Iproniazid Phosphate Research Articles

Synthesis, crystal structures, molecular docking, in vitro monoamine oxidase-B inhibitory activity of transition metal complexes with 2-{4-[bis (4-fluorophenyl)methyl]piperazin-1-yl} acetic acid

Three novel complexes, [Cu(L)2(H2O)](1), [Zn(L)2(H2O)2]·CH3OH·1.5H2O(2), and [Ni(L)2(H2O)1.8]·CH3OH·1.2H2O (3) (HL = 2-{4-[bis(4-fluorophenyl)methyl]pipera-zin-1-yl} acetic acid), were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential Monoamine oxidase B inhibitory activity. All acquired compounds were tested against rat brain MAO-B in vitro. In accordance with the result of calculation, it showed complex 1 (IC50 = 1.85 ± 0.31 μM) have good inhibitory activity against MAO-B at the same micromolar concentrations with positive control Iproniazid Phosphate (IP, IC50 = 7.59 ± 1.17 μM). These results indicated that complex 1 was a potent MAO-B inhibitor.

Flow-injection with chemiluminescence detection for the determination of iproniazid

A new FIA — direct chemiluminescence method is proposed for the determination of iproniazid phosphate, based upon the oxidation of the drug by cerium(IV) in sulfuric acid medium at room temperature in presence of sulfite. The calibration graph is linear over the range 0.1–4.0 ppm of iproniazid phosphate, with a rsd ( n=50, 1.0 mg l −1) of 3.1%, LOD ( s/ n=2) of 3 μg l −1 and sample throughput of 121 h −1. The influence of different foreign compounds (soluble starch, lactose, sodium saccharine, sucrose, glucose, sodium chloride, and isoniazid) which can be found accompanying iproniazid phosphate in pharmaceutical preparations is tested, no serious interferences are observed. The method is applied to determination of iproniazid phosphate in a synthetic sample (1.0 mg l −1 of iproniazid phosphate, three replicates) as well as in human urine (0.5 mg l −1 of iproniazid phosphate, three replicates). The obtained mean relative errors are of +0.17 and +0.66%, for the synthetic sample and urine sample, respectively.

Spectrophotometric Determination of Some Hydrazine Derivatives Using 2,3-Dichloro-5,6-Dicyano-p-Benzoquinone

Abstract A simple, sensitive, and rapid spectrophotometric method for determining isoniazid, isocarboxazid, and iproniazid phosphate is described. In this method, 2,3-dichloro-5,6-dicyano-p-benzoquinone (a π-acceptor) is used to form charge-transfer complexes with cited drugs (n-donors). The procedure is sensitive enough to permit unit dose assay of the individual drugs in their pharmaceutical formulations. The assay results are in accord with the pharmacopoeial assay results.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone as a redox titrant

An oxidimetric titrant, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in anhydrous acetic acid is used for the semimicro-determination of hydrazine hydrate, phenylhydrazine hydrochloride, isoniazid and iproniazid phosphate in pure forms as well as in some pharmaceutical preparations containing isoniazid and iproniazid phosphate. The end point was detected potentiometrically using a platinum-calomel combination electrode. The results obtained are compared statistically with those obtained by the official methods and they are in good agreement.

Transport of exogenous 5-hydroxytryptamine across the outer plasma membrane of the syncytial tegument ofHymenolepis diminutais by simple diffusion

