Skin and Mucous Membrane Ulceration in Beagle Dogs following Oral Dosing with an Experimental Aminoglycoside Antibiotic

ROCCA, PAUL T. LA; BAKER, FRED; FRANTZ, JERRY D.; Szot, R.J.; BLACK, HUGH E.; SCHWARTZ, EDWARD

doi:10.1093/toxsci/5.5.986

Cited by 4 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…La Roca et al (23) reported mouth and genital ulceration in beagles 7-14 days after a single oral dose of 50 mg/kg (2.5% estimates LD 50 ). Also, emesis, loose stools, and decreased food consumption were observed.…”

Section: Pharmacokinetic Behavior Of Geneticin In Hemophilia Mouse Plmentioning

confidence: 99%

A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin

Yang¹,

Feng²,

Song³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Aminoglycosides can bypass nonsense mutations and are the prototypic agents for translational bypass therapy (TBT). Initial results demonstrate the need for more potent drugs and an in vivo model system for quantitative assessment of TBT. Herein, we present an in vivo system for evaluating the efficacy of premature stop codon management therapies: in vivo quantitative stop codon management repli-sampling TBT efficacy assay (IQSCMaRTEA). Application of IQSCMaRTEA reveals that geneticin is much more efficacious in vivo than gentamicin. Treatment with geneticin elicits a multiday response, and residual F9 antigen can be detected after 3 weeks. These data demonstrate the utility of IQSCMaRTEA for evaluating drugs that bypass nonsense mutations. In addition, IQSCMaRTEA may be helpful for testing inhibitors of nonsensemediated decay, as stop codon management therapy will sometimes require inhibition of nonsense-mediated decay and translational bypass of the nonsense mutation. Furthermore, geneticin, its metabolites, or better tolerated analogues should be evaluated as a general treatment with multiday response for severe genetic disease caused by nonsense mutation.cancer chemotherapy ͉ oncology ͉ nonsense-mediated decay ͉ aminoglycoside ͉ hemophilia A minoglycosides can cause extensive misreading of the mRNA code in vitro (1) and bypass nonsense mutations as demonstrated in Escherichia coli (2), tetrahymena (3), wheat embryo (4), yeast (5), cultured animal cells (6) and human cells (4, 7-9). Barton-Davis et al. (10) described gentamicin-mediated translational bypass therapy (TBT) in the dystrophin gene in a mouse model for muscular dystrophy. Two other mouse models (6, 11) have been described, and clinical trials have been initiated (12,13). The clinical studies have been difficult to perform and disappointing to date, suggesting the need for a better animal model to explore the dose-response relationships of compounds that mediate TBT. No in vivo animal system was heretofore available for direct and quantitative functional assessment of TBT efficacy.We describe such an in vivo system: in vivo quantitative stop codon management repli-sampling TBT efficacy assay (IQSCMaRTEA). Three mutant human minigenes are used as models, two with nonsense mutations with and without dramatic nonsense-mediated decay (NMD) and one with a missense mutation.Hemophilia is the oldest known hereditary bleeding disorder affecting Ϸ1 in 10,000 males. There are Ϸ20,000 hemophilia patients in the United States. Each year, Ϸ400 babies are born with this disease, Ϸ80% with hemophilia A and 20% with hemophilia B (HB). Approximately 70% of hemophilia patients have severe hemophilia, including those with nonsense mutations. TBT has the potential to provide an inexpensive prophylaxis in hemophilia and greatly improve or eliminate symptoms from any severe genetic disease caused by a nonsense mutation (15% of severe inherited genetic disease). However, NMD and sequence context effects complicate the practical application of TBT (14, 15).IQSCMaRTEA allo...

show abstract

Section: Pharmacokinetic Behavior Of Geneticin In Hemophilia Mouse Plmentioning

confidence: 99%

A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin

Yang¹,

Feng²,

Song³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Dosing of neonates can be complicated by drug toxicity or bioavailability issues that are either inherent to the proof-of-concept compound itself as is the case for G418 (7,23,24), or arise due to developmental differences of neonate mice (43)(44)(45). Our data show HR, PR, QRS, and heart rate variability measures are sensitive biomarkers that can be passively monitored in awake neonate mice to provide quantitative insight into drug and genotype effects.…”

