Effective Route Of Administration Research Articles

Recent advances in mesenchymal stem cell therapy for myocardial infarction.

Myocardial infarction refers to the ischemic necrosis of myocardium, characterized by a sharp reduction or interruption of blood flow in the coronary arteries due to the coronary artery occlusion, resulting in severe and prolonged ischemia in the corresponding myocardium and ultimately leading to ischemic necrosis of the myocardium. Given its high risk, it is considered as one of the most serious health threats today. In current clinical practice, multiple approaches have been explored to diminish myocardial oxygen consumption and alleviate symptoms, but notable success remains elusive. Accumulated clinical evidence has showed that the implantation of mesenchymal stem cell for treating myocardial infarction is both effective and safe. Nevertheless, there persists controversy and variability regarding the standardizing MSC transplantation protocols, optimizing dosage, and determining the most effective routes of administration. Addressing these remaining issues will pave the way of integration of MSCs as a feasible mainstream cardiac treatment.

Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial.

Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707. DERR1-10.2196/53092.

On implications of somatostatin in diabetic retinopathy.

Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.

Anti-fibrotic Effect of Oral Versus Intraperitoneal Administration of Gold Nanoparticles in Hepatic Schistosoma mansoni-Infected Mice.

Schistosomiasis significantly impacts public health, as it causes severe morbidity. Infections caused by Schistosoma mansoni (S. mansoni) can be treated with gold nanoparticles (AuNPs). This study aims to determine the most effective route of AuNPs administration and the magnitude of its anti-fibrotic effect. In the five groups' in vivo assay design, AuNPs were administered intraperitoneally (1mg/kg) and orally (1mg/100g) to S. mansoni-infected mice. Biochemical parameters (serum levels of albumin and liver enzymes alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. The histological changes of the liver in distinct groups were evaluated using Hematoxylin and Eosin, Masson's trichrome, and immunohistochemical stains. Infection with S. mansoni was associated with substantial changes in the histological architecture of liver tissue and abnormal levels of hepatic function tests (albumin, AST, and ALT). Schistosoma infected hepatocytes exhibited an abnormal microscopic morphology, granuloma formation and aggressive fibrosis. AuNPs restored the liver histological architecture with a highly significant anti-fibrotic effect and significantly corrected hepatic function test levels. Intraperitoneal administration of AuNPs resulted in the most significant anti-fibrotic effect against hepatic S. mansoni infection as observed in all histological sections with Masson's trichrome being the best stain to represent this fact. For treating S. mansoni-induced chronic liver fibrosis, intraperitoneal administration of AuNPs is a successful and effective route of administration that can be recommended.

OR17-06 Clinical And Mechanistic Insight For The Therapeutic Potential Of Intranasal Kisspeptin Administration To Treat Reproductive Disorders In Humans

Abstract Disclosure: E.G. Mills: None. M. Swedrowska: None. V. Delli: None. K. Chachlaki: None. M. Silva: None. L. Decoster: None. G. Ternier: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S.A. Clarke: None. B. Muzi: None. E.C. Alexander: None. M. Choudhury: None. P. Bech: None. A. Abbara: None. B. Forbes: None. P. Giacobini: None. V. Prevot: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Kisspeptin is a key regulator of hypothalamic GnRH neurons with emerging potential to treat reproductive, psychosexual and bone disorders. However, current therapeutic application is limited to the subcutaneous or intravenous routes, which presents significant barriers to further development. Alternative delivery routes could overcome this and capitalise on the clinical utility of kisspeptin-based therapeutics. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies. Methods:Human studies: Healthy men (n=12) and a patient group of women with Hypothalamic Amenorrhoea (HA) (n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration (doses 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs 0.9% saline placebo). Plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Thereafter, we conducted rodent studies in adult C57BL/6J male mice to elucidate the possible mechanism by which intranasal kisspeptin induces reproductive hormone release, using intranasal administration of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. From a medicines development perspective, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time. Results:Human studies: in healthy men, intranasal kisspeptin dose-dependently increased plasma kisspeptin at doses 6.4-25.6nmol/kg (p<0.01 for all doses vs placebo), with the maximal rises achieved within 15-30 minutes. Correspondingly, intranasal kisspeptin acutely and potently increased serum LH at doses 6.4-25.6nmol/kg (p<0.01 all doses vs placebo) with maximal rises at 30 minutes. Likewise, in women with HA, intranasal kisspeptin acutely increased plasma kisspeptin (p=0.004 vs placebo) and serum LH (p=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C demonstrating realistic pharmaceutical potential. Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive, safe and effective kisspeptin administration route for the management of common reproductive disorders that would be far preferable to patients and clinicians and so transform the ongoing rapid development of kisspeptin-based therapeutics. Presentation: Saturday, June 17, 2023

Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound

Insulin therapy is the most effective way to control the blood glucose value of diabetic patients. The most effective administration route for insulin is subcutaneous injection because bioavailability for non-injection administration is low and unstable. However, patients often need a multiple daily insulin injection regimen to control basal and postprandial blood glucose, which causes various complications. Controlled pulsatile drug release technology using ultrasound as an external stimulus source is a very promising method to avoid multiple injections of insulin. However, most of the drug-loaded microbubbles used for ultrasound-mediated treatment have a short half-life, which limits their use in controlled pulsatile drug release. More importantly, how to control insulin release is still a challenge. In this paper, chitosan poly-acrylic acid nanobubbles as drug carriers of insulin were prepared to achieve a visually controlled pulsatile release of insulin triggered by focused ultrasound. The experimental results in vivo demonstrated that nanobubbles were stable enough to achieve long-term visualization for 7 days after intramuscular injection in rats. Under the guidance of ultrasound imaging, it is visible to find the position and observe the gray values change of nanobubbles. Thus, when triggered by focused ultrasound, the amount of insulin could be accurately pulsatile released from nanobubbles. In vivo experiments in rats showed that the visually controlled pulsatile release of insulin could be achieved for a long time, up to 3 consecutive days. The blood glucose level could be repeatedly reduced by focused ultrasound irradiation with just one injection. Our research provided a promising way for visually controlled pulsatile release of insulin, which would significantly reduce the injection frequency of insulin.

Comparative Study of Sublingual versus Rectal Route of Misoprostol Administration in Prevention of Primary Post-partum Haemorrhage in Women with Risk Factors in ESUT Teaching Hospital, Enugu, Nigeria

Background: Post-partum haemorrhage is a major cause of maternal death globally but more in low-income countries. While various studies recognized the efficacy of misoprostol in decreasing intraoperative blood loss, there is no consensus on the most effective route of administration of misoprostol. 
 Objective: This study compared the effect of sublingual misoprostol with rectal misoprostol in preventing primary post-partum haemorrhage in women with risk factor(s) to PPH. 
 Methodology: This is a comparative study that involved 200 participants who were randomized to two groups by 1:1 computer-based randomization (group A & group B). Each participant in group A received a 600mcg sublingual misoprostol plus rectal placebo, and participants in group B received a 600mcg rectal misoprostol plus sublingual placebo after delivery. The delivery mat already in use and soaked with liquor was removed once delivery was imminent, a new pre-weighed mat was replaced under the patient's buttocks, and also a pre-weighed sanitary pad was placed in her vulva to collect all the blood loss. The need for additional uterotonics and blood transfusion was assessed, and findings were documented appropriately in the proforma. Blood loss throughout a period of 24 hours after the delivery was measured by the gravimetric method. Weight gain from the sanitary pad/ delivery mat was calculated as 1g = 1 ml. The sanitary pad/mat was weighed in triplicate, and the mean of the three weights was entered into the database. The difference was the amount of blood loss, assuming 1g to be equivalent to 1 ml of blood. 
 Result: The median 24-hour post-partum blood loss was less in sublingual group when compared with the rectal group (110ml vs 170ml) P=0. 001.The mean post-partum Hb was higher in sublingual group 10.00±1.21 vs 9.00± 0.61 P=0.30. Both sublingual and rectal routes of misoprostol administration were effective in preventing PPH, P-value=1.0 and there was no indication for extra-uterotonic or blood transfusion.
 Conclusion: It is concluded that even though sublingually and rectally administered misoprostol showed equal efficacy in preventing PPH, sublingual route is associated with less blood loss.

