Alternative Routes Of Administration Research Articles

Safe Management of Adverse Effects Associated with Prescription Opioids in the Palliative Care Population: A Narrative Review

In the palliative care population, prescription opioids are often considered viable pain relief options. However, in this complex patient population, the adverse effects of opioid medications should be identified and managed without delay. Common adverse effects can include constipation, nausea, somnolence, dizziness, vomiting, and pruritus. Less common adverse effects can include potentially lethal respiratory depression and cardiovascular effects. Critical aspects of safe opioid prescribing are recognition of side effects and knowledge of effective management strategies; prompt management is necessary for uninterrupted pain relief. Most complications are managed with general approaches such as dose reduction, opioid rotation, alternate routes of administration, and symptomatic management. The only opioid-induced complication for which US Food and Drug Administration-approved treatments currently exist is constipation. Treating laxative-refractory opioid-induced constipation (OIC) with peripherally acting mu-opioid receptor antagonists (PAMORAs), which block gastrointestinal opioid receptors, can restore gastrointestinal motility and fluid secretion. This narrative review discusses key complications of prescription opioid treatment and their management in the palliative care setting.

HPLC-MS/MS Method for the Quantitative Determination of Metformin in Rat Plasma and Its Application to Comparative Bioavailability Assessment

Background: Metformin is a biguanide derivative utilized as a first-line treatment for type 2 diabetes for people over 60 years. However, it faces certain limitations due to its incomplete absorption, resulting in a 50-60% bioavailability. In addition to its blood glucose-lowering effect, the antiproliferative effect of metformin has been demonstrated in vitro. Therefore, it is necessary to consider alternative administration routes that can enhance the bioavailability of metformin, expanding its clinical use beyond its role as an antidiabetic agent. Objective: The aim of the study was to develop a reliable bioanalytical method for the quantitation of metformin in male Sprague-Dawley rat plasma and explore the promising alternative administration route for metformin use. Methods: A robust, high-performance liquid chromatography-tandem mass spectrometry method for the quantification of metformin in rat plasma was developed and validated according to the latest regulatory guidance for bioanalysis. Results: Based on the area under the curves obtained from the rat pharmacokinetic study, subcutaneous injection increased the systemic exposure of metformin by 1.79-fold compared to oral administration in rats. Conclusion: Subcutaneous administration of metformin enhances its bioavailability compared to oral administration, leading to increased antidiabetic effects and potential antitumor activity.

IJCM_294A: COVID-19 vaccination status and willingness for booster dose among staff and students of tertiary care institute

Background: Exposure to new COVID-19 variants and decline in herd immunity may result in new or repeat infection. The booster dose may face certain challenges that result in low uptake. The aim of the study was to assess the COVID-19 vaccination status and willingness of medical staff and students to receive further booster doses. Objectives: 1. To assess the willingness of staff and students regarding booster dose of any COVID-19 vaccine. 2. Explore reason behind the willingness of booster dose and nasal route. Methodology: A cross sectional study was conducted among the staff and students of a tertiary care institute. With 5% margin of error, 95% confidence interval, intention to receive booster vaccine as 55.3% and 10% non-response rate, the sample size was calculated as 312. The participants received a web based semi-structured questionnaire through email and WhatsApp. The data was analyzed using SPSS version 24. Descriptive analysis was performed in the form of frequency and proportions for categorical variables. Results: About 302 participants responded to the survey. About 51.3% of them were females and 61.2% belonged to 18-29 year age group. The health workers, ancillary staff and students were 37.7%, 40% and 22.2% respectively. About 49.3% received a precaution dose while 49% had received 2 doses of any COVID-19 vaccine. About 72.1% of the participants were willing to receive another booster dose. Perception of vaccine as an immunity booster was the top reason for the willingness. About 34.2% (25/73) of them preferred nasal route for the booster with 66.3% (21/33) perceiving it convenient to administer. Conclusion: Knowledge about the acceptance of COVID-19 vaccine and perceptions regarding the booster dose may help to increase the readiness of medical community to uptake the booster. Alternative routes of administration and reasons for willingness may reduce the skepticism for booster dose.

Postnatal steroids in the treatment of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is an adverse outcome of prematurity which affects approximately 40% of newborns with a gestational age (GA) <29 weeks. This review article describes the current consensus over the use of postnatal steroids in the treatment of BPD, providing an insight into historical clues, optimal patient selection, timing of the therapy, alternative routes of administration, and therapeutic strategies.

