bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural products as targeted modulators of the nuclear factor-κB pathway
Authors: Bremner Paul , Heinrich Michael 
Published: October 2002

Abstract
The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-κB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-κB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-κB activation will first be summarised, leading to the Ikk (IkB kinase) complex, that subsequently initiates phosphorylation of the NF-κB inhibitory protein (IkB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-κB inhibitors. A large number of compounds are currently known as NF-κB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.
Efficacy of lactosaminated and intact N-succinyl-chitosan-mitomycin C conjugates against M5076 liver metastatic cancer
Authors: Kato Yoshinori , Onishi Hiraku , Machida Yoshiharu 
Published: October 2002

Abstract
In this study, lactosaminated N-succinyl-chitosan (Lac-Suc) was investigated for its liver targeting ability in the early metastatic stage of liver cancer, and subsequently Lac-Suc-mitomycin C conjugate (Lac-Suc-MMC) and highly-succinylated N-succinyl-chitosan (Suc(II))-MMC conjugate (Suc(II)-MMC) were examined for efficacy against the liver metastasis. Mice into which M5076 cells were inoculated intravenously were used as liver metastatic models. Fluorescently labelled Lac-Suc (Lac-Suc-FTC) was intravenously administered at a daily dose of 0.2 mg/mouse for 4 days or at a single dose of 0.8 mg/mouse at 3 days post-inoculation. At a dose of 0.2 mg/mouse for 4 days, liver accumulation of Lac-Suc-FTC was increased after all except the fourth injection, indicating that the capacity of accumulation might be limited to around 110μg per mouse with repeated daily administration at 0.2 mg/mouse. As to the efficacy of intravenous administration at 7 days post-inoculation, Lac-Suc-MMC was less effective at a dose of 1 mg kg−1 for 4 days than a single dose of 4 mg kg−1. This result was not in accordance with that expected from the biodistribution study. On the other hand, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC was more effective on repeated administration, and it showed higher efficacy than Lac-Suc-MMC at both 1 mg kg−1 for 4 days and 4 mg kg−1 as a single dose. Further, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC exhibited a much higher survival effect at a dose of 4 mg kg−1 for 4 days.
Preventive effects of a traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang, on intimal thickening of carotid artery injured by balloon endothelial denudation in rats
Authors: Kim Dong-Wook , Chung Hwa-Jin , Nose Katsuya , Maruyama Ikuro , Tani Tadato 
Published: October 2002

Abstract
We report here that the traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang (CLM), significantly inhibited the increase in intimal thickening in rat carotid artery injured by balloon endothelial denudation, which mimics many aspects of restenosis after percutaneous coronary intervention (PCI) in humans. CLM, Saiko-ka-Ryukotsu-Borei-to in Japanese, is commonly prescribed for symptoms accompanying hypertension and atherosclerosis in Japanese kampo medical care. CLM administered orally 1 week before and 1, 4 and 8 weeks after balloon injury inhibited the increase in intimal area, intimal/medial ratio and stenosis ratio. To our knowledge, this is the first report demonstrating inhibitory effects of a traditional Chinese formulation on intimal thickening of carotid artery after balloon injury. It is worth noting that CLM maintained its inhibitory effect up to 8 weeks after balloon injury. The reduction in intimal thickening by CLM could have resulted from inhibition of intimal smooth muscle cell proliferation, which was assessed by immuno-histochemical analysis using monoclonal antibody against proliferating cell nuclear antigen. Therefore, CLM may be a favourable candidate for prevention of restenosis after PCI. Moreover CLM may have a therapeutic value in the prevention of atherosclerosis, because restenosis after PCI is considered to be an accelerated atherosclerosis.
Non-steroidal anti-inflammatory drugs inhibit epinephrine- and cAMP-mediated lipolysis in isolated rat adipocytes
Authors: de Piña M Zentella , Vázquez-Meza H , Piña-Zentella G , Pimentel L , Piña E 
Published: October 2002