The impact of tranexamic acid on perioperative outcomes in urological surgeries: A systematic review and meta-analysis.

Tranexamic acid (TXA) is an antifibrinolytic agent widely used in surgery to decrease bleeding and reduce the need for blood product transfusion. The role of TXA in urology is not well summarized. We conducted a systematic review of studies reporting outcomes of TXA use in urological surgery. A comprehensive search was conducted from the following databases: PubMed, Embase, Cochrane Library, and Web of Science. Two reviewers performed title and abstract screening, full text review, and data collection. Primary outcomes included estimated blood loss (EBL), decrease in hemoglobin, decrease in hematocrit, and blood transfusion rates. Secondary outcomes included TXA administration characteristics, length of stay, operative time, and postoperative thromboembolic events. A total of 26 studies consisting of 3201 patients were included in the final analysis. These included 11 studies on percutaneous nephrolithotomy, 10 on transurethral resection of the prostate, three on prostatectomy, and one on cystectomy. Estimated blood loss (EBL), transfusion rate, hemoglobin drop, operative time, and length of stay were significantly improved with TXA administration. In addition, the use of TXA was not associated with an increased risk of venous thromboembolism (VTE). The route, dosage, and timing of TXA administration varied considerably between included studies. TXA use may improve blood loss, transfusion rates, and perioperative parameters in urological procedures. In addition, there is no increased risk of VTE associated with TXA use in urological surgery; however, there is still a need to determine the most effective TXA administration route and dose. This review provides evidence-based data for decision-making in urological surgery.

A Network Meta-Analysis of Intravenous Versus Oral Acetaminophen for Patent Ductus Arteriosus.

The use of acetaminophen to close a PDA in preterm infants is increasing; however, the most effective route of administration is not yet known. This network meta-analysis compares the efficacy of IV versus PO routes of acetaminophen administration on clinical outcomes related to the presence of a PDA in preterm neonates. Medline, Embase, Cochrane Central Register of Controlled Trials, Embase, Web of Science, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched from inception to October 2020. A total 21 randomized controlled trials in neonates less than 37weeks at birth, comparing oral or intravenously administered acetaminophen to close a PDA based on study criteria were included. Two authors extracted data independently and in duplicate. All outcomes were binary, and a frequentist network meta-analysis was performed. After one or two courses, both PO and IV acetaminophen were efficacious in closing a PDA with oral ranking higher than IV (low confidence). Neither medication was better than no treatment for secondary outcomes of NEC or BPD (moderate and low confidence respectively). We did not test the rectal route of acetaminophen administration and cannot make generalized statements. This study suggests oral acetaminophen increases the odds of being able to close a PDA in preterm neonates when compared to IV acetaminophen.

A chitosan derivative-crosslinked hydrogel with controllable release of polydeoxyribonucleotides for wound treatment

Nucleic acid-based agents have advantages in therapeutic efficacy and biological safety. However, due to its facile degradability, it lacks an effective route of administration in wound treatment. Designing smart hydrogels for the spatiotemporally controllable delivery of nucleic acids is of great significance for clinical applications. Here, a near-infrared (NIR)-responsive nanocomposite hydrogel was prepared using methyl methacrylate (GMA)-modified chitosan as the macromolecular cross-linker, N-isopropylacrylamide (NIPAAm) as the backbone, and molybdenum disulfide nanosheets (MoS2 NSs) as the nanocomponents. The polydeoxyribonucleotide (PDRN), a nucleic acid-based agent that promotes tissue regeneration, was loaded and delivered. The photothermal conversion capability of MoS2 NSs enables customized care of PDRNs and antibacterial enhancement. In a full-thickness skin defect model, high-quality wound healing effects were demonstrated under the action of nanocomposite hydrogels. The proposed nanocomposite hydrogel provides a new reference for local delivery of nucleic acid-based agents.

