I. INTRODUCTION 



infiltrates may be present. Chronic interstitial 

 lung disease may also result after nitrofurantoin 

 therapy of 6 months or longer, according to these 

 authors. Development of progressive dyspnea 

 and diffuse interstitial infiltration was stated to 

 be characteristic. Both acute and chronic forms 

 are usually reversible after discontinuation of 

 nitrofurantoin therapy or with discontinuation 

 of nitrofurantoin and corticosteroid treatment. 

 Rats (male, Sprague Dawley, 350 g) adminis- 

 tered 300-500 mg/kg nitrofurantoin by subcuta- 

 neous injection developed lung injury (severe 

 respiratory distress, pulmonary edema, and 

 hemorrhage) (Boyd et al., 1979b). Rats raised on 

 a vitamin E-deficient diet or fed enriched vita- 

 min E diets and exposed in an oxygen-rich envi- 

 ronment were stated to have increased suscep- 

 tibility to nitrofurantoin toxicity Selenium- 

 deficient or control rats (male, Holtzman, 2 5 

 months old) administered 100 mg nitrofuran- 

 toin/kgdid not have lung injury (Burk and Lane, 

 1983). 



Anttinen et al. (1982) reported a focal nodular 

 hyperplasia of the liver which developed in a 

 young girl after 7 months of nitrofurantoin 

 treatment for infection. No epidemiologic stud- 

 ies were found on the use of nitrofurantoin, other 

 than for adverse reactions. 



Behar et al. (1965) reported that rats (male and 

 female, Sabra, age unspecified) administered ni- 

 trofurantoin orally (0, 20, 50, or 100 mg/kg, two 

 times per day) developed structural and func- 

 tional changes in the sciatic nerve. Nitrofuran- 

 toin plasma levels were dependent on the dose 

 and the duration of administration. The degree 

 of axonal degeneration was time related but not 

 dose related. Decreases in the conduction ve- 

 locity of sciatic nerve transmission were time 

 and dose related, but clinical neurologic changes 

 were not observed. Toole et al. (1968) prospec- 

 tively examined volunteers (male and female, 

 age 22-58 with normal renal and hematologic 

 function) who received 100 mg nitrofurantoin, 

 four times per day for 14 consecutive days. This 

 treatment was associated with impaired nerve 

 conduction velocity (normal renal function); 8/14 

 subjects had no side effects. Five subjects com- 

 plained of epigastric discomfort, nausea, or ano- 

 rexia, and two had clinical vasomotor changes 

 (ataxia) that were reversed after treatment was 



stopped. In an evaluation of four case reports, 

 Yiannikas et al. (1981) stated that neuropatho- 

 logic effects in all the patients were directly 

 associated with nitrofurantoin treatment and 

 were characterized by acute, severe axonal de- 

 generation: they concluded that a direct neuro- 

 toxic effect was responsible. Hepatic injury 

 (hepatocellular and cholestatic) (Goldstein et al., 

 1974), granulomatous formation (Strohscheer 

 and Wegener, 1977), and chronic active hepatitis 

 and necrosis (Sharp et al., 1980) have been asso- 

 ciated with nitrofurantoin therapy. 



Glucose-6-phosphate dehydrogenase deficiency 

 and nitrofurantoin administration have been as- 

 sociated with the development of megaloblastic 

 anemia (Pritchard et al., 1965; Toole et al., 

 1968). Glucose-6-phosphate dehydrogenase is 

 required for the NADPH-dependent reduction of 

 glutathione, which is required for erythrocyte 

 protection from peroxides. Initiation of nitrofu- 

 rantoin administration may result immediately 

 in dizziness, weakness, headache, anorexia, and 

 intermittent vomiting. Loss of erythrocytes, 

 oxygen deficiency, and possibly renal problems 

 are associated with lysis of erythrocytes and 

 methemoglobinemia. 



Reproductive and Developmental Toxicity 



Paul and Harrington (1967) found that nitro- 

 furantoin did not inhibit maternal or neonatal 

 liver or kidney glucuronyl transferase in rabbits 

 (male and female, strain unspecified; neonatal, 

 1-2 days old; adult, age unspecified) or rats (male 

 and female, strain unspecified; neonatal, 2 hours 

 to 3 days old; adult, 11 months old) There were 

 no differences in nitrofurantoin metabolism be- 

 tween adult or neonatal rabbit liver or kidney 

 and rat liver, but neonatal rat kidney metabo- 

 lized nitrofurantoin significantly more slowly 

 than did adult rat kidney. 



Oral administration of nitrofurazone, a 5-nitro- 

 furan analog of nitrofurantoin, has been re- 

 ported to inhibit spermatogenesis at the sperma- 

 tocyte or spermatid stage in rats (sex, strain, and 

 age unspecified), which under long-term admin- 

 istration results in testicular atrophy. Gener- 

 ally, this effect was reversible upon discontinua- 

 tion of drug administration. A similar effect was 

 also reported in mice, along with interstitial cell 

 hyperplasia and seminal vesicle hypertrophy 



Nitrofurantoin, NTPTR341 



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