DOCSLIB.ORG

Review of HPLC and LC-MS/MS Methods for Determination of ZT-1 and Its Active Metabolite, Huperzine a in Various Biological Matri

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Review of HPLC and LC-MS/MS Methods for Determination of ZT-1 and Its Active Metabolite, Huperzine a in Various Biological Matri A tica nal eu yt c ic a a m A r a c Suresh, Pharm Anal Acta 2016, 7:11 t h a P Pharmaceutica Analytica Acta DOI: 10.4172/2153-2435.1000521 ISSN: 2153-2435 Review Article Open Access Review of HPLC and LC-MS/MS Methods for Determination of ZT-1 and Its Active Metabolite, Huperzine A in Various Biological Matrices Suresh PS* Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Yeshwanthpur, Bangalore, India Abstract Huperzine A is an alkaloid isolated from Huperzia serrata. It belongs to anticholinesterase class and used for neurological conditions like Alzheimer’s disease. Huperzine A is the metabolite of ZT-1, which is also used for the treatment of memory disorders and inhibits the effect of enzyme and brings back sufficient levels of acetylcholine. This review provides an overview of various HPLC, LC-MS and LC-MS/MS methods for quantitation of Huperzine A alone or along with ZT-1 in different biological fluids (plasma, serum and blood). In addition, this review provides complete details on sample preparation, extraction recoveries, matrix effect, internal standard selection, selectivity optimization, chromatographic separations, mass spectrometric spectrometry and other detection techniques etc. Keywords: Huperzine A; ZT-1; HPLC; LC-MS/MS; Bioanalytical applicable conclusions; (b) Discussed details about sample preparation, methods; Spectrometry internal standard selection, matrix effect, chromatography and various detection systems. Tables 1 and 2 lists the complete information Introduction about the published methods on HPLC, LC-MS and LC-MS/MS on Huperzine A is a novel sesquiterpene alkaloid isolated from Huperzia Huperzine A and ZT-1. serrata [1,2] and it is also derived from other Huperzia species including Bioanalytical related discussion H. elmeri, H. carinat and H. aqualupian [3]. Huperzine A (CAS No.: 102518-79-6; Figure 1), chemically [(5R,9R,11E)-5-amino-1-ethyldiene- A bioanalytical method is useful tool for the quantification of 5,6,9,10-tetrahydro-7-methyl-5,9-methanocloocta-[B]-pyri-din-2(1H)- the drugs from the biological matrices (plasma, serum and blood). one] is a potent, selective and slow reversible Acetylcholinesterase Extraction methods play a crucial role for the estimation of drugs from (AChE) inhibitor [4,5], which has a mechanism of action similar to these matrices. A good bioanalytical method defined as it is free from donepezil, rivastigmine and galantamine. Huperzine A readily crosses other interference substances such as salts, proteins and phospholipids blood brain barrier and shows high specificity for AChE. By using X-ray except our analyte of interest. A proper bioanalytical method should be crystallography it was confirmed that the complexity of huperzine A free from endogenous substances like salts, proteins and phospholipids etc. with AChE Crystal Structure of AChE complexed with huperzine A Sample preparation confirm the specificity of inhibitor [6]. The outcome of clinical trials showed that huperzine A capsule shows is efficient and safe to treat To eliminate endogenous components from the matrix, a better mild to moderate Alzheimer’s disease and also enhance the memory sample cleaning process is required. To obtain a better sensitivity and learning performance of adolescence students [7]. Huperzine A and reproducibility the biological matrix should be extracted with an has been approved in China for the treatment of Alzheimer’s disease organic solvent(s). For the extraction of huperzine A alone or along (in the form of immediate release tablets and capsules) and vascular with ZT-1 from the biological matrix most of the researchers have used dementia without any notable side effects [8-12]. It is being marketed as ethyl acetate alone [15-17,18-22] or mixture of other solvent(s) like a dietary supplement in USA [12]. Huperzine A is administered orally n-hexane:DCM:2-propanol and CHCl3:IPA combination [19,20,23-25] at a dose range of 0.2-0.4 mg/day for Alzheimer’s disease and 0.06-0.4 or ethyl acetate with isopropanol [20]. Apart from these methodologies mg/day (intramuscularly) for dementia. Following