RF34 | PMON222 Reproductive Hormone Secretion is Increased by Intranasal Kisspeptin in Humans

Abstract Background Kisspeptin is a critical activator of hypothalamic gonadotrophin releasing hormone (GnRH) neurons and has significant potential to treat common reproductive disorders. To date, kisspeptin has solely been administered to humans via the intravenous or subcutaneous routes, however intranasal administration could offer a novel non-invasive delivery route, which is preferred by patients. We therefore sought to determine the effects of intranasal kisspeptin on reproductive hormone release in humans for the first time. Methods Randomised, double-blinded, placebo-controlled, cross-over study in 12 healthy men (mean±SEM age 28.3±1.7 yrs; BMI 24.5±0.7 kg/m2). After monitored self-administration of intranasal kisspeptin-54 (3.2, 6.4, 12.8 and 25.6 nmol/kg) or 0.9% saline, serum reproductive hormone levels were measured every 15 minutes for four hours. Subsequently, four women (mean age 29.8±3.7 yrs; BMI 21.2±1.1 kg/m2) with hypothalamic amenorrhoea (HA) attended for the same protocol comparing intranasal kisspeptin-54 (12.8 nmol/kg) and 0.9% saline. Mean ±SEM was presented unless otherwise stated. Time profiles of hormone levels during the four-hour study were compared using two-way ANOVA with Bonferroni's multiple comparison test. Multiple means were compared using one-way ANOVA with Bonferroni's multiple comparison test. Results In healthy men, intranasal kisspeptin dose-dependently increased mean luteinising hormone (LH) levels at doses between 3.2-12.8 nmol/kg (p=0.008 and <0.0001 for 6.4 and 12.8 nmol/kg vs saline, respectively), with the maximal rises occurring at 30-45 minutes post-administration. Correspondingly, the area under the curve (AUC) for the LH change was significantly elevated following all doses of kisspeptin compared to saline (saline: -25.4±70.5 h.IU/L; 3.2 nmol/kg: 172.2±64.2 h.IU/L [p=0.03]; 6.4 nmol/kg: 300.2±79.2 h.IU/L [p=0.002]; 12.8 nmol/kg: 595.7±98.3 h.IU/L [p=0.001]; 25.6 nmol/kg: 549.0±108.6 h.IU/L [p<0.0001]). Follicle stimulating hormone (FSH) levels followed a similar trajectory to LH in response to intranasal kisspeptin. Moreover, kisspeptin at 12.8 nmol/kg increased serum testosterone from 120 minutes onwards (p=0.02), with a maximal change from baseline of 4.9±0.7 nmol/L (p=0.03). In women with HA, intranasal kisspeptin increased mean LH (p=0.002 vs saline), with the peak levels occurring at 30-45 minutes post-administration. The AUC for the LH change was 508.4±77.5 h.IU/L (p=0.02 vs saline AUC for LH). The maximal LH change from baseline was 4.1±0.9 IU/L compared to 0.2±0.4 IU/L for saline (p=0.03). Intranasal kisspeptin increased mean FSH (p=0.01 vs saline). No significant changes in downstream serum oestradiol or progesterone were observed during the acute four-hour study. Conclusion We report the first investigation of the effects of intranasal kisspeptin delivery on reproductive hormone release in humans. Our results demonstrate that intranasal kisspeptin robustly and dose-dependently stimulates reproductive hormone release in healthy men and crucially in a patient-group of women with hypogonadism. Given the ongoing development of kisspeptin therapeutics, intranasal kisspeptin therefore offers a novel, safe, effective and non-invasive route of administration for the management of reproductive disorders. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:36 p.m. - 12:41 p.m.

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep.

