Showing papers in "Journal of Pharmacy and Pharmacology in 2011"

Nitric Oxide Scavenging by Curcuminoids

Abstract: Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly. Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity. The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.

The concept of dissolution efficiency.

Abstract: The recent interest in drug availability has resulted in a proliferation of in vitro dissolution testing, now standard for many dosage forms. The usual method of evaluation is the comparison of the time taken for given proportions of the active drug to be released into solution and figures such as the t20, t50 and t90 % times are often quoted. Alternatively the fraction of drug in solution after a given time is used for comparison, i.e. 60% release in 30 min. A further parameter suitable for the evaluation of in vitro dissolution has been suggested by Khan & Rhodes (1972), who introduced the idea of Dissolution Efficiency. This is defined as the area under the dissolution curve up to a certain time, t, expressed as a percentage of the area of the rectangle described by 100% dissolutionin the sametime. The simplest case, shown in Fig. 1 where, dissolution of a tableted drug, is

Evidence for dopamine receptor stimulation by apomorphine

Abstract: Sm,-Recently, Ernst (1967) has reported that the apomorphine-induced compulsive gnawing in rats is not mediated via the release of catecholamines, since it is not reduced by the catecholamine synthesis inhibitors a-methyl-3,4dihydroxyphenylalanine and a-methyltyrosine. On the other hand, the gnawing seen after treatment with (+)-amphetamine is blocked by these synthesis inhibitors. Since the apomorphine-induced gnawing requires an intact corpus striatum and gnawing can also be produced by the catecholamine precursor dihydroxyphenylalanine, Ernst (1967) suggested that apomorphine acts on the dopamine receptors whereas amphetamine acts by releasing dopamine. In the present paper supporting evidence for this view is given by further functional, biochemical and histochemical studies. The functional influence of apomorphine on dopamine neurotransmission in the corpus striatum was examined after unilateral removal of the corpus striatum of adult hooded rats weighing about 200 g (And& Dahlstrom & others, 1966a). A possible action of apomorphine on the noradrenaline receptors of the spinal cord was tested in acutely spinalized adult hooded rats by evaluating the changes in the flexor reflex evoked by pinching the hind limbs. The effect of apomorphine on the dopamine and noradrenaline levels of the brain and spinal cord was determined biochemically (Bertler, Carlsson & Rosengren, 1958; Carlsson & Waldeck, 1958) and histochemically (Falck, Hillarp & others, 1962; Dahlstrom & Fuxe, 1964; Hamberger, Malmfors & Sachs, 1965). Function. These studies were made mainly on rats which had been pretreated with reserpine (10 mg/kg i.p., 3 hr) plus a-methyltyrosine methylester (H 44/68, 500mg/kg, i.p., 2 hr) after removal of the left corpus striatum by suction. After this treatment all the operated animals turned towards the unoperated side (cf. And6n & others, 1966a). After injection of apomorphine (1-25 mg/kg s.c.) these rats changed their position and turned or rotated towards the operated side. This effect began about 5 min after the injection and was evident for about 45-60 min. If apomorphine was given to operated rats not pretreated with reserpineH 44/68 combination, this action of apomorphine, like the gnawing, seemed to be less pronounced. If haloperidol (5 mg/kg i.p.) was given 15-20 min after apomorphine all the rats turned from the operated towards the unoperated side in about 15 min and the gnawing ceased. (+)-Amphetamine (0.5-25 mg/kg s.c.), like apomorphine, made the rats turn or rotate towards the operated side. In contrast to apomorphine, however, this action of amphetamine was not seen after pretreatment with reserpine plus H 44/68 (cf. Weissman, Koe & Tenen, 1966; Hanson, 1967; Ernst, 1967). Apomorphine (25 mg/kg s.c.), in contrast to (+)-amphetamine (05-25 mg/kg s.c.) and ~-3,4-dihydroxyphenylalanine (50-75 mg/kg i.v. 2 hr after nialamide 50 mg/kg i.p.), did not cause a definite increase of the flexor reflex in spinalized rats. Chemistry. The biochemical results obtained in unoperated adult hooded rats are presented in Table 1. Apomorphine caused a retardation of the depletion in brain dopamine produced by H 44/68. The difference between the dopamine levels in the apomorphine-H 44/68 group and in the H 44/68 group is statistically significant (P < 0.001, Student’s r-test). This action of apomorphine on the brain dopamine was blocked by haloperidol. The disappearance of noradrenaline from the brain and the spinal cord after H 44/68 did not seem to be influenced by apomorphine. (+)-Amphetamine did not cause any significant retardation of the dopamine and noradrenaline loss after H 44/68.

