine transporter receptor occupancy following single doses of long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) as well as the plasma concentration of Vanoxerine and 17-hydroxyl Vanoxerine. Safety was assessed by adverse event reporting. Results: Of 2600 participants, mean (SD) age was 28.5 (±5.5) years and 598 (23%) were women. 1300 individuals were randomized to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and 1300 to receive injections of Placebo. 1417 participants (54.5.0%) completed the trial. Primary Endpoints: Confirmed Cocaine Abstinence: Complete abstinence was sustained by 72% (n = 936) of Vanoxerine patients (patients treated with Vanoxerine Consta 394.2 mg, long-acting depot formulations) compared with 37% (n = 481) of patients treated with Placebo, during weeks 5 - 12. The difference was significant as evaluated using a Chi-square test (χ2 = 672.34, P < 0.0001). Secondary Endpoint: Craving: A statistically and clinically significant reduction in cocaine craving was observed with Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) vs. Placeboby week 4 (P = 0.0048), which persisted every week through 12 (P < 0.0001). Patients given Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) had a 87% decrease in craving from baseline to 12th week. Patients given a Placebo had a 2% increase in craving from baseline to 12th week. Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) helped significantly more patients complete 12 weeks treatment (n = 936, 72%) compared with Placebo (n = 481, 37%) (χ2 = 635.53, P < 0.0001). Patients on the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) had longer treatment retention than patients on Placebo. Concentrations of Vanoxerine and 17-Hydroxyl Vanoxerinein Plasma: Analyses were made of 275 study samples. There was no statistically significant difference for plasma Vanoxerine concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Vanoxerine were 70.4 and 94.3 ng/ml and concentrations of 17-hydroxyl Vanoxerine were 10.5 and 13.2 ng/ml, respectively. Plasma levels of Vanoxerine remained above 70 ng/ml for approximately 12 weeks after administration of Vanoxerine, long-acting depot formulations (Vanoxerine Consta 394.2 mg). PET Assessments: Very high central dopamine transporter receptor occupancy by Vanoxerine was detected 1 day after treatments, at which time point the occupancy was 100.0% after Vanoxerine injection (Vanoxerine Consta 394.2 mg). At days 7, 28, 56 and 84 post-Vanoxerine Consta 394.2 mg administration, occupancies were 95% to 79%. Vanoxerine Consta 394.2 mg injection (long-acting intramuscular formulation of Vanoxerine) led to very high occupancy of Central Dopamine transporter receptors in all brain areas examined;nucleus accumbens, caudate nucleus and putamen. Depending on the brain area Central Dopamine transporter receptor occupancy varied between 95.0% and 79% at days 7, 28, 56 and 84 after dosing. High Vanoxerine occupancy (77%) persisted at 12 weeks after the dosings. Adverse Reactions: Adverse events were similar in cocaine-dependent patients treated with the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) vs. patients treated with Placebo. Conclusions and Relevance: Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) were more effective than Placebo injection in maintaining short-term abstinence from cocaine and should be considered as a treatment option for cocaine-dependent individuals.展开更多
Early knee osteoarthritis(KOA)is characterized by progressive degeneration of the articular cartilage,synovial inflammation,and excessive accumulation of reactive oxygen species(ROS).At present,intra-articular injecti...Early knee osteoarthritis(KOA)is characterized by progressive degeneration of the articular cartilage,synovial inflammation,and excessive accumulation of reactive oxygen species(ROS).At present,intra-articular injection of hyaluronic acid(HA)is widely used to alleviate symptoms;however,its lubrication persistence,antioxidant,and anti-inflammatory abilities are limited,and it is difficult to effectively delay the early process of cartilage degeneration.Based on this,hyaluronic acid-g-lipoic acid(HA-LA)was synthesized by esterification reaction,and HA-LA microspheres were prepared by a reversed-phase emulsion method,which was combined with a macromolecular HA-LA solution to form injectable hydrogels.The objective of this study was to evaluate the efficacy of an injectable hydrogel based on hyaluronic acid-g-lipoic acid microspheres(HA-LA MS)for the treatment of KOA and to verify its injectability,lubricity,reactive oxygen species(ROS)scavenging ability,and anti-inflammatory effects.The results show that the HA-LA MS hydrogel has excellent shear thinning characteristics and continuous injectability,and its microsphere structure significantly reduces the interfacial friction coefficient through the rolling effect.In vitro experiments have shown that the hydrogel can efficiently scavenge ROS,reduce the expression of inflammatory factors,and is non-cytotoxic.The HA-LA MS injectable hydrogel has excellent lubricity,ROS scavenging ability,and anti-inflammatory effects in vivo,which can effectively delay the degeneration of early KOA cartilage,and its efficacy is significantly better than that of traditional hyaluronic acid,making it a promising intra-articular injection preparation.展开更多
In the present study,we aimed to determine the pharmacokinetics(PK),pharmacodynamics(PD),adverse events(AEs),and their relationships in Chinese patients with schizophrenia after a single dose of long-acting risperidon...In the present study,we aimed to determine the pharmacokinetics(PK),pharmacodynamics(PD),adverse events(AEs),and their relationships in Chinese patients with schizophrenia after a single dose of long-acting risperidone.Schizophrenic patients(six females and seven males)were enrolled in this study.Serial blood samples were collected after drug administration during 63 d,and the drug concentrations were analyzed by LC-MS/MS.Safety and tolerance were evaluated by monitoring the AEs,changes in clinical laboratory results,12-lead ECG,vital signs,physical examination,and injection-site reactions.The extrapyramidal symptoms were evaluated using the ESRS.Efficacy was evaluated by the PANSS and BPRS.Twelve out of the 13 participants completed the trial.There were few clinically meaningful changes in mean clinical laboratory values,vital signs,or ECG parameters,except for the prolactin level and body weight.There were no serious AEs,and those observed were reversible.Significant clinical improvements in PANSS and PANSS-derived BPRS total scores were observed.The mean(standard deviation,coefficient of variation)values for these PK parameters were as follows:C_(max),8.954(8.059,90.0%)ng/mL;area under the curve AUC_(0-t),2453(1156,47.1%)ng·h/mL;AUC_(0-∞),2472(1160,46.9%)ng·h/mL;t_(max),830.0(min:744.0,max:984.0,11.8%)h;and t_(1/2),68.56(10.77,15.7%)h.The PK characteristics of long-acting risperidone showed a high level of inter-individual variation,while there were no clear correlations between PK,efficacy and AEs among the patients in the present study.展开更多
Despite advances in treatment of chronic arthritis,there is still a strong need for the development of long-acting formulations that can enable local and sustained drug release at the inflamed tissues.In this work,we ...Despite advances in treatment of chronic arthritis,there is still a strong need for the development of long-acting formulations that can enable local and sustained drug release at the inflamed tissues.In this work,we fabricated microcrystals of an acid-sensitive stearoxyl-ketal-dexamethasone prodrug for treatment of arthritis.Microcrystals of the prodrug with two sizes were successfully engineered and showed pH-dependent hydrolysis kinetics in vitro.In a collagen-induced arthritis rat model,we evaluated the influence of particle size and injection dose on anti-inflammatory effect after intra-articular injection.Such prodrug demonstrated long-acting anti-arthritis effects with good safety.Our results indicate ketal-based prodrugs are promising for the development of long-acting injectables and may stimulate the development of new treatments for chronic diseases.展开更多
