Components of convolvulin from <Emphasis Type="Italic">Quamoclit</Emphasis> × <Emphasis Type="Italic">multifida</Emphasis>

Alkaline hydrolysis of the ether-insoluble resin glycoside (convolvulin) fraction of the seeds of Quamoclit × multifida (syn. Q. sloteri House, Convolvulaceae), a hybrid between Q. pennat and Q. coccinea, gave three new glycosidic acids (maltifidinic acids C, D, and E) along with three known glycosidic acids (quamoclinic acids B, C, and D) and four organic acids (2S-methylbutyric, tiglic, 2R,3R-nilic, and 7S-hydroxydecanoic acids). The structures of the new glycosidic acids were characterized on the basis of spectroscopic data as well as chemical evidence.     

The interaction of host genetic factors and <Emphasis Type="Italic">Helicobacter</Emphasis> <Emphasis Type="Italic">pylori</Emphasis> infection

Helicobacter pylori plays an important role in the development of atrophic gastritis that represents the most recognized pathway in multistep gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of Helicobacter pylori infection. As to bacterial virulence factors, a high proportion of Japanese strains are cagA⁺vacAs1. The CagA protein is injected from attached Helicobacter pylori into gastric epithelial cells and the CagA-SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. Host cytokine gene polymorphisms and a frequent single nucleotide polymorphism in the PTPN11 gene that encodes SHP-2 may associate with gastric atrophy among Helicobacter pylori-infected subjects. Prevention of gastric cancer requires the development of better screening strategies for determining eradication candidates and further improvement of treatments of Helicobacter pylori infection. Received 6 August 2006; accepted 21 August 2006     

Synthesis and pharmacological properties of alkylammonium salts of <Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>′-malonyl-<Emphasis Type="Italic">bis</Emphasis>-<Emphasis Type="Italic">p</Emphasis>-aminobenzoic acid

A series of ammonium salts of N,N′-malonyl-bis-p-aminobenzoic acid with some alkylamines have been obtained. It is established that these compounds possess hypotensive, antiarrhythmic, and anticoagulative activities depending on the structure of the alkylamine constituents.     

Two new <Emphasis Type="Italic">β</Emphasis>-carboline alkaloids from the stems of <Emphasis Type="Italic">Picrasma quassioides</Emphasis>

Two new β-carboline alkaloids, 1-acetyl-4-methoxy-8-hydroxy-β-carboline (1) and 1-acetyl-4,8-dimethoxy-β-carboline (2), together with 10 known compounds; seven β-carboline alkaloids (3–9), two canthin-6-one alkaloids (10 and 11), and one quassinoid (12) were isolated from the stems of Picrasma quassioides. The structure of the new compounds 1 and 2 were determined by spectroscopic analyses including 1D- and 2D-NMR and HRMS interpretation. All the isolates (1–12) were evaluated for their cytotoxicity against human ovarian carcinoma A2780 and SKOV3 cell lines using MTT assays. Of the isolates, compounds 5–7 exhibited the most potent cytotoxicity on both A2780 and SKOV3 cell lines in vitro.     

<Emphasis Type="Italic">Buddlejol</Emphasis>, a new α-chymotrypsin inhibitor from <Emphasis Type="Italic">Buddleja asiatica</Emphasis>

Buddlejol (1), a new sterol, has been isolated from the ethyl acetate soluble fraction of the antispasmodic plant Buddleja asiatica along with stigmasterol (2), lignoceric acid (3), taraxerol (4) and α-amyrin (5), respectively. The structure of Buddlejol (1) was established as (24S)-stigmast-5,22-diene-7β-ethoxy-3β-ol by spectral analysis and comparison with closely related structures. Buddlejol revealed to be a competitive inhibitor of chymotrypsin with the Ki value of 10.60 µM as indicated by Lineweaver–Burk and Dixon plots and their re-plots against its chymotrypsin inhibition assay, while the other compounds showed less inhibitory potential. The bioassay-guided isolation was stimulated by the preliminary cytotoxic screening of various fractions of B. asiatica.     