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

Intranasal administration of a single dose of MVA-based vaccine candidates against COVID-19 induced local and systemic immune responses and protects mice from a lethal SARS-CoV-2 infection

Current coronavirus disease-19 (COVID-19) vaccines are administered by the intramuscular route, but this vaccine administration failed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection in the upper respiratory tract, mainly due to the absence of virus-specific mucosal immune responses. It is hypothesized that intranasal (IN) vaccination could induce both mucosal and systemic immune responses that blocked SARS-CoV-2 transmission and COVID-19 progression. Here, we evaluated in mice IN administration of three modified vaccinia virus Ankara (MVA)-based vaccine candidates expressing the SARS-CoV-2 spike (S) protein, either the full-length native S or a prefusion-stabilized [S(3P)] protein; SARS-CoV-2-specific immune responses and efficacy were determined after a single IN vaccine application. Results showed that in C57BL/6 mice, MVA-based vaccine candidates elicited S-specific IgG and IgA antibodies in serum and bronchoalveolar lavages, respectively, and neutralizing antibodies against parental and SARS-CoV-2 variants of concern (VoC), with MVA-S(3P) being the most immunogenic vaccine candidate. IN vaccine administration also induced polyfunctional S-specific Th1-skewed CD4+ and cytotoxic CD8+ T-cell immune responses locally (in lungs and bronchoalveolar lymph nodes) or systemically (in spleen). Remarkably, a single IN vaccine dose protected susceptible K18-hACE2 transgenic mice from morbidity and mortality caused by SARS-CoV-2 infection, with MVA-S(3P) being the most effective candidate. Infectious SARS-CoV-2 viruses were undetectable in lungs and nasal washes, correlating with high titers of S-specific IgGs and neutralizing antibodies against parental SARS-CoV-2 and several VoC. Moreover, low histopathological lung lesions and low levels of pro-inflammatory cytokines in lungs and nasal washes were detected in vaccinated animals. These results demonstrated that a single IN inoculation of our MVA-based vaccine candidates induced potent immune responses, either locally or systemically, and protected animal models from COVID-19. These results also identified an effective vaccine administration route to induce mucosal immunity that should prevent SARS-CoV-2 host-to-host transmission.

Healthcare practitioner perceptions on barriers impacting cannabis prescribing practices

BackgroundCanadians seeking medical cannabis (MC) may encounter difficulties in finding a healthcare provider (HCP) who authorizes their access to it. Barriers that HCPs face in authorizing MC are unclear. The objectives of this study were to evaluate HCP opinions, knowledge, comfort, and practice in MC prescribing and counseling on recreational cannabis use, and whether the COVID-19 pandemic affected MC prescribing practices.MethodsEligible participants included HCPs (e.g., attending physicians, nurses, pharmacists) in Canada. A questionnaire evaluating their knowledge, comfort, and practice in medical and recreational cannabis was designed based on instruments developed in previous studies. Between April 13th-December 13th 2021, ninety-one healthcare associations were asked to distribute the survey to their members, and an advertisement was placed in the online Canadian Medical Association Journal. Descriptive statistics were used to analyze the results.ResultsTwenty-four organizations agreed to disseminate the survey and 70 individuals completed it. Of respondents, 71% were attending physicians or medical residents, while the remainder were nurses, pharmacists or other HCPs. Almost none (6%) received training in MC in professional school but 60% did receive other training (e.g., workshops, conferences). Over half (57%) received more questions regarding MC since recreational cannabis was legalized, and 82% reported having patients who use MC. However, 56% felt uncomfortable or ambivalent regarding their knowledge of MC, and 27% were unfamiliar with the requirements for obtaining MC in Canada. The most common symptoms for recommending MC were pain and nausea, whereas the most common conditions for recommending it were cancer and intractable pain. The strongest barrier to authorizing MC was uncertainty in safe and effective dosage and routes of administration. The strongest barrier to recommending or authorizing MC was the lack of research evidence demonstrating its safety and efficacy. During the pandemic, many respondents reported that a greater number of their patients used cannabis to relieve anxiety and depression.ConclusionsOur results suggest that HCPs across Canada who responded to our survey are unfamiliar with topics related to MC. The strongest barriers appear to be lack of clinical research, and uncertainty in safe and effective MC administration. Increasing research, training, and knowledge may help HCPs feel more equipped to make informed treatment/prescribing decisions, which may help to improve access to MC.

