Parenteral Injection Research Articles

Seizure solver- pyridoxine dependent seizures

Pyridoxine dependency is a rare cause of seizures. Pyridoxine dependent seizures (PDS) occur despite normal vitamin B6 levels and is due to defective binding of pyridoxine to its apoenzyme, glutamate decarboxylase, which converts glutamic acid to gamma aminobutyric acid (GABA). Pyridoxine-dependent seizure is a rare autosomal recessive disorder that usually presents with neonatal intractable seizures. Parenteral pyridoxine injection test is a highly effective and reproducible test in confirming the diagnosis. Hunt, et al.(l) described the first case of PDS with autosomal recessive inheritance. Since then, several cases have been reported with onset of seizures after neonatal period (2-6). Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medication that are responsive clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). This is true across a phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1. Intellectual disability is common, particularly in classic PDE-ALDH7A1.(7)

Microneedles with Implantable Tip-Accumulated Therapeutics for the Long-Term Management of Psoriasis.

Methotrexate is successfully used as the gold standard for managing moderate-to-severe psoriasis. However, the low bioavailability and short half-life of the oral pills and the invasiveness of the parenteral injections make these suboptimal therapeutic options. Microneedles, bridging the advantages of the former forms, are successfully used to deliver methotrexate for different therapeutic purposes. However, the utilized dissolving microneedles demand frequent administration, potentially compromising patients' compliance. Additionally, the high toxicity of methotrexate prompts a quest for safer alternatives. Phloretin, a natural compound with confirmed antipsoriatic potential, emerges as a promising candidate. Herein, microneedle patches with separable, slow-degrading tips are developed for the sustained delivery of methotrexate and phloretin, as a comprehensive solution for long-term psoriasis management. Both compounds are individually loaded at varying doses and display sustained-release profiles. The developed microneedle patches demonstrate high mechanical strength, favorable drug delivery efficiency, and remarkable antipsoriatic potential both in vitro in keratinocytes and in vivo in a psoriasis mouse model. Comparative analysis with two subcutaneous injections reveals a similar antipsoriatic efficacy with a single patch of either compound, with prominent phloretin safety. Therefore, the developed patches present a superior alternative to methotrexate's current marketed forms and provide a viable alternative (phloretin) with comparable antipsoriatic efficacy and higher safety.

Preparation and characterization of BSA-loaded liraglutide and platelet fragment nanoparticle delivery system for the treatment of diabetic atherosclerosis

BackgroundDiabetic atherosclerosis is one of the main causes of morbidity and mortality worldwide, but its therapeutic options are limited. Liraglutide (LIR), a synthetic analog of GLP-1 approved as an anti-obesity drug by the FDA, has been reported as a promising drug for diabetic atherosclerosis. However, the main problem with LIR is its use that requires regular parenteral injections, which necessitates the improvement of drug delivery for increased efficiency and minimization of injection numbers.ResultsThe objective of our present study was to prepare and characterize nanoparticles (BSA@LIR-PMF) for targeted drug delivery using LIR-encapsulated platelet membrane fragments (PMF) coated bovine serum albumin (BSA). We used various methods to characterize the prepared nanoparticles and evaluated their efficiency on diabetes-induced atherosclerosis in vitro and in vivo. The results showed that the nanoparticles were spherical and had good stability and uniform size with intact membrane protein structure. The loading and encapsulation rates (LR and ER) of BSA@LIR-PMF were respectively 7.96% and 85.56%, while the cumulative release rate was around 77.06% after 24 h. Besides, we also examined the impact of BSA@LIR-PMF on the proliferation, migration, phagocytosis, reactive oxygen species (ROS) levels, oxidative phosphorylation, glycolysis, lactate and ATP levels, and lipid deposition in the aortas. The results indicated that BSA@LIR-PMF could effectively inhibit ox-LDL-stimulated abnormal cell proliferation and migration, reduce the level of ROS and lactate concentration, and enhance the level of ATP, thereby improving oxidative phosphorylation in ox-LDL-treated cells.ConclusionBSA@LIR-PMF significantly inhibited diabetes-induced atherosclerosis. It was anticipated that the BSA@LIR-PMF nanoparticles might be used for treating diabetes-associated cardiovascular complications.

