Phase I clinical study of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641).
John D. HainsworthKenneth R. HandeW. SatterleeJohn F. KutteschDavid H. JohnsonGerald B. GrindeyLinda E. JacksonFilippo Greco
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Between February 1987 and July 1988, 45 patients with advanced refractory cancer were treated with LY186641, a diarylsulfonylurea that has shown a broad spectrum of activity in preclinical testing. Patients received a weekly p.o. dose of LY186641 for 6 consecutive weeks; responding and stable patients continued weekly therapy until progression occurred. Using a standard phase I study design, the first three patients received LY186641 at 30 mg/m2 week; the dose was escalated in subsequent patients until dose-limiting toxicity occurred. Methemoglobinemia was the major toxicity observed and was dose related. Methemoglobin levels peaked approximately 24 h after LY186641 was administered and fell to low levels after 48 h. Six patients developed fatigue, cyanosis, and dyspnea associated with serum methemoglobinemia levels of greater than 20%; four of these patients were subsequently removed from the study. Hemolytic anemia was also observed but was clinically significant in only 10 patients. Other side effects were mild and infrequent. The maximum tolerated dose of LY186641, when given at this schedule, was 2550 mg/m2/week. No objective tumor responses were observed.Keywords:
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The metabolism and toxicity of dapsone was compared in vitro and in vivo in rat, mouse and man. Metabolism was assessed by high-pressure liquid chromatography-mass spectrometry and methemoglobin formation has been used as a toxic endpoint. The greatest toxicity in vitro was seen in microsomes prepared from male Wistar rats (36.6 +/- 1.5% methemoglobin), although toxicity was also seen in microsomes from the female rat (8.2 +/- 1.3%), male CD1 (4.2 +/- 1.6%) and human (10. 9 +/- 1.1%). The rank order of toxicity agreed with the formation of the hydroxylamine metabolite in vitro. All microsomes were also capable of catalyzing the reverse reaction, i.e., reduction of the hydroxylamine to dapsone. However, in vivo administration of dapsone resulted in significant (P < 0.05) methemoglobinemia only in male rats and humans. This species difference in the susceptibility to dapsone toxicity could not be attributed solely to the sensitivity of the target erythrocytes, because the order of sensitivity to dapsone hydroxylamine was human > mouse > rat. Analysis of bile and urine revealed the formation of dapsone hydroxylamine and its glucuronide in male rats and humans, but not in female rats or mice. This species difference in the metabolism and toxicity of dapsone has important implications in the safety evaluation of related compounds for man.
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Methylene blue (MB) is the drug of choice in the treatment of methemoglobinemia (MTHB) in humans and most domesticated animals, but is reported contraindicated in cats. Although prolonged treatment of cats for urologic syndromes with MB-containing antiseptics causes Heinz body (HB) hemolytic anemia, there is no evidence to suggest that single or repeated therapeutic doses of MB cause hemolytic anemia. We investigated the efficacy and safety of MB in reversing nitrite-induced MTHB in cats. Forty random-bred adult cats (20 males and 20 females) were divided as follows: Group 1, 1.5 mL saline/kg bw iv (control); Group 2, 1 dose of 1.5 mg MB/kg bw iv; Group 3, 2 doses of 1.5 mg MB/kg bw iv 4 h apart; Group 4 1 dose of 1.5 mg sodium nitrite/kg bw iv; Group 5, 1 dose of 1.5 mg sodium nitrite/kg bw iv followed by 1 dose of 1.5 mg MB/kg bw iv 1 h later; and Group 6, 1.5 mg sodium nitrite/kg bw iv followed in 2 h by 2 doses of 1.5 mg MB/kg iv 4 h apart. One iv dose of MB sufficiently and rapidly reversed MTHB in the cats without increasing circulating HB-containing red blood cells. Giving 2 iv doses of MB without or after sodium nitrite significantly increased the frequency of circulating HB-containing red blood cells. Pre-exposure to sodium nitrite potentiated the HB-inducing effect of 2 doses of MB. Hemolytic anemia was not observed or demonstrated in any of the cats groups.
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Journal Article The Role of Methemoglobin in Acute Butyl Nitrite Toxicity in Mice Get access DAVID P. McFADDEN, DAVID P. McFADDEN Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue UniversityWest Lafayette, Indiana 47907 Search for other works by this author on: Oxford Academic PubMed Google Scholar GARY P. CARLSON, GARY P. CARLSON Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue UniversityWest Lafayette, Indiana 47907 Search for other works by this author on: Oxford Academic PubMed Google Scholar ROGER P. MAICKEL ROGER P. MAICKEL Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue UniversityWest Lafayette, Indiana 47907 Search for other works by this author on: Oxford Academic PubMed Google Scholar Toxicological Sciences, Volume 1, Issue 6, November 1981, Pages 448–451, https://doi.org/10.1093/toxsci/1.6.448 Published: 01 November 1981
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A 2-month-old kitten was referred for depression and partial anorexia since 3 days and chronic diarrhea lasting for over 3 weeks. General physical examination showed pale and cyanotic mucous membranes. Blood sample was of brownish appearance. Venous blood gas analysis and complete blood count showed 16% methemoglobin level and severe regenerative anemia with Heinz bodies in about 40% of the erythrocytes, respectively. The kitten was transfused with fresh whole blood and treated with supportive care, antimicrobial and antioxidant agents. The kitten totally recovered. To the authors' knowledge, this represents the first case report of severe Heinz body hemolytic anemia and methemoglobinemia with concurrent chronic diarrhea in a young kitten. Diarrhea resolution coincided with Heinz bodies and methemoglobin disappearance. The possibility that diarrhea might have stimulated an inflammatory state causing release of oxygen radicals and prolonged erythrocytes oxidative damage has been discussed.Ein zwei Monate altes Kätzchen wurde wegen Depression und partieller Anorexie seit drei Tagen und chronischem Durchfall während mehr als 3 Wochen überwiesen. Die allgemeine klinische Untersuchung zeigte blasse und zyanotische Schleimhäute. Das Blut war von bräunlicher Farbe. Die venöse Blutgasanalyse und das vollständige Blutbild zeigten 16% Methämoglobin und eine schwere regenerative Anämie mit Heinz-Körpern bei etwa 40% der Erythrozyten. Das Kätzchen wurde mit frischem Vollblut transfundiert, gepflegt und mit Antibiotika und Antioxidanten behandelt. Das Kätzchen erholte sich vollständig. Nach Wissen der Autoren stellt dies den ersten Fallbericht von schwerer Heinz-Körper hämolytischer Anämie und Methämoglobinämie mit gleichzeitig chronischem Durchfall bei einem jungen Kätzchen dar. Die Besserung des Durchfalles fiel mit dem Verschwinden von Heinz-Körpern und Metämoglobin zusammen. Die Möglichkeit, dass Durchfall einen entzündlichen Zustand verursacht haben könnte, der zu Freisetzung von Sauerstoffradikalen und Iänger anhaltenden oxidativen Erythrozyten Schäden führte, wird diskutiert.
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