bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Monoamine Oxidase from Bovine Retina by β-Carbolines
Authors: De Arribam A. Fernández , Lizcano J M , Balsa M D , Unzeta M
Published: April 2011

The behaviour of some β-carboline derivatives as inhibitors of monoamine oxidase has been studied in bovine retina. Inhibition was found not to show any significant time dependence. Di- and tetrahydro-β-carbolines were shown to behave as reversible and competitive inhibitors. In contrast, the fully unsaturated β-carbolines harmane, harmine and harmaline, which showed deviation from linearity at high substrate concentrations, behaved as tight-binding inhibitors. In these cases, the concentration of the enzyme and the inhibitor were of the same order. This was confirmed by the Ki values for these compounds in the nanomolar concentration range. Consistent with this was that inhibition was only partly reversed by dialysis for 18 h at 4°C, although complete reversal was observed after dialysis for the same period at 37°C. Structure-activity relationships indicated that substitution of a methoxy group at the C7 position of the aromatic ring is determinant for this tight-binding behaviour; a substitution of this group at the C6 position greatly reduced inhibition. Since β-carbolines have been reported to be formed endogenously, this suggests that they might have important physiological actions on monoamine oxidase activity in-vivo. In contrast, all the β-carbolines investigated in this study had low potencies as inhibitors of monoamine oxidase B.
The Anticonvulsant FCE 26743 is a Selective and Short-acting MAO-B Inhibitor Devoid of Inducing Properties towards Cytochrome P450-dependent Testosterone Hydroxylation in Mice and Rats
Authors: Benedetti M Strolin , Marrari P , Colombo M , Castelli M G , Arand M , Oesch F , Dostert P
Published: April 2011

The effects of the potent anticonvulsant FCE 26743 ((S)-2-(4-(3-fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in-vitro and ex-vivo using rat tissue homogenates. In-vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO-B, with IC50 values about 10−7  m for MAO-B and higher than 10−5  m for MAO-A. When determined ex-vivo in brain, the ED50 value for the inhibition of MAO-B was 1·1 mg kg−1 (p.o.) 1 h post-dosing, whereas MAO-A remained virtually unaffected after administration of 60 mg kg−1. Similar effects were seen in liver. Following oral administration of 5 mg kg−1 FCE 26743 to rats, brain MAO-B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short-acting MAO-B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0–8 h urines after administration of a 119 mg kg−1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.
The Effect of Indobufen on the Activities of Selected Rat Liver Phase I and Phase II Drug Metabolizing Enzymes, Peroxisomal β-oxidation and Hepatic Glutathione Status
Authors: Thomas H , Benedetti M Strolin , Dostert P , Oesch F
Published: April 2011

Oral administration of indobufen to male rats for three days at daily doses of 5, 10 and 20 mg kg−1 resulted in no changes in liver total glutathione, cytosolic glutathione S-transferases or microsomal epoxide hydrolase. Reduced glutathione appeared slightly diminished to about 84% of control at the highest dose level. Microsomal cytochrome P450-dependent ethoxyresorufin O-de-ethylase and pentoxyresorufin de-alkylase activities were decreased to 64% (not significantly) and 67% of control at the lowest dose level. 6α- and 7α-Hydroxytestosterone activities were decreased to 67 and 68% of control at the highest dose level. Cyanide-insensitive peroxisomal fatty acid β-oxidation was increased to 223, 261 and 232% of control at doses of 5, 10, and 20 mg kg−1, respectively. The results obtained in this study are indicative of the action of indobufen as a weak peroxisome proliferator in male rat liver, and suggest a slight but toxicologically insignificant inhibitory action of this drug on microsomal cytochrome P450-dependent enzyme activities.
The effect of pectin on the gastric emptying rates and blood glucose levels after a test meal
Authors: Iftikhar S Y , Washington N , Wilson C G , MacDonald I A , Homer-Ward M D
Published: April 2011

This study was designed to evaluate the effect of pectin given in a palatable form on the gastric emptying rates of the solid and liquid phases of a test meal and to ascertain whether pectin affected blood glucose levels in ten healthy male and female volunteers. Gastric emptying was measured using dual isotope gamma scintigraphy. Allocation to the treatment group was double-blind and randomized. Sequential blood sampling was used to measure blood glucose levels. The times for the stomach to empty half the radiolabelled meal were similar after both pectin and placebo; however, a significant difference was seen between the AUC values of the meal between the two treatments. This can be attributed to the divergence of the emptying curves after the time point at which 50% of the meal had emptied, as pectin delayed the emptying of the last 20% of the meal. The initial phase of emptying for both pectin and placebo was significantly faster than the meal. No significant difference was found between blood glucose levels when either pectin or placebo was administered.
A Shape Factor to Characterize The Quality of Spheroids
Authors: Podczeck Fridrun , Newton John Michael
Published: April 2011