Abstract
Acute ethanol intoxication increased triacylglycerides (TAG) and thiobarbituric acid reactive substances (TBARS) in liver and promoted the liberation of epinephrine. Four non-steroidal anti-inflammatory drugs (NSAIDs) - aspirin, naproxen, nimesulide and piroxicam - prevented this increase in TAG and TBARS. Because fatty acids provided by adipose tissue contribute substantially to elevated hepatic TAG in ethanol-intoxicated rats, it was thought that the NSAIDs might reduce epinephrine-stimulated lipolysis in these rats. Isolated rat adipocytes were activated with epinephrine in the presence or absence of the NSAIDs. The NSAIDs inhibited epinephrine-stimulated lipolysis. These drugs did not modify the binding of dihydroalprenolol (β-adrenergic agonist) to their receptors in isolated guinea-pig liver membranes. The NSAIDs, at concentrations 3000-fold lower than that of cAMP, inhibited stimulated lipolysis by this messenger. In conclusion, aspirin, naproxen, nimesulide and piroxicam reduce the release of fatty acids from adipose tissue to the liver by inhibiting the epinephrine-stimulated lipolysis, and this, in part, explains the protective action of these NSAIDs against hepatic signs of acute ethanol intoxication.
Development of a lyophilised RH1 formulation: a novel DT diaphorase activated alkylating agent
Authors: Elliott M A , Ford S J , Walker A A , Hargreaves R H J , Halbert G W 
Published: October 2002

Abstract
RH1 is a novel aziridinylbenzoquinone alkylating agent, which is activated in tumour cells by DT diaphorase. In common with previous aziridinylbenzoquinones, RH1 exhibits limited aqueous stability and solubility. The aim of this study was to examine the pharmaceutical properties of RH1 with a view to preparing a suitable formulation for clinical trial. Stability in a neutral phosphate-buffered solution was poor with a degradation half-life of 50 h at 55°C, indicating that lyophilisation was preferable. The reaction kinetics indicated a similarity with previous studies for base-catalysed degradation of aziridinylbenzoquinones. Intrinsic aqueous solubility at 0.5 mg mL−1 may be increased in solvent systems or by the use of polymers such as polyvinylpyrrolidone (PVP) or complexing agents like hydroxypropyl-β-cyclodextrin (HPBCD). In the latter case this increased solubility by an order of magnitude to around 5 mg mL−1. Four potential formulations based on lyophilisation of RH1 (1 mg mL−1) from buffered solution (pH 7, 0.01 M NaH2PO4) containing either 50 mg mL−1 mannitol, 40 mg mL−1 dextran, 20 mg mL−1 PVP or 50 mg mL−1 HPBCD were prepared and examined for stability characteristics. All formulations exhibited a temperature-dependent degradation. The mannitol and dextran formulations had limited stability and degraded rapidly at all temperatures. The PVP and HPBCD formulations degraded at elevated temperatures but remained stable for up to twelve months at 4°C. Examination of the degradation kinetics in the latter systems demonstrated similarity to the solution degradation mechanism, while in the former alternative degradation pathways appeared to be occurring. The chemical stability of RH1 in lyophilised formulations is dependent upon the excipient employed and storage temperature. Either the PVP or HPBCD formulation would be suitable clinical trial formulations of RH1. The results indicate that the choice of lyophilisation excipient for aziridinylbenzoquinones cannot be based on previous literature studies of related agents.
Pharmacological properties and SAR of new 1,4-disubstituted piperazine derivatives with hypnotic-sedative activity
Authors: Chilmonczyk Zdzislaw , Mazgajska Maria , Iskra-Jopa Joanna , Chojnacka-Wójcik Ewa , Tatarczyńka Ewa , Klodzińska Aleksandra , Nowak Jerzy Z 
Published: October 2002