β-secretase (BACE1) inhibitors from <Emphasis Type="Italic">Perilla frutescens</Emphasis> var. <Emphasis Type="Italic">acuta</Emphasis>

In the course of screening for anti-dementia agents from natural products, two β-secretase (BACE1) inhibitors were isolated from the methanolic extract of Perilla frutescens var. acuta and identified as luteolin (1) and rosmarinic acid (2) with IC₅₀ values of 5.0×10⁻⁷ M and 2.1×10⁻⁵ M, respectively. They inhibited BACE1 in a non-competitive manner with a substrate in Dixon plots, suggesting that they might bind to either β-secretase subsite or to another regulatory site. Ki values of 1 and 2 were 6.2×10⁻⁵ M and 3.9×10⁻⁵ M, respectively. They were less inhibitory against other enzymes such as α-secretase (TACE), acetylcholine esterase (AchE), chymotrypsin, and elastase, indicating that they were relatively specific inhibitors of BACE1.     

A glycerol α-<Emphasis Type="SmallCaps">d</Emphasis>-glucuronide and a megastigmane glycoside from the leaves of <Emphasis Type="Italic">Guettarda</Emphasis><Emphasis Type="Italic">speciosa</Emphasis> L.

From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Guettarda speciosa L., two new compounds (1, 2) were isolated together with six known compounds. Spectroscopic analysis of 1 and 2 established their structures to be derivatives of a glycerol α-glucuronide and a megastigmane glycoside, respectively. HPLC analysis of the hydrolyzate of 1 confirmed the presence of d-glucuronic acid in the structure, and the modified Mosher’s method established the absolute structure of 2.     

Structure–activity relationship study of secondary metabolites from <Emphasis Type="Italic">Mesua beccariana</Emphasis>, <Emphasis Type="Italic">Mesua ferrea</Emphasis> and <Emphasis Type="Italic">Mesua congestiflora</Emphasis> for anti-cholinesterase activity

Our search for potential anti-acetylcholinesterase (AChE) inhibitors for treatment of Alzheimer’s disease has led to the discovery of two bioactive compounds, α-mangostin (11) and congestiflorone acetate (13). This discovery was achieved from a preliminary screening of the anti-AChE activity on the extracts of three Mesua species namely M. ferrea, M. beccariana and M. congestiflora using Ellman’s method. The pure metabolites, 1–12 which were isolated from the Mesua species, along with a synthetic derivative, compound 13 were then evaluated for their activities in order to identify the compounds that correspond to the enzyme inhibitory activities. Compounds 11 and 13 were found to give significant anti-AChE activities with IC₅₀ values of 17.51 and 20.25 µM.     

Synthesis of novel <Emphasis Type="Italic">N</Emphasis>-acyl-<Emphasis Type="Italic">β</Emphasis>-<Emphasis Type="SmallCaps">d</Emphasis>-glucopyranosylamines and ureas as potential lead cytostatic agents

Novel classes of acetylated and fully deprotected N-acyl-β-d-glucopyranosylamines and ureas have been synthesized and biologically evaluated. Acylation of the per-O-acetylated β-d-glucopyranosylurea (5), easily prepared via its corresponding phosphinimine derivative, by zinc chloride catalyzed reaction of the corresponding acyl chlorides RCOCl (a–f) gave the protected N-acyl-β-d-glucopyranosylureas (6a–f), in acceptable-to-moderate yields. Subsequent deacetylation of analogues 6a–f under Zemplén conditions afforded the fully deprotected derivatives 7a,b,d,e,f, while the desired urea 7c was formed after treatment of 6c with dibutyltin oxide. All protected and unprotected compounds were examined for their cytotoxic activity in different L1210, CEM and HeLa tumor cell lines and were also evaluated against a broad panel of DΝΑ and RNA viruses. Derivative 7c exhibited cytostatic activity against the three evaluated tumor cell lines (IC₅₀ 9–24 μΜ) and might be the basis for the synthesis of structure-related derivatives with improved cytostatic potential. Only analogue 6f weakly but significantly inhibited the replication of parainfluenza-3 virus, Sindbis virus and Coxsackie virus B4 in cell cultures at concentrations of 45–58 μM.     

