Do brushings taken during bronchoscopy for suspected primary lung cancer increase diagnostic yield? An audit of real-world clinical practice.

We reviewed clinical records to determine whether the use of bronchial brushings improved diagnostic yield in a setting where bronchoscopy for suspected primary lung cancer is routinely guided by prior chest computed tomography but endobronchial ultrasound-guided sampling is unavailable. For 29% of cases who had brushings and at least one other test taken (bronchial biopsies or washings), the histological diagnosis was made solely on the basis of samples obtained by brushings.

Dual versus single long-acting bronchodilator use could raise acute coronary syndrome risk by over 50%: A population-based nested case-control study.

BACKGROUND: Coronary heart disease occurs more frequently among patients with chronic obstructive pulmonary disease (COPD) compared to those without COPD. While some research suggests that long-acting bronchodilators might confer an additional risk of acute coronary syndrome (ACS), information from real-world clinical practice about the cardiovascular impact of using two versus one long-acting bronchodilator for COPD is limited. We undertook a population-based nested case-control study to estimate the risk of ACS in users of both a long-acting muscarinic antagonist (LAMA) and a long-acting beta2-agonist (LABA) relative to users of a LAMA. METHODS: The study was based on the primary care PREDICT Cardiovascular Disease Cohort and linked data from regional laboratories and the New Zealand Ministry of Health's national data collections. The underlying cohort (n = 29,993) comprised patients aged 45-84 years, who initiated treatment with a LAMA and/or LABA for COPD between 1 February 2006 and 11 October 2016. 1490 ACS cases were matched to 13,550 controls by date of birth, sex, date of cohort entry (first long-acting bronchodilator dispensing), and COPD severity. RESULTS: Relative to current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a significantly higher risk of ACS (adjusted OR = 1.72; [95% CI: 1.28-2.31]). CONCLUSION: Dual long-acting bronchodilator therapy, rather than LAMA mono-therapy, could increase the risk of ACS by more than 50%. This has important implications for decisions about the potential benefit/harm ratio of COPD treatment intensification, given the modest benefits of dual therapy.

Underuse of beta-blockers by patients with COPD and co-morbid acute coronary syndrome: A nationwide follow-up study in New Zealand.

BACKGROUND AND OBJECTIVE: Clinical guidelines recommend the use of beta-blockers and other cardiovascular prevention drugs in patients with acute coronary syndrome (ACS). Studies in several countries have found that beta-blockers are underused in patients with chronic obstructive pulmonary disease (COPD) and co-morbid heart disease, although most have only examined use in subgroups of patients. We undertook a nationwide follow-up study in New Zealand to describe the use of beta-blockers and other cardiovascular prevention drugs in patients with COPD and ACS. METHODS: National health and pharmaceutical dispensing data were used to derive the study cohort, identify patients who were admitted to hospital with ACS and/or heart failure before cohort entry and during follow-up, and ascertain drug use. RESULTS: The study cohort included 83 435 patients aged ≥45 years, with 290 400 person-years of follow-up. Among 2637 patients with ≥1 ACS admission during follow-up, only 56.6% received a beta-blocker in the 6 months following the first admission, while 87.7% and 81%, respectively, received aspirin and a statin. Patients with higher COPD severity were less likely to receive a beta-blocker than those with lower severity, as were those with no history of previous ACS and/or heart failure. CONCLUSION: Use of beta-blockers following an ACS admission was much lower than expected based on the findings of general audits of ACS management in New Zealand. Along with the higher proportions using aspirin and statins, and the differences in beta-blocker dispensing by COPD severity, this suggests a particular reluctance to prescribe beta-blockers to patients with COPD.

Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand.

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.

Health Care Utilisation and Health Needs of People with Severe COPD in the Southern Region of New Zealand: A Retrospective Case Note Review.

We examined health care utilisation and needs of people with severe COPD in the low-population-density setting of the Southern Region of New Zealand (NZ). We undertook a retrospective case note review of patients with COPD coded as having an emergency department attendance and/or admission with at least one acute exacerbation during 2015 to hospitals in the Southern Region of NZ. Data were collected and analysed from 340 case notes pertaining to: demographics, hospital admissions, outpatient contacts, pulmonary rehabilitation, advance care planning and comorbidities. Geometric mean (95%CI) length of stay for hospital admissions in urban and rural hospitals was 3.0 (2.7-3.4) and 4.0 (2.9-5.4) days respectively. More patients were from areas of higher deprivation but median hospital length of stay for patients from the least deprived areas was 2.0 days longer than others (p = 0.04). There was a median of 4 (range 0-16) comorbidities and 10 medications (range 0-25) per person. Of 169 cases where data was available, 26 (15%) were offered, 17 (10%) declined, and 5 (3%) completed, pulmonary rehabilitation at or in the year prior to the index admission. Patients were less likely to be offered pulmonary rehabilitation if they lived >20km away from the hospital where it took place (odds ratio of 0.12 for those living further away [95%CI 0.02-0.93, p = 0.04]). There were deficits in care: provision and uptake of non-pharmacological interventions was suboptimal and unevenly distributed across the region. Further research is needed to develop and evaluate strategies for delivering non-pharmacological interventions in this setting.

