bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological Evaluation of the Anti-inflammatory Activity of a Citrus Bioflavonoid, Hesperidin, and the Isoflavonoids, Duartin and Claussequinone, in Rats and Mice
Authors: Emim José Artur Da Silva , Oliveira Alaíde Braga , Lapa Antonio José 
Published: April 2011

Abstract
Pretreatment of rats with hesperidin (50 and 100 mg kg−1, s.c.) reduced the paw oedema induced by carrageenan by 47 and 63%, respectively, within 5 h. The effect was equivalent to that produced by indomethacin (10 mg kg−1, p.o.), although unrelated to the administered dose, particularly at high doses. At 100 mg kg−1 hesperidin decreased the rat paw oedema induced by dextran by 33%, without influencing the histamine-induced paw oedema. Hesperidin also inhibited pleurisy induced by carrageenan, reducing the volume of exudate and the number of migrating leucocytes by 48 and 34%, respectively, of control values. Equal doses of duartin and claussequinone were ineffective in all the above tests. Pretreatment of mice with hesperidin (100 mg kg−1, s.c.) reduced acetic acid-induced abdominal constriction by 50%, but did not affect the tail flick response. Hyperthermia induced by yeast in rats was slightly reduced by hesperidin. No lesions of the gastric mucosae were detected in rats pretreated with hesperidin. The results indicate that hesperidin obtained from citrus cultures may present a potential therapeutical use as a mild antiinflammatory agent, being also useful as a precursor of new flavonoids endowed with such activity.
High Resolution 1H NMR Spectroscopic Studies of the Metabolism and Excretion of Ampicillin in Rats and Amoxycillin in Rats and Man
Authors: Connor S C , Everett J R , Jennings K R , Nicholson J K , Woodnutt G 
Published: April 2011

Abstract
High resolution proton nuclear magnetic resonance (1H NMR) spectroscopy has been used to investigate the metabolism and urinary excretion of the aminopenicillins, ampicillin and amoxycillin, in rats and of amoxycillin in man. 1H NMR resonances of the aminopenicillins, together with those for their 5R, 6R and 5S, 6R penicilloic acids and diketopiperazine metabolites were detected, assigned and quantified in urine samples with the aid of spin-echo NMR techniques. The dimer of amoxycillin was detected in rat urine for the first time together with novel drug-related resonances assigned to amoxycillin carbamate. Quantitative 1H NMR spectroscopic results were consistent with HPLC and microbiological data considering that only single measurements were recorded. Due to the short analysis time and simple sample preparation, NMR was particularly useful for studying the metabolism of the aminopenicillins for which sample degradation poses analytical problems. The non-invasive character of 1H NMR spectroscopic analysis of urine also provided unique information on a reversible reaction between amoxycillin and bicarbonate, an endogenous urinary metabolite.
The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats
Authors: Dehpour A R , Zolfaghari M E , Samadian T , Vahedi Y 
Published: April 2011

Abstract
We have examined the protective effect of liquorice or its derivatives against gastric ulcer induced by aspirin. A granular mixture of aspirin alone and coated with liquorice or its derivatives including the deglycyrrhized form, a high glycyrrhized form, carbenoxolone, and enoxolone were studied. Aspirin coated with liquorice reduced the number and size of ulcers, reducing the ulcer index from 1·5±0·12 to 0·5 ± 0·12 and the incidence from 96% to 46%. Coating with derivatives was less effective (ulcer index, 0·70–0·94; incidence 62–76%).
Behavioural consequences of cocaine withdrawal in rats
Authors: Fung Yiu K , Richard Lori A 
Published: April 2011