Abstract
Preparation, pharmacological properties and structure-activity relationships of new pyrimidylpiperazine derivatives, exhibiting sedative and hypnotic activity in mice, are reported. The hypnotic activity of the compounds was comparable with that of zopiclone (the known hypnotic-sedative agent), their interaction with ethanol, however, being much lower. The obtained results suggested that zopiclone and pyrimidylpiperazines 2, 4 and 5 exerted their pharmacological activity through a different mechanism — zopiclone through the interaction with benzodiazepine receptors and compounds 2, 4 and 5 through an unidentified molecular target. The pharmacological properties of compound 3 could be the result of a mixed mechanism of action, combining the properties of zopiclone and those of compounds 2, 4 and 5. A common feature of zopiclone and compounds 2 and 3 was that, after their systemic administration, independently of mechanism of action, together with the hypnotic effect a reduction of the 5-HT turnover in the mouse brain was observed. Minimum structural requirements for the hypnotic activity were formulated. Structural considerations have shown that removing the α-carbonyl group did not influence the drug's ability to inhibit the locomotor activity. However, it did influence its ability to disturb motor coordination or abolish the righting reflex within non-lethal doses.
Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats
Authors: Doggrell Sheila A , Nand Vinita 
Published: October 2002

Abstract
The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at ≤3 times 10−5 M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10−6 to 3 times 10−5 M relaxed the KCl-contracted aorta. Dofetilide at 10−9-10−7 M augmented the force of contraction of left ventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17–21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12-and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10−7-10−5 M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.
Estimation of cyclodextrin affinity to steroids
Authors: Khomutov S M , Sidorov I A , Dovbnya D V , Donova M V 
Published: October 2002

Abstract
A nonlinear spectrometric method for determination of the stability constant (KS) for cyclodextrin complex with steroid was developed. The method is based on calculation of the parameters of competitive cyclodextrin complexation by simultaneous fitting of two types of curves. Those of the first type are the dependencies of absorbance of methyl orange solution on the cyclodextrin concentration, the second type being the absorption curves of displacement of the dye, by steroid, from the cyclodextrin complex. With the method proposed, KS values were calculated with standard deviation less than 10%. This method is validated by determination of KS values using the phase-solubility technique. For neutral steroid molecules, the effect of pH on KS was found to be insignificant. KS values for the cyclodextrin-dye complex were determined for randomly methylated β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin. More hydrophobic steroids were characterised by higher KS values. Anionic β-cyclodextrins showed high affinity for the steroids studied. Simple equipment and sufficient computing allowed recommendation of the method for express estimation of cyclodextrin's affinity for hydrophobic substrates.
Disordered drug delivery: destiny, dynamics and the Deborah number
Authors: Hancock Bruno C 
Published: October 2002

Abstract
“Disordered drug delivery” is an innovative approach to improving the performance of new chemical entities delivered to the human body. In this technique, the molecules of the drug and/or its delivery system are kinetically trapped in a high energy non-crystalline state. The resulting disordered or “amorphous” material offers potential increases in solubility and biological activity of many thousand fold compared with more conventional crystalline forms of the drug. Despite having a molecular level structure akin to that of liquids, amorphous materials have macroscopic properties that are typical of solids and thus they may be presented to the patient in the form of a convenient solid dosage form. Significant advances in the fundamental understanding of amorphous pharmaceutical materials in the past ten years have permitted major steps forward in the rational design of disordered drug delivery systems. Recognition of significant levels of molecular mobility in the glassy regime and an in-depth appreciation of molecular relaxation times and their distributions have enabled rapid progress to be made in this field. Needs for the future include analytical techniques that can elucidate the complex, dynamic and heterogeneous structure of amorphous materials and reliable models to predict the physical stability and in-vivo performance of disordered drug delivery systems. There are also significant opportunities for the production of disordered drug delivery systems with tailor-made properties through the careful engineering of custom amorphous alloys.
Reversal of cannabinoids (Δ9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction
Authors: Dhawan Kamaldeep , Kumar Suresh , Sharma Anupam 
Published: October 2002

