bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Binding of Two Dihydropyridines to Isolated and Native Plasma Lipoproteins
Authors: Oravcová Jana , Sojková Dagmar 
Published: April 2011

Abstract
The objectives of this study were to investigate the mechanisms involved in the interaction of two calcium antagonists, isradipine and amlodipine, with isolated lipoprotein fractions in-vitro and to determine the distribution of isradipine among individual plasma lipoproteins ex-vivo in healthy volunteers (n = 8) and in hypercholesterolaemic patients (n = 12).
The total binding affinity of isradipine to isolated low density lipoprotein (LDL) was markedly higher compared with amlodipine; total binding affinity (nKa) of isradipine vs amlodipine was 1·60 ± 0·08 times 107 vs 4·14 ± 0·33 times 106 m-1, respectively. Binding to high density lipoprotein (HDL) was also higher with isradipine, nKa = 1·04 ± 0·04 times 105 m−1, compared with that of amlodipine, nKa = 3·82 ± 0·18 times 104 m−1. The distribution study ex-vivo demonstrated the different relative affinity of isradipine for the plasma lipoproteins: HDL &gt; LDL &gt; very-low density lipoprotein (VLDL). Isradipine binding correlated linearly with the cholesterol levels in LDL and VLDL; however, binding to HDL did not correlate with the cholesterol level in this fraction. There was no significant competitive binding effect of cyclosporin A (1–5 μgmL−1) on isradipine binding to individual lipoprotein fractions.
It is likely that, in addition to the structure of surface apoproteins, the factors determining the interaction of calcium antagonists with plasma lipoproteins also include the plasma level of each lipoprotein fraction as well as the lipophilicity of the drug.
Rat Liver Cytochrome P450-mediated Metabolic Activation of Methoxsalen and Structurally Related Compounds and its Relation to Enzyme Inhibition
Authors: Wilkinson David J , Fry Jeffrey R 
Published: April 2011

Abstract
The metabolic activation and enzyme inhibition characteristics of methoxsalen were investigated in rat liver microsomes obtained from untreated animals and those treated with a number of prototypic inducers of cytochrome P450.
Glutathione depletion assays have been carried out which show reactive metabolite generation to be markedly increased following phenobarbitone and β-naphthoflavone induction. Moreover, isoniazid induction led to levels of glutathione depletion significantly higher than those seen with other forms of induction, suggesting an important role for the cytochrome P4502E1 isozyme in the metabolic activation process.
Methoxsalen was shown to be an extremely potent inhibitor of 7-ethoxycoumarin-O-de-ethylase activity, with inhibition constants of the order of μm with microsomes obtained from untreated, phenobarbitone- and β-aphthoflavone-induced animals. In contrast, constants obtained with microsomes obtained from isoniazid-induced animals were found to be markedly higher.
Comparisons of the inhibition of 7-ethoxy and 7-pentoxyresorufin-O-dealkylase activities by methoxsalen and a number of structurally-related compounds have shown that a complete tricyclic ring system and an unsaturated 4′,5′-bond are structural prerequisites in the formation of reactive metabolites which inhibit cytochrome P450. These data implicate the furan ring system as the source of these metabolites and rule out the involvement of the pyrone ring system in the inhibition process.
Comparative Convulsant Potencies of Two Carbapenem Derivatives in C57 and DBA/2 Mice
Authors: De Sarro A , Imperatore C , Mastroeni P , De Sarro G 
Published: April 2011

Abstract
The behavioural and convulsant effects of imipenem and meropenem were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizure, and in C57 mice, a strain not prone to seizure.
DBA/2 mice were more susceptible than C57 mice to seizures induced by imipenem-cilastatin or meropenem. Imipenem was also 1·9 times more potent than meropenem in inducing clonus in DBA/2 mice.
To investigate the possibility that the seízure-inducing activity of imipenem might be due to a probenecid-like effect of cilastatin, animals were treated with imipenem alone.
No significant differences were observed between imipenem-cilastatin and imipenem-treated animals. Thus, it is reasonable to exclude a probenecid-like effect of cilastatin. Although the main mechanism for seizure-like activity of imipenem cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of imipenem from the CNS may be postulated. Cilastatin did not induce seizures. In addition, meropenem, a compound structurally related to imipenem, showed weak or no convulsant effects.
Contributions of β-Adrenoceptor Subtypes to Responses to Isoprenaline in Rat Isolated Distal Colon
Authors: McKean Jennifer , MacDonald Allan 
Published: April 2011

