Hydrazine production in children receiving isoniazid for the treatment of tuberculous meningitis.
OBJECTIVE
To study the generation of the hepatotoxin hydrazine in 32 malnourished children receiving isoniazid for the treatment of tuberculous meningitis.


METHODS
This observational study was undertaken in the pediatric ward of a teaching hospital admitting children with advanced forms of tuberculous meningitis for treatment and management of complications.


METHODS
Thirty-two children (mean age 2.28 years) receiving isoniazid 20 mg/kg/d were studied. Plasma isoniazid, acetylisoniazid, and hydrazine concentrations were determined by an HPLC method. Fourteen children were studied at weekly intervals for the first month of treatment and again after six months of therapy; 18 additional children were studied on one or more occasions during the first month of treatment only.


RESULTS
The area under the curve for hydrazine two to five hours after the isoniazid dose correlated with the isoniazid elimination rate and with acetylisoniazid generation. Hydrazine production increased significantly during the first month of treatment, but decreased to approximate initial values at six months. No correlation was found between any clinical or biochemical indicator of liver dysfunction and hydrazine production.


CONCLUSIONS
Hydrazine is formed in significant concentrations during the metabolism of isoniazid in young children. However, additional factors such as preexisting liver damage (e.g., from viral hepatitis) may be necessary for it to reach its toxic potential.
Donald
P R
PR
Department of Paediatrics and Child Health, Tygerberg Hospital, University of Stellenbosch, Republic of South Africa.
Seifart
H I
HI
Parkin
D P
DP
van Jaarsveld
P P
PP
D002648:Child; D015362:Child Nutrition Disorders / Q000150:complications; D002675:Child, Preschool; D005260:Female; D006207:Half-Life; D006784:Hospitals, Teaching; D006801:Humans; D006834:Hydrazines / Q000097:blood / Q000378:metabolism* / Q000506:poisoning; D007223:Infant; D007538:Isoniazid / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008111:Liver Function Tests; D008297:Male; D013019:South Africa; D014390:Tuberculosis, Meningeal / Q000097:blood / Q000188:drug therapy*
D006834:Hydrazines; C029424:hydrazine; D007538:Isoniazid