bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological investigation on nigrescigenin-a cardenolide from Parquetina nigrescens (Afzel.) Bullock: comparative studies on cardiotonic effects of Parquetina nigrescens, g-strophanthin and noradrenaline in guinea-pig isolated atria
Authors: Datté J Y , Ziegler A 
Published: July 2003

Abstract
The cardiotonic and catecholamine-like effects of Parquetina nigrescens extract-induced contractile force of guinea-pig left and right atria were investigated in-vitro. Isometric contractions were recorded. P. nigrescens extract, 5–150 μg mL−1, increased the force of contraction dose dependently in electrically driven left atria. The concentration of P. nigrescens extract producing 50% of the maximal effect (EC50 value) was 7.5 μg mL−1. The positive inotropic response differed from that of g-strophanthin by its high rate of onset and its complete reversibility upon removal of the extract from the incubation medium. In spontaneously beating right atrial muscle, P. nigrescens extract increased the rate of contractions. Its positive chronotropic and inotropic effects were partly antagonized by propranolol and atenolol indicating the presence of an adrenergic acting principle in P. nigrescens extract. In contrast, the inotropic response to P. nigrescens extract could not be completely suppressed by β-blocking agents, suggesting that the force of contraction is not only increased by a sympathomimetic ingredient of P. nigrescens extract but also by the cardenolides known to be present in P. nigrescens.
Anti-inflammatory activity of abietic acid, a diterpene isolated from Pimenta racemosa var. grissea
Authors: Fernández M A , Tornos M P , García M D , de las Heras B , Villar A M , Sáenz M T 
Published: July 2003

Abstract
The anti-inflammatory activity of abietic acid, a diterpene isolated from Pimenta racemosa var. grissea (Myrtaceae), was evaluated in-vivo and in-vitro. This compound significantly inhibited rat paw oedema induced by carrageenan in a time- and dose-dependent manner, and mouse ear oedema induced by 12-O-tetradecanoylphorbol acetate, after oral or topical administration. The inhibition of myeloperoxidase enzyme showed that its topical activity was influenced by neutrophil infiltration into the inflamed tissues (ears). In addition, the effect of abietic acid on some macrophage functions was analysed in-vitro. Non-toxic concentrations of abietic acid inhibited prostaglandin E2 (PGE2) production in lipopolysaccharide-treated macrophages, whereas nitrite, tumour necrosis factor α and interleukin-1β production were only weakly affected by this diterpene. PGE2 production from A23187-stimulated macrophages was only inhibited at high doses (100 μM) and it failed to modify leukotriene C4 production. These results indicate that abietic acid exerts in-vivo anti-inflammatory activity after oral or topical administration and has partial ability to prevent the production of some inflammatory mediators.
Expression and function of P-glycoprotein in rats with carbon tetrachloride-induced acute hepatic failure
Authors: Huang Zhao-Hui , Murakami Teruo , Okochi Atsuko , Yumoyo Ryoko , Nagai Junya , Takano Mikihisa 
Published: July 2003

Abstract
Acute hepatic failure was induced experimentally in rats by intraperitoneal injection of 2.5 mL kg−1 carbon tetrachloride (CCl4), and the effects on the expression and function of P-glycoprotein in the liver, kidney and brain were evaluated. The CCl4 injection significantly increased the indicators of hepatic function (glutamate oxaloacetate transaminase, glutamate pyruvate transaminase), but not of renal function (blood urea nitrogen, glomerular filtration rate). In rats with acute hepatic failure, the hepatic P-glycoprotein concentration increased 1.5-fold and the ATP concentration decreased to approximately 40% that in control rats. In contrast, P-glycoprotein concentrations in the kidney and brain and ATP concentrations in the kidney remained unchanged. The in-vivo P-glycoprotein function in these tissues was suppressed as evaluated by biliary and renal secretory clearances and brain distribution of rhodamine 123, a P-glycoprotein substrate. These findings suggest that factors other than P-glycoprotein concentration are involved in the systemic suppression of P-glycoprotein function in diseased rats. In Caco-2 cells, plasma collected from CCl4-treated rats exhibited a greater inhibitory effect on P-glycoprotein-mediated transport of rhodamine 123 than that from control rats, suggesting the accumulation of an endogenous P-glycoprotein substrate/inhibitor in the plasma of diseased rats. In fact, the plasma concentration of corticosterone, an endogenous P-glycoprotein substrate, increased 2-fold in CCl4-treated rats compared with control rats. It was demonstrated that P-glycoprotein function is systemically suppressed in rats with CCl4-induced acute hepatic failure, not only in the target organ (liver), but also in other organs (kidney and brain), although the P-glycoprotein concentration remained unchanged in the kidney and brain, and increased in the liver. In the systemic suppression of the P-glycoprotein function in the diseased state, the alteration of plasma concentrations or components of endogenous P-glycoprotein-related compounds, such as corticosterone, would likely be involved.
Arachidonic acid and its metabolites are involved in the expression of neocortical spike-and-wave spindling episodes in DBA/2J mice
Authors: Capasso A , Loizzo A 
Published: July 2003

