Injection Route Research Articles

The Effect of Two Novel Substituted Thiazole and Thiadiazine Derivatives on Experimental Type-1 Diabetes Mellitus

Thiazole and thiadiazine derivatives are heterocyclic compounds containing nitrogen and sulfur. They have a wide range of medicinal applications. The present study aimed to investigate the anti-hyperglycemic and antioxidant properties of two novel thiazole and thiadiazine derivatives using streptozotocin (STZ)-induced diabetic mice. The two synthesized compounds significantly reduced hyperglycemia and restored pancreatic insulin secretion in the treated diabetic mice. Also, the two compounds lead to a decrease in the serum triglyceride level and an increase in pancreatic SOD activity in the treated diabetic mice. The LD50 value of the two compounds using the IP injection route was greater than 300 mg/kg body weight. Further studies on these two compounds, especially mechanisms of action, are required to develop them into potential anti-diabetic drugs.

A facile and smart strategy to enhance bone regeneration with efficient vitamin D3 delivery through sterosome technology

The spontaneous healing of critical-sized bone defects is often limited, posing an increased risk of complications and suboptimal outcomes. Osteogenesis, a complex process central to bone formation, relies significantly on the pivotal role of osteoblasts. Despite the well-established osteogenic properties of vitamin D3 (VD3), its lipophilic nature confines administration to oral or muscle injection routes. Therefore, a strategic therapeutic approach involves designing a multifunctional carrier to enhance efficacy, potentially incorporating it into the delivery system. Here, we introduce an innovative sterosome-based delivery system, utilizing palmitic acid (PA) and VD3, aimed at promoting osteogenic differentiation and facilitating post-defect bone regeneration. The delivery system exhibited robust physical characteristics, including excellent stability, loading efficiency, sustained drug release and high cellular uptake efficiency. Furthermore, comprehensive investigations demonstrated outstanding biocompatibility and osteogenic potential in both 2D and 3D in vitro settings. A critical-sized calvarial defect model in mice recapitulated the notable osteogenic effects of the sterosomes in vivo. Collectively, our research proposes a clinically applicable strategy for bone healing, leveraging PA/VD3 sterosomes as an efficient carrier to deliver VD3 and enhance bone regenerative effects.

Effects of different immunomodulating liposome-based adjuvants and injection sites on immunogenicity in pigs

Vaccine adjuvants, such as liposome-based cationic adjuvant formulations (CAFs), are able to boost immune responses and, by incorporation of distinct immunomodulators, steer immunity towards a desired direction in mice, non-human primates and humans, while less studied in pigs. Here we used commercial pigs to investigate polarizing adjuvant effects of CAFs with immunomodulators: C-type lectin receptor ligands trehalose-6,6ʼ-dibehenate and monomycolyl glycerol, toll-like receptor 3 ligand Poly(I:C) or retinoic acid. Vaccines were formulated with a recombinant Chlamydia model protein antigen and administered via three injection routes. All adjuvants significantly increased antigen-specific IgG in serum, compared to non-adjuvanted antigen. Administering the vaccines through intramuscular and intraperitoneal routes induced significantly higher antigen-specific IgG and IgA serum antibodies, than the perirectal route. Although immunizations triggered cell-mediated immunity, no significant differences between adjuvants or injection sites were detected. Genes depicting T cell subtypes revealed only minor differences. Our findings suggest that specific signatures of the tested adjuvant immunomodulation do not translate well from mice to pigs in standard two-dose immunizations. This study provides new insights into immune responses to CAFs in pigs, and highlights that adjuvant development should ideally be carried out in the intended species of interest or in models with high predictive validity/translational value.

