Some observations on the toxicology of morphine-N-oxide

Abstract

The intravenous and subcutaneous acute toxicities of morphine-Noxide (MNO) in mice were respectively 3.2 and 8 times less than that of morphine. Amiphenazole or tacrine reduced the acute toxicity of MNO but not that of morphine in mice. The chronic toxicity of MNO was examined in mice and rats. Daily oral doses of 100 mg/kg did not significantly affect growth or condition, or produce gross or microscopic lesions in mice treated for 3 weeks or rats treated for 3 months. No teratogenic effect of MNO or of bromolysergic acid diethylamide was observed in rats.Woo, Gaff & Fennessy (1968) identified morphine-N-oxide (MNO) in the urine of patients treated with morphine in combination with either amiphenazole (2,4-diamino-5-phenylthiazole) or tacrine (1,2,3,4-tetrahydr0-9-aminoacridine) but not after morphine alone. They suggested that MNO was an intermediate metabolite in the breakdown of morphine. Earlier reports suggested that MNO was without analgesic activity (Freund & Speyer, 1910;Rosenthaler, 1933; Keil, Schmidt & Giinther, 1933;Anton, Theiss & Weissig, 1935;Braenden, Eddy & Halbach, 1955). However, Fennessy (1968) found it to have a weak analgesic activity which was markedly potentiated when it was administered with either amiphenazole or tacrine to rats and mice. The potentiation of the analgesic action of MNO and its presence in urine after morphine was suggested to be due to impairment of metabolism of MNO in the liver by amiphenazole and tacrine.MNO may be of clinical interest as a metabolite of morphine or as an analgesic in its own right. We have examined its toxicology. E X P E R I M E N T A L Acute toxicitySwiss mice of either sex, about 25 g were randomly assigned to groups of 10; various doses of morphine, MNO, amiphenazole, tacrine or nalorphine, given subcutaneously, were randomly assigned to these groups and the mice dead in each group after 24 h were recorded. The LD50 values with 95% confidence limits were calculated (Litchfield & Wilcoxon, 1949).The intravenous LD50 values for morphine and MNO were also determined in normal mice and in mice pretreated 30 min before with amiphenazole, tacrine or nalorphine injected subcutaneously in doses corresponding to one-third and two-thirds of their subcutaneous LD50 doses. Subacute toxicityFemale Swiss mice, 4 weeks old, about 15 g, were randomly assigned to 3 equal

Mass Spectrometric Structure Elucidation of the Trivalent and Pentavalent Nitrogen Contaminants of Pholcodine in the Cough Relief Medical Form Tuxidrin

“…As is mentioned in [1], and earlier in [5], N-oxides of some opium alkaloids are less toxic than original alkaloids, and often have higher specific activity than the original alkaloids alone. The toxicity of morphine-Noxide was studied, as described in [5].…”

“…The toxicity of morphine-Noxide was studied, as described in [5]. The authors of [5] The N-oxides of pholcodine mimic quaternary ammonium ions; but, they are not equivalent.…”

“…The toxicity of morphine-Noxide was studied, as described in [5]. The authors of [5] The N-oxides of pholcodine mimic quaternary ammonium ions; but, they are not equivalent. However, researchers have not yet studied the tendency of quaternary ammonium ions of degradation contaminants in medical formulations containing pholcodine to provoke allergies.…”