Abstract
The newly reported benzoflavone moiety from the plant Passiflora incarnata Linneaus has been evaluated in light of traditional reports on the use of P. incarnata in breaking down cannabis addiction. In the modern or allopathic system of therapeutics, there has been no suitable remedy to combat the severe withdrawal effects of various cannabis products, including marihuana, marijuana, bhang, hashish, ganja, etc., the world-wide consumption of which has attained alarming proportions especially among the younger generation. Mice were given a 10-mg-kg−1 twice-daily dose of δ9-tetrahydrocannabinol (δ9-THC) by mouth for six days to make them dependent upon cannabinoids. Concurrently, other groups of mice were administered δ9-THC along with a 10- or 20-mg-kg−1 twice-daily dose of the benzoflavone moiety from P. incarnata orally for 6 days. Upon measuring locomotor activity during the treatment regimen, it was noticed that the mice receiving the P. incarnata extract and δ9-THC together developed significantly less tolerance and dependence, relative to the mice receiving δ9-THC alone. Upon administration of SR-141716A, a selective cannabinoid-receptor antagonist (10 mg kg−1, p.o.) to all the groups of mice on the 7th day, an artificial withdrawal was produced due to an abrupt decline of δ9-THC levels in mouse brain. However, the typical withdrawal effects like paw tremors and head shakes were significantly less in the mice given δ9-THC + P. incarnata benzoflavone moiety for 6 days. Upon administration of 20 mg kg−1 of the P. incarnata benzoflavone moiety to mice showing severe symptoms of withdrawal due to administration of SR-141716A, there was a marked attenuation of withdrawal effects, thereby suggesting the usefulness of the benzoflavone moiety in δ9-THC withdrawal. Thus, the benzoflavone moiety of P. incarnata, when administered concurrently with δ9-THC, prevented the development of tolerance and dependence of cannabinoids in mice. Even an acute administration of the benzoflavone moiety (20 mg kg−1, p.o.) significantly blocked the expression of withdrawal effects in δ9-THC-dependent mice.
In-vitro release of bupivacaine from injectable lipid formulations investigated by a single drop technique — relation to duration of action in-vivo
Authors: Söderberg Lars , Dyhre Henrik , Roth Bodil , Björkman Sven 
Published: October 2002

Abstract
The aim of this study was to develop an in-vitro release method suitable for injectable slow-release lipid formulations of local anaesthetics (or other drugs). We also aimed that the results of the in-vitro measurements should have a clear relationship to duration of action in-vivo. Six formulations of bupivacaine base in medium-chain triglyceride-glyceryl dilaurate mixtures were developed. A new apparatus was constructed for determination of their in-vitro release profiles. A bulbous glass tube was fixed inside a standard glass bottle, which was then filled with release medium. A stirring magnet was enclosed in the perforated polypropylene cylinder holding the glass tube. The stirring created a continuous, rotating downward flow of medium inside the tube, which kept the lipid phase, introduced by means of a syringe, suspended as a single, free drop. Release profiles were obtained by sampling of the release medium for up to 72 h and analysis by gas-liquid chromatography. The duration of action in-vivo of the respective formulations was tested by the hot-plate method in rats. The release profiles of bupivacaine in-vitro were mono-exponential for four formulations and bi-exponential for the other two. There was a positive correlation between the proportion of glyceryl dilaurate in the formulation and the slow half-life of release of bupivacaine. All formulations showed prolonged duration of action in-vivo, median values within the range 4.5–12 h, as compared with a 2-h effect of bupivacaine hydrochloride solution. A comparison of in-vitro release curves and durations of action in-vivo suggested that to maintain nerve blockade in-vivo the formulations must release bupivacaine at a rate of approximately 350 μg h−1 under the in-vitro conditions. To conclude, we designed and tested a novel apparatus for measuring release of a local anaesthetic (or other drug) from a fluid or semi-solid formulation in-vitro. Release rates obtained in-vitro by means of this technique may be used to guide the development of formulations with suitable durations of action in-vivo. The apparatus is, however, as yet a prototype. Rigorous evaluation of performance should be carried out on devices built to specific standards according to their intended application.
Interaction of double-chained cationic surfactants, dimethyldialkylammoniums, with erythrocyte membranes: stabilization of the cationic vesicles by phosphatidylcholines with unsaturated fatty acyl chains
Authors: Kitagawa Shuji , Hiyama Fuyuko , Kato Miwa , Watanabe Reiho 
Published: October 2002