Post-traumatic stress disorder in crack/cocaine users

IntroductionCocaine use has become popular in the form of crack and has spread throughout the world. Crack/cocaine use is often linked to serious social and psychiatric disorders, including post-traumatic stress disorder, and users appear to be at increased risk of physical and mental illness and social harm.ObjectivesTo determine the prevalence of post-traumatic stress disorder in patients followed and hospitalized in the addictology department at the Arrazi psychiatric hospital in Salé for management of crack/cocaine use disorder.MethodsThis is a descriptive cross-sectional study using a questionnaire including sociodemographic and clinical criteria and a post-traumatic stress scale (PCLS) to investigate the existence of post-traumatic stress disorder in patients monitored and hospitalized for crack/cocaine use disorder in the addictology department at the Arrazi psychiatric hospital in Salé.ResultsWe collected 77 participants. The majority of patients were born in the city The average age of the participants was 27, with a male predominance (67%). The majority were unemployed at the time of the study, single, separated or divorced. For more than 50%, the start of drug use was more than 4 years ago. The smoked route (crack) is the most predominant, followed by the inhaled route and 1% for the injectable route. Some 37% were hospitalized in an addictology unit. Almost 65% of participants had a history of post-traumatic stress disorder.ConclusionsCo-morbidity between crack/cocaine use disorder and post-traumatic stress disorder is frequent among patients monitored and hospitalized in the addictology department at the Arrazi psychiatric hospital in Salé. There seems to be a need to develop new therapeutic strategies and to adapt existing programs to patients’ needs. In addition, understanding the profiles of patients suffering from this comorbidity in mental health facilities could help clinical staff to better accept their problems and behaviours, thus promoting treatment adherence and better outcomes.Disclosure of InterestNone Declared

Apoptosis as a therapeutic strategy for breast cancer: the role of Thymax, a gross thymic extract, in modulating cell death pathways

Background Breast cancer is a prevalent disease in women and a leading cause of cancer-related health issues. Thymax, a thymic extract, has shown potential for inducing breast cancer cell apoptosis in vitro. Objective This study aims to investigate how Thymax induces apoptosis and inhibits breast cancer growth and metastasis in vivo. Materials and methods Thymax treatment was divided into five groups: the first group (negative control) − normal rats without tumors. In the second group (positive control), rats were injected subcutaneously in the mammary gland with a single dose of 50 mg/kg b.w. of 7,12-Dimethylbenz(a)anthracene (in 2 ml of corn oil) and allowed to develop tumors for 120 days. Group 3: Thymax was orally administered 6 days a week to tumor-bearing rats (0.4 mg/rat) and continued for 5 weeks. Tumor-bearing rats in group 4 (Thymax injection) received 0.1 ml of Thymax solution through intraperitoneal injection twice weekly for 5 weeks. The last group was Thymax mix (oral and injection); tumor-bearing rats received Thymax solution by dual routes: orally with 0.4 ml six times per week and intraperitoneally with 0.1 ml twice weekly for 5 weeks. Thymax treatment, beginning after 120 days of tumor induction, continued for 5 weeks. Results and conclusion Thymax- induced apoptosis in breast cancer cells by increasing cytochrome c, tumor necrosis factor receptor type 1-associated death domain protein (TRADD), and Fas associated death domain (FADD) levels. It also activated the mitochondrial-dependent pathway with up-regulation of tumor protein gene (P53) expression and cysteine-dependent, aspartate-specific peptidase (caspase-8) activation. Thymax restored normal renal and hepatic cell function and enhanced the immune system by improving total antioxidant levels and inhibiting malondialdehyde levels in treated animals. Histopathological results showed a significant apoptotic effect in the group receiving Thymax injections, demonstrating its capability to induce apoptosis without tumors or atypia in mammary glands. Our findings indicate that Thymax has a significant effect on enhancing tumor cell death and inducing apoptosis in vivo. Thymax may also modulate proapoptotic and antiapoptotic protein expression and activity, regulate the penetrability of the mitochondrial membrane, and release cytochrome c. Furthermore, our findings show that the injection route of Thymax is the fastest and most efficient method to deliver the extract to the tumor site and exert its antitumor effects. These results suggest that Thymax has the potential to be a novel adjuvant in the treatment of breast cancer, as it can enhance the efficacy of conventional therapies and reduce the risk of recurrence and metastasis.

Isolation, Identification, and Pathogenicity of a Goose Astrovirus Genotype 1 Strain in Goslings in China.

