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PubMed1992

Central nervous system toxicity after abrupt monoamine oxidase inhibitor switch: a case report.

DESCRIPTION: There have been numerous case reports of adverse reactions involving monoamine oxidase inhibitors (MAOIs), including reactions that developed when one MAOI was substituted for another. Although most reports have usually described a switch from isocarboxazid or phenelzine to tranylcypromine, we report a case of acute central nervous system toxicity possibly associated with a switch from phenelzine to isocarboxazid. SYMPTOMATOLGY: Predominant symptoms included stuporous sensorium, hypertension, tachycardia, tremor, and urinary retention. Onset of symptoms began within 48 hours after the abrupt MAOI switch. CONCLUSIONS: Clinicians must allow a sufficient washout period before adding any agent that has a known potential to interact adversely with MAOIs. In addition, patients who are unusually sensitive to one type of MAOI may also be at increased risk for developing problems with a different MAOI secondary to unforeseen pharmacokinetic or pharmacodynamic effects, even at doses that are usually considered subtherapeutic.

Brain↗
PubMed1979

Studies on some possible biochemical treatments of primary hyperoxaluria.

The effects of some putative inhibitors of oxalate production or urinary oxalate excretion have been investigated in the Cynamolgus monkey and in patients with Type I primary hyperoxaluria (hyperoxaluria with glycollic aciduria). Sodium-1-hydroxybutan-sulphonate, D,L-phenyllactate, succinimide and isocarboxazide did not reduce the urinary oxalate excretion in the monkeys. Pyridoxine reduced the excretion of oxalate and glycollate in some patients, and its therapeutic use has been documented over a five-year period. Succinimide, which has been used by other workers for the treatment of non-hyperoxaluric stone formers, did not decrease the excretion of either oxalate or glycollate in three patients in whom it was tried. It did not change the inhibitory activity of the urine with respect to the growth and aggregation of calcium oxalate crystals in any of the three patients, and it did not have any consistent effect on the excretion of calcium oxalate crystals in the one patient who had detectable crystaluria before treatment. We have identified several metabolites of succinimide in the urine of patients taking the drug. These include 2,3-dehydrosuccinamic, 2-hydroxysuccinamic and 3-hydroxysuccinamic acids. Isocarboxazide, cholestyramine and thiamine did not affect the urinary oxalate excretion in the patients. The significance of these observations from the viewpoint of the treatment of primary hyperoxaluria is discussed.

Adolescent↗
PubMed1975

[Combination of tricyclic antidepressants and MAOI in the depressions].

This study was aimed at the assessment of therapeutic and side effects of simultaneous administration of tricyclic antidepressants and MAOI. The sample consisted of 122 patients with depressive syndromes, treated at the "Centro de Psicología Médica San Martín de Tours" (period 1970/1973), with Isocarboxazide and Trimiprimine. All patients received both drugs three times a day. The average daily dose was 20 mg of Isocarboxazide together with 125 mg of Trimiprimine. The average treatment was 70 days long. The study lead to the following conclusions: 1. There were no serious side effects. 2. The scarce side effects registered were not very different from those of the other anti-depressants. 3. The therapeutic doses were lower than those required when each drug is used alone. 4. The speed of action was higher than for each drug separately. 5. The overall percentage of improvement in patients was higher than the percentage obtained for each drug alone. 6. The lack of side effects for a theoretically risky combination of drugs is likely to be attributed to the neuroleptic action of Trimipramine.

Administration, Oral↗
PubMedDate not supplied

Behavioral effects of perinatal administration of antidepressant drugs in the rat.

The monoamine reuptake blockers, imipramine, desipramine, and chlorimipramine, and the monoamine-oxidase inhibitors, iproniazid and isocarboxazid, were administered to pregnant rats (acutely at day 15 of pregnancy, or subchronically from day 10 of pregnancy to the delivery) or to newborn pups (from day 1 to day 5 of life). Prenatal acute injection of the antidepressant drugs failed to modify the development of neonatal reflexes of the rat pups and their adult behavior. Prenatal subchronic administration of the antidepressant drugs was followed by an increase in the number of pups showing neonatal reflexes, but also by an inhibition of the open field behavior and the acquisition of active avoidance responses tested in adulthood. In this respect, monoamine-oxidase inhibitors appeared to be more potent than monoamine reuptake blockers. Furthermore, neonatal administration of all the antidepressant drugs caused an inhibition of the acquisition of active avoidance responses tested in adulthood, but only the monoamine-oxidase inhibitor, isocarboxazid, significantly inhibited also the open field behavior of adult rats. Neither prenatal nor neonatal administration of the antidepressant drugs affected sexual activity of adult rats. The present results suggest that only a prolonged treatment with antidepressant drugs can affect neonatal or adult behavior of the rat, probably through an interference with central monoamine neurotransmission.