oral administration Pan et al. have adopted on-line column clean-up process to remove of 0.4 mg huperzine A tablets to healthy human volunteers peak plasma the endogenous components present in the biological sample(s), thus concentrations (Cmax: 2.59 ng/mL ± 0.37 ng/mL) achieved at around 1 h providing the interference free samples for analysis for the quantification (Tmax). The mean α and β half-life was is 21.13 min ± 7.28 min and 716 [16,17]. Li et al. have used single step liquid-liquid extraction of rat min ± 130 min, respectively [13]. blood samples with ethyl acetate and isopropanol mixture (containing internal standard) and vortex mixed, centrifuged, evaporated and ZT-1, N-[2-hydroxy-3-methoxy-5-chlorobenzilidene] huperzine A is a novel AChE inhibitor, which rapidly transformed non-enzymatically into its active metabolite huperzine A. The dual mode of action of ZT-1 as an N-methyl-D-aspartate (NMDA) receptor antagonist and an AChE *Corresponding author: Suresh PS, Sr. Research Scientist, Drug Metabolism inhibitor, positions it as a third generation anti-Alzheimer’s product by and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore-560022, India, Tel: 080666 28400; E-mail: [email protected] improving the general condition and cognitive functions of affected patients as well as having the potential of being a neuroprotectant [14]. Received October 27, 2016; Accepted November 18, 2016; Published November 21, 2016 Scope Citation: Suresh PS (2016) Review of HPLC and LC-MS/MS Methods for Determi- nation of ZT-1 and Its Active Metabolite, Huperzine A in Various Biological Matrices. The aim of this review is to provide: (a) A brief compilation of Pharm Anal Acta 7: 521. doi: 10.4172/2153-2435.1000521 various analytical methodologies on HPLC, LC-MS and LC-MS/MS for the analysis of huperzine A and ZT-1 in plasma and other biological Copyright: © 2016 Suresh PS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted fluids, which we have captured in a tabular format. It contains sample use, distribution, and reproduction in any medium, provided the original author and processing, chromatographic conditions, validation parameters and source are credited. Pharm Anal Acta, an open access journal ISSN: 2153-2435 Volume 7 • Issue 11 • 1000521 Citation: Suresh PS (2016) Review of HPLC and LC-MS/MS Methods for Determination of ZT-1 and Its Active Metabolite, Huperzine A in Various Biological Matrices. Pharm Anal Acta 7: 521. doi: 10.4172/2153-2435.1000521 Page 2 of 8 Analyte(s) Samples processing details Chromatographic conditions Validation parameters Applicable conclusions Reference Regression type: linear fit with weighing factor (1/x). Calibration range: 0.01-4.0 ng/mL. System: LC-ESI-MS/MS by MRM in Recovery: 85.2, 81.8, 85.7 and 89.2% positive mode. at LLOQC, LQC, MQC and HQC, respectively. Column: Zorbax SB-C18 (100 mm × 2.1 mm, 3.5 µm) maintained at 25oC. Matrix: 1 mL of human plasma. Selectivity: no endogenous interference at retention time of analyte and IS Extraction: To an aliquot of plasma, 20 µL Mobile phase: isocratic mixture evaluated from six different sources of of IS solution and 100 µL of 100 mM NaOH comprising 10 mM ammonium human blank plasma samples. The validated method were and vortexed briefly. To this 5 mL of acetate: MeOH: 0.1% formic acid successfully applied to PK ethyl acetate was added, vortex mixed for (18:82:0.1, v/v/v) at a flow rate of 0.2 Matrix effect: no significant matrix study to estimate plasma 3 min and centrifuged for 10 min at 4000 mL/min. Huperzine A effect was observed after analyzing five concentrations of huperzine [15] rpm. The supernatant was evaporated to different lots of human plasma. The % A in human volunteers (n=20) dryness under stream of nitrogen at 50oC. Injection volume: 20 µL. matrix effect was found to be 101.1- following oral administration The residue was reconstituted with 100 µL 110.6. of 0.1 mg tablet of mobile phase. Mass spectrometric detection: huperzine A: m/z 243.1 → 210.1 and Accuracy and precision: within- and Internal standard: Trimetazidine (0.1 µg/mL IS: m/z 267.2 → 166.0. between-day accuracy (% RE) ranged in MeOH) from -13.0 to 0.4 and -10.2-8.2%, Retention time: ~2.0 ± 0.2 min for respectively; whereas the within- and huperzine A and IS. between-day precision (% RSD) ranged from 3.78-9.22 and 7.35-11.57%, Total run time: ~3.0 min respectively. Stability: Stable under a battery of tests viz., room temperature (8 h), three F/T cycles and long term stability for 28 days at -20oC Regression type: linear fit with weighing factor (1/x). System: LC-ESI-MS/MS by positive Calibration range: 0.0508-5.08 ng/mL (r: mode. 0.9998). Recovery: 83.6 ± 2.5, 73.6 ± 1.0 and Column: Lichrospher C18 (150 mm × Matrix: 1 mL of human plasma. 