Goose astrovirus genotype 1 (GAstV-1) has emerged in goose farms in some provinces of China in recent years and is considered to be one of the pathogens of gout in goslings in China. However, few studies have been conducted on the dynamic distribution, tissue tropism, and pathogenesis of GAstV-1 in goslings. In 2022, an epidemiological investigation of goose astrovirus (GAstV) in goslings was conducted in seven provinces of China. During the investigation, a GAstV-1 designated as GAstV-JSXZ was identified in the kidney of an 8-day-old gosling and was successfully isolated from a goose embryo. The full genome sequence of GAstV-JSXZ was determined using the next-generation sequencing technique. The complete genome of GAstV-JSXZ was 7299-nt-long. Interestingly, the phylogenetic analysis revealed that Chinese GAstV-1 has formed two distinct subgroups based on the ORF 2 genomes, designated GAstV-1 1a and GAstV-1 1b. The GAstV-JSXZ shared the highest identity with GAstV-1 1a strain FLX and TZ03 in nucleotides (ORF1a: 98.3-98.4%; ORF1b: 92.3-99.1%; ORF2: 95.8-98.8%) and amino acid sequences (ORF1a: 99.4-99.5%; ORF1b: 98.2-98.8%; ORF2: 97.0-99.4%). To evaluate the pathogenicity of GAstV-1, 1-day-old goslings were inoculated with the virus by oral and subcutaneous injection routes, respectively. The results revealed that the virus causes extensive pathological organ damage, especially in the kidney, liver, and thymus. Virus-specific genomic RNA could be detected in the cloacal swabs and tissues of infected goslings throughout the experiment. The viral copy numbers examined in the kidney and intestine were the highest, followed by the liver and spleen. These results are likely to provide a new understanding of the pathogenicity of GAstV-1 in geese.

Comparison of Wrinkle Patterns Generated by Intradermal and Intramuscular Botulinum Toxin Injections by Clinical Evaluation.

Botulinum toxin has played a remarkable role in management of forehead wrinkles. Most used is intramuscular technique due to its deposition into the muscles, however, with adverse effects like brow ptosis. This study has been designed for the evaluation of efficacy for intradermal v/s intramuscular route of botulinum toxin injections for forehead wrinkles using clinical correlation. This study included a clinical trial of 32 facial halves divided equally into intradermal and intramuscular injection technique groups, receiving total dose of 8 U. Results were assessed by clinical examination upto 2weeks and 4weeks with parameters; objective wrinkle rate, eyebrow height, eyebrow movement, pain, and satisfaction after treatment. Results showed least mean for objective wrinkle rate in intramuscular group, showing statistically significant improvement. Overall improvement in eyebrow height and eyebrow movement were slightly more for intramuscular group. Pain was lesser for intradermal group, whereas satisfaction of patient of patient post treatment is similar for both the groups. Among intradermal and intramuscular botulinum toxin injection technique, the effect and potency were better for intramuscular technique, whereas the patient comfort and compliance were better for intradermal technique.

Recent development of oral vaccines (Review).

Oral immunization can elicit an effective immune response and immune tolerance to specific antigens. When compared with the traditional injection route, delivering antigens via the gastrointestinal mucosa offers superior immune effects and compliance, as well as simplicity and convenience, making it a more optimal route for immunization. At present, various oral vaccine delivery systems exist. Certain modified bacteria, such as Salmonella, Escherichia coli and particularly Lactobacillus, are considered promising carriers for oral vaccines. These carriers can significantly enhance immunization efficiency by actively replicating in the intestinal tract following oral administration. The present review provided a discussion of the main mechanisms of oral immunity and the research progress made in the field of oral vaccines. Additionally, it introduced the advantages and disadvantages of the currently more commonly administered injectable COVID-19 vaccines, alongside the latest advancements in this area. Furthermore, recent developments in oral vaccines are summarized, and their potential benefits and side effects are discussed.

