bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine Derivatives in Pain and Antidepressant Tests in Mice
Authors: Rubat C , Coudert P , Mavel S , Fialip J , Couquelet J 
Published: April 2011

Abstract
The antinociceptive and antidepressant effects of two pyrazolotriazine derivatives, 2-phenyl-3,3α-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl)methyl-pyrazolo[1,5-d][1,2,4]-triazine (SMI) and 2-phenyl-3,3α-dihydro-4-oxo-5-[4-(4-fluorophenyl)piperazin-1-yl]methylpyrazolo[1,5-d][1,2,4] triazine (SM3) have been investigated in mice using classical pharmacological tests.
The intraperitoneal LD50 values of SMI and SM3 were 253.4 and 218.8 mg kg− respectively. SMI and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 ≅ 10–15 mgkg−, i.p.) and in the hot-plate test. The antinociceptive effects of the triazines were significantly reduced by administration of naloxone (1 and 3.2 mgkg−, s.c.) and yohimbine (1 mgkg−, p.o.). Acute intraperitoneal administration of both compounds (1 mgkg− SMI or 1.5 mgkg− SM3) potentiated morphine (0.15 mgkg−, s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mgkg−, i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50 mgkg−, i.p.) in conjunction with carbidopa (25 mgkg−, i.p.). Furthermore, neither compound (at 100 mgkg−, i.p.) significantly reduced the duration of immobility of mice in the forced swimming test, and both (at 75 mgkg−, i.p.) were ineffective at enhancing the toxic effects of yohimbine (30 mgkg−, s.c). Only SM3 (ED50 = 74.5 mgkg−, i.p.) significantly antagonized reserpine (2.5 mgkg−, i.p.)-induced ptosis.
Thus, the results suggest that SMI and SM3 have antinociceptive properties related to co-involvement of opioidergic and α2-adrenoceptor mechanisms without associated antidepressant properties.
Interaction between Pefloxacin and Aminophylline in Genetically Epilepsy-prone Rats
Authors: Imperatore C , Trimarchi G R , De Sarro A 
Published: April 2011

Abstract
The effects of a chronic treatment with pefloxacin on aminophylline-induced seizures in genetically epilepsyprone rat have been investigated. Two series of experiments were performed. In the first, animals received pefloxacin orally twice a day for five days, then were administered aminophylline intraperitoneally and the occurrence of seizures was evaluated. In the second series of experiments, theophylline serum concentration was evaluated in rats subject to the same experimental protocol.
Pefloxacin significantly, and in a dose-dependent manner, increased the occurrence of seizure phases induced by aminophylline, but did not influence theophylline serum levels measured at different times after the injection of aminophylline.
We suggest that additive neurotoxic effects of both pefloxacin and aminophylline might contribute to the increased severity of seizure score. The possible role of GABA-benzodiazepine, excitatory amino acid and purinergic mechanism, and the role of pharmacokinetic factors are discussed.
Beneficial Effects of Clonidine in Streptozotocin-induced Diabetes and DOCA-hypertensive Rats
Authors: Satia Milan C , Damani Rushabh R , Goyal Ramesh K 
Published: April 2011

Abstract
This investigation was undertaken to study the effects of chronic treatment with clonidine on cardiovascular complications in streptozotocin-induced diabetes and DOCA-hypertensive rats.
Injection of streptozotocin induced glucosuria, hyperglycaemia, hypoinsulinaemia, hypothyroidism, hypercholesterolaemia, hypertriglyceridaemia, bradycardia and a decrease in left ventricular developed pressure (LVDP). DOCA by itself did not induce any change in blood-glucose levels in non-diabetic animals. However, in diabetic animals DOCA significantly reduced blood-glucose levels. Treatment of diabetic and diabetic hypertensive animals with clonidine (25 μg kg− every day for six weeks) significantly prevented diabetes-induced loss of body weight, bradycardia, cardiac hypertrophy and hypothyroidism. It also partially, but significantly, prevented diabetes-induced hyperglycaemia and hypoinsulinaemia in both diabetic and diabetic-hypertensive animals. There was a significant reduction in diabetes-induced elevation of cholesterol and triglyceride levels and an improvement in LVDP at higher filling pressure in diabetic and diabetic hypertensive animals.
This investigation shows that chronic treatment with clonidine produces a number of beneficial effects such as prevention of hyperlipidaemia and hypothyroidism and improvement in cardiomyopathy and glycaemic control in diabetic and diabetic hypertensive rats.
Assessment of the Antitussive Efficacy of Codeine in Cough Associated with Common Cold
Authors: Freestone C , Eccles R 
Published: April 2011

