Intramuscular Research Articles

Synergistic Pain-Reducing Effects of Bixa orellana (Chronic® and Chronic In®) and Cannabidiol-Rich Cannabis sativa Extracts in Experimental Pain Models

Background: The present study aimed to evaluate the potential synergy between pharmaceutical formulations containing Bixa orellana L. (granulated—CHR OR and injectable nanodispersion—CHR IN) in conjunction with a cannabidiol (CBD)-rich extract of Cannabis sativa L. (CSE) on experimental pain models in Wistar rats. Methods: Chemical analysis was performed using gas chromatography (GC-MS). The pain tests employed were acetic acid-induced writhing (injection i.p. of 0.9% acetic acid), formalin (solution 1%), hot plate (55 ± 0.5 °C), and cold-water tail withdrawal tests. Results: Chemical analyses by chromatography confirmed that the oil from B. orellana is rich in δ-tocotrienol (72.0 ± 1.0%), while the oil from Cannabis sativa highlighted the presence of cannabidiol (CBD). The results from the experimental pain tests indicated that the combined administration of formulations containing Bixa orellana and C. sativa, such as the granulated CHR OR (400 mg/kg, orally) with CSE (40 mg/kg, orally) or the nanodispersion CHR IN (10 mg/kg, intramuscularly) with CSE (40 mg/kg, orally), demonstrated significant results (p < 0.001) in pain reduction. Although the formulations containing Bixa orellana extract showed statistical significance in the tests when used in isolation, their effects were inferior compared to the combined use with CSE or the isolated use of CSE. These findings suggest that combining formulations containing extracts of these plant species may represent a viable therapeutic option, considering the synergistic action in reducing pain under the experimental conditions employed. Conclusions: these results imply that combining the phytocomplexes present in B. orellana and C. sativa may be a promising approach for pain treatment.

A potentially fatal meningoencephalitis following intramuscular anti-inflammatory injection.

A potentially fatal meningoencephalitis following intramuscular anti-inflammatory injection.

Case report: Vitamin B12 deficiency-associated hemolytic anemia

Vitamin B12 deficiency is commonly known to cause hematological, neurological, and gastrointestinal disturbances including anemia, pancytopenia, sub-acute combined degeneration, and glossitis, among others. Hemolytic anemia is a rare but possible presentation of vitamin B12 deficiency. We present a case series of three elderly females with different past medical histories but with similar presentations of severe anemia. Initial investigation revealed pancytopenia and hemolytic anemia. Further evaluation indicated vitamin B12 deficiency and subsequently, pernicious anemia, as confirmed by low serum vitamin B12 levels and positive intrinsic cell antibody respectively. These findings directed the diagnosis toward vitamin B12 deficiency-induced hemolytic anemia, a rare clinical entity. All three patients responded to treatment with intramuscular vitamin B12 injections, showing significant improvement in their pancytopenia and hemolytic anemia. This case series highlight the importance of considering vitamin B12 deficiency as a potential cause of hemolytic anemia in patients presenting with pancytopenia and ineffective hematopoiesis. Further research is necessary to illuminate the therapeutic implications of this rare condition.

Evaluation of dimethandrolone undecanoate in non-human primates as a candidate for long-acting injectable male contraceptive.

