bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control of the Dispersing Process and Pharmacokinetics in Rats for Lipid A Analogue, E5531
Authors: Asai Yasuyuki , Sano Yoshihisa , Kikuchi Kiyomi , Iwamoto Kiyoshi , Watanabe Sumio 
Published: July 2003

Abstract
E5531 is a synthetic disaccharide analogue of lipid A which has a low toxicity but retains the ability to reduce production of tumour necrosis factor. This analogue has potential for use in the treatment of septic shock. An injectable formulation of E5531 would be useful, but dispersion in aqueous solution is a problem. In the present study the dispersing process for E5531 was evaluated using the pH-jump method (pH 11·0·7·3). The size of the aggregates was decreased (reaching 20 nm) with increasing dispersing time in 0·003 M NaOH (pH 11·0). The membrane fluidity of the aggregates increased with increasing dispersing time. When prepared by the normal dilution method (pH 7·3·7·3), the size of the aggregates remained constant at 140 nm and the membrane fluidity was smaller than that of samples prepared by the pH-jump method. This indicates that during dispersing at basic pH, the hydration proceeded in a normal manner, but then stopped, just after adjustment of the pH to 7·3. This suggests that the degree of hydration of the membrane is dependent on the dispersing time at pH 11·0. Using samples with different degrees of hydration and different membrane fluidity prepared by the pH-jump method, the pharmacokinetics and stability of the aggregates were evaluated after intravenous injection into rats. The data thus obtained confirmed that the membrane fluidity was correlated with the pharmacokinetics and stability in rat plasma.
It was concluded that the pharmacokinetics of E5531 in rats can be controlled by changing the degree of hydration and membrane fluidity by means of using different dispersing times in alkaline solution (pH 11·0).
Effect of Pentobarbital Anaesthesia on Intestinal Absorption and Hepatic First-pass Metabolism of Oxacillin in Rats, Evaluated by Portal-Systemic Concentration Difference
Authors: Ueda Shinya , Yamaoka Kiyoshi , Nakagawa Terumichi 
Published: July 2003

Abstract
The effects of anaesthesia on intestinal drug absorption and hepatic first-pass metabolism in rats were investigated by observing the difference in the drug concentration between portal and systemic bloods. Oxacillin and pentobarbital were selected as a model drug and as an anaesthetic, respectively. Rats were divided into a conscious control group and an anaesthetized group. All rats were cannulated simultaneously in the portal vein and in the femoral artery, and oxacillin was orally administered after its intra-arterial injection (double dosing). For the anaesthetized group, pentobarbital was intrasubcutaneously administered twice, first before intra-arterial injection and again before oral administration of oxacillin. The arterial blood alone was sampled from the cannula in the femoral artery before oral administration, whereas the arterial and portal bloods were simultaneously sampled from both cannulated sites after oral administration. Oxacillin concentrations in plasma were assayed by HPLC.
The anaesthesia increased the absolute bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (FH), but caused little change in the local absorption ratio into the portal system (Fa) and the total clearance (CL). The hepatic clearance (CLH) was significantly decreased, resulting in an apparent small change in CL—CLH which is considered to be renal clearance.
By this method, it was shown directly that an increase in F due to pentobarbital anaesthesia was attributable to the significant increase in FH. It is expected that the method is useful not only to evaluate the effect of anaesthesia on the first-pass effect, but also to assess the effect of co-administration of drugs on first-pass metabolism.
Molecular Basis of Indomethacin-Human Serum Albumin Interaction
Authors: Trivedi Vishwa D , Vorum Henrik , Honoré Bent , Qasim Mohammad A 
Published: July 2003

Abstract
Studies on the strength and extent of binding of the non-steroidal anti-inflammatory drug indomethacin to human serum albumin (HSA) have provided conflicting results. In the present work, the serum-binding of indomethacin was studied in 55 mM sodium phosphate buffer (pH 7·0) at 28°C, by using a fluorescence quench titration technique.
The interaction of indomethacin with human serum albumin has been studied as a function of temperature, ionic strength and pH. The results suggest that electrostatic interaction plays a major role in the binding. The possible role of lysine residues in this interaction was studied by modifying exposed and buried lysine residues of HSA with potassium cyanate and studying indomethacin binding with the modified HSA. The data suggest that the interaction takes place via a salt bridge formation between the carboxylate group of indomethacin and a buried lysine residue of HSA.
A technique involving fluorescence enhancement of bilirubin upon its interaction with HSA was used to study its displacement by indomethacin. The displacement, although apparently competitive in nature, was not strong suggesting that the primary sites of interaction of bilirubin and indomethacin are different.
Pharmacokinetics of Buspirone following Oral Administration to Rhesus Monkeys
Authors: Marathe Punit H , Shen Frank , Markham Peter , Greene Douglas S 
Published: July 2003

