Ontogeny of midazolam glucuronidation in preterm infants

Purpose: In preterm infants, the biotransformation of midazolam (M) to 1-OH-midazolam (OHM) by cytochrome P450 3A4 (CYP3A4) is developmentally immature, but it is currently unknown whether the glucuronidation of OHM to 1-OH-midazolam glucuronide (OHMG) is also decreased. The aim of our study was to investigate the urinary excretion of midazolam and its metabolites OHM and OHMG in preterm neonates following the intravenous (IV) or oral (PO) administration of a single M dose. Methods: Preterm infants (post-natal age 3-13 days, gestational age 26-34 4/7 weeks) scheduled to undergo a stressful procedure received a 30-min IV infusion (n=15) or a PO bolus dose (n=7) of 0.1 mg/kg midazolam. The percentage of midazolam dose excreted in the urine as M, OHM and OHMG up to 6 h post-dose was determined. Results: The median percentage of the midazolam dose excreted as M, OHM and OHMG in the urine during the 6-h interval after the IV infusion was 0.44% (range 0.02-1.39%), 0.04% (0.01-0.13%) and 1.57% (0.36-7.7%), respectively. After administration of the PO bolus dose, the median percentage of M, OHM and OHMG excreted in the urine was 0.11% (0.02-0.59%), 0.02% (0.00-0.10%) and 1.69% (0.58-7.31%), respectively. The proportion of the IV midazolam dose excreted as OHMG increased significantly with postconceptional age (r=0.73, p <0.05). Conclusion: The glucuronidation of OHM appears immature in preterm infants less than 2 weeks of age. The observed increase in urinary excretion of OHMG with postconceptional age likely reflects the combined maturation of glucuronidation and renal function

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

Concentration and Duration of Ethylene Treatment Influences the Response of Banana to 1-Methylcyclopropene

We examined the effect of ethylene concentration and duration on 1-MCP efficacy with regards to shelf life and fruit quality in bananas (cv. Williams) from the middle section of bunches harvested during winter 2004 and summer 2005. Before storage, fruit was treated with ethylene (2, 20, 50 or 100 µL•L⁻¹) for two consecutive days or 100 µL•L⁻¹ for the first and 2 µL•L⁻¹ for the second day, prior to 1-MCP (300 nL•L⁻¹) exposure for 24 hrs at 22°C. To examine the effect of duration, bananas were treated with 100 µL•L⁻¹ ethylene for 30, 40 or 50 hrs prior to 1-MCP treatment (300 nL•L⁻¹) at 22°C. 1-MCP was most effective at increasing shelf life and firmness when fruit were treated with 100 µL•L⁻¹ ethylene for the first day and 2 µL•L⁻¹ for the second day. Interestingly, fruit harvested in winter initially treated with ethylene at the lowest concentration (2 µL•L⁻¹) or exposed to the shorter duration of ethylene (30 hrs) did not ripen and remained green when treated with 1- MCP. However, winter-harvested bananas that were exposed to ethylene for 50 hrs had a longer shelf life compared to bananas treated with ethylene for 40 hrs. 1-MCP was only more effective in summer-harvested fruit when they were exposed to ethylene for 40 hrs with an increase in firmness. The discolouration index (DI) of 1- MCP treated fruit increased significantly when fruit were exposed to the ethylene for shorter durations than 50 hrs in winter, but no differences were observed in DI of 1-MCP treated bananas that were ripened with ethylene at different concentrations. These observations suggest that the efficacy of l-MCP to improve shelf life and quality of bananas is reliant on not only the harvest season of fruit but also the concentration and duration of ethylene application prior to 1-MCP usage

Variability of responses to 1-methylcyclopropene by banana: influence of time of year at harvest and fruit position in the bunch

To examine the effect of early-climacteric (postripening) 1-methylcyclopropene (1-MCP) exposure on the shelf-life and quality of green Cavendish bananas ('Musa acuminata' cv. Williams) from the middle section of the bunch, bananas were harvested bimonthly and treated with 100 μL L−¹ ethylene for 2 consecutive days prior to exposure to 0, 100, 300, 1000, 3000 or 10 000 nL L−¹ 1-MCP for 24 h prior to storage at 22°C. 1-MCP treatment at a concentration of 300 nL L−¹ or above increased banana shelf-life significantly compared with the control, regardless of the month in which fruit were harvested except March where a higher concentration was needed (3000 nL L−¹). Fruit harvested in May were the most responsive with a greater than twofold increase in shelf-life. To examine the effect of fruit position in the bunch on 1-MCP efficacy, green fruit from the top or bottom of bunches were treated with 100 μL L−1 ethylene for 2 consecutive days prior to early-climacteric 1-MCP (300 nL L−1) exposure for 24 h at 22°C. In spring and autumn but not in summer, application of 1-MCP to early-climacteric fruit was more effective in fruit from the top than in those treated from the bottom of the bunch, increasing shelf-life. Firmness of 1-MCP-treated fruit was up to 19% greater than that of the control across the year, except in fruit from the bottom of the bunch. Given that 1-MCP is less effective in extending the shelf-life of summer-harvested fruit (particularly those from the bottom of the bunch), we conclude that preharvest conditions and fruit position in the bunch affect their responsiveness to ethylene and their behaviour during the ripening process