Nanoparticle uptake by the rat gastrointestinal mucosa : quantitation and particle size dependency

Abstract: Polystyrene microspheres in the size range 50 nm to 3 microns were fed by gavage to female Sprague Dawley rats daily for 10 days at a dose of 1.25 mg/kg-1. Previous histological evidence of the uptake of these particles and their absorption across the gastrointestinal tract and passage via the mesentery lymph supply and lymph nodes to the liver and spleen was confirmed by analysis of tissues for the presence of polystyrene by gel permeation chromatography. Measurement of radioactivity of tissues following administration of 100 nm and 1 micron I125-labelled polystyrene latex particles for 8 days was corroborative although less secure because of the potential lability of the labelled particles. The extent of absorption of 50 nm particles under the conditions of these experiments was 34% and of the 100 nm particles 26% (as measured by determination of polystyrene content), of which total, about 7% (50 nm) and 4% (100 nm), was in the liver, spleen, blood and bone marrow. Particles larger than 100 nm did not reach the bone marrow, and those larger than 300 nm were absent from blood. No particles were detected in heart or lung tissue.

The fate of pharmaceutical chemicals in the aquatic environment

Abstract: Increased demands for potable water, especially where supplies are drawn from lowland rivers has necessitated a greater degree of water re-use. As water undertakings have a duty to maintain the wholesome quality of potable water supplies, increasing concern is being expressed over the presence of organic micro-contaminants (contaminants found at microgram litre-1 concentrations). This study outlines some of the problems encountered in assessing the risk from pharmaceutical chemicals which might enter the water cycle from domestic and industrial sources. Analytical chemistry was of value for only a few of the 200 compounds studied. However, much useful information was derived from the human metabolic routes of the drugs and is collated in Appendix I. Biodegradation studies and other ecotoxicity/environmental toxicology data may be required to a greater extent in the future. Particular consideration is given to vulnerable sections of the population.

Drug-delivery products and the Zydis fast-dissolving dosage form.

Abstract: Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medication as prescribed. It is estimated that 50% of the population is affected by this problem which results in a high incidence of non-compliance and ineffective therapy. The difficulty is experienced in particular by paediatric and geriatric patients, but it also applies to people who are ill in bed and to those active working patients who are busy or travelling, especially those who have no access to water. Such problems can be resolved by means of the Zydis dosage form which does not require water to aid swallowing. The Zydis fast-dissolving dosage form is a unique freeze dried medicinal tablet, made from well known and acceptable materials. When Zydis units are put into the mouth, the freeze dried structure disintegrates instantaneously releasing the drug which dissolves or disperses in the saliva. The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach. In these cases, the bioavailabilities of drugs from Zydis formulations are significantly greater than those observed from standard dosage forms. This paper deals with the formulation and process technology of the Zydis dosage form. The bioavailability characteristics of Zydis products are summarized, and in particular, the design of Zydis products for the enhancement of oral bioavailability and the improvement of clinical activity, through transmucosal delivery and pregastric absorption, is discussed.