Examination of Particulate Contamination in Parenteral Injections and Infusions Following Fluid Withdrawal Utilizing Conventional Needles and Filter Needles: Assessment of Compliance and Comparative Analysis

Particulate contamination, the unintentional presence of particles in parenteral fluids, is associated with potential risks such as phlebitis and thrombophlebitis. Recent guidelines recommend the use of filter needles when withdrawing parenteral fluid from vials with a rubber stopper. However, the literature is limited and lacks clarity regarding the advantages of filter needles over conventional needles. The aim of this study was to assess the compliance of parenteral fluids regarding particulate contamination after withdrawing fluid using both conventional needles and filter needles, following the guidelines of European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP). Visible particles were counted through visual inspection and sub-visible particles were quantified utilizing the light obscuration particle count test. Particle counts for both types of needles were compared to Ph. Eur. and USP standards and differences in particle contamination were assessed using a Mann-Whitney U test. Both types of needles demonstrated compliance with Ph. Eur. and USP standards regarding particulate contamination of visible and sub-visible particles. However, filter needles exhibited a significantly higher particle count for particles with a size of ≥25 µm compared to conventional needles (p = 0.0029). In conclusion, both types of needles demonstrate suitability for aspirating fluid from vials featuring rubber stoppers regarding particulate contamination. Nevertheless, non-filter needles are preferred for withdrawing fluid from vials with a rubber stopper over filter needles due to their lower cost.

An Evaluation of a Parenteral Antibiotic Treatment of Cattle with Non-Healing Claw Horn Lesions.

Non-healing claw horn disorders are a serious problem in dairy herds because of the long duration of the disorder and the chronic pain derived from it, seriously affecting animal welfare and causing decreased production and premature culling from the herd. In a clinical trial, 40 cows in 13 herds (12 dairy herds and 1 herd with cow-calf operations) with toe necrosis (TN, 27x) or a non-healing white line disorder (NHWLD, 13x) were treated topically with an unguent-containing zinc sulphate and acetyl acid in combination with a parenteral injection of tilmycosin. An evaluation was conducted 3 months after treatment using locomotion scoring (LS), a clinical observation of the lesion, and the lactation value (the lactation value is the Net Profit of the individual animal divided by the average Net Profit of the entire herd. The mean is 100, so >100 is related to better production (combination of kg milk, %fat, and protein)) (LV) before and after treatment. The mean LS improved significantly from 4.0 (SD: 0.2) before treatment to 1.2 (SD: 0.4) 3 months after treatment (p < 0.001). The clinical presentation showed that all of the cows were cured from horn shoe infection (both TN and NHWLD). The LVs of the treated cows increased significantly from 111.2 (SD: 12.2) to 116.8 (SD: 15.1; p = 0.003).

Exploring experiences of patients with adrenal insufficiency (AI) using parenteral hydrocortisone injection device to manage adrenal crisis: a qualitative interview study

Exploring experiences of patients with adrenal insufficiency (AI) using parenteral hydrocortisone injection device to manage adrenal crisis: a qualitative interview study

Novel protocol for multiple-dose oral administration of the L-type Ca2+ channel blocker isradipine in mice: A dose-finding pharmacokinetic study

ABSTRACT Studies in genetically modified animals and human genetics have recently provided new insight into the role of voltage-gated L-type Ca2+ channels in human disease. Therefore, the inhibition of L-type Ca2+ channels in vivo in wildtype and mutant mice by potent dihydropyridine (DHP) Ca2+ channel blockers serves as an important pharmacological tool. These drugs have a short plasma half-life in humans and especially in rodents and show high first-pass metabolism upon oral application. In the vast majority of in vivo studies, they have therefore been delivered through parenteral routes, mostly subcutaneously or intraperitoneally. High peak plasma concentrations of DHPs cause side effects, evident as DHP-induced aversive behaviors confounding the interpretation of behavioral readouts. Nevertheless, pharmacokinetic data measuring the exposure achieved with these applications are sparse. Moreover, parenteral injections require animal handling and can be associated with pain, discomfort and stress which could influence a variety of physiological processes, behavioral and other functional readouts. Here, we describe a noninvasive oral application of the DHP isradipine by training mice to quickly consume small volumes of flavored yogurt that can serve as drug vehicle. This procedure does not require animal handling, allows repeated drug application over several days and reproducibly achieves peak plasma concentrations over a wide range previously shown to be well-tolerated in humans. This protocol should facilitate ongoing nonclinical studies in mice exploring new indications for DHP Ca2+ channel blockers.

Investigation into the safety, and serological responses elicited by delivery of live intranasal vaccines for bovine herpes virus type 1, bovine respiratory syncytial virus, and parainfluenza type 3 in pre-weaned calves.

