A Phase IIa Clinical Trial of 2-Iminobiotin for the Treatment of Birth Asphyxia in DR Congo, a Low-Income Country

Aim The main burden of hypoxic-ischemic encephalopathy falls in low-income countries. 2-Iminobiotin, a selective inhibitor of neuronal and inducible nitric oxide synthase, has been shown to be safe and effective in preclinical studies of birth asphyxia. Recently, safety and pharmacokinetics of 2-iminobiotin treatment on top of hypothermia has been described. Since logistics and the standard of medical care are very different in low-resource settings, the aim of this study was to investigate safety and pharmacokinetics of Two-IminoBiotin in the Democratic Republic of Congo (TIBC).Methods Near-term neonates, born in Kinshasa, Democratic Republic of Congo, with a Thompson score >= 7 were eligible for inclusion. Excluded were patients with (1) inability to insert an umbilical venous catheter for administration of the study drug; (2) major congenital or chromosomal abnormalities; (3) birth weight < 1800 g; (4) clear signs of infection; and (5) moribund patients. Neonates received six infusions of 2-iminobiotin 0.16 mg/kg started within 6 h after birth, with 4-h intervals, targeting an AUC(0-4h) of 365 ng*h/mL. Safety, defined as vital signs, the need for clinical intervention after administration of study drug, occurrence of (serious) adverse events, and pharmacokinetics were assessed.Results After parental consent, seven patients were included with a median Thompson score of 10 (range 8-16). No relevant changes in vital signs were observed over time. There was no need for clinical intervention due to administration of study drug. Three patients died, two after completing the study protocol, one was moribund at inclusion and should not have been included. Pharmacokinetic data of 2-iminobiotin were best described using a two-compartment model. Median AUC(0-4h) was 664 ng*h/mL (range 414-917). No safety issues attributed to the administration of 2-iminobiotin were found.Conclusion The present dosing regimen resulted in higher AUCs than targeted, necessitating a change in the dose regimen in future efficacy trials. No adverse effects that could be attributed to the use of 2-iminobiotin were observed.Neurolog

Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990.

BACKGROUND: Intrapartum hypoxic events ("birth asphyxia") may result in stillbirth, neonatal or postneonatal mortality, and impairment. Systematic morbidity estimates for the burden of impairment outcomes are currently limited. Neonatal encephalopathy (NE) following an intrapartum hypoxic event is a strong predictor of long-term impairment. METHODS: Linear regression modeling was conducted on data identified through systematic reviews to estimate NE incidence and time trends for 184 countries. Meta-analyses were undertaken to estimate the risk of NE by sex of the newborn, neonatal case fatality rate, and impairment risk. A compartmental model estimated postneonatal survivors of NE, depending on access to care, and then the proportion of survivors with impairment. Separate modeling for the Global Burden of Disease 2010 (GBD2010) study estimated disability adjusted life years (DALYs), years of life with disability (YLDs), and years of life lost (YLLs) attributed to intrapartum-related events. RESULTS: In 2010, 1.15 million babies (uncertainty range: 0.89-1.60 million; 8.5 cases per 1,000 live births) were estimated to have developed NE associated with intrapartum events, with 96% born in low- and middle-income countries, as compared with 1.60 million in 1990 (11.7 cases per 1,000 live births). An estimated 287,000 (181,000-440,000) neonates with NE died in 2010; 233,000 (163,000-342,000) survived with moderate or severe neurodevelopmental impairment; and 181,000 (82,000-319,000) had mild impairment. In GBD2010, intrapartum-related conditions comprised 50.2 million DALYs (2.4% of total) and 6.1 million YLDs. CONCLUSION: Intrapartum-related conditions are a large global burden, mostly due to high mortality in low-income countries. Universal coverage of obstetric care and neonatal resuscitation would prevent most of these deaths and disabilities. Rates of impairment are highest in middle-income countries where neonatal intensive care was more recently introduced, but quality may be poor. In settings without neonatal intensive care, the impairment rate is low due to high mortality, which is relevant for the scale-up of basic neonatal resuscitation

Nitric Oxide Synthase Inhibitors into the Clinic at Last

The 1998 nobel prize in medicine and physiology for the discovery of nitric oxide, a nitrogen containing reactive oxygen species (also termed reactive nitrogen or reactive nitrogen/oxygen species) stirred great hopes. Clinical applications, however, have so far pertained exclusively to the downstream signaling of cgmp enhancing drugs such as phosphodiesterase inhibitors and soluble guanylate cyclase stimulators. All clinical attempts, so far, to inhibit nos have failed even though preclinical models were strikingly positive and clinical biomarkers correlated perfectly. This rather casts doubt on our current way of target identification in drug discovery in general and our way of patient stratification based on correlating but not causal biomarkers or symptoms. The opposite, no donors, nitrite and enhancing no synthesis by enos/nos3 recoupling in situations of no deficiency, are rapidly declining in clinical relevance or hold promise but need yet to enter formal therapeutic guidelines, respectively. Nevertheless, nos inhibition in situations of no overproduction often jointly with enhanced superoxide (or hydrogen peroxide production) still holds promise, but most likely only in acute conditions such as neurotrauma (stover et al., j neurotrauma 31(19):1599–1606, 2014) and stroke (kleinschnitz et al., j cereb blood flow metab 1508–1512, 2016; casas et al., proc natl acad sci u s a 116(14):7129–7136, 2019). Conversely, in chronic conditions, long-term inhibition of nos might be too risky because of off-target effects on enos/nos3 in particular for patients with cardiovascular risks or metabolic and renal diseases.graphical abstractnitric oxide synthases (nos) and their role in health (green) and disease (red). Only neuronal/type 1 nos (nos1) has a high degree of clinical validation and is in late stage development for traumatic brain injury, followed by a phase ii safety/efficacy trial in ischemic stroke. The pathophysiology of nos1 (kleinschnitz et al., j cereb blood flow metab 1508–1512, 2016) is likely to be related to parallel superoxide or hydrogen peroxide formation (kleinschnitz et al., j cereb blood flow metab 1508–1512, 2016; casas et al., proc natl acad sci u s a 114(46):12315–12320, 2017; casas et al., proc natl acad sci u s a 116(14):7129–7136, 2019) leading to peroxynitrite and protein nitration, etc. Endothelial/type 3 nos (nos3) is considered protective only and its inhibition should be avoided. The preclinical evidence for a role of high-output inducible/type 2 nos (nos2) isoform in sepsis, asthma, rheumatic arthritis, etc. Was high, but all clinical development trials in these indications were neutral despite target engagement being validated. This casts doubt on the role of nos2 in humans in health and disease (hence the neutral, black coloring).keywordsnitric oxidenitric oxide synthasenosnos inhibitor nos isoforms