Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependent on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. METHODS: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n=48 participants). The model was verified using separate IV and oral validation datasets (n=26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. RESULTS: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67 % and Tmax from 2.6 to 3.2 and 0.4 to 1.0 hours following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. CONCLUSIONS: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 minutes and be maintained above this level for approximately 3 hours, achieving systemic exposure (AUC0-6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended

Sustained low-efficiency dialysis (SLED) with prostacyclin in critically ill patients with acute renal failure

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Nitrate and nitrite contamination in drinking water and cancer risk: A systematic review with meta-analysis

BACKGROUND: Pollution of water sources, largely from wide-scale agricultural fertilizer use has resulted in nitrate and nitrite contamination of drinking water. The effects on human health of raised nitrate and nitrite levels in drinking water are currently unclear. OBJECTIVES: We conducted a systematic review of peer-reviewed literature on the association of nitrate and nitrite in drinking water with human health with a specific focus on cancer. METHODS: We searched eight databases from 1 January 1990 until 28 February 2021. Meta-analyses were conducted when studies had the same exposure metric and outcome. RESULTS: Of 9835 studies identified in the literature search, we found 111 studies reporting health outcomes, 60 of which reported cancer outcomes (38 case-control studies; 12 cohort studies; 10 other study designs). Most studies were set in the USA (24), Europe (20) and Taiwan (14), with only 3 studies from low and middle-income countries. Nitrate exposure in water (59 studies) was more commonly investigated than nitrite exposure (4 studies). Colorectal (15 studies) and gastric (13 studies) cancers were the most reported. In meta-analyses (4 studies) we identified a positive association of nitrate exposure with gastric cancer, OR = 1.91 (95%CI = 1.09-3.33) per 10 mg/L increment in nitrate ion. We found no association of nitrate exposure with colorectal cancer (10 studies; OR = 1.02 [95%CI = 0.96-1.08]) or cancers at any other site. CONCLUSIONS: We identified an association of nitrate in drinking water with gastric cancer but with no other cancer site. There is currently a paucity of robust studies from settings with high levels nitrate pollution in drinking water. Research into this area will be valuable to ascertain the true health burden of nitrate contamination of water and the need for public policies to protect human health

What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies

Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis. We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis. We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory. TXA concentrations of 10–15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries.

BACKGROUND: Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. METHODS: The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. RESULTS: Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. CONCLUSIONS: Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure

Assessing urban population vulnerability and environmental risks across an urban area during heatwaves - Implications for health protection.

Heatwaves can lead to a range of adverse impacts including increased risk of illness and mortality; the heatwave in August 2003 has been associated with ~70,000 deaths across Europe. Due to climate change, heatwaves are likely to become more intense, more frequent and last longer in the future. A number of factors may influence risks associated with heat exposure, such as population age, housing type, and location within the Urban Heat Island, and such factors may not be evenly distributed spatially across a region. We simulated and analysed two major heatwaves in the UK, in August 2003 and July 2006, to assess spatial vulnerability to heat exposure across the West Midlands, an area containing ~5 million people, and how ambient temperature varies in relation to factors that influence heat-related health effects, through weighting of ambient temperatures according to distributions of these factors across an urban area. Additionally we present quantification of how particular centres such as hospitals are exposed to the UHI, by comparing temperatures at these locations with average temperatures across the region, and presenting these results for both day and night times. We find that UHI intensity was substantial during both heatwaves, reaching a maximum of +9.6°C in Birmingham in July 2006. Previous work has shown some housing types, such as flats and terraced houses, are associated with increased risk of overheating, and our results show that these housing types are generally located within the warmest parts of the city. Older age groups are more susceptible to the effects of heat. Our analysis of distribution of population based on age group showed there is only small spatial variation in ambient temperature that different age groups are exposed to. Analysis of relative deprivation across the region indicates more deprived populations are located in the warmest parts of the city

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.

BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0·5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov)

Comparison of built environment adaptations to heat exposure and mortality during hot weather, West Midlands region, UK

There is growing recognition of the need to improve protection against the adverse health effects of hot weather in the context of climate change. We quantify the impact of the Urban Heat Island (UHI) and selected adaptation measures made to dwellings on temperature exposure and mortality in the West Midlands region of the UK. We used 1) building physics models to assess indoor temperatures, initially in the existing housing stock and then following adaptation measures (energy efficiency building fabric upgrades and/or window shutters), of representative dwelling archetypes using data from the English Housing Survey (EHS), and 2) modelled UHI effect on outdoor temperatures. The ages of residents were combined with evidence on the heat-mortality relationship to estimate mortality risk and to quantify population-level changes in risk following adaptations to reduce summertime heat exposure. Results indicate that the UHI effect accounts for an estimated 21% of mortality. External shutters may reduce heat-related mortality by 30-60% depending on weather conditions, while shutters in conjunction with energy-efficient retrofitting may reduce risk by up to 52%. The use of shutters appears to be one of the most effective measures providing protection against heat-related mortality during periods of high summer temperatures, although their effectiveness may be limited under extreme temperatures. Energy efficiency adaptations to the dwellings and measures to increase green space in the urban environment to combat the UHI effect appear to be less beneficial for reducing heat-related mortality