Abstract
This study was designed to examine the impact of cocaine withdrawal on several behavioural parameters in rats. After 1 and 3 day withdrawal from continuous cocaine administration (50 mg kg−1 for 28 days, subcutaneous infusion via osmotic minipumps), rats showed significant changes in spontaneous locomotor activity, conditioned avoidance response and increased levels of anxiety. However, cocaine withdrawal did not alter the motor co-ordination, body weight, food and water consumption of these animals. The neurochemical effects of cocaine on central dopaminergic neuronal systems may account for locomotor deficit observed in these cocaine-withdrawal animals.
Predicting the Solubility of Drugs in Solvent Mixtures: Multiple Solubility Maxima and the Chameleonic Effect
Authors: Escalera J B , Bustamante P , Martin A 
Published: April 2011

Abstract
An approach to reproduce the solubility profile of a drug in several solvent mixtures showing two solubility maxima is proposed in this work. The solubility of sulphamethoxypyridazine was determined at 25°C in several mixtures of varying polarity (hexane: ethyl acetate, ethyl acetate:ethanol and ethanol: water). Sulphamethoxypyridazine was chosen as a model drug because of its proton-donor and proton-acceptor properties. A plot of the mole fraction of the drug vs the solubility parameter of the solvent mixtures shows two solubility peaks. The two peaks found for sulphamethoxypyridazine demonstrate the chameleonic effect as described by Hoy and suggest that the solute-solvent interaction does not vary uniformly from one mixture to another. The different behaviour of the drug in mixtures of two proton-donor and proton-acceptor solvents (alcohol and water), and in mixtures of one proton acceptor (ethyl acetate) and one proton donor-proton acceptor (ethanol) is rationalized in terms of differences in the proton donor-acceptor ability of the solvent mixtures. An approach based on the acidic and basic partial solubility parameters together with the Hildebrand solubility parameter of the solvent mixtures is developed to reproduce the experimental results quantitatively. The equation predicts the two solubility maxima as found experimentally, and the calculated values closely correspond to the experimental values through the range composition of the solvent mixtures. These results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid-base interactions; this approach can assist the product formulator to choose the proper solvent mixture for a new drug. A good solvent blend should result in a solubility parameter close to that of the drug; the acidic and basic partial solubility parameter values should provide maximum acid-base interaction of the mixed solvent with the drug. The failure in one of these conditions results in decreased solubility. Solubility parameters as well as the acidic and basic parameters are tabulated or they can be obtained from group contribution methods, making easier the evaluation of the best solvent mixture for a drug.
Fluconazole: Interspecies Scaling and Allometric Relationships of Pharmacokinetic Properties
Authors: Jezequel Serge G 
Published: April 2011

Abstract
Fluconazole is a novel azole antifungal agent with low lipophilicity and high metabolic stability which has been investigated pharmacokinetically in six animal species and in man. The pharmacokinetic parameters of this drug have been compared across species and allometric relationships for fluconazole have been established. The volume of distribution was an ‘invariant’ parameter. When expressed in units corrected for bodyweight, the volume of distribution was constant across species, in keeping with being distributed throughout body water. Allometric relationships were obtained for total and renal clearance parameters. The closeness of the allometric exponents was in keeping with renal elimination accounting for most of the clearance in all species investigated. It also follows from the invariant characteristics of the volume of distribution term that an allometric relationship for plasma elimination half-life (t½) was also evident. Fluconazole thus possesses pharmacokinetic properties which are predictable for all terrestrial mammals. More detailed analysis of renal clearance (CLR) with regard to its relationship with glomerular filtration rate (GFR) has also been carried out. The data suggest that CLR is a direct function of GFR, involves only passive diffusion phenomena and that the extent of tubular re-absorption (approx. 80%) is constant across species. These observations are in keeping with the moderate lipophilicity and plasma protein binding of fluconazole and the incomplete re-absorption of the drug from the kidney tubules. It follows from these investigations that a knowledge of GFR in patients with altered renal function should allow a mechanistically based prediction of elimination characteristics of fluconazole.
The Effects of Transcervical Monofilament Insertion on the Microbial Status of the Uterus in Guinea-pigs
Authors: Bilbruck J , Hanlon G W , Gard P R , Martin G P 
Published: April 2011

