Harmine Research Articles

Simultaneous determination of harmine, harmaline and their metabolites harmol and harmalol in beagle dog plasma by UPLC–ESI-MS/MS and its application to a pharmacokinetic study

Harmine (HAR) and harmaline (HAL) were metabolized by demethylation to form harmol (HOL) and harmalol (HAM) both in vivo and in vitro. It has been demonstrated tremendous value of HAR, HAL and their metabolites in the therapy of Alzheimer's disease. A rapid, selective and sensitive UPLC–ESI-MS/MS method was firstly developed and validated for the simultaneous determination of HAR, HAL, HOL, and HAM in beagle dog plasma with 9-aminoacridine as the internal standard (IS). After protein precipitation with acetonitrile, the analytes were separated within 4.5min on an ACQUITY UPLC BEH C18 column with a gradient elution system composed of 0.1% formic acid and acetonitrile at a flow rate of 0.4ml/min. Detection was performed using multiple reactions monitoring mode under a positive ionization condition. The calibration curves of four analytes showed good linearity (r2>0.9959) within the tested concentration ranges. The low limit of quantification for HAR, HAL, HOL, and HAM were all 1.00ng/ml. The mean accuracy of the analytes was within the range of 94.56–112.23%, the R.S.D. values of intra-day and the inter-day precision were less than 6.26% and 7.51%, respectively. Matrix effects and extraction recoveries of the analytes from the beagle dog plasma were within the range of 94.48–105.77% and 89.07–101.44%, respectively. The validated method was successfully applied to a pharmacokinetic study of HAR, HAL, HOL, and HAM in beagle dogs after intravenous administration of HAR and HAL both of 1.0mg/kg. The main pharmacokinetic parameters of Cmax, Vd, CL, AUC and MRT, except Ke and t1/2 values, showed significant difference between the two parent drug HAR and HAL, respectively (p<0.05–0.001). Because of the different metabolic rate of HAR and HAL in vivo, the two metabolites, HOL and HAM, exhibited unique pharmacokinetic properties.

Application of the central composite design to optimize the preparation of novel micelles of harmine

Lactose–palmitoyl–trimethyl–chitosan (Lac-TPCS), a novel amphipathic self-assembled polymer, was synthesized for administration of insoluble drugs to reduce their adverse effects. The central composite design was used to study the preparation technique of harmine (HM)-loaded self-assembled micelles based on Lac-TPCS (Lac-TPCS/HM). Three preparation methods and single factors were screened, including solvent type, HM amount, hydration volume, and temperature. The optimal preparation technique was identified after investigating the influence of two independent factors, namely, HM amount and hydration volume, on four indexes, ie, encapsulation efficiency (EE), drug-loading amount (LD), particle size, and polydispersity index (PDI). Analysis of variance showed a high coefficient of determination of 0.916 to 0.994, thus ensuring a satisfactory adjustment of the predicted prescription. The maximum predicted values of the optimal prescription were 91.62%, 14.20%, 183.3 nm, and 0.214 for EE, LD, size, and PDI, respectively, when HM amount was 1.8 mg and hydration volume was 9.6 mL. HM-loaded micelles were successfully characterized by Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and a fluorescence-quenching experiment. Sustained release of Lac-TPCS/HM reached 65.3% in 72 hours at pH 7.4, while free HM released about 99.7% under the same conditions.

New insights into the photo-tautomerisation process in β-carboline derivatives revealed by NMR spectroscopy

In this work, we present a spectroscopic study of the interactions of harmine (HI), 2-methylharmine (2MHI) and harmaline (HLINE) with acetic acid (AcOH) in low polarity media, such as 1,4-dioxane and chloroform. UV-Vis absorption, fluorescence spectroscopy and 1H NMR measurements show that, in all cases, a complex between these β-carboline derivatives (BCD) and acetic acid is formed. In addition, this complex exists in two different tautomeric forms in solution, depending on the concentration of acetic acid. The NMR data also indicates that electronic charge transfer takes place differently, depending on which tautomer (T1 or T2) is the most stable. Thus, when T1 is the most stable tautomer species, charge transfer induced by hydrogen bond interactions takes place from the pyrrole to the pyridine ring; however, for T2, the charge transfer occurs in reverse. We have also shown that loss of aromaticity in the pyridine ring strongly increases the acidity of the NH group of the pyrrolic ring of these derivatives.

Effect of harmine and harmaline hydrochloride on pregnancy in white rats.

Summary The effect of a harmine: harmaline 2:1 mixture on early and late pregnancy was studied in rats by assessing the abortifacient action of this alka-loidal preparation in animals injected subcutaneously with one-tenth of the LD 50 of the preparation daily for five successive days. The possible causes of foetal death are discussed. Zusammenfassung Die Wirkung von Harmin und Harmalin-Hydrochlorid auf der Graviditat weiser Ratten Der abortive Effekt einer Mischung von Harmin und Harmalin im Verhaltnis 2:1 bei kurz- und langtrachtigen Ratten wurde untersucht. Das Pflanzenalkaloid wurde wahrend funf aufeinander folgenden Tagen in einer Dosis von je 1/10 des LD 50 subkutan injiziert. Die Ursachen des Fruchttodes werden besprochen. Resume Effet de l'hydrochlorure d'harmine et d'harmaline sur la gestation chez des rats blancs On etudie l'effet d'un melange d'harmine: harmaline 2:1 sur le debut et la fin de la gestation chez des rats. On determine l'action abortive de ces alcaloides chez des animaux injectes par voie sous-cutanee, chaque jour, pendant 5 jours successifs, avec la preparation dosee a 1/10 de la LD50. On discute les causes possible de la mort foetale. Resumen Efecto de la harmina y clorhidrato de harmalina sobre la gestacion en ratas blancas Se estudio el efecto de la mezcla harmina: harmalina 2:1 sobre la gestacion temprana y avanzada en ratas, avaluando la accion abortiva de esta especialidad alcaloidea en los animales inyectados a diario por via subcutanea con la decima parte de la DL50 de la preparacion durante cinco dias consecutivos. Se discuten las causas posibles de la muerte fetal.

