Establishment of an Olfactory Region-specific Intranasal Delivery Technique in Mice to Target the Central Nervous System

We have recently developed a region-specific catheter-based intranasal application method in mice by using CT scan-based 3D cast models of the murine nose (DOI: 10.2376/0005-9366-17,102). This technique is able to specifically deliver drugs to the olfactory region or to the respiratory region only. Thereby, intranasally administered drugs could be delivered either via neuronal connections to the central nervous system or via the well-perfused rostral parts of the nasal mucosa to the systemic circulation. In the present study, we transferred successfully this novel delivery technique to C57Bl/6 mice and determined parameters such as insertions depth of the catheter and maximum delivery volume in dependence to the weight of the mouse. Breathing was simulated to verify that the volume remains at the targeted area. A step-by-step procedure including a video is presented to adopt this technique for standardized and reproducible intranasal central nervous system (CNS) delivery studies (DOI: 10.3390/pharmaceutics13111904).

Characterization and Design for Last Mile Logistics: A Review of the State of the Art and Future Directions

One of the most challenging problems in last mile logistics (LML) has been the strategic delivery due to various market risks and opportunities. This paper provides a systematic review of LML-related studies to find current issues and future opportunities for the LML service industry. To that end, 169 works were selected as target studies for in-depth analysis of recent LML advances. First, text mining analysis was performed to effectively understand the underlying LML themes in the target studies. Then, the novel definition and typology of LML delivery services were suggested. Finally, this paper proposed the next generation of LML research through advanced delivery technique-based LML services, environmentally sustainable LML systems, improvement of LML operations in real industries, effective management of uncertainties in LML, and LML delivery services for decentralized manufacturing services. We believe that this systematic literature review can serve as a useful tool for LML decision makers and stakeholders.

Implementation of Video Feedback Within a Community Based Naturalistic Developmental Behavioral Intervention Program for Toddlers With ASD: Pilot Study

Video feedback (VF) is an intervention delivery technique that complements naturalistic developmental behavioral interventions (NDBI) and parent-mediated interventions (PMI) by using caregiver-child interaction videos reviewed with a clinician to facilitate behavioral change in caregivers. Although VF has been implemented in PMI with young children with ASD, examinations of feasibility and acceptability, as well as the potential effectiveness of VF in community settings, have been limited. In this pilot randomized control trial (NCT03397719; https://clinicaltrials.gov/ct2/show/NCT03397719), families were randomized into a state-funded Early Intervention (EI) NDBI program or the NDBI program augmented with VF. Results demonstrated high levels of implementation and acceptability of VF augmenting the community-based EI program in caregivers and clinicians. Both groups showed significant improvements after 6 months in social communication symptoms and some areas of developmental and adaptive skills.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03397719, identifier: NCT03397719.

The Mediating Effect of Intention to Use on the Relationship between Mobile Learning Application and Knowledge and Skill Usage

Mobile learning (m-learning) has evolved as an alternative way of training delivery in a variety of businesses and sectors. Mobile device technology is continuously developing and improving, resulting in more mobile device use. In a corporate setting, the usage of mobile devices as learning aids has become a new delivery technique. Telekom Malaysia (TM) has also adopted this learning tool for staff training. This research has been conducted to determine the mediating effect of intention to use on the relationship between mobile learning applications and knowledge and skill usage. There are five objectives for this research. Hypotheses have been generated to be tested according to the Technology Acceptance Model (TAM) and Kirkpatrick Evaluation Model. The questionnaire was used for data collection. SmartPLS version 3.2.8 and IBM SPSS Statistics version 26 statistical software were used in the analysis. The finding revealed that there was an effect of perceived ease of use (PEOU) and perceived usefulness (PU) on TM employee knowledge and skill usage. In addition, the study also found there was a mediating effect of Intention to Use (ITU) on the relationship between PEOU and PU with TM employee knowledge and skill usage.