Animals↗
PubMed1984

MAO inhibitor therapy in trichotillomania associated with depression: case report.

Trichotillomania may sometimes be an atypical variant of depressive illness. A case is reported in which the MAO inhibitor isocarboxazid was successfully used to treat both depression and associated trichotillomania. The symptoms recurred upon discontinuation of the drug and were ameliorated by reintroduction of isocarboxazid .

Adult↗
PubMed1999

Characterization of eprinomectin N-deacetylase in rats.

The enzyme system responsible for the N-deacetylation of eprinomectin in rats was characterized. Tissue and subcellular studies showed that the hydrolysis activity was localized mainly in liver microsomes. Apparent KM and Vmax values calculated from Lineweaver-Burk plots were 53 microM and 0.81 nmol/mg/min for male rats and 70 microM and 4.99 nmol/mg/min for female rats, respectively. Pretreatment of male rats with dexamethasone, phenobarbital, and pregnenolone 16alpha-carbonitrile increased the activity by more than 3-fold. Paraoxon and bis-4-nitrophenylphosphate strongly inhibited the deacetylase activity at concentrations as low as 1 microM. The hydrolysis activity also was inhibited by SKF525, but less effectively. Eserine strongly inhibited the activity at 1 x 10(-4) M. HgCl2 decreased the activity to about 40% at a concentration of 1 x 10(-4) M. FeCl3, CaCl2, MgCl2, and EDTA had little effect on the hydrolysis of eprinomectin, whereas NaF slightly increased the activity to 118%. Thus, the inhibition study suggested that eprinomectin deacetylase resembled "B" type carboxylesterase/amidases. The hydrolysis activity of eprinomectin and isocarboxazid, a specific substrate of RL2 [Hosokawa, M, Maki T and Satoh T (1987) Mol Pharmacol 31:579-584], by liver microsomes from rats treated with various cytochrome P-450 inducers correlated well (r = 0.92). Also, elusion profiles of esterase by gel filtration and ion exchange chromatography demonstrated that the active protein(s) for eprinomectin and isocarboxazid hydrolysis coeluted. Thus, RL2 or an enzyme system similar to RL2 is responsible for the N-deacetylation of eprinomectin.

Amidohydrolases↗
PubMed2001

Antidepressants versus placebo for people with bulimia nervosa.

BACKGROUND: Bulimia Nervosa (BN) represents an important public health problem and is related to serious morbidity and even mortality. This review attempted to systematically evaluate the use of antidepressant medications compared with placebo for the treatment of bulimia nervosa. OBJECTIVES: The primary objective of this review was to determine whether using antidepressant medications was clinically effective for the treatment of bulimia nervosa. The secondary objectives were: (i) to examine whether there was a differential effect for the various classes/types of antidepressants with regard to effectiveness and tolerability (ii) to test the hypothesis that the effect of antidepressants on bulimic symptoms was independent of its effect on depressive symptoms SEARCH STRATEGY: (1) electronic searches of MEDLINE (1966 to December 2000), EMBASE (1980-December 2000), PsycLIT (to December 2000), LILACS & SCISEARCH (to 1997) (2) the Cochrane Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register - ongoing (3) inspection of the references of all identified trials (4) contact with the pharmaceutical companies and the principal investigator of each included trial (5) inspection of the International Journal of Eating Disorders - ongoing SELECTION CRITERIA INCLUSION CRITERIA: every randomized, placebo-controlled trial in which antidepressant medications were compared to placebo to reduce the symptoms of bulimia nervosa in patients of any age or gender. Quality criteria: reports were considered adequate if they were classified as A or B according to the Cochrane Manual. The Jadad scale, with a cut off of 2 points, was applied to check the validity of the above referred criterion but was not used as an inclusion criterion. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers for each included trial. Dichotomous data were evaluated by the relative risk with 95% confidence intervals (CI) around this measure, based on the random effects model; continuous data were evaluated by the standardised mean difference with the 95% CI. NNT was calculated using the inverse of the absolute risk reduction. MAIN RESULTS: Currently the review includes 16 trials comparing antidepressants with placebo: 6 trials with TCAs (imipramine, desipramine and amitryptiline), 3 with SSRIs (fluoxetine), 4 with MAOIs (phenelzine, isocarboxazid and brofaromine) and 3 with other classes of drugs (mianserine, trazodone and bupropion). Similar results were obtained in terms of efficacy for these different groups of drugs. The pooled RR for remission of binge episodes was 0.88 (95% CI 0.83-0.93; p<0,001) favoring drugs. The NNT for a mean treatment duration of 8 weeks, taking the non-remission rate in the placebo controls of 92% as a measure of the baseline risk was 9 (95% CI 6 - 16). The RR for clinical improvement, defined as a reduction of 50% or more in binge episodes was 0.63 (95% CI 0.55-0.74) and the NNT for a mean treatment duration of 9 weeks was 4 (95% CI 3 - 6), with a non-improvement rate of 67% in the placebo group. Patients treated with antidepressants were more likely to interrupt prematurely the treatment due to adverse events. Patients treated with TCAs dropped-out due to any cause more frequently that patients treated with placebo. The opposite was found for those treated with fluoxetine, suggesting it may be a more acceptable treatment. Independence between antidepressant and antibulimic effects could not be evaluated due to incomplete published data. REVIEWER'S CONCLUSIONS: The use of a single antidepressant agent was clinically effective for the treatment of bulimia nervosa when compared to placebo, with an overall greater remission rate but a higher rate of dropouts. No differential effect regarding efficacy and tolerability among the various classes of antidepressants could be demonstrated.