Pharmacology of diferuloyl methane (curcumin), a non‐steroidal anti‐inflammatory agent*

Abstract: Some pharmacological actions of curcumin (diferuloyl methane) have been examined in rats, mice and cats. The compound possesses significant anti-inflammatory activity in acute as well as in chronic models of inflammation. It is as potent as phenylbutazone in the carrageenan oedema test but only half as potent in chronic tests. Curcumin possesses a much lower ulcerogenic index than phenylbutazone. It prevents the inflammation induced increase in SGOT and SGPT levels. It lacks analgesic and antipyretic activity. It has no other significant pharmacological effects. The oral LD50 in mice is more than 2m0 g kg−1.

A Survey of the Antibacterial Activity of Some New Zealand Honeys

Abstract: To assess the variation in antibacterial activity of honey a survey was carried out on 345 samples of unpasteurized honey obtained from commercial apiarists throughout New Zealand. Most of the honeys were considered to be monofloral, from 26 different floral sources. The honeys were tested against Staphylococcus aureus in an agar well diffusion assay, with reference to phenol as a standard. Antibacterial activity was found to range from the equivalent of less than 2% (w/v) phenol to 58% (w/v) phenol, with a median of 13.6 and a standard deviation of 12.5. Neither the age of the honey samples nor whether they had been processed by the apiarist was associated with lower activity. However, the difference between floral sources in the antibacterial activity was very highly significant. Kanuka (Kunzea ericoides (A. Rich.) J. Thompson. Family: Myrtaceae), manuka (Leptospermum scoparium J. R. et G. Forst. Family: Myrtaceae), ling heather (Calluna vulgaris (L.) Hull. Family: Ericaceae) and kamahi (Weinmannia racemosa Linn. f. Family: Cunoniaceae) were shown to be sources likely to give honey with high antibacterial activity. When antibacterial activity was assayed with catalase added to remove hydrogen peroxide, most of the honeys showed no detectable antibacterial activity. Only manuka and vipers bugloss (Echium vulgare L. Family: Boraginaceae) honeys showed this type of activity in a significant proportion of the samples. The high antibacterial activity of manuka honey was in many cases due entirely to this non-peroxide component.

The quantitative measurement of motor inco-ordination in naive mice using an accelerating rotarod

Abstract: A simple modification of the standard rotarod apparatus is described which eliminates the necessity of time-consuming training and consequently gives a truer measure of motor co-ordination since any effects on memory are avoided. The sensitivity and reproducibility of the procedure are much greater than those obtained with constant speed rotarods and less animals are required to obtain statistically significant results.

Stimulation of locomotor activity following injection of dopamine into the nucleus accumbens

Abstract: Recently we have observed that bilateral injection of ergometrine into the nucleus accumbens of rats results in a strong and long-lasting enhancement of locomotor activity (Pijnenburg, Woodruff & van Rossum, 1973). This effect was antagonized by low doses of haloperidol and pimozide. The hypothesis was proposed that this enhanced locomotor activity was elicited by a stimulation of dopamine receptors in the nucleus accumbens. We now report that administration of dopamine directly into the nucleus accumbens of nialamide-pretreated rats produces a pattern of enhanced locomotor activity similar to that seen after ergometrine. Seven male Wistar rats (200-220 g) were implanted with double barrelled cannulas in each side of the nucleus accumbens (coordinates A 9.4, L 1.2 and H -0.6 according to the atlas of Konig & Klippel, 1963). These animals were used for all experiments with 5-8 days between experiments. The animals were subsequently killed and brains were sectioned to determine the position of the cannulas. For details of the experimental procedure see Pijnenburg & others (1973). Injections were made by means of a 5 pl Hamilton syringe with a 31 gauge needle. The injection volume was 0.5 pl. Dopamine HCl and (-)-noradrenaline (-)-hydrogen tartrate were dissolved in saline. Locomotor activity was measured in activity cages, equipped with photoelectric cells and recorded on a cumulative recorder. The rats were always pretreated with the monoamine oxidase inhibitor nialamide (100 mg kg-l i.p.) 18 h before administration of saline, dopamine or noradrenaline. Injection of dopamine ( 5 pg) to each side of the nucleus produced a strong enhancement of locomotor activity, which started in 5 animals within 10 min of injection and lasted for up to 4 h, reaching a peak at about 1 h returning to 0 over the next 3 h with the most rapid decline over the last 30 min. In two rats, in which the injection site was found to be at the border of the nucleus accumbens, stimulation of locomotor activity started after 20 and 30 min respectively and failed to reach the level seen in the other rats. This is probably the reason for the large variability in the results (see Table 1). Injection of noradrenaline (5.0 pg) into each side of the nucleus accumbens of the same rats produced enhanced locomotor activity in 5 of the 7 animals but this was