Abstract
This work was undertaken to study the effects of dexamethasone, indometacin and mifepristone plus dexamethasone on the neocortical spike-and-wave spindling episodes (S&W) in the electrocorticogram of DBA/2J mice. Our data indicate that both dexamethasone and indometacin (1, 10, 100 μg kg−1, i.p.) reduced the S&W of DBA/2J mice. This effect appeared 30 min after drug administration and lasted for the duration of the recording period (240 min). Mifepristone, a glucocorticoid receptor antagonist (1, 10, 100 μg kg−1, i.p.), injected 2 h before dexamethasone, totally blocked the steroid effect. These results indicate that both dexamethasone and indometacin significantly reduce the S&W of DBA/2J mice, suggesting a possible involvement of arachidonic acid and its metabolites in the development of brain excitability.
A tryptamine analog with high affinity to the heart tissues is a potential antiarrhythmic agent
Authors: Bodor Nicholas , Farag Hassan H , Polgar Peter 
Published: July 2003

Abstract
A novel tryptamine analog, 1-methyl-3-[N-(3-indolyl)ethyl]carbamoyl-1,4-dihydropyridine (T-CDS) was synthesized and converted into a stable, solid complex with 2-hydroxypropyl-β-cyclodextrin. An aqueous solution of the complex was given intravenously to dogs and the concentration of T-CDS and its corresponding quaternary (T-Q+) forms were monitored in the blood for 50 min. The effect of the drug on vital heart parameters was monitored throughout the studies. At the end of the experiment the dogs were sacrificed and the concentration of the quaternary pyridinium form (T-Q+) was determined in the different heart tissues, as well as in the kidney, liver, lung, brain, urine and cerebrospinal fluid. The compound was found to be selectively bound to the heart muscles and showed different concentrations in different heart tissues. The T-Q+ concentrations were much higher in the heart after administration of the dihydro form (T-CDS), than after administering T-Q+ directly. The compound was found to be active on certain vital signs of the cardiovascular system and could be an effective and safe antiarrhythmic agent.
Azo-containing urethane analogues for colonic drug delivery: synthesis, characterization and in-vitro evaluation
Authors: Chavan M S , Sant V P , Nagarsenker M S 
Published: July 2003

Abstract
A urethane-based analogue containing an azo aromatic linkage in the backbone was synthesized for use in colon-specific delivery systems by reacting toluene-2,6-diisocyanate with a mixture of an aromatic azo diol, (bis-4-hydroxyphenyl)-4,4′-diazobiphenyl, poly(ethylene glycol) (Mn = 4000; number-average molecular weight) and 1,2-propanediol (propylene glycol). The resultant compounds (UR-1 and UR-2) were characterized by IR spectroscopy, 1H NMR spectroscopy, DSC studies, X-ray diffraction studies and molecular weight determination by gel permeation chromatography. The compounds exhibited low molecular weight, lacked film-forming properties and crystallinity in the structure. An in-vitro bacterial degradation test to demonstrate the susceptibility of azo bond to bacterial enzymes was performed using media inoculated with lactobacillus culture. The results indicated degradation of films by azoreductase. In-vitro permeation of 5-aminosalicylic acid was studied in control and lactobacilli-treated films. The permeability of the lactobacilli treated films was significantly increased suggesting the potential of these compounds for application in colonic targeting.
Evaluation of absorbability of centpropazine in rats: in-situ and in-vivo approaches
Authors: Atul Bhattaram V , Paliwal Jyoti K , Gupta Ram C 
Published: July 2003