Nanostructured Lipid Carriers of Donepezil Hydrochloride for the Treatment of Alzheimer's Disease.

Alzheimer's Disease (AD) is a long-term brain disorder that worsens over time. A cholinesterase inhibitor called Donepezil HCl (DNZ) is used to treat and control AD. Due to its failure to reach the appropriate concentration in the brain cells, its efficacy upon oral administration is limited, and thus investigation of alternative administration route is necessary. The objective of this study was to develop donepezil HCl-loaded Nanostructured Lipid Carriers (NLCs) that can bypass the blood-brain barrier and thus be directly delivered to the brain through the nasal route. This method improves availability at the site of action, reduces the negative effects of oral medication, and ensures an expedited commencement of action. High-pressure homogenization and ultrasonication were used to formulate NLCs. Glyceryl Monostearate (GMS) as a solid lipid, Tween 80 as a surfactant, and Poloxamer 407 as a co-- surfactant were used. In this study, argan oil was employed as a liquid lipid as well as a penetration enhancer. The chosen NLCs displayed a particle size of 137.34 ± 0.79 nm, a PDI of 0.365 ± 0.03, and a zeta potential of -10.4 mV. The selected formulation showed an entrapment efficiency of 84.05 ± 1.30% and a drug content of 77.02 ± 0.23%. The concentration of the drug in the brain after intravenous and intranasal administration of DNZ NLCs at 1 h was found to be 0.490 ± 0.007 and 4.287 ± 0.115, respectively. Thus, the concentration of DNZ achieved in the brain after intranasal administration of DNZ NLCs was approximately 9 times more than the concentration when administered by intravenous route. The DNZ-loaded NLCs, when administered via nasal route, showed markedly improved drug availability in the brain, suggesting an efficient drug delivery strategy to treat Alzheimer's disease.

A Nanocomposite Dynamic Covalent Cross-Linked Hydrogel Loaded with Fusidic Acid for Treating Antibiotic-Resistant Infected Wounds.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high levels of morbidity and is considered a difficult-to-treat infection, often requiring nonstandard treatment regimens and antibiotics. Since over 40% of the emerging antibiotic compounds have insufficient solubility that limits their bioavailability and thus efficacy through oral or intravenous administration, it is crucial that alternative drug delivery products be developed for wound care applications. Existing effective treatments for soft tissue MRSA infections, such as fusidic acid (FA), which is typically administered orally, could also benefit from alternative routes of administration to improve local efficacy and bioavailability while reducing the required therapeutic dose. Herein, we report an antimicrobial poly(oligoethylene glycol methacrylate) (POEGMA)-based composite hydrogel loaded with fusidic acid-encapsulating self-assembled polylactic acid-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (PLA-POEGMA) nanoparticles for the treatment of MRSA-infected skin wounds. The inclusion of the self-assembled nanoparticles (380 nm diameter when loaded with fusidic acid) does not alter the favorable mechanical properties and stability of the hydrogel in the context of its use as a wound dressing, while fusidic acid (FA) can be released from the hydrogel over ∼10 h via a diffusion-controlled mechanism. The antimicrobial studies demonstrate a clear zone of inhibition in vitro and a 1-2 order of magnitude inhibition of bacterial growth in vivo in an MRSA-infected full-thickness excisional murine wound model even at very low antibiotic doses. Our approach thus can both circumvent challenges in the local delivery of hydrophobic antimicrobial compounds and directly deliver antimicrobials into the wound to effectively combat methicillin-resistant infections using a fraction of the drug dose required using other clinically relevant strategies.

