Drug Product Formulation and Fill/Finish Manufacturing Process Considerations for AAV-based Genomic Medicines.

Adeno-associated viruses (AAVs) have become the delivery medium of choice for a variety of genomic medicine applications i.e., gene therapy, gene editing/regulation, and ex-vivo cell therapy. AAVs are protein-DNA complexes which have unique stability characteristics that are susceptible to various stress exposure conditions commonly seen in the drug product (DP) life cycle. This review takes a comprehensive look at AAV DP formulation and process development considerations that could impact critical quality attributes (CQAs) during manufacturing, packaging, shipping, and clinical use. Additional aspects related to AAV development reviewed herein are: (1) Different AAV serotypes with unique protein sequences and charge characteristics potentially leading to discrete stability profiles; (2) Manufacturing process challenges and optimization efforts to improve yield, recovery and purity especially during early development activities; and (3) Defining and identifying CQAs with analytical methods which are constantly evolving and present unique characterization challenges for AAV-based products.

Attentional ERPs in consumers of smoked and insufflated cocaine associated with neuropsychological performance.

BACKGROUND: Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced amplitude of the P3a, while both SCD and IC dependent (ICD) would show reduced amplitude of the P3b. METHODS: We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks. RESULTS: At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. The amplitude of P3a and P3b was lower in Users groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down. CONCLUSIONS: Different routes of administration lead to distinct attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance Dependence.

Comparative dose effectiveness of intravenous and intrathecal AAV9.CB7.hIDS, RGX-121, in mucopolysaccharidosis type II mice.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.

Maximum Pain at Rest in Pediatric Patients Undergoing Elective Thoracic Surgery and the Predictors of Moderate-to-Severe Pain-Secondary Data Analysis.

INTRODUCTION: Pain management among children following thoracic surgery is an area of significant practice variability. Understanding the risk factors of moderate-to-severe pain intensity will allow for adequate pain relief. The aim of the study was to assess the maximum intensity of pain at rest in pediatric patients within 24 h of thoracic surgery and to investigate the prevalence and predictors of moderate-to-severe pain. METHODS AND FINDINGS: This is a prospective cohort study of patients in observational and randomized controlled trials following thoracic surgery. A secondary analysis of data was conducted using data collected from 446 patients aged 7-18 years undergoing thoracic surgery. The primary endpoint was maximum pain intensity (Numerical Rating Scale; NRS; range: 0-10) and the secondary endpoint was the prevalence and predictors of moderate-to-severe pain (NRS > 2/10). The median maximum pain in the cohort was 3 [0; 4]. During the immediate postoperative period, 54% of patients reported a maximum NRS > 2/10. The infusion of morphine by an intravenous route (vs. epidural route) was a protective factor against moderate-to-severe pain. Taking into account the findings related to the type of epidural analgesia (vs. intravenous morphine), it was found that only the administration of 0.25% bupivacaine combined with morphine or fentanyl was a protective factor against moderate-to-severe postoperative pain. Patients aged 14-18 years (vs. aged 7-13 years) had an increased risk of reporting pain as moderate-to-severe. CONCLUSIONS: The route of analgesic administration, type of multimodal analgesia, and patients' age predict moderate-to-severe pain in pediatric patients after thoracic surgery.

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery.

The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature revealed that oral CBD strategies are primarily focused on lipid-based and emulsion solutions or encapsulations, which improve the overall pharmacokinetics (PK) of CBD. Some emulsion formulations demonstrate more rapid systemic delivery. Variability in the PK effects of different oral CBD products is apparent across species. Several novel administration routes exist for CBD delivery that may offer promise for specific indications. For example, intranasal administration and inhalation allow quick delivery of CBD to the plasma and the brain, whereas transdermal and transmucosal administration routes deliver CBD systemically more slowly. There are limited but promising data on novel delivery routes such as intramuscular and subcutaneous. Very limited data show that CBD is generally well distributed across tissues and that some CBD products enable increased delivery of CBD to different brain regions. However, evidence is limited regarding whether changes in CBD PK profiles and tissue distribution equate to superior therapeutic efficacy across indications and whether specific CBD products might be suited to particular indications.