Dimethandrolone undecanoate (DMAU) is under development as a single agent hormonal male contraceptive. DMAU is a prodrug hydrolyzed by esterase(s) to the active metabolite dimethandrolone (DMA) which has dual androgenic and progestogenic actions. Phase 1 clinical trial results show DMAU to be well-tolerated as an oral contraceptive in healthy men; however, delivery of DMAU as a long-acting injectable rather than a daily oral formulation would provide user compliance benefits and address oral bioavailability concerns. To assess the safety, pharmacokinetics (PK), and long-acting contraceptive potential of DMAU in male non-human primates (NHP) when delivered as an injectable or oral formulation. DMAU was administered to cynomolgus macaques orally for 9 months or as five weekly intramuscular (IM) injections and to rhesus macaques as a single IM injection. Evaluations of safety, fertility indicators, and serum levels of DMAU and DMA were followed>2 years post-dose. Repeat dose oral and IM administrations were well-tolerated with no significant toxicological findings. Dramatic reductions in serum testosterone concentration occurred within days of administration followed by sustained suppression of additional fertility indicators (e.g., serum inhibin B, sperm count, and testicular spermatogenesis). Slight body weight increases and reductions in testes weight also occurred. Repeat DMAU injections resulted in DMA serum concentrations above the lower limit of quantification (1ng/mL) for>500 days. DMAU PK parameters increased with increasing IM dose, while dose dependence was not seen for serum DMA concentrations suggesting a depot effect with a reservoir of non-circulating prodrug remaining at the injection site which gets slowly hydrolyzed to DMA and absorbed into circulation. Testosterone levels and spermatogenesis returned by the end of the recovery period. Nonclinical safety, PK, and pharmacodynamic data in male NHP demonstrate the safe, well-tolerated, long-acting, and reversible contraceptive potential of injectable DMAU.

The Use of Botulinum Toxin Type A and the Occurrence of Anaphylaxis: A Descriptive Analysis of Data from the European Spontaneous Reporting System.

Botulinum toxin type A (BTA) is a protein produced by Clostridium botulinum bacteria. It is the most widely used among botulinum toxin types, and it is recommended for the treatment of many clinical conditions, including muscle hyperactivity syndromes and for esthetic indications too. BTA is generally considered safe, and the most reported adverse events (AEs) include eyelids ptosis, immunogenicity, neuromuscular disorders and hypersensitivity reactions. In addition, serious idiosyncratic AEs, such as anaphylactic shock, have been highlighted. Taking into account that BTA skin toxicity has been already investigated recently by our research group and that, in many cases, the BTA-induced skin toxicity represents a symptom of an hypersensitivity reaction, the aim of the present study was to better characterize cases of anaphylaxis occurring after intramuscular administration of BTA by analyzing Individual Case Safety Reports (ICSRs) sent to the EudraVigilance database. A total of 86 ICSRs, covering 449 Preferred Terms, reporting BTA as suspected drug and "anaphylactic reaction," "anaphylactic shock," "anaphylactoid reaction" or "anaphylactoid shock" as ADR were suitable for our analysis. The majority of patients who experienced BTA-induced anaphylaxis were female (89.5%) and mostly belonged to the age group 18-64years. The most common outcome was "recovered/resolved," while the seriousness criteria was mostly reported as "caused/prolonged hospitalization." Our results showed that anaphylactic reactions may occur after esthetic use of BTA; thus, a close monitoring before, during and after BTA intramuscular injection is highly recommended in order to prevent the occurrence of this event and ensure an appropriate management of the patients receiving this drug. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Mucosal SARS-CoV-2 S1 adenovirus-based vaccine elicits robust systemic and mucosal immunity and protects against disease in animals.

This publication presents an assessment of the immune response and effectiveness of a vaccine containing genetically modified non-replicating recombinant that expresses the S1 subunit protein of SARS-CoV-2. We conducted a comparative analysis of the immune response potency, durability, and protective effectiveness of this vaccine using intramuscular (IM) and intranasal (IN) inoculation in mice and Syrian hamsters. Our findings indicate that both vaccinations were effective in stimulating strong and long-lasting immune responses, both locally and across the body, when administered through either IM or IN methods. Crucially, our study demonstrated that the IN vaccination outperformed the IM vaccine by effectively and significantly suppressing the multiplication of the virus in the lungs and nasal turbinates. Additionally, the IN vaccine provided protection against disease-related weight loss and lung damage in the animals. This work showcases the potential of intranasal administration as a viable method to stimulate both mucosal and systemic immunity. This technique provides improved defense against SARS-CoV-2 and maybe additional variations.