The uptake of 5-hydroxytryptamine (5HT) from a 10 μM solution of exogenous [3H]5HT into the tegument of Hymenolepis diminuta was linear for the first 20 min of incubation. The rate of transport was 0.04 ± 0.01 pmol∙mg wet mass−1∙min−1, and there were no significant differences in the rate of uptake by the anterior, middle, and posterior regions of the body. The initial uptake was not Na+-dependent, was not saturable at up to 100 μM, was not highly temperature-dependent (Q10~ 1.2), and displayed activation energy of 11.8 kJ∙mol−1. Furthermore, uptake was not inhibited by p-chloromercuriphenyl sulphonic acid, imipramine, amiloride, or 5HT analogues, which collectively support a non-carrier-mediated uptake mechanism. Washing of the tissues with 10 mM 5HT after incubation in 10 μM [3H]5HT displaced less than 10% of the remaining [3H]5HT associated with the tissues, and little radioactivity was extracted by washing in acetone or chloroform. The uptake of [3H]5HT, however, was pH-dependent, the rate of uptake being closely correlated with the proportion of unprotonated 5HT. Only a small portion of the transported [3H]5HT was metabolized to a product associated with 5-hydroxyindoleacetic acid, and metabolism was significantly inhibited by the monoamine oxidase inhibitors iproniazid phosphate, deprenyl, and clorgyline. The present study showed that small amounts of [3H]5HT were taken up by H. diminuta by simple diffusion, little of the [3H]5HT was adsorbed to the surface of the worms or dissolved in the lipid phase of the plasma membrane, and some of the [3H]5HT taken up was metabolized by a monoamine oxidase-like enzyme.

Colorimetric Determination of Some Important Hydrazine Derivatives

ABSTRACT A simple and rapid colorimetric method for the determination of isoniazid, iproniazid phosphate, phenylhydrazine hydrochloride and hydrazine hydrate is described. The method is based on the formation of a Schiff base when these compounds react with 4-dimethylaminocinnamaldehyde and measurement of the condensed products at 370–555nm. The procedure has been successfully applied to the assay of the pharmaceutical preparations containing the studied drugs and hydrazine, and phenylhydrazine mixture, and the results are compared to the official methods. All the different experimental conditions are studied and incorporated into the procedure.

Structure of iproniazid phosphate

All hydrogen positions in the structure of a potent monoamine oxidase inhibitor, iproniazid phosphate, 1-isonicotinoyl-2-isopropylhydrazinium phosphate, C 9 H 14 N 3 O + .H 2 PO 4 - , have been determined and refined. The isopropylhydrazine side chain is protonated and extended. N and O atoms of the iproniazid cation and O atoms of the H 2 PO 4 - anion are held together by a hydrogen-bond network

Colorimetric determination of some important hydrazine derivatives

A simple and rapid colorimetric method for the determination of isoniazid, isocarboxazid, iproniazid phosphate, phenelzine sulphate and phenylhydrazine hydrochloride is described. The method is based on the formation of ferroin, when the studied drugs react with a mixture of iron (III) and 1,10-phenanthroline, and measurement of the absorbance at 512 nm. The procedure has been successfully applied to the assay of the pharmaceutical preparations of the studied drugs and the results are favorably comparable to the official methods.

Spectrophotometric determination of some MAO inhibitors using 7,7,8,8-tetracyanoquinodimethane and iodine monochloride

Two simple and sensitive spectrophotometric methods are described for the assay of three MAO inhibitors: isocarboxazid, tranylcypromine sulphate and iproniazid phosphate. The first method is based on the formation of a highly coloured stable radical anion between the drug as an n-donor and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as a pi-electron acceptor. Beer's law is obeyed in the concentration range 0.2-3, 0.2-4 and 0.5-4 micrograms ml-1 for isocarboxazid, tranylcypromine sulphate and iproniazid phosphate, respectively. The second method involves the use of iodine monochloride (ICl) as an sigma-acceptor. It was found that ICl reacts quantitatively only with isocarboxazid and tranylcypromine sulphate; with iproniazid phosphate results were very poor. Beer's law is obeyed in the concentration range 2-20 micrograms ml-1 for both drugs. The optimum experimental parameters for colour production in each case were determined. The percentage recoveries obtained were in accordance with those obtained by the official methods. The proposed methods are characterized by high sensitivity.

Release of octopamine by Leydig cells in the central nervous system of the leech Macrobdella decora, and its possible neurohormonal role.