Antidepressive Agents↗
PubMed1984

Gonadal hormone-induced changes in hepatic microsomal carboxylesterase in rats.

Hepatic microsomal carboxylesterase (E.C. 3.1.1.1) from rat liver microsomes showed a different capacity for the hydrolysis of various substrates. In castrated male rats, the enzyme activities towards p-nitrophenylacetate and malathion were decreased. When testosterone propionate was administered to castrated male rats, the activities of p-nitrophenylacetate and malathion hydrolases were reversely increased. However, in ovariectomized female rats, the carboxylesterase activities showed substrate-dependent changes, i.e., increase in p-nitrophenylacetate and malathion hydrolases and decrease in acetanilide and isocarboxazid hydrolases. When estradiol benzoate was administered to ovariectomized female rats, the activities of p-nitrophenyl-acetate and malathion hydrolases were decreased; and acetanilide and isocarboxazid hydrolases were increased. These results suggest that hepatic microsomal carboxylesterases may be, at least in part, regulated by gonadal hormones which exert different effects on the several isozymes of carboxylesterases.

Acetanilides↗
PubMed1981

DNA-damaging activity in vivo and bacterial mutagenicity of sixteen hydrazine derivatives as related quantitatively to their carcinogenicity.

Sixteen hydrazine derivatives (hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine, phenylhydrazine, procarbazine, isoniazid, isocarboxazid, nialamide, 2,4-dinitrophenylhydrazine, phenelzine, hydralazine, dihydralazine, carbamylhydrazine, mebanazine, iproniazid, and 1-carbamyl-2-phenylhydrazine) were tested for DNA-damaging activity by the alkaline elution technique and for mutagenic activity in the Salmonella-microsome (Ames) test. The first nine compounds listed (56%) were found to induce a significant DNA fragmentation in the liver and/or in the lung of i.p.-treated male Swiss mice. The DNA-damaging potency varied over an approximately 30-fold range. Thirteen of the first 14 compounds listed (81% of the total), isocarboxazid being inactive, were positive in the Ames test, with a broad range of activity towards the five bacterial strains of Salmonella typhimurium used (TA1535, TA100, TA1537. TA1538, and TA98) and of metabolic behavior in the presence of S-9 mix containing rat liver, mouse liver, or mouse lung postmitochondrial preparations from Aroclor-treated animals. The mutagenic potency varied over an almost 7000-fold range. For 11 of the 16 hydrazine derivatives tested, homogeneous carcinogenicity data (induction of pulmonary tumors in mice chronically treated p.o.) were available from literature. Elaboration of these data showed that carcinogenic potency varied over an approximately 1900-fold range. The five most potent carcinogens were all positive in the DNA damage test. Their carcinogenic potency varied over a 130-fold rage and their DNA-damaging potency varied over a 22-fold range. DNA-damaging potency seemed to vary on a more compressed scale, but regression analysis indicated the existence of a strong positive correlation between in vivo DNA-damaging and carcinogenic potencies, while a lack of correlation was found between mutagenic and carcinogenic potencies. There was no correlation between DNA-damaging and mutagenic potencies.