Intramuscular injections can cause damage to arteries, veins and nerves. Achieving maximum effects of medications through precise intramuscular (IM) injections must be assured and with certainty, particularly with lon...Intramuscular injections can cause damage to arteries, veins and nerves. Achieving maximum effects of medications through precise intramuscular (IM) injections must be assured and with certainty, particularly with long-acting injection drugs (LAI). The purpose of this study is to determine precision in IM LAIs of patients with schizophrenia. These evidences estimate “Distance from the Epidermis to the Under-Fascia” (DEUF) and “Distance from Epidermis to the Upper-Arm Bone” (DEB) of the deltoid muscle. Explanatory variables include body height, weight, body-mass index (BMI), deltoid-muscle circumference, fat percentage and muscle mass measured by body composition monitor. Sixty nine subjects are included based on the Diagnostic Statistical Manual of Mental Disorders (DSM-IV, 1994), and receive treatments of typical and atypical antipsychotic LAI. There are 46 males and 23 females with average age of 51.41 (Standard Deviation = 13.58) and ranging from 21 to 81 years who are all right-handed. Ultrasonographic data and those from explanatory variables are calculated using Spearman’s rank correlation coefficients. Multiple regression analysis (step-wise method/forced input method) is performed assuming DEUF or DEB as dependent variables. Significant correlations are found with highest adjusted R-square. Paired t-tests show differences in average values of actual ultrasonographic measurements assigned to DEUF or DEB, and the regression equations for accuracy. Ultrasonographic values are assigned multiple-regression equations as true values, and the calculated values are compared with those obtained by regression equations. There are no significant differences observed for either the right or left arm. The multiple regression equations for BMI and fat percentages (upper extremity estimation) of DEUF, and for BMI and injection site circumference of estimated DEB, successfully value the DEUF and DEB. By using these multiple regression equations for IM injection to the deltoid-muscle, DEUF can better ensure accurate LAI into the muscle through body monitor, DEB, and measured values of the deltoid-muscle injection site circumference.展开更多
Oral antiretroviral drugs have been a fundamental component of human immunodeficiency virus(HIV)treatment for over three decades,and their continuously improving safety and efficacy have directly contributed to revers...Oral antiretroviral drugs have been a fundamental component of human immunodeficiency virus(HIV)treatment for over three decades,and their continuously improving safety and efficacy have directly contributed to reversing the initially devastating course of the HIV epidemic.Long-acting antiretroviral(ARV)regimens are necessary to sustain viral suppression in people living with HIV who express a strong desire to alleviate pill fatigue or avoid the potential stigma associated with daily oral regimens.The development of innovative long-acting ARVs remains an unmet requirement in the fields of HIV treatment and prevention.In this review,we provide an overview of lenacapavir,a first-in-class picomolar long-acting capsid inhibitor for HIV-1 that operates through multiple stages without any known cross-resistance to other existing antiretroviral drug classes.展开更多
Myocardial infarction(MI)continues to be a leading cause of morbidity and mortality in cardiovascular diseases worldwide,severely compromising cardiac structure and function.While conventional treatments-including pha...Myocardial infarction(MI)continues to be a leading cause of morbidity and mortality in cardiovascular diseases worldwide,severely compromising cardiac structure and function.While conventional treatments-including pharmacological interventions,coronary artery bypass grafting(CABG),and percutaneous coronary intervention(PCI)-can effectively restore coronary blood flow,their ability to regenerate cardiomyocytes and substantially improve cardiac function remains limited.In this context,injectable hydrogels have emerged as a groundbreaking therapeutic approach,presenting remarkable potential for MI treatment owing to their exceptional biocompatibility,tunable mechanical properties,and versatile functionality.These hydrogels can form stable three-dimensional networks within infarcted myocardium,not only providing mechanical support to mitigate ventricular wall stress but also serving as delivery platforms for bioactive components such as growth factors,therapeutic drugs,and stem cells.Through multiple mechanisms-including attenuation of oxidative stress and calcium overload to protect cardiomyocytes,stimulation of angiogenesis to enhance tissue perfusion,and regulation of inflammatory responses to reduce fibrotic scarring-injectable hydrogels significantly promote myocardial repair and regeneration.Preclinical studies have consistently validated the therapeutic efficacy of various injectable hydrogel formulations in improving cardiac outcomes post-MI,highlighting their transformative potential in cardiovascular medicine.展开更多
Myocardial infarction (MI) continues to be the primary cause of death globally. Oxidative stress in the initial phase of MI, followed by uncontrolled and excessive myocardial fibrosis, significantly impedes cardiac re...Myocardial infarction (MI) continues to be the primary cause of death globally. Oxidative stress in the initial phase of MI, followed by uncontrolled and excessive myocardial fibrosis, significantly impedes cardiac repair efficiency post-MI, culminating in adverse ventricular remodeling and potential heart failure. To address the diverse pathological stages of MI, an injectable composite hydrogel containing versatile nanoparticles was developed. In this study, mesoporous silicon nanoparticles (MSNs) served as carriers for encapsulating microRNA-29b (miR-29b) mimics with antifibrotic activity, subsequently coated with a complex of natural antioxidant tannic acid and zinc ions (TA/Zn). These nanoparticles were then embedded into a biocompatible alginate hydrogel to enhance retention within the infarcted myocardium. Upon injection into the infarcted region of MI mice, the composite hydrogel gradually released the nanoparticles as it degraded. Initially, the TA/Zn complex on the outer layer scavenged reactive oxygen species, thereby inhibiting cell apoptosis. The subsequent dissociation of the TA/Zn complex led to the release of the encapsulated miR-29b mimics that could inhibit the activation of cardiac fibroblasts and collagen production, thereby alleviating fibrosis progression. Overall, this composite hydrogel demonstrated the potential to reduce infarct size and improve cardiac function, suggesting its promise as a synergistic therapeutic approach for repairing infarcted myocardium.展开更多
In clinical settings,regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods,restricted bone growth medications,and a scarcity of commercial bone gra...In clinical settings,regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods,restricted bone growth medications,and a scarcity of commercial bone grafts.To treat this life-threatening issue,improved biofunctional grafts capable of properly healing critical-sized bone defects are required.In this study,we effectively created anti-fracture hydrogel systems using spongy-like metal-organic(magnesium-phosphate)coordinated chitosan-modified injectable hydrogels(CPMg)loaded with a bioinspired neobavaisoflavone(NBF)component.The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphatebuffered saline.They also demonstrated prolonged and stable release profiles of Mg^(2+)and NBF.Importantly,CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells.To better understand the underlying mechanism of Mg^(2+)and NBF component,as well as their synergistic effect on osteogenesis,we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways.Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins(Runx2,OCN,OPN,BMPS and ALP).In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects.Based on these findings,we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.展开更多
Postoperative recurrence and metastasis are still the main challenges of cancer therapy.Tumor vaccines that induce potent and long-lasting immune activation have great potential for postoperative cancer therapy.Howeve...Postoperative recurrence and metastasis are still the main challenges of cancer therapy.Tumor vaccines that induce potent and long-lasting immune activation have great potential for postoperative cancer therapy.However,the clinical effects of therapeutic tumor vaccines are unsatisfactory due to immune escape caused by the lack of immunogenicity after surgery and the local fibrosis barrier of the tumor which limits effector T cell infiltration.To overcome these challenges,we developed an injectable hydrogelbased tumor vaccine,RATG,which contains whole tumor cell lysates(TCL),Toll-like receptor(TLR)7/8 agonist imiquimod(R837)and an antifibrotic drug ARV-825.TCL and R837 were loaded onto the hydrogel to achieve a powerful reservoir of antigens and adjuvants that induced potent and lasting immune activation.More importantly,ARV-825 could be slowly and sustainably released in the tumor resection cavity to downregulateα-smooth muscle actin(α-SMA)and collagen levels,disintegrate fibrosis barriers and promote T cell infiltration after immune activation to reduce immune escape.In addition,ARV-825 also directly acted on the remaining tumor cells to degrade bromodomain-containing protein 4(BRD4)which is a critical epigenetic reader overexpressed in tumor cells,inhibiting tumor cell migration and invasion.Therefore,our injectable hydrogel created a powerful immune niche in postoperative tumor resection cavity,significantly enhancing the efficacy of tumor vaccines.Our strategy potently activates the immune system and disintegrates the fibrotic barrier of residual tumors with immune microenvironment remodeling in situ,showing anti-recurrence and anti-metastatic effects,and provides a new paradigm for postoperative treatment of tumors.展开更多
