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At least 19 recordsLinked to original sources
PubMed1999

[Auxiliary hepatic transplantation in iproniazid-induced subfulminant hepatitis. Should iproniazid still be sold in France?].

We report a new case of subfulminant hepatitis due to iproniazid, a MAO-inhibitor antidepressant, in a 27-year-old man. An auxiliary liver transplantation was performed. Liver function returned to normal and the patient was discharged from the hospital. However, the patient's native liver did not regenerate, and immunosuppressive therapy had to be maintained. Iproniazid hepatotoxicity is characterized by jaundice in 1% of cases, with a fulminant or subfulminant course in 20% of icteric patients. Although iproniazid is no longer sold in most countries, it is still commercialized in France. Because of the frequency and severity of hepatic injury, commercialization of iproniazid in France should no longer be authorized.

Adult↗
PubMed1975

The possible mode of action of iproniazid. I. Differential luteolytic effect of iproniazid before and after the establishment of placental adolescence.

Iproniazid, a very specific monoamine oxidase inhibitor, at a dose level of 200 mg/kg body weight induced luteolysis and caused lysis of deciduomata as well as resorption of the established embryos. Exogenous replacement of prolactin, a most consistent stimulant of the endocrine functioning of corpus luteum, or progesterone absolutely reversed the adversity developed following iproniazid injection. Moreover, failure of iproniazid even at a higher dose level in the deviation of the normal sequence of pregnancy after the establishment of placental adolescence strongly tempting to suggest that iproniazid could only show its luteolytic effect when the hypothalamic-pituitary complex is exclusively involved in the maintennance of pregnancy.

Animals↗
PubMed1978

Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine.

Iproniazid (1-isonicotinoyl-2-isopropylhydrazine), an antidepressant drug removed from clinical use because of hepatic injury, and isopropylhydrazine, a metabolite of iproniazid, were found to be potent hepatotoxins in rats. This animal model was used in studies in vivo and in vitro to define better the biochemical and chemical mechanism(s) by which iproniazid and isopropylhydrazine mediate hepatotoxicity. Phenobarbital, an inducer of a class of hepatic microsomal cytochrome P-450 enzymes, greatly potentiated the necrosis, whereas inhibitors of these microsomal enzymes such as cobalt chloride, piperonyl butoxide and alpha-naphthylisothiocyanate, prevented the necrosis. Bis-para-nitrophenyl phosphate, an inhibitor of esterase and amidase enzymes, prevented the necrosis caused by iproniazid but had no effect on the necrosis caused by isopropylhydrazine. Iproniazid and isopropylhydrazine labeled with tritium or carbon-14 in the isopropyl group were found to bind covalently to hepatic tissue macromolecules, and those pretreatments that increased hepatic necrosis significantly increased covalent binding, whereas those pretreatments which prevented necrosis significantly decreased covalent binding. Iproniazid labeled with tritium in the pyridine ring or carbon-14 in the carbonyl group did not bind significantly to hepatic tissue. Rats that were given iproniazid or isopropylhydrazine, labeled specifically with tritium and carbon-14 on the c-2 methine position of the isopropyl group, expired acetone and carbon dioxide labeled with carbon-14. More importantly, propane was expired and contained a ratio of 3H/14C that was identical to that in the administered iproniazid or isopropylhydrazine and also identical to the 3H/14C ratio of the metabolite that was covalently bound to hepatic tissue macromolecules. Experiments carried out with rat liver microsomes and isopropylhydrazine specifically labeled with deuterium, tritium and carbon-14 support the view that isopropylhydrazine is the metabolite of iproniazid that is oxidized by a microsomal P-450 enzyme to a species that alkylates tissue macromolecules. Some of the urinary metabolites excreted by rats that were administered hepatotoxic doses of iproniazid and isopropylhydrazine have been identified by cochromatography and isotope dilution with synthetic standards and by comparative mass spectra. Compounds excreted into the urine of rats dosed with iproniazid include iproniazid, iproniazid-1-oxide, isonicotinic acid, isonicotinoyl glycine, acetylisoniazid, isopropylhydrazine, 1-acetyl-2-isopropylhydrazine and acetone. Isopropylhydrazine, 1-acetyl-2-isopropylhydrazine, and acetone have been found in the urine of animals administered toxic doses of isopropylhydrazine.