Comprehensive ocular and systemic pharmacokinetics of dexamethasone after subconjunctival and intravenous injections in rabbits

Even though subconjunctival injections are used in clinics, their quantitative pharmacokinetics has not been studied systematically. For this purpose, we evaluated the ocular and plasma pharmacokinetics of subconjunctival dexamethasone in rabbits. Intravenous injection was also given to enable a better understanding of the systemic pharmacokinetics. Dexamethasone concentrations in plasma (after subconjunctival and intravenous injections) and four ocular tissues (iris-ciliary body, aqueous humour, neural retina and vitreous) were analysed using LC-MS/MS.Population pharmacokinetic modelling for plasma data from both injection routes were used, and for first time the constant rate of absorption of dexamethasone from the subconjunctival space into plasma was estimated (ka,plasma = 0.043 min−1, i.e. absorption half-life of 17.3 min). Non-compartmental analysis was used for the ocular data analysis and resulting in ocular drug exposure of iris-ciliary body (AUC0-∞= 41984 min·ng/g) > neural retina (AUC0-∞= 25511 min·ng/g) > vitreous (AUC0-∞= 7319 min·ng/mL) > aqueous humour (AUC0-∞= 6146 min·ng/mL). The absolute bioavailability values after subconjunctival injection, reported for the first time, were 0.74 % in aqueous humour (comparable to topical dexamethasone suspensions), and 0.30 % in vitreous humour (estimated to be higher than in topical administration).These novel and comprehensive pharmacokinetic data provide valuable information on the potential for exploiting this route in ocular drug development for treating both, anterior and posterior segment ocular diseases. Moreover, the new generated dexamethasone-parameters are a step-forward in building predictive pharmacokinetic models to support the design of new subconjunctival dexamethasone formulations, which may sustain drug effect for longer period of time.

Investigation of Antibody Pharmacokinetics in the Brain Following Intra-CNS Administration and Development of PBPK Model to Characterize the Data.

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders.

Abstract B007: Establishment of patient-derived brain metastasis initiating cells as a novel preclinical model of breast cancer metastatization

Abstract Brain metastasis from breast cancer (BCBM) are lethal tumors occurring in 10-15% of IV stage breast cancers against which only limited therapeutic options are available. A critical hindrance to the design of novel therapeutic approaches is the narrow set of preclinical models to study BCBM pathophysiology, chiefly those resembling the stem-like population which is thought be the main source of BCBM dissemination and progression. We aimed to isolate patient-derived metastasis-initiating cells (MICs) to furnish novel preclinical models of metastatization. MICs were cultured as stem-enriching tumorspheres, which we characterized in term of i) brain/breast/stem markers expression ii) tumorigenicity, iii) growth and in vitro/in vivo self-renewal, iv) adhesion to organ-specific endothelium, v) metastatic potential and vi) drug responsiveness. Further, we transcriptionally profiled MIC-driven organ-specific metastasis. Patient-derived MICs expressed epithelial markers while the expression of brain markers was poor, coherently with their epithelial origins. About 90% of MICs were positive to the expression of the putative stem cell markers CD15, CD24 and CD44, while CD133 and ALDH1A1 were less represented. MICs were grown indefinitely in stem cell medium and successfully formed spheres in serial clonogenic assays, suggesting their endowment with stem-like traits. Similarly, their ability to form tumors when orthotopically injected in mice brain was maintained upon serial transplantation and under in vivo limiting dilution conditions. The representative PR60 MICs showed metastatic potential to mice brain and bones upon either intracardiac or intranipple transplantation. Of note, independently of the route of injection, this metastatization pattern wholly mirrored the clinical course of the patient they had been derived from. PR60-driven brain metastasis also recapitulated patient tumor histology, cytoarchitecture and marker expression. Further confirming their brain-tropism, PR60 MICs preferentially adhered to human brain compared to non-brain endothelium under shear stress mimicking in vivo hemodynamic conditions. Transcriptomically, PR60 MICs displayed high correlation with the BCBM of origin but retain the ability to form intra-nipple tumors resembling patient primitive breast tumor. PR60-derived brain and bone metastasis reveal a distinct expression profile suggesting that PR60 MICs can colonize different organs rewiring their transcriptomic landscape. Compared to the whole tumor of origin, MICs revealed an up-regulation of drug resistance signatures, which are often linked with stem-like traits, and that were functionally validated by a high throughput drug screening. Altogether, we established a robust and versatile MIC model that reliably mirrors the brain metastasis of origin and mimics the different steps of brain metastatic dissemination for in vitro and in vivo studies. This model has the potential to provide further knowledge for future therapy development for BCBM management. Citation Format: Stefania Faletti, Cristina Richichi, Daniela Osti, Elena Ceccacci, Massimiliano Del Bene, Camilla Cerutti, Giovanni Bertalot, Monica Patanè, Bianca Pollo, Giuliana Pelicci. Establishment of patient-derived brain metastasis initiating cells as a novel preclinical model of breast cancer metastatization [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B007.

