Iproniazid side effects

As early as 1961, the first generation of MAO inhibitors (iproniazid, isocarboxazide) were employed for the treatment of Parkinson s disease (PD). However, because of the severe side effects, such as cheese reaction, they were abandoned. The realization that the basal ganglia (extrapyramidal region) of human brain contained mostly MAO-B, which metabolized... 

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

The first inhibitors of flavin-dependent MAO that were developed for clinical use were hydrazines and hydrazides. The chance discovery that the antitubercular drug, 4-pyridine carboxylic acid hydrazide (isoniazid, 40), was also a potent MAO inhibitor led to the development of the related drug, iproniazid (41), used for the treatment of depressive illness. Although this compound demonstrated remarkable antidepressant action, its clinical value was seriously compromised by side effects [19]. 

About the same time as the reserpine finding, physicians noticed that some of the drugs used to treat other diseases appeared to have a beneficial side effect—raising the patient s mood. Upon further testing, a chemically modified version of one of these drugs effectively reduced the symptoms of depressed patients. This drug, iproniazid, inhibits MAO, the enzyme that destroys the monoamine neurotransmitters— dopamine, norepinephrine, and serotonin. As a result, more of these... 

Hydrazines. The hydrazines have only historic significance. The entire group of MAOIs was discovered through the euphoric side effect of isoniazid (8.36, isonicotinyl-hydrazide), a successful antituberculotic drug introduced in 1952. Iproniazid (8.37) is the corresponding isopropyl derivative. All of the hydrazides are highly hepatotoxic, and are no longer available. 

The antidepressant properties of these earlier antidepressants were chance discoveries. Imipramine was first developed as a potential antipsychotic, but when Kuhn (2) tested the clinical efficacy of this agent, he found that it only benefited depressed schizophrenic patients. This observation prompted him to test it in patients who were suffering from melancholia. Iproniazid was developed as an antitubercular drug, but the observation that euphoria was a side effect led George Crane ( 3) to conduct clinical trials, which found it useful in purely depressed patients. A year later, Nathan Kline ( 4), following up on this observation, reported positive results when he administered iproniazid to another depressed group. 

The depletion of the neurotransmitters—as observed with reserpine—came under study as the possible cause of depression and became known as the amine hypothesis of depression. The drug iproniazid reversed some of these negative side effects, confirming the usefulness of drugs in the treatment of depression. 

Iproniazid 24, an alkyl analog of the antituberculous drug isoniazid 25 (Figure 2.8), surprisingly showed mood-improving activity in several depressed tuberculosis patients, which turned out to result from a monoamine oxidase (MAO) inhibitory activity. Since the compound was already registered as an antituberculosis drug and since it constituted the very first effective treatment of depression, more than 400 000 patients received it within only one year after the first announcement of its antidepressant activity [2, 33], Later it was withdrawn from therapy, due to hepatotoxic side effects. 

The discovery of the mood-elevating effect of MAO inhibitors was a classic example of serendipity in drug research. In 1951, isoniazid and its isopropyl derivative, iproniazid, were successfully introduced for the treatment of tuberculosis. In contrast to isoniazid, iproniazid was found to produce undesirable stimulation in some patients. In 1952, Zeller and his co-workers demonstrated that iproniazid was capable of inhibiting MAO, whereas isoniazid was ineffective (Zeller and Barsky 1952 Zeller et al. 1952). In 1956, Crane analyzed the psychiatric side-effects of iproniazid and came to the conclusion that it might be beneficial in the treatment of depression (Crane 1956). In 1957 Kline introduced it as a psychic energizer (Kline 1958). At the same time Kuhn discovered the antidepressant effect of imipramine (Kuhn 1957). This opened the way to the most powerful antidepressant therapy to date. 

Crane GE (1956) Psychiatric side effects of iproniazid. Am J Psychiatr 112 494-499... 

The monoamine oxidases are a widespread group of enzymes which catalyse the oxidative deamination of amines to aldehydes (for reviews, see [13, 94, 121, 176, 265]). The prototype of the monoamine oxidase inhibitors, iproniazid, first attracted attention because of its tuberculostatic effect, until it was discovered that it exerted a marked antidepressant action in man. Hypotension was observed as a side effect of iproniazid and numerous other monoamine oxidase inhibitors, and this finally led to the development of one compound belonging to this group-pargyhne-which was specifically intended for use as an antihypertensive. Pargyhne has a gradual onset of action and the hypotension it produces... 

As a consequence, several drugs have been developed by enhancing the side effect of another drug. For example, the mood-improving effect of iproniazid was discovered when it was tested as an antituberculous drug antidepressant inhibitors of neurotransmitter reuptake, like imipramine and desipramine, stem from the antipsychotic dopamine antagonist chlorpromazine, which itself was derived from Hi antihistaminics [35,36,51]. 

The amount of this enzyme present in the liver is genetically determined. In some populations, as in Japanese and Eskimo populations, the level is almost never affected— the gene responsible for the slower metabolism is almost absent. However, in other populations, as in African populations, up to 80 percent (four of every five.O have lower levels of this enzyme and could be affected in situations where it is needed to destroy the chemicals in the body. (It should be noted that iproniazid, the example chemical used above, is no longer available in the United States because of other types of toxic side effects it has had on people. However, acetyl-transferase is an enzyme that acts on many different chemicals that are still in use in drug therapy and released into the environment.)... 

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