Animals↗
PubMed1987

A comparative trial of a MAOI, iproniazide, and a polycyclic agent, mianserine, for the search of the most rapidly and frequently active treatment of depressive syndromes in an oncology service.

Many cancer patients of the "Service des Maladies Sanguines et Tumorales" of Hôpital Paul-Brousse, Villejuif, are psychologically studied by: the objective and quantified Szondi test, and in the case a depressive syndrome clinical diagnosis is confirmed, this state is quantified by a quintile questionnaire requiring 25 "yes or no" answers (determined by five grades and five stages), in case an inhibition or/and hysteric component is found, the subjects are submitted to the care of a psychoanalyst. A comparative trial of the MAOI, iproniazide, and the tetracyclic analog, mianserine, has been conducted for the search of the most frequently and rapidly active antidepressant agent among them both. The hypothesis that mianserine is less frequently and rapidly active than iproniazide was drawn from our previous experience of 20 years: thus patients presenting a score less than or equal to 12/25 were given mianserine (20 up to 30 mg/day to be possibly increased according to medical decision), while those presenting a score greater than or equal to 13/25 received iproniazide (50 up to 75 mg/day). The patients who failed with mianserine received iproniazide, while those who failed with iproniazide were supposed to receive mianserine. The registered results are the following: a) out of the 25 patients with major depressive syndromes (score greater than or equal to 13) submitted to iproniazide, 16 (61%) were in complete remission (score at 0/25) and five in partial regression (score decreased by more than half); this makes 21 responses in all, i.e. 80%, obtained between the 10th and the 30th days, which is superior to all placebo responses which have varied in the reliable literature from 13 to 70%; b) out of 18 depressive patients submitted to mianserine, only one had benefited of a complete remission and four of a partial regression at the 30th day, which makes 28% responses. Among the side effects of iproniazide, they were two colon meteorism syndromes, easily corrected by prostigmine, five hyposomnia cases corrected by dipotassium chlorazepate, four anejaculation or delay at ejaculation cases which needed eserine when the patients require their disappearance or attenuation. We did not register either hepatic or hyperthermic or hypertensive complications: this is in good agreement with the true incidences, especially that of hypertensive crisis which could be found in serious and scientifically documented articles, to be 0.3 to 0.5% for their appearance, and 1 per 100,000 for their fatal evolution. Among the side effects of mianserine, we have not registered any of the hepatic, renal and cardiac complications mentioned in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents, Tricyclic↗
PubMed1985

Propane and propylene formation during the microsomal metabolism of iproniazid and isopropylhydrazine.

Both iproniazid and isopropylhydrazine were metabolized to the hydrocarbon products, propane and propylene, with nearly identical Michaelis constants and rates. This reaction appeared to be catalyzed by microsomal cytochrome P-450. Isonicotinic acid, a product of iproniazid hydrolysis by various amidases, was produced in only very small quantities, suggesting that the other amidase product, isopropylhydrazine, may not be an obligatory intermediate in the pathway of hydrocarbon formation from iproniazid. Hydrocarbon formation from iproniazid was more sensitive to inhibition in vitro by bis-p-nitrophenylphosphate (used in vivo as an amidase inhibitor) than was isopropylhydrazine. Iproniazid must be directly metabolized by cytochrome P-450 to yield propane and propylene, presumably via an azo ester intermediate which could give rise to an isopropyl radical, the chemical species presumed to be responsible for the hepatoxicity apparent after administration of large doses of iproniazid in vivo.

Alkenes↗
PubMed1987

Spin trapping of free radical intermediates produced during the metabolism of isoniazid and iproniazid in isolated hepatocytes.