A Health Economic Analysis of Non-injectable Epinephrine Compared with Intramuscular Epinephrine

BackgroundNon-injectable epinephrine to treat allergic reactions addresses an unmet need. Intranasal epinephrine is approved and a sublingual form is under development. Inhaled epinephrine is poorly studied for anaphylaxis. These forms have unknown cost-effectiveness. ObjectiveThe aim of this research was to evaluate cost-effectiveness of commercially available non-injectable epinephrine compared with intramuscular epinephrine for treatment of anaphylaxis. MethodsMarkov cohort analyses evaluated the cost-effectiveness of non-injectable epinephrine forms. The base-case assumed exaggerated anaphylaxis fatality rates (50-fold increase) for using inhaled epinephrine given low certainty evidence in anaphylaxis, and deliberately reduced fatality risk for nasal or sublingual forms (10-fold reduction) theorizing higher adherence and early use during an allergic reaction. ResultsIn the base-case scenario, assuming a 10-fold decreased risk in peanut allergy fatality associated with intranasal or sublingual epinephrine treatment for a severe allergic reaction (net monetary benefit [NMB] $2,189,134) vs. intramuscular (IM) epinephrine use (NMB, 2,189,114), intranasal or sublingual epinephrine was the most cost-effective option (incremental cost-effectiveness ratio [ICER] $83,748/QALY), but only at a marginal annual cost of $4. IM epinephrine was cost-effective (ICER, $17,900/QALY) vs. inhaled epinephrine (NMB, $2,183,531), although inhaled epinephrine reached cost-effectiveness (Willingness To Pay [WTP $100,000/QALY]) if associated fatality risk fell below 2.5-fold. Substituting a single non-injectable form of epinephrine for a second injectable device (in patients prescribed two autoinjectors already) would be cost-effective; however, adding a supplemental non-injectable device was not cost-effective, even assuming a 10-fold risk reduction with multiple device carriage (ICER $858,462). ConclusionNon-injectable routes of epinephrine can be cost-effective options provided fatality risk is not significantly elevated. Carriage of redundant epinephrine autoinjectors with non-injectable forms is not cost-effective if associated with excess cost of redundant device packs.

Improvement in Kidney damage resulting from stanozolol intramuscular injections in rats by Natural Cocoa Powder (NCP) Administration.

BackgroundStanozolol, an anabolic steroid, has been shown to induce kidney damage through mechanisms involving oxidative stress and inflammation. Natural Cocoa Powder (NCP), known for its high antioxidant content, may offer protective effects against such damage. AimThis study aimed to evaluate the potential of Natural Cocoa Powder (NCP) in ameliorating kidney damage caused by stanozolol intramuscular injections in rats. MethodsThirty rats were randomly assigned into five groups (G1–G5) and fed with standard rat chow. G1 and G3 received 2 mg/kg stanozolol intramuscularly twice weekly, G2 and G4 received 5 mg/kg stanozolol twice weekly, while G5 served as the control with no stanozolol. G1, G2, and G5 had 24-hour access to water, while G3 and G4 had water replaced with 2% NCP from 6 am to 6 pm daily. After 8 weeks, kidneys were perfusion-fixed and analyzed histomorphometrically for proximal/distal tubules, Bowman's space, glomerular tuft, and renal corpuscle composition.Before and after treatments, renal function was measured by serum creatinine and blood urea nitrogen, whilst systemic inflammation was monitored by erythrocyte sedimentation rate and serum C-reactive protein tests. Results & DiscussionStanozolol administration significantly increased kidney damage in a dose-dependent manner, with marked rises in the volume densities of the proximal convoluted tubule (PCT), distal convoluted tubule (DCT), glomerular tuft, and renal corpuscle. At higher doses, PCT and DCT volume densities increased by 143% and 223%, respectively, compared to controls. Natural cocoa powder (NCP) mitigated these effects, reducing PCT, DCT, and glomerular tuft volume densities by 92%, 77%, and 86%, respectively. Stanozolol also elevated serum markers of kidney dysfunction and inflammation, such as blood urea nitrogen (BUN), serum creatinine (SCr), and C-reactive protein (CRP). While NCP significantly lowered BUN and SCr levels, it did not fully normalize CRP, which remained elevated in stanozolol-treated rats. ConclusionIncreased volume density of kidney components indicated hypertrophy, which was associated with elevated serum creatinine, blood urea nitrogen (BUN), and C-reactive protein (CRP) levels, reflecting impaired renal function and heightened systemic inflammation. The reduction in these markers with NCP ingestion suggests its potential to mitigate stanozolol-induced renal damage. It is proposed that the antioxidant properties of NCP may have reduced inflammation by counteracting oxidative stress, thereby contributing to the observed improvement in kidney function and structure.