Despite the fact that pneumonia remains a leading cause of mortality and morbidity in pre-weaned calves, relatively little is known regarding the effects of the concurrent administration of intranasal pneumonia virus vaccines, particularly in calves with high levels of maternally derived antibodies. The objective of this study was to use a cohort of 40 dairy and dairy-beef female and male calves (27 females and 13 males) to determine serological responses to concurrent administration at 3 weeks of age (22 ± 4.85 days) of two commercially available intranasal (IN) vaccines for the viruses: bovine respiratory syncytial virus (BRSV), bovine herpes virus 1 (BoHV-1), and parainfluenza-3-virus (PI3-V). The study groups were as follows: (i) Bovilis IBR Marker Live only® (IO), (ii) Bovilis INtranasal RSP Live® only (RPO), (iii) Concurrent vaccination with Bovilis IBR Marker Live® & Bovilis Intranasal RSP Live® (CV), and (iv) a control group of non-vaccinated calves (CONT). The calves' serological response post-IN vaccination, clinical health scores, rectal temperatures, and weights were measured. Data were analyzed in SAS using mixed models and logistic regression. The CV calves had an average daily weight gain (ADG) of 0.74 (±0.02) kg, which was similar to CONT (0.77 ± 0.02 kg). Despite no significant differences in the antibody levels between study groups 3 weeks post-IN vaccination, following the administration of subsequent parenteral injections in the form of Bovilis Bovipast RSP®(antigens; inactivated BRSV, inactivated PI3-V, inactivated Mannheimia haemolytica) and Bovilis IBR Marker Live®, the antibody levels of the BRSV and PI3-V increased in both the CV and RPO study groups. Concurrent vaccination resulted in no increase in fever and no difference in health scores when compared to CONT.

Assessing Abuse-Deterrent formulations utilizing Ion-Exchange resin complexation processed via Twin-Screw granulation for improved safety and effectiveness

Opioid misuse is a public health crisis in the United States. In response, the FDA has approved drug products with abuse-deterrent features to reduce the risk of prescription opioid abuse. Abuse-deterrent formulations (ADFs) typically employ physical or chemical barriers or incorporate agonist–antagonist combinations as mechanisms to deter misuse. This study aims to assess the impact of abuse-deterrent properties, specifically ion-exchange resin complexation as a chemical barrier, on a model drug, promethazine hydrochloride (PMZ) tablets. Various formulations were developed through twin-screw wet granulation (TSWG) followed by twin-screw melt granulation (TSMG). In the TSWG process, the drug interacts with the resin through an exchange reaction, forming a drug-resin complex. Additionally, the study explored factors influencing the complex formation between the drug and resin, using the drug loading status as an indicator. DSC and ATR studies were carried out to confirm the formation of the drug-resin complex. Subsequently, hot melt granulation was employed to create a matrix tablet incorporating Kollidon® SR and Kollicoat® MAE 100P, thereby enabling sustained release properties. The drug-resin complex embedded in the matrix effectively deters abuse through methods like smoking, snorting, or parenteral injection, unless the drug can be extracted. In order to assess this, solvent extraction studies were conducted using an FDA-recommended solvents, determining the potential for abuse. Further investigations involved dissolution tests in change-over media, confirming the extended-release properties of the formulation. Results from dissolution studies comparing the ground and intact tablets provided positive evidence of the formulation's effectiveness in deterring abuse. Finally, alcohol-induced dose-dumping studies were conducted in compliance with FDA guidelines, concluding that the formulation successfully mitigates dose dumping in the presence of alcohol.

Pain-free oral delivery of biologic drugs using intestinal peristalsis-actuated microneedle robots.

Biologic drugs hold immense promise for medical treatments, but their oral delivery remains a daunting challenge due to the harsh digestive environment and restricted gastrointestinal absorption. Here, inspired by the porcupinefish's ability to inflate itself and deploy its spines for defense, we proposed an intestinal microneedle robot designed to absorb intestinal fluids for rapid inflation and inject drug-loaded microneedles into the insensate intestinal wall for drug delivery. Upon reaching the equilibrium volume, the microneedle robot leverages rhythmic peristaltic contraction for mucosa penetration. The robot's barbed microneedles can then detach from its body during peristaltic relaxation and retain in the mucosa for drug releasing. Extensive in vivo experiments involving 14 minipigs confirmed the effectiveness of the intestinal peristalsis for microrobot actuation and demonstrated comparable insulin delivery efficacy to subcutaneous injection. The ingestible peristalsis-actuated microneedle robots may transform the oral administration of biologic drugs that primary relies on parenteral injection currently.