By the use of spin trapping agents phenyl-t-butyl nitrone (PBN) and 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) free radical species were detected in isolated hepatocytes incubated with either isoniazid, iproniazid and their respective metabolites acetyl-hydrazine and isopropyl-hydrazine. The addition of bis-nitrophenyl phosphate, an inhibitor of the acylamidase enzymes, to isolated hepatocytes decreased the free radical activation of isoniazid and iproniazid, but not that of acetyl- and isopropyl-hydrazine, confirming that the radical species were originating from the biotransformation of these latter compounds. The ESR spectra were ascribed to the trapping of, respectively, acetyl and isopropyl free radicals on the basis of the analogies of the spectral feature with those of chemically-prepared spin adducts. Comparable ESR spectra were also observed during the metabolism of acetyl- and isopropyl-hydrazines by liver microsomes and their formation was inhibited by the omission of NADP+, anaerobic incubation and enzyme denaturation. In the microsomal preparations inhibitors of the mixed function oxidase system decreased to various extents the free radical formation and a similar effect was also observed following the destruction of cytochrome P-450 induced by pretreating the rats with CoCl2. The addition of reduced glutathione also decreased the radical trapping indicating that GSH can effectively compete with the spin traps for the reaction with the free radicals. The incubation of isolated hepatocytes with isoniazid or acetyl-hydrazine reduced by 20-25% the intracellular GSH content, while a 50% decrease in GSH was present in the cells exposed to iproniazid and isopropyl-hydrazine. In the same hepatocyte preparations stimulation of lipid peroxidation and leakage of LDH were also observed during cell incubation with iproniazid and isopropyl-hydrazine, but not with isoniazid or acetyl-hydrazine and the extent of both phenomena correlated with the susceptibility of the above compounds to the free radical activation.

Animals↗
PubMed1987

Reductive destruction of dacarbazine, procarbazine hydrochloride, isoniazid, and iproniazid.

Reductive destruction of dacarbazine, procarbazine hydrochloride, isoniazid, and iproniazid using nickel-aluminum alloy in basic solution is described. Solutions of dacarbazine 10 mg/mL were prepared by adding dacarbazine 100 mg, citric acid 100 mg, and mannitol 50 mg to 10 mL of water. Aqueous solutions of procarbazine hydrochloride 10 mg/mL were prepared from commercially available capsules, and aqueous solutions of isoniazid 10 mg/mL and iproniazid 5 mg/mL were prepared from powdered drug. Reductive destruction of drugs was accomplished by mixing each solution with an equal volume of 1 M potassium hydroxide solution and adding 1 g of nickel-aluminum alloy for each 20 mL of basified solution. The resulting mixtures were stirred for 20 hours (96 hours for iproniazid) and analyzed by high-performance liquid chromatography and gas chromatography for the presence of residual drug and degradation products. Dacarbazine solutions were also subjected to destruction by photolysis and by oxidation using potassium permanganate in sulfuric acid, and the results were compared with those obtained by reductive destruction. All reaction mixtures were tested for mutagenicity in Salmonella strains. All drugs subjected to reductive destruction were completely degraded to the limits of detection of the assay and produced only nonmutagenic reaction mixtures. The only acceptable results for dacarbazine were obtained by the reductive destruction method. Reduction of dacarbazine, procarbazine hydrochloride, isoniazid, and iproniazid with nickel-aluminum alloy in dilute base appears to be a good method for the destruction of these toxic compounds.

Alloys↗
PubMed1983

[Iproniazid-induced hepatitis. The diagnostic value of a new antimitochondrial antibody anti-M6].

The authors report the observations of four patients with iproniazid hepatitis. Three of these patients died. An antimitochondrial antibody was found in the 4 patients at a high titer. This antibody differed from the antimitochondrial antibodies which have been described previously (anti-M1, anti-M5). This new antibody was called anti-M6. The evolution of the anti-M6 titer has been studied in the patient who survived. This titer progressively decreased; the antibody was no longer detectable 6 months after the withdrawal of iproniazid. Anti-M6 has not been found in other hepatic diseases. It was not detected in 15 patients receiving iproniazid without hepatitis or in 6 patients receiving isoniazid. Anti-M6 appears as a useful serologic marker for the diagnosis of iproniazid hepatitis.

