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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
As data are readily available through routine therapeutic drug monitoring, population studies on the aminoglycoside antibiotics have proved popular. Dosage recommendations arising from these studies have changed over the years on account of the increasing survival of very premature neonates and the greater emphasis on high peak and low trough concentrations. Although the majority of studies have focussed on neonates, more recent research, especially with the newer aminoglycosides, has included wider age ranges.
Reactive Oxygen Metabolites and Iron in Toxic Acute Renal Failure
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Karl A. Nath, Norishi Ueda, Patrick D. Walker, Sudhir V. Shah
Aminoglycoside antibiotics including gentamicin are widely used in the treatment of Gram-negative infections. A major complication of the use of these drugs is nephrotoxicity, accounting for 10 to 15% of all cases of acute renal failure.15 The specificity of gentamicin for renal toxicity is apparently related to its preferential accumulation in the renal proximal convoluted tubules (50 to 100 times greater than serum) and the effect of gentamicin on biological membranes appears to be critical in the pathogenetic sequence.15
The Special Sense Organs and Their Disorders
Published in Walter F. Stanaszek, Mary J. Stanaszek, Robert J. Holt, Steven Strauss, Understanding Medical Terms, 2020
Walter F. Stanaszek, Mary J. Stanaszek, Robert J. Holt, Steven Strauss
Ototoxicity is defined as the condition of having a toxic or poisonous effect upon the ear. A number of drugs can result in hearing loss because of their ototoxicity. Aminoglycoside antibiotics have a high degree of ototoxicity, possibly because of their high concentrations in the inner ear fluids that are retained for long periods of time. This can result in both auditory (hearing) and vestibular (equilibrium) effects. Auditory effects are manifested by high-frequency hearing loss.
Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies
Published in Expert Opinion on Drug Discovery, 2023
The concept of targeting RNAs with small molecules is not a novel one. In the late 1980s, it was discovered that the target of aminoglycoside antibiotics are bacterial ribosomal RNAs [12]. Thereafter, aminoglycosides were revealed to promiscuously bind RNA [13,14], and while some viewed this promiscuity as an opportunity to optimize aminoglycosides for targeting other RNAs, many opted to divert to more drug-like small molecules. Thus far, more than 200 bioactive small molecules were reported to bind RNA molecules with diverse structural motifs (Figure 1(b)) [15,16]. The RNA binders can be classified into two: (1) ‘traditional’ small molecules with properties satisfying Lipinski’s rules (MW ~ 500 Da) and (2) larger, multivalent ligands (~2000 Da). The consensus is that drug-like small molecules would bind structurally complex RNAs with protein-like binding pockets, while multivalent ligands would bind low-complexity RNAs (Figure 1(c)) [17,18].
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Published in Expert Opinion on Orphan Drugs, 2021
Ruofan Connie Han, Lewis E. Fry, Ariel Kantor, Michelle E. McClements, Kanmin Xue, Robert E. MacLaren
If an mRNA transcript containing a premature PTC escapes nonsense-mediated decay, during translation the PTC results in termination of the protein, leading to a truncated protein product. Normal binding of tRNA with its matching site on mRNA takes place within the ribosome ‘A’ site during translation. A cognate tRNA matches three of its mRNA base pairs, while a near-cognate tRNA matches only two. The normal levels of near-cognate tRNA matches compared to cognate tRNA are less than 0.1% in normal translation [78]. When a PTC exists, no cognate tRNA exists: instead, eukaryotic release factor 1 (eRF1) binds to the stop codon at the ‘A’ site and initiates release of the polypeptide from the ribosomal complex. Nonsense suppression therapy works by promoting read-through of transcripts with a PTC by promoting binding of near-cognate tRNAs at the PTC instead of eRF1. In clinical usage, aminoglycoside antibiotics exploit this mechanism by binding to bacterial ribosomes and causing fatal translational errors. Eukaryotic cells have greater resistance to the substitution of near-cognate tRNAs due to differences in ribosomal structure. Nonetheless, aminoglycosides such as gentamicin, paromomycin, streptomycin among others promote read-through at eukaryotic PTC sites. Moosajee et al. showed that in a zebrafish model of choroideremia, where homozygous REP1 knockout caused by chmru848 usually confers embryonic lethality, administration of gentamicin and paromomycin improved read-through and conferred a 1.5- to 1.7-fold improvement in survival [79].
Nephroprotective Effect of Moringa Oleifera Seed Oil on Gentamicin-Induced Nephrotoxicity in Rats: Biochemical Evaluation of Antioxidant, Anti-inflammatory, and Antiapoptotic Pathways
Published in Journal of the American College of Nutrition, 2020
C. O. Edeogu, Michael E. Kalu, Ademola C. Famurewa, Nnaemeka T. Asogwa, Gertrude N. Onyeji, Kelechi O. Ikpemo
Infectious diseases are a challenging cause of mortality and morbidity worldwide. Antibiotic agents are broadly efficient for the treatment of different infections. Nonetheless, their use may trigger adverse effects such as nephrotoxicity as the kidney is one of the most vulnerable organs to aminoglycoside antibiotic toxicity (3). GM is a clinically effective antibiotic widely used in the treatment of Gram-negative bacterial infections. It is a therapeutic alternative to overcome antimicrobial resistance scenarios (30). However, the clinical utility of GM is constrained due to its nephrotoxicity. Oil is a food component integrated into the culinary culture of populations worldwide. MOO is emerging as functional food oil with a growing number of pharmacological properties (17,18). Thus, we assayed to explore the nephroprotective effect of MOO against GM nephrotoxicity and to decipher the possible underlying mechanisms in Wistar rats.