The first-in-human study of QHRD106 functioning as a safe and effective long-acting kallikrein drug potentially aiding ischemic stroke

ABSTRACT Background This study assessed the pharmacokinetics (PK), pharmacodynamics (PD) and safety of QHRD106, and made a comparison with urinary kallindinogenase (UKN) in healthy volunteers. Methods This study comprised a randomized, double-blind, placebo-controlled, single-dose escalation phase and an open-label, multiple-dose escalation phase. 94 subjects received intramuscular injections of QHRD106/placebo only once and 30 subjects received QHRD106 four times. 6 subjects received 0.15 PNA units UKN intravenously for 7 d. PK and PD analysis were conducted by using a electrochemiluminescent assay and a liquid chromatography/mass spectrometry methodology respectively. Cerebral circulation was assessed by the magnetic resonance imaging system. Results QHRD106 exhibited a slow absorption profile in the human body. Compared to UKN, QHRD106 induced changes in bradykinin concentration later, but with a noticeably prolonged duration. Compared to baseline, cerebral blood flow exhibited a significant improvement on d 7 after a single dose of 18,900 IU and an improvement from d 2 to d 14 after multiple dose of 8400 IU of QHRD106. QHRD106 appeared generally good safety and no severe adverse events occurred in all the groups. Conclusions This study provided initial evidence of potential treatment for ischemic strokes that the QHRD106 injection functioned as a safe and effective long-acting kallikrein drug. Registration This study was registered on ClinicalTrials.gov with the identifier NCT06380699 and NCT06388772.

In vitro and in vivo characterization of Invega Sustenna® (paliperidone palmitate long-acting injectable suspension).

The aim of this study was to comprehensively characterize paliperidone palmitate (PP) long-acting suspension (Invega Sustenna®) through reverse engineering. We developed a series of analytical methods to assess critical quality attributes of four batches of Invega Sustenna®. The size distributions of the four batches of suspensions were measured using laser diffraction, and variations in the D50 and D90 parameters were observed. The morphology of suspension was determined through scanning electron microscope (SEM), which exhibited irregular granular shape across all batches. The size distributions determined by SEM images were similar to the laser diffraction results. Thermal characteristics were detected using differential scanning calorimetry (DSC) and crystalline properties were assessed by powder X-ray diffraction (PXRD), displaying consistency among the four batches in these two aspects. In vitro dissolution methods (sample separation and dialysis bag methods) were developed to evaluate the release behaviors of Invega Sustenna® and four lots showed a similar dissolution pattern. Furthermore, following a single-dose intramuscular administration to rats, two batches of Invega Sustenna® with the largest size differences demonstrated comparable plasma concentration-time profiles and pharmacokinetics parameters, indicative of one month long-acting release. In summary, we established a systematic quality characteristics assessment for Invega Sustenna®, including particle size distribution, particle morphology, thermal characteristics, crystalline properties, in vitro dissolution kinetics and in vivo pharmacokinetics. Our work will assist pharmaceutical companies and regulatory agencies in the development and regulatory assessment of novel or generic products of long-acting injectable suspension.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: A randomised, comparator-controlled, phase 2 trial