Evaluation of parenteral injection skills of medical undergraduates on mannequins in a tertiary care teaching hospital in South India – A cross-sectional study

Abstract Appropriate knowledge and expertise of parenteral injection is vital in the medical field. Hence we impart training on mannequins before the students practice on patients. This study was conducted to evaluate the skill exhibited by the students in parenteral injection skills, namely intravenous, intramuscular, intradermal and subcutaneous injections. The students were assessed for step based on the pre-validated check list created for Objective Structured Practical Examination. In this study, 16 % of the students failed to check the prescription order before starting the procedure. The name and the expiry date of the drug was not checked by 22 % of the students. Hundred percent of the students sterilized their hands. Loading of drug was done properly by 80 % of the students and 88 % of the students checked for air bubbles in the syringe and removed them properly. The site for injection was not sterilized by 26 percent of the students. Tourniquet was not applied by 19 percent of the students and 28 % of the students did not hold the bevel up during insertion for intravenous route. The steps where frequent faltering happened needs to be emphasized for them to perform better in a more efficient manner during the summative assessment as well as for future practice.

Iatrogenic Hyperhydration in Sickle Cell Disease Patients Admitted for Acute Pain Crisis Management: A Retrospective Analysis from a Single Institution

Background: Parenteral fluids are an important component of acute pain crisis management in sickle cell disease patients. However, lack of uniform guidelines for fluid replacement coupled with underlying host comorbidities result in risk to patients from complications associated with hyperhydration. Contributing factors include inappropriate choice of fluid, rapid fluid infusion rates with prolonged time periods and inadequate monitoring of signs of hyperhydration. Complications of fluid replacement include excessive weight gain, extremity swelling, pulmonary edema and heart failure. In our study we examined the prevalence of hyperhydration in sickle cell anemia patients admitted for acute pain crisis management at our hospital. Methods: We conducted a retrospective chart review on EPIC of sickle cell anemia patients treated for acute pain crisis in the inpatient unit of John Dempsey Hospital, University of Connecticut between January 2022-December 2022, following IRB approval. To capture patients with signs and symptoms of hyperhydration and its clinical consequences, we looked at surrogate markers such as excessive weight gain during admission, signs of fluid retention, charting of patient fluid intake and output, increased oxygen use, diuretic (Lasix) administration, bronchodilator use, abnormal chest x ray findings indicative of fluid overload pattern, activation of rapid response team for patients developing acute symptoms of fluid overload, and urgent patient transfer to a higher level of care including intensive care unit. Results: 256 admitted patient charts were analyzed representing a total of 95 unique sickle cell disease patients. The median length of hospital stay (LOS) was 3 days. 168 patients had LOS from 3 to 10 days. We observed that 10.7% of the patients experienced an increase in oxygen requirements during their hospital stay. Daily weight was collected in only 27 patients (10.5%) for 3 or more days limiting its usefulness to detect subclinical hyperhydration( figure 1). 69 patients (27%) received parenteral Lasix injection for acute symptoms whose chest x rays also showed pulmonary edema or pleural effusions. 13 patients (18%) were transferred to a higher level of care that included 9 patients to step-down unit and 4 to intensive care for endotracheal intubations and ventilatory support. The median hospital stay was 4 days in patients requiring Lasix compared to 3 days in those who did not. Conclusion : Hyperhydration is undesirable complication associated with fluid administration of sickle cell anemia patients admitted with acute vaso-occlusive pain crisis. It occurs in a significant proportion of affected patients that can result in life threatening complications and prolonged hospitalization. Hyperhydration were missed in this retrospective analysis since daily weight measurements were not available in the majority of patients. Strict charting of fluid intake and output, choice of half normal saline for hydration, as well as clinical monitoring of signs and symptoms of subclinical hyperhydration will help reduce this complication and improve patient outcomes. Improving awareness of this complication among health care providers is important towards achieving this goals. Findings from this study are used to design a prospective quality improvement project in our hospital to improve outcomes and reduce hospitalization in sickle cell anemia patients admitted for acute vaso-occlusive pain crisis.

