Metabolic acidosis didanosine

Stavudine possesses several clinically significant interactions with other drugs. Although hydroxyurea enhances the antiviral activity of stavudine and didanosine, combination therapy that includes stavudine and didanosine, with or without hydroxyurea, increases the risk of pancreatitis. Combinations of stavudine and didanosine should not be given to pregnant women because of the increased risk of metabolic acidosis. Zidovudine inhibits the phosphorylation of stavudine thus, this combination should be avoided. 

A Fanconi syndrome with nephrogenic diabetes insipidus was reported in a patient wifh AIDS who was receiving didanosine (and ofher medications) [115] and also in a patient treated with stavudine and lamivudine [116]. The metabolic acidosis in this case was partly due to lactic acidosis, perhaps related to mitochondrial dysfunction. Abacavir was recently implicated as a... 

Two HIV-1-positive women, both of whom had taken regimens containing stavudine and didanosine for at least 2 years, presented in the third trimester of pregnancy, one with acute lactic acidosis and one with acute pancreatitis and lactic acidosis (32). In the first case both mother and baby died. It is not known whether pregnancy is a risk factor for NRTI-induced lactic acidosis, perhaps in combination with riboflavin deficiency or a metabolic defect in the fetus, or whether NRTIs independently cause lactic acidosis through mitochondrial toxicity. 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, and didanosine which has also been attributed to mitochondrial DNA toxicity [95-106]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [91-93,101,105-108]. The link between NRTl effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

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