Even experts cannot agree on the optimal use of platelet-rich plasma in lateral elbow tendinopathy: an international Delphi study

Background Platelet-rich plasma (PRP) is widely used in the management of lateral elbow tendinopathy (LET) despite conflicting evidence on its effectiveness. With high levels of user experience, this study aimed to assess consensus amongst experts on its clinical use. Methods A three-round international Delphi study was conducted. Participants were invited through national society mailing lists and contact lists derived from a systematic search of the literature on PRP. In round one, a primary working group developed 40 statements on PRP preparation and clinical application. In rounds two and three, an international group of researchers on PRP and clinical users of the device scored their levels of agreement with the statements on a five-point scale. Consensus was defined as an interquartile range of ≤ 1. Results Consensus of agreement was only reached for 17/40 (42.5%) statements. For statements on PRP formulation, consensus of agreement was reached in 2/6 statements (33%). Only limited consensus on the contraindications, delivery strategy and delivery technique was achieved. Conclusion Experts reached very limited consensus on the use of PRP in LET. High levels of user experience have not resulted in a convergence of opinion on the technical components of PRP formulation and delivery, substantiating the need for further studies and improved trial reporting.

Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa

Intranasal drug delivery is a promising approach for the delivery of drugs to the CNS, but too heterogenous, unprecise delivery methods without standardization decrease the quality of many studies in rodents. Thus, the lack of a precise and region-specific application technique for mice is a major drawback. In this study, a previously developed catheter-based refined technique was validated against the conventional pipette-based method and used to specifically reach the olfactory or the respiratory nasal regions. This study successfully demonstrated region-specific administration at the olfactory mucosa resulting in over 20% of the administered fluorescein dose in the olfactory bulbs, and no peripheral bioactivity of insulin detemir and Fc-dependent uptake of two murine IgG1 (11C7 and P3X) along the olfactory pathway to cortex and hippocampus. An scFv of 11C7 showed hardly any uptake to the CNS. Elimination was dependent on the presence of the IgG’s antigen. In summary, it was successfully demonstrated that region-specific intranasal administration via the olfactory region resulted in improved brain targeting and reduced peripheral targeting in mice. The data are discussed with regard to their clinical potential.

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

Formulation and Evaluation of Topical Microemulgel Containing Terbinafine Hydrochloride

The purpose of this study is to create and test a Terbinafine hydrochloride microemulgel. Terbinafine hydrochloride is an FDA-approved antifungal medication used to treat fungal infections on the skin. It's a BCS class II medication with little bioavailability. In the realm of pharmaceutical sciences, microemulgel has evolved into one of the most intriguing topical preparations. Microemulgel as a delivery technique has several advantages over simple traditional formulations, including simplicity of administration, increased residence duration at the application site, consistent drug release with improved bioavailability, superior thermodynamic stability, and excellent transdermal permeability. Terbinafine hydrochloride microemulgels were made with carbopol 940 and HPMC as gelling agents, oleic acid as an oil, parabens as a preservative, and tween 20 as an emulgent and penetration enhancer. The appearance, spreadability, homogeneity, viscosity, pH, percent drug content, and in vitro diffusion studies of the generated microemulgel formulation were all visually checked. The findings show that developing a terbinafine-containing microemulgel is more effective, but clinical efficacy must be determined through clinical trials.

TOTAL ABDOMINAL HYSTERECTOMY FOLLOWED BY BILATERAL SALPINGO-OOPHORECTOMY AND SUBMUCOUS FIBROID REMOVAL

There was abnormal uterine bleeding and recurrent lower abdominal pain in a 50 year-old female. A bilateral salpingo-oophorectomy is surgery to extract ovaries and fallopian tubes of both the sides. By the age of 60, more than a third of women in the US have had a hysterectomy. The expected anatomy, the patient's body habits, the degree of pelvic relaxation, the need for concurrent abdominal and vaginal procedures, and the surgeon's expertise all play a role in deciding the uterus delivery technique and route. The hysterectomy and bilateral salpingo-oophorectomy will both be done during one procedure. The uterus, ovaries, cervix & fallopian tubes are remove through surgery. For a large sub mucous fibroid uterus, the patient opted to have a complete abdominal hysterectomy along bilateral salpingo-oophorectomy. Abdominal hysterectomy & bilateral salpingo-oophorectomy were performed in midline vertical incision under general anesthesia. A uterus with sub mucous fibroid (polyps) was confirmed by pathology. The option of surgical method in a hysterectomy based on clinical conditions, the professional skill of the surgeon, and the preference of patients. As this case indicates, for many patients, abdominal hysterectomy is an important choice where the use of other methods may pose a serious danger. This method may be sufficient for the treatment of sub-mucous fibroids. There are broad range of studies that demonstrate beneficial effects in the various therapies created, serving as a basis for guiding physiotherapeutic approaches in hysterectomy, aiming at complementary tools for better treatment of the patient undergoing this procedure.