A comprehensive review of oral chitosan drug delivery systems: Applications for oral insulin delivery

Abstract Pharmaceutical scientists have long struggled to develop reliable and efficient systems of administering insulin orally due to multiple barriers, including stomach acidity, enzymatic degradation, and mucus barriers. However, various strategies were developed to avoid insulin degradation in the gastrointestinal tract (GIT) and promote membrane permeability and biological activity. Among these strategies, chitosan polymer-based carriers are widely researched due to their ability to protect insulin in the alimentary canal and deliver it effectively through the intestinal mucosa, improving its bioavailability. To improve chitosan properties, chemical and physical modifications have been developed, and recently, nanoparticles, microparticles, and beads of chitosan exhibited potential systems for oral insulin delivery (OID). This review facilitates an outline of the types of diabetes mellitus, insulin biosynthesis, and gastrointestinal barriers against oral insulin. Moreover, the limitations of subcutaneous insulin delivery and alternative routes of administration are also discussed. As an ideal and most convenient oral administration route, the challenges of safe insulin delivery through the GIT and strategies to elevate its bioavailability are highlighted. In addition, this review focuses on recent advancements in chitosan based carriers for OID and their potential future applications.

Inhaled delivery of cetuximab-conjugated immunoliposomes loaded with afatinib: A promising strategy for enhanced non-small cell lung cancer treatment.

Afatinib (AT), an FDA-approved aniline-quinazoline derivative, is a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Combining it with cetuximab (CX), a chimeric human-murine derivative immunoglobulin-G1 monoclonal antibody (mAb) targeting the extracellular domain of epidermal growth factor receptor (EGFR), has shown significant improvements in median progression-free survival. Previously, we developed cetuximab-conjugated immunoliposomes loaded with afatinib (AT-MLP) and demonstrated their efficacy against NSCLC cells (A549 and H1975). In this study, we aimed to explore the potential of pulmonary delivery to mitigate adverse effects associated with oral administration and intravenous injection. We formulated AT-MLP dry powders (AT-MLP-DPI) via freeze drying using tert-butanol and mannitol as cryoprotectants in the hydration medium. The physicochemical and aerodynamic properties of dry powders were well analyzed firstly. In vitro cellular uptake and cytotoxicity study revealed concentration- and time-dependent cellular uptake behavior and antitumor efficacy of AT-MLP-DPI, while Transwell assay demonstrated the superior inhibitory effects on NSCLC cell invasion and migration. Furthermore, in vivo pharmacokinetic study showed that pulmonary delivery of AT-MLP-DPI significantly increased bioavailability, prolonged blood circulation time, and exhibited higher lung concentrations compared to alternative administration routes and formulations. The in vivo antitumor efficacy study carried on tumor-bearing nude mice indicated that inhaled AT-MLP-DPI effectively suppressed lung tumor growth.

Pediatric sedation for emergency, imaging and endoscopic procedures: a worldwide review from the last five years

Introduction: Anatomical, physiological, pharmacokinetic, pharmaco dynamic and behavioral particularities relevant to the pediatric population make its sedation challenging for quick and low-complexity procedures. Robust evidence on this subject is still scarce, and the variety of drugs available, with their multiple routes of administration and dosage schemes, makes it difficult for providers to make a decision. Methods: Through research in four databases, we found 170 articles that addressed pediatric sedation and, after applying the exclusion criteria, we selected 32 articles for analysis. Results: In sedation for invasive or painful procedures, Esketamine in monotherapy was effective, despite the significant incidence of adverse effects. Satisfactory responses were also obtained with associations between Esketamine and Propofol and Fentanyl with Propofol or Midazolam. To perform imaging tests, continuous infusions of Propofol or Dexmedetomidine were sufficient, with associations with Esketamine or opioids associated with a higher incidence of adverse effects. Endoscopic procedures have been successfully performed after administration of continuous infusion of Propofol or Dexmedetomidine, associated with Remifentanil infusion or Fentanyl bolus. Esketamine in monotherapy was also effective. Discussion: The drugs studied have an adverse effect profile compatible with safe pediatric sedation, whether administered by a specialist or not. However, alternative administration routes and dosages still need further studies before being routinely applied. Conclusion: Sedation in pediatrics is still an open field for research in our country.

PORT: A Randomized, Cross-Over, Phase 2 Study of Melflufen Peripheral Versus Central Intravenous Administration in Patients With Relapsed/Refractory Multiple Myeloma

BackgroundMelflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable. Patients and MethodsPORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-∞)) and frequency and severity of PVC-related local reactions. ResultsThe 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (Cmax 0.946 [90% CI: 0.849, 1.053]; AUC(0-t) 0.952 [90% CI: 0.861, 1.053]; AUC(0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred. ConclusionMelflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration.

Early investigation of a novel SI306 theranostic prodrug for glioblastoma treatment.