Abstract
Pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinyl piperazine (1-PP) following oral administration were assessed in rhesus monkeys at doses used in chronic toxicology studies. The study was conducted over four periods in three male and three female rhesus monkeys. In the first three periods, buspirone hydrochloride solution was administered in a randomized manner by oral gavage at doses (expressed as buspirone free base) of 12·5, 25 and 50 mg kg−1 once a day on days 1 and 7 and twice a day on days 2–6. In the last period, all monkeys received 25 mg kg−1 buspirone as a single daily dose for 7 days. Serial plasma samples were collected for analysis of buspirone and 1-PP on days 1 and 7 in the first three periods and on day 7 in the last period for assessment of single dose and steady-state pharmacokinetics.
Inter-animal variability in the pharmacokinetics of buspirone was high. Examination of Cmin vs time plots revealed that the steady state was attained by day 7 except for one monkey who demonstrated much higher Cmin values. For buspirone, dose proportionality was concluded for both Cmax and AUC on day 1 but not on day 7. The accumulation factor on day 7 for buspirone was nearly 5 for Cmax and 7 for AUC when compared with day 1. For 1-PP, dose proportionality was concluded except for Cmax in male monkeys on day 7. In contrast to buspirone, 1-PP showed less than 2-fold accumulation in Cmax and AUC values on day 7 compared with those on day 1. Exposure at a dose of 25 mg kg−1 once daily was in between the 12·5 mg kg−1 and 25 mg kg−1 twice-a-day regimens.
These results document dose-dependency in the steady-state pharmacokinetics of buspirone in rhesus monkeys.
Distribution of Ciprofloxacin into the Central Nervous System in Rats with Acute Renal or Hepatic Failure
Authors: Naora Kohji , Ichikawa Nobuhiro , Hirano Hidenari , Iwamoto Kikuo 
Published: July 2003

Abstract
Pharmacokinetic changes of various drugs have been reported in renal or hepatic failure. The present study employed ciprofloxacin, a quinolone antibiotic having neurotoxic side effects, to assess the influence of these diseases on distribution of ciprofloxacin into the central nervous system (CNS).
After intravenous dosing of ciprofloxacin (10–30 mg kg−1), ciprofloxacin levels in plasma and brain were measured in normal rats (Wistar, male, 10-week-old) and those with acute renal and hepatic injuries which were induced by uranyl nitrate and carbon tetrachloride (CCl4), respectively. In the uranyl nitrate-treated rats, the plasma elimination half-life of ciprofloxacin was prolonged and the total body clearance was reduced when compared with those in the normal rats. Similar but smaller changes were observed in the CCl4-treated group. Brain levels of ciprofloxacin were significantly increased by both uranyl nitrate and CCl4 treatments. A proportional correlation between serum unbound levels and brain levels of ciprofloxacin was observed in the normal group. However, brainto-serum unbound concentration ratios of ciprofloxacin were reduced in the rats with renal or hepatic failure.
These results suggest that renal failure as well as hepatic failure retards elimination of ciprofloxacin from the blood, leading to elevation of the CNS level, and also that ciprofloxacin distribution in the brain is reduced in these disease states.
Effects of Mebudipine and Dibudipine, Two New Calcium-channel Blockers, on Rat Left Atrium, Rat Blood Pressure and Human Internal Mammary Artery
Authors: Mirkhani H , Omrani G R , Ghiaee S , Mahmoudian M 
Published: July 2003

Abstract
Mebudipine and dibudipine are two new dihydropyridine calcium-channel blockers that have been synthesized in our laboratory. In a previous study, they showed considerable relaxant effect on vascular and ileal smooth muscle. Here, the pharmacological effects of mebudipine and dibudipine on isolated rat left atrium, rat blood pressure and isolated human internal mammary artery are described. Results are compared with those obtained for nifedipine.
Mebudipine and dibudipine reduced contraction force of rat left atrium (pIC30 values: 5·37 ± 0·13 and 5·49 ± 0·15, respectively) but their negative inotropic effects were significantly weaker than that of nifedipine (pIC30 value: 6·63 ± 0·11). Mebudipine and dibudipine lowered rat blood pressure. The hypotensive effect of mebudipine was similar to that of nifedipine while dibudipine was weaker than nifedipine. It was found that the half-life of the hypotensive action of dibudipine (41·91 ± 3·77 min, 31·13 ± 2·26 min and 28·20 ± 4·37 min at 2, 4 and 8 mg kg−1 orally administered doses, respectively) was longer than that of nifedipine (11·85 ± 2·88 min, 16·65 ± 2·42 min and 14·03 ± 0·10 min at the same doses, respectively). Also, it appeared that mebudipine had a slower rate of absorption compared with nifedipine (the time to reach peak hypotensive action at 2, 4 and 8 mg kg−1 orally administered doses were, respectively, 24·00 ± 6·96 min, 23·75 ± 2·39 min and 15·00 ± 2·04 min for mebudipine and 7·80 ± 0·86 min, 13·75 ± 3·15 min and 8·33 ± 0·88 min for nifedipine). The two new compounds, as well as nifedipine, relaxed KCl-treated isolated human internal mammary artery (pEC50 values; 7·87 ± 0·12, 7·22 ± 0·24 and 7·67 ± 0·12 for mebudipine, dibudipine and nifedipine, respectively). The relaxant effects of mebudipine and dibudipine did not show any significant difference compared with that of nifedipine.
It is concluded that these new compounds are weak cardiodepressants and, with due attention to its significant vasorelaxant action, mebudipine is a vasoselective compound. In addition, these two compounds have potent blood pressure lowering effects. Also, their vasorelaxant action can be reproduced in human vascular preparations.
Paradoxical Cholinergic and Purinergic Vascular Reactivity of Rabbit Thoracic Aorta Cold-stored in University of Wisconsin Solution
Authors: Alexander B , Gryf-Lowczowski J V D , Sherlock D , Salisbury J , Benjamin I S 
Published: July 2003