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine. This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18years of age and older, were eligible. Participants were randomised by age (18-59, ≥60years) to receive one of three treatments by intramuscular injection twice, 28days apart: COVIVAC at 3μg or 6μg, or AstraZeneca COVID-19 vaccine VAXZEVRIA™. Participants and personnel assessing outcomes were masked to treatment. The vaccine dose was selected based on Phase 1 results. A 6μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The study's aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14days (day 43) and 6months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194. During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18-59years of age achieved the following geometric mean titers of PNA 14days after vaccine dose two: 153⋅28 (95 % CI 124·2-189⋅15) for COVIVAC 3μg, 176⋅2 (95 % CI 141⋅45-220.27) for COVIVAC 6μg, and 99⋅92(95 % CI 80.80-123⋅56) for VAXZEVRIA. Subjects ≥60years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4-252⋅61) for COVIVAC 3μg, 257⋅87 (95 % CI 181⋅6-367⋅18) for COVIVAC 6μg, and 79⋅49(95 % CI 55⋅68-113⋅4) for VAXZEVRIA. On day 43, the geometric mean fold rise of 50% neutralising antibody titers for subjects age 18-59years was 31·20 (COVIVAC 3μgN=82, 95 % CI 25·14-38·74), 35·80 (COVIVAC 6μg; N=83, 95 % CI 29·03-44·15), 18·85 (VAXZEVRIA; N=82, 95 % CI 15·10-23·54), and for subjects age≥60years was 37·27 (COVIVAC 3μg; N=42, 95% CI 27·43-50·63), 50·10 (COVIVAC 6μg; N=40, 95% CI 35·46-70·76), 16·11 (VAXZEVRIA; N=40, 95 % CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6μg/VAXZEVRIA) was 1·77 (95 % CI 1·30-2·40) for subjects age 18-59years and 3·24 (95% CI 1·98-5·32) for subjects age≥60years. On day 197, the age-specific ratios were 1·11 (95% CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28days after vaccinations was similar among treatments (COVIVAC 3μg 29·0%, COVIVAC 6μg 23·2%, VAXZEVRIA 31·2%); no vaccine-related AE was reported. Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine. ClinicalTrials.govNCT05940194.

Ketamine for treatment-resistant obsessive-compulsive disorder: Double-blind active-controlled crossover study.

Obsessive-Compulsive Disorder (OCD) may respond to ketamine treatment. To examine the responsiveness and tolerability of treatment-refractory OCD to intramuscular (IM) ketamine compared to IM fentanyl. This was a randomised double-blind psychoactive-controlled study with single doses of racemic ketamine 0.5 mg/kg, 1.0 mg/kg or fentanyl 50 µg (psychoactive control). Pre-dosing with 4 mg oral ondansetron provided nausea prophylaxis. Eligible participants were aged between 18 and 50 years with severe treatment-resistant OCD. The primary efficacy measure was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Tolerability was measured with the Clinician-Administered Dissociative States Scale (CADSS). Repeated measures analysis of variance with orthogonal polynomial trends was used to assess the effect of drug treatment on Y-BOCS and CADSS scores. Twelve participants were randomised and 10 completed the study (7 females, 3 males, mean age 33 years). Two participants dropped out due to not tolerating dissociative effects associated with the study medication. The reductions in Y-BOCS scores were greater and statistically dose-related for both ketamine doses than fentanyl (dose [linear], F(1, 9) = 6.5, p = 0.031). Score changes for all treatments were maximal at 1-2 h with a steady separation of scores out to 168 h. Ketamine was associated with short-term dissociative and cardiovascular effects. We provide further preliminary evidence for the efficacy and tolerability of IM ketamine in an outpatient cohort of OCD. Additional work is required to establish the optimal dosing regimen and longer-term role of ketamine for OCD. These findings are encouraging given the well-known limitations that exist for treatments in this area.

Vaginal administration of 17-alpha hydroxyprogesterone caproate appears to be safe in non-pregnant female rats and rabbits

Intramuscular (250 mg once weekly) or subcutaneous (275 mg once weekly) injections of 17-hydroxyprogesterone caproate (17-OHPC) has been utilised to prevent recurent spontaneous preterm birth in pregnant women with a short cervix or those with a prior preterm birth but its efficacy in these conditions has been questioned. It is unclear whether adequate concentrations of 17-OHPC reach the suspected target organs such as the cervix and uterus following either IM or SC administration. The objective of this study was to determine feasibility and safety of vaginal administration of 17-OHPC in adult female Sprague Dawley rats and female New Zealand rabbits. Gels containing 17-OHPC were administered intravaginally to rats and rabbits for 10 consecutive days. After the last dose, serial blood samples and terminal uterine and adipose tissue samples were collected. 17-OHPC concentrations were measured by LC-MS-MS. Tissue histology showed that intravaginal administration of 17-OHPC was safe. There was no renal or hepatic toxicity as measured by liver function and kidney function tests. Intravaginal administration of 17-OHPC resulted in low systemic plasma concentrations but substantially higher uterus and adipose tissue concentrations of 17-OHPC. Composition of the formulation affected the tissue distribution of 17-OHPC. Future studies warrant further evaluation of the effect and safety of daily intravaginal administration of 17-OHPC gel in pregnant animals.