Glioblastoma multiforme (GBM) is one of the most aggressive malignancies with a high recurrence rate and poor prognosis. Theranostic, combining therapeutic and diagnostic approaches, arises as a successful strategy to improve patient outcomes through personalized medicine. Src is a non-receptor tyrosine kinase (nRTK) whose involvement in GBM has been extensively demonstrated. Our previous research highlighted the effectiveness of the pyrazolo[3,4-d]pyrimidine SI306 and its more soluble prodrug CMP1 as Src inhibitors both in in vitro and in vivo GBMmodels. In this scenario, we decided to develop a theranostic prodrug of SI306, ProSI-DOTA(68 Ga) 1, which was designed to target GBM cells after hydrolysis and follow-up on the disease's progression and improve the therapy's outcome. First, the corresponding nonradioactive prodrug 2 was tested to evaluate its ADME profile and biological activity. It showed good metabolic stability, no inhibition of CYP3A4, suboptimal aqueous solubility, and slight gastrointestinaland blood-brain barrierpassive permeability. Compound 2 exhibited a drastic reduction of cell vitality after 72 h on two different GBM cell lines (GL261 and U87MG). Then, 2 was subjected to complexation with the radionuclide Gallium-68 to give ProSI-DOTA(68 Ga) 1. The cellular uptake of 1 was evaluated on GBM cells, highlighting a slight but significant time-dependent uptake. The data obtained from our preliminary studies reflect the physiochemical properties of 1. The use of an alternative route of administration, such as the intranasal route, could overcome the physiochemical limitations and enhance the pharmacokinetic properties of 1, paving the way for its future development.

Preparation and characterization of diclofenac transdermal patch using ethyl cellulose and polyvinyl alcohol by electrospinning

In recent years, the adverse effects linked to the oral administration of diclofenac, a non-steroidal anti-inflammatory drug (NSAID), have urged interest in exploring alternative administration routes, specifically transdermal drug delivery (TDD). Among the techniques emerging for creating nanoscale fibres suitable for TDD systems, electrospinning has attracted attention. The primary objective of this study was to formulate and evaluate nanofibers loaded with diclofenac diethylamine using ethylcellulose (EC) and polyvinyl alcohol (PVA) polymers. The influence of penetration enhancers, namely farnesol and nerolidol, on the properties of these fibres was investigated. Employing the electrospinning technique, nanofibers composed of EC or PVA polymers, with or without penetration enhancers, were fabricated, all maintaining a constant drug-to-polymer ratio. Mechanical strength and release kinetics from a cellophane membrane for the obtained nanofibers were investigated. A Franz diffusion cell was employed to determine the drug penetration rates through rat skin for selected fibre formulations. To gain insights into potential interactions and changes in the drug's solid state, FTIR spectroscopy, DSC, and XRD analyses were conducted. Microscopic examination unveiled that EC-based fibres exhibited homogeneity and lacked bead formations, albeit with larger diameters than other formulations. In contrast, both EC and PVA-based fibres displayed bead formations and nanometer-scale widths. The incorporation of penetration enhancers led to the production of uniform, bead-free nanofibers, with minor impacts on fiber size. EC fibres exhibited the lowest tensile strength and modulus of elasticity, but maximum flexibility. The addition of PVA and penetration enhancers contributed to enhanced fibre toughness and resistance to deformation. These alterations also positively influenced drug release rates, as observed in experiments conducted on cellophane membranes. Notably, when comparing drug release on rat skin to cellophane membranes, a slower initial release followed by a steeper slope was noted, attributed to the beneficial role of penetration enhancers on skin permeation. Analyzing results from DSC revealed the transition of the crystalline form of diclofenac diethylamine to an amorphous state within the nanofiber matrix which was also supported by XRD data. In light of these findings, electrospun nanofibers comprising a combination of EC and PVA polymers, alongside a penetration enhancer and diclofenac diethylamine, exhibit considerable promise for utilization as transdermal patches.

Retrospective subgroup analysis of fecal microbiota, live-jslm (REBYOTA®) administered by colonoscopy under enforcement discretion for the prevention of recurrent Clostridioides difficile infection.