Large language models(LLMs)have revolutionized AI applications across diverse domains.However,their widespread deployment has introduced critical security vulnerabilities,particularly prompt injection attacks that man...Large language models(LLMs)have revolutionized AI applications across diverse domains.However,their widespread deployment has introduced critical security vulnerabilities,particularly prompt injection attacks that manipulate model behavior through malicious instructions.Following Kitchenham’s guidelines,this systematic review synthesizes 128 peer-reviewed studies from 2022 to 2025 to provide a unified understanding of this rapidly evolving threat landscape.Our findings reveal a swift progression from simple direct injections to sophisticated multimodal attacks,achieving over 90%success rates against unprotected systems.In response,defense mechanisms show varying effectiveness:input preprocessing achieves 60%–80%detection rates and advanced architectural defenses demonstrate up to 95%protection against known patterns,though significant gaps persist against novel attack vectors.We identified 37 distinct defense approaches across three categories,but standardized evaluation frameworks remain limited.Our analysis attributes these vulnerabilities to fundamental LLM architectural limitations,such as the inability to distinguish instructions from data and attention mechanism vulnerabilities.This highlights critical research directions such as formal verification methods,standardized evaluation protocols,and architectural innovations for inherently secure LLM designs.展开更多
The Southern Advanced Photon Source(SAPS)is a diffraction-limited synchrotron light source under design,which employs longitudinal injection as its primary injection scheme.This kind of injection scheme requires that ...The Southern Advanced Photon Source(SAPS)is a diffraction-limited synchrotron light source under design,which employs longitudinal injection as its primary injection scheme.This kind of injection scheme requires that the injected beam has a short bunch length and low emittance,and the preferred injector should offer high stability and low cost.Therefore,an injector based on a booster synchrotron was developed.The proposed injector includes a 250 MeV linac,a booster synchrotron that ramps the beam energy to 3.5 GeV,and two beam transport lines to ensure efficient beam delivery and beam quality preservation.The linac utilizes a thermionic high-voltage DC gun for reliable operation and features a bunching system with an advanced focusing system to preserve the emittance.To meet the injection requirements of the SAPS,a comprehensive design for the booster has been conducted.The booster synchrotron employs a threefold lattice structure,incorporating modified theoretical minimum emittance cells with a small momentum compaction factor and a high voltage to achieve an emittance of 3.98 nm rad and a bunch length of 4.8 mm.The injector has the potential to deliver a high charge,reducing the injection period of the storage ring to less than 1 min.Simulations demonstrated the expected performance,with a transmission efficiency of 90%,confirming its capability to meet the injection requirement of the SAPS storage ring.This design offers a stable and efficient solution for the SAPS.展开更多
Background:Penile augmentation through injectable substances is becoming increasingly common.A growing number of aesthetic clinics are developing penile enlargement procedures using various injectable materials.Althou...Background:Penile augmentation through injectable substances is becoming increasingly common.A growing number of aesthetic clinics are developing penile enlargement procedures using various injectable materials.Although these procedures are now performed in more controlled and medically supervised environments,their long-term outcomes remain poorly understood.The promotion of such medical treatments contributes to an increasing interest among adult males in self-injection as a method to alleviate psychological distress associated with penile size concerns.At the same time,access to injectable substances through unofficial or unregulated sources has become increasingly easy.Tor our knowledge,we report the first documented case of self-injection with Garamycin®(gentamicin)cream,contributing to the literature on the often multidisciplinary management of penile enlargement injections,a field still lacking well-established guidelines.Case Description:This case report describes a young patient who self-injected Garamycin®into the penis for the purpose of enlargement.He presented to our urology department with worsening symptoms,including severe and poorly tolerated pain.His primary request was prompt relief of pain while preserving,as much as possible,the aesthetic appearance and functional integrity of his penis.This case required a multi-stage surgical approach to salvage the penis and preserve both its structural integrity and functional outcome.Conclusions:To our knowledge,this case report documents the first reported instance of Garamycin®injection performed for the purpose of penile enlargement.It provides insight into the clinical course of such penile cream injections,demonstrates that a two-stage scrotal flap can achieve both functional and aesthetic outcomes,and highlights the importance of comprehensive management particularly addressing the traumatic impact of penile deformity secondary to inflammation and/or infection,as well as the body dysmorphic concerns often associated with these cases.展开更多
Objective:To explore the therapeutic effect of double-puncture tympanic membrane puncture and tympanic cavity drug injection in patients with acute secretory otitis media.Methods:A total of 84 patients with acute secr...Objective:To explore the therapeutic effect of double-puncture tympanic membrane puncture and tympanic cavity drug injection in patients with acute secretory otitis media.Methods:A total of 84 patients with acute secretory otitis media admitted to our hospital from June 2024 to June 2025 were selected and randomly divided into two groups by drawing lots.The control group(42 cases)was treated with the traditional single-puncture tympanic membrane puncture and tympanic cavity drug injection method,while the observation group(42 cases)was treated with the double-puncture tympanic membrane puncture and tympanic cavity drug injection method.The therapeutic effects of the two groups were compared.Results:The overall treatment response rate,overall complication rate,time to symptom relief,and improvement in hearing threshold in the observation group were all superior to those in the control group,with statistically significant differences(P<0.05).Conclusion:For acute secretory otitis media,the treatment method of double-puncture tympanic membrane puncture and tympanic cavity drug injection demonstrates definite efficacy,significantly reducing the incidence of complications,accelerating symptom relief,and improving hearing function,making it worthy of promotion.展开更多
The present studies were conducted to compose an injectable solution of colistin sulfate containing local anaesthesia, antioxidant and other additions. Results showed that the novel preparation was stable either to he...The present studies were conducted to compose an injectable solution of colistin sulfate containing local anaesthesia, antioxidant and other additions. Results showed that the novel preparation was stable either to heat or to light. The term of validity of the preparation was 2 years at room temperature.The preparation containing 25. 0 mg ml-1 colistin sulfate showed no local tissue irritation, but the concentration of 50. 0 mg ml-1 colistin sulfate showed obvious local tissue irritation. Result of acute toxicity test showed that the LD50 of intramuscular injection in mice was 38. 72 mg kg-1, and oral LD50 was 431. 39 mg kg-1. The evidence of neurotoxicity was observed in mice in the acute toxicity test. A dose of 10.0 mg kg-1 b. w. or 15:0 mg kg-1b. w. was administered intramuscularly to piglet once daily for 5 days. No changes were detected in the piglet body except for the slight epithelial tissue's granular degenerations in the kidney and liver at the dose of the 10.0 mg kg-1. While at the dose of 15. 0 mg kg-1, the obvious neurotoxicity was observed at 4-5 days. The epithelial tissues in the kidney and liver showed moderate granular degenerations, especially in the tubuli renales cells. Blood cell's morphosis indexes were normal. With relation to liver's function, the indexes went beyond the normal scope. But with relation to kidney's function, the indexes showed mostly normal.When the preparation was separately administered into muscle(i. m.) in piglets with the dose of 2. 5 and 5. 0 mg kg-1 b. w, whose Cmax were 3.73±0. 28 and 6. 40±0.18 Abstract:g ml-1; Tmax were 32±1. 5 and 34±1.8min; t1/2β were 256±14 min and 264±29 min, respectively. t1/2βt was 251±13 min for the injection given into aural vein( i. v.) with the dose of 2.5 mg kg1-1 b. w.. Samples of the experimentally determined plasma concentration of colistin sulfate generated two-exponential model with first-order absorption. The mean absolute bioavail-ability coefficient of 2.5 and 5. 0 mg kg-1 b. w. (i. m.) were 98. 30 and 88. 54%, respectively. The high bio-availability and the long maintaining time of the valid blood-drug concentration showed that the injectable solution was suitable for i. m. in pigs, whose recommended dose was 2.5 mg kg-1 b. w. , twice daily.展开更多