Animals↗
PubMed1995

Interindividual variation in carboxylesterase levels in human liver microsomes.

Microsomal carboxylesterase activities in 12 human livers were determined using 10 kinds of carboxylesterase substrates (p-nitrophenylacetate, p-nitrophenylpropionate, p-nitrophenylbutyrate, butanilicaine, isocarboxazid, palmitoyl-coenzyme-A, malathion, clofibrate, acetanilide, and phenacetin). There were large individual differences in the 12 humans based on experimental results in the past several years in our laboratory. We found that all human liver microsomes have RH1-immunoreactive carboxylesterase, and the carboxylesterase content in liver also showed large individual differences. The RH1-immunoreactive carboxylesterase concentration correlated well with those of p-nitrophenylesters, clofibrate, butanilicaine, and isocarboxazid, and anti-RH1 immunoglobulin G strongly inhibited human liver hydrolase activity. These findings indicate that one major carboxylesterase isozyme that is immunoreactive with anti-RH1 in human liver microsomes has catalytic activity on major carboxylesterase substrates, and thus hydrolase activity in human liver depends on the expression level of this carboxylesterase isozyme. These observations should be useful in understanding the action of carboxylesterases on drug metabolism in humans.

Adult↗
PubMed1992

Influence of higher rates of agitation on release patterns of immediate-release drug products.

The dissolution procedure serves as a quality control test to assure batch-to-batch uniformity and bioequivalence of a product once the bioavailability of the product has been established. It can also be used to detect manufacturing and/or process variations that could reduce product bioavailability. Dissolution testing must be conducted at an appropriate agitation rate. Tests conducted at high agitation rates may lose the ability to differentiate between good and bad products. Although the effect of high agitation rates has been known for some time, several immediate-release drug products still have United States Pharmacopeia (USP) monograph dissolution procedures that require very high agitation rates. A systematic survey was conducted on marketed tablets of chloroquine phosphate, griseofulvin, hydroxychloroquine sulfate, isocarboxazide, primaquine phosphate, and sulfadiazine. Each of these products has a USP monograph requiring a dissolution test at a paddle speed of 100 rpm. To study the influence of agitation rate on the dissolution rate of these products, dissolution studies were conducted at paddle speeds of 50, 75, and 100 rpm with the USP apparatus 2 (paddle method). The dissolution rate increased with an increase in the agitation rate from 50 to 75 rpm. However, no significant increase in the dissolution rate was noted with an increase in the agitation rate from 75 to 100 rpm. The data support the position that the higher agitation rate of 100 rpm is not necessary for a quality control procedure or a compendial standard for the products tested.

Chloroquine↗
PubMed1982

Effects of monoamine oxidase inhibitors on performance during differential reinforcement of low response rate.

The effects of three monoamine oxidase inhibitors (MAOI) on performance under a differential-reinforcement-of-low-rate 72-s schedule (DRL 72-s) for water reinforcement were determined. All three drugs (isocarboxazid, iproniazid, phenelzine) reduced response rate and increased reinforcement rate in rats performing under the DRL schedule. Drugs from other classes (alcohol, chlordiazepoxide, morphine, pentobarbital) did not produce similar effects. The ability of MAOI to increase reinforcement rate under a DRL 72-s schedule is similar to that recently reported for tricyclic antidepressants and the two atypical antidepressants mianserin and iprindole. These findings support the contention that the DRL schedule may be useful as a test for identifying new antidepressants and for elucidating the neurochemical effects of antidepressants that are responsible for their therapeutic actions.

Animals↗
PubMed1984

Concomitant isocarboxazid/mianserin treatment of major depressive disorder.

This paper reports combined antidepressant treatment with isocarboxazid /mianserin in 60 patients with endogenous depression/melancholia. The combination was used as the first drug treatment choice in 33 cases. Thirty-two patients obtained complete remission and one responded only incompletely. The depression improved after a few days' treatment, and full recovery was obtained after approximately 2 weeks. There were no serious side-effects or interactions, but weight gain was a common problem.

Adult↗
PubMedDate not supplied

MAOI treatment response: multiaxial assessment.

While studying the effectiveness of the MAOI isocarboxazid for the treatment of depression, we noted that many patients experienced a reduction of symptoms without equivalent improvement in other areas of their lives. We evaluated four outcome areas: symptoms, work, family functioning and social functioning. After 6 weeks on medication, symptoms improved the most, significantly more so than the other three areas. For the group of patients who completed 24 weeks on medication, all four outcome areas were further improved compared to the 6-week levels, with the improvement in work functioning reaching statistical significance. We conclude that the assessment of treatment outcome is more complex than the simple measurement of symptom reduction, and that different outcome areas are likely to improve at different rates and to different extents.