A shape factor eR has been devised to describe how the form of spherical particles approaches that of a true spheroid, based on a two-dimensional image analysis. Both the deviation of shape from a circle towards an ellipse and surface irregularities influence the value of eR. Using a set of model figures such as squares, triangles, diamonds and stars, it could be shown that eR clearly differentiates between different polygonally symmetric figures, even in the case where common shape descriptors such as the aspect ratio provide equal values. The value of eR is 1·0 in the case of a perfect spheroid, while ellipticity and surface roughness lead to a significant change in the value.
Ulcer-protecting Effects of Naringenin on Gastric Lesions Induced by Ethanol in Rat: Role of Endogenous Prostaglandins
Authors: Motilva V , De La Lastra C Alarcón , Martín M J
Published: April 2011

This study was designed to determine the cytoprotective properties of naringenin and the involvement of endogenous prostaglandins on mucosal injury produced by absolute ethanol. Gastric glands were also histologically analysed. Oral pretreatment with the highest dose of naringenin (200 mg kg−1), 240 min before absolute ethanol, was the most effective in ulcer prevention. Subcutaneous administration of indomethacin (10 mg kg−1) to the animals treated with naringenin (200 mg kg−1) partially inhibited the gastric protection but there was no increase in prostaglandin E2. All treated groups showed a marked increase in gastric mucus, although this increase was less in animals pretreated with indomethacin. Total proteins and hexosamine content decreased in the groups receiving indomethacin. Histomorphometric evaluation of the gastric damage, with the highest dose of naringenin (200 mg kg−1), confirmed a significant increase of mucus production accompanied by a parallel reduction of gastric lesion.
Effects of β-Adrenoceptor Antagonists on Portal Vein Hypertension and Ethanol-induced Gastric Mucosal Damage in Rats
Authors: Woo Patrick Chiu Yat , Cho Chi Hin
Published: April 2011

The effects of various β-adrenoceptor antagonists, with different pharmacological properties, on systemic and portal vein blood pressure and on ethanol-induced gastric mucosal damage were examined in surgically-induced portal hypertensive rats. Propranolol (5, 10 or 20 mg kg−1), nadolol (5 or 10 mg kg−1), metoprolol (10 or 20 mg kg−1), labetalol (20 or 40 mg kg−1) and pindolol (3 or 6 mg kg−1) reduced systemic blood pressure to a similar degree in both portal vein-ligated and sham-operated rats. All β-adrenoceptor antagonists, except for pindolol, significantly reduced portal venous pressure and ethanol-induced macroscopic gastric mucosal damage in portal hypertensive animals. Sham-operated rats had lower portal venous pressure and less gastric damage compared with portal hypertensive rats, but both were unaffected by β-adrenoceptor antagonist pretreatment. We conclude that: propranolol, nadolol, metoprolol and labetalol are effective in reducing the portal venous pressure and ethanol-induced gastric mucosal damage in portal hypertensive rats, but not in portal normotensive animals; there was no direct relationship between the reduction of portal vein and systemic blood pressure; and local anaesthetic action is probably important in reducing the portal vein pressure and ethanol-induced gastric mucosal lesions, while the intrinsic sympathomimetic effect can counteract the actions of the β-adrenoceptor antagonists on portal venous pressure and gastric mucosa.
Studies on the Mechanism of Spasmolytic Activity of (O-Methyl-)-N-(2,6-dihydroxybenzoyl)tyramine, a Constituent of Aniba riparia (Nees) Mez. (Lauraceae), in Rat Uterus, Rabbit Aorta and Guinea-pig Alveolar Leucocytes
Authors: Thomas George , Branco U J V Castelo , Filho J M Barbosa , Bachelet M , Vargaftig B B
Published: April 2011