Abstract
The effects of the non-selective β-adrenoceptor antagonist propranolol and the β1 and β2-adrenoceptor-selective antagonists, respectively CGP 20712A (((±)-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanol hydrochloride)) and ICI 118,551 ((erythro(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol-hydrochloride)), on isoprenaline-induced inhibition of methacholine contractions in rat distal colon were investigated to determine the contributions of β-adrenoceptor subtypes to relaxation of smooth muscle.
Longitudinal segments of rat distal colon were suspended in Krebs solution at 37°C for isometric recording. The Krebs solution contained EDTA (30 μm), ascorbic acid (30 μm) and prazosin (0·1 μm) and was gassed with 95% O2−5% CO2. Isoprenaline produced a concentration-dependent inhibition of methacholine-induced contractions. Propranolol produced a small (4–6-fold) significant shift of the isoprenaline concentration-response curve at 0·003–0·01 μm. Larger shifts were produced by 0·3 μm (13-fold) and 1 μm (20-fold). CGP 20712A produced a small (3–5-fold) significant shift at 0·03–1 μm. ICI 118,551 produced small non-significant shifts (2–3-fold) at 0·03–1 μm. A combination of ICI 118,551 (0·3 μm) and CGP 20712A (0·1 μm) produced a 13-fold shift, a significantly greater shift than expected from the individual shifts. The shift produced by the combination of antagonists was slightly less than that produced by 1 μm propranolol (20-fold).
The effects of propranolol appear to be due mainly to a combination of β1 and β2-adrenoceptor blockade, although an additional action of propranolol at β3-adrenoceptors is likely.
Percutaneous Absorption of Indomethacin from Pluronic F127 Gels in Rats
Authors: Miyazaki Shozo , Tobiyama Takeshi , Takada Masahiko , Attwood David 
Published: April 2011

Abstract
Thermally reversible gels of the poly(oxyethylene)-poly(oxypropylene)-(polyoxyethylene) triblock copolymer, Pluronic F127, were evaluated as vehicles for the percutaneous administration of drugs using indomethacin as a model drug.
In-vivo percutaneous absorption studies using a rat model suggest that a 20% w/w aqueous gel of Pluronic F127 may be of practical use as a base for topical administration of the drug. The addition of isopropyl myristate or (+)-limonene to the gel formulation significantly improved percutaneous absorption, particularly when the gel was applied using an occlusive dressing technique.
Usefulness of the Pain-induced Functional Impairment Model to Relate Plasma Levels of Analgesics to Their Efficacy in Rats
Authors: Hoyo-Vadillo Carlos , Pèrez-Urizar José , López-Muñoz Francisco J 
Published: April 2011

Abstract
In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen.
Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered.
The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.
Improving the Oral Bioavailability of Sulpiride by Sodium Oleate in Rabbits
Authors: Naasani Imad , Kohri Naonori , Iseki Ken , Miyazaki Katsumi 
Published: April 2011

Abstract
To improve the limited oral bioavailability of sulpiride, a dosage form containing sodium oleate as an absorption enhancer was developed and evaluated using gastric-emptying-controlled rabbits in a cross-over manner.
In addition to the known properties of sodium oleate with respect to modifying the permeability of biomembranes, it was found to be capable of improving the physicochemical properties of sulpiride toward a higher lipophilicity (by ion-pair association) and a higher solubility (by micellar solubilization). Nonetheless, the incorporation of sodium oleate with sulpiride as a mixture filled in hard gelatin capsules failed to increase intestinal absorption, whereas the use of enteric capsules, instead of the hard gelatin capsules resulted in a significant increase (P &lt; 0·05) in the oral bioavailability.
Development of a Colon Delivery Capsule and the Pharmacological Activity of Recombinant Human Granulocyte Colony-stimulating Factor (rhG-CSF) in Beagle Dogs
Authors: Takaya Tomohiro , Ikeda Chikako , Imagawa Naoya , Niwa Kiyoshi , Takada Kanji 
Published: April 2011

