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1.
J Control Release ; 315: 85-96, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31655131

RESUMO

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. Interstitial administration, however, is hindered by the presence of hyaluronan (HA), a glycosaminoglycan that is a major fluid barrier in the interstitial space. The transient removal of HA with recombinant human hyaluronidase (rHuPH20) helps facilitate the interstitial administration of often high therapeutic doses of mAb in the clinic. rHuPH20's impact on the systemic pharmacokinetics of several mAbs has been previously described, however effects on route of absorption (lymph vs blood) are unknown. The current study has therefore explored the lymphatic transport and bioavailability of cetuximab and trastuzumab after SC and ID coadministration in the presence and absence of rHuPH20 in rats. After SC administration cetuximab absolute bioavailability increased from 67 % to 80 % in the presence of rHuPH20. Cetuximab recovery in the lymphatics also increased after SC (35.8 % to 49.4 %) and ID (26.7 % to 58.8 %) administration in the presence of rHuPH20. When the injection volume (and therefore dose) was increased 10-fold in the presence of rHuPH20 cetuximab plasma exposure increased approximately linearly (12- and 8.9-fold respectively after SC and ID administration), although the proportional contribution of cetuximab lymphatic transport reduced slightly (6.2-fold increase for both administration routes). In contrast, co-administration with rHuPH20 did not lead to increases in plasma exposure for trastuzumab after SC or ID administration, most likely reflecting the fact that the reported absolute bioavailability of trastuzumab (in the absence of rHuPH20) is high (∼77-99 %). However, lymphatic transport of trastuzumab did increase when coadministered ID with rHuPH20 in spite of the lack of change to overall bioavailability. The data suggest that co-administration with rHuPH20 is able to increase the volume of mAb that can be administered interstitially, and in some instances can increase the amount absorbed into both the blood and the lymph. In the current studies the ability of rHuPH20 to enhance interstitial bioavailability was higher for cetuximab where intrinsic interstitial bioavailability was low, when compared to trastuzumab where interstitial bioavailability was high.

2.
Res Social Adm Pharm ; 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31375358

RESUMO

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. METHODS: Qualitative research methods were used to assess barriers and enablers associated with pre-determined domains: regulatory approval, pricing, supply and demand side advocacy, policy inclusion, end-user training and drug supply. Data were collected through focus group discussions and in-depth interviews with community members, healthcare providers and key informants. Verbatim transcripts were translated to English and analyzed using a thematic content framework. RESULTS: Approval from stringent regulatory bodies was an enabler for gaining national regulatory approval. Purchasers (government and patients) expressed price sensitivity but would be willing to pay a price comparable to or higher than current alternatives if improved quality is delivered. Endorsement from the World Health Organization was described as critical for national policy inclusion. Supply side advocacy should be directed towards the Ministry of Health, which is receptive to advice from reputable agencies with whom they have an existing relationship. Demand side advocacy should be delivered through existing health system channels such as Ministry of Health authorities (for healthcare workers) and community health workers (for community members). The requirement to purchase the product directly from a single manufacturer was highlighted as a potential barrier for entry into the local supply chain. CONCLUSION: This study highlighted several barriers and enablers associated with the introduction of a new drug product into the health system of Ethiopia. An advanced understanding of these influences can inform the design of locally-appropriate implementation strategies.