Adult↗
PubMed1982

Influence of iproniazid on the combination effect of reserpine with antitumor agents on l1210.

The influence of two antidepressants, iproniazid and imipramine, was examined on the antileukemic combination effect of reserpine with 1-gamma-chloropropyl-2-chloromethylpiperidine hydrobromide (CAP-2), mitomycin C, or vinblastine on L1210. While reserpine synergistically increased the life span at the dose of 2.5 mg/kg in combination with these antitumor agents, the mice given reserpine showed considerable reduction of food intake and hypothermia. Iproniazid reduced all these effects of reserpine, while imipramine slightly potentiated hypothermia among these effects of reserpine. Starvation scarcely influenced the effect of the antitumor agents. On the other hand, reserpine also enhanced the antiproliferating effect of CAP-2 against L1210 cells in vitro. Iproniazid did not influence the combined antiproliferating effect of these agents in vitro. These results indicate that iproniazid reduced the antileukemic combination effect of reserpine with antitumor agents through an antireserpic effect such as inhibition of hypothermia. Therefore, it seems likely that the antileukemic combination effect of reserpine is closely related to the marked hypothermia, and only partially related to the direct effect on L1210 cells.

Animals↗
PubMed1996

Human anti-mitochondria autoantibodies appearing in iproniazid-induced immunoallergic hepatitis recognize human liver monoamine oxidase B.

Anti-mitochondria (anti-M6) autoantibodies have been found in the serum of patients with immunoallergic iproniazid (Marsilid)-induced hepatitis, but to date the identity of the protein antigen has not been determined. Here we show, using immunoprecipitation of pargyline-labelled proteins, that among the mitochondrial proteins, liver MAO-B is specifically recognized by the sera containing anti-M6 antibodies. Moreover the enzymatic activity of MAO-B towards phenylethylamine and tyramine is also suppressed after this immunoprecipitation, contrary to the MAO-A activity towards 5-hydroxy-tryptamine. As MAO is irreversibly inhibited by iproniazid, these results suggest that the mechanism of iproniazid-induced appearance of anti-M6 antibodies could be another example of the reactive metabolite/enzyme haptenization mechanism already proposed in the case of tienilic acid for the appearance of anti-organelle antibodies in a drug-induced hepatitis.

Antibody Specificity↗
PubMed1991

Cytochrome P-450- and peroxidase-dependent activation of procarbazine and iproniazid in mammalian cells.

Metabolism of hydrazine derivatives, procarbazine and iproniazid, to reactive free radical intermediates has been studied using spin-trapping techniques in intact human promyelocytic leukemia (HL60) and mouse hepatic cell lines. While HL60 cells have been shown to contain both myeloperoxidase and cytochrome P-450 enzymes, the hepatic cell line shows only cytochrome P-450 activity. Both peroxidases and cytochrome P-450 have been reported to catalyze biotransformation of hydrazines. Procarbazine and iproniazid were rapidly metabolized in these cell lines to methyl and isopropyl radicals, respectively. However, in HL60 cells, procarbazine was metabolized by myeloperoxidase while iproniazid was metabolized mostly by the cytochrome P-450 system. In the hepatic cells, both of these compounds were metabolized by the P-450 system.

Biotransformation↗
PubMed1960

Clinical observations on iproniazid in idiots with epilepsy.

In contradistinction to the observation made before that iproniazid has a potentiating effect on certain amines in guinea pigs, human studies have shown that this effect has very little clinical importance, when both the amines and the amine oxidase inhibitor are given in the usual therapeutic doses. However, neither in man nor in the guinea pig pretreatment with iproniazid showed a potentiating effect on amines which are not substrates of monoamine oxidase (ephedrine and amphetamine). Patients with epilepsy and allergic disease may receive iproniazid.

Amines↗
PubMed1980

The effects of reserpine, iproniazid and L-dopa on electrically-induced spinal cord seizures.