Abstract
The monofilament marker tail attached to intra-uterine contraceptive devices (IUCDs) has been implicated in the development of pelvic infection because it acts as a substrate for bacterial adhesion, and facilitates the transmission of vaginal bacteria into the uterus. A guinea-pig model was used to investigate the role of transcervical monofilaments in the transmission of vaginal bacteria into the uterus. By 21 days the degree of uterine contamination was significantly lower than after 24 h (P &lt; 0·05), but was still significantly greater than control values (P &lt; 0·01). Coating the monofilaments with poly (2-hydroxyethyl-ethacrylate) (polyHEMA) had no effect on uterine bacterial counts at 24 h. After 21 days, however, contamination within the uteri fitted with polyHEMA-coated monofilaments had significantly increased from levels observed at 24 h (P &lt; 0·01). These counts were also significantly greater than those recorded for the uncoated and control groups at the same time interval. In animals fitted with monofilaments, in which chlorhexidine had been incorporated into the polyHEMA coating, the level of uterine contamination after 24 h was significantly lower than that observed with uncoated threads at the same time interval (P &lt; 0·02). After 21 days there was no significant difference between uterine bacterial counts from the chlorhexidine group and control animals. It is concluded that the use of such drug-loaded monofilaments offers the potential to minimize infections associated with the transcervical insertion of IUCDs.
Comparison of the Free Radical-scavenging Ability of Captopril and Ascorbic Acid in an In-vitro Model of Lipid Oxidation. Implications for Reperfusion Injury and ACE Inhibitor Therapy
Authors: Kaufman Michael J 
Published: April 2011

Abstract
The free radical-scavenging activity of captopril and ascorbic acid was determined by assessing their ability to inhibit the peroxidation of linoleic acid in sodium dodecyl sulphate (SDS) micelles at 37°C. The extent of peroxidation was monitored polarographically using an oxygen electrode to determine oxygen consumption rates. Ascorbic acid was observed to inhibit the peroxidation in a concentration-dependent fashion with an IC50 value of 17 μm. In contrast, the addition of captopril at concentrations up to 500 μm did not result in any detectable inhibition. Unlike ascorbic acid, no synergistic effect, as evidenced by the duration of inhibition, was observed with captopril/α-tocopherol mixtures. Measurements of the partitioning of captopril between SDS micelles and the aqueous phase show that 37% of the bulk captopril concentration is localized within the micellar phase; this indicates that phase separation of captopril from the lipid peroxyl radicals is not the cause of the observed lack of inhibitory activity.
Comparative 5-HT2-Receptor Antagonist Activity of Amesergide and its Active Metabolite 4-Hydroxyamesergide in Rats and Rabbits
Authors: Cohen Marlene L , Kurz Kenneth D , Fuller Ray W , Calligaro David O 
Published: April 2011

Abstract
Amesergide is an orally active ergoline amide, 5-HT2-receptor antagonist with a long duration of action. Since a major metabolite of amesergide is 4-hydroxyamesergide, we questioned whether the formation of this metabolite might contribute to the pharmacological activity and long duration of action observed after oral administration of amesergide. 4-Hydroxyamesergide was a potent 5-HT2-receptor antagonist with an affinity equal to or greater than amesergide under in-vitro conditions as measured by blockade of vascular 5-HT2 receptors, and 5-hydroxytryptamine (5-HT)-amplified ADP-induced rabbit platelet aggregation. Furthermore, 4-hydroxyamesergide, like amesergide, inhibited the pressor response to 5-HT after its intravenous administration to rats and was about 3-fold more potent than amesergide in this regard. 4-Hydroxyamesergide was also a potent inhibitor of vascular 5-HT2 receptors after oral administration to rats. After oral administration, 4-hydroxyamesergide had a similar or slightly greater duration of activity than the parent molecule. 4-Hydroxyamesergide, again like amesergide, also blocked central 5-HT2 receptors after its in-vivo administration to rats as measured by its ability to inhibit quipazine-induced increases in serum corticosterone. Thus, the formation of 4-hydroxyamesergide after oral administration of amesergide to animals and man may contribute to the potency and long duration of action of amesergide as a 5-HT2-receptor antagonist.
Influence of Age on the Disposition and Renal Handling of Enprofylline in Rats
Authors: Muraoka Isao , Hasegawa Takaaki , Nadai Masayuki , Wang Li , Tagaya Osamu , Nabeshima Toshitaka 
Published: April 2011