Comparison of vaginal and buccal misoprostol after mifepristone for medication abortion through 70 days of gestation: A retrospective chart review

ObjectiveTo determine the proportion of complete abortion without surgical intervention for patients who chose medication abortion with vaginal compared to buccal misoprostol following oral mifepristone through 70 days of gestation. MethodsWe performed a retrospective cohort study. We reviewed charts via electronic medical record data abstraction of patients receiving medication abortion with mifepristone and buccal or vaginal misoprostol between September 1, 2017 and August 1, 2019. Primary outcome was complete abortion without surgical intervention for any indication. Secondary outcomes were ongoing pregnancy and uterine aspiration for indications other than ongoing pregnancy. ResultsThere were 14,504 encounters included in the data set. Of the 4814 patients who took vaginal misoprostol and the 4011 patients who took buccal misoprostol for whom follow up data is available, 4640 (96.4%) and 3917 (97.7%) had a complete abortion without surgical intervention, respectively (p = 0.002). At <64 days of gestation, complete abortion was 96.6% for vaginal administration compared to 98.0% for buccal (p = 0.001). At 64 to 70 days of gestation, complete abortion was 92.7% for vaginal administration compared to 93.2% for buccal (p = 0.08). Of the 1128 patients who took vaginal misoprostol at less than 6 hours after mifepristone, 95.3% experienced a complete abortion. ConclusionBuccal administration of misoprostol is associated with a higher proportion of complete abortion before 64 days of gestation compared to vaginal misoprostol. Clinically, vaginal misoprostol is an effective route of administration through 70 days of gestation. ImplicationsMedication abortion with vaginal misoprostol is effective when administered through 70 days of gestation and with shorter intervals between mifepristone and misoprostol. Prospective research to better estimate effectiveness is warranted. Expanding medication abortion options promotes patient autonomy amid increasing restrictions and bans on abortion.

Synthesis of selenium nanoparticles with the use of "green" technologies

Traditional selenium supplements are usually highly toxic and have low levels of absorption, so developing systems that are using selenium compounds as a carrier to increase the bioavailability of the element and control its release in the body is extremely important. Nano-sized selenium is of great interest as a dietary supplement, especially in selenium-deficient states, as well as as a therapeutic agent without significant adverse effects. Emphasis is placed on the incorporation of nanotechnologi cal applications, the study of an effective route of administration, and generalized knowledge about selenium nanoparticles, their biological effects and advantages, and mechanisms of absorption. Nanotechnical modifications of nanoparticles, the use of SeNPs as a nutritional supplement, and the effects they exert on the body are considered. Various methods for the synthesis of SeNPs are considered. The study focuses on the problems of traditional forms of dietary selenium and the benefits of SeNPs. The mechanisms of nanoparticles passage through the intestinal mucosa and the features of their oral administration are elucidated. The presented materials prove that the importance of Selenium lays on regulation in the composition of selenoproteins of many physiological processes, influence on the productive and reproductive properties. Correction of selenium content in the diet prevents a number of selenium deficiency diseases, and selenium in nano form is most appropriate for use because of its high bioavailability and low toxicity, which is especially relevant for ruminants. Further preclinical and clinical studies in vitro and in vivo will enable the development of novel nanopreparative systems for transport in selenium, alter the physicochemical properties of SeNPs, increase their stability in the gastrointestinal tract for controlled release of the element to provide dietary and therapeutic benefits. Key words: nanoparticles, selenium, biomedicine, oxidative stress, biomedical application of nanoparticles.

In Silico Prediction of Skin Permeability Using a Two-QSAR Approach.