Rats chasing the dragon: A new heroin inhalation method

BackgroundDespite extensive human use of inhalation for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; “e-cigarettes”) have shown efficacy in rodent models but these do not faithfully mimic the most popular human inhalation method of heating heroin to the point of vaporization. New methodMiddle aged rats were exposed to vapor created by direct heating of heroin HCl powder in a ceramic e-cigarette type atomizer. Efficacy was determined with a warm water tail withdrawal nociception assay, rectal temperature and self-administration. ResultsTen minutes of inhalation of vaporized heroin slowed response latency in a warm water tail withdrawal assay and increased rectal temperature in male rats, in a dose-dependent manner. Similar antinociceptive effects in female rats were attenuated by the opioid antagonist naloxone (1.0 mg/kg, s.c.). Female rats made operant responses for heroin vapor in 15-minute sessions, increased their response rate when the reinforcement ratio increased from FR1 to FR5, and further increased their responding when vapor delivery was omitted. Anti-nociceptive effects of self-administered volatilized heroin were of a similar magnitude as those produced by the 10-minute non-contingent exposure. Comparison with existing methodsInhalation of directly volatilized heroin successfully produces heroin-typical effects, comparable to EDDS inhalation delivery. ConclusionsThis study shows that “chasing the dragon” methods of inhalation of heroin can be modeled successfully in the rat. Inhalation techniques may be particularly useful for longer term studies deep into the middle age of rats.

FRI415 Patient Preference And Proof-of-concept For A Once-daily Follicle Stimulating Hormone (FSH) Biosimilar Delivered Via An Orally Ingestible Robotic Pill (RT-112)

Abstract Disclosure: A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. V. Tran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.T. Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. R. Medida: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. J.T. Myers: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Kaminskaya: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. D. Mohan: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. V. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M.A. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. Background: Biotherapeutics offer effective treatments for reproductive disorders, but require painful parenteral (e.g., subcutaneous (SC)) injections, representing a burden for patients which interferes with comfort and quality of life. We have developed an orally ingestible robotic pill (RP) that can deliver biotherapeutic agents with bioavailability rivalling or surpassing that of parenteral injections. Here, we provide 1) clinical evidence of patient preference for the daily oral RP over parenteral injection therapy and 2) data from a study of awake canines demonstrating comparable serum exposures of FSH via the oral RP versus SC injection. Methods:Patient Preference Study: A total of 150 participants currently using parenteral injections were enrolled and given a mock-RP having the same physical characteristics of a RP but without a needle or drug inside. After swallowing the mock-RP, participants were asked to complete a questionnaire evaluating their experience and their preference for a pill vs. parenteral injection. Nonclinical Proof-of-Concept: Single doses of RT-112 (150 IU (n=7) and 450 IU (n=8)) were orally administered to awake, fasted Beagle dogs (7.0-13.0 kg body weight); a control group (n=3) received a dose of 20 IU/kg (∼180 IU) FSH via SC injection. Serial blood samples were collected over 5 days and serum FSH concentrations were quantified via a qualified ELISA. Results: All participants (150/150) in the patient preference study were able to swallow the mock-RP without any adverse events. Based on the questionnaire, the overall preference for an oral pill over parenteral injection was 91%, irrespective of age (21-50, 51-65, 66-75 years). Oral administration of FSH at the 2 doses via RT-112 to awake canines elicited dose proportional increases in serum drug concentrations. AUC0-t values for the 150 IU and 450 IU dose groups were 2101 ± 185 and 8179 ± 733 mIU*hr/mL, and Cmax values were 65 ± 13 and 224 ± 24 mIU/mL, respectively. The pharmacokinetic (PK) profile of the lower RT-112 dose was similar to that of the SC Control dose (AUC0-t: 2131 ± 67 mIU*hr/mL, Cmax: 52 ± 1 mIU/mL), with a relative bioavailability nearly identical (99%) to that of the SC injection. Conclusions: Patients strongly prefer an oral therapeutic option over parenteral therapy. In awake canines, FSH delivered via oral RP yielded bioavailability very similar to SC injection. These data provide early proof-of-concept of the feasibility of replacing the current parenteral injections of FSH with orally ingestible capsules utilizing the RP. Presentation: Friday, June 16, 2023

SAT235 An Orally Administered Robotic Pill (RP) Reliably And Safely Delivers the Human Parathyroid Hormone Analog hPTH(1-34) (Teriparatide) With High Bioavailability in Healthy Human Volunteers: A Phase 1 Study