Abstract
Endothelial dysfunction has been reported in donor blood vessels destined for organ transplantation following cold-storage preservation with University of Wisconsin solution (UW). This was investigated in the present work. Segments of rabbit thoracic aorta were mounted on isometric fine-wire myographs at 37°C and gassed with 95% O2/5% CO2. Concentration-dependent vasodilatations to acetylcholine and adenosine-5′-triphosphate (ATP) were obtained in freshly-harvested rabbit aortic rings, with and without the endothelium, and after 8 days of cold-storage, at 4°C, in either UW, Krebs-Bülbring buffer (KBB) or saline. The action of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (100 μM) was evaluated upon the concentration-response curves to determine whether nitric oxide (NO) exerted any modulatory actions.
Endothelium-dependent, NO-mediated responses to acetylcholine were unaltered after eight days of storage in UW, reduced after storage in KBB and absent after removal of the vascular endothelium, saline storage or after testing in the presence of L-NAME, suggesting improved NO-mediated endothelial function with the use of UW. Structural preservation was also confirmed using scanning electron microscopy. In contrast, endothelium-dependent responses to ATP were unchanged after eight days of storage in KBB but were reduced after storage in UW and saline, suggesting purinergic (ATP) endothelial dysfunction after storage in UW. L-NAME markedly reduced vasodilatation to ATP in freshly harvested rings and after eight days of storage in KBB. This reduction was statistically significant (P &lt; 0·05, Student's two tailed, unpaired t-test) at —log (M) ATP concentrations of 5·5, 5·0, 4·5, 4·0 and 3·5. NO-dependent vasodilatation to ATP was not attenuated by L-NAME in UW-stored rings. Eight days' UW-storage of rabbit thoracic aortic rings appeared to have differential and paradoxical effects upon NO-dependent vasodilatation to acetylcholine and ATP.
Morphological observations using electron microscopy suggested that UW preserved the vascular endothelium and this was verified by retained vascular reactivity of endothelium-dependent vasodilatations to acetylcholine. UW-storage however, significantly reduced endothelium-dependent relaxation to ATP thereby suggesting that P2Y-purinoceptors, which are located on the vascular endothelium, may be more susceptible to biodegradation than cholinergic receptors and may be responsible for endothelial dysfunction following transplantation.
Effects of Tetraethylammonium, 4-Aminopyridine and Bretylium on Cardiovascular Tissues from Normo- and Hypertensive Rats
Authors: Nand Vinita , Doggrell Sheila A 
Published: July 2003

Abstract
Our objective was to test whether potassium-channel blockade is a potential positive inotropic mechanism for heart failure. Thus we studied the effects of tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action potentials, left ventricular contractility in the absence and presence of hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs).
Tetraethylammonium at 10−3-10−2M, 4-aminopyridine at 10−4-10−3M and bretylium at 10−6-10−4M prolonged the action potentials of the WKY left ventricular strip. Similar concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the peak force, prolonged the contractions, and did not cause arrhythmias in the absence or presence of isoprenaline on left ventricular strips from 12-month-old WKY. The 12-monthold SHR has hypertrophy of the left ventricle with reduced contractility and prolongation of relaxation. The effects of tetraethylammonium and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine were reduced on SHR left ventricular contractility, which suggests that the function of the transient outward-blocking potassium channel may be impaired in hypertrophy. Bretylium at · 10−4M had no effect on the portal vein, intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at · 10−5M increased the duration or amplitude, or both, of the portal vein contractions. Tetraethylammonium at · 10−2M and 4-aminopyridine at · 3 × 10−4M contracted the mesenteric artery, and 4-aminopyridine also contracted the intralobar pulmonary artery.
In summary, we have demonstrated that the action potential prolonging effects of potassium-channel blockade is associated with a positive inotropic effect on the rat left ventricle. The non-specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential as positive inotropes in heart failure because of their widespread effects, including vasoconstriction. The potential of bretylium and some of the newer selective potassium-channel blockers as positive inotropes requires further evaluation.
The Scientific Basis for the Reputed Activity of Valerian
Authors: Houghton P J 
Published: July 2003