文摘BACKGROUND Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy.Long-acting injectable(LAI)antipsychotics have been widely used to improve adherence and prevent relapse in patients with various severe psychotic disorders,but there is a lack of high-quality data from previous research on the safety of LAI antipsychotics during pregnancy.AIM To summarize relevant data on maternal,pregnancy,neonatal,and developmental outcomes from published cases of LAI antipsychotic use in pregnancy.METHODS A literature search was performed through November 11,2023,using three online databases:PubMed/MEDLINE,Scopus,and Web of Science.Case reports or case series that reported information about the outcomes of pregnancy in women who used LAI antipsychotics at any point in pregnancy,with available full texts,were included.Descriptive statistics,narrative summation,and tabulation of the extracted data were performed.RESULTS A total of 19 publications satisfied the inclusion criteria:3 case series,15 case reports,and 1 conference abstract.They reported the outcomes of LAI antipsychotic use in 74 women and 77 pregnancies.The use of secondgeneration LAI antipsychotics was reported in the majority(n=47;61.0%)of pregnancies.First-generation LAI antipsychotics were administered during 30 pregnancies(39.0%).Most of the women(approximately 64%)had either satisfactory control of symptoms or no information about relapse,while approximately 12%of them had developed gestational diabetes mellitus.A minority of cases reported adverse outcomes such as stillbirth,spontaneous abortion,preterm birth,low birth weight,congenital anomalies,and neurological manifestations in newborns.However,there were no reports of negative long-term developmental outcomes.CONCLUSION Currently available data seem reassuring,but further well-designed studies are required to properly evaluate the risks and benefits of LAI antipsychotic use during pregnancy.
文摘The objectives of e-STAR Romania (NCT00283517) were to collect clinical outcome data of Romania schizophrenia or schizo-affective disorder patients;prospectively to assess the reasons of treatment initiation, medication usage patterns;to document (long-term) clinical efficacy;and to collect safety data, as well as recording 2-year corresponding retrospective data. In total, 378 eligible subjects were enrolled who were initiated either on risperidone long-acting injectable (RLAI) (290) or on an oral antipsychotic (OA) (88) at baseline as required by the local Summary of the Product Characteristics. Data were collected from per patient both retrospectively and prospectively over a 24-month period at 3-month intervals after starting treatment. The results indicated that subjects suffering from schizophrenia or schizo-affective disorder initiated on RLAI were less likely to be hospitalized within the first 24 months after the initiation of treatment. Moreover, subjects treated with RLAI experienced significant improvements in their illness severity and functioning. Discontinuation rates for RLAI were low and doses were stable throughout the 24 months following the initiation of treatment. In addition, the necessity for supplementary concomitant medication was reduced. Adverse events were reported in 20.3% (RLAI) and 11.4% (OA) of the subjects. In general, patients initiated on RLAI and OA at baseline both clinically improved on all assessed parameters but a larger improvement was observed for patients on RLAI. Incidences of reported AEs during the use of RLAI in a naturalistic setting are comparable with those described in clinical studies;however, the incidence of extrapyramidal signs and weight gain was lower than expected.
文摘Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) for the treatment of opioid-dependent patients. Design, Setting, and Participants: A 12 weeks, open-label, randomised controlled trial conducted between June 2009-July 2011, at 14 Hospital-based drug clinics, in the 12 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder. Of the 3200 individuals screened, 3000 (93.7%) adults were randomized 1500 participants to receive injections of Long-acting depot formulations ofNalmefene (Nalmefene Consta 393.1 mg) given intramuscularly once in 12 weeks and 1500participants to receive extended-release Naltrexone (Vivitrol 380 mg), administered intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Opioid abstinence (percentage i.e. the number of patients who achieved complete abstinence during week 12). Confirmed abstinence or “opioid-free” was defined as a negative urine drug test for opioids and no self-reported opioid use. Weeks 1 - 4 were omitted from this endpoint to allow for stabilization of abstinence. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of mu-opioid receptor occupancy following single doses of Nalmefene extended-release injection (Nalmefene Consta 393.1 mg) as well as the plasma concentration of Nalmefene and Nalmefene-3-O-glucuronide. Safety was assessed by adverse event reporting. Results: Of 3000 participants, mean (SD) age was 27.1 (±4.8) years and 831 (27.7%) were women. 1500 individuals were randomized to receive injections of Long-acting depot formulations of Nalmefene (Nalmefene Consta 393.1 mg) and 1500 to receive injections of extended-release Naltrexone (Vivitrol 380 mg);2088 participants (69.6.0%) completed the trial. Primary endpoints: Confirmed Opioid Abstinence: Complete abstinence was sustained by 86% (n = 1290) of Nalmefene patients (patients treated with Nalmefene Consta 393.1 mg, long-acting depot formulations) compared with 43% (n = 645) of patients treated with extended-release Naltrexone 380 mg (Vivitrol), during weeks 5 - 12 (χ2 = 672.34, P Secondary Endpoint: Craving: A statistically and clinically significant reduction in opioid craving was observed with Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot formulations) vs. Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) by week 4 (P =0.0048), which persisted every week through 12 (P < 0.0001). Patients given Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot formulations) had a 75% decrease in craving from baseline to week 12. Patients given a Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) had a 3% increase in craving from baseline to week 12 (Mean change in self-reporting craving). Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) helped significantly more patients complete 12 weeks treatment (n = 1245, 83%) compared with extended-release Naltrexone (Vivitrol 380 mg) (n = 570, 38%) (χ2 = 635.53, P < 0.0001). Patients on long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) had longer treatment retention than patients on extended-release Naltrexone (Vivitrol 380 mg). Concentrations of Nalmefene and Nalmefene-3-O-Glucuronide in Plasma: Analyses were made of 275 study sample. There was no statistically significant difference for plasma nalmefene concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Nalmefene were 20.3 and 28.5 ng/ml and concentrations of nalmefene-3-O-glucuronide were 2.1 and 4.1 ng/ml, respectively. Plasma levels of Nalmefene remained above 20 ng/ml for approximately 12 weeks after administration of Nalmefene, long-acting depot formulations (Nalmefene Consta 393.1 mg). PET Assessments: Very high mu-opioid receptor occupancy by Nalmefene was detected 1 day after treatments at which time point the occupancy was 100.0% after Nalmefene injection (Nalmefene Consta 393.1 mg). Nalmefene Consta 393.1 mg injection (long-acting intramuscular formulation of Nalmefene) led to a very high occupancy ofmu-opioid receptors in all brain areas examined;the thalamus, caudate nucleus, and frontal cortex. Depending on the brain area mu-opioid receptor occupancy varied between 83.0% and 85.8% 84 days after dosing. Adverse Reactions: Adverse events were similar in opioid-dependent patients treated with long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) vs. patients treated with extended-release Naltrexone (Vivitrol 380 mg). Conclusions and Relevance: Long-acting depot formulations of Nalmefene (Nalmefene Consta 393.1 mg) was more effective then extended-release Naltrexone (Vivitrol 380 mg) in maintaining short-term abstinence from heroin and should be considered as a treatment option for opioid-dependent individuals.