Abstract Disclosure: J.T. Myers: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Dasari: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Battiwala: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Toledo Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. J. Van Dam: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. Background/Purpose: Teriparatide, an effective osteoanabolic agent, requires a chronic regimen of daily subcutaneous (SC) injections, representing a burden for patients which may interfere with compliance and quality of life. We have developed a novel oral robotic pill (RP) to deliver biotherapeutic agents with bioavailability rivaling or surpassing that of parenteral injections. Here we present data from a Phase 1 study in healthy women volunteers designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of 20- and 80 µg of hPTH (1-34) administered orally via RP (RT-102) at single doses. Methods: The study was approved by the Alfred Health HREC in Australia. Participants received a single dose of either RT-102 at 20 µg (RT-102/20 µg group; N=15) or 80 µg (RT-102/80 µg group; N=14) or a single 20 µg dose of the commercially available teriparatide (Forteo®) via SC injection (SC group; N=10). Fluoroscopic images were taken to track the transit/deployment of RT-102 and confirm excretion of remnants. Drug concentration in serum samples serially collected over 6 hours were measured by a validated ELISA assay. Results: All 29 participants in the RT-102 arms were able to swallow RT-102 and none experienced any adverse events (AEs) upon device deployment. Both doses of RT-102 were safe and well-tolerated with no serious adverse events (SAEs) reported. In the SC group, a total of six drug-related AEs were reported in four participants. There were no AEs reported in the RT-102/20 µg group. Mild and transient AEs attributed to the drug were observed in one participant in the RT-102/80 µg group. No AEs related to the RP were reported. Imaging confirmed excretion of all RP device remnants within an average of 2.7 ± 1.4 days. Based on serum analyses, drug was successfully delivered by RT-102 in 12 of 15 participants in the 20 µg group and in all 14 participants in the 80 µg group. PK analyses indicated that RT-102 delivered drug with more sustained peak concentrations than the SC group. The Cmax of RT-102 was 98 ± 10 pg/mL for the 20 µg dose and 971 ± 223 pg/mL for the 80µg dose compared to 128 ± 20 pg/mL for the 20 µg SC injection group. The Tmax for RT-102 delivery was 68 and 60 min for the 20 µg and 80 µg doses, respectively, compared to 13 min for the SC injection. Based on AUC calculations of the PK curves, the relative bioavailability of RT-102 dose groups was 3- to 4-fold higher compared to the SC injection group. Conclusions: This study provides the first clinical evidence of safe and successful delivery of hPTH (1-34) via an orally administered RP with high reliability and bioavailability. These data suggest that RT-102 can potentially offer an easier and more convenient treatment option to osteoporosis patients, and given the high bioavailability, RT-102 may be effective at doses lower than the currently approved 20 µg SC dose of teriparatide. Presentation: Saturday, June 17, 2023

Intracerebral Hemorrhage Among Blood Donors and Their Transfusion Recipients

Recent reports have suggested that cerebral amyloid angiopathy, a common cause of multiple spontaneous intracerebral hemorrhages (ICHs), may be transmissible through parenteral injection of contaminated cadaveric pituitary hormone in humans. To determine whether spontaneous ICH in blood donors after blood donation is associated with development of spontaneous ICH in transfusion recipients. Exploratory retrospective cohort study using nationwide blood bank and health register data from Sweden (main cohort) and Denmark (validation cohort) and including all 1 089 370 patients aged 5 to 80 years recorded to have received a red blood cell transfusion from January 1, 1970 (Sweden), or January 1, 1980 (Denmark), until December 31, 2017. Receipt of red blood cell transfusions from blood donors who subsequently developed (1) a single spontaneous ICH, (2) multiple spontaneous ICHs, or (3) no spontaneous ICH. Spontaneous ICH in transfusion recipients; ischemic stroke was a negative control outcome. A total of 759 858 patients from Sweden (median age, 65 [IQR, 48-73] years; 59% female) and 329 512 from Denmark (median age, 64 [IQR, 50-73] years; 58% female) were included, with a median follow-up of 5.8 (IQR, 1.4-12.5) years and 6.1 (IQR, 1.5-11.6) years, respectively. Patients who underwent transfusion with red blood cell units from donors who developed multiple spontaneous ICHs had a significantly higher risk of a single spontaneous ICH themselves, compared with patients receiving transfusions from donors who did not develop spontaneous ICH, in both the Swedish cohort (unadjusted incidence rate [IR], 3.16 vs 1.12 per 1000 person-years; adjusted hazard ratio [HR], 2.73; 95% CI, 1.72-4.35; P < .001) and the Danish cohort (unadjusted IR, 2.82 vs 1.09 per 1000 person-years; adjusted HR, 2.32; 95% CI, 1.04-5.19; P = .04). No significant difference was found for patients receiving transfusions from donors who developed a single spontaneous ICH in the Swedish cohort (unadjusted IR, 1.35 vs 1.12 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.84-1.36; P = .62) nor the Danish cohort (unadjusted IR, 1.36 vs 1.09 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.70-1.60; P = .73), nor for ischemic stroke as a negative control outcome. In an exploratory analysis of patients who received red blood cell transfusions, patients who underwent transfusion with red blood cells from donors who later developed multiple spontaneous ICHs were at significantly increased risk of spontaneous ICH themselves. This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of cerebral amyloid angiopathy might explain this association.