3.
BMJ Open ; 9(7): e029083, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350247

RESUMO

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. Differences in labelled storage requirements can lead to uncertainties among stakeholders around the relative stability of oxytocin products and specifically whether ≤25°C products are more resistant to degradation. Such confusion can potentially influence policies associated with procurement, distribution, storage and the use of oxytocin in resource-poor settings. OBJECTIVES: To compare the stability of oxytocin injection ampoules formulated for storage at ≤25°C with those labelled for refrigerated storage. DESIGN: Accelerated and temperature cycling stability studies were performed with oxytocin ampoules procured by the United Nations Population Fund (UNFPA) from four manufacturers. METHOD: Using oxytocin ampoules procured by UNFPA, accelerated stability (up to 120 days) and temperature cycling (up to 135 days between elevated and refrigerated temperatures) studies were performed at 30°C, 40°C and 50°C. Oxytocin content was quantified using a validated HPLC-UV method. RESULTS: All ampoules evaluated exhibited similar stability profiles under accelerated degradation conditions with the exception of one product formulated for ≤25°C storage, where the rate of degradation increased at 50°C relative to other formulations. Similar degradation trends at elevated temperatures were observed during temperature cycling, while no significant degradation was observed during refrigerated periods of the study. CONCLUSION: Oxytocin ampoules formulated for non-refrigerated storage demonstrated comparable stability to those labelled for refrigerated storage and should not be interpreted by stakeholders as offering a more stable alternative. Furthermore, these products should not be procured for use in territories with high ambient temperatures, where all oxytocin injection products should be supplied and stored under refrigerated conditions.

4.
J Control Release ; 307: 32-43, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31152749

RESUMO

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. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a 3H-labelled PEGylated liposome loaded with a model drug (ciprofloxacin) after intratracheal administration to healthy rats and rats with bleomycin-induced lung inflammation by following both 3H label and drug. Cell- and cytokine-based markers of lung inflammation were used to evaluate the response of healthy and inflamed lungs to the liposome. Liposomes were initially cleared more rapidly from inflamed lungs than from healthy lungs, but exhibited similar rates of lung clearance after 3 days. This was interesting given that mucociliary clearance was more efficient from healthy lungs, despite evidence of higher mucus retention in inflamed lungs and reduced association of the liposome with lung tissue. Although the plasma pharmacokinetics of ciprofloxacin did not differ between rats with healthy or inflamed lungs after pulmonary administration, the plasma pharmacokinetics of 3H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1ß were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in lung inflammatory markers were identified in healthy or bleomycin-challenged rats.

5.
Curr Nanosci ; 14(5): 448-453, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30532669

RESUMO

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. We and others, however, have found that when water-immiscible solvents are used for the synthesis of PLGA nanoparticles, particle aggregation, non-uniform particle size and multimodal size distribution are commonly encountered problems. This suggests that the synthesis of PLGA nanoparticles using water immiscible solvents is highly sensitive to small procedural variations that affect overall reproduc-ibility. Objective: This study presents a simple and robust procedure for the preparation of PLGA nanoparti-cles with very small batch to batch variability (<5% variability in size (z-average) as determined by dynamic light scattering). Results: The results showed that the emulsification solvent diffusion method teamed with partially water-miscible solvents, such as ethyl acetate, is a versatile approach for the preparation of PLGA na-noparticles with highly reproducible sizes (between 50 and 400 nm) and zeta potentials (between -30 and +30 mV), with relatively narrow polydispersity. Conclusion: Emulsification-diffusion with ethyl acetate is, therefore, a more reliable alternative to sev-eral existing procedures for the reproducible and refined synthesis of PLGA nanoparticles.

6.
BMJ Open ; 8(10): e022140, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30361400

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 providers and community members highlighted that midwives and volunteer auxiliary midwives would be key advocates for promoting community acceptance of the product. Healthcare providers perceived the ease of use and lack of dependence on cold storage as the main enablers for IOT compared with the current gold standard oxytocin injection. A single-use disposable device with clear pictorial instructions and a price that would be affordable by the poorest communities was suggested. Appropriate training was also said to be essential for the future induction of the product into community settings. CONCLUSION: In Myanmar, where home births are common, access to cold storage and skilled personnel who are able to deliver injectable oxytocin is limited. Among community members and healthcare providers, IOT was perceived to be an acceptable and feasible intervention for use by lower cadres of healthcare workers, and thus may be an alternative solution for the prevention of postpartum haemorrhage in community-based settings in the future.