1. The release of octopamine by the central nervous system of the leech Macrobdella decora was examined. Isolated ganglia or chains of ganglia were incubated in salines of varying composition, and the release of octopamine into the perfusate was measured using a radioenzymatic method. In some experiments this release was correlated with the electrical activity of the octopamine-containing Leydig cells, as measured via a microelectrode in the cell body. 2. Chains of ganglia incubated in normal saline released 0.04 pmol octopamine/ganglion/3 min incubation period. This amount was not significantly increased by either the monoamine oxidase inhibitor iproniazid phosphate (0.1 mM) or the uptake inhibitor desipramine (10 microM) alone, but was by both together. Nominally calcium-free saline containing 20 mM Mg++ significantly decreased octopamine release. 3. High K+ saline increased octopamine release significantly in both standard saline and one containing the blocking agents. This increase was sevenfold in saline containing iproniazid phosphate and desipramine, and was significantly greater than that obtained in saline without the blockers. This provides further evidence for the role of octopamine as a neuroactive substance in the leech by indicating the existence of possible mechanisms for its uptake and/or inactivation. 4. Octopamine release was positively correlated with the firing frequency of Leydig cells. No release was detectable when the cells were prevented from firing by the injection of hyperpolarizing current. Release was frequency-dependent when the cells fired at frequencies of 0.1-1.0 spikes/s. Elevating the external calcium concentration from 1.8 to 5.4 mM significantly increased octopamine release at all frequencies tested, except for 0 spikes/s, at which release remained below detectabilty.(ABSTRACT TRUNCATED AT 250 WORDS)

The synthesis of 5-hydroxytryptamine from tryptophan and 5-hydroxytryptophan in the cestode Hymenolepis diminuta

The synthesis of 5-HT in Hymenolepis diminuta was investigated. Homogenates of H. diminuta incubated in 3H-5-HTP or 13H-tryptophan resulted in the formation of a substantial radioactive product which comigrated on several TLC systems with 5-HT. Furthermore, considerable 3H-5-HTP was produced on incubation of homogenates of H. diminuta with 3H-tryptophan. Boiled homogenates were not effective in the synthesis of these products from 3H-tryptophan or 3-5-HTP. The formation of 3H-5-HT from precursor 3H-5-HTP was stimulated by addition of pyridoxal phosphate. On the other hand, addition of iproniazid phosphate increased the amount of extractable 3H-5-HT indicating the presence of a mammalian-like monoamine oxidase. Incubation of intact H. diminuta in saline containing 3H-tryptophan for 3 and 12 h resulted in substantial radioactivity in 5-HT. The present study clearly demonstrates the enzymatic capacity of H. diminuta for the synthesis of 5-HT from both tryptophan and 5-HTP and suggests that this pathway is of significance to the parasite in its natural environment.

Characteristics of dihydroxyphenylalanine/5-hydroxytryptophan decarboxylase activity in brain and liver of cat.

Abstract: Dihydroxyphenylalanine/5‐hydroxytryptophan (DOPA/5‐HTP) decarboxylase activity varied widely in different parts of the CNS, being highest in the neostriatum and lowest in the frontal cortex. The addition of 2.5 μm‐pyridoxal 5′‐phosphate (PLP), the coenzyme, increased enzyme activity in brainstem and liver, while higher concentrations led to a decrease in activity. In brainstem, the addition of 1000 μm PLP shows activity similar to that obtained without exogenous PLP. The effects of different monoamine oxidase (MAO) inhibitors on decarboxylase activity were demonstrated. Iproniazid phosphate and harmaline significantly decreased the decarboxylation in liver and brainstem, while pargyline inhibited only liver decarboxylation. Some decarboxylase inhibitors such as RO4–4602 and α‐methyl DOPA, as well as piribedil, a dopaminergic receptors agonist, were added in vitro to measure their action on decarboxylase with or without exogenous PLP or with double concentrations of substrate (5‐HTP). Piribedil (5000 μm) affected the enzymic reaction and triggered a higher inhibition in liver. Inhibition in brainstem needed less RO4–4602 (50 μm) than in liver (300 μm). Addition of PLP did not reverse this inhibition, while doubling the concentration of 5‐HTP nullified the inhibitory effect in liver only. Inhibition induced by α‐methyl DOPA (5 μm) was easily reversed by doubling the concentration of substrate. However, the presence of exogenous PLP restored the enzymic activity in liver only. We conclude from this work thus that the enzyme can decarboxylate its substrate without exogenous PLP, that MAO inhibitors might inhibit decarboxylase activity, and that decarboxylase inhibitors react differently when brain and liver are used as enzymic source. PLP seems to act as a protective agent on the active site of the enzyme in the brainstem and preferentially with the substrate in the liver.