BIOCHEMICAL CHANGES OF CHRONIC GENERALIZED PERIODONTITIS IN CHRONIC VIRAL HEPATITIS B, C AND MIXED INFECTIONS

Viral hepatitis (VH) belongs to the category of infectious diseases of the human body that develop under the influence of viruses, which are diverse in nature, in the ways of their spread and transmission from a patient to a healthy person and have one identical attribute - liver damage. VG is an atroponous infection, which means that their pathogens in natural conditions can only be present in the human body. In hepatitis of viral origin, pathogens have a selective similarity (tropism) to liver cells. For this reason, the early location of viruses and their replication (reproduction) are manifested mainly in the liver tissue, primarily in liver cells (hepatocytes). According to the nature and duration of development, hepatitis of viral origin is divided into acute and chronic. The threshold among these two types of disease is relatively taken into account 6 months from the onset of the disease or in certain patients from the onset of infection (if the disease does not develop) and up to 6 months - acute hepatitis B or acute virus carrier, after 6 months - chronic hepatitis or chronic virus carrier. [4; 8]. According to WHO, in different countries of the world more than 2 billion people are infected with viral hepatitis (VH), while about 350 million are carriers of hepatitis B and 500 million of hepatitis C [3; 5]. All known hepatitis viruses are present in the CIS countries. In relation to parenteral infections of viral hepatitis, the CIS countries belong to the region with a moderate incidence rate (35.2 cases per 100,000 people). In Tatarstan, the share of viral hepatitis "B" and "C" in the total number of viral hepatitis is 80%. According to some authors [1], the number of so-called "virus carriers" of infection is growing in our republic, more than 10,000-12,000 primary carriers of hepatitis B and C viruses are registered annually. However, the registered incidence is only a part of the true incidence and only the visible part of the "iceberg". This is due to the fact that most cases of hepatitis B occur outside the scope of medical diagnosis, without jaundice and with minor clinical symptoms. However, the anicteric form of parenteral hepatitis is less dangerous than the icteric form in terms of infection and consequences [10]. Viral hepatitis B and C belong to the group of viral hepatitis with a parenteral transmission mechanism. These pathogenic viruses are taxonomically distinct. Common features are the parenteral transmission mechanism and the obligatory circulation of the virus in the blood [7]. Viral hepatitis B is a strictly parenteral infection caused by the IIBV virus, including CMV; IIBV is highly resistant to cold, heat, chemical and physical attack. It persists for 3 months at room temperature and 25 years in dried plasma; a direct correlation has been demonstrated between IIBV duration and blood levels. [6]. The source of transmission of the virus (HBV) can be all forms of acute and chronic HBV, as well as virus carriers. More important as the main source of infection for the epidemic potential are chronic forms of HBV infection than acute ones. An important role is played by chronic carriers of HbsAg and patients with clinically icteric form of IIBV; the ability of IIBV to persist for a long time, often for life, in the human body is considered as an ecological form of its existence [3; 5]. The most fully studied artificial (artifacial) ways of HBV infection as a result of various parenteral therapeutic, diagnostic, therapeutic and non-medical manipulations, leading to a violation of the integrity of the mucous membranes and skin. The source of infection can be contaminated blood products, medical equipment and instruments, transplanted organs and tissues; transfusion of blood or blood products containing HBV can also cause infection (post-transfusion hepatitis) [8; 11]. In addition to medical procedures, non-medical parenteral injections are of paramount importance in the transmission of IIBV infections. This is especially true of intravenous administration of drugs, which has become widespread in recent years. According to a number of authors [2], it has been shown that in recent years there has been a rapid increase in the number of patients with acute viral hepatitis "B", which is associated with the use of intravenous drugs, and a quantitative increase in the incidence is observed among young men aged 15 to 30 years. . Below is a list of the most common causes of acute viral hepatitis B. The purpose of this study is to substantiate the functional features of periodontal tissues in chronic hepatitis B, C and mixed infection B + C.

