Homocysteine and the methotrexate toxicity in trisomy 21

Lejeune, J; Peeters, Marie; Rethoré, M O; Blois, M.-C. De

doi:10.1007/bf00685122

Cited by 9 publications

(9 citation statements)

References 9 publications

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“…The median anti-HBs titers at week 15 post initiation of monotherapy in the 6 patients who experienced seroconversion ( Fig. 1) was 25 [IQR: [23][24][25][26][27][28][29][30]] mIU/mL.…”

Section: Resultsmentioning

confidence: 99%

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Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Shekhtman

Cotler

Hershkovich

et al. 2020

Sci Rep

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Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) for its assembly and release. Current HBV treatments are only marginally effective against HDV because they fail to inhibit HBsAg production/secretion. However, monotherapy with the nucleic acid polymer REP 2139-Ca is accompanied by rapid declines in both HBsAg and HDV RNA. We used mathematical modeling to estimate HDV-HBsAg-host parameters and to elucidate the mode of action and efficacy of REP 2139-Ca against HDV in 12 treatment-naive HBV/HDV co-infected patients. The model accurately reproduced the observed decline of HBsAg and HDV, which was simultaneous. Median serum HBsAg half-life (t 1/2) was estimated as 1.3 [0.9-1.8] days corresponding to a pretreatment production and clearance of ~10 8 [10 7.7-10 8.3 ] IU/day. The HDV-infected cell loss was estimated to be 0.052 [0.035-0.074] days −1 corresponding to an infected cell t 1/2 = 13.3 days. The efficacy of blocking HBsAg and HDV production were 98.2 [94.5-99.9]% and 99.7 [96.0-99.8]%, respectively. In conclusion, both HBsAg production and HDV replication are effectively inhibited by REP 2139-Ca. Modeling HBsAg kinetics during REP 2139-Ca monotherapy indicates a short HBsAg half-life (1.3 days) suggesting a rapid turnover of HBsAg in HBV/ HDV co-infection. Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection affects an estimated 15-40 million persons worldwide 1,2 and is the most aggressive form of viral hepatitis 3. Therapy with pegylated interferon-α2a (pegIFN) is suboptimal in controlling HDV infection 4,5 and no other therapies are approved for the treatment of HDV. HDV requires hepatitis B surface antigen (HBsAg) for assembly and release. While the large isoform (L-HBsAg) is not requisite for HDV assembly and release, it is necessary for infectivity 6. Drugs that directly target HDV and reduce HDV levels are in development 7 , however the only anti-HBV treatment that affects HBsAg production is the nucleic acid polymer (NAP) REP 2139-Ca, which is accompanied by declines in both HBsAg and HDV RNA 8-11. Therefore, analyzing antiviral response during REP 2139-Ca monotherapy provides a unique opportunity to examine HBsAg production and clearance rates in HBV/HDV co-infected patients and to obtain a deeper understanding of REP 2139-Ca mode of action and efficacy against HDV. The aim of this study was to analyze the kinetics of HBV DNA, HBsAg, ALT and HDV RNA during REP 2139-Ca monotherapy and investigate the dynamics of HDV RNA and HBsAg using mathematical modelling.

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“…The median anti-HBs titers at week 15 post initiation of monotherapy in the 6 patients who experienced seroconversion ( Fig. 1) was 25 [IQR: [23][24][25][26][27][28][29][30]] mIU/mL.…”

Section: Resultsmentioning

confidence: 99%

“…For HDV, the lower limit of quantification (LLoQ) was 3.26 log U/mL, for HBsAg, LLoQ = −1.3 log IU/mL and for HBV DNA, LLoQ=1 log IU/mL. For anti-HBs the architect LLoQ is 2mIU/mL and the current convention, which we followed, is to define seroconversion as a titer> 10mIU/mL 24 . The upper limit of normal for ALT was 50 U/L.…”

Section: Methodsmentioning

confidence: 99%

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Shekhtman

Cotler

Hershkovich

et al. 2020

Sci Rep

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“…The overexpression of these genes has been observed and causes a cascade of metabolic disturbances: low concentrations of folates, methionine, homocysteine, S-adenosyl methionine and serine and high levels of cysteine, cystathionine and methylated DNA (Figure 1) [7], [14], [21], [22], [23]. These disturbances partly account for the macrocytosis [24], glossitis and methotrexate hypersensitivity usually observed in these patients [25], [26], [27], [28], which can be partially corrected by folic acid treatment [27]. One previous study reported that folate treatment might improve the psychomotor development of DS patients [29], [30].…”