Abstract
The effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline (&gt; 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (Vmax) (223·33,160·24 and 142·98 μg min−1 kg−1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (Vmax/Km) of enprofylline (75·45, 51·03 and 44·13 mL min−1 kg−1, respectively), while a slight change in the Michaelis-Menten constant (Km) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.
A New Method of Estimating Volume During Powder Compaction and the Work of Compaction on a Rotary Tablet Press from Measurements of Applied Vertical Force
Authors: Oates R J , Mitchell A G 
Published: April 2011

Abstract
The volume per unit mass of a powder bed, V’, during compaction on a rotary tablet press has been expressed as a function of pressure, P using a modification of Kawakita’s equation: V = (V’o –V’)P’/(P+P’)+V’, where V’o, V and P’ constitute a set of unique values for a given powder or powder mix under specified tableting conditions. The volume, V, is determined from the machine deformation constant which is the relationship between applied vertical force and the deformation of the tablet press and the punches. An iterative method is described which allows the determination of V’o, V’ and P’ from the slope and intercept of V vs 1/(P+P’) where all values are evaluated at peak pressure. By substituting these values into the equation, the volume of a given powder bed during compaction up to peak pressure can be accurately predicted from the pressure vs time curve. This method of estimating volume and hence punch displacement, is much simpler than an earlier analytical method which was derived from direct measurements of punch displacement under running conditions. Since volume is an explicit function of pressure, the work of compaction is also a function of pressure. Estimates of the work of compaction are in good agreement with values calculated using our previous method. Values of V’o, V’ and P’ are reported for 35 pharmaceutical materials and could be incorporated into a database library of drugs and tableting excipients. This database could then be used for the quality control of incoming raw materials (batch to batch assessment) and for the comparison of materials from alternative sources. The experimental methodology and method of calculation should, in principle, be applicable to any rotary tablet press and together with other tableting parameters (such as compression time, peak offset time, decompression time, elastic recovery and work of compaction) would provide a simple, inexpensive method for the in process validation of tablet compression.
Is Desensitization of Intestinal 5-Hydroxytryptamine Receptors an In-vitro Phenomenon?
Authors: Hardcastle J , Hardcastle P T , Carstairs J W M , Franks C M 
Published: April 2011

Abstract
The responses of proximal jejunum and distal ileum to successive applications of 5-hydroxytryptamine (5-HT) were examined in-vitro and in-vivo by measuring the electrical changes that reflect the stimulation of Cl− secretion. In stripped intestinal sheets the second application of a maximal concentration of 5-HT failed to elicit any response, indicating that complete desensitization had occurred. If submaximal concentrations were used, a second response was observed, although it was smaller than the first, indicating partial desensitization. Replacing the bathing solutions following application of a maximal 5-HT concentration also reduced, but did not abolish, the degree of desensitization observed with a second application of 5-HT. In an in-vivo preparation, however, there was no diminution of the responses to four successive maximal doses of 5-HT. This lack of desensitization was also evident in the cardiovascular responses to 5-HT. It is concluded that desensitization to 5-HT is a phenomenon that is readily observed only in-vitro and which is probably related to the inability of a small amount of isolated tissue to eliminate 5-HT.
The Protective Effect of Glycine in Cisplatin Nephrotoxicity: Inhibition with NG-Nitro-l-arginine Methyl Ester
Authors: Li Q , Bowmer C J , Yates M S 
Published: April 2011