Antipyrine estimations in the rabbit using gas-liquid chromatography: A reliable method for studying factors affecting oxidative drug metabolism

The application of a gas-liquid chromatographic (GLC) method to measurements of antipyrine in plasma for the estimation of antipyrine half-life ( T 1 2 ) in the rabbit is described and is compared with previous GLC methods. It has been established that the estimation of antipyrine can be achieved with acceptable precision and that rabbits can act as their own controls in the study of factors that might alter T 1 2 . Iproniazid phosphate, 50 mg/kg IP, was shown to produce a mean increase of 170% in T 1 2 .

Octopamine in leeches—II. Synthesis, release and reuptake of octopamine by the ventral nerve cord of Erpobdella octoculata

1. Octopamine was synthesized by the ventral nerve cords of E. octuculata during in vitro incubation in radiolabelled tyrosine and tyramine. Trace amounts of dopamine were also synthesized from tyrosine and tyramine. 2. In vitro uptake of 3H-octopamine revealed the presence of a sodium sensitive and a sodium insensitive component which was linear up to 10.54 μM. The sodium sensitive component showed at least one component that was fully saturated at 1.54 μM octopamine, possessed a K m of approximately 4 × 10 −7 M and a V max of 15.5 mM/10 ventral nerve cord ganglia/min. 3. Release of preloaded 3H-octopamine from ventral nerve cords was by a calcium-dependent process. A high-potassium-induced calcium-dependent release was also demonstrated. 4. Hydroxymandelic acid production was decreased in the presence of iproniazid phosphate suggesting the presence of a monoamine oxidase. 5. The synthesis, release, reuptake and metabolism of octopamine are discussed in the light of octopamine as a central transmitter in the leech.

Metabolism of the hallucinogen N, N-dimethyltryptamine in rat brain homogenates

The metabolism of the hallucinogen N, N-dimethyltryptamine (DMT) in whole rat brain homogenate is reported. Studies were conducted using tritiated DMT and DMT- N-oxide (DMT-NO), and metabolites were identified and quantified using thin-layer chromatography and liquid scintillation counting techniques. Metabolite confirmation was obtained by incubation of α,α,β,β-tetradeutero-DMT (DDMT) with whole brain homogenate followed by combined gas chromatographic/mass spectrometric analyses. The metabolites of DMT were identified as indoleacetic acid (IAA), DMT-NO, N-methyltryptamine (NMT), 2-methyl-1,2,3,4-tetrahydro-β-carboline (2-MTHBC), tryptamine (TA) and 1,2,3,4- tetrahydro-β-carboline (THBC). DMT-NO was metabolized to give DMT, NMT, IAA and 2-MTHBC. Formation of these metabolites from DMT-NO was stimulated by anaerobic incubation. Mechanisms for the formation of β-carbolines from DMT and DMT-NO are discussed. The effects of the monamine oxidase inhibitor iproniazid phosphate on DMT metabolism were also studied. Iproniazid inhibited the formation of IAA from DMT by 83 per cent. However, the formation of NMT and DMT-NO was inhibited by 90 per cent under these conditions. Thus, the reported extension of half-life and potentiation of DMT behavioral effects by iproniazid may be due to inhibition of NMT and DMT-NO formation rather than inhibition of monoamine oxidase. A cyclic pathway for the synthesis and metabolism of DMT in brain tissue is proposed.

