Assessing a Theoretical Risk of Dolutegravir-Induced Developmental Immunotoxicity in Juvenile Rats

Rhodes, Melissa C.; Laffan, Susan; Genell, Caroline; Gower, Jill; Maier, Curtis C.; Fukushima, Tamio; Nichols, Garrett; Bassiri, Ashlyn Eaton

doi:10.1093/toxsci/kfs220

Cited by 15 publications

(6 citation statements)

References 20 publications

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“…The NOAEL of compound 1 was determined to be greater than 500 mg/kg/day, which provides a significant exposure margin in antiviral therapeutic applications. Dolutegravir had an NOAEL in adult rats of 50 mg/kg/day (Rhodes et al, 2012) and raltegravir showed an NOAEL of 120mg/kg/day (Merck, 2007), although the dosage and study durations were somewhat different from our studies. The maximum tolerated dose (MTD) for compound 1 is also considered to be greater than 500 mg/kg/day.…”

contrasting

confidence: 78%

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor

Nair¹,

Okello²,

Mishra³

et al. 2014

Antiviral Research

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Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the “point of no return” in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound 1 and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound 1 in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound 1 exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (> 500 mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.

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contrasting

confidence: 78%

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor

Nair¹,

Okello²,

Mishra³

et al. 2014

Antiviral Research

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“…Histone methylation plays a key role in and as such regulates transcription, replication, cell differentiation, genome stability, and apoptosis [62][63][64][65][66]. Mounting evidence points to a role for histone lysine methylation in DSB repair [67][68][69][70][71][72].…”

Section: Histone H3 Dimethylation Of Lys36 At Dsb Sitesmentioning

confidence: 99%

Emerging Features of DNA Double-Strand Break Repair in Humans

Kim¹,

Hromas²,

Lee³

2013

New Research Directions in DNA Repair

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Additional information is available at the end of the chapter http://dx.doi.org/10.5772/53811 . IntroductionIonizinμ radiation IR and various cytotoxic chemicals includinμ reactive oxyμen species ROS induce DN" double-strand breaks DS"s when they attack the phosphate backbones oλ the two DN" strands simultaneously. DS"s, once μenerated, not only cause a discontinuity in the μenetic code, but also are vulnerable to λurther loss oλ DN" λrom a nuclease attack or the λormation oλ abnormal DN" structures λrom chromosomal translocation, all oλ which can siμniλicantly increase μenomic instability leadinμ to cancer. Repair oλ DS" damaμe is thereλore crucial λor maintaininμ the physical and μenetic inteμrity oλ the μenome. DN" damaμe sensors are the λirst responder to various types oλ DN" damaμes. Upon DS" damaμe, Mre -Rad -Nbs MRN complex initially recoμnizes DN" damaμe, and recruits and activates the ataxia-telanμiectasia mutated "TM throuμh protein interaction with Nbs Fiμ. [ , ]. "TM is a member oλ the phosphoinositide -kinase PI K -related protein kinase PIKK λamily oλ serine/threonine protein kinases that phosphorylates a number oλ tarμet proteins containinμ conserved phosphorylation motiλ SQ/TQ in response to DN" damaμe [ ] that include MRN complex, a histone variant, H "X, a checkpoint mediator, MDC , a checkpoint kinase, CHK and p [ ]. Phosphorylations oλ MRN complex, H "X and MDC are necessary λor recruitment oλ the λactors involved in siμnal transduction and homoloμous recombination HR to λacilitate the repair process [ -]. " marμinal repair deλect was observed in "T cells, which could be due to the reduced eλλiciency oλ homoloμous recombination [ ]. Damaμe-induced phosphorylation oλ CHK and activation oλ p also induce the cell cycle arrest at the G phase [ , , ]. Three major DSB repair pathways in mammals. Following recognition of DSB damage by MRN complex and ATM, leading to phosphorylation of H2AX, DSB repair can occur through nonhomologous end joining (NHEJ), homologous recombination (HR), or microhomology-mediated end joining (MMEJ) repair pathways. The error-free pathway of HR in the late S-and G2-phases of the cell cycle requires a sister chromatid to restore broken DNA to its original sequence, whereas the error-prone pathway of NHEJ often processes the DNA by adding or deleting nucleotides before joining the ends. In some circumstances one or more of the broken ends is refractory to Ku mediated NHEJ. In this case, MMEJ can proceed by nucleolytic processing and resection of the 3'-end until a short region of complimentary bases is revealed. Pairing of this microhomology stabilizes the broken ends, displaced flaps are removed and ligation can occur. Although many of the proteins involved in these major DSB repair pathways have been identified, the precise mechanisms involved remain poorly understood.In mammals, DS" damaμes are larμely repaired by non-homoloμous end joininμ NHEJ pathway throuμhout the cell cycle that directly liμates the break ends without the need λor a homoloμous template Fiμ. , so NH...