Patterns of use of long-acting bronchodilators in patients with COPD: A nationwide follow-up study of new users in New Zealand.

BACKGROUND AND OBJECTIVE: While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long-acting beta2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow-up study to describe treatment patterns in new users of long-acting bronchodilators. METHODS: National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan-Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non-use during follow-up. RESULTS: The study cohort included 83 435 patients with 290 400 person-years of follow-up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over- and under-treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non-use were common. CONCLUSION: In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

Lung function and cardiovascular risk at age 45 in a cohort of the general population.

BACKGROUND: Impaired lung function is associated with cardiovascular mortality, but the origins of this association are poorly understood. We investigated associations between lung function and cardiovascular risk scores in a general population cohort of men and women aged 45 years. METHODS: Participants are members of an unselected birth cohort followed to adulthood. Lung function determined at ages 32 and 45 by spirometry, body plethysmography, gas diffusion, and airway conductance were the main predictors. Future cardiovascular risk was estimated at age 45 using a multivariable cardiovascular risk algorithm - PREDICT. Risk scores were log-transformed and used as the dependent variable in linear regression analyses. We investigated cross-sectional associations with lung function at age 45 and longitudinal associations using changes in lung function between ages 32-45 as the predictors. RESULTS: 863 of 1037 original cohort participants had data for analysis. Low lung volumes (FEV1, FVC, VA, TLC, and FRC) were associated with greater cardiovascular risk scores in the cross-sectional analyses at age 45 and the longitudinal analyses. These associations were stronger in women than in men, were independent of smoking history, and present in never smokers, even after adjusting for body mass index. Associations were not found for measures of airway function (FEV1/FVC ratio and sGaw) or gas transfer (TLco/VA). CONCLUSIONS: Low lung volumes at age 45 and accelerated pulmonary function decline are associated with a higher estimated cardiovascular risk scores in mid-adulthood. This association is stronger in women and is not explained by smoking or obesity.

The quest to deliver high-dose rifampicin: can the inhaled approach help?

INTRODUCTION: Tuberculosis (TB) is a global health problem that poses a challenge to global treatment programs. Rifampicin is a potent and highly effective drug for TB treatment; however, higher oral doses than the standard dose (10 mg/kg/day) rifampicin may offer better efficacy in TB treatment. AREAS COVERED: High oral dose rifampicin is not implemented in anti-TB regimens yet and requires about a 3-fold increase in dose for increased efficacy. We discuss inhaled delivery of rifampicin as an alternative or adjunct to oral high-dose rifampicin. Clinical results of safety, tolerability, and patient compliance with antibiotic dry powder inhalers are reviewed. EXPERT OPINION: Clinical trials suggest that an approximately 3-fold increase in the standard oral dose of rifampicin may be required for better clinical outcomes. On the other hand, animal studies suggest that inhaled rifampicin can deliver a high concentration of the drug to the lungs and achieve approximately double the plasma concentration than that from oral rifampicin. Clinical trials on inhaled antibiotics suggest that dry powder inhalation is a patient-friendly and well-tolerated approach in treating respiratory infections compared to conventional treatments. Rifampicin, a well-known anti-TB drug given orally, is a good candidate for clinical development as a dry powder inhaler.

A review of formulations and preclinical studies of inhaled rifampicin for its clinical translation.

Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans.

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

An expert opinion on respiratory delivery of high dose powders for lung infections.

INTRODUCTION: High dose powder inhalation is evolving as an important approach to to treat lung infections. It is important to its identify applications, consider the factors affecting high dose powder delivery, and assess the effect of high dose drugs in patients. AREA COVERED: Both current and pipeline high dose inhalers and their applications have been summarized. Challenges and opportunities to high dose delivery have been highlighted after reviewing formulation techniques in the context of factors affecting aerosolization, devices, and patient factors. EXPERT OPINION: High dose inhaled delivery of antimicrobials is an innovative way to increase treatment efficacy of respiratory infections, tackle drug resistance, and the scarcity of new antimicrobials. The high dose inhaled technology also has potential for systemic action; however, innovations in formulation strategies and devices are required to realize its full potential. Advances in formulation strategies include the use of excipients or the engineering of particles to decrease the cohesive property of microparticles and their packing density. Similarly, selection of a synergistic drug instead of an excipient can be considered to increase aerosolization and stability. Device development focused on improving dispersion and loading capacity is also important, and modification of existing devices for high dose delivery can also be considered.