4.6 mm, 5 µm) maintained at 25oC. 82.3 ± 3.9% at LQC, MQC and HQC, respectively. Extraction: To an aliquot of plasma, 20 µL Mobile phase: isocratic elution of IS solution and 100 µL of 0.1 mM NaOH Selectivity: No endogenous interference consists of MeOH:0.2% formic acid A sensitive method were added and vortexed briefly. To this at the retention time of analyte and IS. (85:15, v/v) at a flow rate of 0.7 mL/ was developed for the 5 mL of ethyl acetate was added, vortex min.
Load more

Recommended publications
  • Redox Signaling and Alzheimer's Disease
    Chen et al. Biomarker Research (2020) 8:42 https://doi.org/10.1186/s40364-020-00218-z REVIEW Open Access Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy Yuan-Yuan Chen1†, Min-Chang Wang2†, Yan-Ni Wang1, He-He Hu1, Qing-Quan Liu3*, Hai-Jing Liu4* and Ying-Yong Zhao1* Abstract Aging and average life expectancy have been increasing at a rapid rate, while there is an exponential risk to suffer from brain-related frailties and neurodegenerative diseases as the population ages. Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide with a projected expectation to blossom into the major challenge in elders and the cases are forecasted to increase about 3-fold in the next 40 years. Considering the etiological factors of AD are too complex to be completely understood, there is almost no effective cure to date, suggesting deeper pathomechanism insights are urgently needed. Metabolites are able to reflect the dynamic processes that are in progress or have happened, and metabolomic may therefore provide a more cost-effective and productive route to disease intervention, especially in the arena for pathomechanism exploration and new biomarker identification. In this review, we primarily focused on how redox signaling was involved in AD-related pathologies and the association between redox signaling and altered metabolic pathways. Moreover, we also expatiated the main redox signaling-associated mechanisms and their cross-talk that may be amenable to mechanism-based therapies. Five natural products with promising efficacy on AD inhibition and the benefit of AD intervention on its complications were highlighted as well.
    [Show full text]
  • Healthy Aging: Antioxidants, Adaptogens & Cognition
    Healthy Aging: Antioxidants, Adaptogens & Cognition Karen Butler Michael Altman, CN, RH (AHG) Kieron Edwards, Ph.D. Senior Editor Herbalist Nutritionist Chief Scientific Officer Informa Markets Anthocyanins International LLC Sibelius Natural Products (SeattleCancerCareAlternatives.com) David Heber, M.D., Ph.D., FACP, FASN Katie Stage, N.D., RH (AHG) Professor Emeritus and Founding Director, Therapeutics Division Director UCLA Center for Associate Professor, Southwest Human Nutrition College of Naturopathic Medicine (SCNM) Booth #5310 Towards healthy aging Kieron Edwards PhD MBA www.sibeliusnaturalproducts.com OCTOBER 2019 1 Talk outline Booth #5310 . The trends and challenges of aging . What occurs during aging? . Theories, effects, and pathways of aging . Supporting healthy aging 2 Aging: The monster at the end of the Booth #5310 book 3 The trends and challenges of aging Booth #5310 4 What is aging? Booth #5310 . Ageing results from the impact of the accumulation of a wide variety of molecular and cellular damage over time. This leads to a gradual decrease in physical and mental capacity, a growing risk of disease, and ultimately, death. But these changes are neither linear nor consistent, and they are only loosely associated with a person’s age in years (WHO) 5 Age-related changes to health Booth #5310 . Physical aging . Sensory loss, body composition changes, osteoarthritis . Cognitive aging . Immune aging . Immunosenecence, inflammation . Cardiovascular health . CVD is still the leading cause of death in older adults . Metabolic health . Cancer . Second leading cause of death in older adults 6 Living longer and better? Booth #5310 . Human lifespan is increasing . Almost 2 years increase per decade . Age is a major risk-factor in many human diseases and conditions .