Commercial hydrogel product for drug delivery based on route of administration.

Hydrogels are hydrophilic, three-dimensional, cross-linked polymers that absorb significant amounts of biological fluids or water. Hydrogels possess several favorable properties, including flexibility, stimulus-responsiveness, versatility, and structural composition. They can be categorized according to their sources, synthesis route, response to stimulus, and application. Controlling the cross-link density matrix and the hydrogels' attraction to water while they're swelling makes it easy to change their porous structure, which makes them ideal for drug delivery. Hydrogel in drug delivery can be achieved by various routes involving injectable, oral, buccal, vaginal, ocular, and transdermal administration routes. The hydrogel market is expected to grow from its 2019 valuation of USD 22.1 billion to USD 31.4 billion by 2027. Commercial hydrogels are helpful for various drug delivery applications, such as transdermal patches with controlled release characteristics, stimuli-responsive hydrogels for oral administration, and localized delivery via parenteral means. Here, we are mainly focused on the commercial hydrogel products used for drug delivery based on the described route of administration.

Current Status and Prospects of Viral Vector-Based Gene Therapy to Treat Kidney Diseases.

Inherited kidney diseases are among the leading causes of chronic kidney disease, reducing the quality of life and resulting in substantial socioeconomic impact. The advent of early genetic testing and the growing understanding of the molecular basis and pathophysiology of these disorders have opened avenues for novel treatment strategies. Viral vector-based gene therapies have evolved from experimental treatments for rare diseases to potent platforms that carry the intrinsic potential to provide a cure with a single application. Several gene therapy products have reached the market, and the numbers are only expected to increase. Still, none target inherited kidney diseases. Gene transfer to the kidney has lagged when compared to other tissue-directed therapies such as hepatic, neuromuscular, and ocular tissues. Systemic delivery of genetic information to tackle kidney disease is challenging. The pharma industry is taking steps to take on kidney disease and to translate the current research into the therapeutic arena. In this review, we provide an overview of the current viral vector-based approaches and their potential. We discuss advances in platforms and injection routes that have been explored to enhance gene delivery toward kidney cells in animal models, and how these can fuel the development of viable gene therapy products for humans.

(334) Worldwide Interest in Testosterone Replacement Therapy

Abstract Introduction Testosterone therapy has gained popularity in recent decades, with various methods of administration available, such as oral, topical, injection, and implantable routes. As a wider variety of treatment options arise, knowledge regarding the public interest in varying modalities may give providers an insight to patient preferences and assist in the counseling of patients seeking to initiate testosterone replacement therapy. Objective To examine public interest in the different methods of testosterone administration across the United States and compare their relative popularity to intramuscular injections. Methods Utilizing Google Trends, data pertaining to searches related to diverse testosterone administration methods were collected over a ten-year duration. The categories under analysis encompassed 1) testosterone injections, 2) implanted testosterone, 3) oral testosterone, and 4) topical testosterone. Controlled search terms, including news and weather queries, were employed. Search term trends were quantified in arbitrary units (a.u.) and plotted against the corresponding time period. Results Testosterone injection had the highest average search intent from Google Trends during the past 10 years (63.08 +/- 12.7 a.u.), followed by testosterone pills (60.56 +/- 13.4 a.u.), testosterone pellets (53.14 +/- 19.4 a.u.), testosterone patches (51.03 +/- 16.2 a.u.), and lastly testosterone gel (17.29 +/- 21.5 a.u.) A notable upward trend was recorded for all searches, with the highest increase in searches seen for implanted testosterone (m = 0.433), testosterone injections (m = 0.297), oral testosterone (m = 0.222), and lastly topical testosterone (m = 0.050) (Figure 1). Conclusions This study provides compelling evidence that all modes of testosterone administration had increasing search trends, most notably implantable testosterone therapies followed by testosterone injections, and oral testosterone, which may be in line with recent FDA approvals since 2019 for newer oral (Jatenzo, Tlando, Kyzatrex) and implantable (ex: Xyosted) options. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Antares Pharma, Clarus Therapeutics, Coloplast.