Topical and transdermal drug delivery is an effective, safe, and preferred route of drug administration. As such, skin permeability is one of the critical parameters that should be taken into consideration in the process of drug discovery and development. The ex vivo human skin model is considered as the best surrogate to evaluate in vivo skin permeability. This investigation adopted a novel two-QSAR scheme by collectively incorporating machine learning-based hierarchical support vector regression (HSVR) and classical partial least square (PLS) to predict the skin permeability coefficient and to uncover the intrinsic permeation mechanism, respectively, based on ex vivo excised human skin permeability data compiled from the literature. The derived HSVR model functioned better than PLS as represented by the predictive performance in the training set, test set, and outlier set in addition to various statistical estimations. HSVR also delivered consistent performance upon the application of a mock test, which purposely mimicked the real challenges. PLS, contrarily, uncovered the interpretable relevance between selected descriptors and skin permeability. Thus, the synergy between interpretable PLS and predictive HSVR models can be of great use for facilitating drug discovery and development by predicting skin permeability.

Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy.

Novel effective therapeutic strategies are needed to treat brain neurodegenerative diseases and to improve the quality of life of patients affected by Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral sclerosis (ALS) as well as other brain conditions. At present no effective treatment options are available; current therapeutics for neurodegenerative diseases (NDs) improve cognitive symptoms only transiently and in a minor number of patients. Further, most of the amyloid-based phase III clinical trials recently failed in AD, in spite of promising preclinical and phase I-II clinical trials, further pinpointing the need for a better knowledge of the early mechanisms of disease as well as of more effective routes of drug administration. In fact, beyond common pathological events and molecular substrates, each of these diseases preferentially affect defined subpopulations of neurons in specific neuronal circuits (selective neuronal vulnerability), leading to the typical age-related clinical profile. In this perspective, key to successful drug discovery is a robust and reproducible biological validation of potential new molecular targets together with a concomitant set up of protocols/tools for efficient and targeted brain delivery to a specific area of interest. Here we propose and discuss Focused UltraSound aided drug administration as a specific and novel technical approach to achieve optimal concentration of the drug at the target area of interest. We will focus on drug delivery to the brain through the nasal route coupled to FUS as a promising approach to achieve neuroprotection and rescue of cognitive decline in several NDs.

Synthesis and Characterization of Fatty Acid Grafted Chitosan Polymeric Micelles for Improved Gene Delivery of VGF to the Brain through Intranasal Route.

Multifunctional fatty acid grafted polymeric micelles are an effective and promising approach for drug and gene delivery to the brain. An alternative approach to bypass the blood–brain barrier is administration through intranasal route. Multifunctional fatty acid grafted polymeric micelles were prepared and characterized for pVGF delivery to the brain. In vitro pVGF expression was analyzed in bEnd.3 cells, primary astrocytes, and neurons. Comparative in-vivo pVGF expression was analyzed to evaluate the effective route of administration between intranasal and intravenous. Biocompatible, multifunctional polymeric micelles were prepared, having an average size of 200 nm, and cationic zeta potential. Modified polymers were found to be hemo- and cyto-compatible. When transfected with the different modified chitosan formulations, significantly (p < 0.05) higher VGF expression was observed in primary astrocytes and neurons using the mannose, Tat peptide, and oleic acid grafted chitosan polymer. Compared to intravenous administration, intranasal administration of pVGF in polyplex formulation led to significantly (p < 0.05) higher pVGF expression. Developed multifunctional polymeric micelles were an effective pVGF delivery platform to the brain. Mannose and Tat ligand tagging improved the pVGF delivery to the brain.

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice.

Viral-mediated gene augmentation, silencing, or editing offers tremendous promise for the treatment of inherited and acquired deafness. Inner-ear gene therapies often require a safe, clinically useable and effective route of administration to target both ears, while avoiding damage to the delicate structures of the inner ear. Here, we examined the possibility of using a cisterna magna injection as a new cochlear local route for initiating binaural transduction by different serotypes of the adeno-associated virus (AAV2/8, AAV2/9, AAV2/Anc80L65). The results were compared with those following canalostomy injection, one of the existing standard inner ear local delivery routes. Our results demonstrated that a single injection of AAVs enables high-efficiency binaural transduction of almost all inner hair cells with a basal-apical pattern and of large numbers of spiral ganglion neurons of the basal portion of the cochlea, without affecting auditory function and cochlear structures. Taken together, these results reveal the potential for using a cisterna magna injection as a local route for binaural gene therapy applications, but extensive testing will be required before translation beyond mouse models.