文摘Risperidone long-acting injectable (RLAI) is approved for the treatment of schizophrenia in many countries. The suggested site is the gluteal muscle with a needle length of two inches (50 mm) in Japan, which is longer than the ordinarily used needle for intramuscular injections. The aim of this study was to determine the optimal needle insertion length for accurate delivery of RLAI procedure among subjects who have normal body mass index (BMI: 18 to 25) and high BMI (>25). Thirty-seven patients with schizophrenia were administered RLAI intramuscularly into the dorsogluteal muscle. The standard procedure required inserting 80% of the two inch needle. By using data collected by ultrasonography, the findings confirmed that the median needle insertion lengths for subjects with normal and high BMI were 39.0 and 45.5 mm, respectively. To deliver RLAI effectively and safely, the authors strongly recommend that a specialized needle be used that is “marked” at the 40 mm point from the tip of the needle to the base. In this way regardless of subcutaneous fat content, the RLAI can be safely delivered into the muscle without causing untoward or side effects.
文摘In some cases, if the insertion depth is shallower than expected, intramuscular (IM) injection of risperidone long-acting injectable (RLAI) may not penetrate the muscle fascia. However, if needle insertion depth is deeper than anticipated, needle penetration may cause damage to nerves, arteries and veins. Few clinical studies were done to evaluate the depth of needle length insertion reaching the intended gluteal muscle. The aim of this study was to evaluate the suitable depth of injecting RLAI. Twenty-six patients with schizophrenia were treated with RLAI, and randomly divided into two groups: 50 mm needle inserted group (Group-D, deep insertion, n = 13) and 20 mm needle insertion group (Group-S, shallow insertion, n = 13). For Group-S, the needle length was marked with a spacer at exactly 20 mm. Injections were performed by the psychiatrist or nurse, alternating between the two gluteal sites by double-cross method every two weeks. Clinical psychotic symptoms and injection site reactions were recorded throughout the study period. Experienced psychologists who were blinded from the needle-length experimental variable evaluated patients’ psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS) every two weeks. The plasma 9-hydroxyrisperidone (9-OH-RIS) concentrations were measured every two weeks;comparison data were determined on the 8th week and the 14th week. No significant difference was observed in 9-OH-RIS concentrations, psychotic symptoms, injection site skin reactions of subjects in both groups. However, in Group-D, injection site adverse reactions were confirmed in two subjects (15%). In Group-S, injection site reactions were confirmed in six subjects (46%). Although effective 9-OH-RIS concentrations were obtained with the insertion using both depth, it was concluded that the 50 mm insertion length was more suitable for dorsogluteal IM injections in adult patients with schizophrenia as demonstrated by the incidence of local adverse skin reactions.
文摘Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participants: A 12-week, A multicenter, randomized, placebo-controlled trial conducted between June 2009-July 2011, at 17 Hospital-based drug clinics, in the 15 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 cocaine use disorder. Of the 2800 patients who were assessed between March 10, 2009 to August 10, 2010, 2600 (93%) were eligible and willing to take part in the trial and were enrolled: 1300 were randomly assigned to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks and 1300 to receive Placebo injections, given intramuscularly once in 12 weeks. Only 100 of 2800 patients (3.6%) did not meet the inclusion criteria. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Cocaine abstinence (percentage i.e. the number of patients who achieved complete abstinence during 12 weeks). Confirmed abstinence or “cocaine-free” was defined as a negative urine drug test for cocaines and no self-reported cocaine use. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of Central Dopamine transporter receptor occupancy following single doses of long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) as well as the plasma concentration of Vanoxerine and 17-hydroxyl Vanoxerine. Safety was assessed by adverse event reporting. Results: Of 2600 participants, mean (SD) age was 28.5 (±5.5) years and 598 (23%) were women. 1300 individuals were randomized to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and 1300 to receive injections of Placebo. 1417 participants (54.5.0%) completed the trial. Primary Endpoints: Confirmed Cocaine Abstinence: Complete abstinence was sustained by 72% (n = 936) of Vanoxerine patients (patients treated with Vanoxerine Consta 394.2 mg, long-acting depot formulations) compared with 37% (n = 481) of patients treated with Placebo, during weeks 5 - 12. The difference was significant as evaluated using a Chi-square test (χ2 = 672.34, P < 0.0001). Secondary Endpoint: Craving: A statistically and clinically significant reduction in cocaine craving was observed with Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) vs. Placeboby week 4 (P = 0.0048), which persisted every week through 12 (P < 0.0001). Patients given Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) had a 87% decrease in craving from baseline to 12th week. Patients given a Placebo had a 2% increase in craving from baseline to 12th week. Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) helped significantly more patients complete 12 weeks treatment (n = 936, 72%) compared with Placebo (n = 481, 37%) (χ2 = 635.53, P < 0.0001). Patients on the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) had longer treatment retention than patients on Placebo. Concentrations of Vanoxerine and 17-Hydroxyl Vanoxerinein Plasma: Analyses were made of 275 study samples. There was no statistically significant difference for plasma Vanoxerine concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Vanoxerine were 70.4 and 94.3 ng/ml and concentrations of 17-hydroxyl Vanoxerine were 10.5 and 13.2 ng/ml, respectively. Plasma levels of Vanoxerine remained above 70 ng/ml for approximately 12 weeks after administration of Vanoxerine, long-acting depot formulations (Vanoxerine Consta 394.2 mg). PET Assessments: Very high central dopamine transporter receptor occupancy by Vanoxerine was detected 1 day after treatments, at which time point the occupancy was 100.0% after Vanoxerine injection (Vanoxerine Consta 394.2 mg). At days 7, 28, 56 and 84 post-Vanoxerine Consta 394.2 mg administration, occupancies were 95% to 79%. Vanoxerine Consta 394.2 mg injection (long-acting intramuscular formulation of Vanoxerine) led to very high occupancy of Central Dopamine transporter receptors in all brain areas examined;nucleus accumbens, caudate nucleus and putamen. Depending on the brain area Central Dopamine transporter receptor occupancy varied between 95.0% and 79% at days 7, 28, 56 and 84 after dosing. High Vanoxerine occupancy (77%) persisted at 12 weeks after the dosings. Adverse Reactions: Adverse events were similar in cocaine-dependent patients treated with the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) vs. patients treated with Placebo. Conclusions and Relevance: Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) were more effective than Placebo injection in maintaining short-term abstinence from cocaine and should be considered as a treatment option for cocaine-dependent individuals.