Establishment and mechanism of thioacetamide-induced hepatopancreas injury model in red swamp crayfish Procambarus clarkii

The red swamp crayfish (Procambarus clarkii), widely farmed in China, frequently suffers from hepatopancreatic diseases due to the expansion and environmental degradation of aquaculture. Hepatopancreatic injury models are essential for studying disease mechanisms and treatments, yet few exist for crustaceans. This study aims to establish a hepatopancreatic injury model in P. clarkii using the hepatotoxic compound thioacetamide (TAA) and investigate the underlying damage mechanisms. P. clarkii were intramuscularly injected with TAA at concentrations of 0.2, 0.4, and 0.8 mg/g and observed at 6, 12, 24, and 48 h. The results showed that TAA at 0.2–0.8 mg/g significantly affected hepatopancreatic function and oxidative stress-related enzymes in P. clarkii. However, only 0.8 mg/g TAA produced a time-dependent damage effect suitable for a hepatopancreatic injury model. Histopathological analysis revealed that P. clarkii injected with 0.8 mg/g TAA exhibited key model features, including R cell adhesion and swelling, hepatic tubule rupture, and numerous small vacuoles. Therefore, 0.8 mg/g TAA intramuscular injection can effectively establish a hepatopancreatic injury model in P. clarkii. Transcriptomic and metabolomic analyses revealed that metabolic disruptions in energy, amino acid, lipid, and nucleotide pathways are central to TAA-induced hepatopancreatic injury in P. clarkii. CYP2L1X1, CYP2U1lX1, and CYP2D14l are likely key contributors to the hepatopancreatic injury induced by TAA in P. clarkii. The results of this study will provide support for further research on the mechanisms of hepatopancreatic diseases in freshwater crayfish and the development of preventive and therapeutic drugs.

Arsenic Toxicosis in Animals: Mechanism Clinical Manifestations and Treatment Approaches for Arsenic Poisoning in Animals

Arsenic is a naturally occurring element present in the earth in various form (arsenate, arsenite) contaminates soil, water and causes toxicity to animal as well as human beings. The main routes of exposure of humans and most animals to arsenic through the ingestion then absorption through the skin. Animals having Arsenic intoxication showing various form peracute, acute and chronic form. First treatment is to removal of contaminants, emesis is first step (in capable species), followed by activated charcoal with a cathartic and then oral administration of demulcents. If diagnosis were confirmed early treatment should be started with Dimercaprol, even is given within two hours after ingestion of the toxic metal. Intramuscular injection or intravenous injection in peanut oil because of water insolubility was the reason. Supportive therapy include fluid therapy produce additive effect and animal will improve the health condition.

Exosomes secreted from human-derived adipose stem cells prevent progression of osteonecrosis of the femoral head

