Aminoglycoside research 1975-1985: prospects for development of improved agents

Price, K. E.

doi:10.1128/aac.29.4.543

Cited by 53 publications

(43 citation statements)

References 34 publications

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“…To confirm the role of intestinal bacteria in the overall process of oxindole synthesis, rats were orally administered neomycin, a broad-spectrum, locally acting antibiotic agent. This procedure, which has been reported to reduce significantly the number of intestinal bacteria (Price, 1986), also decreased blood and brain oxindole content (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…1), which is mostly present in bacteria (Vederas et al, 1978;Kawata et al, 1991). Figure 4 shows that rats treated for 5 days with oral neomycin, a widely used procedure to decrease levels of intestinal bacteria (Price, 1986), had a reduced concentration of oxindole in their blood (from 0.04 ± 0.003 to 0.01 ±0.001 nmol/ml) and brain (from 0.05 ±0.01 to 0.01 ±0.001 nmol/g). Figure 4 also shows that this antibiotic significantly reduced blood and brain oxindole content in…”

Section: Effects Of Neomycin Treatment On Oxindole Content In Blood Omentioning

confidence: 99%

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Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Carpenedo

Mannaioni

Moroni

1998

Journal of Neurochemistry

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Rats treated with oxindole (10-100 mg/kg p.), a putative tryptophan metabolite, showed decreased spontaneous locomotor activity, loss of the righting reflex, hypotension, and reversible coma. Brain oxindole levels were 0.05 ± 0.01 nmol/g in controls and increased to 8.1 ± 1.7 or 103 ±15 nmol/g after its administration at doses of 10 or 100 mg/kg i.p., respectively. To study the role that oxindole plays in the neurological symptoms associated with acute liver failure, we measured the changes of its concentration in the brain after massive liver damage, and we investigated the possible metabolic pathways leading to its synthesis. Rats treated with either thioacetamide (0.2 and 0.4 g/kg i.p., twice) or galactosamine (1 and 2 g/kg i.p.) showed acute liver failure and a large increase in blood or brain oxindole concentrations (from 0.05 ± 0.01 nmol/g in brains of controls to 1.8 ± 0.3 nmol/g in brains of thioacetamidetreated animals). Administration of tryptophan (300-1,000 mg/kg p.o.) caused a twofold increase, whereas administration of indole (10-100 mg/kg p.o.) caused a 200-fold increase, of oxindole content in liver, blood, and brain, thus suggesting that indole formation from tryptophan is a limiting step in oxindole synthesis. Oral administration of neomycin, a broad-spectrum, locally acting antibiotic agent able to reduce intestinal flora, significantly decreased brain oxindole content. Taken together, our data show that oxindole is a neurodepressant tryptophan metabolite and suggest that it may play a significant role in the neurological symptoms associated with acute liver impairment.

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Neomycin Treatment On Oxindole Content In Blood Omentioning

confidence: 99%

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Carpenedo

Mannaioni

Moroni

1998

Journal of Neurochemistry

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“…With quinolones, for example, tests that measure their effects on developing joint cartilage in young dogs, central nervous system and ocular toxicity in adult dogs, and mutagenicity in both cell culture and animals are usually required (25,76,80,99). Other examples of supportive drug safety tests include in vivo immediate hypersensitivity tests for beta-lactams and tests evaluating the nephrotoxicity of aminoglycosides (126,141).…”

Section: Safety Studies In Animalsmentioning

confidence: 99%

“…A number of factors have limited the introduction of new aminoglycosides, including their inherent potential to cause ototoxicity and nephrotoxicity. A large number of modifying enzymes have also been identified that spread among clinical isolates, limiting the antibacterial potency of these agents (35,36,81,106,126). Aminoglycosides can be inactivated by more than 12 different classes of bacterial enzymes that can modify a reactive hydroxyl or amino group by phosphorylation, acetylation, or adenylylation (Fig.…”

Section: Discovery Of Penicillin Gmentioning

confidence: 99%

“…The development of new aminoglycosides followed a pattern aimed at identifying SAR that blocked susceptible sites for enzymatic modification on the molecule while retaining the acceptable safety profile of the earlier agents (9,17). While many new analogs were tested clinically (33,126,138), amikacin remains one of the most useful due to the relatively infrequent occurrence of resistance encountered (13,107). Amikacin use was often restricted in many hospitals in hopes of preventing the emergence of resistant strains, but its use for empiric therapy in combination with beta-lactams has been widely adopted in centers where resistance to the older aminoglycosides is common.…”

Section: Discovery Of Penicillin Gmentioning

confidence: 99%

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Discovery and development of new antimicrobial agents

Gootz

1990

Clin Microbiol Rev

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The unprecedented growth in the number of new antibiotics over the past two decades has been the result of extensive research efforts that have exploited the growing body of knowledge describing the interactions of antibiotics with their targets in bacterial cells. Information gained from one class of antimicrobial agents has often been used to advance the development of other classes. In the case of beta-lactams, information on structure-activity relationships gleaned from penicillins and cephalosporins was rapidly applied to the cephamycins, monobactams, penems, and carbapenems in order to discover broad-spectrum agents with markedly improved potency. These efforts have led to the introduction of many new antibiotics that demonstrate outstanding clinical efficacy and improved pharmacokinetics in humans. The current review discusses those factors that have influenced the rapid proliferation of new antimicrobial agents, including the discovery of new lead structures from natural products and the impact of bacterial resistance development in the clinical setting. The development process for a new antibiotic is discussed in detail, from the stage of early safety testing in animals through phase I, II, and III clinical trials.

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Aminoglycosides

Mcgregor

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Aminoglycosides are members of the class of antibacterial antibiotics, the structures of which are derived from D ‐streptamine, D ‐2‐deoxystreptamine, or closely related compounds. The term aminocyclitol is sometimes used to identify this group of compounds. In 1991, the most widely used aminoglycosides in medical practice were gentamicin, tobramycin, amikacin, and netilmicin. In general, the aminoglycosides are useful for the treatment of serious infections involving aerobic or facultative gram‐negative bacilli. The most common resistance mechanism involves the inactivation of the aminoglycoside by reactions catalyzed by plasmid‐borne enzymes. Less common resistance mechanisms include decreased affinity for the antibiotic by the bacterial ribosome and decreased rate of transport into the bacterial cytoplasm. The aminoglycosides are administered primarily by intravenous infusion or intramuscular injection. Most of the administered dose is eliminated unmetabolized in the urine. Potential toxicity is a primary limiting factor in the clinical use of aminoglycosides. The most important toxicities are nephrotoxicity, ototoxicity, and to a lesser extent, neuromuscular blockade. All the aminoglycosides in medical practice are capable of causing these adverse events. The effect of this potential is to prevent the use of significantly increased doses to cover difficult infections. The bactericidal mechanisms employed by aminoglycosides are incompletely understood. In the cytoplasm, ribosomal binding leads to misreading of the genetic code and production of abnormal proteins and protein synthesis inhibition. The cause of cell death is uncertain. A large amount of research has been conducted aimed at reducing the limitations in the areas of toxicity and susceptibility to bacterial resistance mechanisms while maintaining the advantages by modification of the aminoglycoside molecular structure. Overall, structural modification has been successful in reducing susceptibility to bacterial inactivation. It has not been possible, however, to substantially dissociate the toxicity potential from the antibacterial activity.

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Aminoglycoside research 1975-1985: prospects for development of improved agents

Cited by 53 publications

References 34 publications

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Discovery and development of new antimicrobial agents

Aminoglycosides

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