Abstract
Intestinal absorption of centpropazine was studied in rats by both in-situ (closed-loop method) and in-vivo (portal-venous difference) approaches. The drug was found to be well absorbed from solution in in-situ studies. However, the results obtained in-vivo suggested that very low amounts of drug reach the portal circulation after oral dosing. This could imply extensive binding to the mucosa or metabolism in the intestinal wall. The presence of higher amounts of metabolites in the portal vein compared with the inferior vena cava samples signal their formation in the gastrointestinal tract or enterohepatic recirculation. These findings will be useful in incorporating suitable structural and formulation modifications for enhancing the bioavailability of centpropazine and its analogues.
Acute cardio-respiratory effects in rats of PS4α, an antineoplastic peptidoglycan from Mycobacterium vaccae
Authors: Villar Vincent M , Morcillo Esteban J , Cortijo Julio , Reed Ann , Groves Michael J 
Published: July 2003

Abstract
PS4α is a high molecular weight peptidoglycan extracted from Mycobacterium vaccae, which has demonstrated considerable antineoplastic activity in-vivo without apparent toxicity. Available for testing in only small quantities, a sensitive in-vivo method for measuring pulse and breathing rates in cannulated rats was applied to this compound at doses of 5, 50 and 500 μg kg−1. Various parameters (mean arterial pressure, maximum transpulmonary pressure, compliance, heart rate, minute volume, respiratory rate and tidal volume) were followed for up to 1 h and demonstrated no significant deviation in the baseline values obtained before injection. This compound at doses up to 500 μg kg−1 had no apparent acute toxicity in rats, but chronic effects at this and higher doses have to be determined by more conventional toxicological methods before proceeding to evaluate PS4α as an antineoplastic agent.
Effect of fudosteine, a new cysteine derivative, on mucociliary transport
Authors: Takahashi Koichi , Kai Hirofumi , Mizuno Hiroyuki , Koda Tadayuki , Miyata Takeshi 
Published: July 2003

Abstract
We examined the effect of fudosteine ((—)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid) on the mucociliary transport (MCT) rate in quails. The MCT rate was estimated by ash transport velocity on the tracheal mucosa of quails. Fudosteine (500 mg kg−1, p.o.) did not affect the normal MCT rate. However, topical application of fudosteine to the tracheal mucosa dose-dependently protected the impairment of the MCT rate caused by exposure to cigarette smoke. The results suggest that fudosteine may participate in the defence mechanism in the respiratory tract against irritant gases.
Potentiation of nerve growth factor-induced elongation of neurites by gelsemiol and 9-hydroxysemperoside aglucone in PC12D cells
Authors: Li Yu-Shan , Matsunaga Kimihiro , Kato Ryoko , Ohizumi Yasushi 
Published: July 2003

Abstract
In PC12D cells, nerve growth factor (NGF) increased the proportion of neurite-bearing cells and made neurites longer. A methanol extract of Verbena littoralis H. B. K. collected in Paraguay only slightly potentiated the proportion of PC12D cells with neurites but markedly increased the length of neurites in the presence of NGF (2 ng mL−1). The methanol extract was partitioned between ethyl acetate and water followed by further extraction of water fraction with n-butanol. The potentiating activity of NGF-action was observed in the ethyl acetate and n-butanol fractions. The n-butanol fraction was separated by silica gel chromatography, monitoring the NGF-potentiating activity to give gelsemiol and 9-hydroxysemperoside aglucone (9-OHSA). Neither compound (30–300 μM) exhibited neurite-inducing activity alone. Gelsemiol (100–300 μM) markedly enhanced an increase in the proportion of neurite-bearing cells and an extension of the neurite length in the presence of NGF (2 ng mL−1). Interestingly, in the presence of NGF (2 ng mL−1), 9-OHSA (100–300 μM) enhanced the elongation of neurites without affecting the increase in the proportion of cells with neurites. These results suggested that gelsemiol and 9-OHSA were major active components of V. littoralis in the NGF-potentiating action. It was possible that the mechanism of neurite elongation by NGF was different from that of the increase in the proportion of neurite-bearing cells, and that 9-OHSA selectively affected the neurite elongation mechanism.
Non-invasive assessment of the effects of iontophoresis on human skin in-vivo
Authors: Curdy Catherine , Kalia Yogeshvar N , Guy Richard H 
Published: July 2003