BackgroundOsteonecrosis of the femoral head (ONFH) primarily affects young individuals and is a leading cause of total hip arthroplasty in this population. Joint-preserving regenerative therapies involving core decompression (CD), enhanced with cells, growth factors, and bone substitutes, have been developed but lack extensive validation. Exosomes are emerging as a promising regenerative therapy. Human adipose stem cell (hADSC)-derived exosomes exhibit angiogenic and wound-healing effects on damaged and diseased tissues, suggesting their potential efficacy in treating early-stage ONFH. We aimed to investigate the efficacy of hADSC-derived exosomes based on CD in a medium-sized animal model (rabbit).MethodsExosomes were extracted using the ultrafiltration filter technique from the culture supernatants of two types of hADSCs. Characterization of exosomes was performed through nanoparticle tracking analysis, transmission electron microscopy, and the detection of specific biomarkers (CD9, CD63, and CD81) by western blotting. Eighteen rabbits underwent surgical vascular occlusion and intramuscular corticosteroid injections to induce ONFH. Concurrently, CD treatment with local administration of hADSC-derived exosomes (exosome group) or saline (control group) was performed. Femoral heads were harvested at 4, 8, and 12 weeks postoperatively and evaluated using micro-computed tomography and tissue staining to assess the protective effects on osteonecrosis, angiogenesis, and osteogenesis.ResultsExosomes had average particle concentrations of 1.8 × 1012 or 1.8 × 109 particles/mL, with particle size distributions averaging 61.2 ± 14.7 or 123.1 ± 46.3 nm, and were confirmed by specific biomarkers. The exosome group exhibited a significant reduction in the severe progression of ONFH to stages 3 or 4 of the modified Ficat and Arlet classification, compared to the control group, which had four cases of stages 3 or 4. The exosome group showed significantly fewer empty lacunae in the subchondral bone area (p < 0.05) and significantly less articular cartilage injury (p < 0.05) compared to the corresponding in the control group. There were no significant differences in the microvessel number, bone trabecular structure, or volume of new bone in the medial region of the CD.ConclusionshADSC-derived exosomes can prevent the progression of ONFH by inhibiting osteonecrosis and cartilage damage. The ultrafiltration filter technique is effective for exosome extraction, indicating that exosomes hold potential as a therapeutic agent for ONFH.

Phase I Trial to Assess the Safety, Tolerability, and Preliminary Efficacy of OBI-858 for Treatment of Glabellar Lines.

OBI-858 is a brand-new botulinum Type A complex toxin with a specific molecular weight of 760kDa intended for development for both aesthetic and therapeutic applications.This is a phase I, dose-escalation study to evaluate the safety and preliminary efficacy of OBI-858 in subjects with moderate to severe glabellar lines. Each subject received OBI-858 by intramuscular injections with an assigned dose (10 U, 20 U, and 30 U). The safety and preliminary efficacy were evaluated at each of the in-person visits. A total of 36 subjects (12 subjects per cohort) were enrolled. The response rates (≥ 1 point) for all groups at maximum frown were assessed at week 4 were 100%. The initial improvement for 30 U occurred at day 3. Response rates revealed benefits lasting 4-6months or longer. Subject satisfaction at week 4 was high in all groups. Adverse effects were mild and infrequent. Among them, one subject had drug-related AE, and one subject had grade ≥ 3 unrelated AE. This study demonstrated that OBI-858 is well tolerated and showed preliminary efficacy. Overall, the OBI-858 has a clinically favorable profile of safety and efficacy that warrants proceeding to the next studies.

Dual-route administration of balanced anesthesia using medetomidine, midazolam, and butorphanol provides both suitable anesthetic depth and reduced tissue injury in rabbits.

Medetomidine, midazolam, and butorphanol (MMB) anesthesia is the preferred choice for rodents but requires excess volume of intramuscular injection in rabbits, which can lead to muscular damage. This study aimed to evaluate a dual-route MMB administration via the intravenous and subcutaneous routes in rabbits. MMB was administered to male Kbs:JW rabbits with an intravenous injection of 0.2 mL/kg followed by a subcutaneous injection of 0.8 mL/kg, totaling 0.2 mg/kg medetomidine, 2.0 mg/kg midazolam, and 2.0 mg/kg butorphanol. We compared the anesthetic effects of this dual-route method with those of intramuscular administration. The dual-route method resulted in a shorter induction time and similar anesthetic duration compared with those of the intramuscular route. While it induced a temporary decrease in body temperature within 30 min post-injection, other vital signs, such as respiration rate, heart rate, and O2 saturation, remained similar. Notably, unlike intramuscular administration, dual-route administration did not increase tissue injury marker levels. This dual-route MMB administration provided sufficient anesthetic depth during surgery, eliminating pain reflexes. Double-dose administration extended anesthetic duration but resulted in rare fatalities, indicating room for protocol improvement. In conclusion, the novel anesthetic method is preferable for injectable anesthesia in rabbits, providing rapid induction and sufficient anesthetic duration, while potentially minimizing muscle injury. This technique may be beneficial for both laboratory and companion animals and significantly enhance animal welfare in anesthesia by reducing the pain associated with injectable anesthesia.