Comparison of the developmental effects of 5-methoxy-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-diisopropyltryptamine (Foxy) to (±)-3,4-methylenedioxymethamphetamine (ecstasy) in rats

Rationale  We have previously shown that (±)-3,4-methylenedioxymethamphetamine (MDMA) treatment from postnatal days (P)11 to P20 leads to learning and memory deficits when the animals are tested as adults. Recently, the club drug 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) has gained popularity. Objective  Due to the similarities between MDMA and 5-MeO-DIPT and the substitution of 5-MeO-DIPT for MDMA, the purpose of this study was to compare the developmental effects of these drugs. Methods  Within a litter, animals were treated from P11 to P20 with either MDMA, 5-MeO-DIPT, or saline. Results  MDMA-treated animals showed increased anxiety in a measure of defensive marble burying, as well as deficits in spatial and path integration learning. 5-MeO-DIPT-treated animals showed spatial learning deficits; however, there were no deficits observed in spatial memory or path integration learning. 5-MeO-DIPT-treated animals also showed hyperactivity in response to a challenge dose of methamphetamine. Conclusions  The results show that treatment with either 5-MeO-DIPT or MDMA during development results in cognitive deficits and other behavioral changes but the pattern of effects is distinct for each drug. Supported by NIH grants DA021394 (CV) and training grant T32 ES07051 (MRS, TLS).     

Side Effects of Interferon-<Emphasis Type="Italic">α</Emphasis> Therapy

Aim

Interferon-α (IFN-α) has been extensively explored for its efficacy in various disease conditions and is currently used as a standard treatment in several of these. Its use is accompanied by a wide variety of possible side effects. These side-effects may hamper reaching and maintaining the dose needed for maximal therapeutic effect while their occurrence can outweigh clinical benefit of IFN-α treatment. This review addresses the toxicity profile of IFN-α, the presumed pathophysiology of the different side effects and the strategies to handle these.

Methods

Computerized searches were used and cross-references of articles and books were checked.

Results

Adverse effects due to IFN-α have been described in almost every organ system. Many side-effects are clearly dose-dependent. Taken together, occurrence of flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue, and psychiatric sequelae are the most frequently encountered. Although insight in the mechanisms accounting for IFN-α-related toxicities has improved in recent years, much remains to be elucidated. Guidelines on the management of these untoward sequelae are mostly based on clinical experience, while many side-effects can only be adequately handled by dose adjustment or cessation of treatment.

Conclusion

Further research on the mechanisms underlying both therapeutic effects and adverse events is warranted. Hopefully, this will lead to better identification of those patients who are likely to benefit from treatment without experiencing severe toxicities.

     

Lignan and neolignan glucosides,and tachioside 2′-<Emphasis Type="Italic">O</Emphasis>-4″-<Emphasis Type="Italic">O</Emphasis>-methylgallate from the leaves of <Emphasis Type="Italic">Glochidion rubrum</Emphasis>

Thirteen compounds (1–13) were isolated from a MeOH extract of leaves of Glochidion rubrum. The structures of four new compounds were elucidated to be (−)-isolariciresinol 2a-O-β-d-glucopyranoside (1), (7R,8S)- and (7R,8R)-4,7,9,9′-tetrahydroxy-3,3′-dimethoxy-8-O-4′-neolignan 7-O-β-d-glucopyranosides (2 and 3, respectively), and tachioside 2′-O-4″-O-methylgallate (4) on detailed inspection of one- and two-dimensional NMR spectral data.     