Abstract
A peroral dosage form was examined to deliver recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the colon in beagle dogs. A new gelatin capsule with its inside surface coated with ethylcellulose was prepared for this purpose. RhG-CSF was dissolved with propylene glycol and was filled in the capsule. Several kinds of ethylcellulose-gelatin capsules with an ethylcellulose layer of thickness 46 to 221 mm were used. The capsule was filled with propylene glycol solution containing fluorescein as an absorption marker, castor oil derivative and citric acid. The hardness of the capsule was tested after the gelatin layer was dissolved using a hardness tester and was dependent on the thickness of the ethylcellulose layer of the capsule.
The time, Tmax, at which plasma fluorescein level reaches its maximum following oral administration of ethylcellulose capsules was used as a parameter for the in-vivo disintegration time of the ethylcellulose capsule into the colon. Capsules of thickness 84 mm with a Tmax of 4–6 h were filled with rhG-CSF solution containing fluorescein and were administered to dogs. After administration, blood samples were collected for 96 h and the blood total leucocyte (BTL) counts were measured as a pharmacological index of rhG-CSF.
The maximum BTL count appeared at 10 h then gradually decreased and returned to its normal level at 48 h. These results suggest the usefulness of ethylcellulose capsules for the delivery of rhG-CSF to the colon and the possibility of a new oral rhG-CSF dosage form has been elucidated.
Comparison of Body Distribution of Poly(vinyl alcohol) with Other Water-soluble Polymers after Intravenous Administration
Authors: Yamaoka Tetsuji , Tabata Yasuhiko , Ikada Yoshito 
Published: April 2011

Abstract
The body distribution of poly(vinyl alcohol) (PVA) with molecular weights (MW) from 14800 to 434000 Da was investigated after intravenous administration and compared with that of other water-soluble polymers such as poly(ethylene glycol) (PEG), gelatin, dextran, and pullulan.
The half-life of PVA in the circulation was prolonged from 90 min (MW 14800 Da) to 23 h (MW 434000 Da), similar to that of PEG which had a half-life of 30 min (MW 6000) and 20 h (MW 170000). However, the half-life of PVA was much longer than that of other polymers when compared at a similar molecular weight. PVA was located in most organs but with very small accumulation. An insignificant interaction of PVA with cell components, such as macrophages and blood cells, was observed. Similar to PEG, the excretion rate of PVA at the glomeruli was rapidly reduced around 30000 Da, as the molecular weight increased.
These results indicate that the half-life of intravenously injected PVA in the blood was mainly determined by the permeation characteristics of the kidney.
Role of Acid Back-diffusion in the Formation of Mucosal Ulceration and Its Treatment with Drugs in Diabetic Rats
Authors: Hung Chen-Road , Huang Eng-Yen 
Published: April 2011

