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Critical care, neurology and analgesia
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Inhaled NO is thought to immediately react with oxyhaemoglobin to form bioinactive nitrates, thereby limiting its diffusion to the nearby pulmonary vascular endothelium. Animal studies, however, have shown that inhaled NO reduces systemic vascular resistance [30], and restores blood flow to the intestine after an infusion of a NOS inhibitor [31]. Similarly, inhaled NO has been shown to increase coronary blood flow in patients with coronary artery disease [32], and peripheral blood flow after blockade of NO followed by forearm exercise test in normal humans [33]. While these observations are consistent with intravascular biostabilisation, transport and delivery of NO, the therapeutic relevance remains uncertain. Recently, cell-free haemoglobin induced by intravascular haemolysis has been shown to limit NO bioavailability in sickle-cell disease, thereby favou-ring the frequent vascular occlusive crisis complications observed in this disease [34]. As a consequence, low blood levels of arginine have been found in this disease, and oral L-arginine supplementation has been shown to reduce estimated pulmonary artery systolic pressure [35]. Likewise, infants with PPHN have been shown to have low plasma concentrations of arginine and NO metabolites, and a genetically predetermined capacity of the urea cycle, in particular the efficiency of carbamoyl-phosphate synthetase, which may contribute to the availability of precursors for nitric oxide synthesis [36].
The Sparse-Fur (Otcspf) and Abnormal Skin and Hair (Otcash) Mutations, Chromosome X
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
John P. Sundberg, Donald P. Doolittle
Ornithine transcarbamylase is a mitochondrial enzyme in the urea cycle that catalyzes the formation of citrulline from carbamoyl phosphate and ornithine.6 Mutant forms of this enzyme have been described in sparse-fur and in abnormal skin and hair mice.2,7 The enzymatic abnormality can be detected in the liver, duodenum, jejunum, and ileum.8 Mouse ornithine transcarbamylase is a trimer, similar to that in other species. The sparse-fur mutation does not affect the molecular weight of this enzyme. The affinity for ornithine and norvaline is decreased in mutant mice.9 Livers of hemizygous abnormal skin and hair mice synthesize two distinct ornithine transcarbamylase precursor polypeptides; one is normal in size, and the second is elongated. Both enzymes are processed by mitochondria, but only the one of normal size is assembled into the active trimer.10 The molecular lesion is a C to A transversion of the ornithine transcarbamylase gene in the sparse-fur mouse mutation that alters a histidine residue to an asparagine residue at amino acid 117.11 Correction of this enzymatic deficiency has been successful using transgenic approaches.12–16
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In hyperammonemia, the only established biochemical defect is the elevated blood ammonia level. This even may be associated with the deficiency of ornithine transcarbamylase or carbamyl phosphate synthetase. These enzymes are located in the liver and both types of disorders have been demonstrated. Consumption of a low-protein-containing diet reduces blood ammonia.
Hyperammonemia in the setting of Roux-en-Y gastric bypass presenting with osmotic demyelination syndrome
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Carly Rosenberg, Michael Rhodes
The question we ask ourselves now is can hyperammonemia cause osmotic demyelination syndrome? A case report by Langer et al. [5] described a pediatric patient with carbamoyl phosphate synthetase deficiency who developed osmotic demyelination and transient cortical blindness after rapid correction of hyperammonemia. The hypothesized underlying mechanism was due to disruption of the blood–brain barrier and re-equilibration of osmolytes, in particular glutamine. Similarly, another case had been reported earlier by Mattson et al. [6] of a child with ornithine carbamoyl transferase deficiency who presented with hyperammonemic encephalopathy with a maximum ammonia level of 376 mmcol/L. Her ammonia was corrected with hydration and protein restriction; however, 5 days after correction of her hyperammonemia, she developed seizures and fell into a coma. MRI brain imaging ultimately revealed characteristic findings of central pontine myelinolysis.
Novel considerations on drug safety in epilepsy
Published in Expert Opinion on Drug Safety, 2021
Various genes have also been identified which are associated with some of the more severe adverse effects of valproate. The T1405 polymorphism variant in the carbamoyl phosphate synthetase 1 (CPS1) was found to be a significant risk factor for the occurrence of hyperammonemia with valproate.A retrospective study in Japanese patients showed that the Val16Ala polymorphism of the Superoxide Dismutase2 (SOD2) gene has an impact on the relationship between valproate exposure and GT elevation [13].Weight gain, a common adverse reaction of valproate, has been associated with leptin receptor (LEPR) and ankyrin repeat kinase domain containing 1 (ANKK1) gene polymorphisms in a cohort of Han Chinese people with epilepsy.In a pediatric cohort, it was found that CYP2C9 variant-guided treatment significantly reduced valproate misdosing [13].
Sirtuin modulators: where are we now? A review of patents from 2015 to 2019
Published in Expert Opinion on Therapeutic Patents, 2020
Nicola Mautone, Clemens Zwergel, Antonello Mai, Dante Rotili
Initially identified as a weak deacetylase of the carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme for the ammonia detoxification in the urea cycle [46,47], SIRT5 is the major responsible in human cells of protein lysine demalonylation, desuccinylation, and deglutarylation due to an isoform-specific Arg at the bottom of the substrate acyl binding channel [9,48–50]. Similarly to other mitochondrial SIRTs, SIRT5 can modulate the activity of many substrates with crucial roles in the energetic metabolism that span from glycolysis and TCA cycle to fatty acid oxidation and ketone body formation, from ROS detoxification to nitrogenous waste management [49,50]. In particular, SIRT5 seems very important in cardiac physiology, especially in relation to aging and various stress conditions [49,50]. Moreover, there is mounting evidence about SIRT5 protective functions in the setting of neurodegenerative disorders [49–51], while in cancer it can act as both tumor promoter and suppressor in a context-specific manner [49,50].