Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: investigations in hairless mice.

The oral antidiabetics glibenclamide, glipizide, glymidine, tolazamide and tolbutamide and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, furosemide, hydrochlorothiazide, hydroflumethiazide and trichlormethiazide were investigated for phototoxic effects in hairless mice. The back of the animals (hr/hr-c3H/TifBom) was covered with Duoderm dressing, and at the site of two punched out holes 0.05 ml of the test substances at 0.25 mol/l concentration and the solvent alone as control were injected intradermally, respectively. Both test and control sites were irradiated with 6-12 J/cm2 of longwave UVA light from a "Bluelight 2000" apparatus (Hönle, Martinsried, Germany). Skin reactions were read at 24 and 48 h. Compared to the solvent alone, all of the test substances induced reactions (necrosis or oedema)--most frequently seen by macroscopic and histologic investigation and by measurements with a thickness gage. Injection of the test substance or solvent alone without or with subsequent UVA irradiation, as well as UVA alone, did not induce measurable skin changes in this model. Three oral antidiabetics and four diuretics, not yet described to induce photosensitivity in vitro nor in vivo, were detected as potential photosensitizers using our animal model.

Photohemolytic potency of oral antidiabetic drugs in vitro: effects of antioxidants and a nitrogen atmosphere.

The sulphonamide-derived oral antidiabetic drugs carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of chlorpropamide, glipizide, gliquidone, glymidine and tolbutamide (all in the concentration 10(-3) mol/l). Except for glymidine, which exerted photohemolysis in the concentration 10(-4) mol/l, no hemolytic effects were seen in the concentration of 10(-4) mol/l or 10(-5) mol/l. Irradiation with TL 12 light bulbs (UVB), a UVASUN 5000 apparatus (UVA) or an experimental lamp (visible light) did not induce phototoxic hemolysis with either of the test substances. Addition of the antioxidants ascorbic acid, alpha-tocopherol or superoxide dismutase significantly inhibited the phototoxic hemolysis. Investigations carried out in a nitrogen-rich atmosphere reduced the hemolysis as well. These findings indicate an involvement of reactive oxygen species in the mechanism of action of the hemolytic process in the presence of oral antidiabetic drugs.

Profound hypoglycemia with the addition of a tricyclic antidepressant to maintenance sulfonylurea therapy.

Cases of profound hypoglycemia after the initiation of tricyclic antidepressant therapy in two patients taking sulfonylureas are described. To the authors' knowledge, this is the first report of a potential drug interaction between tricyclic antidepressants and sulfonylureas.

Transketolase abnormality in tolazamide-induced Wernicke's encephalopathy.

We studied a thiamine-dependent enzyme, transketolase, from fibroblasts of a diabetic patient who developed Wernicke's encephalopathy when treated with tolazamide, in order to delineate if this patient also had transketolase abnormality [high Km for thiamine pyrophosphate (TPP)], as previously reported in postalcoholic Wernicke-Korsakoff syndrome. In addition to this patient, we also studied this enzyme from three diabetic kindreds without any history of Wernicke's encephalopathy and from four normal controls. We found that the above-mentioned patient and one of the diabetic kindreds with no history of Wernicke's encephalopathy had abnormal transketolase as determined by its Km for TPP. These data suggest a similarity between postalcoholic Wernicke-Korsakoff syndrome and the patient with tolazamide-induced Wernicke's encephalopathy from the standpoint of transketolase abnormality.

A case of chronic liver disease due to tolazamide.

Although chlorpropamide and tolbutamide are well recognized as causes of hepatotoxicity, there are only 3 reported cases of hepatic injury caused by a third oral hypoglycemic agent, tolazamide. In 2 of these cases, the liver-function tests returned to normal when the drug was discontinued. In the third case, the patient had cholestasis from chlorpropamide before administration of tolazamide and developed chronic liver disease. We are reporting the second instance of chronic liver disease induced by tolazamide. Our patient had been taking chlorpropamide, but she had no evidence of liver disease before administration of tolazamide. Tolazamide should be considered as a drug capable of producing hepatotoxicity that on occasion may be chronic.