An in-vitro investigation of mucosa-adhesive materials for use in controlled drug delivery

Abstract: An in-vitro test system was developed to investigate the adhesiveness of various materials to mucus. The results obtained showed good agreement with the findings of previous in-vivo evaluations of mucosa-adhesives. Further investigations found that these materials become adhesive on hydration. Chain length, and the presence of ionizable groups in the molecule, were found to be determinate factors. The physical nature of the gel, and the location at which the mucoadhesive materials hydrated, were of less importance.

Menthol and related cooling compounds.

Abstract: Menthol and related cooling compounds such as 'coolant agent 10', are widely used in products ranging from common cold medications to toothpastes, confectionery, cosmetics and pesticides. The review brings together a range of information on production and chemistry of menthol, and its metabolism, mechanism of action, structure-activity relationships, pharmacology and toxicology. In particular, the coolant action and carminative actions of menthol are discussed in terms of actions on calcium conductance in sensory nerves and smooth muscle. The actions of menthol on the nose, respiratory reflexes, oral cavity, skin and gastrointestinal tract are reviewed.

Curcuminoids as Potent Inhibitors of Lipid Peroxidation

Abstract: Earlier studies showed that curcumin is a potent inhibitor iron-catalysed lipid peroxidation Demethoxycurcumin, bisdemethoxycurcumin and acetylcurcumin were tested for their ability to inhibit iron-stimulated lipid peroxidation in rat brain homogenate and rat liver microsomes Comparison of the results with curcumin showed that all compounds are equally active, and more potent than alpha-tocopherol These results showed that the methoxy and phenolic groups contribute little to the activity Spectral studies showed that all compounds could interact with iron Thus, the inhibition of iron-catalysed lipid peroxidation by curcuminoids may involve chelation of iron

The preparation and properties of niosomes--non-ionic surfactant vesicles.

Abstract: Vesicles were prepared on hydration of a mixture of a single or double alkyl-chain, non-ionic surfactant with cholesterol. These vesicles, or 'niosomes', are capable of entrapping and retaining water soluble solutes such as carboxyfluorescein, are osmotically active and can be formulated to release entrapped solute slowly. The physical characteristics of the vesicles were found to be dependent on the method of production and three such methods, based on liposome technology, are described. The vesicles have been characterized by photon correlation spectroscopy, freeze fracture electron micrography, measurement of solute entrapment efficiency, and solute release rates. Vesicular forms of the single chain surfactant which could be formed under certain conditions in the absence of cholesterol are also described.

Polycyanoacrylate nanocapsules as potential lysosomotropic carriers: preparation, morphological and sorptive properties

Abstract: p. COUVREUR*§, B. KANTE*, M. ROLAND', P. C h O T I ' , P. BAUDUIN'f, P. SPEISER~, Laboratoire de Pharmacie Galinique, Universite' Catholique de Louvain, B-1200 Bruxelles Belgium. t Laboratoire de Chimie Physiologique, UniversitP Catholique de Louvain and International Institute of Cellular and Molecular Pathology, B-1200 Bruxelles, Belgium. '$ Phartnareutische Institut, Eidgenossische Technische Hochschule, CH-Zurich, Switzerland.