Adult↗
PubMed1995

A 3-year follow-up of a group of treatment-resistant depressed patients with a MAOI/tricyclic combination.

Treatment-resistant depression is a clinical complication that not infrequently affects a certain number of patients. Within the treatment strategies proposed for this condition, the association of a MAO inhibitor (MAOI) with a tricyclic antidepressant has gained reputation both for its unusual efficacy, as for its potential toxicity. However, when cautions are taken, it may be safely administered. Most reports on this combination have been carried in nonresistant patients and, when resistant patients are included, only the acute phase of the treatment is reported. In this study, a group of well-defined resistant patients received an open trial with the association of isocarboxazide and amitryptiline (n = 25). Those who responded were followed during the next 3 years (n = 12) and every 6 months an attempt was made to discontinue the MAOI and continue only with amitryptiline. At the end of the study, 4 patients maintained response with single medication, 6 still required both drugs and 2 relapsed. No clinical differences were apparent between the outcome groups, except that those who maintained their response only with the 2 combined drugs had more previous depressive episodes than the others. The isocarboxazide/amitryptiline combination may be a good treatment option for at least some forms of resistant depression. The safety of this treatment modality is confirmed, even when given for long periods of time. The study also suggest that there are no clinical characteristics in resistant depression that may predict the treatment outcome but, perhaps in some patients, a combined treatment is required to obtain a broader biochemical effect that could convert them from nonresponders to responders.

Adolescent↗
PubMed1982

Monoamine oxidase inhibitor-responsive depression.

Double-blind, placebo-controlled trials have documented the efficacy of some monoamine oxidase (MAO) inhibitors in treating certain depressed patients. This preliminary report of a 6-week, double-blind, placebo-controlled study of the MAO inhibitor isocarboxazid (Marplan) examines the time course of platelet MAO inhibition and treatment response, and describes symptoms that distinguish markedly improved from slightly improved responders. Thirty male outpatients, ages 28-64, randomly divided into placebo (n = 15) and active medication (n = 15) groups, were followed weekly. Medication was started at 20 mg daily and increased to achieve 90% platelet MAO inhibition. Data were analyzed for 24 patients who completed at least 3 weeks of the study. A clinician's global change rating at the study's conclusion showed that 12 of 13 patients (92%) in the active medication group improved, while 3 of 11 (27%) patients in the placebo group improved. Significant symptomatic improvement occurred in the active treatment group by week 3. Trends suggest that anxiety improved first (week 2), followed by depression (week 3), and finally cognitive outlook (week 6). Only minimal difficulties were observed with orthostatic hypotension, hypertensive crises, or other side effects. At baseline, the only significant difference between the markedly improved and slightly improved groups was greater psychomotor retardation in the markedly improved group. Trends suggest that the markedly improved group showed less depression, anxiety, sleep disturbance, and weight loss, fewer gastrointestinal complaints, and more helplessness and worthlessness.

Adult↗
PubMed1988

A comparative evaluation of three discriminant scales for endogenous depression.

Three discriminant scales for diagnosing endogenous depression were examined in 56 depressed inpatients. These scales were the Newcastle 1 (N1), Newcastle 2 (N2), and Michigan Index (MI). The scales agreed on diagnosis in 17 (30%) patients; respective frequencies of endogenous depression were 23%, 57%, and 78% for the N2, N1, and MI scales. Relationships were examined between treatment response to isocarboxazid, drug dose, and diagnostic type for each scale. Significant dose X diagnosis interactions were noted for N1 and N2, but not for MI. A correlational within-dose analysis of all three scales revealed that actual diagnostic score was related to outcome only for high-dose patients on the Newcastle-1 scale; no other significant correlations emerged.

Adult↗
PubMed2005

Synthesis of novel N-substituted imidazolecarboxylic acid hydrazides as monoamine oxidase inhibitors.

Novel 2-alkylsulfanyl-1-benzyl-5-imidazolecarboxylic acid hydrazides (15a,b) were synthesized as analogues of isocarboxazide, which is a known nonselective irreversible monoamine oxidase inhibitor and tested for monoamine oxidase A and B inhibitory activity. Neither of the compounds showed any inhibition of MAO B activity up to a high concentration of 100 microM. An MAO A activity was only slowly inhibited at this high concentration after prolonged incubation with either compound. This suggests any observed inhibition is not very specific.

Humans↗