Lichenoid drug reactions to chlorpropamide and tolazamide.

Many medications, including gold, antimalarials, quinidine, and thiazide diuretics have been implicated in lichenoid drug reactions. Chlorpropamide and tolazamide are sulfonylurea oral hypoglycemic agents, neither of which has previously been implicated in cutaneous lichenoid reactions. We report a case of lichenoid drug reaction related to both chlorpropamide and tolazamide.

Bioavailability of tolazamide from tablets: comparison of in vitro and in vivo results.

The relative bioavailability of tolazamide was determined, in healthy male volunteers, from four different tablet formulations manufactured by direct compaction or granulation processes and the results were compared with in vitro disintegration and dissolution values. Serum tolazamide levels were determined by a high-pressure liquid chromatographic method developed in this laboratory. Serum tolazamide levels from the formulation that gave rise to rapid absorption were described by one-compartment model kinetics with a mean absorption half-time of 1.0 hr and an elimination half-life of 4.6 hr. Peak serum levels occurred at 3.3 hr after drug administration. Marked differences were observed in drug bioavailability from the four tablets, and the mean cumulative relative fraction of dose absorbed was 1.0, 0.42, 0.75, and 0.91 from Formulations A, B, C, and D, respectively. The hypoglycemic effect was closely related to serum tolazamide levels. Disintegration times did not predict in vivo tolazamide bioavailability. Dissolution rates provided an approximate rank order correlation with in vivo absorption but failed to be predictive among formulations. Currently available in vitro tests do not accurately predict tolazamide in vivo bioavailability characteristics among different formulations and manufacturing processes but may be useful to ensure lot-to-lot uniformity in bioavailability for a given formulation and specific method of manufacture.

Pseudoinsulinoma syndrome from inadvertent tolazamide ingestion.

A 70-year-old woman with rheumatoid arthritis presented with fasting hypoglycemia, inappropriately elevated insulin and C-peptide levels, and negative insulin antibodies, all compatible with the diagnosis of an insulinoma. However, results of a 72-hour fast were subsequently negative. Medication identification revealed that the patient had been taking tolazamide (Tolinase; The Upjohn Company, Kalamazoo, Michigan) instead of tolmetin (Tolectin; McNeil Laboratories, Inc., Fort Washington, Pennsylvania).

Tolazamide-induced cholestasis.

The sulfonylurea hypoglycemic agent tolazamide is thought to be a rare cause of jaundice and to exhibit no hepatic cross-sensitivity with other sulfonylurea compounds. We have described a patient who had self-limited cholestatic jaundice after treatment with chlorpropamide. Subsequent treatment with tolazamide resulted in recurrence of jaundice, which disappeared after cessation of treatment. Tolazamide may exhibit hepatic cross-sensitivity with chlorpropamide.

Tolazamide-induced hepatic dysfunction.

A case of tolazamide-induced hepatic injury is reported. Injury was documented by abnormal liver tests, including an elevated alkaline phosphatase, 5' nucleotidase and serum glutamic oxaloacetic transaminase. Liver biopsy confirmed the degree and type of injury which consisted of severe portal inflammation, bile duct proliferation and early fibrosis. The case is reported to further establish tolazamide as a drug capable of producing hepatic injury and to report a new form of hepatic injury attributable to a sulfonylurea agent.

In vivo cytogenetic activity of sulphonylurea drugs in man.

A cytogenetic investigation of diabetic patients undergoing treatment with sulphonylurea drugs, particularly chlorpropamide, shows that significantly more chromatid aberrations and chromosome exchange aberrations are present in the lymphocytes of these patients compared with controls. This is taken as evidence of possible mutagenic activity by these drugs, although the possibility cannot be ruled out that the diabetic state itself is a contributory factor.