Delivery Strategies for Colchicine as a Critical Dose Drug: Reducing Toxicity and Enhancing Efficacy.

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies.

Malaria vaccine acceptance among next of kin of children under 5 years of age in Gulu, northern Uganda in 2023: a community-based study.

Malaria is a leading cause of death among children under 5 years of age in sub-Saharan Africa. The malaria vaccine is an important preventive measure introduced by the World Health Organization to reduce malaria and its associated mortality and morbidity. We aimed to assess the acceptance of the malaria vaccine among next of kin of children under 5 years of age in Gulu City, Northern Uganda. Between October and December 2023, we conducted a cross-sectional study in Pece-Laroo division, Gulu City, Uganda. Socio-demographic, vaccine profile and health system factors were collected. Multivariable logistic regression was performed using STATA 16 to determine factors associated with acceptance of the malaria vaccine among next of kin of children under 5 years. A total of 432 participants were enrolled. Of these, the majority were female (72.5%, n = 313) with most aged 30 years and above (51.2%, n = 221). Overall, 430 (99.5%) participants had good knowledge about malaria. The majority (91.4%, n = 395) had good acceptance of the malaria vaccine. Factors independently associated with acceptance of the malaria vaccine were knowing a child who died of malaria [adjusted prevalence ratio (aPR): 1.07, 95% confidence interval (CI): 1.01-1.13, p = 0.022] and preferring the injection route for a malaria vaccine (aPR: 1.1, 95% CI: 1.06-1.22, p < 0.001). All 395 participants with good knowledge of malaria had good acceptance of the malaria vaccine (p = 0.007). There was a high acceptance of the malaria vaccine in Laroo-Pece division, Gulu, Uganda. However, there is a need for further health education to achieve universal acceptability of the malaria vaccine in preparation for the malaria vaccine implementation program in Uganda.

INVEST: A phase Ib window of opportunity study of atezolizumab administered either intravesically or direct tumour injection in patients with bladder cancer prior to radical cystectomy.

TPS710 Background: High-risk non-muscle invasive bladder cancer is a common and difficult to manage disease. The treatment of choice is radical cystectomy (RC), as BCG-unresponsive tumours have a poor prognosis. RC negatively impacts health related quality of life and therefore clinicians have explored alternative treatments. The FDA approved systemic pembrolizumab for BCG-refractory carcinoma in situ, but uptake is low, reflecting concerns around efficacy and safety for a non-invasive cancer. We hypothesize that intravesical administration of a PDL1 inhibitor could be effective with less systemic toxicity. However, it is unknown whether antibodies delivered via this route can reach the tumour vasculature. INVEST is a phase Ib window of opportunity study aiming to investigate the safety and preliminary activity of both passive instillation and direct injection into the tumour/bladder wall of intravesical atezolizumab prior to RC. Methods: Eligible participants (ECOG performance status 0-2) are awaiting RC for urothelial cell carcinoma of the bladder (any stage). Those with muscle invasive cancer must be ineligible for or refuse cisplatin based neo-adjuvant chemotherapy. RC will not be delayed by study treatment. Each dose confirmation stage uses a conventional 3+3 design to establish safety based upon dose limiting toxicities. The recommended single dose will be determined first of either 600mg or 1200mg (n=3-12). This dose will then be evaluated further to determine the recommended multiple dose of either 600mg or 1200mg administered weekly for 3-6 weeks (n=3-12). A dose expansion stage will then treat 10 patients at the recommended multiple dose to further evaluate safety and toxicity. This schema will be followed independently for both the passive instillation and direct injection routes of intravesical atezolizumab administration. Efficacy signals will be explored via progression-free survival at two years and pathological complete response rate. INVEST will assess the pharmacokinetic profile of intravesical atezolizumab, anti-drug antibodies to atezolizumab. Samples are being prospectively collected for future translational research. Sampling (fresh, frozen, and FFPE blocks) of scar, tumour and background urothelium is being performed on cystectomy specimens. Tissue microarrays will be created from TURBT and cystectomy tissue. Translational samples include pre- and post-treatment blood cfDNA, PBMCs and serum and urine cfDNA. We will assess drug penetration into the bladder wall and the effects of treatment on circulating tumour cells, and local and systemic immune cell composition. Enrolment began in May 2023. This is a single-site UK-based study and we are not currently seeking additional recruiting centres. Clinical trial information: ISRCTN15842444 .