Abstract
Codeine is generally accepted as the standard antitussive against which new antitussive medications are compared. This presents a problem because the support for codeine's antitussive activity comes from studies on cough in animals, and chronic and induced cough models in man, whereas antitussives are almost exclusively used for the treatment of cough associated with acute upper respiratory tract infection (URTI). The aims of this study were twofold. Firstly, to study the antitussive efficacy of codeine in cough associated with URTI and, secondly, to validate a sound meter as tool for quantifying cough.
The efficacy of codeine was assessed in a double-blind, stratified, placebo-controlled, parallel-group, clinical trial using three different measures of cough: cough sound-pressure levels (CSPLs) measured on a sound meter; subjective scores of cough severity; and cough frequency recorded by means of a microphone connected to an ink-pen recorder. A group of 82 subjects (51 females and 31 males; mean age 23.5 years, range 18–46 years) with cough owing to acute URTI were included in the study. The study took place on two separate study days. On study day 1 cough measurements were made before and 90 min after treatment with a single dose of either 50 mg codeine or matched placebo in capsule form. The same three measures of cough were repeated 2–5 days later (study day 2). On study day 1 a highly significant (P &lt; 0.0001) decrease in all three measures of cough was found after treatment with both placebo and codeine yet there was no significant difference between the treatment groups. A highly significant (P &lt; 0·0001) decrease in the three measures of cough was also found between days 1 and 2.
The results demonstrate that codeine is no more effective than placebo in reducing cough associated with acute URTI, as measured by CSPLs, cough frequency or subjective symptom scores. This result might be explained on the basis of two central pathways for cough; a reflex pathway via the brain-stem which is sensitive to codeine and a voluntary pathway via the cortex which is unaffected by codeine. The results also demonstrate that the sound-level meter appears to be a potentially useful investigative tool for the assessment of cough and antitussive efficacy.
Bioadhesive Microspheres for Ophthalmic Administration of Acyclovir
Authors: Genta I , Conti B , Perugini P , Pavanetto F , Spadaro A , Puglisi G 
Published: April 2011

Abstract
The bioavailability of acyclovir to the ophthalmic epithelium is low and when the drug is administered in ophthalmic ointment it must be applied every four hours. An emulsification technique has been used to prepare acyclovir-loaded chitosan microspheres with the aim of promoting the prolonged release of drug and increasing its ocular bioavailability.
The microparticulate drug-delivery systems obtained have been characterized for their morphology and physicochemical characteristics by in-vitro dissolution tests and in-vivo ocular administration to rabbits. The results show that the microspheres obtained are always quite small—the diameters of 90% of the particles are ≤ 25 μm (i.e. d90% never exceeds 25 μm) and physicochemical characterization shows that the drug is homogeneously dispersed in an amorphous state inside the microspheres. The in-vitro dissolution profile of acyclovir from chitosan microspheres is slower than that for the raw drug. Results from in-vivo ocular administration of acyclovir-loaded microspheres to the rabbit eye show prolonged high concentrations of acyclovir and increased AUC values.
The microparticulate drug-carrier seems a promising means of topical administration of acyclovir to the eye.
Study of the Effective Dose of a Topical Antifungal Agent, Omoconazole Nitrate, on the Basis of Percutaneous Pharmacokinetics in Guinea-pigs and Mice
Authors: Hashiguchi Terushi , Ryu Akie , Itoyama Toshio , Uchida Katsuhisa , Yamaguchi Hideyo 
Published: April 2011