Assuntos
Ocitocina/administração & dosagem , Aceitação pelo Paciente de Cuidados de Saúde , Hemorragia Pós-Parto/prevenção & controle , Administração por Inalação , Adulto , Serviços de Saúde Comunitária/métodos , Parto Obstétrico , Estudos de Viabilidade , Feminino , Grupos Focais , Acesso aos Serviços de Saúde , Parto Domiciliar , Humanos , Entrevistas como Assunto , Tocologia/métodos , Mães , Mianmar , Gravidez , Pesquisa Qualitativa , Adulto Jovem
7.
PLoS One ; 13(9): e0203810, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30252860

RESUMO

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). 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 IDIs were translated to English and analysed according to a thematic content analysis framework. FINDINGS: Stakeholder awareness of oxytocin heat sensitivity and the requirement for cold storage of the drug was widespread in Ethiopia but more limited in Myanmar and India. A consistent finding across all study regions was the significant barriers to maintaining a consistent cold chain, with the lack of refrigeration facilities and unreliability of electricity cited as major challenges. Perceptions of compromised oxytocin quality were expressed by some stakeholders in each country. CONCLUSION: Knowledge of the heat sensitivity of oxytocin and the potential impacts of inconsistent cold storage on product quality is not widespread amongst healthcare providers, policy makers and supply chain experts in Myanmar, Ethiopia and India. Targeted training and advocacy messages are warranted to emphasise the importance of cold storage to maintain oxytocin quality.


Assuntos
Armazenamento de Medicamentos/métodos , Ocitocina/química , Ocitocina/normas , Temperatura Baixa , Países em Desenvolvimento , Estabilidade de Medicamentos , Armazenamento de Medicamentos/normas , Etiópia , Feminino , Grupos Focais , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Índia , Entrevistas como Assunto , Mianmar , Ocitocina/uso terapêutico , Hemorragia Pós-Parto/prevenção & controle , Gravidez , Serviços de Saúde Rural , Serviços Urbanos de Saúde
8.
J Glob Health ; 8(2): 020415, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30202518

RESUMO

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. International efforts continue to further understand the issues relating to oxytocin quality in LMICs and this study is the first to assess oxytocin quality in the Democratic Republic of Congo (DRC), a country that bears one of the highest global rates of maternal mortality (693 maternal deaths per 100 000 live births). Importantly, the study methodology includes the use of investigative analytical techniques to understand the cause of quality deficiencies and inform remedial measures. Methods: The study involved sampling of oxytocin injection ampoules from public and private health care facilities (n = 15) in urban and rural areas within five provinces of the DRC. Where available, each sample comprised 20 ampoules of oxytocin injection (10 IU/mL) with smaller numbers collected where supplies were limited. Sample collection used overt sampling and mystery shopper approaches, as appropriate. Analysis of ampoules for oxytocin content and known degradation products utilised validated HPLC and LCMS methods, respectively. Sterility testing was conducted in accordance with the United States Pharmacopeia monograph. Results: Eighty percent of ampoules collected contained less than 90% of the specified content. Known degradation products of oxytocin were identified, indicating likely exposure to elevated temperatures post-manufacture. All samples contained an unknown impurity at a level of approximately 12.3% (8.0-20.5%) of the oxytocin main band peak. No samples failed sterility testing. Conclusions: There is evidence of a high prevalence of poor quality oxytocin ampoules in health facilities in the DRC likely resulting from both manufacturing quality issues and uncontrolled storage. A more comprehensive post-marketing surveillance study of oxytocin quality is warranted.


Assuntos
Instalações de Saúde/estatística & dados numéricos , Ocitocina/normas , Controle de Qualidade , República Democrática do Congo , Feminino , Humanos , Ocitocina/provisão & distribução , Hemorragia Pós-Parto/prevenção & controle , Gravidez
9.
Int J Nurs Stud ; 84: 61-77, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29772447