A preclinical model of THC edibles that produces high-dose cannabimimetic responses.

No preclinical experimental approach enables the study of voluntary oral consumption of high-concentration Δ9-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here, we developed a palatable THC formulation and an optimized access paradigm in mice to drive voluntary consumption. THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowed ad libitum access for 1 and 2 hr. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain tissue. Acute acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior. When allowed access for 2 hr to THC-E-gel on the second day of a 3-day exposure paradigm, adult mice consumed up to ≈30 mg/kg over 2 hr, which resulted in robust cannabimimetic behavioral responses (hypolocomotion, analgesia, and hypothermia). Consumption of the same gelatin decreased on the following third day of exposure. Pharmacokinetic analysis shows that THC-E-gel consumption led to parallel accumulation of THC and its psychoactive metabolite, 11-OH-THC, in the brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following THC intraperitoneal (i.p.) injections. THC-E-gel consumption increased the acoustic startle response in males but not in females, demonstrating a sex-dependent effect of consumption. Thus, while voluntary consumption of THC-E-gel triggered equivalent cannabimimetic responses in male and female mice, it potentiated acoustic startle responses preferentially in males. We built a dose-prediction model that included cannabimimetic behavioral responses elicited by i.p. versus THC-E-gel to test the accuracy and generalizability of this experimental approach and found that it closely predicted the measured acoustic startle results in males and females. In summary, THC-E-gel offers a robust preclinical experimental approach to study cannabimimetic responses triggered by voluntary consumption in mice, including sex-dependent psychotomimetic responses.

Nanoemulsions: summary of a decade of research and recent advances.

Nanoemulsions consist of a combination of several components such as oil, water, emulsifiers, surfactants and cosurfactants. Various techniques for producing nanoemulsions include high-energy and low-energy approaches such as high-pressure homogenization, microfluidization, jet disperser and phase inversion methods. The properties of a formulation can be influenced by elements such as the composition, concentration, size and charge of droplets, which in turn can affect the technique of manufacture. Characterization is conducted by the assessment of several factors such as physical properties, pH analysis, viscosity measurement and refractive index determination. This article offers a thorough examination of the latest developments in nanoemulsion technology, with a focus on their wide-ranging applications and promising future possibilities. It also discusses the administration of nanoemulsions through several methods.

Tranexamic acid by the intramuscular or intravenous route for the prevention of postpartum haemorrhage in women at increased risk: a randomised placebo-controlled trial (I'M WOMAN).

BACKGROUND: Postpartum haemorrhage (PPH) causes about 70,000 maternal deaths every year. Tranexamic acid (TXA) is a life-saving treatment for women with PPH. Intravenous (IV) TXA reduces deaths due to PPH by one-third when given within 3 h of childbirth. Because TXA is more effective when given early and PPH usually occurs soon after childbirth, giving TXA just before childbirth might prevent PPH. Although several randomised trials have examined TXA for PPH prevention, the results are inconclusive. Because PPH only affects a small proportion of births, we need good evidence on the balance of benefits and harms before using TXA to prevent PPH. TXA is usually given by slow IV injection. However, recent research shows that TXA is well tolerated and rapidly absorbed after intramuscular (IM) injection, achieving therapeutic blood levels within minutes of injection. METHODS: The I'M WOMAN trial is an international, multicentre, three-arm, randomised, double-blind, placebo-controlled trial to assess the effects of IM and IV TXA for the prevention of PPH in women with one or more risk factors for PPH giving birth vaginally or by caesarean section. DISCUSSION: The trial will provide evidence of the benefits and harms of TXA for PPH prevention and the effects of the IM and IV routes of administration. The IM route should be as effective as the IV route for preventing bleeding. There may be fewer side effects with IM TXA because peak blood concentrations are lower than with the IV route. IM TXA also has practical advantages as it is quicker and simpler to administer. By avoiding the need for IV line insertion and a slow IV injection, IM administration would free up overstretched midwives and doctors to focus on looking after the mother and baby and expand access to timely TXA treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05562609. Registered on 3 October 2022. ISRCTN Registry ISRCTN12590098. Registered on 20 January 2023. Pan African Clinical Trial Registry PACTR202305473136570. Registered on 18 May 2023.