Abstract
The effect of glycine on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin was investigated in the rat. Cisplatin (6·0 mg kg−1, i.v.) injection in anaesthetized rats produced, over a period of 2 h, falls of approximately 50% in renal blood flow (RBF) and the clearance of [3H]inulin (CLIN), effects which were prevented by co-administration of glycine (1·0 g kg−1). Infusion of the nitric oxide (NO) synthase-inhibitor NG-nitro-l-arginine methyl ester, l-NAME (10 μg min−1 kg−1, i.v.), abolished glycine’s ability to maintain RBF in cisplatin-injected rats whilst partially inhibiting the ability of glycine to preserve CLIN. Treatment of cisplatin-injected rats with glycine (1·0 g kg−1, i.v.) significantly ameliorated the nephrotoxic effects of cisplatin (6·0 mg kg−1) as judged by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, CLIN and the clearance of [14C]p-aminohippurate. Administration of l-NAME (1·0 mg kg−1, i.v.) to rats which received cisplatin and glycine significantly inhibited the reno-protective effect of glycine. However, l-NAME administration to rats which were treated only with cisplatin did not result in any potentiation of cisplatin nephrotoxicity. The findings of this study suggest that glycine can block the acute falls in RBF and CIN produced by cisplatin by a mechanism which involves the production of NO. Furthermore, the results indicate that these renal haemodynamic actions of glycine are responsible, at least in part, for the ability of this amino acid to ameliorate cisplatin nephrotoxicity.
Possible Isozyme-specific Effects of Experimental Malaria Infection with Plasmodium berghei on Cytochrome P450 Activity in Rat Liver Microsomes
Authors: Glazier A P , Kokwaro G O , Edwards G 
Published: April 2011

Abstract
We have investigated the effect of experimental malaria infection on rat cytochrome P450-mediated drug metabolism using ethoxyresorufin and metoprolol as probe compounds. Malaria infection caused a significant reduction in total intrinsic clearance of ethoxyresorufin in both low and high parasitaemia malaria compared with control (control 18·7 ± 7·2; low parasitaemia 10·5 ± 4·1; high parasitaemia 4·3 ± 1·4 mL min−1). However, clearance of metoprolol was unchanged in malaria infection compared with control (control 2·7±1·2; malaria 4·0±1·7 mL min−1). The change in clearance of ethoxyresorufin was the result of a decrease in Vmax, with no apparent change in Km. There was no change in either Vmax or Km of metoprolol. These results indicate a possible isozyme-selective effect of experimental malaria.
Interactions of Monoamine Oxidase Inhibitors, N-Acetylenic Analogues of Tryptamine, with Rat Liver Microsomal Cytochrome P450
Authors: Valoti Massimo , Costanzo Marisa , Sgaragli Gian Pietro , Perez Virgili , Fernandez-Alvarez Eldiberto , Unzeta Mercedes 
Published: April 2011

Abstract
Interactions between some novel and potent monoamine oxidase inhibitors (MAOIs), acetylenic analogues of tryptamine, and rat liver microsomal cytochrome P450 (P450) as evidenced by visible spectra analysis were analysed. Compounds with a secondary aliphatic amine moiety throughout induced type II difference spectra and exhibited the highest affinity for P450, whereas tertiary amines induced type I spectral changes and showed diminished affinity. P450 dependent aniline hydroxylase activity was inhibited by all compounds in an irreversible time-dependent manner. Only tertiary aliphatic amines constituted the substrate for P450-dependent N-demethylase activity, with comparable kinetic parameters. The N-demethylated metabolites were identified by thin-layer chromatography and mass-spectrometric analyses. These findings describe the role of P450-dependent microsomal mono-oxygenase systems in the metabolism of some MAOI acetylenic tryptamine derivatives and the possible hepatic contribution to adverse interactions between MAOIs, endobiotics and sympathomimetic compounds.