    [Show full text]
  • Smart Drugs: a Review
    International Journal for Innovation Education and Research www.ijier.net Vol:-8 No-11, 2020 Smart Drugs: A Review Sahjesh Soni, Dr Rashmi Srivastava, Ayush Bhandari Mumbai Educational Trust, India Abstracts Smart drugs can change the way our mind functions. Smart drugs are also known as nootropics, which literally means the ability to bend or shape our mind. Smart drugs are classified into two main categories. They are classified based on their pharmacological action and their availability. The stimulant category of drugs is highly used and misused. There has been a rampant increase in the sale of smart drugs, which could be attributed to the rise in competition all over the world. Two major criteria for selecting a good drug are its mechanism of action and bioavailability. Owing to the short-term benefits of smart drugs, many countries have openly accepted this concept. There is still no concrete scientific evidence backing the safety and efficacy of these drugs. Some believe that this is just a fad that will soon pass, while others believe that this is something that will revolutionize our future. Key Words: Smart drugs, Nootropics, Cognitive enhancers, Stimulants, Uses and Side effects. What are Smart Drugs? "Smart drugs" are a group of compounds that can promote brain performance. They have got a lot of attention due to our stressful lifestyle, and these drugs help to boost our memory, focus, creativity, intelligence, and motivation. The origin of the word comes from the Greek language meaning “to bend or shape the mind”.1 These chemicals have many mechanisms of action.
    [Show full text]
  • Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders
    Int. J. Biol. Sci. 2018, Vol. 14 341 Ivyspring International Publisher International Journal of Biological Sciences 2018; 14(3): 341-357. doi: 10.7150/ijbs.23247 Review Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders Ghulam Hussain1,3, Azhar Rasul4,5, Haseeb Anwar3, Nimra Aziz3, Aroona Razzaq3, Wei Wei1,2, Muhammad Ali4, Jiang Li2, Xiaomeng Li1 1. The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China 2. Dental Hospital, Jilin University, Changchun 130021, China 3. Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, 38000 Pakistan 4. Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, 38000 Pakistan 5. Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science. 2-1 Hirosawa, Wako, Saitama 351-0198 Japan Corresponding authors: Professor Xiaomeng Li, The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, 5268 People's Street, Changchun, Jilin 130024, P.R. China. E-mail: [email protected] Tel: +86 186 86531019; Fax: +86 431 85579335 or Professor Jiang Li, Department of Prosthodontics, Dental Hospital, Jilin University, 1500 Tsinghua Road, Changchun, Jilin 130021, P.R. China. E-mail: [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2017.10.09; Accepted: 2017.12.18; Published: 2018.03.09 Abstract Neurodegenerative diseases are conventionally demarcated as disorders with selective loss of neurons.
