Lula 3d Multi2 Isoniazid
Contents.History Iproniazid was originally developed for the treatment of, but in 1952, its antidepressant properties were discovered when researchers noted that patients became inappropriately happy when given, a of iproniazid. Subsequently N-isopropyl led to development as an antidepressant and was approved for use in 1958. It was withdrawn in most of the world a few years later in 1961 due to a high incidence of, and was replaced by less drugs such as. Canada surprisingly withdrew iproniazid in July 1964 due to interactions with food products containing tyramine. Nevertheless, iproniazid has historic value as it helped establish the relationship between psychiatric disorders and the metabolism of neurotransmitters.Although iproniazid was one of the first ever marketed, (marketed as from 1935, for 'mild depression', amid other indications) predates it; and has been marketed traditionally for millennia for, among other things, altering mood, although it was not until 2012 that one of the components of its smoke was found to have antidepressant effects in mice.
Structure and reactivity The structure of iproniazid is chemically, in both structure and reactivity, similar to isoniazid. Iproniazid is a substituted hydrazine of which the isopropyl hydrazine moiety is essential for the inhibition of monoamine oxidase activity. Synthesis. This figure shows the multiple synthesis pathways towards iproniazid.There are multiple routes to synthesize iproniazid. The most common precursor is which formes when it reacts with. Isonicotinohydrazide can be converted into iproniazid via different pathways.One synthesis pathway involves AcMe which results in the formation of N'-(propan-2-ylidene)isonicotinohydrazide.
Subsequently, the C=N linkage is selectively in the presence of a platinum catalyst and with water, alcohol or acetic acid as solvent.In another pathway isonicotinohydrazide reacts with either 2-bromopropane or 2-chloropropane in an N-isopropyl addition reaction to the hydrazine moiety. This directly results in the formation of iproniazid. Reactions and mechanism of action Iproniazid is a known, it inhibits the activity of (MAOs) by itself and through an active metabolite,. The formation of isopropylhydrazine from iproniazid has been observed without MAOs present. Both iproniazid and isopropylhydrazine react near the of MAOs.
The reaction is a progressive with a high. In the presence of oxygen it is an, as of iproniazid at the active site of the enzyme takes place. This dehydrogenation resembles the first step of amine. After dehydrogenation iproniazid further reacts with the enzyme.Inhibition of MAOs by iproniazid is and sensitive to changes in pH and temperature, similar to oxidation of the monoamine substrate. Inhibition cannot be reversed by addition of the substrate. Iproniazid is able to displace non-hydrazine inhibitors, but not other hydrazine inhibitors from the active site of the enzyme.To increase the inhibition of monoamine oxidase, can be used.
The reaction however remains oxygen-dependent. MAO inhibition can be decreased by addition of, suggesting non enzymatic conjugation of either iproniazid or isopropylhydrazine with glutathione. Metabolism and toxicity. This figure shows the metabolism of iproniazid. The most important (proposed) metabolite is the isopropyl radical which is thought to be responsible for the heptatoxicity of iproniazid.Iproniazid is in the body. Iproniazid is converted to isopropyl hydrazine and isonicotinic acid in an initial. Isopropyl hydrazine can either be released in the blood or it can be metabolically activated by microsomal enzymes.
This oxidation of isopropyl hydrazine is a reaction that eventually can lead to the formation of an agent: the isopropyl radical. Hepatic was found in rats with doses as low as 10 mg/kg. Isopropyl radical The presence of the isopropyl radical was indicated by another observed product of the metabolism of iproniazid: the gas propane.agents have the capability to bind to chemical groups such as, and groups. The formed isopropyl radical is able to form S-isopropyl conjugates. This diminishes covalent binding to other proteins, however it was only observed in vitro., hepatotoxic doses of isopropyl hydrazine, the precursor of the isopropyl radical, did not deplete sulfhydryl-group containing compounds. Liver necrosis The isopropyl radical formed as a result of the metabolism of iproniazid, is able to covalently bind to proteins and other in the liver. These interactions are the reason for the hepatotoxicity of iproniazid.
Covalent binding results in liver by presumably changing protein function leading to stress and acute toxicity. However, the exact mechanism of how the binding of iproniazid derivatives to liver proteins would induce liver necrosis remains unclear.Cytochrome P450 enzymes are present at the highest concentrations in the liver, causing most alkylating agents to be produced in the liver. This explains why the liver is mostly damaged by covalent binding of alkylating agents such as the isopropyl radical. Rat models and other animal models have shown that cytochrome P450 enzymes convert isopropyl hydrazine to alkylating compounds that induce liver necrosis. An inducer of a class of hepatic microsomal cytochrome P450 enzymes, highly increased the chance of necrosis.
