Amidopyrine agranulocytosis:drug inhibition of granulocyte colonies in the presence of patient's serum.

Abstract

Phenazopyridine is a commonly prescribed urinary analgesic, used either alone (Pyridium) or in combination with an antibiotic-for example, in Azo Gantrisin, Azotrex, Uro Gantanol. This report describes an addition to the three recorded cases of hepatitis due to phenazopyridine sensitivityl 2 and indicates that this agent may be unusual in causing both a hypersensitivity-mediated hepatitis and a direct toxic effect on the liver. Case reportOn four occasions a previously healthy Caucasian housewife developed symptoms of hepatitis after being given phenazopyridine for a urinary tract infection. There was no personal or family history of adverse drug reactions or allergy.TREATMENT AND ADVERSE EFFECTS When she was 22 the patient received sulfisoxazole and phenazopyridine for dysuria, frequency, and pyuria. Ten days later she developed diarrhoea, nausea, epigastric distress, and fever (39,C), and she was found to be jaundiced with hepatomegaly. Haemaglobin was 11-6 g/dl, sedimentation rate 70 mm in lh, white blood count 9 05 x 10'/l (9050/mm3) (8 % eosinophils).bilirubin 81-6,umol/l (4-8 mg/100 ml) of which 50 was direct-reacting, and alkaline phosphatase 10 6 Bodansky units. Rapid improvement followed discontinuation of her medication and she was discharged, asymptomatic, after 21 days.When Two weeks later, dysuria recurred and she took one tablet (200 mg) of phenazopyridine. Within a couple of hours nausea, malaise, and epigastric distress recurred and persisted for five or six hours. She then restarted ampicillin and completed a 10-day course with no ill-effects. When reviewed four months later there were no residual clinical or laboratory abnormalities. CommentGenerally drugs induce hepatic injury by either a direct toxic effect or an indirect hypersensitivity mechanism. The major differences between these two types of hepatic injury have been defined by Klatskin. ' A direct dose-related hepatic injury has been reported in dogs given average daily doses 15 to 46 times greater than the therapeutic dose of phenazopyridine, and three infants who received high doses of phenazopyridine subsequently showed evidence of hepatic dysfunction.' 2Thus phenazopyridine may under certain Lircumstances act as a direct hepatotoxin.By contrast, the case described here fulfills the most important criteria for a diagnosis of hypersensitivity hepatitis: the reaction was not dose-related (occurring on the fourth occasion after only one tablet). Despite widespread use, phenazopyridine has been implicated in hypersensitivity hepatitis in only three patients4 5; the latent period varied from 10 days to a few hours; fever and eosinophilia were documented on at least one occasion.Phenazopyridine therefore shares with a few other drugs-for example, isoniazid, sulphonamides, chlorambucil '-the ability to produce both a dose-related toxic hepatitis and hepatic damage mediated by a hypersensitivity reaction. The ability of a drug to produce dose-dependent liver damage does not preclude it from inducing hypersensitivity-mediated hepatic damage...

Role of Drug Disposition in Drug Hypersensitivity: A Chemical, Molecular, and Clinical Perspective

“…Furthermore, infusion of blood from a sensitive patient 3 h after administration of aminopyrine into a normal subject led to granulocytopenia. In a separate investigation, serum from a patient with agranulocytosis was found to inhibit granulocyte colony formation in the presence of drug, while serum from a normal control had no effect (144).…”

Stem cells in myelotoxicity

“…CFU-GM clonogenic assays were initially utilized in toxicology to confirm the origin in drug-induced agranulocytosis (Ascencao et al, 1984;Barrett et al, 1976;Boogaerts et al, 1984;Irvine et al, 1983;Kelton et al, 1979;Lind et al, 1973;Young and Vincent, 1980). The development of predictive in vitro hematotoxicity assays using CFU-GM was developed further.…”

Drug-Induced Agranulocytosis

“…Promyelocytes and myelocytes can be absent (Ruvidic & Jelic 1972), and granulocytic/monocytic colony formation (CFU-GM) could be inhibited by incubation with the patient's serum in the presence of the offending drug (Barrett et al 1976). Promyelocytes and myelocytes can be absent (Ruvidic & Jelic 1972), and granulocytic/monocytic colony formation (CFU-GM) could be inhibited by incubation with the patient's serum in the presence of the offending drug (Barrett et al 1976).…”