Abstract
The stratum corneum (SC), the outermost layer of the skin, presents a formidable barrier to transdermal drug delivery. As a result, different strategies have been developed to enhance drug transport into and through skin. Iontophoresis involves the application of a small electrical current which drives molecules across the skin and controls relatively well the rate of delivery. Although the technique has been widely investigated in-vitro, the evaluation of skin integrity in-vivo after iontophoresis is absolutely necessary for the future clinical application of this approach. This paper reviews the non-invasive biophysical techniques which have been used to assess the effects of current application on human skin in-vivo. Specifically, transepidermal water loss, infrared spectroscopy, impedance spectroscopy and skin blood flow measurements are discussed. After first presenting the basic principles of these methods, their application to the determination of SC barrier function and skin integrity is addressed, and the criteria for selecting the most appropriate approach are considered.
Triton-X-100-modified polymer and microspheres for reversal of multidrug resistance
Authors: Liu Zhi , Bendayan Reina , Wu Xiao Yu 
Published: July 2003

Abstract
Triton X-100 is a non-ionic detergent capable of reversing multidrug resistance (MDR) due to its interaction with cell membranes. However, it interacts with cells in a non-specific way, causing cytotoxicity. This work aimed to develop polymeric chemosensitizers that possess the ability to reverse MDR and lower toxic side effects. When being delivered to tumours, the polymeric chemosensitizers may also have longer retention times in tumours than the free detergent. Triton-X-100-immobilized dextran microspheres (T-MS) and inulin (T-IN) were prepared and characterized. Their cytotoxicity against multidrug-resistant Chinese hamster ovary cells (CHRC5) was compared with that of free Triton X-100 solutions. The in-vitro effect of the products on 3H-vinblastine accumulation by CHRC5 cells was determined. Both T-MS and T-IN showed a marked decrease in the cytotoxicity, as compared with free Triton solutions at equivalent concentrations. Drug accumulation by CHRC5 cells was increased over two fold in the presence of T-MS or T-IN. These results suggest that polymeric drug carriers with MDR-reversing capability and lower cytotoxicity may be prepared by immobilization of chemosensitizers.
Novel approach to improve permeation of ondansetron across shed snake skin as a model membrane
Authors: Takahashi Koichi , Rytting J Howard 
Published: July 2003

Abstract
The purpose of this study was to investigate the feasibility of transdermal drug delivery of ondansetron, an antagonist of the 5-HT3 receptor, used for the treatment of chemotherapy-induced emesis. The permeability of ondansetron from an aqueous suspension through shed snake skin as a model membrane was very low and in order to improve it, several enhancers were tested. Ethanol increased the flux at a concentration of 40% or more. The solubility of ondansetron also increased as the ethanol concentration increased. The permeability coefficient increased after pretreatment of the shed snake skin with Azone, oleic acid or lauryl alcohol. Further improvement of the permeability was observed when ethanol was combined with other enhancers and was maximum for the combination of ethanol and oleic acid. Oleic acid dramatically increased the partition of ondansetron to n-hexane and shed snake skin. Oleic acid may enhance the permeation of ondansetron in two ways: by a direct effect on the stratum corneum or via counterion formation of an ion-pair. The maximum flux obtained from the combination of ethanol and other enhancers seems to be high enough to obtain a therapeutic effect.
Nefiracetam metabolism by human liver microsomes: role of cytochrome P450 3A4 and cytochrome P450 1A2 in 5-hydroxynefiracetam formation
Authors: Fujimaki Yuko , Arai Nobuko , Nakazawa Tsunenori , Fujimaki Masayoshi 
Published: July 2003

Abstract
An in-vitro study was conducted to investigate the metabolism of nefiracetam in human liver microsomes and to identify the enzymes responsible for the metabolism. Nefiracetam was hydroxylated by human liver microsomes to 5-hydroxynefiracetam (5-OHN). Eadie-Hofstee plots for the formation of 5-OHN suggested substrate activation. The kinetic parameters, apparent Km, Vmax, and Hill coefficient, for the formation of 5-OHN by pooled human liver microsomes were 4012 μM, 2.66 nmol min−1 (mg protein)−1, and 1.65, respectively. The formation of 5-OHN was significantly correlated with cytochrome P450 (CYP) 3A4-mediated testosterone 6β-hydroxylase activity and dextromethorphan N-demethylase activity. The 5-OHN formation was inhibited (94%) by antibody to human CYP3A4/5. The 5-OHN formation was also inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin, but not significantly inhibited by several other P450 inhibitors. The microsomes containing cDNA-expressed CYP3A4 formed 5-OHN with sigmoidal kinetics. CYP3A5-containing microsomes did not form 5-OHN. These results indicated that CYP3A, most likely CYP3A4, was the major isozyme responsible for the formation of 5-OHN in human liver microsomes. CYP1A2 and CYP2C19 microsomes were also capable of forming 5-OHN. However, the contribution of CYP1A2 was considered to be relatively minor compared with that of CYP3A4, and the contribution of CYP2C19 was assumed to be negligible, based on the result of the immunoinhibition study and taking into account both the turnover rate by each isozyme and the relative abundance of each isozyme in human liver. We conclude that on average the formation of 5-OHN, the major metabolite of nefiracetam, is principally mediated by CYP3A4 with a relatively minor contribution by CYP1A2.
Effect of experimental renal dysfunction on bioavailability of ajmaline in rats
Authors: Hashimoto Yukiya , Aiba Tetsuya , Yasuhara Masato , Hori Ryohei 
Published: July 2003