Section: Discussionmentioning

confidence: 89%

“…Further, we were able to resolve significant heart block in a small number of mice at end stages of G418 toxicity, indicating ECG and the PR interval can be used to detect drug toxicities in young mice. Previously, G418 has been found to display general toxicity in mice and dogs with damage to the liver, kidney and immune systems (23,24). Side effects of primary concern for clinical aminoglycoside antibiotics include kidney damage and hearing loss, both associated with disrupted ion homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, this produces an increase in motor function of SMNdelta7 mice (7). However, G418 treatment ultimately results in toxicity in healthy mice and dogs (23,24). Regardless of this toxicity, the clear efficacy of G418 at causing translational readthrough establishes it as a powerful proof-of- Author Manuscript concept compound in basic science studies (7,(25)(26)(27).…”

Section: Hhs Public Accessmentioning

confidence: 99%

See 1 more Smart Citation

ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy

Heier

DiDonato

2015

Front Biosci

View full text Add to dashboard Cite

Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias. INTRODUCTIONSpinal muscular atrophy (SMA) results from a clearly defined genetic deficit ultimately leading to death in children affected by its most frequent form (Type I, or Werdnig-Hoffman disease). SMA can be modeled and treated in animals. From patient studies, SMA is caused by insufficient dosage of the survival motor neuron (SMN) gene product. This insufficiency typically results from homozygous deletion of the SMN1 gene (1, 2). In most organisms Send correspondence to: Christine J. DiDonato, Ann and Robert H. Lurie Children's Hospital, 225 E. Chicago Ave., Chicago, IL 60611, Box 211,. (6), and aminoglycoside antibiotics which work through a translational readthrough drug mechanism to stabilize the SMNdelta7 protein (7-9). HHS Public AccessPreclinical mouse studies have been important in drug discovery for disorders in which heart rhythms are affected by disease (10-12). Recently, we found multiple mouse models of SMA display cardiac arrhythmias (13)(14)(15). These models present relatively severe phenotypes, in which mice are grossly undersized and die within days or weeks after birth (13,15,16). Studies of these models require that phenotyping assays be performed in neonates. However, many functional outcome measures are invalid in neonates due to mouse size, assay invasiveness, equipment incompatibility, or the large number of mice required (17). For electrocardiography (ECG) in particular, the invasiveness, restraint or surgery required by many systems can interfere with the heart rate itself or endanger the life of a fragile, neonatal disease model mouse (18)(19)(20)(21)(22). Preclinical outcome measures used in place of established clinical tests in neonates typically have a subjective component that demands inter-rater reliability testing, and that can...

show abstract

“…Owing to putative severe side effects of G-418, 33 in a first therapeutic trial we tested whether subcutaneous gentamicin and amikacin injections can alleviate obesity of Mc4r X16/X16 knock-in mice. Both aminoglycosides were published as potent nonsense suppressors in vivo without evoking adverse effects.…”

Section: Aminoglycoside Treatmentmentioning

confidence: 99%

Characterization of the melanocortin-4-receptor nonsense mutation W16X in vitro and in vivo

et al. 2011

View full text Add to dashboard Cite

Several genetic diseases are triggered by nonsense mutations leading to the formation of truncated and defective proteins. Aminoglycosides have the capability to mediate a bypass of stop mutations during translation thus resulting in a rescue of protein expression. So far no attention has been directed to obesity-associated stop mutations as targets for nonsense suppression. Herein, we focus on the characterization of the melanocortin-4-receptor (MC4R) nonsense allele W16X identified in obese subjects. Cell culture assays revealed a loss-of-function of Mc4r(X16) characterized by impaired surface expression and defect signaling. The aminoglycoside G-418 restored Mc4r(X16) function in vitro demonstrating that Mc4r(X16) is susceptible to nonsense suppression. For the evaluation of nonsense suppression in vivo, we generated a Mc4r(X16) knock-in mouse line by gene targeting. Mc4r(X16) knock-in mice developed hyperphagia, impaired glucose tolerance, severe obesity and an increased body length demonstrating that this new mouse model resembles typical characteristics of Mc4r deficiency. In a first therapeutic trial, the aminoglycosides gentamicin and amikacin induced no amelioration of obesity. Further experiments with Mc4r(X16) knock-in mice will be instrumental to establish nonsense suppression for Mc4r as an obesity-associated target gene expressed in the central nervous system.

show abstract

Skin and Mucous Membrane Ulceration in Beagle Dogs following Oral Dosing with an Experimental Aminoglycoside Antibiotic

Cited by 4 publications

References 0 publications

A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin

A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin

ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy

Characterization of the melanocortin-4-receptor nonsense mutation W16X in vitro and in vivo

Contact Info

Product

Resources

About