Letters to the Editor: Linearization of dissolution rate curves by the Weibull distribution

Abstract: The quantitative interpretation of dissolution rate data is greatly facilitated by the application of a general mathematical expression which describes the entire curve in terms of meaningful parameters. In special case, the equation can be derived from a theoretical treatment of the process, e.g. the cube-root law or zero-order kinetics, see Wagner (1970). In the most general case of tablets, coated tablets, capsules, or sustained-release preparations, however, no such theoretical basis is available and a suitable function has to be found empirically. First-order kinetics were proposed by Gibaldi & Feldman (1967) and Wagner (1969) introduced the lognormal presentation for this purpose. Although these two models together describe most dissolution curves observed, they exclude each other and are, thus, of limited applicability: for example, see the discussion of Wagner (1970) relative to Figs. 20.2 and 20.3. A more general function which may be applied successfully to all common types of dissolution curves, was described by Weibull (1951). All characteristics of this distribution function are discussed in detail by Kao (1959) and Ruzicka (1962). A concise survey is given by Grant (1964). When applied to dissolution rate data, the Weibull equation expresses the accumulated fraction, m, of the material in solution at time t, by

Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase activity.

Abstract: WE have previously reported that cutting the nigrostriatal dopamine-carrying axons unexpectedly results in a transient increase in the rate of tyrosine hydroxylation in the rat forebrain (Carlsson, Kehr & others, 1972). It was suggested that striatal tyrosine hydroxylase activity is controlled via dopamine receptors at the synaptic cleft : when the impulse flow is interrupted by axotomy, the concentration of dopamine in the synaptic cleft decreases, and the ensuing reduction of dopamine receptor activity gives rise to a feedback activation of tyrosine hydroxylase, located in the striatal dopaminecarrying nerve terminals. The experiments now reported were made to test the above hypothesis. We argued that stimulation and blockade of dopamine receptors should result in inhibition and activation, respectively, of striatal tyrosine hydroxylase activity. Male Sprague-Dawley rats, 210-340 g, were used. Axotomy of the nigrostriatal dopamine fibres was performed under ether anaesthesia on the left side by means of a transverse cerebral hemisection, as previously described (BCdard, Carlsson&Lindqvist, 1972). At the same time (or in some experiments after 1 h) the aromatic amino-acid decarboxylase was inhibited by an intraperitoneal injection of NSD 101 5 (3-hydroxybenzylhydrazine HCl, 100 mg/kg). The animals were decapitated 30 min after the injection. The forebrains were analysed for dopa (Kehr, Carlsson & Lindqvist, 1972) and dopamine (Atack, to be published). For a direct activation of dopamine receptors, apomorphine HCl, 15 mg/kgf was injected intraperitoneally 7 min before the transection, and for blockade of these receptors haloperidol was given 1 h before the transection ( 5 mg/kg intraperitoneally, for references see AndCn, Carlsson & Haggendal, 1969). In some experiments both agents were given to the same animals. The levels of dopa in the forebrains are given in Fig. 1. As previously reported, inhibition of the aromatic amino acid decarboxylase causes the accumulation of dopa, which cannot be detected in the normal brain. This accumulation appears to be a useful indicator of the rate of tyrosine hydroxylation (Carlsson, Davis & others, to be published). In animals transected and treated simultaneously with NSD 101 5, the

Biological properties of carrageenan

Abstract: During the past decade carrageenan has become much used experimentally mainly for its ability to induce an acute inflammation. Despite the lack of knowledge on the pathogenesis of this reaction, the fate of hundreds of new compounds as anti-inflammatory drugs still depends on their ability to suppress carrageenan foot oedema in the rat. Nevertheless the range of the biological properties displayed by carrageenan extends much further. Thus the peculiar features of granuloma induced by carrageenan, its actions on blood coagulation and the kinin system, the contrasting observations reported on its effects on peptic ulcer, its recently discovered immunological properties as well as its interference in immune phenomena, all indicate an increasing interest in carrageenan. Since the comprehensive review of Anderson (1967), many stimulating results in subsequent years have prompted this review with the aim of clarifying its biological properties and examining its future use as a tool to investigate physiological and pathological processes.