<Emphasis Type="Italic">In Vitro</Emphasis> and<Emphasis Type="Italic">in vivo</Emphasis> studies on the complexes of vinpocetine with hydroxypropyl-β-cyclodextrin

The purpose of this study was to evaluate complexes of vinpocetine (VIN), a poorly water-soluble base type drug, with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous environment and in solid state, with or without citric acid (CA) as an acidifier of the complexation medium. The apparent stability constant (Kc) calculated by phase solubility was 282 M(-1) and the complexation in solution was structurally characterized by 1H-NMR which showed VIN was likely to fit into the cyclodextrin cavity with its phenyl ring and ethyl ester bond. Solid complexes of VIN and HP-beta-CD were prepared by kneading (KE), co-evaporating (CE) and freeze-drying (FD) methods. Physical mixtures were prepared for comparison. The study in the solid state included the differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and infrared absorption spectroscopy (IR). From these analyses, CE and FD products were found in amorphous state, allowing to the conclusion of strong evidences of inclusion complex formation. However, the dissolution test showed that only VIN/HP-beta-CD+CA complexes by CE and FD method could provide satisfying dissolution behavior (rapid, complete and lasting) when compared to that of VIN/HP-beta-CD complexes. Interestingly, the addition of CA in inclusion complexes could significantly decrease the amount of HP-beta-CD needed to solubilize the same amount of VIN and thereby reducing the formulation bulk. Furthermore, in-vivo study revealed that the bioavailability of VIN after oral administration to rabbits (n=6) was significantly improved by VIN/HP-beta-CD+CA inclusion complex.     

Poly(ε-caprolactone)-<Emphasis Type="Italic">Block</Emphasis>-poly(ethyl Ethylene Phosphate) Micelles for Brain-Targeting Drug Delivery: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Valuation

Purpose  

The purpose of this work was to investigate the potential of poly(ε-caprolactone)-block-poly(ethyl ethylene phosphate) (PCL-PEEP) micelles for brain-targeting drug delivery.     

Cocaine and heroin (‘speedball’) self-administration: the involvement of nucleus accumbens dopamine and <Emphasis Type="Italic">μ</Emphasis>-opiate,but not <Emphasis Type="Italic">δ</Emphasis>-opiate receptors

Rationale The combined administration of heroin and cocaine (speedball) is common among intravenous drug users. Dopamine receptors in the nucleus accumbens play a key role in cocaine self-administration; however, their role in speedball self-administration is unknown, as is the role of opiate receptors in this region.Objectives The effect of blocking dopamine D1, D2, -opiate or -opiate receptors in the nucleus accumbens on the intravenous self-administration of combined heroin and cocaine was examined in rats.Methods Rats with bilateral cannulae implanted into the nucleus accumbens were trained to self-administer intravenous speedball (ratio of cocaine/heroin, 17:1) under a progressive ratio (PR) schedule. Prior to their self-administration session, rats were then microinjected with the dopamine D1 receptor antagonist SCH 23390 (1 and 6 nmol side^–1), the D2 receptor antagonist raclopride (3 and 10 nmol side^–1), the -opiate receptor antagonist CTOP (0.1, 0.3 and 1.0 nmol side^–1), the -opiate receptor antagonist naltrindole (1.0, 3.0 and 10 nmol side^–1) or a cocktail of SCH 23390 (1 nmol side^–1) and CTOP (0.1 nmol side^–1) into the nucleus accumbens.Results Microinjection of SCH 23390, raclopride or CTOP into the nucleus accumbens produced dose-dependent decreases in breakpoints under the PR schedule, while naltrindole was without effect. The highest dose of SCH 23390 also significantly reduced locomotor activity measured during speedball self-administration. The combination of SCH 23390 and CTOP significantly reduced breakpoints, while not affecting locomotor activity.Conclusions These results indicate that dopamine and -opiate receptors, but not -opiate receptors, in the nucleus accumbens are involved in the reinforcing effects of speedball. Combined administration of D1 and -opiate receptor antagonists may be more selective at reducing the reinforcing effects of speedball self-administration than either drug alone.     