基金financially supported by the National Natural Science Foundation of China(Nos.82272472 and 52373146)。
文摘Early knee osteoarthritis(KOA)is characterized by progressive degeneration of the articular cartilage,synovial inflammation,and excessive accumulation of reactive oxygen species(ROS).At present,intra-articular injection of hyaluronic acid(HA)is widely used to alleviate symptoms;however,its lubrication persistence,antioxidant,and anti-inflammatory abilities are limited,and it is difficult to effectively delay the early process of cartilage degeneration.Based on this,hyaluronic acid-g-lipoic acid(HA-LA)was synthesized by esterification reaction,and HA-LA microspheres were prepared by a reversed-phase emulsion method,which was combined with a macromolecular HA-LA solution to form injectable hydrogels.The objective of this study was to evaluate the efficacy of an injectable hydrogel based on hyaluronic acid-g-lipoic acid microspheres(HA-LA MS)for the treatment of KOA and to verify its injectability,lubricity,reactive oxygen species(ROS)scavenging ability,and anti-inflammatory effects.The results show that the HA-LA MS hydrogel has excellent shear thinning characteristics and continuous injectability,and its microsphere structure significantly reduces the interfacial friction coefficient through the rolling effect.In vitro experiments have shown that the hydrogel can efficiently scavenge ROS,reduce the expression of inflammatory factors,and is non-cytotoxic.The HA-LA MS injectable hydrogel has excellent lubricity,ROS scavenging ability,and anti-inflammatory effects in vivo,which can effectively delay the degeneration of early KOA cartilage,and its efficacy is significantly better than that of traditional hyaluronic acid,making it a promising intra-articular injection preparation.
基金Foundation items:The National Major Scientific and Technological Special Project for"Significant New Drug Development"during the Twelfth Five-year Planning Period of China(Grant No.2014ZX09303303).
文摘In the present study,we aimed to determine the pharmacokinetics(PK),pharmacodynamics(PD),adverse events(AEs),and their relationships in Chinese patients with schizophrenia after a single dose of long-acting risperidone.Schizophrenic patients(six females and seven males)were enrolled in this study.Serial blood samples were collected after drug administration during 63 d,and the drug concentrations were analyzed by LC-MS/MS.Safety and tolerance were evaluated by monitoring the AEs,changes in clinical laboratory results,12-lead ECG,vital signs,physical examination,and injection-site reactions.The extrapyramidal symptoms were evaluated using the ESRS.Efficacy was evaluated by the PANSS and BPRS.Twelve out of the 13 participants completed the trial.There were few clinically meaningful changes in mean clinical laboratory values,vital signs,or ECG parameters,except for the prolactin level and body weight.There were no serious AEs,and those observed were reversible.Significant clinical improvements in PANSS and PANSS-derived BPRS total scores were observed.The mean(standard deviation,coefficient of variation)values for these PK parameters were as follows:C_(max),8.954(8.059,90.0%)ng/mL;area under the curve AUC_(0-t),2453(1156,47.1%)ng·h/mL;AUC_(0-∞),2472(1160,46.9%)ng·h/mL;t_(max),830.0(min:744.0,max:984.0,11.8%)h;and t_(1/2),68.56(10.77,15.7%)h.The PK characteristics of long-acting risperidone showed a high level of inter-individual variation,while there were no clear correlations between PK,efficacy and AEs among the patients in the present study.
基金We acknowledge financial support from the National Natural Science Foundation of China(51773098,81670817,81970772,21908019 and 21776044)Natural Science Foundation of Tianjin City of China(18JCYBJC28300)the Fundamental Research Funds for Central Universities(China).
文摘Despite advances in treatment of chronic arthritis,there is still a strong need for the development of long-acting formulations that can enable local and sustained drug release at the inflamed tissues.In this work,we fabricated microcrystals of an acid-sensitive stearoxyl-ketal-dexamethasone prodrug for treatment of arthritis.Microcrystals of the prodrug with two sizes were successfully engineered and showed pH-dependent hydrolysis kinetics in vitro.In a collagen-induced arthritis rat model,we evaluated the influence of particle size and injection dose on anti-inflammatory effect after intra-articular injection.Such prodrug demonstrated long-acting anti-arthritis effects with good safety.Our results indicate ketal-based prodrugs are promising for the development of long-acting injectables and may stimulate the development of new treatments for chronic diseases.
文摘Intramuscular injections can cause damage to arteries, veins and nerves. Achieving maximum effects of medications through precise intramuscular (IM) injections must be assured and with certainty, particularly with long-acting injection drugs (LAI). The purpose of this study is to determine precision in IM LAIs of patients with schizophrenia. These evidences estimate “Distance from the Epidermis to the Under-Fascia” (DEUF) and “Distance from Epidermis to the Upper-Arm Bone” (DEB) of the deltoid muscle. Explanatory variables include body height, weight, body-mass index (BMI), deltoid-muscle circumference, fat percentage and muscle mass measured by body composition monitor. Sixty nine subjects are included based on the Diagnostic Statistical Manual of Mental Disorders (DSM-IV, 1994), and receive treatments of typical and atypical antipsychotic LAI. There are 46 males and 23 females with average age of 51.41 (Standard Deviation = 13.58) and ranging from 21 to 81 years who are all right-handed. Ultrasonographic data and those from explanatory variables are calculated using Spearman’s rank correlation coefficients. Multiple regression analysis (step-wise method/forced input method) is performed assuming DEUF or DEB as dependent variables. Significant correlations are found with highest adjusted R-square. Paired t-tests show differences in average values of actual ultrasonographic measurements assigned to DEUF or DEB, and the regression equations for accuracy. Ultrasonographic values are assigned multiple-regression equations as true values, and the calculated values are compared with those obtained by regression equations. There are no significant differences observed for either the right or left arm. The multiple regression equations for BMI and fat percentages (upper extremity estimation) of DEUF, and for BMI and injection site circumference of estimated DEB, successfully value the DEUF and DEB. By using these multiple regression equations for IM injection to the deltoid-muscle, DEUF can better ensure accurate LAI into the muscle through body monitor, DEB, and measured values of the deltoid-muscle injection site circumference.
基金supported by National Key R&D Program of China(No.2023YFC2306800)Natural Science Foundation of Shandong Province(No.ZR2024QH201)+4 种基金the Postdoctoral Fellowship Program of CPSF(No.GZC20231489)China Postdoctoral Science Foundation(No.2023M742101)the Key Research and Development Program,Ministry of Science and Technology of the People’s Republic of China(No.2023YFC2606500)the Shandong Laboratory Program(No.SYS202205)Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘Oral antiretroviral drugs have been a fundamental component of human immunodeficiency virus(HIV)treatment for over three decades,and their continuously improving safety and efficacy have directly contributed to reversing the initially devastating course of the HIV epidemic.Long-acting antiretroviral(ARV)regimens are necessary to sustain viral suppression in people living with HIV who express a strong desire to alleviate pill fatigue or avoid the potential stigma associated with daily oral regimens.The development of innovative long-acting ARVs remains an unmet requirement in the fields of HIV treatment and prevention.In this review,we provide an overview of lenacapavir,a first-in-class picomolar long-acting capsid inhibitor for HIV-1 that operates through multiple stages without any known cross-resistance to other existing antiretroviral drug classes.