Section: Introductionmentioning

confidence: 99%

Effect of Leucovorin (Folinic Acid) on the Developmental Quotient of Children with Down's Syndrome (Trisomy 21) and Influence of Thyroid Status

et al. 2010

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BackgroundSeven genes involved in folate metabolism are located on chromosome 21. Previous studies have shown that folate deficiency may contribute to mental retardation in Down's syndrome (DS).MethodologyWe investigated the effect of oral folate supplementation (daily dose of 1.0±0.3 mg/kg) on cognitive functions in DS children, aged from 3 to 30 months. They received 1 mg/kg leucovorin or placebo daily, for 12 months, in a single-centre, randomised, double-blind study. Folinic acid (leucovorin, LV) was preferred to folic acid as its bioavailability is higher. The developmental age (DA) of the patients was assessed on the Brunet-Lezine scale, from baseline to the end of treatment.ResultsThe intent-to-treat analysis (113 patients) did not show a positive effect of leucovorin treatment. However, it identified important factors influencing treatment effect, such as age, sex, and concomitant treatments, including thyroid treatment in particular. A per protocol analysis was carried out on patients evaluated by the same examiner at the beginning and end of the treatment period. This analysis of 87 patients (43 LV-treated vs. 44 patients on placebo) revealed a positive effect of leucovorin on developmental age (DA). DA was 53.1% the normal value with leucovorin and only 44.1% with placebo (p<0.05). This positive effect of leucovorin was particularly strong in patients receiving concomitant thyroxin treatment (59.5% vs. 41.8%, p<0.05). No adverse event related to leucovorin was observed.ConclusionThese results suggest that leucovorin improves the psychomotor development of children with Down's syndrome, at least in some subgroups of the DS population, particularly those on thyroxin treatment.Trial RegistrationClinicalTrials.gov, NCT00294593

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“…In recent years, the present authors have examined the in vitro metabolic behaviour of lymphocytes from patients with various chromosomal anomalies, trying to better understand the metabolic consequences of additional chromosomal material as well as the pathophysiological basis of mental retardation (Lejeune et al 1986(Lejeune et al , 1991Peeters etal. 1989).…”

Section: Introductionmentioning

confidence: 99%

Differences in purine metabolism in patients with Down's syndrome

Peeters¹,

Mégarbané²,

Cattaneo³

et al. 1993

J intellect Disabil Res

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ABSTRACT. Three enzymes intervening in de novo purine synthesis, as well as cystathionine B‐synthetase, have been mapped to chromosome 21. In order to gain a better understanding of purine synthesis anomalies in Down's syndrome, the present authors studied the variations in mitotic index of lymphocyte cultures to which various inhibitors or metabolites of purine synthesis had been added. In spite of common gene dosage effects, unexpected and highly significant differences were noted between Down's syndrome patients without complications and those presenting with additional psychotic features. In Down's syndrome patients without complications, a highly significant decrease in mitotic index was noted in the presence of exogenous inosine. A significant decrease in the presence of adenosine and guanosine was also noted. These findings are in keeping with the expected metabolic repercussions of genes mapped to chromosome 21. In Down's syndrome patients with psychotic complications, the in vitro reactions were quite different. A paradoxal increase in mitotic index was noted in the presence of inosine and of adenosine, but the response to guanosine did not differ from that observed in normal controls. These findings were unexpected and seem to indicate that, in spite of the gene dosage effect, psychotic Down's syndrome patients are unable to compensate abnormal purine synthesis and resulting imbalances. Furthermore, a marked difference in purine metabolic reactions was noted between Down's syndrome patients receiving supplemental folic/folinic acid and those on no therapy. This suggests that some modulation of the gene dosage effect may be possible.

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Homocysteine and the methotrexate toxicity in trisomy 21

Cited by 9 publications

References 9 publications

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Effect of Leucovorin (Folinic Acid) on the Developmental Quotient of Children with Down's Syndrome (Trisomy 21) and Influence of Thyroid Status

Differences in purine metabolism in patients with Down's syndrome

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