Fecal microbiota, live-jslm (RBL; REBYOTA®), is the first Food and Drug Administration (FDA)-approved, single-dose, rectally administered, microbiota-based live biotherapeutic product for preventing Clostridioides difficile infection (CDI) recurrence. Alternative routes of administration are of clinical interest. Evaluate the safety and efficacy of RBL administration via colonoscopy. Retrospective analysis of electronic medical records of participants administered RBL via colonoscopy under FDA enforcement discretion. The number of participants with treatment and/or procedure-emergent adverse events (TEAEs) was evaluated. Treatment success and sustained clinical response, defined as the absence of CDI recurrence within 8 weeks and 6 months, respectively, were evaluated. TEAEs were experienced by 75% (6/8) of participants; most were mild to moderate in severity, and none due to RBL or its administration. Most participants had treatment success (80%; 8/10); 75% (6/8) had sustained clinical response. Real-world safety and efficacy of RBL administered via colonoscopy were consistent with clinical trials of rectally administered RBL.

Revolutionizing transdermal drug delivery: unveiling the potential of cubosomes and ethosomes.

The area of drug delivery systems has witnessed significant advancements in recent years, with a particular focus on improving efficacy, stability, and patient compliance. Transdermal drug delivery offers numerous benefits compared to conventional methods of drug administration through the skin. It helps in avoiding gastric irritation, hepatic first-pass metabolism, and gastric degradation of the drug. It bypasses the gastrointestinal tract, eliminating the risk of first-pass metabolism and allowing drugs to be administered without being affected by pH, enzymes, or intestinal bacteria. Additionally, it allows for sustained release of the drug, is noninvasive, and enhances patient adherence to the treatment regimen. The transdermal drug delivery system (TDDS) can serve as an alternative route for drug administration in individuals who cannot tolerate oral medications, experience nausea, or are unconscious. When compared to intravenous, hypodermic, and other parenteral routes, TDDS stands out due to its ability to eliminate pain, reduce the risk of infection, and prevent disease transmission associated with needle reuse. Consequently, the overall patient compliance is significantly improved with the utilization of TDDS. Among the noteworthy developments are cubosomes and ethosomes, two distinct yet promising carriers that have garnered attention for their unique properties. In conclusion, this review synthesizes the current knowledge on cubosomes and ethosomes, shedding light on their individual strengths and potential synergies. The exploration of their application in various therapeutic areas underscores their versatility and establishes them as key players in the evolving landscape of drug delivery systems.

Nose-to-Brain (N2B) Delivery: An Alternative Route for the Delivery of Biologics in the Management and Treatment of Central Nervous System Disorders.

In recent years, there have been a growing number of small and large molecules that could be used to treat diseases of the central nervous system (CNS). Nose-to-brain delivery can be a potential option for the direct transport of molecules from the nasal cavity to different brain areas. This review aims to provide a compilation of current approaches regarding drug delivery to the CNS via the nose, with a focus on biologics. The review also includes a discussion on the key benefits of nasal delivery as a promising alternative route for drug administration and the involved pathways or mechanisms. This article reviews how the application of various auxiliary agents, such as permeation enhancers, mucolytics, in situ gelling/mucoadhesive agents, enzyme inhibitors, and polymeric and lipid-based systems, can promote the delivery of large molecules in the CNS. The article also includes a discussion on the current state of intranasal formulation development and summarizes the biologics currently in clinical trials. It was noted that significant progress has been made in this field, and these are currently being applied to successfully transport large molecules to the CNS via the nose. However, a deep mechanistic understanding of this route, along with the intimate knowledge of various excipients and their interactions with the drug and nasal physiology, is still necessary to bring us one step closer to developing effective formulations for nasal-brain drug delivery.

Nanosized ethosomal dispersions for enhanced transdermal delivery of nebivolol using intradermal/transfollicular sustained reservoir: in vitro evaluation, confocal laser scanning microscopy, and in vivo pharmacokinetic studies