Abstract
The effect of renal dysfunction on the bioavailability of ajmaline has been investigated in rats, where experimental renal dysfunction was induced by subcutaneous injection of uranyl nitrate (10 mg kg−1). Renal dysfunction did not cause any change in the blood ajmaline concentration after intravenous administration (2 mg kg−1), but it increased the blood ajmaline concentration by approximately 2.8-fold after intraduodenal administration (10 mg kg−1). The availability of ajmaline in control rats was 16.7%, whereas the availability was increased to 41.1% in rats with renal dysfunction. The unbound fraction in the blood and the metabolic activity in the liver, was assessed with the 10000-g supernatant fraction and with isolated hepatocytes, respectively. The values were found to be similar in both groups. The blood concentration following intraportal infusion was only slightly increased in rats with renal dysfunction, but the hepatic first-pass extraction was infusion rate-dependent and saturable. The initial absorption rate of ajmaline from the small intestine in rats with renal dysfunction was significantly greater compared with control rats. These results indicated that the increased availability of ajmaline in renal dysfunction was mainly a result of partially saturated extraction in the liver, which was caused by an increased absorption rate in the intestine and non-linear extraction in the liver.
Contradistinction between doxorubicin and epirubicin: in-vitro interaction with blood components
Authors: Ramanathan-Girish Sandhya , Boroujerdi Mehdi 
Published: July 2003

Abstract
The molecular structure and anti-tumour activity of doxorubicin and epirubicin are similar. However, the incidence of their cardiotoxicity occurs at different cumulative dose concentrations. The purpose of this study was to investigate the in-vitro interaction of these two drugs with different blood components, namely intact erythrocytes, haemoglobin and erythrocyte ghosts. Plasma protein binding was also evaluated. The intended goal was to identify the most relevant samples among total blood, plasma or blood cells for pharmacokinetic analysis. The methodology involved the incubation of each of the blood components (the intact erythrocytes, erythrocyte ghosts, haemoglobin and plasma proteins) at physiological pH and temperature with different concentrations of each drug, followed by measurement by HPLC and fluorometry at excitation and emission wavelengths of 480 and 580 nm, respectively. The results indicated that the binding of doxorubicin and epirubicin to plasma proteins, erythrocyte ghosts and intact erythrocytes was essentially the same. However, the binding of both compounds to intact erythrocytes was significantly different from erythrocyte ghosts, which indicates that haemoglobin plays an important role in the binding to and uptake by erythrocytes. The isotherms of binding to haemoglobin revealed that the maximum binding of doxorubicin was approximately 0.42 μg mg−1 haemoglobin; for epirubicin this value was ten times greater than for doxorubicin. The Scatchard plot of binding of both drugs to haemoglobin exhibited two distinct binding sites for each drug. The constant of association of high affinity and low capacity binding sites was significantly greater for epirubicin, whereas the constant of association of low affinity and high capacity binding sites was significantly higher for doxorubicin. The number of high affinity binding sites per mg of haemoglobin was estimated to be 0.072 for doxorubcin and 0.030 for epirubicin. The number of low affinity binding sites was significantly greater for epirubicin (1.963) than for doxorubicin (0.305). Since the combined number of binding sites for epirubicin was more than doxorubicin, and the total uptake by erythrocytes remained the same for both drugs, it was concluded that epirubicin, being a more lipophilic compound, may diffuse more freely into the cells. Therefore, it binds more to haemoglobin, whereas doxorubicin remains more adsorbed on the surface of the cells due to its self-association property. It was concluded that the interaction of both drugs with erythrocytes, although it appears to be similar, is significantly different due to the interaction with haemoglobin. The difference in this interaction is expected to influence the disposition of both drugs in-vivo.