RESUMO

BACKGROUND: One to one specialling is a type of care which is provided to ensure the safety of patients who may be suffering from cognitive impairment, exhibit challenging behaviour, or may be at risk of falls or of causing harm to themselves or others. Care such as this, often referred to as 'specialling' or 'sitting' is common practice in most hospitals around the world, but there is a lack of evidence regarding its cost effectiveness and the quality of care provided. AIM: The aim of this scoping review was to explore the breadth and scope of literature on one to one specialling, sitters and similar types of care in acute secondary care settings, in order to identify the challenges and concerns relating to the quality of care (process and outcomes) and cost effectiveness emerging from the literature, and determine the implications of this for policy, practice and future research. DESIGN: This review was based on scoping review methodology following a five stage scoping review process. A keyword search was conducted in the following databases: MEDLINE, Scopus, CINAHL Plus, Web of Science, ProQuest Social Science, and ProQuest Nursing and Allied Health. The time limit placed on the search was January 2000 to April 2016. Inclusion and exclusion criteria were applied. The Mixed Methods Appraisal Tool was used to assess the quality of primary research articles. FINDINGS: Forty-four articles were included in the review. We found a lack of clarity in the terms used to describe one to one specialling and variability in what this type of care entails, who provides the care and the needs of patients requiring this type of care. High costs of specialling are often seen as a concern, but there was a lack of economic evaluations considering the full cost of specialling and balancing these against the benefits. Some of the articles proposed alternatives to one to one specialling or the use of sitters, but only some of these were evaluated. CONCLUSION: There is wide variation in what specialling and one to one care entails, which can in turn lead to the provision of poor quality care. A reduction in this variation and improved quality care might be achieved through the development of guidelines, training and standardized decision-making tools. Further research on the impact of one to one specialling on patient outcomes and cost would be beneficial, as well as robust evaluations of the alternatives to specialling.


Assuntos
Transtornos Cognitivos/enfermagem , Administração Hospitalar , Recursos Humanos em Hospital , Humanos
10.
J Antimicrob Chemother ; 73(6): 1570-1578, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29506207

RESUMO

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). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). Results: Bacterial killing of no more than ∼3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2 = 0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. Conclusions: Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin-resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically.


Assuntos
Antibacterianos/farmacocinética , Técnicas de Cultura de Células , Fosfomicina/farmacocinética , Pseudomonas aeruginosa/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Modelos Teóricos
11.
Eur J Pharm Biopharm ; 125: 1-12, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29309835

RESUMO

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. This study therefore aimed to describe and compare the pulmonary pharmacokinetic behaviour and patterns of lung clearance of two commonly explored inhalable nanocarriers (anionic ∼150 nm liposomes and solid lipid nanoparticles [SLNs]) in rats by following the 3H-labelled structural lipids (phosphatidylcholine and tristearin respectively). The data showed that SLNs and liposomes were cleared from the lungs at similar rates, despite SLNs being deposited after intratracheal instillation in the upper respiratory track, and primarily via the mucociliary escalator, but this process was more pronounced for SLNs. Structural lipids were mainly associated with plasma proteins rather than nanocarrier in plasma. The lipids also exhibit prolonged lung exposure and are associated with the lung tissue (rather than BALF) over 2 weeks.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Metabolismo dos Lipídeos/fisiologia , Pulmão/metabolismo , Nanopartículas/metabolismo , Trítio/metabolismo , Animais , Lipídeos/administração & dosagem , Lipossomos , Pulmão/efeitos dos fármacos , Masculino , Nanopartículas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Trítio/administração & dosagem
12.
EBioMedicine ; 22: 249-255, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28781129

RESUMO

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. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50µg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600µg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed. FINDINGS: Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n=3; IH oxytocin n=12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400µg most closely matched IM oxytocin 10IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters. INTERPRETATION: These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings.


Assuntos
Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Administração por Inalação , Adulto , Área Sob a Curva , Esquema de Medicação , Feminino , Voluntários Saudáveis , Humanos , Injeções Intramusculares , Ocitocina/efeitos adversos , Pré-Menopausa , Adulto Jovem
13.
Eur J Pharm Biopharm ; 119: 408-418, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28713018

RESUMO

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. These results suggest that the conjugation of hydrophobic drug on the surface of a PEGylated dendrimer is likely to accelerate lung clearance when compared to a fully PEGylated dendrimer.


Assuntos
Dendrímeros/química , Metotrexato/química , Polietilenoglicóis/química , Polilisina/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Pulmão/metabolismo , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
Artigo em Inglês | MEDLINE | ID: mdl-27821445

RESUMO

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. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.


