Transcellular transport characteristics of huperzine alone or in combination with ginkgolide B across Caco-2 and Madin-Darby canine kidney cell monolayer

Objective:To study the various processes involved in transcellular transport(TT) of huperzine A alone or in combination with ginkgolide B in Caco-2 and Madin-Darby canine renal(MDCK)cell monolayer.Methods:The transepithelial passage was assayed in the apical-to-basolateral(AP to BL) direction and opposite direction(BL to AP) in both cell lines.The determination of huperzine A and ginkgolide B were performed by high performance liquid chromatography(HPLC).The passage rates of huperzine A and ginkgolide B were calculated.Bi-directional TT(absorption and secretion) were taken in huperzine A and ginkgolide B in Caco-2 and MDCK cell monolayer.Results:TT absorption and secretion kinetics of huperzine A and ginkgolide B across two cells existed at the same time.The passage rates of huperzine A were increased significantly with adding different concentrations of ginkgolide B.Conclusions:The compound preparations of HA in combination with CB for dementia caused by cerebral ischemic have synergistic effects on the pharmacodynamics,and improve the bioavailability through BBB.

Pharmacokinetics and Tolerability of Oral Dosage Forms of Huperzine A in Healthy Chinese Male Volunteers: a Randomized,Single Dose, Three-period, Six-sequence Crossover Study

Huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations with the established reference formulation of huperzine A in a fasting, healthy Chinese male population. This was a randomized, single-dose, 3-period, 6-sequence crossover study. The plasma concentrations of huperzine A were determined by liquid chromatography tandem mass spectrometry. Tolerability was assessed based on subject interview, vital sign monitoring, physical examination, and routine blood and urine tests. The mean（SD） pharmacokinetic parameters of the reference drug were Cmax, 1.550（0.528） ng/m L; t1/2, 12.092（1.898） h; AUC0-72 h, 17.550（3.794） ng·h/m L. Those of the test formulation A and test formulation B were Cmax, 1.412（0.467）, 1.521（0.608） ng/m L; t1/2, 12.073（2.068）, 12.271（1.678） h; AUC0-72 h, 15.286（3.434） ng·h/mL, 15.673（3.586） ng·h/m L. The 90% confidence intervals for the AUC0-72 h and Cmax were between 0.80 and 1.25. No adverse events were reported by the subjects or found with results of clinical laboratory test. The test and reference products met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. All three formulations appeared to be well tolerated.

SYNTHESIS OF ANALOGUES OF HUPERZINE A

A new Lycopodium alkaloid huperzine A (1) possesses a potent inhibitory activity of acetylcholinesterase. Six structurally simplified analogues of huperzine A, compound 6, 7, 8, 12, 13 and 15, were prepared and the inhibitory activities were evaluated.

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

Huperzine A(Hup-A) is a poorly water-soluble drug with low oral bioavailability. A selfmicroemulsifying drug delivery system(SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion(SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve(AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension(P <0.01).The absorption rate constant(K_a) and the apparent permeability coefficient(P_(app)) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of K_a and P_(app) of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration(C_(max)) of the blocking model were significantly lower than those of the control model(P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%,respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

A new approach to the bicyclo[3.3.1]nonane framework of huperzine A-like molecules via palladium-catalyzed intramolecular γ-arylation

In our synthetic studies toward huperzine A, a diastereoselective α＇-alkylation of the α-amido-γ-methyl hexenone 4 was real- ized through a dianion intermediate which significantly enhanced the reactivity. Under the attempted Heck reaction conditions, an unexpected and unprecedented palladium-catalyzed intramolecular T-arylation of 3 was observed, which generated 18 with bicyclo[3.3, l]nonane framework in satisfactory yield.

Huperzine V,A New Lycopodium Alkaloid from Huperzia serrata

Huperzine V, a new Lycopodium alkaloid, was isolated from the whole plant of Huperzia serrata, and the absolute stereochemistry was determined by X-ray crystallographic analysis.

Huperzine W,a Novel 14 Carbons Lycopodium Alkaloid from Huperzia serrata

Huperzine W, a novel 14 carbons Lycopodium alkaloid, was isolated from the whole plant of Huperzia serrata, and its stucture was determined by spectroscopic analysis.

Huperzine H, a New Lycopodium Alkaloid from Huperzia serrata

A new lycopodium alkaloid with a novel skeleton was isolated from Huperzia serrata. Its structure was determined on the basis of spectral evidences.

