Pharmacokinetics of N-acetylcysteine after oral and intravenous administration to healthy cats

Buur, Jennifer L.; Diniz, Pedro; Roderick, Kursten V.; KuKanich, Butch; Tegzes, John H.

doi:10.2460/ajvr.74.2.290

Cited by 19 publications

(28 citation statements)

References 10 publications

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“…Finally, this study showed that some people with PD had worsening of their parkinsonian symptoms with high doses of NAC that resolved with discontinuation of therapy. The NAC PK parameter estimates were consistent with published literature, 26,27 and there were no discernable differences between patients with PD and healthy individuals. However, the limited number of subjects did not allow for robust comparisons.…”

Section: Discussionsupporting

confidence: 88%

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Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Coles

Tuite

Öz

et al. 2017

The Journal of Clinical Pharma

127

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Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

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Section: Discussionsupporting

confidence: 88%

“…The NAC PK parameter estimates were consistent with published literature, and there were no discernable differences between patients with PD and healthy individuals. However, the limited number of subjects did not allow for robust comparisons.…”

Section: Discussionsupporting

confidence: 86%

Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Coles

Tuite

Öz

et al. 2017

The Journal of Clinical Pharma

127

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“…In addition, we have characterised the ability of two drugs of interest with respect to future therapeutic options for autism—NAC and eletriptan—to normalise the stress-induced phenotypes observed in 16p11.2 DEL mice, showing dissociable effects on hyperactivity, anxiety-like behaviour and sociability. Both NAC and eletriptan are rapidly absorbed in rodents and other species 44 – 46 , allowing the assessment of their effects on the post-injection phenotypes observed. Both drugs are also completely cleared by 24 h after administration 44 , 46 , 47 , so no carry-over effects are expected in our counter-balanced repeated measures design.…”

Section: Discussionmentioning

confidence: 99%

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

Mitchell

Thomson

Openshaw

et al. 2020

Sci Rep

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There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT 1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT 1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment. Autism is extremely common, affecting males more than females (estimated to affect roughly 4/1,000 boys and 1/1,000 girls) 1,2 , and characterised by communication difficulties, social dysfunction, and repetitive or restricted behaviour patterns, with a high rate of comorbid conditions such as anxiety. There are no available drug treatments for autism. Development of improved treatments will only be enabled by increased understanding of the causes of the disease and how they impact on neurobiology, informed by better preclinical models of facets of the disease. The genetic architecture of autism is complex 3. While a large number of common sequence variations increase disease risk, each has only a very small effect individually, and it is the cumulative burden of a range of risk, and protective, gene variants that underlies the aetiological mechanisms ultimately resulting in the manifestation of the common, sporadic disease. However, it is now clear that very rare copy number variants (CNVs), where small numbers of genes are present in one or three, rather than two, copies, substantially increase disease risk. For example, carriers of the deletions of the 16p11.2 locus have dramatically increased risk of autism-spectrum disorders (ASD) and also intellectual disability (8-40x) 4-6. Interestingly, a high proportion of carriers of the corresponding 16p11.2 duplication develop schizophrenia, suggesting that studying the neurobiological impact of CNVs at this locus may be particularly informative. The 16p11.2 deletion is one of the most powerful genetic risk factors for autism 3. Various drug classes have been tested in mouse models relevant to ASD, for efficacy in reversing behavioural...

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“…Because of the frequent prescription of antioxidant medications by veterinarians for dogs with suspected liver disease and our target being within dog correlations between serum or urine and liver antioxidant/oxidative biomarkers, such treatments were not exclusion criteria. However, to minimize the impact antioxidant supplementation could have in finding a correlation between serum and liver any antioxidant supplementation must have been taken by each dog long enough to achieve steady state: 7 days for a glutathione source (S‐adenosyl methionine (SAMe), N‐acetylcysteine (NAC), or milk thistle), and 21 days for vitamin E …”

Section: Methodsmentioning

confidence: 99%

Biomarkers of oxidative stress as an assessment of the redox status of the liver in dogs

Barry‐Heffernan¹,

Ekena

Dowling³

et al. 2019

Veterinary Internal Medicne

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Background Oxidative stress is associated with a diverse group of liver disorders across species. Objectives Determine whether glutathione (GSH) concentration in plasma and red blood cells correlates with liver GSH concentration in dogs and evaluate whether other markers of systemic oxidative stress, plasma vitamin E and urine 8‐isoprostanes/creatinine (F2‐IsoPs/Cr) concentrations, correlate with liver GSH. Animals Thirty‐four client‐owned dogs undergoing clinically indicated liver biopsy and 15 healthy control dogs. Methods Prospective, observational cross‐sectional study. Urine and blood were collected before liver biopsy. Plasma, erythrocyte, and liver GSH were measured using high performance liquid chromatography (HPLC); vitamin E was measured by HPLC, and F2‐IsoPs/Cr was measured by gas chromatography/mass spectrometry. Results All dogs were treated at the discretion of the attending clinician (24/34 received antioxidants; 4/34 fed therapeutic liver diet), which included dogs with primary or secondary liver disease (inflammatory (n = 21), metabolic (n = 9), vascular (n = 2), and neoplastic (n = 2)). Median GSH concentrations in plasma, erythrocyte, and liver were 0.18 mg/dL (range 0.14 to 0.56 mg/dL), 56.7 mg/dL (18.3 to 79.2 mg/dL), and 181 mg/dL (39.9 to 527 mg/dL), respectively. No significant correlations were found between liver GSH and erythrocyte GSH, plasma GSH, vitamin E, or F2‐IsoPs/Cr. Dogs undergoing clinically indicated liver biopsy had significantly higher urine F2‐IsoPs/Cr than did healthy controls (5.89 vs 2.98 ng/mg; P < .0001). Conclusions and Clinical Importance Erythrocyte and plasma GSH are not indicative of liver GSH concentration in dogs. In addition, dogs undergoing clinically indicated liver biopsy have evidence of increased systemic oxidative stress compared to healthy controls.

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Pharmacokinetics of N-acetylcysteine after oral and intravenous administration to healthy cats

Cited by 19 publications

References 10 publications

Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

Biomarkers of oxidative stress as an assessment of the redox status of the liver in dogs

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