Application of immunocapture and nanoflow LC-MS/MS to overcome the barriers to the quantitation of oxytocin in plasma of women in third stage labour.

Aims: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. To prevent PPH, the WHO recommends administration of oxytocin (OT) immediately after birth, i.e.

Exploring the role of ex vivo metabolism on blood and plasma measurements of oxytocin among women in the third stage of labour: A post hoc study.

Aims: To examine the role of ex vivo oxytocin metabolism in post-dose peptide measurements.

Methods: The stability of oxytocin (Study 1) and oxytocinase activity (Study 2) in late-stage pregnancy blood was quantified using liquid-chromatography tandem mass-spectrometry (LC-MS/MS) and a fluorogenic assay, respectively. Analyses were conducted using blood from pregnant women (>36 weeks gestation) evaluated in lithium heparin (LH), ethylenediaminetetraacetic acid (EDTA) and BD P100 blood collection tubes with or without protease inhibitors.

Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep.

Purpose: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization.

Pharmacokinetics and safety of inhaled oxytocin compared with intramuscular oxytocin in women in the third stage of labour: A randomized open-label study.

Aims: To compare pharmacokinetics (PK) and safety of heat-stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety.

Methods: A phase 1, randomized, cross-over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception).

Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system.

The WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to engage a global network of laboratories to experimentally quantify the pH-dependent solubility of the highest therapeutic dose of 16 APIs using a harmonized protocol. Intra-laboratory variability was ≤5 %, and no apparent association of inter-laboratory variability with API solubility was discovered.

The impact of size and charge on the pulmonary pharmacokinetics and immunological response of the lungs to PLGA nanoparticles after intratracheal administration to rats.

Polylactide-co-glycolide (PLGA) nanoparticles are one of the most commonly explored biodegradable polymeric drug carriers for inhaled delivery. Despite their advantages as inhalable nanomedicine scaffolds, we still lack a complete understanding of the kinetics and major pathways by which these materials are cleared from the lungs. This information is important to evaluate their safety over prolonged use and enable successful clinical translation.

Cost-effectiveness of inhaled oxytocin for prevention of postpartum haemorrhage: a modelling study applied to two high burden settings.

Background: Access to oxytocin for prevention of postpartum haemorrhage (PPH) in resource-poor settings is limited by the requirement for a consistent cold chain and for a skilled attendant to administer the injection. To overcome these barriers, heat-stable, non-injectable formulations of oxytocin are under development, including oxytocin for inhalation. This study modelled the cost-effectiveness of an inhaled oxytocin product (IHO) in Bangladesh and Ethiopia.

Oxytocin quality: evidence to support updated global recommendations on oxytocin for postpartum hemorrhage.

Background: The use of quality injectable oxytocin effectively prevents and treats postpartum hemorrhage, the leading cause of maternal death worldwide. In low- and middle-income countries (LMICs), characteristics of oxytocin-specifically its heat sensitivity-challenge efforts to ensure its quality throughout the health supply chain. In 2019, WHO, UNFPA and UNICEF released a joint-statement to clarify and recommend that oxytocin should be kept in the cold chain (between 2 and 8 °C) during transportation and storage; however, confusion among stakeholders in LMICs persists.

Removal of interstitial hyaluronan with recombinant human hyaluronidase improves the systemic and lymphatic uptake of cetuximab in rats.

Interstitial, e.g. subcutaneous (SC) or intradermal (ID), administration of monoclonal antibodies (mAb) is less invasive than intravenous administration and leads to mAb uptake into both lymphatic and blood capillaries draining the injection site.

Qualitative formative implementation research to inform introduction of a new essential medicine.

Background: The launch of novel pharmaceuticals in the developing world faces significant barriers that can delay or ultimately inhibit uptake. Implementation research can provide an understanding of factors influencing the introduction and scale up of a new product and thus can inform implementation strategy development.

Objective: This study explored the factors likely to influence introduction of a novel oxytocin formulation for the prevention of postpartum hemorrhage in Ethiopia.

Temperature stability of oxytocin ampoules labelled for storage at 2°C-8°C and below 25°C: an observational assessment under controlled accelerated and temperature cycling conditions.

Introduction: Oxytocin, administered via injection, is recommended by WHO for the prevention and treatment of postpartum haemorrhage. However, the susceptibility of oxytocin injection to thermal degradation has led WHO and UNICEF to recommend cold-chain storage of all oxytocin products. Nevertheless, some oxytocin products supplied to the global market are labelled for storage at ≤25°C, often with a shorter shelf-life relative to products labelled for refrigeration.

Local inflammation alters the lung disposition of a drug loaded pegylated liposome after pulmonary dosing to rats.

The development of inhalable 'nanomedicines' based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease.

Suggested Procedures for the Reproducible Synthesis of Poly(d,l-lactide-co-glycolide) Nanoparticles Using the Emulsification Solvent Diffusion Platform.