Δ9-tetrahydrocannabinol discrimination: Effects of route of administration in mice.

Background: Route of administration is an important pharmacokinetic variable in development of translationally relevant preclinical models. Humans primarily administer cannabis through smoking, vaping, and edibles. In contrast, preclinical research has historically utilized injected Δ9-tetrahydrocannabinol (THC). The present study sought to examine how route of administration affected the potency and time course of THC's discriminative stimulus properties. Methods: Adult female and male C57BL/6 mice were trained to discriminate intraperitoneal (i.p.) THC from vehicle in a drug discrimination procedure. After discrimination was acquired, a dose-effect curve was determined for i.p., oral (p.o.), subcutaneous (s.c.), and aerosolized THC. Subsequently, the time course of effects of each route of administration was determined. Results: THC administered i.p., p.o., s.c., or via aerosolization fully substituted for i.p. THC. The potency of THC's psychoactive effects was similar for i.p., p.o., and s.c., except that THC was more potent when administered s.c. vs p.o. in females. All routes of administration had a similar potency in both sexes. The duration of THC's psychoactive effects was similar across i.p., s.c., and p.o. routes of administration, whereas aerosolized THC produced a faster onset and shorter duration of effects compared to the other routes. Conclusion: THC administered via multiple routes of administration, including those commonly used in preclinical research (i.p. and s.c.) and more translationally relevant routes (aerosol and p.o.), produced THC-like discriminative stimulus effects in mice trained to discriminate i.p. THC. More precise predictions of THC's effects in humans may result from use of these translationally relevant routes of administration.

Association between culture and the preference for, and perceptions of, 11 routes of medicine administration: A survey in 21 countries and regions.

Medicines can be taken by various routes of administration. These can impact the effects and perceptions of medicines. The literature about individuals' preferences for and perceptions of the different routes of administration is sparse, but indicates a potential influence of culture. Our aim was to determine: (i) any association between one's culture and one's preferred route of medicine administration and (ii) individual perceptions of pain, efficacy, speed of action and acceptability when medicines are swallowed or placed in the mouth, under the tongue, in the nose, eye, ear, lungs, rectum, vagina, on the skin, or areinjected. A cross-sectional, questionnaire-based survey of adults was conducted in 21 countries and regions of the world, namely, Tunisia, Ghana, Nigeria, Turkey, Ethiopia, Lebanon, Malta, Brazil, Great Britain, United States, India, Serbia, Romania, Portugal, France, Netherlands, Japan, South Korea, Hong Kong, mainland China and Estonia, using the Inglehart-Welzel cultural map to ensure coverage across all cultures. Participants scored the pain/discomfort, efficacy, speed of onset and acceptability of the different routes of medicine administration and stated their preferred route. Demographic information was collected. A total of 4435 participants took part in the survey. Overall, the oral route was the most preferred route, followed by injection, while the rectal route was the least preferred. While the oral route was the most preferred in all cultures, the percentage of participants selecting this route varied, from 98% in Protestant Europe to 50% in the African-Islamic culture. A multinomial logistic regression model revealed a number of predictors for the preferred route. Injections were favoured in the Baltic, South Asia, Latin America and African-Islamic cultures while dermal administration was favoured in Catholic Europe, Baltic and Latin America cultures. A marked association was found between culture and the preference for, and perceptions of the different routes by which medicines are taken. This applied to even the least favoured routes (vaginal and rectal). Only women were asked about the vaginal route, and our data shows that the vaginal route was slightly more popular than the rectal one.

Extracellular vesicles of the probiotic bacteria E. coli O83 activate innate immunity and prevent allergy in mice.