Standardization of extract mixture of <Emphasis Type="Italic">Chaenomeles sinensis</Emphasis> and <Emphasis Type="Italic">Phyllostachys bambusoides</Emphasis> for anti-obesity by HPLC–UV

JM-101 is a developed functional food formula using water extract of Chaenomeles sinensis and Phyllostachys bambusoides for anti-obesity. Standardization and quality control of herb mixture is more difficult than those of single herb. Additionally, the estimation of mixing ratio is an essential requirement for standardization. This study aimed to develop an efficient analytical method for the standardization of JM-101 based on C. sinensis and P. bambusoides. Protocatechuic acid and p-coumaric acid were selected as marker compounds of JM-101. A mixture of the two medicinal materials (1:1 w/w) was extracted by water and then liquid–liquid extracted (LLE) by ethyl acetate. The supernatant was evaporated to dryness and dissolved in methanol for analysis. The extraction time, material-to-water ratio and ethyl acetate-to-water ratio were optimized by multi-response optimization based on response surface methodology (RSM). The established methods were validated in terms of linearity, precision, accuracy, repeatability, stability and recovery. The novel method based on LLE and RSM provides a sensitive, accurate analysis and excellent extraction efficiency of marker compounds in JM-101, without interruption of other compounds in JM-101. In conclusion, the developed simultaneous analytical method contributes to the standardization of two materials (C. sinensis and P. bambusoides) and JM-101.     

On the Nature of Physiologically-Based Pharmacokinetic Models –<Emphasis Type="Italic">A Priori</Emphasis> or <Emphasis Type="Italic">A Posteriori</Emphasis>? Mechanistic or Empirical?

Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be “bottom up” as opposed to “top down”. Modeling approaches can be characterized as either a posteriori (observational) or a priori (based solely on theory). Furthermore, approaches can be mechanistic (structure and components based on mechanisms) or empirical (based on observations alone). Both “bottom up” and “top down” approaches can incorporate either empirical or mechanistic components. In this perspective, we discuss some of the methods and assumptions of current PBPK modeling approaches. Specifically, we discuss drug partitioning into phospholipids and neutral lipids, use of blood-plasma ratios to estimate basic drug tissue partitioning, and clearance of neutral and acidic drugs. Based on these discussions, we believe that current PBPK models are mechanistic but a posteriori and semi-empirical.     

Toxicity of two fungicides in <Emphasis Type="Italic">Daphnia</Emphasis>: is it always temperature-dependent?

The joint effect of increasing temperature and pollution on aquatic organisms is important to understand and predict, as a combination of stressors might be more noxious when compared to their individual effects. Our goal was to determine the sensitivity of a model organism (Daphnia spp.) to contaminants at increasing temperatures, allowing prior acclimation of the organisms to the different temperatures. Prior to exposure, two Daphnia genotypes (Daphnia longispina species complex) were acclimated to three temperatures (17, 20, and 23 °C). Afterwards, a crossed design was established using different exposure temperatures and a range of concentrations of two common fungicides (tebuconazole and copper). Daphnia life history parameters were analysed in each temperature × toxicant combination for 21 days. Temperature was the most influencing factor: Daphnia reproduced later and had lower fecundity at 17 °C than at 20 and 23 °C. Both copper and tebuconazole also significantly reduced the fecundity and survival of Daphnia at environmentally-relevant concentrations. Temperature-dependence was found for both toxicants, but the response pattern was endpoint- and genotype-specific. The combination of contaminant and high temperature often had severe effects on survival. However, unlike some literature on the subject, our results do not support the theory that increasing temperatures consistently foment increasing reproductive toxicity. The absence of a clear temperature-dependent toxicity pattern may result from the previous acclimation to the temperature regime. However, a proper framework is lacking to compare such studies and to avoid misleading conclusions for climate change scenarios.