Octopamine in leeches—I. Distribution of octopamine in Macrobdella decora and Erpobdella octoculata

1. The nervous and other tissues of the leeches M. decora and E. octoculata were asayed for octopamine using a radiochemical-enzymatic technique. 2. Octopamine was found at mean concentrations of 12–40 ng/mg tissue protein in the ganglionated nervous tissue; lesser amounts of 7.4–19 ng/mg tissue protein were observed in the non-ganglionated nervous tissue. 3. The lowest levels of octopamine, from not detected to a mean of ∼ 3.7 ng/mg tissue protein, were found in the non-nervous tissues. The blood contained a mean octopamine concentration of 1.96 × 10 −6 M. 4. Injections of p-chlorophenylalanine and iproniazid phosphate resulted in a significant increase in the concentration of octopamine in the ventral nerve cord of both M. decora and E. octoculata: Furasic acid and reserpine resulted in a significant depletion.

Induction of hypertrehalosemia by excitation in Periplaneta americana

An excitation-induced hypertrehalosemic (EXIT) response has been demostrated in the American cockroach, Periplaneta americana. The response occurs in normal insects and in insects that were ligated at the neck 24 hr prior to experimentation. Several known and putative insect neurotransmitters were tested for their ability to elicit rapidly a hypertrehalosemic state in the cockroach. Octopamine was the most effective hypertrehalosemic agent, and produced a 100% increase in haemolymph trehalose levels within 15 min of being injected into the haemocoel. Less pronounced hypertrehalosemic responses were obtained with dopamine and tyramine, but not with synephrine or 5-hydroxytryptamine. Hypertrehalosemia was observed also with normetanephrine, but not with isoproterenol. A slight inhibition of the EXIT response occurred with the β-blocking agents, propranolol and dichloroisoproterenol, but the monoamine oxidase inhibitors, iproniazid phosphate and nialamide, were without effect. It is suggested that the EXIT-response may be one of several octopamine-mediated responses to excitation in the insect.

Experience and correlation of bacterial mutagenic tests

This chapter discusses the iproniazid phosphate. The discovery of iproniazid constitutes a notable case of serendipity of great importance in the chemotherapy of mental diseases. Its trade name is marsilid and euphazid. Its molecular weight is 277.22. It is white to slightly yellowish powder. Its melting range is 175-184°C. The excitation, fluorescence and phosphorescence characteristics of iproniazid phosphate have been studied in ethanol at 77K. Thermogravimetry can be used to determine moisture or residual solvents in ipronfazid phosphate. The beneficial effects of iproniazid phosphate are: development of euphoria, relief of pain, overcoming anorexie, weight again in dobiliteted patients, temperature reduction, wound healing, marked control of tuberculosis in bones and joints in addition to decalcification of osseous structure without weakness.

Pharmacological induction of ovulation in old and neonatally androgenized rats

Pharmacological manipulations previously reported to induce ovulation in aged female rats were administered to females sterilized by neonatal androgen. L-DOPA or iproniazid phosphate were found to induce ovulation in some females which had received 5 μg testosterone propionate (TP) at 5 days of age but not in females exposed to higher dosages of TP. A second experiment directly compared the effectiveness of progesterone as well as L-DOPA and iproniazid phosphate to induce ovulation in aged and androgenized females. While the effects are similar, it appears that the aged female is more responsive to these treatments than the young female exposed to 5 μg TP neonatally. It is concluded that age related changes in reproductive physiology might be accounted for by changes in the activity of brain monoamines or brain steroid receptor mechanisms or both. The neonatally androgenized female would appear to be a useful preparation for the study of age-related changes in reproductive function.

Catabolism of tryptamine by cockroach head enzyme preparation

An enzyme preparation from the homogenate of American cockroach heads [ Periplaneta americana (L.)] converted tryptamine hydrochloride to a toluene-extractable material. Optimum conditions for the reaction were obtained with 0.3 M sodium phosphate buffer, pH 6.6, at 30°C. The enzyme was very unstable. Its activity was scarcely inhibited by such typical monoamine oxidase inhibitors as iproniazid phosphate and tranylcypromine hydrochloride. Enzyme activity was not affected by the addition of NADPH 2, but was accelerated by acetyl coenzyme A or coenzyme A. A main product of the enzymic reaction was isolated and identified as N-acetyltryptamine by chromatography and spectroscopic analyses, which suggests that the enzyme is a kind of N-acetyltransferase.