Abstract
The underground organs of members of the genus Valeriana (Valerianaceae), as well as related genera such as Nardostachys, are used in the traditional medicine of many cultures as mild sedatives and tranquillizers and to aid the induction of sleep. V. officinalis is the species most commonly used in northern Europe and still retains its official pharmaco-poeial status although it is most commonly encountered as an ingredient of herbal medicines. This plant is still the subject of considerable research aimed at establishing the chemical and pharmacological basis of the activity which has been clearly shown in a number of animal and clinical studies.
The constituents of the volatile oil are very variable due to population differences in genetics and to environmental factors. The major constituents include the monoterpene bornyl acetate and the sesquiterpene valerenic acid, which is characteristic of the species, in addition to other types of sesquiterpene. Some of these have been shown to have a direct action on the amygdaloid body of the brain and valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain resulting in sedation. The non-volatile monoterpenes known as valepotriates were first isolated in 1966 and contribute to the overall activity by possessing sedative activity based on the CNS although the mode of action is not clearly known. The valepotriates themselves act as prodrugs which are transformed into homobaldrinal which has been shown to reduce the spontaneous motility of mice. More recent studies have shown that aqueous extracts of the roots contain appreciable amounts of GABA which could directly cause sedation but there is some controversy surrounding the bioavailability of this compound. Another recent finding is the presence of a lignan, hydroxypinoresinol, and its ability to bind to benzodiazepine receptors.
Valerian is a good example of both the negative and positive aspects of herbal drugs. The considerable variation in its composition and content as well as the instability of some of its constituents pose serious problems for standardization but the range of components which contribute to its overall activity suggest that it may correct a variety of underlying causes of conditions which necessitate a general sedative or tranquillizing effect.
Hypericum perforatum Extracts as Potential Antidepressants
Authors: Vitiello Benedetto 
Published: July 2003

Abstract
Extracts of Hypericum perforatum have been used in the treatment of mild to moderate depression for many years in Europe. More recently, these extracts have become available in the USA as dietary supplements and have been popularly used to improve mood. In support of this practice, data from several controlled clinical studies suggest that Hypericum perforatum is better than placebo and as effective as established antidepressant drugs. These data have, however, several limitations that should temper our enthusiasm and argue for more research before accepting Hypericum perforatum extracts into our pharmacopoeia of established antidepressants. Extant data on the possible effects of Hypericum perforatum extracts in depression are here critically reviewed and plans for further research presented.
Flavonoids and the Central Nervous System: from Forgotten Factors to Potent Anxiolytic Compounds
Authors: Paladini A C , Marder M , Viola H , Wolfman C , Wasowski C , Medina J H 
Published: July 2003

Abstract
The list of activities of plant flavonoids did not include effects on the central nervous system (CNS) up to 1990, when our laboratory described the existence of natural anxiolytic flavonoids. The first of these was chrysin (5,7-dihydroxyflavone), followed by apigenin (5,7,4′-trihydroxyflavone) and flavone itself. Semisynthetic derivatives of flavone obtained by introducing halogens, nitro groups or both in its molecule, give rise to high affinity ligands for the benzodiazepine receptor, active in-vivo; 6,3′-dinitroflavone, for example, is an anxiolytic drug 30 times more potent than diazepam.
The data collected in this paper make clear that some natural flavonoids are CNS-active molecules and that the chemical modification of the flavone nucleus dramatically increases their anxiolytic potency.
Medicinal Plants and Alzheimer's Disease: from Ethnobotany to Phytotherapy
Authors: Perry Elaine K , Pickering Anne T , Wang Wei Wei , Houghton Peter J , Perry Nicolette S L 
Published: July 2003

Abstract
The use of complementary medicines, such as plant extracts, in dementia therapy varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive- or memory-enhancing plants have not been widely investigated in the context of current models of Alzheimer's disease. An exception is Gingko biloba in which the gingkolides have antoxidant, neuroprotective and cholinergic activities relevant to Alzheimer's disease mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer's disease in placebo controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Gingko are minimal. Old European reference books, such as those on medicinal herbs, document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory-improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activity in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically-based hypothesis of cholinergic derangement in Alzheimer's disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesia- and dementia-inducing properties.