Nebivolol (NBV), a BCS class II anti-hypertensive drug, suffers from limited solubility and oral bioavailability. Nanosized ethosomes were adopted as an approach to solubilize and deliver NBV transdermally, as a substitute to oral route. Ethosomal dispersions were prepared employing thin film hydration method. Formulation variables were adjusted to obtain entrapment efficiency; EE > 50%, particle size; PS < 100 nm, zeta potential; ZP > ±25 mV, and polydispersity index; PDI < 0.5. The optimized ethosomal dispersion (OED) showed accepted EE 86.46 ± 0.15%, PS 73.50 ± 0.08 nm, ZP 33.75 ± 1.20 mV, and PDI 0.31 ± 0.07. It also showed enhanced cumulative amount of NBV permeated at 8 h (Q8) 71.26 ± 1.46% and 24 h (Q24) 98.18 ± 1.02%. TEM images denoted spherical vesicles with light colored lipid bi-layer and dark core. Confocal laser scanning microscopy showed deeply localized intradermal and transfollicular permeation of the fluorolabelled OED (FL-OED). Nanosized FL-OED (<100 nm) can permeate through hair follicles creating a drug reservoir for enhanced systemic absorption. OED formulated into transdermal patch (OED-TP1) exhibited accepted physicochemical properties including; thickness 0.14 ± 0.01 mm, folding endurance 151 ± 0.07, surface pH 5.80 ± 0.15, drug content 98.64 ± 2.01%, mucoadhesion 8534 ± 0.03, Q8 87.61 ± 0.11%, and Q24 99.22 ± 0.24%. In vivo pharmacokinetic studies showed significantly enhanced bioavailability of OED-TP1 by 7.9 folds compared to oral Nevilob® tablets (p = 0.0002). It could be concluded that OED-TP1 can be a promising lipid nanocarrier TDDS for NBV and an efficacious alternative route of administration for hypertensive patients suffering from dysphagia.

Development and evaluation of regorafenib loaded liquid suppository for rectal delivery: In vitro, in vivo analyses

Regorafenib (RG), a multi-targeting kinase inhibitor, has recently been used in the colorectal cancer (CRC) treatment. However, its clinical effectiveness is severely constrained by its poor water solubility, extensive hepatic metabolism, low oral bioavailability, and serious side effects like Hand-foot skin reaction (HFSR), rashes, fatigue, stomatitis, diarrhea, dizziness and hypertension. Therefore, it is necessary to investigate alternative administration routes in order to increase RG efficacy. The aim of this study was to develop RG loaded liquid suppository with enhanced bioavailability and reduced toxicity. RG loaded liquid suppository was optimized using Design Experts® software, with various quantities of drug (RG), polymers [poloxamer 407 (P407), and poloxamer 188 (P188)], surfactant [Tween® 80, (T80)] and distilled water. Physicochemical characterization and in vitro study of RG release behavior from liquid suppository [RG/P188/P407/T80/distilled water: 1.25/15/11/10/62.75; %] were investigated followed by in vitro cell lines study on Caco-2 and HCT 116 cell lines. Additionally, pharmacokinetics, in vivo safety and in vivo localization studies were carried out following rectal administration in Sprague-Dawley rats. Results showed that increased P407 and T80 concentrations significantly lowered the temperature and time required for gelation, while the strength and mucoadhesion of gel was meaningfully enhanced. However, RG concentration increased didn't show significant effect on all these parameters. RG loaded liquid suppository displayed a significantly improved in vitro release, augmented in vivo localization, and enhanced bioavailability, when compared with the RG suspension. In vitro cell lines data demonstrated that unlike normal saline treated cell lines, the RG loaded liquid suppository and RG suspension has significantly reduced the cancer cell burden, which was also observed through their lower IC50 values. Histopathology study confirmed the formulation's safety for rectal administration, whereas, RG suspension instigated severe damage to the rectal tissues. It can be concluded from the results that RG loaded liquid suppository has a great potential to target CRC with enhanced drug localization, improved bioavailability and no toxic effects at the application's site.

Pharmacokinetics of hydrorphone hydrochloride after intravenous and subcutaneous administration in ferrets (Mustela putorius furo)