Assuntos
Antibacterianos/farmacocinética , Colistina/análogos & derivados , Colistina/farmacocinética , Pulmão/metabolismo , Modelos Estatísticos , Administração por Inalação , Administração Intravenosa , Animais , Antibacterianos/sangue , Líquido da Lavagem Broncoalveolar/química , Colistina/sangue , Estudos Cross-Over , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Humanos , Nebulizadores e Vaporizadores , Ovinos
15.
Macromol Rapid Commun ; 38(2)2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27859945

RESUMO

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.


Assuntos
Aminas/síntese química , Cobre/química , Peptídeos/química , Polimerização , Ácidos Polimetacrílicos/química , Água/química , Aminação , Aminas/química , Metanol/química , Estrutura Molecular
16.
Biomacromolecules ; 17(8): 2755-66, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27419537

RESUMO

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. The purpose of this study was to develop N-terminal amine targeted PEGylation strategies utilizing both linear PEG and polyPEG "comb" polymers as an effective method for stabilizing solution formulations of this peptide for prolonged storage in the absence of efficient cold-chain storage. The conjugation chemistries investigated herein include irreversible amine targeted conjugation methods utilizing NHS ester and aldehyde reductive amination chemistry. Additionally, one reversible conjugation method using a Schiff base approach was explored to allow for the release of the native peptide, thus, ensuring that biological activity remains unaffected. The reversibility of this approach was investigated for the different polymer architectures, alongside a nonpolymer oxytocin analogue to monitor how pH can tune native peptide release. Elevated temperature degradation studies of the polymer conjugates were evaluated to assess the stability of the PEGylated analogues in comparison to the native peptide in aqueous formulations to mimic storage conditions in developing nations and regions where storage under appropriate conditions is challenging.


Assuntos
Ocitocina/química , Polietilenoglicóis/química , Polímeros/química , Água/química , Humanos , Estabilidade Proteica , Temperatura
17.
J Antimicrob Chemother ; 71(8): 2218-29, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27118778

RESUMO

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. 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 log10 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.


Assuntos
Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Interações Medicamentosas , Fosfomicina/farmacologia , Polimixina B/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Farmacorresistência Bacteriana , Humanos , Viabilidade Microbiana/efeitos dos fármacos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/fisiologia
18.
Nanomedicine ; 12(6): 1703-24, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27033834

RESUMO

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. The safety of biodegradable nanomaterials in the lungs is discussed and latest updates are provided on the impact of inflammation on the pulmonary pharmacokinetics of inhaled nanomaterials. Overall, the review provides an in-depth and critical assessment of the lung clearance mechanisms for inhaled biodegradable nanomedicines and highlights the opportunities and challenges for their translation into the clinic.


Assuntos
Nanomedicina/tendências , Nanoestruturas , Implantes Absorvíveis , Administração por Inalação , Sistemas de Liberação de Medicamentos , Humanos , Pulmão
19.
J Antimicrob Chemother ; 70(11): 3042-50, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26209311

RESUMO

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. 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. RESULTS: 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 indicated heteroresistance in all isolates tested. Time-kill studies showed moderate (maximum killing ∼3 log10 cfu/mL), time-dependent killing at the low inoculum with regrowth at 24 h. Most concentrations resulted in complete replacement of fosfomycin-susceptible colonies by fosfomycin-resistant colonies. Bacterial killing was virtually eliminated at the high inoculum. The PAE ranged from 0.3 to 5.5 h. CONCLUSIONS: These data suggest monotherapy with fosfomycin may be problematic for the treatment of infections caused by P. aeruginosa. Further investigation of fosfomycin combination therapy is warranted.


Assuntos
Antibacterianos/farmacologia , Fosfomicina/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Austrália , Farmacorresistência Bacteriana , Hospitais , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/fisiologia , Seleção Genética , Fatores de Tempo
20.
Bioconjug Chem ; 26(4): 633-8, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25741601

RESUMO

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.


Assuntos
Reagentes para Ligações Cruzadas/química , Maleimidas/química , Ocitócicos/química , Ocitocina/química , Fenóis/química , Resinas Acrílicas/química , Dissulfetos/química , Feminino , Radicais Livres/química , Humanos , Polietilenoglicóis/química , Polimerização , Estabilidade Proteica , Soluções
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