SARS-CoV2 mRNA vaccine intravenous administration induces myocarditis in chronic inflammation.

The current COVID-19 mRNA vaccines were developed and applied for pandemic-emergent conditions. These vaccines use a small piece of the virus's genetic material (mRNA) to stimulate an immune response against COVID-19. However, their potential effects on individuals with chronic inflammatory conditions and vaccination routes remain questionable. Therefore, we investigated the effects of mRNA vaccines in a mouse model of chronic inflammation, focusing on their cardiac toxicity and immunogenicity dependent on the injection route. mRNA vaccine intravenous administration with or without chronic inflammation exacerbated cardiac pericarditis and myocarditis; immunization induced mild inflammation and inflammatory cytokine IL-1beta and IL-6 production in the heart. Further, IV mRNA vaccination induced cardiac damage in LPS chronic inflammation, particularly serum troponin I (TnI), which dramatically increased. IV vaccine administration may induce more cardiotoxicity in chronic inflammation. These findings highlight the need for further research to understand the underlying mechanisms of mRNA vaccines with chronic inflammatory conditions dependent on injection routes.

Different leukocyte subsets are targeted by systemic and locoregional administration despite conserved nanomaterial characteristics optimal for lymph node delivery.

Lymph nodes (LNs) house a large proportion of the body's leukocytes. Accordingly, engineered nanomaterials are increasingly developed to direct therapeutics to LNs to enhance their efficacy. Yet while lymphatic delivery of nanomaterials to LNs upon locoregional injection has been extensively evaluated, nanomaterial delivery to LN-localized leukocytes after intravenous administration has not been systematically explored nor benchmarked. In this work, a panel of inert, fluorescent nanoscale tracers and drug delivery vehicles were utilized to interrogate intravenous versus locoregionally administered nanomaterial access to LNs and leukocyte subsets therein. Hydrodynamic size and material effects on LN accumulation extents were similar between intravenous versus intradermal injection routes. Nanomaterial distribution to various LN leukocyte subsets differed substantially with injection route, however, in a manner not proportional to total LN accumulation. While intravenously administered nanomaterials accumulated in LNs lowly compared to systemic tissues, in sharp contrast to locoregional delivery, they exhibited size-dependent but material-independent access to immune cells within the LN parenchyma, which are not easily accessed with locoregional delivery.

Supraneural transforaminal epidural injection in the treatment of radiculopathy in the lumbar spine – a brief descriptive overview and technique of manipulation

Fluoroscopy guided epidural injection is often used to treat radicular pain in the lumbar spine. Risk and effectiveness data vary depending on injection routes and underlying pathology. There are several options for accessing the epidural space in the lumbosacral spine to perform an analgesic injection – caudal, interlaminar and transforaminal. Transforaminal epidural injection is currently the most studied and widespread in the foreign practice of treating chronic pain. A brief overview describes transforaminal accesses to the epidural space of the lumbar spine and needles used for this purpose, lists possible adverse events and complications, and also provides a detailed illustrated description of supraneural transforaminal access.