The mechanism of action of a nonspecific smooth muscle relaxant, (O-methyl-)-N-(2,6-dihydroxybenzoyl)tyramine (riparin), a constituent of Aniba riparia (Nees) Mez. (Lauraceae) was studied in relation to Ca2+ metabolism in smooth muscle tissues and in guinea-pig alveolar leucocytes. In rat depolarized uterus, riparin inhibited in a reversible and noncompetitive manner CaCl2-induced contraction, a response mediated through voltage-dependent Ca2+ channels. The pD2 value (mean±s.e.m.) for riparin was 4·98±006. When compared with sodium nitroprusside (IC50 2·5 μm), an antagonist of receptor-operated Ca2+ channels, riparin was ineffective in suppressing noradrenaline-induced sustained contractions of rabbit aortic strips. However, in the aorta, the compound inhibited intracellular calcium-dependent transient contractions of noradrenaline and riparin (IC50 10·1 μm), was approximately two and a half times more potent than procaine (IC50 25·5 μm), a known inhibitor. In guinea-pig alveolar leucocytes, riparin (IC50 3·2 μm), inhibited intracellular Ca2+ accumulation induced by the calcium ionophore A23187. The results suggest that the inhibition of Ca2+ influx and of Ca2+ release from intracellular stores contribute to the spasmolytic effects of riparin, which may not involve cyclic AMP generation as the levels of this nucleotide were not increased in alveolar macrophages treated with riparin (10–100 μm).
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

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

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

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

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

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

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

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 < 0·05), but was still significantly greater than control values (P < 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 < 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 < 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

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

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

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 (> 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

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

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

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

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

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.
The Disposition of (R)-α-Methylhistamine, a Histamine H3-Receptor Agonist, in Rats
Authors: Yamasaki Seiji , Sakurai Eiichi , Hikichi Noboru , Sakai Naruhiko , Maeyama Kazutaka , Watanabe Takehiko
Published: April 2011

Using a modified HPLC method with a fluorescence spectrophotometer and a weak cation exchanger, it was possible to separate (R)-α-methylhistamine (α-methylhistamine) from histamine in plasma and various tissues. The assay was used to study the disposition and pharmacokinetic analysis of α-methylhistamine after a bolus intravenous administration to rats. After rapid intravenous administration (12·6 mg kg−1), the plasma concentration declined biexponentially with a half-life of 1·3 min in the elimination phase. The area under the plasma concentration-time curve and total body clearance were 130 μg min mL−1 and 97 mL min−1 kg−1, respectively. After administration, α-methylhistamine was immediately transferred to various tissues. The concentration was high in the kidney, lung, and liver (kidney > lung > liver), but low in the brain. The tissue-to-plasma concentration ratios in peripheral tissues were greater than 1, suggesting that the transfer of α-methylhistamine to peripheral tissues was due to a specialized transport mechanism or possibly to tissue binding. However, the finding that the tissue/plasma ratio in the brain was lower than unity suggests that the transport system in this tissue depends on a concentration gradient, and that α-methylhistamine crosses the blood-brain barrier in rats with difficulty.
In-vitro potencies of histamine H2-receptor antagonists on tetraethylammonium uptake in rat renal brush-border membrane vesicles
Authors: Somogyi A A , Simmons N , Gross A S
Published: April 2011

The histamine H2 antagonists cimetidine, ranitidine and famotidine are organic bases that are cleared from the body by active renal tubular secretion involving the organic cation transporter in the proximal tubule. To determine the potential for competition for the transporter between these drugs and other drugs, their inhibitory potencies were assessed in-vitro, using rat renal brush-border membrane vesicles and tetraethylammonium as the substrate. The concentration-dependent effect of cimetidine, ranitidine and famotidine on the 15-s proton-stimulated uptake of tetraethylammonium into the membrane vesicles was studied using five different rat kidneys. The order of inhibition potencies was: cimetidine (mean IC50= 1·07 μm) > famotidine (2·43 μm) > ranitidine (55·4 μm). The results indicate the potential for drug interactions in the kidney, especially for cimetidine and famotidine.
Reversal of chlorpromazine-induced avoidance depression by the N-methyl-d-aspartate antagonist, dizocilpine, in mice
Authors: Mele Andrea , Battaglia Mario , Sansone Mario
Published: April 2011

The non-competitive N-methyl-d-aspartate (NMDA) antagonist MK-801 (dizocilpine) was tested, alone or in combination with chlorpromazine, in mice previously trained in the shuttle-box. The lowest doses of dizocilpine (0·02 and 0·04 mg kg−1) attenuated the disrupting action of the neuroleptic (1·5 mg kg−1) on avoidance-performance, while avoidance depression induced by 1·5 and 2 mg kg−1 chlorpromazine was completely or almost completely reversed by 0·08 mg kg−1 NMDA antagonist. The highest dose (0·16 mg kg−1) of dizocilpine did not ameliorate avoidance-performance of mice receiving 2 mg kg−1 chlorpromazine, perhaps because of ataxic effects produced by the drug combination, at these doses. The results support suggestions for a potential use of NMDA antagonists in the treatment of extrapyramidal side-effects of neuroleptics.
Evidence for a dopaminergic involvement in the renal action of centrally administered JA116a, a novel compound with possible dopaminergic activity, in rats
Authors: Orfila G Luz , Angel Jorge , Torres Marysabel , Barbella Yarisma , Israel Anita
Published: April 2011