    [Show full text]
  • Neuroprotective Effect of Cannabidiol, a Non-Psychoactive Component from Cannabis Sativa, on Β-Amyloid-Induced Toxicity in PC12
    Journal of Neurochemistry, 2004, 89, 134–141 doi:10.1111/j.1471-4159.2003.02327.x Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa,onb-amyloid-induced toxicity in PC12 cells Teresa Iuvone, Giuseppe Esposito, Ramona Esposito, Rita Santamaria, Massimo Di Rosa and Angelo A. Izzo Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy )7 )4 Abstract Treatment of the cells with cannabidiol (10 )10 M) prior to Alzheimer’s disease is widely held to be associated with oxi- b-amyloid peptide exposure significantly elevated cell survival dative stress due, in part, to the membrane action of b-amyloid while it decreased ROS production, lipid peroxidation, peptide aggregates. Here, we studied the effect of cannabi- caspase 3 levels, DNA fragmentation and intracellular cal- diol, a major non-psychoactive component of the marijuana cium. Our results indicate that cannabidiol exerts a combina- plant (Cannabis sativa)onb-amyloid peptide-induced toxicity tion of neuroprotective, anti-oxidative and anti-apoptotic in cultured rat pheocromocytoma PC12 cells. Following effects against b-amyloid peptide toxicity, and that inhibition exposure of cells to b-amyloid peptide (1 lg/mL), a marked of caspase 3 appearance from its inactive precursor, reduction in cell survival was observed. This effect was pro-caspase 3, by cannabidiol is involved in the signalling associated with increased reactive oxygen species (ROS) pathway for this neuroprotection. production and lipid peroxidation, as well as caspase 3 (a key Keywords: Alzheimer’s disease, apoptosis, b-amyloid, enzyme in the apoptosis cell-signalling cascade) appearance, cannabidiol, cannabinoid, neuroprotection. DNA fragmentation and increased intracellular calcium.
    [Show full text]
  • Treating Senile Dementia with Traditional Chinese Medicine
    REVIEW Treating senile dementia with traditional Chinese medicine Han Yan1 Abstract: Senile dementia is a syndrome in the elderly involving defi cits in memory and Lin Li2 cognition. There has been a long history of research and medical practice in dementia in China, Xi Can Tang1 during which the ancient Chinese people have formed a whole theory and accumulated abundant experience in the treatment of dementia. During recent decades, with new theories and tech- 1State Key Laboratory of Drug Research, Shanghai Institute of nologies being digested and integrated, progress has been made in the medical and pharmacy Materia Medica, Chinese Academy research on senile dementia in China. In this review, we will focus on the traditional opinion, of Sciences, Shanghai, China; clinical practice, and recent progress in pharmacological research in China towards the treatment 2Unilever Research China, Shanghai, China of dementia. We also discuss the potential trends of global convergence. Keywords: senile dementia, Alzheimer’s disease, vascular dementia, traditional Chinese medicine The term “senile dementia” refers to a clinical syndrome seen in the elderly charac- terized by impairment of memory and cognition. With the dramatic improvement of average life expectancy and the fast increasing of the aged population in recent years, senile dementia has become a major problem of public health. Alzheimer’s disease (AD) is the most common type of dementia, which is a pro- gressive neurodegenerative disease and has become the third greatest threat to elderly, inferior only to cardiovascular disease and cancer. Since 1907, when German surgeon Alois Alzheimer reported the fi rst case of dementia that now bears his name, great efforts have been made in attempt to discover the pathology and remedy of AD.
    [Show full text]
  • Natural Product for the Treatment of Alzheimer's Disease
    J Basic Clin Physiol Pharmacol 2017; 28(5): 413–423 Review Thanh Tung Bui* and Thanh Hai Nguyen Natural product for the treatment of Alzheimer’s disease https://doi.org/10.1515/jbcpp-2016-0147 Received September 27, 2016; accepted May 28, 2017; previously Pathogenesis of Alzheimer’s disease published online July 14, 2017 Until now, the pathogenesis of AD is not yet completely Abstract: Alzheimer’s disease (AD) is related to increas- understood. The genetic susceptibility and environmental ing age. It is mainly characterized by progressive neu- factors are responsible for late onset sporadic AD, which rodegenerative disease, which damages memory and is the most common form of the disease. Many studies cognitive function. Natural products offer many options have attempted to understand the disease mechanism and to reduce the progress and symptoms of many kinds of develop a disease-modifying drug. Two main factors are diseases, including AD. Meanwhile, natural compound responsible for the development of AD: β-amyloid protein structures, including lignans, flavonoids, tannins, poly- and abnormal tau protein, or both of them. AD is charac- phenols, triterpenes, sterols, and alkaloids, have anti- teristized by the overproduction of β-amyloid proteins (Aβ) inflammatory, antioxidant, anti-amyloidogenic, and and hyperphosphorylated Tau protein, which can lead to anticholinesterase activities. In this review, we summa- the loss of synaptic connections and neurons in the hip- rize the pathogenesis and targets for treatment of AD. We pocampus and cerebral cortex, a decline in cognitive func- also present several medicinal plants and isolated com- tion, and dementia [2]. The accumulation of β-amyloid pounds that are used for preventing and reducing symp- protein and neurofibrillary tangles have been shown in toms of AD.