BACKGROUND: E. coli O83 (Colinfant Newborn) is a Gram-negative (G-) probiotic bacterium used in the clinic. When administered orally, it reduces allergic sensitisation but not allergic asthma. Intranasal administration offers a non-invasive and convenient delivery method. This route bypasses the gastrointestinal tract and provides direct access to the airways, which are the target of asthma prevention. G- bacteria such as E. coli O83 release outer membrane vesicles (OMVs) to communicate with the environment. Here we investigate whether intranasally administered E. coli O83 OMVs (EcO83-OMVs) can reduce allergic airway inflammation in mice. METHODS: EcO83-OMVs were isolated by ultracentrifugation and characterised their number, morphology (shape and size), composition (proteins and lipopolysaccharide; LPS), recognition by innate receptors (using transfected HEK293 cells) and immunomodulatory potential (in naïve splenocytes and bone marrow-derived dendritic cells; BMDCs). Their allergy-preventive effect was investigated in a mouse model of ovalbumin-induced allergic airway inflammation. RESULTS: EcO83-OMVs are spherical nanoparticles with a size of about 110 nm. They contain LPS and protein cargo. We identified a total of 1120 proteins, 136 of which were enriched in OMVs compared to parent bacteria. Proteins from the flagellum dominated. OMVs activated the pattern recognition receptors TLR2/4/5 as well as NOD1 and NOD2. EcO83-OMVs induced the production of pro- and anti-inflammatory cytokines in splenocytes and BMDCs. Intranasal administration of EcO83-OMVs inhibited airway hyperresponsiveness, and decreased airway eosinophilia, Th2 cytokine production and mucus secretion. CONCLUSIONS: We demonstrate for the first time that intranasally administered OMVs from probiotic G- bacteria have an anti-allergic effect. Our study highlights the advantages of OMVs as a safe platform for the prophylactic treatment of allergy. Video Abstract.

Efficacy/Safety of the Use of Glucocorticoids in Oral and Maxillofacial Surgery.

INTRODUCTION: Glucocorticoids, also known as corticosteroids or steroids, are drugs derived from cholesterol. They are synthesized by the adrenal cortex, along with other hormones, such as cortisol and aldosterone. Glucocorticoids are drugs recommended for patients undergoing surgery on the oral cavity, facial skeleton, and related cervical structures due to their high efficacy against inflammatory and immune processes. However, these drugs are restricted due to their multiple and serious adverse effects. The objective of this study was to verify the efficacy of corticosteroids administered in major surgeries of the oral cavity, as well as of the cervical and facial structures, based on the characteristics of the patient so as to select the best therapeutic strategy. METHODS: Articles in the databases of PubMed, Nature Portfolio, Medline, Cochrane Library, and Google Scholar were thoroughly examined. RESULTS: A total of 54 articles were selected to address the proposed objectives. The results obtained show that it is effective and safe to use glucocorticoids as pre- or postsurgical therapy in oral and maxillofacial surgery to control the processes of inflammation, pain, lockjaw, and edema. However, when referring to the use of these drugs, one must proceed with caution and pay particular attention when handling them. The concentration of the glucocorticoids used must be individualized, as well as the selection of the route of administration. Various studies show that, although the oral route is the most used route, the most effective route is the intramuscular route due to its easy absorption. However, for patients who have recurrent inflammatory and vesiculobullous ulcerative lesions, the topical route should be chosen to mitigate side effects, considering that recurrent applications must be made to prevent the worsening of the lesion and to avoid having to use medications enterally. In patients with cervicofacial infections, antibiotics continue to be the main drugs used to manage the condition in conjunction with corticosteroids. It is important to know the possible interactions of glucocorticoids with other medicines or food: it has been described that the interaction between Ritonavir, an antiretroviral drug that inhibits human immunodeficiency virus (HIV) proteases, and prednisone causes an increase in the concentration of prednisone, leading to possible toxicity in normally safe doses and, in many cases, iatrogenic Cushing's syndrome. It is also important to know the systemic or topical adverse effects of the chronic or high-dose use of glucocorticoids. CONCLUSIONS: It can be concluded that by making adequate use of glucocorticoid therapy in oral and maxillofacial surgery to manage clinical manifestations, it is possible to attenuate the morbidities of treatment and intervention.