Intracerebroventricular (i.c.v.) administration of JA116a, induces an increase in urinary volume and sodium excretion in conscious male hydrated rats. The involvement of brain dopaminergic neurons in the JA116a renal action was investigated. Diuretic and natriuretic action of JA116a was blocked by haloperidol pretreatment. The renal effect was prevented by selective dopaminergic neuron, denervation by i.c.v. administration of 6-hydroxydopamine in combination with desmethylimipramine. Our results suggest that JA116a acts centrally, at least in part, via an interaction with endogenous dopamine neurons.
Diuretic effect of NG-nitro-l-arginine methyl ester in the rat
Authors: Li Q , Bowmer C J , Yates M S
Published: April 2011

Intravenous infusion of the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester, l-NAME (10 μg kg−1 min−1), to anaesthetized rats produced a diuresis and natriuresis. By contrast, infusion of the same dose of NG-nitro-d-arginine methyl ester had no effect on either urine output or sodium excretion. The effects of l-NAME were first evident 120 min after the start of infusion and by 170 min a fivefold increase in urine volume and sodium excretion was recorded. l-NAME also produced a transient fall in inulin clearance and a persistent decline in renal blood flow. These renal effects of l-NAME were associated with a gradual elevation of mean arterial blood pressure, although this only attained statistical significance, in comparison with saline-infused animals, 170 min after the start of infusion. The findings indicate the diuresis and natriuresis evoked by l-NAME in the rat is a result of a direct tubular action together with a pressure diuresis.
The effect of theophylline on parkinsonian symptoms
Authors: Mally Judit , Stone T W
Published: April 2011

Adenosine is known to inhibit the release of dopamine from central synaptic terminals. The present open trial was therefore conducted to determine whether the adenosine receptor-antagonist theophylline would be of value in Parkinson’s disease. Fifteen parkinsonian patients were treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg day−1), yielding serum theophylline levels of 4·44 mg L−1 after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement. It is suggested that theophylline might be a useful adjunct to the routine therapy of parkinsonian patients.
The determination of ofloxacin in human skin tissue by high-performance liquid chromatography and correlation between skin tissue concentration and serum level of ofloxacin
Authors: Ohkubo Tadashi , Kudo Masakiyo , Sugawara Kazunobu , Sawada Yukimasa
Published: April 2011

A simple high-performance liquid chromatographic (HPLC) assay was developed for the measurement of ofloxacin in skin tissue, and the correlation between serum levels and skin tissue levels of ofloxacin was determined. The homogenized skin samples were directly introduced into an HPLC system after filtering through a Molcut II membrane filter to remove proteins. The filtrate was concentrated on a pre-column using a phenyl-stationary phase and was then introduced to an analytical column using an ODS-stationary phase by column-switching techniques. Ofloxacin and lomefloxacin as an internal standard were detected by UV absorbance at 300 nm. Determination was possible for ofloxacin over the concentration range 250–3000 ng (g skin tissue)−1; the limit of detection was 100 ng g−1. The absolute recovery of ofloxacin added to skin tissue homogenate was over 72% with a coefficient of variation of less than 4·1%. This method is applied to determination of skin tissue level of ofloxacin in patients after treatment with ofloxacin. The correlation between serum levels and skin tissue levels of ofloxacin was determined for 30 patients after oral administration of ofloxacin. Good correlation was obtained and the coefficient of correlation was 0·84.
Moment analysis of hepatic local disposition of allopurinol and oxipurinol: metabolism kinetics from allopurinol to oxipurinol in the rat isolated perfused liver
Authors: Yasui Hiroyuki , Yamaoka Kiyoshi , Nishimura Masuhiro , Naito Shinsaku , Nakagawa Terumichi
Published: April 2011

Drug metabolism in the liver was examined by the rat isolated perfused liver using the single-pass bolus-input technique. The test compounds, allopurinol and its metabolite oxipurinol, were independently introduced into the liver from the portal vein, and the concentration profiles in the venous outflow were monitored and kinetically analysed by moment theory. The recovery ratios of allopurinol and oxipurinol after the individual administration of each drug were estimated to be 0·17 (±0·08 s.d.) and 1·03 (± 0·02 s.d.), respectively. The outflow recovery ratio of oxipurinol as the metabolite after allopurinol administration was estimated to be 0·80 (±0·07 s.d.). These results indicate that the combined outflow recovery of the precursor and the metabolite after allopurinol administration is almost 100% in the rat liver.
Kinetic analysis of propranolol-induced impairment of its own metabolism in rats
Authors: Kagimoto Noriko , Masubuchi Yasuhiro , Fujita Shoichi , Narimatsu Shizuo , Suzuki Tokuji
Published: April 2011