    [Show full text]
  • Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction
    pharmaceutics Review Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction Maria D. Auxtero 1, Susana Chalante 1,Mário R. Abade 1 , Rui Jorge 1,2,3 and Ana I. Fernandes 1,* 1 CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; [email protected] (M.D.A.); [email protected] (S.C.); [email protected] (M.R.A.); [email protected] (R.J.) 2 Polytechnic Institute of Santarém, School of Agriculture, Quinta do Galinheiro, 2001-904 Santarém, Portugal 3 CIEQV, Life Quality Research Centre, IPSantarém/IPLeiria, Avenida Dr. Mário Soares, 110, 2040-413 Rio Maior, Portugal * Correspondence: [email protected]; Tel.: +35-12-1294-6823 Abstract: Late-life mild cognitive impairment and dementia represent a significant burden on health- care systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treat- ment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmaco- logical interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration.
    [Show full text]
  • Huperzine for Use in the Treatment of Neuropathic
    (19) TZZ_Z_¥¥_T (11) EP 1 901 733 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/215 (2006.01) A61K 31/74 (2006.01) 06.04.2016 Bulletin 2016/14 A61K 9/20 (2006.01) (21) Application number: 06770999.8 (86) International application number: PCT/US2006/019985 (22) Date of filing: 23.05.2006 (87) International publication number: WO 2006/127748 (30.11.2006 Gazette 2006/48) (54) HUPERZINE FOR USE IN THE TREATMENT OF NEUROPATHIC PAIN HUPERZIN ZUR VERWENDUNG BEI DER BEHANDLUNG VON NEUROPATHISCHEN SCHMERZEN HUPERZINE POUR SON UTILISATION DANS LE TRAITEMENT DE LA DOULEUR NEUROPATHIQUE (84) Designated Contracting States: US-A1- 2004 214 863 US-A1- 2005 065 176 AT BE BG CH CY CZ DE DK EE ES FI FR GB GR US-A1- 2005 129 783 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR • GALEOTTI, NICOLETTA ET AL: "Antinociceptive profile of the natural cholinesterase inhibitor (30) Priority: 23.05.2005 US 683745 P huperzine A", DRUG DEVELOPMENT 04.01.2006 US 756141 P RESEARCH , 54(1), 19-26 CODEN: DDREDK; ISSN: 0272-4391, 2001, XP002632199, (43) Date of publication of application: • RAJENDRAN V ET AL: "Synthesis of more potent 26.03.2008 Bulletin 2008/13 analogues of the acetylcholinesterase inhibitor, huperzine B", BIOORGANIC AND MEDICINAL (73) Proprietor: President and Fellows of Harvard CHEMISTRY LETTERS, vol. 12, no. 11, 3 June College 2002 (2002-06-03), pages 1521-1523, Cambridge, MA 02138-3805 (US) XP002632200, ISSN: 0960-894X • DATABASECA [Online] CHEMICAL ABSTRACTS (72) Inventor: SCHACHTER, Steven, C.
    [Show full text]
  • Plants As Potential Sources for Drug Development Against Alzheimer's
    International Journal of Biomedical and Pharmaceutical Sciences ©2007 Global Science Books Plants as Potential Sources for Drug Development against Alzheimer’s Disease Keyvan Dastmalchi • H. J. Damien Dorman* • Heikki Vuorela • Raimo Hiltunen Faculty of Pharmacy, Division of Pharmaceutical Biology, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FIN-00014, Finland Corresponding author : * [email protected] ABSTRACT Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that primarily affects the elderly population and is considered to be responsible for ca. 60% of all dementia in people aged 65 or older. Due to its debilitating nature, an enormous social and economic burden is placed on society. The significance of AD is further compounded as the number of identified cases is estimated to double or triple by 2050. Currently there is no cure for the disorder and much of the treatments available have been able to only delay the progression of the disease or provide symptomatic relief for a short period of time. Therefore there is a need for a different approach to the treatment of these diseases. Plants have been used since antiquity in the treatment of various diseases including cognitive disorders, such as AD. Therefore ethnopharmacological screening of plants may provide useful leads in the discovery of new drugs for AD therapy. This article reviews screening of the plants, belonging to 21 families, used in traditional systems of medicine (e.g. Chinese, Indian and European) for treat- ment of cognitive dysfunction. Electronic data bases were used for searching information related to the studies done on the plants in the last 20 years.