Abstract
We have studied the role of acid back-diffusion in the formation of gastric mucosal ulceration and its treatment with several drugs in streptozotocin-induced diabetic rats. After vagotomy, the stomach of 1–8 week-old diabetic rats and age-matched control rats were irrigated with acid solutions of graded concentrations (50–150 mm HCl) for 1 or 3 h.
A marked increase in acid back-diffusion and in haemorrhagic ulceration was found in diabetic rats. The extent of acid back-diffusion and the severity of mucosal ulceration were dependent on the concentration and the time of contact of acid solutions with the gastric mucosa. A high correlation (r = −0·9227) between acid back-diffusion and mucosal ulceration was found in 3-h acid-irrigated diabetic rats.
In the 2-week diabetic rat, intragastric cimetidine (300 mg kg−1) or NaHCO3 (52 mg kg−1) significantly (P &lt; 0·05) reduced both acid back-diffusion and haemorrhagic ulcer formation, while atropine (1·0 mg kg−1) or bupivacaine (0·5%, 0·4 mL/rat) was ineffective. High blood glucose levels in diabetic rats were not influenced by these agents. Acid back-diffusion and ulceration in the diabetic rat were markedly reduced by daily administration but not single injection of insulin (50 units kg−1, s.c.).
Taken together, in the early stage of diabetes development, chronic insulin deficiency rather than nerve degeneration or hyperglycaemia may be responsible for the disruption of mucosal barriers. It is concluded that acid back-diffusion played an important role in the formation of acute haemorrhagic ulceration that can be inhibited by intragastric cimetidine, NaHCO3 or daily injection of insulin.
Fluid and Protein Secretion by the Submandibular Glands of Weanling Rats in Response to Cholinergic and Peptidergic Agonists at Various Doses
Authors: Baba Atsuko , Taniguchi Kunihisa , Motokawa Wataru , Ishibashi Kazunari , Okina Atsuhito , Abe Kimio 
Published: April 2011

Abstract
Fluid and protein secretion by the submandibular glands of 25-day-old rats were examined and compared in response to three cholinergic and four peptidergic sialogogues at various doses.
All cholinergic and peptidergic agonists used were potent sialogogues for the submandibular glands of the weanling rats over the wide range of doses used. The cholinergic agonists, bethanechol and methacholine and the peptidergic agonists, substance P, substance PTyr8 and eledoisin-related peptide used intravenously, acted similarly to each other on the submandibular glands of the rats, late in the natural weaning period, but carbachol and physalaemin had slightly different effects. Of the peptidergic agonists, physalaemin was the most potent sialogogue among four tachykinins tested at the low dose. The types of protein secreted by the submandibular glands of the weanling rats in response to all sialogogues used here were typical of the β-type.
These results indicate that all agonists used could mainly stimulate the acinar cells of the submandibular glands of the weanling rats which have already fully developed functionally at this time.
Enthalpy and Entropy Contributions to the Solubility of Sulphamethoxypyridazine in Solvent Mixtures Showing Two Solubility Maxima
Authors: Bustamante P , Escalera B 
Published: April 2011

Abstract
The solubility of sulphamethoxypyridazine was measured at several temperatures in mixtures of water: ethanol and ethanol: ethyl acetate. Sulphamethoxypyridazine was chosen as a model drug to compare the solvation effects of proton donor-proton acceptor (water and ethanol) and proton acceptor (ethyl acetate) solvents and mixtures of these solvents because this drug contains functional groups capable of Lewis acid-base interaction.
A plot of the mole fraction solubility against the solubility parameter (δ1) of these solvent mixtures showed two solubility maxima, one at δ1 = 30·87 MPa1/2 (20:80 v/v water: ethanol) and another at δ1 = 20·88 MPa1/2 (30:70 v/v ethanol: ethyl acetate) at all the temperatures under study. The enthalpies and entropies of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol to water:ethanol and ethanol:ethyl acetate mixtures were calculated to compare solvation characteristics of the solvent mixtures toward the drug. As ethanol is added to water, the entropy increases and the structure of the solvent mixture became less ordered, favouring the interaction of the drug with the solvent mixture. On the other hand, in the case of the ethanol: ethyl acetate mixture, solubility is favoured by the more negative enthalpy values. This way, the same result, i.e. a solubility maximum, is obtained by different routes.
In the ethanol: water mixtures, the dissolution process is entropy-controlled while enthalpy is the driving force in the case of ethanol: ethyl acetate mixtures. The two solvent systems show enthalpy-entropy compensation. Water deviates from the linear relationship due possibly to its hydrophobic effect.
5-HT3 Receptor-independent Inhibition of the Depolarization-induced 86Rb Efflux from Human Neuroblastoma Cells, TE671, by Ondansetron
Authors: Toral Joyce , Hu William , Critchett Donald , Solomon Andrew J , Barrett James E , Sokol Patricia T , Ziai M Reza 
Published: April 2011