The effect of repetitive oral administration of propranolol (100 mg kg−1 day−1, 5 days) on the kinetics of liver microsomal propranolol metabolism was investigated in the rat. Vmax values of the high-affinity phase for biphasic kinetics of propranolol 4- and 5- hydroxylase activities were decreased by propranolol pretreatment, while those of the low-affinity phase were unchanged. The Vmax value of monophasic 7-hydroxylase activity was also decreased. On the other hand, the Vmax value of N-desisopropylase activity in the propranolol-treated rats was increased more than 2-fold compared with non-treated (control) rats, resulting in a change from monophasic in control rats to biphasic kinetics in propranolol-treated rats. These findings indicate that repetitive administration of propranolol selectively impairs a CYP2D isozyme that is involved in the high-affinity phases for propranolol ring-hydroxylations.
Study of the mutual effects of sulphadiazine and ciprofloxacin on their uptakes by Pseudomonas aeruginosa
Authors: Richards R Michael E , Reid Raymond G , Hamilton Vivienne E S , Xing Dorothy K L
Published: April 2011

A high-performance liquid chromatography (HPLC) assay was developed for ciprofloxacin and sulphadiazine in Isosensitest broth. Combining the HPLC assay with cell dry-weight determinations indicated that both compounds were able to enhance the uptake of the other by log phase Pseudomonas aeruginosa cultured in the presence of the compounds. It is hypothesized that the increased bacterial uptakes are the reason for the enhanced antibacterial activity previously reported for combinations of ciprofloxacin and sulphadiazine.
8-Hydroxypenillic acid: NMR characteristics and facile formation from 6-aminopenicillanic acid
Authors: Casy A F , Lipczynski A
Published: April 2011

High field NMR (1H and 13C) spectral characteristics in D2O of 8-hydroxypenillic acid and 6-aminopenicillanic acid (6-APA)-sodium bicarbonate mixtures are reported. The ready conversion of 6-APA to 8-hydroxypenillic acid is demonstrated.
Investigation of Synergism with Combinations of Dibromopropamidine Isethionate or Propamidine Isethionate and Polymyxin B
Authors: Richards R Michael E , Xing Dorothy K L
Published: April 2011

Combinations of polymyxin B and dibromopropamidine isethionate exhibited synergistic inhibitory and bactericidal activity against Pseudomonas aeruginosa, Enterobacter cloacae, Proteus mirabilis, Escherichia coli and Staphylococcus aureus. Similar results were obtained with polymyxin B plus propamidine combinations except that propamidine was not as active as dibromopropamidine and the combination of polymyxin B plus propamidine against S. aureus only had additive activity. The antibacterial agents were tested in solutions and in a cream formulation. The findings indicate a potential for the use of selected combinations of these antibacterial agents in the treatment of wound and superficial eye infections.
pH-Dependent and Carrier-mediated Transport of Salicylic Acid Across Caco-2 Cells
Authors: Takanaga Hitomi , Tamai Ikumi , Tsuji Akira
Published: April 2011

The transport of monocarboxylic acid drugs such as salicylic acid was examined in the human colon adenocarcinoma cell line, Caco-2 cells that possess intestinal epithelia-like properties. [14C]Salicylic acid transport was pH-dependent and appeared to follow the pH-partition hypothesis. However, 10 Mm unlabelled salicylic acid significantly reduced the permeability coefficient of [14C]salicylic acid. Kinetic analysis of the concentration dependence of the permeation rate of salicylic acid across Caco-2 cells showed both saturable (K1 = 5·28 ± 0·72 Mm Jmax = 36·6 ± 3·54 nmol min−1 (mg protein)−1) and non-saturable (kd = 0·37 ± 0·08 μL min−1 (mg protein)−1) processes. The permeation rate of [14C]salicylic acid was competitively inhibited by both acetic acid and benzoic acid, which were demonstrated in our previous studies to be transported in the carrier-mediated-transport mechanism which is responsible for monocarboxylic acids. Furthermore, certain monocarboxylic acids significantly inhibited [14C]salicylic acid transport, whereas salicylamide and dicarboxylic acids such as succinic acid did not. From these results, it was concluded that the transcellular transport of [14C]salicylic acid across Caco-2 cells is by the pH-dependent and carrier-mediated transport mechanism specific for monocarboxylic acids.