ObjectiveTo determine the pharmacokinetic profile of hydromorphone 0.2 mg kg–1 administered by the intravenous (IV) and subcutaneous (SC) route in ferrets. Study designRandomized, crossover study. AnimalsA group of eight adult ferrets weighting (mean ± standard deviation) 1.02 ± 0.22 kg. MethodsHydromorphone hydrochloride 0.2 mg kg–1 was administered IV or SC with a washout period of 7 days. Blood samples were collected from a jugular catheter before administration of hydromorphone and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 minutes after hydromorphone administration. Plasma hydromorphone concentrations were determined by liquid chromatography/tandem mass spectrometry. Data were analyzed using a non-linear mixed effects model. ResultsThe hydromorphone effective half-life was (t1/2) 45 min–1. Systemic clearance (Cls) and the volume of distribution (Vdss) following IV administration were 84.8 mL kg–1 min–1 and 5.59 L kg–1, respectively. The maximum observed plasma concentration was 59.53 ± 14.02 ng mL–1 within 10 minutes following SC administration. The SC bioavailability was 102.0%. Conclusions and clinical relevanceAdministration of IV and SC hydromorphone (0.2 mg kg–1) was characterized by a high clearance, short terminal half-life and large volume of distribution. Hydromorphone plasma concentrations remained greater than 2 ng mL–1 for 2 hours in most ferrets, a threshold reported to provide antinociceptive effects in other species. Hydromorphone was well absorbed following SC injection, providing an alternative administration route for clinical use in ferrets.

Nebulized and intraperitoneal ketamine have equivalent antidepressant-like effect in the forced swim and tail suspension tests in mice

Major depressive disorder (MDD) is a debilitating illness that affects millions of people worldwide. Currently available antidepressants often take weeks to months to reach their full effect, which leads to an increased risk of suicidal behavior in patients with MMD. Intranasally, esketamine has emerged as an alternative to current antidepressants because of its rapid onset and long-lasting effects in patients with MDD. Animal models are useful for the initial pharmacological screening and for a better understanding of the mechanisms underlying the effects of new drugs with potential against MDD. There is a lack of data on alternative routes of drug administration, either oral or injectable, that can be used in preclinical studies. This study aimed to test whether ketamine has antidepressant-like effects in mice when administered via nebulization using a low-cost apparatus. When mice whose depressive-like behavior was induced by corticosterone were treated with nebulized ketamine at concentrations of 1.3, 2.6, and 5.2 mg/mL, immobility was reduced by 38.6 %, 62.0 %, and 61.1 %, respectively, in the forced swimming test (FST) and 43.6 %, 42.1 %, and 57.9 %, respectively, in the tail suspension test (TST). When depression-like behavior was induced by dexamethasone, nebulization with ketamine reduced immobility by 79.7 %, 49.2 %, and 44.4 % in the FST and 80.9 %, 71.4 %, and 80.4 %, respectively, in the TST. When depression-like behavior was induced by the association between dexamethasone and unpredictable chronic mild stress (UCMS) exposure, immobility was reduced by 26.1 %, 55.3 %, and 19.1 % in FST. Mice treated with nebulized ketamine did not show significant changes in the distance covered or in the time spent moving in the open field test. The efficacy of intraperitoneal and nebulized ketamine is equivalent, which shows that nebulization can be an alternative inexpensive route of drug administration for behavioral studies in rodents.

Systematic review of adoption, reporting and impact of health-related quality of life in phase III non-inferiority trials of systemic oncology treatments

BackgroundQuality of life (QoL) assessment and patient-reported outcomes appear to be crucial in the rationale and interpretation of non-inferiority (NI) trials. The aim of this study was to assess the inclusion of QoL among endpoints in phase III NI oncology trials and the relevance of QoL results in the reporting and interpretation of these studies. Materials and methodsBy PubMed search and hand-search of 11 selected journals, we identified phase III NI trials in adult patients affected by solid tumours, published between 2012 and 2021. Trials were classified according to 4 NI strategies: (1) different drugs; (2) alternative drug administration routes; (3) shorter treatment duration; (4) “deintensification” of treatment schedule. Three main endpoints were: (1) the proportion of publications including QoL among endpoints; (2) the proportion of primary publications reporting QoL results; (3) the proportion of trials with available QoL results actually favoring the experimental treatment out of trials declaring NI. Results106 publications were eligible. QoL was included among endpoints in 59 studies (55.7%), and QoL results were available in 40 primary publications (37.7%). In the 73 trials testing the NI of different drugs, QoL was included in 43 trials (58.9%) and QoL results were present in 31 publications (42.5%). Among the 74 trials formally demonstrating NI, only 19 trials (25.7%) had QoL results actually supporting the experimental treatment. ConclusionsIn many NI trials in oncology, assessment and reporting of QoL are deficient. Furthermore, most trials formally claiming NI cannot count on QoL results actually supporting the experimental arm.