基金supported by the funding listed as follows:National Natural Science Foundation of China(No.32301115)Sichuan Science and Technology Program(2025ZNSFSC0245)+3 种基金National Key Research and Development Program of China(2023YFC2412802)the Fundamental Research Funds for the Central Universities(2023SCUH0011,No.YJ2021115)Med-X Innovation Programme of Med-X Center of Materials,Sichuan University,China(Grant No.MCMGD202303)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences[CIFMS,(No.2021-I2M-5-013)].
文摘Myocardial infarction(MI)continues to be a leading cause of morbidity and mortality in cardiovascular diseases worldwide,severely compromising cardiac structure and function.While conventional treatments-including pharmacological interventions,coronary artery bypass grafting(CABG),and percutaneous coronary intervention(PCI)-can effectively restore coronary blood flow,their ability to regenerate cardiomyocytes and substantially improve cardiac function remains limited.In this context,injectable hydrogels have emerged as a groundbreaking therapeutic approach,presenting remarkable potential for MI treatment owing to their exceptional biocompatibility,tunable mechanical properties,and versatile functionality.These hydrogels can form stable three-dimensional networks within infarcted myocardium,not only providing mechanical support to mitigate ventricular wall stress but also serving as delivery platforms for bioactive components such as growth factors,therapeutic drugs,and stem cells.Through multiple mechanisms-including attenuation of oxidative stress and calcium overload to protect cardiomyocytes,stimulation of angiogenesis to enhance tissue perfusion,and regulation of inflammatory responses to reduce fibrotic scarring-injectable hydrogels significantly promote myocardial repair and regeneration.Preclinical studies have consistently validated the therapeutic efficacy of various injectable hydrogel formulations in improving cardiac outcomes post-MI,highlighting their transformative potential in cardiovascular medicine.
基金supported by the Natural Science Foundation of Jiangsu Province(No.BK20231314)the National Natural Science Foundation of China(No.92168203)+4 种基金the National Key R&D Program of China(No.2022YFA1104300)the Jiangsu Cardiovascular Medicine Innovation Center(No.CXZX202210)the Suzhou“Science and Education Revitalize Health”Youth Science and Technology Project(No.KJXW2021001)the Suzhou“Science and Education Revitalize Health”Youth Science and Technology Project(No.KJXW2021001)the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Myocardial infarction (MI) continues to be the primary cause of death globally. Oxidative stress in the initial phase of MI, followed by uncontrolled and excessive myocardial fibrosis, significantly impedes cardiac repair efficiency post-MI, culminating in adverse ventricular remodeling and potential heart failure. To address the diverse pathological stages of MI, an injectable composite hydrogel containing versatile nanoparticles was developed. In this study, mesoporous silicon nanoparticles (MSNs) served as carriers for encapsulating microRNA-29b (miR-29b) mimics with antifibrotic activity, subsequently coated with a complex of natural antioxidant tannic acid and zinc ions (TA/Zn). These nanoparticles were then embedded into a biocompatible alginate hydrogel to enhance retention within the infarcted myocardium. Upon injection into the infarcted region of MI mice, the composite hydrogel gradually released the nanoparticles as it degraded. Initially, the TA/Zn complex on the outer layer scavenged reactive oxygen species, thereby inhibiting cell apoptosis. The subsequent dissociation of the TA/Zn complex led to the release of the encapsulated miR-29b mimics that could inhibit the activation of cardiac fibroblasts and collagen production, thereby alleviating fibrosis progression. Overall, this composite hydrogel demonstrated the potential to reduce infarct size and improve cardiac function, suggesting its promise as a synergistic therapeutic approach for repairing infarcted myocardium.
基金supported by Natural Science Foundation of China(No.82202664,82172432,U22A20371)Shenzhen Sustainable Development Project(No.KCXFZ20201221173411031)+4 种基金Shenzhen Science and Technology Program(JCYJ20220818102815033,National Science Foundation of Guangdong Province(No.2021A1515220053,2022A1515010034,2021B1515120061)Guangdong Basic and Applied Basic Research Foundation(No.2019A1515110983,2022A1515012663)Guangzhou Basic and Applied Basic Research Foundation(202102021160)the Fundamental Research Funds for the Central Universities(21624221)the Research Fund Program of Guangdong Provincial Key Laboratory of Speed Capability Research(2023B1212010009).
文摘In clinical settings,regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods,restricted bone growth medications,and a scarcity of commercial bone grafts.To treat this life-threatening issue,improved biofunctional grafts capable of properly healing critical-sized bone defects are required.In this study,we effectively created anti-fracture hydrogel systems using spongy-like metal-organic(magnesium-phosphate)coordinated chitosan-modified injectable hydrogels(CPMg)loaded with a bioinspired neobavaisoflavone(NBF)component.The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphatebuffered saline.They also demonstrated prolonged and stable release profiles of Mg^(2+)and NBF.Importantly,CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells.To better understand the underlying mechanism of Mg^(2+)and NBF component,as well as their synergistic effect on osteogenesis,we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways.Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins(Runx2,OCN,OPN,BMPS and ALP).In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects.Based on these findings,we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.
基金supported by the National Natural Science Foundation of China(No.82102202)Key Research and Development Program Social Development Project of Jiangsu Province(No.BE2023845)Natural Science Foundation of Jiangsu Province(No.BK20210424).
文摘Postoperative recurrence and metastasis are still the main challenges of cancer therapy.Tumor vaccines that induce potent and long-lasting immune activation have great potential for postoperative cancer therapy.However,the clinical effects of therapeutic tumor vaccines are unsatisfactory due to immune escape caused by the lack of immunogenicity after surgery and the local fibrosis barrier of the tumor which limits effector T cell infiltration.To overcome these challenges,we developed an injectable hydrogelbased tumor vaccine,RATG,which contains whole tumor cell lysates(TCL),Toll-like receptor(TLR)7/8 agonist imiquimod(R837)and an antifibrotic drug ARV-825.TCL and R837 were loaded onto the hydrogel to achieve a powerful reservoir of antigens and adjuvants that induced potent and lasting immune activation.More importantly,ARV-825 could be slowly and sustainably released in the tumor resection cavity to downregulateα-smooth muscle actin(α-SMA)and collagen levels,disintegrate fibrosis barriers and promote T cell infiltration after immune activation to reduce immune escape.In addition,ARV-825 also directly acted on the remaining tumor cells to degrade bromodomain-containing protein 4(BRD4)which is a critical epigenetic reader overexpressed in tumor cells,inhibiting tumor cell migration and invasion.Therefore,our injectable hydrogel created a powerful immune niche in postoperative tumor resection cavity,significantly enhancing the efficacy of tumor vaccines.Our strategy potently activates the immune system and disintegrates the fibrotic barrier of residual tumors with immune microenvironment remodeling in situ,showing anti-recurrence and anti-metastatic effects,and provides a new paradigm for postoperative treatment of tumors.