In contrast, the compounds, and inhibit microsomal enzymes which resulted in a decreased chance of necrosis due to isopropyl hydrazine. Metabolism to other forms Iproniazid can also be metabolised by O- from iproniazid to.
Isoniazid can undergo further metabolism via multiple metabolic pathways, of which one eventually results in alkylating agents as well. This toxifying metabolic pathway includes N. Reactions involving acetylation are influenced by: the. The toxicological response to isoniazid (and thus iproniazid) can therefore be subjected to interindividual differences.Acetone can also be produced in alternative pathway as a metabolite of isopropyl hydrazine. It is eventually converted to CO 2 and exhaled. Isonicotinic acid , formed during the hydrolysis of iproniazid, is described as a moderately toxic compound and with effects.
Isonicotinic acid is further metabolized by glycine- or glucuronic acid-conjugation. Other toxic effects Iproniazid can also interact with tyrosine-containing food products which may have toxic effects.
Excretion can occur via different routes: via the, the, and sometimes via the. Iproniazid has a molecular weight of 179.219 g/mol, which is far below 500 g/mol, and it is (because of e.g. The N-H groups in the molecule). These two properties together indicate that iproniazid is likely to be excreted in the urine via the kidneys.Iproniazid can also be and excreted afterwards in the form of one of its metabolites which can be found in the figure above. Is hydrophilic and has a molecular weight of 137.139 g/mol.
Isoniazid is therefore expected to be excreted via the urine, if it is not further metabolized in the body. The same holds for. And propane are gaseous which are presumably transported out of the body by exhalation via the lungs.Indication Iproniazid was originally produced as anti- medicine, but found to be more effective as.
When it was discovered that iproniazid is, it was replaced by medicinal that are less harmful to the. Examples of antidepressant drugs that are nowadays used instead of iproniazid are, and.Drugs more effective for treatment of tuberculosis are,. Efficacy and side effects Efficacy Iproniazid was designed to treat, but its most significant positive effect is that it has a mood-stimulating property. Therefore, it was used as an. Adverse effects The most significant adverse effects of using iproniazid is the caused by its. Moreover, usage of iproniazid results in several adverse effects such as (when lying down), of the feet and hands,.
However, these adverse effects disappear after approximately 10 weeks. Effects on animals Rat animal models have been used to investigate the (bio)chemical mechanism of iproniazid. A of iproniazid, was found to be a potent in rats. Hepatic was found in rats with doses as low as 10 mg/kg. It was predicted with admetSAR that iproniazid had a LD50 of 2.6600 mol/kg in rats. Lethality See the table for experimentally determined LD50, TDLo and LDLo values of various organisms. OrganismTest TypeRouteReported Dose (mg/kg)ReferenceDogLD50oral95Annals of the New York Academy of Sciences.
626, 1959.HumanTDLooral2.143 /DActa Neurologia et Psychiatrica Belgica. 977, 1959.HumanLDLooral14 /2W-ICanadian Medical Association Journal. 131, 1958.MonkeyLD50oral640Annals of the New York Academy of Sciences. 626, 1959.MouseLD50Intramuscular615American Review of Tuberculosis. 376, 1952.MouseLD50intraperitoneal475Japanese Journal of Pharmacology.
186, 1963.MouseLD50intravenous719American Review of Tuberculosis. 376, 1952.MouseLD50oral440Pharmaceutical Chemistry Journal Vol. 750, 1996.MouseLD50subcateneous730American Review of Tuberculosis. 376, 1952.RabbitLD50intravenous117American Review of Tuberculosis.
376, 1952.RabbitLD50oral125American Review of Tuberculosis. 376, 1952.RabbitLDLoskin2000Huntingdon Research Center Reports., 1972.RatLD50subcutaneous538Japanese Journal of Pharmacology.
Lula 3d Multi2 Isoniazid Side Effects
186, 1963.RatLD50unreported350Nature. 532, 1960.RatLD50oral365Journal of Pharmacology and Experimental Therapeutics. 444, 1957.RatLD50intraperitoneal375Arzneimittel-Forschung.
Drug Research. 363, 1970.See also.References.
Lula 3d Multi2 Isoniazid 10
Iproniazid, the first of the monoamine-oxidase inhibitor series to be introduced into (1958). It was employed as an until it was found to cause liver damage. Prior to its introduction as an antidepressant, iproniazid was studied as a drug similar in function to the antituberculotic drug, which it resembles in chemical structure. It prevents the enzymatic breakdown of norepinephrine, the brain-neurotransmitter substance concerned with emotional stimulation. It does so by the enzyme monoamine oxidase.Iproniazid has been replaced in antidepressant by other members of the monoamine-oxidase inhibitor series ( e.g., isocarboxazid, phenelzine, and tranylcypromine) and the tricyclic antidepressant drugs ( e.g., amitriptyline, and nortriptyline), which have less severe side effects.