Lifetime cannabis exposure and small airway function in a population-based cohort study.

Background and objective: The long-term effects of cannabis on small airway function remain unclear. We investigated associations between cannabis use and small airway function in a general population sample. Methods: Cannabis use was ascertained at multiple ages from age 18 to 45 years and quantified as joint-years among 895 participants in the Dunedin Multidisciplinary Health and Development Study. Small airway function at ages 38 and 45 years was measured using impulse oscillometry (IOS) before and after inhalation of salbutamol. Analyses used multiple linear regression adjusting for tobacco use, body mass index and height. Longitudinal analyses of cannabis use between 38 and 45 years also adjusted for IOS at age 38 years. Results: Associations between lifetime cannabis joint-years and IOS differed between men and women: in women, cannabis use was associated with pre-bronchodilator resistance at 5 Hz (R 5) and 20 Hz (R 20), reactance at 5 Hz, area of reactance and resonant frequency, and marginally associated with the difference between R 5 and R 20. Cannabis use was only statistically significantly associated with pre-bronchodilator resonant frequency in men. Cannabis use between the ages of 38 and 45 years was associated with a similar pattern of changes in IOS measures. After salbutamol, cannabis use was only statistically significantly associated with R 5 and R 20 among women and none of the IOS measures among men. Conclusions: Cannabis use is associated with small airway dysfunction at age 45 years, indicating an increase in peripheral airway resistance and reactance. These associations were greater and mostly only statistically significant among women. Associations were weaker and mostly nonsignificant after bronchodilator use, suggesting that cannabis-induced changes in small airways may be at least partially reversible.

How to Best Develop and Deliver Generic Long-Term Condition Rehabilitation Programmes in Rural Settings: An Integrative Review.

People living rurally frequently experience health disparities especially if living with a long-term condition (LTC) or multi-morbidity. Self-management support is a key component of LTC management and commonly included in rehabilitation programmes to enhance ability to self-manage health and encourage physical activity. Such programmes are however often condition focussed and despite evidence for their effectiveness, are not always feasible to deliver in rural settings. Generic programmes are arguably more optimal in the rural context and delivery can be face to face or remotely (via telehealth). The aim of this explorative integrative review was to collate and present international evidence for development, delivery, integration, and support of community-based, generic LTC group rehabilitation programmes delivered rurally in person, or remotely using telehealth. Electronic databases were systematically searched using MeSH terms and keywords. For inclusion, articles were screened for relevance to the aim, and practical information pertaining to the aim were extracted, charted, and organized deductively into themes of Development, Delivery, Integration, and Support. Within each theme, data were synthesized inductively into categories (Theory, Context, Interpersonal aspects, and Technology and Programme aspects). Fifty-five studies were included. Five studies contributed information about community based programmes delivered via the internet. Development was the only theme populated by information from all categories. The theme of Support was only populated with information from one category. Our review has drawn together a large body of diverse work. It has focused on finding practical information pertaining to the best ways to develop, deliver, integrate, and support a community-based generic rehabilitation programme for people living with long-term health conditions, delivered rurally and/or potentially via the internet. Practical suggestions were thematically organized into categories of theory, context, interpersonal aspects, and technology and programme aspects. While the findings of this review might appear simple and self-evident, they are perhaps difficult to enact in practice.

Clinical features of patients hospitalised with COVID-19 from February to October 2020, during the early waves of the pandemic in New Zealand.

AIM: As New Zealand transitions towards endemic SARS-CoV-2, understanding patient factors predicting severity, as well as hospital resourcing requirements will be essential for future planning. METHODS: We retrospectively enrolled patients hospitalised with COVID-19 from 26 February to 5 October 2020 as part of the COVID-19 HospitalisEd Patient SeverIty Observational Study NZ (COHESION). Data on demographics, clinical course and outcomes were collected and analysed as a descriptive case series. RESULTS: Eighty-four patients were identified across eight district health boards. Forty-one (49%) were male. The median age was 58 years [IQR: 41.7-70.3 years]. By ethnicity, hospitalisations included 38 NZ European (45%), 19 Pasifika (23%), 13 Maori (15%), 12 Asian (14%) and 2 Other (2%). Pre-existing co-morbidities included hypertension (26/82, 32%), obesity (16/66, 24%) and diabetes (18/81, 22%). The median length of stay was four days [IQR: 2-15 days]. Twelve patients (12/83, 14%) were admitted to an intensive care unit or high dependency unit (ICU/HDU). Ten (10/83, 12%) patients died in hospital of whom seven (70%) were not admitted to ICU/HDU; the median age at death was 83 years. CONCLUSION: Despite initially low case numbers in New Zealand during 2020, hospitalisation with COVID-19 was associated with a high mortality and hospital resource requirements.

