The effect of hydrazine on ATP levels has been investigated in rats in vivo and in hepatocytes in vitro. Hydrazine was found to cause a dose-dependent depletion of hepatic ATP in vivo 3 h after dosing. In isolated hepatocytes in vitro hydrazine also caused a concentration-dependent depletion of ATP which preceded cytotoxicity as indicated by loss of cell viability. The ATP depletion in isolated hepatocytes was also significant at a concentration of hydrazine which was not cytotoxic. Attempts to determine hepatic ATP depletion in vivo over time using topical 31P NMR were confounded by the effects of the thiopentobarbitone used to anaesthetise the animals. This was found to ameliorate the effects of hydrazine on ATP depletion but potentiate the lethality of hydrazine. Consequently, although ATP depletion was detected in some hydrazine-treated animals, this was only observed in animals which subsequently died. The results indicate that ATP depletion may underlie the hepatotoxicity of hydrazine.
Using isolated rat hepatocytes the biochemical effects of hydrazine have been investigated using both conventional assay techniques and high resolution proton NMR. High resolution proton NMR revealed that hydrazine caused a significant increase in alanine and lactate levels in the incubation buffer, whereas levels of beta-hydroxybutyrate were decreased. NMR also detected metabolites of hydrazine notably acetylhydrazine and a cyclised hydrazone formed with alpha-ketoglutarate. Changes were detected in NADH and NADPH, ATP, succinate dehydrogenase (SDH) and total non-protein sulphydryl groups (TNPSH). However, the changes in pyridine nucleotides occurred at higher concentrations than those affecting succinate dehydrogenase and ATP. Similarly, the depletion of TNPSH occurred at a higher concentration and with a different time course to that seen with ATP depletion and inhibition of succinate dehydrogenase.
The Dutch Fatigue In Teenagers on the interNET (FITNET) study claimed that after 6 months, internet based cognitive behaviour therapy in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), led to a 63% recovery rate compared to 8% after usual care, and that this was maintained at long term follow up (LTFU). Our reanalysis shows that their post-hoc definition of recovery included the severely ill, the unblinded trial had no adequate control group and it used lax selection criteria as well as outcomes assessed via questionnaires rather than objective outcomes, further contributing to exaggerated recovery figures. Their decision not to publish the actometer results might suggest that these did not back their recovery claims. Despite these bias creating methodological faults, the trial still found no significant difference in recovery rates (“~60%”) at LTFU, the trial’s primary goal. This is similar to or worse than the documented 54–94% spontaneous recovery rates within 3–4 years, suggesting that both FITNET and usual care (consisting of cognitive behaviour and graded exercise therapies) are ineffective and might even impede natural recovery in adolescents with ME/CFS. This has implications for the upcoming costly NHS FITNET trial which is a blueprint of the Dutch study, exposing it to similar biases.
1 Rats were given various doses of hydrazine orally and their plasma and liver hydrazine levels were determined (at various times up to 270 min after dosing) by gas chromatography/ mass spectrometry. 2 The increase in the peak plasma level and in the area under the plasma concentration-time curve (AUC) were not directly proportional to the dose. 3 The ratio of plasma to liver hydrazine varied with dose suggesting saturation of an uptake mechanism might be occurring. 4 In a separate experiment hydrazine was still detectable in the plasma and liver 24 h after dosing with hydrazine i.p. 5 Rats were given the same doses of hydrazine and urine was collected for 24 h after dosing and assayed for hydrazine and acetylhydrazine. The proportion of hydrazine and acetylhydrazine excreted declined with dose. 6 Liver samples were taken for histopathological examination 96 h after dosing. Only after the highest dose (81 mg kg-1) was there evidence of fatty liver, 96 h after a single dose, and a reduction in both liver and body weight.
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