Sublingual Sufentanil Tablet for Analgesia in Emergency Medical Services and Search and Rescue Agencies

Objectives Pain management in the potentially austere search and rescue (SAR) and emergency medical services (EMS) environments can be challenging. Intravenous (IV) and intramuscular (IM) routes of administration may be less practical. This study assesses the efficacy and safety of the sublingual sufentanil tablet (SST) in prehospital settings and hypothesizes that its use will reduce pain while maintaining a reasonable safety profile. Methods This was a retrospective case analysis examining patient records from Teton County Search and Rescue, Grand Teton National Park EMS, and Jackson Hole Fire/EMS from 2021-2023, based on the criteria that they were administered SST in a prehospital setting. Cases in which SST was used were examined to assess patient characteristics, injury classification, patient reported pain scale before and after SST, other medications administered, and vital signs. Results Seventy patients met the inclusion criteria. Six individuals were excluded due to missing one or more of the key variables, and the analysis was carried out with the remaining (N = 64 cases). The mean pain score decreased from 8.0 ± 1.9 before medication administration to 5.5 ± 2.5 after administration, reflecting a statistically significant difference of 2.6 ± 2.1 (p < 0.001). The results also revealed statistically significant reductions in heart rate (HR) and systolic blood pressure (SBP) following SST administration (mean HR dropped by 4.2 ± 9.1 beats/min, p = 0.004, and mean SBP dropped by 11.1 ± 21.8 mmHg, p = 0.01). Changes in vital signs, although statistically significant, were not clinically significant and did not necessitate additional monitoring or intervention in any patients. Conclusions Our study demonstrated that SST administration led to a significant reduction in pain scores and exhibited a favorable safety profile regarding vital signs, including SBP, HR, respiratory rate (RR), and O2 saturation. These findings support the utilization of SST for pain management in the prehospital setting, particularly in austere environments where traditional routes of administration may be impractical.

Distinct Inflammatory Programs Underlie the Intramuscular Lipid Nanoparticle Response.

Developments in mRNA/lipid nanoparticle (LNP) technology have advanced the fields of vaccinology and gene therapy, raising questions about immunogenicity. While some mRNA/LNPs generate an adjuvant-like environment in muscle tissue, other mRNA/LNPs are distinct in their capacity for multiple rounds of therapeutic delivery. We evaluate the adjuvancy of components of mRNA/LNPs by phenotyping cellular infiltrate at injection sites, tracking uptake by immune cells, and assessing the inflammatory state. Delivery of 9 common, but chemically distinct, LNPs to muscle revealed two classes of inflammatory gene expression programs: inflammatory (Class A) and noninflammatory (Class B). We find that intramuscular injection with Class A, but not Class B, empty LNPs (eLNPs) induce robust neutrophil infiltration into muscle within 2 h and a diverse myeloid population within 24 h. Single-cell RNA sequencing revealed SM-102-mediated expression of inflammatory chemokines by myeloid infiltrates within muscle 1 day after injection. Surprisingly, we found direct transfection of muscle infiltrating myeloid cells and splenocytes 24 h after intramuscular mRNA/LNP administration. Transfected myeloid cells within the muscle exhibit an activated phenotype 24 h after injection. Similarly, directly transfected splenic lymphocytes and dendritic cells (DCs) are differentially activated by Class A or Class B containing mRNA/LNP. Within the splenic DC compartment, type II conventional DCs (cDC2s) are directly transfected and activated by Class A mRNA/LNP. Together, we show that mRNA and LNPs work synergistically to provide the necessary innate immune stimuli required for effective vaccination. Importantly, this work provides a design framework for vaccines and therapeutics alike.