Abstract
The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells.
This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 (M), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205–930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron.
A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(lH)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.
In-vitro Bronchorelaxing Effects of Novel Nitric Oxide Donors GEA 3268 and GEA 5145 in Guinea-pigs and Rats
Authors: Vaali Kirsi , Li Liang , Redemann Beatrix , Paakkari Ilari , Vapaatalo Heikki 
Published: April 2011

Abstract
Endogenously released nitric oxide (NO) in airways might contribute to physiological bronchodilation; induced production of NO might play a role in the pathogenesis of asthma, although it could also be a compensatory mechanism to other factors that cause bronchoconstriction or inflammation. To investigate the efficacy of NO donors on bronchial tone, the bronchorelaxing efficacies of NO donors, new experimental GEA compounds 3268 and 5145 (oxatriazole sulphonylamides) were compared with those of sodium nitroprusside and SIN-1 (3-morpholinosydnonimine) and to the standard β2-adrenergic agonist, salbutamol, in bronchi of guinea-pigs and rats in-vitro. Their relaxing effects were also studied in rat mesentery arteries to compare the selectivity for airways. The capacity of the NO donors to produce nitrites and nitrates was assayed by the Griess reaction.
The novel NO donors GEA 3268 and GEA 5145 were more potent bronchorelaxing agents than the old NO donors sodium nitroprusside and SIN-1. In guinea-pig bronchi, however, salbutamol was most potent. In rat bronchi the GEA compounds induced the strongest relaxation effect when compared with the old NO donors or with salbutamol. The airway selectivity of the drugs studied decreased in the order of salbutamol, SIN-1, GEA 5145, GEA 3268, sodium nitroprusside. The nitrites and nitrates produced spontaneously did not correlate with the efficacy of the relaxants
The results obtained suggest that NO is only partly responsible for the relaxation and the potency is dependent on the animal species and constricting agents used.
Pharmacological Activity of DC−015, a Novel Potent and Selective α1-Adrenoceptor Antagonist
Authors: Yen M H , Sheu J R , Peng I H , Lee Y M , Chern J W 
Published: April 2011

Abstract
The pharmacological activity of 3−((4−(2−methoxyphenyl)piperazin−1−yl)methyl)−2,3−dihydroimidazo(1,2−c)quinazolin−5(6H)-one (DC−015), a newly synthesized quinazoline derivative, was determined in rat isolated thoracic aorta and pressor responses were determined in spontaneously hypertensive rats (SHR).
Experimental results indicated that DC−015 is an α1-adrenoceptor-blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasocontraction (pA2 = 10&#x006d;̇54 ± 0&#x006d;̇55). These effects still persisted in denuded aorta. It was as potent as prazosin (pA2 = 10&#x006d;̇04 ± 0&#x006d;̇63). At higher concentrations (1&#x006d;̇0 μM), DC−015 also expressed 5−hydroxytryptamine (5−HT) receptor competitive antagonism, but this 5−HT blocking effect was not found in the prazosin-administration group. [3H]Inositol monophosphate formation stimulated by phenylephrine (30 μM) in rat thoracic aorta was diminished by DC−015 (3 and 10 nM) and prazosin (10 nM); whereas the cAMP content of rat thoracic aorta was not altered by DC−015 and prazosin. Furthermore, intravenous administration of DC−015 and prazosin (both at 0&#x006d;̇01, 0&#x006d;̇05 and 0&#x006d;̇1 mg kg11) induced a dose-dependent reduction of mean arterial pressure which reached a maximal effect at 5 min after injection and persisted over 2 h in SHR. A higher dose of DC−015 (0&#x006d;̇1 mg kg−1, i.v.) did not cause any significant changes in heart rate, whereas, the same dose of prazosin (0&#x006d;̇1 mg kg−1, i.v.) produced a decrease which seems to parallel the time course of the hypotensive response.
We can conclude that the DC−015 is a potent, highly selective α1-adrenoceptor antagonist in vascular smooth muscle.