Background: Poly(d,l-lactide-co-glycolide) (PLGA) based biodegradable nanoparticles are of key interest for the development of controlled release drug delivery systems and for other biomedical applications. It has been reported that PLGA polymers can be converted into colloidal nanoparticulate systems by various techniques, such as emulsification-diffusion, emulsification-evaporation, interfacial deposition, salting out, dialysis and nanoprecipitation. Emulsification-evaporation with water immisci-ble solvents including dichloromethane and chloroform has been the preferred method for the synthesis of PLGA nanoparticles due to the low boiling point and limited water solubility of these solvents.

Knowledge, perception and practice towards oxytocin stability and quality: A qualitative study of stakeholders in three resource-limited countries.

Background: Oxytocin is the gold standard drug for the prevention of postpartum haemorrhage, but limitations in cold chain systems in resource-constrained settings can severely compromise the quality of oxytocin product available in these environments. This study investigated the perspectives and practices of stakeholders in low and lower-middle income countries towards oxytocin, its storage requirements and associated barriers, and the quality of product available.

Methods: Qualitative inquiries were undertaken in Ethiopia, India and Myanmar, where data was collected through Focus Group Discussions (FGDs) and In-Depth Interviews (IDIs).

Quality of oxytocin ampoules available in health care facilities in the Democratic Republic of Congo: an exploratory study in five provinces.

Background: Oxytocin injection is the first line therapy for the prevention and treatment of postpartum haemorrhage (PPH), the leading cause of maternal mortality. Currently access to high quality oxytocin in low and middle-income countries (LMICs) is compromised by variable manufacturing quality and the requirement for cold chain supply and storage to prevent product deterioration. Previous studies of oxytocin ampoules sampled from Africa, the region with highest maternal mortality rates, indicate that over half do not contain the specified amount of oxytocin.

Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model.

Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT>MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance.

Methods: Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7).

A comparison of the lung clearance kinetics of solid lipid nanoparticles and liposomes by following the H-labelled structural lipids after pulmonary delivery in rats.

The utility of biodegradable nanosized drug carriers for the local and controlled delivery of therapeutics to the lungs has prompted significant interest in the development of inhalable nanomedicines. Still, little is known about how these systems are cleared from the lungs, including the kinetics of the structural lipids. Most preclinical and clinical studies to date have evaluated the lung clearance of loaded drugs, which in many cases poorly reflects the kinetics of the nanocarrier, or the bulk-labelled particles.

Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study.

Background: The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation.

Methods: This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18-45years.

Comb Poly(Oligo(2-Ethyl-2-Oxazoline)Methacrylate)-Peptide Conjugates Prepared by Aqueous Cu(0)-Mediated Polymerization and Reductive Amination.

The controlled synthesis of poly(oligo(2-ethyl-2-oxazoline)methacrylate) (P(OEtOxMA)) polymers by Cu(0)-mediated polymerization in water/methanol mixtures is reported. Utilizing an acetal protected aldehyde initiator for the polymerization, well-defined polymers are synthesized (>99% conversion, Ð < 1.25) with subsequent postpolymerization deprotection resulting in α-aldehyde end group containing comb polymers.

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model.

Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study.

Stability Enhancing N-Terminal PEGylation of Oxytocin Exploiting Different Polymer Architectures and Conjugation Approaches.

Oxytocin, a cyclic nine amino acid neurohypophyseal hormone therapeutic, is effectively used in the control of postpartum hemorrhaging (PPH) and is on the WHO List of Essential Medicines. However, oxytocin has limited shelf life stability in aqueous solutions, particularly at temperatures in excess of 25 °C and injectable aqueous oxytocin formulations require refrigeration (<8 °C). This is particularly problematic in the hot climates often found in many developing countries where daytime temperatures can exceed 40 °C and where reliable cold-chain storage is not always achievable.

Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance.

Objectives: Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bacterial killing and emergence of fosfomycin resistance with fosfomycin combinations against Pseudomonas aeruginosa.

Methods: Four clinical isolates and a reference strain of P.

Disposition and safety of inhaled biodegradable nanomedicines: Opportunities and challenges.

The inhaled delivery of nanomedicines can provide a novel, non-invasive therapeutic strategy for the more localised treatment of lung-resident diseases and potentially also enable the systemic delivery of therapeutics that are otherwise administered via injection alone. However, the clinical translation of inhalable nanomedicine is being hampered by our lack of understanding about their disposition and clearance from the lungs. This review provides a comprehensive overview of the biodegradable nanomaterials that are currently being explored as inhalable drug delivery systems and our current understanding of their disposition within, and clearance from the lungs.

In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.

Background: The use of fosfomycin for treatment of systemic infections due to MDR Pseudomonas aeruginosa is increasing. However, pharmacodynamic data for fosfomycin are limited.

Methods: Sixty-four clinical isolates of P.

In situ conjugation of dithiophenol maleimide polymers and oxytocin for stable and reversible polymer-peptide conjugates.

The in situ one-pot synthesis of peptide-polymer bioconjugates is reported. Conjugation occurs efficiently without the need for purification of dithiophenol maleimide functionalized polymer as a disulfide bridging agent for the therapeutic oxytocin. Conjugation of polymers was demonstrated to be reversible and to significantly improve the solution stability of oxytocin.