Abstract
We studied the interaction of double-chained cationic surfactants, dimethyldialkylammoniums, (CH3)2N+(CnH2n+1)2, with the lipid bilayer of guinea-pig erythrocytes by observing the haemolysis, aggregation and shape change in the erythrocytes. In the presence of sonicated dispersions of the five dimethyldialkylammoniumstested (n = 10,12,14,16 and 18), haemolysiswas induced dose dependently, and at 0.1 mM or higher concentrations, haemolysis was induced more rapidly by dimethyldialkylammoniums with shorter alkyl chains. The cationic surfactants with longer alkyl chains, such as dimethyldipalmitylammonium, induced aggregation of the erythrocytes before haemolysis fully progressed. The vesicles of these long-chain dimethyldialkylammoniums in the presence of phosphatidylcholines with unsaturated fatty acyl chains markedly reduced the haemolysis rates. Furthermore, in the presence of phosphatidylcholines with unsaturated acyl chains the formation of tightly aggregated structures of several erythrocytes was observed. These findings, and analysis by spin label 5-doxylstearic acid, indicate that phosphatidylcholines enriched with unsaturated acyl chains stabilize the cationic vesicles of long-chain dimethyldialkylammoniums and the interaction with the lipid bilayer of erythrocyte membranes as cationic vesicles became prominent.
Pharmacokinetic-pharmacodynamic modelling of insulin: comparison of indirect pharmacodynamic response with effect-compartment link models
Authors: Lin Senshang , Chien Yie W 
Published: October 2002

Abstract
The pharmacokinetic and pharmacodynamic modelling of insulin has been reported using a combined pharmacokinetic/pharmacodynamic (PK/PD) model, in which a hypothetical effect compartment is linked to a pharmacokinetic compartment. Review of the literature, however, indicated that the recently developed PK/PD models have consisted of an indirect pharmacodynamic response component, but none of them has been applied to the modelling of insulin. To study the relative relevance of the indirect pharmacodynamic response model and the effect-compartment link model in modelling the pharmacokinetics and pharmacodynamics of insulin, regular human insulin was administered intravenously at a dose of 0.1 IU kg−1 to healthy Yucatan minipigs (after an overnight fasting). The plasma concentrations of insulin were measured by radioimmunoassay at predetermined time intervals, while blood glucose levels were monitored continuously using a glucose monitor. Analysis of the plasma insulin and the blood glucose profiles was performed by fitting with various PK/PD models and the results indicated that all of the 12 sets of plasma insulin data (after normalizing by the basal levels) have been adequately fitted to the two-compartment open pharmacokinetic model (a mean±s.e. correlation coefficient of 0.996±0.001 was obtained). The mean±s.e. correlation coefficient, the weighted residuals sum of squares (WRSS), and the Akaike's information criterion (AIC) were found, respectively, to be 0.935 ± 0.008, 624±67, and 522 ± 9 for the inhibitory indirect pharmacodynamic response model and 0.941±0.010, 547 ± 63 and 513 ± 9 for the stimulatory indirect pharmacodynamic response model, as compared with 0.725 ± 0.041, 2309 ± 276 and 628 ± 10 for the effect-compartment link model. Based on these results, one may conclude that the indirect pharmacodynamic response model is a more appropriate approach for modelling the PK/PD of insulin than the effect-compartment link model.