Papers by Michelle McIntosh
The Journal of Forensic Odonto-Stomatology, 2019
Back Background ground The high prevalence of poor quality essential medicines in low and middle ... more Back Background ground The high prevalence of poor quality essential medicines in low and middle income countries (LMIC) presents considerable risks in terms of both health outcomes and economic cost. Oxytocin injection, the gold standard therapy for management of postpartum haemorrhage (PPH), presents a particular challenge in this area. Recent studies in India, Nigeria and DRC have identified product failure rates, in terms of low drug content, to be 41%, 74% and 80% respectively. Ethiopia bears a high burden of PPH with over 40% of maternal deaths being directly attributed to haemorrhagic causes. This study assessed the quality of oxytocin injection at points in the public and private supply chains to support national efforts to address PPH in Ethiopia. Methods Methods This study sampled oxytocin injection ampoules from 45 sites across Oromia, Afar regions and the administrative area of Addis Ababa. This included points along the public supply chain from the national point of entry for supplies through regional hubs to points of use (public and private facilities) in urban and rural areas. Collected samples were stored under refrigerated conditions until analysis for oxytocin content, known degradation products and microbiological quality. R Results esults Ninety-six percent of ampoules passed all tests, while two samples (4%) contained less than the specified oxytocin content. Both samples were collected from rural facilities in Afar, a remote, poorly resourced region with a very hot climate. All supplies collected were sourced from European stringent regulatory approved (SRA) suppliers and, where storage conditions could be determined, approximately 95% of samples were stored in the refrigerator at the time of collection. C Conclusions onclusions The study indicates that oxytocin injection in the selected regions is generally of high quality and being stored appropriately. The failed samples detected in Afar suggest challenges remain around maintenance of refrigerated storage in least resourced settings. These findings contrast with recent results in other African countries and support the joint
Journal of Global Health, 2018
BMJ open, Jan 24, 2018
This study assessed the potential operational feasibility and acceptability of a heat-stable, inh... more This study assessed the potential operational feasibility and acceptability of a heat-stable, inhaled oxytocin (IOT) product for community-based prevention of postpartum haemorrhage in Myanmar. A qualitative inquiry was conducted between June 2015 and February 2016 through focus group discussions and in-depth interviews. Research was conducted in South Dagon township (urban setting) and in Ngape and Thanlyin townships (rural settings) in Myanmar. Eleven focus group discussions and 16 in-depth interviews were conducted with mothers, healthcare providers and other key informants. All audio recordings were transcribed verbatim in Myanmar language and were translated into English. Thematic content analysis was done using NVivo software. Future introduction of an IOT product for community-based services was found to be acceptable among mothers and healthcare providers and would be feasible for use by lower cadres of healthcare providers, even in remote settings. Responses from healthcare...
PloS one, 2018
Oxytocin is the gold standard drug for the prevention of postpartum haemorrhage, but limitations ... more 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. Qualitative inquiries were undertaken in Ethiopia, India and Myanmar, where data was collected through Focus Group Discussions (FGDs) and In-Depth Interviews (IDIs). A total of 12 FGDs and 106 IDIs were conducted with 158 healthcare providers (pharmacists, midwives, nurses, doctors and obstetricians) and 40 key informants (supply chain experts, program managers and policy-makers). Direct observations of oxytocin storage practices and cold chain resources were conducted at 51 healthcare facilities. Verbatim transcripts of FGDs and ID...
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, Jan 13, 2017
PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platfor... more PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platforms that have the potential to control the release, absorption kinetics and lung retention time of conjugated drugs. The clinical application of these systems though, would likely require partial substitution of surface PEG groups with drug molecules that are anticipated to alter their lung clearance kinetics and clearance pathways. In the current study, we therefore evaluated the impact of increased surface hydrophobicity via substitution of 50% surface PEG groups with a model hydrophobic drug (α-carboxyl OtButylated methotrexate) on the lung clearance of a Generation 5 PEGylated polylysine dendrimer in rats. PEG substitution with OtBu-methotrexate accelerated lung clearance of the dendrimer by increasing polylysine scaffold catabolism, improving systemic absorption of the intact dendrimer and low molecular weight products of scaffold catabolism, and enhancing mucociliary clearance. Thes...
Macromolecular rapid communications, Jan 17, 2016
The controlled synthesis of poly(oligo(2-ethyl-2-oxazoline)methacrylate) (P(OEtOxMA)) polymers by... more 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. These P(OEtOxMA) are subsequently site-specifically conjugated, via reductive amination, to a dipeptide (NH2 -Gly-Tyr-COOH) as a model peptide, prior to conjugation to the functional peptide oxytocin. The resulting oxytocin conjugates are evaluated in comparison to poly(oligo(ethylene glycol) methyl ether methacrylate) combs synthesized in the same manner for potential effects on thermal stability in comparison to the native peptide.
Antimicrobial Agents and Chemotherapy, 2016
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in ... more 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. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimi...
Biomacromolecules, 2016
is an open access article published under an ACS AuthorChoice License, which permits copying and ... more is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for noncommercial purposes. The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP URL' above for details on accessing the published version and note that access may require a subscription.