A Chemically Defined TLR3 Agonist with Anticancer Activity

ABSTRACT Toll-like receptor 3 (TLR3) agonists such as polyinosinic:polycytidylic acid (poly(I:C)) have immunostimulatory effects that can be taken advantage of to induce anticancer immune responses in preclinical models. In addition, poly(I:C) has been introduced into clinical trials to demonstrate its efficacy as an adjuvant and to enhance the immunogenicity of locally injected tumors, thus reverting resistance to PD-L1 blockade in melanoma patients. Here, we report the pharmacokinetic, pharmacodynamic, mechanistic and toxicological profile of a novel TLR3 agonist, TL-532, a chemically synthesized double-stranded RNA that is composed by blocks of poly(I:C) and poly(A:U) (polyadenylic – polyuridylic acid). In preclinical models, we show that TL-532 is bioavailable after parenteral injection, has an acceptable toxicological profile, and stimulates the production of multiple chemokines and interleukins that constitute pharmacodynamic markers of its immunostimulatory action. When given at a high dose, TL-532 monotherapy reduced the growth of bladder cancers growing on mice. In addition, in immunodeficient mice lacking formylpeptide receptor-1 (FPR1), TL-532 was able to restore the response of orthotopic subcutaneous fibrosarcoma to immunogenic chemotherapy. Altogether, these findings may encourage further development of TL-532 as an immunotherapeutic anticancer agent.

Bacterial contamination of single and multiple-dose parenteral injection vials after opening and antibiotic susceptibility of isolates at Jimma Medical Center, Jimma, Southwest Ethiopia

Single- or multiple-dose vials are prone to bacterial contamination after improper handling and can be potential reservoirs of microorganisms that could be transmitted to the patient through the parenteral route. The present study aims to assess the magnitude of the problem and associated factors at Jimma Medical Center (JMC), Jimma, Southwest Ethiopia. A cross-sectional study design was conducted at JMC from July 2021 to October 2021. A total of 384 parental medications and nurse interviews that were administered in 11 wards and 3 intensive care units were included. Samples were processed and identified by conventional bacterial culture methods. The overall prevalence of vial contamination due to aerobic bacteria was 21 (5.5%) among multiple-dose vials and none of the single-dose vials. The highest level of contamination (8, 38.1%) was found in the paediatric ward. Pseudomonas aeruginosa and Klebsiella pneumoniae were the most common microorganisms identified vial contamination, 6 cases (28.5%) and 5 cases (23.8%) respectively Multidrug resistance was identified in 95.2% of the isolates, with all Gram-negative isolates showing a multidrug resistance against the tested antibiotics. In multivariate logistic regression analysis, vial contamination was strongly associated with reuse of syringe and/or needle, the environment where medication was handled, and the storage conditions. In this study, the prevalence of vial contamination was high. The bacterial isolates from vials were also resistant to commonly prescribed antimicrobial drugs. Healthcare professionals must strictly adhere to basic infection control practices as per standard guidelines to reduce the risk of infection from contaminated vials.

Systemic effects of oral tolerance in bone healing

Bone fractures cause acute inflammation that, despite being important for initial repair, may delay the healing of the damaged bone. Parenteral injection of dietary protein has been shown to decrease inflammation and accelerate the repair of skin wounds and other inflammatory pathologies. Thus, our aim was to evaluate whether the intraperitoneal (i.p.) immunization with zein, an abundant protein in rodent chow, would favor bone healing. Wistar rats received i.p. immunization: saline (SG), adjuvant (AG) and zein associated with adjuvant (ZG). Then, a 2 mm of defect bone was performed on the right tibia, and on days 7, 14, 28 and 45 thereafter, analyses were performed. The results showed that the injection of zein reduced inflammation without impairing bone mineralization. Moreover, biomechanical tests demonstrated higher levels of maximum force (N) in ZG, indicating better mechanical resistance in relation to the others. The computerized tomography also indicated lower levels of medullary content in the ZG than in the SG, suggesting the absence of trabeculae in the medullary region in the ZG. These findings suggest that the injection of zein in previously tolerated animals may improve bone repair, leading to mechanically functional bone formation.