Abstract
The clinically useful optimum dose of omoconazole nitrate, a topical antifungal agent, has been examined by analysing the percutaneous pharmacokinetics of the drug to assess its pharmacological activity in an in-vivo study. Creams containing omoconazole nitrate were prepared on a pilot basis.
The therapeutic effect of the omoconazole nitrate creams was examined in an in-vivo pharmacological dermatophytosis infection model in guinea-pigs. Creams containing 0.25% or higher concentrations of omoconazole nitrate resulted in significant inhibition compared with no treatment and with vehicle-treated controls. In the mycological examination no growth of dermatophytes was observed for creams containing 1% or higher concentrations. In an in-vitro hairless mouse skin-permeability test a non-linear least squares program based on a fast inverse Laplace transform algorithm was used to calculate the partition and diffusion parameters of omoconazole nitrate in the stratum corneum and viable epidermis. The time-course of drug concentrations in the skin of the guinea-pig, estimated on the basis of these parameters, led to predictions that percutaneous drug concentrations on the guinea-pig would require 10 or more days to reach equilibrium in the skin; that drug concentrations in the corneum-viable epidermis border, where dermatophytes are considered to grow, would exceed the minimum effective concentration when 0.1% or higher concentration creams were used; and that for binding to keratin drug concentrations would reach the practical minimum effective concentration when creams containing 0.5% or more omoconazole nitrate were used.
These results show that partition and diffusion parameters obtained from in-vitro skin permeation studies can be used to predict in-vivo percutaneous pharmacokinetics and to estimate therapeutically effective concentrations.
Gastroprotective Effect of MX1 (a Novel Salt of the Active Metabolite of Roxatidine with a Complex of Bismuth and Citric Acid) Against Stress Ulcers in Rats
Authors: Marazova K , Klouchek E , Popov A , Ivanov Ch , Krushkov I 
Published: April 2011

Abstract
We have studied the effect of the newly synthesized agent MX1, a salt of the active metabolite of the H2-blocker roxatidine with a complex of bismuth and citric acid (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide-2-hydroxypropane-1,2,3-tricarboxilate-bismuth(3+) complex), against restraint stress ulcers in rats (24 h immobilization).
The effects of MX1 (12.5, 50, 125, 184 and 250 mg kg−) were compared with the effects of equimolar doses of roxatidine (6.5, 25, 70, 100 and 140 mg kg−) and bismuth subcitrate (6.5, 25, 70, 100 and 140 mg kg−). The results show that MX1-pre-treatment, at all the doses used, significantly reduces the mean number and size of ulcers. Even at the lowest dose the number of ulcers was reduced by 64.3% and the size of the ulcer by 55.9%. Roxatidine (25, 70, 100 and 140 mg kg−) dose-dependently reduces ulcer size and number by 24.6, 55.6, 85.3 and 890% and by (+ 7.2), 14.3, 571 and 67.9%, respectively. Bismuth subcitrate significantly reduces ulcer size and number only at the highest dose employed (−28.5 and −44.8%, respectively). The morphometric results have been confirmed histomorphologically.
The results suggest that MX1 has a gastroprotective effect against stress-induced ulcers which is similar to that of the parent compound and more pronounced than that of bismuth subcitrate.
Chronic Treatment with Prazosin Causes a Subtype-specific Increase in the α1-Adrenoceptor Density of the Stressed Rat Cerebral Cortex
Authors: Takita Manabu , Taniguchi Takanobu , Zhu Jun , Muramatsu Ikunobu 
Published: April 2011

Abstract
The effects of chronic treatment with prazosin and of immobilization stress on the α1-adrenoceptor subtypes in rat cerebral cortex have been examined.
Prazosin-treated rats were allowed free access to tap water containing two different concentrations of prazosin (16 or 156 mg L−) for 5 weeks. The mean plasma concentrations of prazosin were 5 ng mL− in groups treated with a low dose and 8 or 14 ng mL− in those treated with a high dose. Immobilization stress (2 h day−, 2 weeks) or chronic treatment with a low dose of prazosin caused no significant change in the affinity for [3H]prazosin or in the maximum number of α1-adrenoceptor sites (Bmax). However, treatment with prazosin (low dose) combined with stress increased the density of α1-adrenoceptors with low affinity for prazosin. Treatment with a high dose of prazosin increased the density of α1L-adrenoceptors, irrespective of stress loading. The densities of α1A- and α1B-adrenoceptors with high affinity for prazosin were increased only after treatment with a high dose of prazosin in combination with stress.
These results indicate that three distinct α1-adrenoceptor subtypes, α1A, α1B and α1L, might be affected differently by treatment with prazosin and by stress.
Antinociceptive Effect of some Amaryllidaceae Plants in Mice
Authors: Çakici Iclal , Ulug Hediye Y , Inci Sibel , Tunçtan Bahar , Abacioglu Nurettin , Kanzik Ilker , Sener Bilge 
Published: April 2011