基金supported by 2023 Higher Education Scientific Research Planning Project of China Society of Higher Education(No.23PG0408)2023 Philosophy and Social Science Research Programs in Jiangsu Province(No.2023SJSZ0993)+2 种基金Nantong Science and Technology Project(No.JC2023070)Key Project of Jiangsu Province Education Science 14th Five-Year Plan(Grant No.B-b/2024/02/41)the Open Fund of Advanced Cryptography and System Security Key Laboratory of Sichuan Province(Grant No.SKLACSS-202407).
文摘Large language models(LLMs)have revolutionized AI applications across diverse domains.However,their widespread deployment has introduced critical security vulnerabilities,particularly prompt injection attacks that manipulate model behavior through malicious instructions.Following Kitchenham’s guidelines,this systematic review synthesizes 128 peer-reviewed studies from 2022 to 2025 to provide a unified understanding of this rapidly evolving threat landscape.Our findings reveal a swift progression from simple direct injections to sophisticated multimodal attacks,achieving over 90%success rates against unprotected systems.In response,defense mechanisms show varying effectiveness:input preprocessing achieves 60%–80%detection rates and advanced architectural defenses demonstrate up to 95%protection against known patterns,though significant gaps persist against novel attack vectors.We identified 37 distinct defense approaches across three categories,but standardized evaluation frameworks remain limited.Our analysis attributes these vulnerabilities to fundamental LLM architectural limitations,such as the inability to distinguish instructions from data and attention mechanism vulnerabilities.This highlights critical research directions such as formal verification methods,standardized evaluation protocols,and architectural innovations for inherently secure LLM designs.
基金supported by the Guangdong Basic and Applied Basic Research Foundation,China(No.2021B1515140007).
文摘The Southern Advanced Photon Source(SAPS)is a diffraction-limited synchrotron light source under design,which employs longitudinal injection as its primary injection scheme.This kind of injection scheme requires that the injected beam has a short bunch length and low emittance,and the preferred injector should offer high stability and low cost.Therefore,an injector based on a booster synchrotron was developed.The proposed injector includes a 250 MeV linac,a booster synchrotron that ramps the beam energy to 3.5 GeV,and two beam transport lines to ensure efficient beam delivery and beam quality preservation.The linac utilizes a thermionic high-voltage DC gun for reliable operation and features a bunching system with an advanced focusing system to preserve the emittance.To meet the injection requirements of the SAPS,a comprehensive design for the booster has been conducted.The booster synchrotron employs a threefold lattice structure,incorporating modified theoretical minimum emittance cells with a small momentum compaction factor and a high voltage to achieve an emittance of 3.98 nm rad and a bunch length of 4.8 mm.The injector has the potential to deliver a high charge,reducing the injection period of the storage ring to less than 1 min.Simulations demonstrated the expected performance,with a transmission efficiency of 90%,confirming its capability to meet the injection requirement of the SAPS storage ring.This design offers a stable and efficient solution for the SAPS.
文摘Background:Penile augmentation through injectable substances is becoming increasingly common.A growing number of aesthetic clinics are developing penile enlargement procedures using various injectable materials.Although these procedures are now performed in more controlled and medically supervised environments,their long-term outcomes remain poorly understood.The promotion of such medical treatments contributes to an increasing interest among adult males in self-injection as a method to alleviate psychological distress associated with penile size concerns.At the same time,access to injectable substances through unofficial or unregulated sources has become increasingly easy.Tor our knowledge,we report the first documented case of self-injection with Garamycin®(gentamicin)cream,contributing to the literature on the often multidisciplinary management of penile enlargement injections,a field still lacking well-established guidelines.Case Description:This case report describes a young patient who self-injected Garamycin®into the penis for the purpose of enlargement.He presented to our urology department with worsening symptoms,including severe and poorly tolerated pain.His primary request was prompt relief of pain while preserving,as much as possible,the aesthetic appearance and functional integrity of his penis.This case required a multi-stage surgical approach to salvage the penis and preserve both its structural integrity and functional outcome.Conclusions:To our knowledge,this case report documents the first reported instance of Garamycin®injection performed for the purpose of penile enlargement.It provides insight into the clinical course of such penile cream injections,demonstrates that a two-stage scrotal flap can achieve both functional and aesthetic outcomes,and highlights the importance of comprehensive management particularly addressing the traumatic impact of penile deformity secondary to inflammation and/or infection,as well as the body dysmorphic concerns often associated with these cases.
文摘Objective:To explore the therapeutic effect of double-puncture tympanic membrane puncture and tympanic cavity drug injection in patients with acute secretory otitis media.Methods:A total of 84 patients with acute secretory otitis media admitted to our hospital from June 2024 to June 2025 were selected and randomly divided into two groups by drawing lots.The control group(42 cases)was treated with the traditional single-puncture tympanic membrane puncture and tympanic cavity drug injection method,while the observation group(42 cases)was treated with the double-puncture tympanic membrane puncture and tympanic cavity drug injection method.The therapeutic effects of the two groups were compared.Results:The overall treatment response rate,overall complication rate,time to symptom relief,and improvement in hearing threshold in the observation group were all superior to those in the control group,with statistically significant differences(P<0.05).Conclusion:For acute secretory otitis media,the treatment method of double-puncture tympanic membrane puncture and tympanic cavity drug injection demonstrates definite efficacy,significantly reducing the incidence of complications,accelerating symptom relief,and improving hearing function,making it worthy of promotion.
文摘The present studies were conducted to compose an injectable solution of colistin sulfate containing local anaesthesia, antioxidant and other additions. Results showed that the novel preparation was stable either to heat or to light. The term of validity of the preparation was 2 years at room temperature.The preparation containing 25. 0 mg ml-1 colistin sulfate showed no local tissue irritation, but the concentration of 50. 0 mg ml-1 colistin sulfate showed obvious local tissue irritation. Result of acute toxicity test showed that the LD50 of intramuscular injection in mice was 38. 72 mg kg-1, and oral LD50 was 431. 39 mg kg-1. The evidence of neurotoxicity was observed in mice in the acute toxicity test. A dose of 10.0 mg kg-1 b. w. or 15:0 mg kg-1b. w. was administered intramuscularly to piglet once daily for 5 days. No changes were detected in the piglet body except for the slight epithelial tissue's granular degenerations in the kidney and liver at the dose of the 10.0 mg kg-1. While at the dose of 15. 0 mg kg-1, the obvious neurotoxicity was observed at 4-5 days. The epithelial tissues in the kidney and liver showed moderate granular degenerations, especially in the tubuli renales cells. Blood cell's morphosis indexes were normal. With relation to liver's function, the indexes went beyond the normal scope. But with relation to kidney's function, the indexes showed mostly normal.When the preparation was separately administered into muscle(i. m.) in piglets with the dose of 2. 5 and 5. 0 mg kg-1 b. w, whose Cmax were 3.73±0. 28 and 6. 40±0.18 Abstract:g ml-1; Tmax were 32±1. 5 and 34±1.8min; t1/2β were 256±14 min and 264±29 min, respectively. t1/2βt was 251±13 min for the injection given into aural vein( i. v.) with the dose of 2.5 mg kg1-1 b. w.. Samples of the experimentally determined plasma concentration of colistin sulfate generated two-exponential model with first-order absorption. The mean absolute bioavail-ability coefficient of 2.5 and 5. 0 mg kg-1 b. w. (i. m.) were 98. 30 and 88. 54%, respectively. The high bio-availability and the long maintaining time of the valid blood-drug concentration showed that the injectable solution was suitable for i. m. in pigs, whose recommended dose was 2.5 mg kg-1 b. w. , twice daily.