Δ9-Tetrahydrocannabinol Effects on Respiration and Heart Rate Across Route of Administration in Female and Male Mice.

The physiological impact of cannabinoid receptor agonists is of great public health interest due to their increased use in recreational and therapeutic contexts. However, the body of literature on cannabinoid receptor agonists includes multiple confounding variables that complicate comparisons across studies, including route of administration, timeline across which phenotypes are observed, agonist dose, and sex of the study cohort. In this study, we characterized the impact of sex and route of administration on Δ9-tetrahydrocannabinol (THC)-induced changes in cardiopulmonary phenotypes in mice. Using noninvasive plethysmography and telemetry, we monitored heart rate and respiration in the same cohort of animals across aerosol, oral gavage, subcutaneous, and intraperitoneal administrations of THC (0-30 mg/kg THC for oral gavage, subcutaneous, and intraperitoneal, and 0-300 mg/ml THC for aerosol). All routes of THC administration altered respiratory minute volume and heart rate, with the direction of effects typically being consistent across dependent measures. THC primarily decreased respiration and heart rate, but females given oral gavage THC showed increased heart rate. Intraperitoneal and subcutaneous THC produced the longest-lasting effects, including THC-induced alterations in physiological parameters for up to 10 h, whereas effects of aerosolized THC were short lived. The fastest onset of effects of THC occurred for aerosolized and intraperitoneal THC. Altogether, the work herein establishes the impact of dosing route on THC-induced heart rate and respiratory alteration in male and female mice. This study highlights important differences in the timeline of cardiopulmonary response to THC following the most common preclinical routes of administration.

Challenges in tolerogenic dendritic cell therapy for autoimmune diseases: the route of administration.

Tolerogenic dendritic cells (tolDCs) are a promising strategy to treat autoimmune diseases since they have the potential to re-educate and modulate pathological immune responses in an antigen-specific manner and, therefore, have minimal adverse effects on the immune system compared to conventional immunosuppressive treatments. TolDC therapy has demonstrated safety and efficacy in different experimental models of autoimmune disease, such as multiple sclerosis (MS), type 1 diabetes (T1D), and rheumatoid arthritis (RA). Moreover, data from phase I clinical trials have shown that therapy with tolDCs is safe and well tolerated by MS, T1D, and RA patients. Nevertheless, various parameters need to be optimized to increase tolDC efficacy. In this regard, one important parameter to be determined is the most appropriate route of administration. Several delivery routes, such as intravenous, subcutaneous, intraperitoneal, intradermal, intranodal, and intraarticular routes, have been used in experimental models as well as in phase I clinical trials. This review summarizes data obtained from preclinical and clinical studies of tolDC therapy in the treatment of MS, T1D, and RA and their animal models, as well as data from the context of cancer immunotherapy using mature peptide-loaded DC, and data from in vivo cell tracking experiments, to define the most appropriate route of tolDC administration in relation to the most feasible, safest, and effective therapeutic use.

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation.

Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient's white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers.

Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)-approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions.

Practical Considerations for Next-Generation Adjuvant Development and Translation.

Over the last several years, there has been increased interest from academia and the pharmaceutical/biotech industry in the development of vaccine adjuvants for new and emerging vaccine modalities. Despite this, vaccine adjuvant development still has some of the longest timelines in the pharmaceutical space, from discovery to clinical approval. The reasons for this are manyfold and range from complexities in translation from animal to human models, concerns about safety or reactogenicity, to challenges in sourcing the necessary raw materials at scale. In this review, we will describe the current state of the art for many adjuvant technologies and how they should be approached or applied in the development of new vaccine products. We postulate that there are many factors to be considered and tools to be applied earlier on in the vaccine development pipeline to improve the likelihood of clinical success. These recommendations may require a modified approach to some of the common practices in new product development but would result in more accessible and practical adjuvant-containing products.

The Secretome of Mesenchymal Stromal Cells in Treating Intracerebral Hemorrhage: The First Step to Bedside.