Journal of Antimicrobial Chemotherapy, 2016
Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bac... more 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. aeruginosa were employed. Combinations of fosfomycin plus polymyxin B, tobramycin or ciprofloxacin were examined over 24 h using time-kill studies (inocula 10 6 cfu/mL) incorporating clinically relevant concentrations (fosfomycin, 30, 150 or 300 mg/L; polymyxin B, 0.5, 1 or 2 mg/L; tobramycin, 0.5, 1.5 or 4 mg/L; ciprofloxacin, 0.5, 1 or 2.5 mg/L). Microbiological response was examined by log changes and population analysis profiles. Results: Against susceptible isolates, monotherapy produced varying degrees of initial killing followed by rapid regrowth. Fosfomycin plus polymyxin B or tobramycin produced greater initial killing (up to 4 log 10 cfu/mL) with many concentrations compared with monotherapy against fosfomycin-susceptible (FOF S) isolates. With these combinations, synergy or additivity was observed in 54 (67%) and 49 (60%) of 81 cases (nine combinations across three isolates at three timepoints) for polymyxin B and tobramycin, respectively. Substantial improvements in killing were absent against fosfomycin-resistant (FOF R) isolates. For fosfomycin/ciprofloxacin combinations, synergy or additivity was observed against FOF R isolates in 33 of 54 (61%) cases (nine combinations across two isolates at three timepoints), while improvements in killing were largely absent against FOF S isolates. No combination prevented emergence of fosfomycin resistance. Conclusions: Against P. aeruginosa, fosfomycin in combination with polymyxin B or tobramycin (FOF S isolates) or ciprofloxacin (FOF R isolates) increased bacterial killing, but did not suppress emergence of fosfomycin resistance.
The Journal of antimicrobial chemotherapy, Jan 24, 2015
The use of fosfomycin for treatment of systemic infections due to MDR Pseudomonas aeruginosa is i... more The use of fosfomycin for treatment of systemic infections due to MDR Pseudomonas aeruginosa is increasing. However, pharmacodynamic data for fosfomycin are limited. Sixty-four clinical isolates of P. aeruginosa (MDR and non-MDR) from two Australian hospitals were collected; 59 isolates were from patients with cystic fibrosis and 5 isolates were from critically ill patients. The in vitro pharmacodynamic properties of fosfomycin (disodium) were investigated via MICs (all isolates) and, for selected isolates, via time-kill kinetics (static and dynamic models; concentration range, 1-1024 mg/L), population analysis profiles (PAPs) and post-antibiotic effect (PAE). Two inocula (∼10(6) and ∼10(8) cfu/mL) were included in static time-kill studies to examine the effect of inocula on bacterial killing. MICs ranged from 1 to >512 mg/L, with 61% of isolates considered fosfomycin susceptible (MIC ≤64 mg/L). The MIC distributions for MDR and non-MDR isolates were similar. Baseline PAPs indica...
Bioconjugate chemistry, Jan 5, 2015
The 'in-situ' one-pot synthesis of peptide-polymer bioconjugates is reported. Conjugation... more 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.
Journal of Aerosol Medicine and Pulmonary Drug Delivery, 2015
Background: Pulmonary immunization has recently gained increased interest as a means to induce bo... more Background: Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules. Methods: Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes. Results: The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (T g) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma. Conclusions: The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.
D32. AEROSOLS THERAPY, 2012
PLoS ONE, 2013
Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the... more Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG) activity in postpartum ewes following pulmonary (in vivo) administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb). In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s) than intramuscular injection (275 ± 22 s). This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.
Journal of Pharmaceutical and Biomedical Analysis, 2001
The development and validation of an effective and simplified LC assay for the quantitation of et... more The development and validation of an effective and simplified LC assay for the quantitation of etomidate in beagle plasma is described. The methodology employs a rapid and simple protein precipitation procedure in combination with previously reported chromatographic conditions. Using a 0.3 ml aliquot of plasma, the assay is linear in the concentration range of 50 to 5000 ng/ml, with an extraction efficiency between 97 to 104% and accuracy between 98 and 105%.
Current Alzheimer Research, 2006
Most drug discovery efforts for Alzheimer's disease (AD) have focused on prevention or clearance ... more Most drug discovery efforts for Alzheimer's disease (AD) have focused on prevention or clearance of βamyloid (Aβ) fibrils or oligomers, with far less attention to prevention of τ abnormalities that lead to neurofibrillary tangles (NFTs). Much evidence now indicates that Aβ multimers can trigger neurodegenerative changes that involve formation of dystrophic neurites and cytoskeletal collapse, possibly due loss of microtubule (MT) stabilization by the τ protein. We have found that several MT-stabilizing agents such as Taxol significantly enhanced neuronal survival in the presence of Aβ and identified agents that enter the brain, a necessity for in vivo testing in animal models of τ pathology. Studies were designed to test two agents in the τ mutant (JNPL3) mouse that develops severe motor deficits at about seven months of age, accompanied by neuropathological markers of τ pathology. In addition to using motor performance tests through the planned period of drug administration, we designed a simple appetitive memory test that required a reduction in ad lib food intake. Although the neurochemical data are still being analyzed, we were surprised to find that all of the JNPL3 mice, whether receiving the drug or not, developed no signs of motor impairment up to 10 months of age. This is considerably beyond the age at which free-fed mice survived and suggests that the food restriction alone may have delayed the pathological process. A study is ongoing with free-fed mice to determine if the drug interventions do have any beneficial effects in these mutant mice.
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Papers by Michelle McIntosh