Iproniazid tuberculosis

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

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). 

Monoamine Oxidase inhibitors (MAOis). The first antidepressant discovered was iproniazid. This medication was developed in the early 1950s as a treatment for tuberculosis but was unexpectedly found to improve mood in depressed patients. It was later found that its antidepressant effect was due to its action on the MAO enzymes. Unfortunately, iproniazid was subsequently found to cause liver damage and was withdrawn from the market. 

Iproniazid, originally developed for the treatment of tuberculosis, exhibited mood-elevating properties during clinical trials in tuberculosis patients with depression. The distinguishing biochemical feature between iproniazid and other chemically similar antituberculosis compounds was the ability of the former to inhibit MAO. Thus, a series of hydrazine and non-hydrazine-related... 

Similar to the discovery of other psychiatric medications, the mood-enhancing effects of monoamine oxidase inhibitors (MAOIs) were identified serendipi-tously mood improvements were observed in patients with tuberculosis treated with iproniazid (Bloch et ah, 1954) The early enthusiasm for the MAOIs was based on significant and unprecedented antidepressant effects and the link between antidepressant efficacy and their... 

In the early 1950s, the MAOI iproniazid was tried to treat tuberculosis. Researchers noticed that even when iproniazid was not effective in treating the tuberculosis, many of their patients seemed to be happier. Soon, iproniazid was put to use to treat depression. Later, MAOIs became the first antidepressants shown to be effective for the treatment of social anxiety disorder, and have since been used in the treatment of all of the anxiety disorders. 

Although many antibiotics are effective to some extent in arresting the progress of tuberculosis, none is uniformly successful. One of the most effective is isonicotinic hydrazide (73), available from methyl isonicotinate by reaction with hydrazine (B-75MI20903). Extensive clinical use of this agent showed the drug to possess an additional antidepressant effect and led to the development of iproniazid (74), an established antidepressant (53JOC994). 

The first generation of antidepressants, MAO (monoamine oxidase) inhibitors, inhibited neurotransmitter degradation by inhibiting monoamine deoxidase, a flavin containing enzyme, found in the mitochondria of neurons and other cell types, that oxidatively deaminates naturally occurring sympathomimetic monoamines, such as norepinephrine, dopamine, and serotonin within the presynapse. In 1952, isoniazid and its isopropyl derivative, iproniazid (1), were developed for the treatment of tuberculosis, where it was subsequently found that these agents had a mood enhancing effect on... 

Isoniazid and iproniazid are chemically similar drugs having different pharmacological effects they may both cause liver damage after therapeutic doses are given. Isoniazid is still widely used for the treatment of tuberculosis, but iproniazid is now rarely used as an antidepressant. 

During clinical studies of iproniazid (201) in the treatment of tuberculosis it was found to have a mood-elevating effect. It was later found to be an inhibitor of monoamine oxidase (MAO), the enzyme which oxidatively deaminates such neurotransmitters as noradrenaline and serotonin, and it was tried in the treatment of depression in 1957. Other MAO inhibitors were introduced later, most of them being hydrazine derivatives. Heterocyclic examples include isocarboxazid (202) and nialamide (203). They are toxic and cause dangerous hypertensive crises if food with a high tyramine content is eaten, and on this account their use is limited. 

One such accident occurred in the 1950s, when scientists searching for a tuberculosis treatment observed that the drug iproniazid caused mood elevation. Since there were few treatments for depression, the findings were exciting. 

The discovery of the antidepressant effect of medications was coincidental to their use for other disorders. Initial work published in 1952 reported that iproniazid (originally used for the treatment of tuberculosis) could elevate mood. Although the use of iproniazid was discontinued due to toxicity, many other additional medications have been tested and approved for the treatment of depression. These include monoamine oxidase inhibitors, tricyclics, selective serotonin reuptake inhibitors, and a heterogeneous class of atypical drugs. 

The immediate uptake of iproniazid for use in people with depression illustrates the appetite that existed for a pharmacological treatment for this sort of problem. Kline himself later commented that probably no drug in history was so widely used so soon after the announcement of its application in the treatment of a specific disease. Kline attributed this partly to the fact that iproniazid was already available because it was a recognised treatment for tuberculosis, but he also records the feeling of the time that there was an overwhelming need for an effective antidepressant medication (Kline 1970, p. 202). 

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. 

Antidepressants were developed in the 1950s. Iproniazid, an agent used to treat tuberculosis, was inadvertently found to produce an improvement in mood. Ultimately, it was discovered to be an inhibitor of monoamine oxidase (MAO)—an enzyme used to break down catecholamines (dopamine, norepinephrine, and serotonin) in neurons. This led to the development of an entire class of antidepressants the monoamine oxidase inhibitors or MAOIs. 

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. 

The early pioneering work by Zeller et al. (115) on the potent MAO inhibitory effect of iproniazid—a structural modification of the tuberculostat Isoniazid—and his realization of the physiologic consequences that might arise from such a profound alteration in catecholamine metabolism, the actual confirmation by Brodie, Pletscher, and Shore (27) of the rise in brain monoamine levels following the administration of iproniazid and JB-516 (a-methylphen-ethylhydrazine), and the early euphoric effects noted by Selikoff, Robitzek, and Omstein (96) in tuberculosis patients on iproniazid therapy led Kline and his associates (67) to investigate the possible application of iproniazid in the treatment of mental depression. It was their conclusion that MAO inhibition and antidepressant effect had a causal relationship and that a new approach for the treatment of mental depression had been uncovered. The subject of the MAO inhibitors has been reviewed extensively up to 1960 by Pletscher, Gey, and Zeller (84) and by Biel, Horita, and Drukker (21) to 1963, in comprehensive reviews of the chemistry, biochemistry, pharmacology, clinical application, and structure-activity relationships of the MAO inhibitors. 

It was observed (in the 1960s) that the antihistamine imipramine and the anti-tuberculosis drug iproniazid had antidepressant activities. Imipramine was found to inhibit neuronal uptake of noradrenaline and serotonin by pre-synaptic neurons in the brain. Iproniazid was found to inhibit monoamine oxidase, the enzyme that breaks down monoamines. Both these actions result in raised levels of monoamines at the synapse. In addition, drugs that reduce the availability of monoamines cause symptoms of depression. 

The monoamine oxidase inhibitors form yet another group of drugs which were introduced into psychiatry as a result of observations in a different field. It was noticed that tuberculosis patients under treatment with iproniazid frequently became euphoric. The further observation that iproniazid inhibited brain amine oxidase prompted the development of... 

The disoovery of MAOIs resulted from a search for derivatives of Isoniazid (isonlootinlo aold hydrazide) (Fig. 21.25) with antitubercular activity. During clinical trials with this hydrazine derivative, a rather consistent beneficial effect of mood elevation was noted in depressed patients with tuberculosis. Although no longer used clinically, iproniazid (Fig. 21.25), the first derivative to be synthesized, was found to be hepatotoxic at dosage levels required for antituberoular and antidepressant activity. The antidepressant activity of iproniazid, however, prompted a searoh for other MAOIs, whioh resulted in... 

The first potent MAOI used in human therapy was iproniazid, originally developed for the treatment of tuberculosis as a congener of isoniazid. Clinical observations soon indicated its favourable action on mental depression and angina pectoris. 

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