New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

Is low dose Tranexamic acid less effective than a standard dose at reducing blood loss and inhibiting hyperfibrinolysis in hemorrhagic caesarean section? Multicenter double–blind placebo-controlled dose-ranging (TRACES) trial.

Objective: To study the effect of a low (0.5g) or a standard (1g) tranexamic acid (TA) dose compared to placebo on clinical and biological endpoints in women experiencing postpartum hemorrhage (PPH) Design: TRACES trial is a double-blind, randomized, placebo-controlled, dose-ranging study Setting: 8 women hospitals in France. Population: Women experiencing PPH > 800 mL during caesarean section. Method: After informed consent, patients were randomized to receive either TA 0.5g (n=57), TA 1g (n=58), or a placebo (n=60). Data were collected at 8 time-points. Main outcome measures: Efficacy: additional blood loss after study drug, maternal morbidity, safety, biology: D-dimers, plasmin-antiplasmin complexes (PAP), simultaneous-generation-thrombin-plasmin-potential. Results: Compared to 1g dose, 0.5g TA was less effective to reduce additional blood loss (300 mL [95% confidence interval (95%CI) 68 to 630] vs 134 mL [95%CI50 to 419] (p=0.042)). Compared to placebo, 1g TA, but not 0.5g, inhibited hyperfibrinolysis as shown by plasmin generation potential, % increase in D-dimers from injection to 120 minutes (93% [95%CI 68 to 118] vs 58% [ 95%CI 32 to 84] (p=0.06) vs 38% [95%CI 13 to 63] (p=0.003) and % increase in PAP from injection to 30 minutes (56% [95%CI 25 to 87] vs 13% [ 95%CI 18 to 43] (p=0,051) vs -2% [95%CI -32 to 28] (p=0.009)). Conclusions: In this study, fibrinolysis inhibition was more sustained after the administration of 1g TA compared to 0.5g TA or a placebo. Further pharmacokinetic-pharmacodynamic modelling will be needed to determine the optimal TA dose to be administered in PPH. NCT 02797119

In Vitro Pharmacokinetic/Pharmacodynamic Modelling and Simulation of Amphotericin B against Candida auris

The aims of this study were to characterize the antifungal activity of amphotericin B against Candida auris in a static in vitro system and to evaluate different dosing schedules and MIC scenarios by means of semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation. A two-compartment model consisting of a drug-susceptible and a drug-resistant subpopulation successfully characterized the time-kill data and a modified Emax sigmoidal model best described the effect of the drug. The model incorporated growth rate constants for both subpopulations, a death rate constant and a transfer constant between both compartments. Additionally, the model included a parameter to account for the delay in growth in the absence or presence of the drug. Amphotericin B displayed a concentration-dependent fungicidal activity. The developed PK/PD model was able to characterize properly the antifungal activity of amphotericin B against C. auris. Finally, simulation analysis revealed that none of the simulated standard dosing scenarios of 0.6, 1 and 1.5 mg/kg/day over a week treatment showed successful activity against C. auris infection. Simulations also pointed out that an MIC of 1 mg/L would be linked to treatment failure for C. auris invasive infections and therefore, the resistance rate to amphotericin B may be higher than previously reported.

Comparative efficacy of rifapentine alone and in combination with isoniazid for latent tuberculosis infection: a translational pharmacokinetic-pharmacodynamic modelling study

Background Rifapentine has facilitated treatment shortening of latent tuberculosis infection (LTBI) in combination with isoniazid once weekly for 3 months (3HP) or daily for 1 month (1HP). Objective We determine the optimal rifapentine dose for a 6-week monotherapy regimen (6wP) and predict clinical efficacy. Methods Rifapentine and isoniazid pharmacokinetics were simulated in mice and humans. Mouse lung colony-forming unit data were used to characterize exposure-response relationships of 1HP, 3HP, and 6wP and translated to predict clinical efficacy. Results A 600 mg daily dose for 6wP delivered greater cumulative rifapentine exposure than 1HP or 3HP. The maximum regimen effect (E max ) was 0.24 day −1 . The regimen potencies, measured as concentration at 50% of E max (EC 50 ), were estimated as 2.12 mg/L for 3HP, 3.72 mg/L for 1HP, and 4.71 mg/L for 6wP, suggesting that isoniazid contributes little to 1HP efficacy. Clinical translation predicted that 6wP reduces bacterial load at a faster rate than 3HP and a greater extent than 3HP and 1HP. Conclusions 6wP (600 mg daily) is predicted to result in equal or better efficacy than 1HP and 3HP for LTBI treatment without the potential added toxicity of isoniazid. Results from ongoing and future clinical studies will be required to support these findings.