The effects of selected drug treatments on spinal cord norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) were compared to the effects of these same treatments on electrically-induced spinal cord seizure. Depletion of monoamine stores by reserpine facilitated spinal cord seizures. In contrast, L-DOPA, given to animals pretreated with iproniazid, exerted an anticonvulsant effect and elevated spinal cord NE and DA levels. L-DPOA administered alone produced a substantial elevation in DA levels but had no effect on spinal cord seizures. Iproniazid had no effect on monoamines, whereas it facilitated seizure activity. These observations support the concept that spinal cord noradrenergic, but not 5-hydroxytryptaminergic or dopaminergic neurons act as attenuators of convulsive activity. The effect of iproniazid on spinal cord seizures, in the absence of an observed alteration in monoamine levels, provides evidence that this effect is mediated through non-monoaminergic mechanisms.

Animals↗
PubMed1963

Morphological and pharmacological effects of reserpine, given alone or after iproniazid, on the catechol amines of the adrenal glands of the rat.

Adrenomedullary cells, after fixation with OsO(4), are filled with well formed granules which are considered to represent their catechol amine content. The submicroscopic appearance of these cells was studied in reserpine-treated rats during the late phase of catechol amine depletion and during the period of its restoration. At 3 days after the beginning of reserpine treatment, the granules appeared to be emptied of their content and small vesicles containing scattered, dense deposits of, presumably, catechol amines began to be seen. At 9 days after the beginning of treatment, these deposits had already become granules and the cells had attained a completely normal appearance. The submicroscopic structure of the adrenomedullary cells of rats pretreated with iproniazid (before reserpine), in which a complete inhibition of monoamine oxidase activity had thus been obtained, was similar to that seen in non-treated animals. In numerous cases, however, some characteristic features were noted: the sacs which usually contained a dense granule of catechol amines appeared swollen and many fine granules could be seen around them; the latter were dispersed in a way suggesting that they may represent a partial breakdown of the large granules which, under the inhibitory action of iproniazid, do not release the catechol amines contained within them.

Adrenal Glands↗
PubMed1980

Binding of iproniazid to the polymeric forms of iodide peroxidase.

14C labelled iproniazid binds to iodide peroxidase more effectively in low ionic strength buffer than in high ionic strength buffer, suggesting preferential binding to the monomeric form of iodide peroxidase. During column chromatography, under conditions that separate iodide peroxidase into multiple forms, iproniazid is bound selectively to the monomeric form. Thus, this antithyroid agent appears to bind preferentially to the monomeric enzyme form, or possibly to cause dissociation of the polymeric to the monomeric form.

Animals↗
PubMed1977

Effect of dexamethasone on monoamine oxidase inhibiton by iproniazid in rat brain.

Chronic (6 days) dexamethasone administration caused a slight decrease of rat brain MAO enzyme activity which was reflected by lower levels of 14C-homovanillic acid (HVA) and increased levels of 14C-3-methoxytyramine (3MT) following intracisternal injections of 14C-dopamine (DA). Opposite results with dexamethasone were obtained in iproniazid (MAO-inhibited)-treated rats. In these animals, brain MAO enzyme activity was significantly increased by dexamethasone. This effect increased with the duration of dexamethasone treatment and appeared to be dose dependent. In the brain areas tested (hypothalamus, midbrain, cerebellum, pons and medulla, olfactory, rest of brain) increases of MAO enzyme activity were also indicated by lower levels of 14C-3MT and increased levels of 14C-HVA formed from intracisternally injected radiolabeled DA. Treatment with other glucocorticoids (16alpha-methyldichlorisone, 16beta-methylprednisone and prednisolone) had a similar effect on 14C-DA metabolism. On the other hand, desoxycorticosterone, progestone, estradiol and testosterone, did not exhibit this property. The data indicate that chronic glucocorticoid treatment may have a slight inhibitory effect on brain MAO and also has the ability to partially reverse or antagonize the inhibition of MAO caused by iproniazid.

Animals↗