Involvement of GABAergic Systems and Benzodiazepine Receptors in the Jumping Behavior Induced by Harmine and Apomorphine in Rats

Harmine (HA) induces a jumping behavior in rats when the central dopaminergic function has been activated. Possible involvement of the GABAergic systems and the benzodiazepine receptors (BZA-R) in the jumping behavior induced by HA and apomorphine (APO) was investigated. Pretreatment with GABAergic agonists, muscimol (0.05-0.2 mg/kg) and diazepam (0.2-1.0 mg/kg), and antagonists, picrotoxin (0.1-0.5 mg/kg) and bicuculline (0.1-0.5 mg/kg), suppressed the jumping behavior in a dose-dependent manner in rats treated with HA (10 mg/ kg) and APO (2 mg/kg). After treatment with 2, 5 or 10 mg/kg of HA in combination with 2 mg/kg of APO, a decrease in 3H-diazepam binding to the brain regional membranes was observed in the corpus striatum (CS) in a dose-dependent manner, but not in the other brain regions. The decrease in the 3H-diazepam binding to the CS membranes was proportional to the increase in the HA levels in the CS, and the HA levels were correlated with the intensity of jumping behavior. Pretreatment with Ro 1 5-1788, an antagonist of BZA-R, suppressed the jumping behavior induced by HA and APO. These results indicated the involvement of the GABAergic systems in the jumping behavior and suggested that HA induced the jumping behavior partly as a result of interacting with the BZA-R.

Involvement of GABAergic systems and benzodiazepine receptors in the jumping behavior induced by harmine and apomorphine in rats.

Harmine (HA) induces a jumping behavior in rats when the central dopaminergic function has been activated. Possible involvement of the GABAergic systems and the benzodiazepine receptors (BZA-R) in the jumping behavior induced by HA and apomorphine (APO) was investigated. Pretreatment with GABAergic agonists, muscimol (0.05-0.2 mg/kg) and diazepam (0.2-1.0 mg/kg), and antagonists, picrotoxin (0.1-0.5 mg/kg) and bicuculline (0.1-0.5 mg/kg), suppressed the jumping behavior in a dose-dependent manner in rats treated with HA (10 mg/kg) and APO (2 mg/kg). After treatment with 2, 5 or 10 mg/kg of HA in combination with 2 mg/kg of APO, a decrease in 3H-diazepam binding to the brain regional membranes was observed in the corpus striatum (CS) in a dose-dependent manner, but not in the other brain regions. The decrease in the 3H-diazepam binding to the CS membranes was proportional to the increase in the HA levels in the CS, and the HA levels were correlated with the intensity of jumping behavior. Pretreatment with Ro 15-1788, an antagonist of BZA-R, suppressed the jumping behavior induced by HA and APO. These results indicated the involvement of the GABAergic systems in the jumping behavior and suggested that HA induced the jumping behavior partly as a result of interacting with the BZA-R.

The chemotherapy of derivatives of harmine and harmaline. II

Research Article| January 01 1934 The chemotherapy of derivatives of harmine and harmaline. II Charles Edward Coulthard Charles Edward Coulthard 1The Bacteriological Laboratory, Boots Pure Drug Co., Ltd., Nottingham Search for other works by this author on: This Site PubMed Google Scholar Biochem J (1934) 28 (1): 264–267. https://doi.org/10.1042/bj0280264 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Charles Edward Coulthard; The chemotherapy of derivatives of harmine and harmaline. II. Biochem J 1 January 1934; 28 (1): 264–267. doi: https://doi.org/10.1042/bj0280264 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1934 CAMBRIDGE UNIVERSITY PRESS1934 Article PDF first page preview Close Modal You do not currently have access to this content.

The chemotherapy of derivatives of harmine and harmaline. I

The chemotherapy of derivatives of harmine and harmaline. I

CCCXCVI.—Harmine and harmaline. Part X. The synthesis of 7- and 8-methoxyketotetrahydro-β-carbolines and the constitution of acetylharmaline

CCCXCVI.—Harmine and harmaline. Part X. The synthesis of 7- and 8-methoxyketotetrahydro-β-carbolines and the constitution of acetylharmaline

I.—Harmine and harmaline. Part IX. A synthesis of harmaline

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LXXVII.—Harmine and harmaline. Part VIII. The constitution of certain harmaline derivatives

LXXVII.—Harmine and harmaline. Part VIII. The constitution of certain harmaline derivatives

CCXXVI.—Harmine and harmaline. Part VI. The synthesis of N-methyltetrahydronorharmine and the constitution of harmaline and of the alkylated harmines

CCXXVI.—Harmine and harmaline. Part VI. The synthesis of N-methyltetrahydronorharmine and the constitution of harmaline and of the alkylated harmines

CLXXXV.—Harmine and harmaline. Part V. The synthesis of norharman

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LXXX.—Harmine and harmaline. Part IV

LXXX.—Harmine and harmaline. Part IV

CXC.—Harmine and harmaline. Part I

The first page of this article is displayed as the abstract.