Is the use of two versus one long-acting bronchodilator by patients with COPD associated with a higher risk of acute coronary syndrome in real-world clinical practice?

BACKGROUND: Cardiovascular comorbidity is common among patients with chronic obstructive pulmonary disease (COPD) and there is concern that long-acting bronchodilators (long-acting muscarinic antagonists (LAMAs) and long-acting beta2 agonists (LABAs)) may further increase the risk of acute coronary events. Information about the impact of treatment intensification on acute coronary syndrome (ACS) risk in real-world settings is limited. We undertook a nationwide nested case-control study to estimate the risk of ACS in users of both a LAMA and a LABA relative to users of a LAMA. METHODS: We used routinely collected national health and pharmaceutical dispensing data to establish a cohort of patients aged >45 years who initiated long-acting bronchodilator therapy for COPD between 1 February 2006 and 30 December 2013. Fatal and non-fatal ACS events during follow-up were identified using hospital discharge and mortality records. For each case we used risk set sampling to randomly select up to 10 controls, matched by date of birth, sex, date of cohort entry (first LAMA and/or LABA dispensing), and COPD severity. RESULTS: From the cohort (n=83 417), we identified 5399 ACS cases during 281 292 person-years of follow-up. Compared with current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a higher risk of ACS (OR 1.28 (95% CI 1.13 to 1.44)). The OR in an analysis restricted to fatal cases was 1.46 (95% CI 1.12 to 1.91). CONCLUSION: In real-world clinical practice, use of two versus one long-acting bronchodilator by people with COPD is associated with a higher risk of ACS.

Studies on the safety and the tissue distribution of inhaled high-dose amorphous and crystalline rifampicin in a rat model.

Inhaled delivery of rifampicin has the potential to achieve high drug concentrations in the lung and the blood for efficient treatment of tuberculosis (TB). Due to its existence as polymorphs, in vivo evaluation of the respiratory tract safety of inhalable amorphous and crystalline rifampicin particles, at clinically relevant high-dose, is necessary. This study investigates the lung and liver safety and the tissue distribution of rifampicin after intra-tracheal administration of high (≥25 mg/kg) doses of amorphous and crystalline powder formulations to Sprague Dawley rats. Powder formulations were administered by intra-tracheal insufflation to rats. Lung and liver safety were evaluated by histopathology. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) assays were performed to study the hepatic effects. Rifampicin was quantified in the tissues using LC-MS/MS. Intra-tracheal administration of rifampicin decreased the drug burden on the liver compared to oral administration based on its lower serum ALT activity. Repeated-dose intra-tracheal rifampicin was well tolerated by rats, confirmed by the absence of drug or delivery induced complexities. The histopathological evaluation of rat lungs, after both single and repeated drug administration for seven days, suggested the absence of drug-induced toxicity. Following single intra-tracheal delivery of 50 mg/kg doses, comparable rifampicin concentrations to that from same oral dose were observed in lung, liver, heart and brain. Inhaled delivery of high-dose rifampicin was safe to rat lungs and liver suggesting its potential for localized as well as systemic drug delivery without toxicity concerns.

Pharmacokinetics of rifampicin after repeated intra-tracheal administration of amorphous and crystalline powder formulations to Sprague Dawley rats.

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.

Monitoring chloramines and bromamines in a humid environment using selected ion flow tube mass spectrometry.

The selectivity and sensitivity of selected ion flow tube mass spectrometry (SIFT-MS) for individual breath analysis of haloamines has been improved by heating the flow tube in a commercial instrument to around 106 degrees C. Data is presented showing the marked reduction in the number density of water clusters of product ions of common breath metabolites that are isobaric with the product ions from monochloramine and monobromamine that are used to monitor the haloamine concentrations. These results have direct relevance to the real-time monitoring of chloramines in drinking water, swimming pools and food processing plants. However, once the isobaric overlaps from water cluster ions are reduced at the higher temperatures, there is no conclusive evidence showing the presence of haloamines on single breath exhalations in the mid parts per trillion range from examination of the breaths of volunteers.