    [Show full text]
  • Huperzine a - an Interesting Anticholinesterase Compound from the Chinese Herbal Medicine
    REVIEW ARTICLE HUPERZINE A - AN INTERESTING ANTICHOLINESTERASE COMPOUND FROM THE CHINESE HERBAL MEDICINE Jiří Patočka Purkyně Military Medical Academy, Hradec Králové; (Head: doc. MUDr. S. Bùma, CSc.) Summary: Huperzine A, alkaloid from the Chinese herbal medicine Qian Ceng Ta, which is prepared from the moss Huperzia serrata, has been used in China for centuries to treat fever and inflammation. Huperzine A is a strong inhibitor of cholinesterases with high selectivity to acetylcholinesterase and in China is developed as therapeutic against Alzheimer’s disease. May be that huperzine A will be better than other centrally active anticholinesterases in treating this neurodegenerative disorder. Huperzine A appears to have additional pharmacological properties that make it an attracti- ve candidate therapy for clinical trials. Key words: Huperzine A; Alkaloid; Inhibitor of Acetylcholinesterase; Alzheimer’s Disease; Treatment Introduction Biochemistry The alkaloid compound, huperzine A, was discovered Huperzine A is a potent reversible inhibitor of choline- in the Chinese herbal medicine called Qian Ceng Ta (14). sterases, i.e. acetylcholinesterase (AChE) and butyrylcholi- This traditional remedy, which is prepared from the moss nesterse (BuChE) with on- and off-rates that depend on Huperzia serrata, has been used in China for centuries to both the type and the source of enzyme. A low dissociation treat fever and inflammation. constants Ki was obtained for mammalian-AChE-huperzine A (20-40 nM) compared to mammalian BuChE-huperzine Chemistry A (20-40 µM) (1). This indicates that the thermodynamic stability of huperzine-cholinesterase complex may depend Huperzine A is an unsaturated sesquiterpenic com- on the number and type of aromatic amino acid residues in pound with pyridone moiety and primary amino group the catalytic pocket region of the enzyme molecule.
    [Show full text]
  • Acetylcholinesterase Inhibitors of Natural Origin
    ® International Journal of Biomedical and Pharmaceutical Sciences ©2009 Global Science Books Acetylcholinesterase Inhibitors of Natural Origin Melanie-Jayne R. Howes1* • Peter J. Houghton2 1 Royal Botanic Gardens, Jodrell Laboratory, Kew, Richmond, Surrey, United Kingdom 2 Department of Pharmacy, King's College London, Franklin-Wilkins Building, London, United Kingdom Corresponding author : * [email protected] ABSTRACT The endogenous neurotransmitter acetylcholine (ACh), found in vertebrates, stimulates cholinergic (muscarinic and nicotinic) receptors to mediate cholinergic neuronal transmission. ACh has a short half-life, as it is rapidly hydrolysed in the neuronal synaptic cleft by the enzyme acetylcholinesterase (AChE). Modulation of cholinergic function has been recognised as a therapeutic target in some disease states and one approach to achieve this is to prolong the action of ACh through the use of AChE inhibitors. Consequently, AChE inhibitors have been investigated for a number of therapeutic applications including glaucoma, myasthenia gravis, anti-muscarinic poisoning and dementia. Many inhibitors of AChE have been derived from natural sources, with alkaloids generally being the most potent, although other compounds including some terpenoids have also been shown to inhibit AChE. It is particularly interesting that of the four drugs currently licensed in Europe to alleviate cognitive symptoms in Alzheimer’s disease, two (galantamine and rivastigmine) are derived from natural sources. Natural products continue to be investigated
    [Show full text]