IR spectrum and normal mode analysis of the antiAlzheimer's disease natural product Huperzine A: A quantum chemistry density-functional theory (DFT) investigation

Quantum chemistry density-functional theory (DFT)B3LYP method with 6-31G+* basis set has been empolyed to study the electronic structure and IR spectrum of Huperzine A. The calculation result showed that the characteristic of the predicted IR bands was in general consistent with the experimental spectrum. 45 vibration modes were assigned clearly from the total of 102 vibration bands. The strongest IR-intensive band corresponds to the stretching vibration of the C O bond of the pyridone ring, and the highest frequency band belongs to the pyridone N H stretch. The investigation showed that the obvious differences between the calculated bands and the experimental spectrum existed at the bands involving the hydrogen atoms of amino and pyridone amide groups, which could form intermolecular hydrogen bond with other Huperzine A in the crystal structure. The hydrogen bonds can not only affect the orientation of these hydrogen atoms, but also can affect the force property of the chemical bond, which can change the vibrational frequencies.

SYNTHESIS OF ANALOGUES OF HUPERZINE A 2． The Preparation of Some Analogues with Huperzine A Skeleton

Huperzine A (1), a new Lycopodium alkaloid isolated from Chinese traditional medicine Huperzia Serrata, is a potent acetylcholinesterase inhibitor and a promising drug candidate of treating Alzheimer's disease as well. Several analogues of huperzine A, compound 8, 10, 14, 15 and 17were prepared and their inhibitory activities of acetylcholinesterase were evaluated

One-step synthesis of Lycopodium alkaloid(-)-huperzine W via Suzuki-Miyaura coupling

The first total synthesis of(-)-huperzine W(1)has been achieved.Key element of the synthesis is a highly convergent assemblage for the two rings system of target molecule utilizing an efficient Suzuki-Miyaura coupling reaction between chiral iodide 2 and 2-allylpyrrolidinone 4.Evaluation of the AchE inhibition of synthetic huperzine W was also carried out.

Eleutheroside B or E enhances learning and memory in experimentally aged rats

Eleutheroside B or E, the main component of Acanthopanax, can relieve fatigue, enhance memory, and improve human cognition. Numerous studies have confirmed that high doses of acetylcholine significantly attenuate clinical symptoms and delay the progression of Alzheimer＇s disease. The present study replicated a rat model of aging induced by injecting quinolinic acid into the hippocampal CA1 region. These rats were intraperitoneally injected with low, medium and high doses of eleutheroside B or E （50, 100, 200 mg/kg）, and rats injected with Huperzine A or PBS were used as controls. At 4 weeks after administration, behavioral tests showed that the escape latencies and errors in searching for the platform in a Morris water maze were dose-dependently reduced in rats treated with medium and high-dose eleutheroside B or E. Hematoxylin-eosin staining showed that the number of surviving hippocampal neurons was greater and pathological injury was milder in three eleutheroside B or E groups compared with model group. Hippocampal homogenates showed enhanced cholinesterase activity, and dose-dependent increases in acetylcholine content and decreases in choline content following eleutheroside B or E treatment, similar to those seen in the Huperzine A group. These findings indicate that eleutheroside B or E improves learning and memory in aged rats. These effects of eleutheroside B or E may be mediated by activation of cholinesterase or enhanced reuse of choline to accelerate the synthesis of acetylcholine in hippocampal neurons.

Steered molecular dynamics simulations of protein-ligand interactions

Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.

热带石松科植物中石杉碱甲的含量差异(英文)

(-) Huperzine A is a bioactive alkaloid from Huperzia serrata (Lycopodiaceae) used for the treatment of Alzheimer's disease. High yielding (-) huperzine A species is of interest for mass propagation since it grows slowly in temperate countries. The content of (-) huperzine A from temperate countries was reported but none reported from tropical species. The aim of this study was to evaluate the content of (-) huperzine A from tropical club mosses and further identify a high yielding species. Club mosses from Lycopodiaceae family were collected from Peninsular Malaysia. The collected club mosses were dried, pulverized and extracted with methanol. A gradient reverse phase HPLC-photodiode array detector method with increasing amount of methanol in 0.01 % trifluoroacetic acid was developed. The calibration curve was linear from 5 to 100 g·mL-1 with correlation coefficient, r2, of 0.998 1. The precision for both intra-and inter-day peak area were between 0.48% to 1.24 % and 0.95% to 3.85 %, respectively. The recovery of the method was between 99.8% to 103.8 %. Though geographically segregated, (-) huperzine A content in Huperzia phlegmaria and H.carinata found in the tropics was highest and similar to species in Australasia. Both species may provide a good source of (-) huperzine A.