Abstract
The antinociceptive effects of ethanolic extracts of Pancratium maritimum L., Narcissus tazetta subspecies tazetta and Leucojum aestivum L. bulbs have been investigated in mice using the p-benzoquinone-induced abdominal constriction and hot-plate tests.
In the p-benzoquinone-induced abdominal constriction test the ethanolic extracts of P. maritimum (300, 600 or 1200 mg lg−, s.c.) and N. tazetta subsp. tazetta (5, 50, 100 or 200 mg kg−, s.c.) caused dose-dependent inhibition of abdominal constrictions whereas a fluctuating response was obtained from ethanolic extracts of L. aestivum (2.5–500 mg kg−, s.c). In the hot-plate test P. maritimum and L. aestivum caused a significant increase of latency only at the highest concentrations used (1200 mg kg− and 500 mg kg−, i.p., respectively). However, at these concentrations they also caused significant toxic effects. In contrast with P. maritimum and L aestivum, N. tazetta subsp. tazetta (5–500 mg kg−, i.p.) extracts had no antinociceptive effect in this test.
These findings indicate that the antinociceptive effect of Amaryllidaceae plants differs depending on the model of nociception investigated.
Pharmacological Studies on Puerariae flos III: Protective Effects of Kakkalide on Ethanol-induced Lethality and Acute Hepatic Injury in Mice
Authors: Yamazaki Takashi , Nakajima Yoshijiro , Niiho Yujiro , Hosono Tsuyoshi , Kurashige Tatsuo , Kinjo Junei , Nohara Toshihiro 
Published: April 2011

Abstract
Kakkalide, one of the major isoflavonoid components of Puerariae flos, has been investigated for its effect on ethanol-induced intoxication and on hepatic injury, including hyperglycaemia, in mice.
Kakkalide reduced mortality associated with administration of ethanol. At doses of 100 and 200 mg kg− the effect of kakkalide was significant. The same dose of kakkalide prevented increased serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activity. At a dose of 200 mg kg− it also counteracted ethanol-induced elevation of glucose levels.
These results suggest that kakkalide might be useful for counteracting the effects of alcohol and might be effective for treating hepatic injury.
Synthesis and Structure-Opioid Activity Relationships of trans-(±)-3,4-Dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides
Authors: Cheng Chen-Yu , Chen Chin-Yuan , Tao Pao-Luh 
Published: April 2011

Abstract
To explore the effects of attaching a hydroxy function to the cyclohexane ring of κ-selective opioid N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamides, trans-(±)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides (1–4) and their benzoates (5–8) have been synthesized in a divergent and stereoselective manner.
When compared with the parent compound U-50488, hydroxy derivatives 1–4 maintained high selectivity towards the κ-opioid receptor (μ/κ ratio = 24 to &gt;91); while displaying significant reduction in binding affinity (Ki,κ = 75–218 nm). The lowest κ-affinity was observed with compound 4, where the hydroxy group is attached at the 5-axial or 5-β position. Further reduction in κ-affinity was observed when the hydroxy function was benzoylated. However, the 4β, 5α, and 5β isomers (6–8) maintained varying degrees of κ-selectivity; the 4α-isomer compound 5, with its benzoate moiety situated at the 4-axial position is now a moderately potent μ-selective opioid (Ki/μ= 168 nm, μ/κ = 0.076).
The results suggest the importance of lipophilicity in binding to opioid receptors and the presence of a specific lipophilic binding site on the μ-opioid receptor.
Algorithms for Skin Permeability Using Hydrogen Bond Descriptors: the Problem of Steroids
Authors: Abraham Michael H , Martins Filomena , Mitchell Robert C 
Published: April 2011