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“…The WHO consolidated guidelines on ARV use recommended Efavirenz (EFV 600 mg) based regimen as a preferred first-line choice for HIV-1 treatment based on efficacy and safety data at that time [11]. At the moment, however, INSTI-based HAART regimens are the most preferred for antiretroviral therapy [11,12,13] because of their potency, safety profile, and rare drug-drug interactions [13,14,15]. Dolutegravir (DTG), a new generation INSTI, acts by inhibiting the incorporation of HIV DNA into the T-lymphocyte genome of the host, thereby limiting viral propagation [13].…”

Section: Introductionmentioning

confidence: 99%

Reproductive and Oxidative Stress Toxicity of Dolutegravir-Based Combination Antiretroviral Therapy in Drosophila melanogaster

Iorjiim

Omale

Bagu

et al. 2020

JAMPS

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Background/Objective: Dolutegravir-based highly active antiretroviral therapy (DTG-HAART) is the preferred regimen in the management of HIV/AIDS. However, the reproductive and oxidative stress toxicity of DTG-HAART is unknown. This study was designed to investigate the reproductive and oxidative stress toxicity of DTG-HAART in Drosophila melanogaster. Materials and Methods: We performed all the experiments at the Centre of Excellence in phytomedicine Research and Development (ACEPRD), University of Jos, Nigeria, in 2019. D. melanogaster, (1-4 days old), were fed with ten different concentrations of DTG-HAART (range 15 mg -595 mg) or 1000 mL distilled water per 10 g food for seven days to calculate the LD50, then treated with 93.11 mg, 46.56 mg, 23.28 mg, 11.64 mg or 1000 µL distilled water each per 10 g fly food for five days in five replicates. Subsequently, longevity, fly fecundity, and negative geotaxis evaluated. Also, activities of Acetylcholinesterase, Glutathione-S-transferase, Superoxide dismutase, Catalase, as well as Total thiol, and Malondialdehyde levels were investigated in the whole fly homogenate. Statistical values at P<0.05 were considered significant. Results: The LD50 of DTG-HAART in D. melanogaster was 106.4 mg. The result showed significantly decrease (P<0.001) in mean lifespan, fly emergence, Total thiol content, Acetylcholinesterase, Glutathione-S-transferase, Catalase, and Superoxide dismutase activities in the exposed groups compared to the unexposed. Inversely, the Malondialdehyde level in the test groups was significantly (P<0.001) elevated compared to unexposed. Conclusion: Collectively, our results suggest that DTG-HAART toxicity was associated with reproductive deficits and oxidative stress induction in D. melanogaster, here observed as reduced fly fecundity, mean lifespan, AChE activity, antioxidant parameters, and elevated MDA level. This study, thus, raised concerns for long term use of DTG-HAART by HIV patients.

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Assessing a Theoretical Risk of Dolutegravir-Induced Developmental Immunotoxicity in Juvenile Rats

Cited by 15 publications

References 20 publications

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor

Emerging Features of DNA Double-Strand Break Repair in Humans

Reproductive and Oxidative Stress Toxicity of Dolutegravir-Based Combination Antiretroviral Therapy in Drosophila melanogaster

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