Intracerebral hemorrhage is an unmet medical need that often leads to the disability and death of a patient. The lack of effective treatments for intracerebral hemorrhage makes it necessary to look for them. Previously, in our proof-of-concept study (Karagyaur M et al. Pharmaceutics, 2021), we have shown that the secretome of multipotent mesenchymal stromal cells (MSC) provides neuroprotection of the brain in a model of intracerebral hemorrhage in rats. Here, we have conducted a systematic study of the therapeutic potential of the MSC secretome in the model of hemorrhagic stroke and provided answers to the questions that need to be addressed in order to translate the secretome-based drug into clinical practice: routes and multiplicity of administration, optimal dose and door-to-treatment time. We have found that MSC secretome reveals prominent neuroprotective activity when administered intranasally or intravenously within 1-3 h after hemorrhage modeling, even in aged rats, and its multiple injections (even within 48 h) are able to reduce the delayed negative effects of hemorrhagic stroke. To our knowledge, this study provides the first systematic investigation of the therapeutic activity of a biomedical MSC-based cell-free drug in intracerebral hemorrhage and is an integral part of its preclinical studies.

Systemic Antimicrobial Treatment of Chronic Osteomyelitis in Adults: A Narrative Review.

Chronic osteomyelitis in adults is a complex condition that requires prolonged and intensive antimicrobial therapy, but evidence on optimal selection and duration of antibiotics is limited. A review of PubMed and Ovid Embase databases was conducted to identify systematic reviews, meta-analyses, retrospective and randomised controlled trials (RCTs) on antibiotic treatment outcomes in adults with chronic osteomyelitis. Three main areas of interest were investigated: short-term versus long-term antibiotic therapy, oral versus parenteral antibiotic therapy, and combination antibiotic therapy with rifampicin versus without rifampicin. A total of 36 articles were identified and findings were synthesised using a narrative review approach. The available literature suffers from limitations, including a lack of high-quality studies, inconsistent definitions, and varying inclusion/exclusion criteria among studies. Most studies are open-labelled and lack blinding. Limited high-quality evidence exists that oral therapy is non-inferior to parenteral therapy and that shorter antibiotic duration might be appropriate in low-risk patients. Studies on the impact of rifampicin are inconclusive. Further well-designed studies are needed to provide more robust evidence in these areas.

Propylene glycol and Kolliphor as solvents for systemic delivery of cannabinoids via intraperitoneal and subcutaneous routes in preclinical studies: a comparative technical note.

BACKGROUND: Substance administration to laboratory animals necessitates careful consideration and planning in order to enhance agent distribution while reducing any harmful effects from the technique. There are numerous methods for administering cannabinoids; however, several parameters must be considered, including delivery frequency, volume of administration, vehicle, and the level of competence required for staff to use these routes properly. There is a scarcity of information about the appropriate delivery method for cannabinoids in animal research, particularly those that need the least amount of animal manipulation during the course of the investigation. This study aims to assess the feasibility and potential side effects of intraperitoneal and subcutaneous injection of CBD and THC using propylene glycol or Kolliphor in animal models. By evaluating the ease of use and histopathological side effects of these solvents, this study intends to help researchers better understand an accessible long-term delivery route of administration in animal experiments while minimizing the potential confounding effects of the delivery method on the animal. METHODS: Intraperitoneal and subcutaneous methods of systemic cannabis administration were tested in rat models. Subcutaneous delivery via needle injection and continuous osmotic pump release were evaluated using propylene glycol or Kolliphor solvents. In addition, the use of a needle injection and a propylene glycol solvent for intraperitoneal (IP) administration was investigated. Skin histopathological changes were evaluated following a trial of subcutaneous injections of cannabinoids utilizing propylene glycol solvent. DISCUSSION: Although IP delivery of cannabinoids with propylene glycol as solvent is a viable method and is preferable to oral treatment in order to reduce gastrointestinal tract degradation, it has substantial feasibility limitations. We conclude that subcutaneous delivery utilizing osmotic pumps with Kolliphor as a solvent provides viable and consistent route of administration for long-term systemic cannabinoid delivery in the preclinical context.