Abstract
Several algorithms that use hydrogen bond descriptors have been published for the permeation of compounds from aqueous solution through human stratum corneum. In the present work, all the skin permeability coefficients, Kp in cm s−, used in these algorithms for non-steroids have been correlated through the Abraham equation to give a new algorithm:
where n is the number of solutes, r is the correlation coefficient, s.d. is the standard deviation, and F is the F-statistic. The solute descriptors are: R2 an excess molar refraction, the dipolarity/polarizability, the overall or effective hydrogen-bond acidity and basicity, and VX the McGowan characteristic volume. Equation 1 is a reasonably good predictor of log Kp values for steroids as given by Johnson et al., but not for those given by Scheuplein.
In-vitro Permeability of the Human Nail and of a Keratin Membrane from Bovine Hooves: Prediction of the Penetration Rate of Antimycotics through the Nail Plate and their Efficacy
Authors: Mertin Dirk , Lippold Bernhard C 
Published: April 2011

Abstract
In contrast to the partition coefficient octanol/water the molecular size of penetrating drugs has a noticeable influence on the permeability of the human nail plate and a keratin membrane from bovine hooves. The relationship between permeability and molecular weight is founded on well-established theories. The correlation between the permeability of the nail plate and that of the hoof membrane allows a prediction of the nail permeability after determination of the drug penetration through the hoof membrane.
The maximum flux of ten antimycotics (amorolfine, bifonazole, ciclopirox, clotrimazole, econazole, griseofulvin, ketoconazole, naftifine, nystatin and tolnaftate) through the nail plate was predicted on the basis of their penetration rates through the hoof membrane and their water solubilities. An efficacy coefficient against onychomycoses was calculated from the maximum flux and the minimum inhibitory concentration.
Accordingly, amorolfine, ciclopirox, econazole and naftifine are expected to be especially effective against dermatophytes, whereas in the case of an infection with yeasts only, amorolfine and ciclopirox are promising.
Liver and Gastrointestinal First-pass Effects of Azosemide in Rats
Authors: Kim Jonghan , Kim So H , Lee Myung G 
Published: April 2011

Abstract
Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats.
The total body clearances of azosemide after intravenous (5 mg kg−) and intraportal (5 and 10 mg kg−) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg−) of the drug was significantly lower than that after intravenous administration (5 mg kg−) of the drug (1000 vs 1270 μg min mL−) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC0–8 h) after oral administration (5 mg kg−) of the drug was considerably smaller than that after intraportal administration (5 mg kg−) of the drug (271 vs 1580 μg min mL−) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC0–8 h after oral administration (5 mg kg−) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg−) of the drug (271 vs 320 μg min mL−), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats.
The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.
Pharmacological and Pharmacokinetic Characteristics of YM435, a Novel Dopamine DA1-Receptor Agonist, in Anaesthetized Dogs
Authors: Yatsu Takeyuki , Miyamoto Ikuo , Kaneko-Takanuki Fumiyo , Watanabe Takashi , Takenaka Toichi 
Published: April 2011

Abstract
Time-course of plasma concentration of unchanged drug of the dopamine DA1-receptor agonist (–)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrate (YM435), and its effects on blood pressure and renal blood flow were investigated in anaesthetized dogs.
Continuous intravenous infusion of YM435 (0.1–3 μg kg− min−) rapidly increased renal blood flow and lowered blood pressure in a dose-dependent manner. These effects remained generally stable throughout the infusion period. Following the start of infusion, plasma concentration of unchanged drug also rose rapidly and dose-dependently and remained virtually constant throughout the infusion period. A significant correlation was observed between log YM435 plasma concentration and the increase in renal blood flow (r = 0.93, P &lt; 0.0001) and between the former and the reduction in blood pressure (r = 0.93, p &lt; 0.0001).
The present results indicate that YM435 produces renal vasodilatation and lowering of blood pressure in a dose-dependent manner and with rapid onset following continuous intravenous infusion, and that these effects are generally stable throughout the period of infusion. These haemodynamic effects of YM435 were in good agreement with the time-course of plasma concentration of unchanged drug.