Kojic Acid, a Cosmetic Skin Whitening Agent, is a Slow-binding Inhibitor of Catecholase Activity of Tyrosinase

Abstract: It was found that kojic acid, which is used in cosmetics for its excellent whitening effect, inhibits catecholase activity of tyrosinase in a non-classical manner. A decrease in the initial velocity to a steady-state inhibited velocity can be observed over a few minutes. This time-dependence, which is unaltered by prior incubation of the enzyme with the inhibitor, is consistent with a first-order transition. The kinetic data obtained correspond to those for a postulated mechanism that involves the rapid formation of an enzyme inhibitor complex that subsequently undergoes a relatively slow reversible reaction. Kinetic parameters characterizing this type of inhibition were evaluated by means of nonlinear regression of product accumulation curves.

Structure; activity relationships.

Abstract: THE relationship between the chemical structure of a compound and its effect on a biological system is most frequently considered in rather a narrow sense, referring only to synthetic organic compounds or even to a limited class of compounds. Moreover, consideration is often restricted to a limited type of biological response, or to an ill-defined end response such as death of the organism. All naturally occurring compounds in living systems are possessed of biological “activity” of some kind, and even if their function is somewhat static as in structural components, they have at least been synthesised by dynamic biochemical processes. Even the simplest of compounds, water, is biologically active, as it participates not only as a solvent but as one of the most important reactants in the living cell. A full analysis of structure-activity relationships must therefore embrace the whole of classical biochemistry, to which must be added the growing mass of knowledge accumulating as the result of the development of chemotherapy, the fermentation industries, the plant protection industry and the control of organisms attacking manufactured goods. The temptation to narrow the field of enquiry is strong, because by doing so, it is possible to arrive at greater precision in correlating structure and activity. Moreover, it is often said, and with a considerable measure of truth, that fundamental knowledge is so fragmentary that any attempt at broad generalisations is premature. This negative attitude should be resisted, for hypotheses are valuable in crystallising thought and suggesting experiments. There are, in fact, certain valuable basic data, or at least practical working rules, which can act as guides, and a broad enquiry can at least help to define those areas where the gaps in knowledge are greatest and upon which research should be concentrated. Living organisms, from the point of view of this essay, are considered as dynamic physico-chemical systems. They are dynamic, not necessarily in the sense of movement, but because the living process is one of rapid and orderly chemical change, from the intake of nutrient to the output of waste products. The structure of every molecule must be viewed in relation to its environment, and to its metabolic precursors and successors. Living organisms vary greatly in their biochemical complexity, and to a large extent the study of structure-activity relationships is dependent on the possibility of biochemical dismemberment of the organism, so that the working of the component parts may be examined in isolation. The metabolic processes of micro-organisms, for example, are susceptible to experimental study not only by correlation of the effect of nutrients and foreign compounds on the metabolism, but also by the isolation and

Interaction of anti-inflammatory drugs with serum proteins, especially with some biologically active proteins

Abstract: The interaction of clinically established anti-inflammatory drugs with some proteins has shown these drugs to strongly inhibit heat coagulation of whole serum at a concentration attainable in the sera of patients. Phenylbutazone and sodium salicylate do not inhibit the biological activity of three biologically active and labile serum proteins, namely, necrotizing factor, heterogenous serum and complement. However, they do influence the effect of heat on these proteins. The relation between this drug action in vitro and the possible mode of action of the proteins in vivo is discussed.

Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (-)-isomer.

Abstract: Ibuprofen, 2-(4-isobutylphenyl)propionic acid, possesses an asymmetric carbon atom and can therefore occur either as the (+)or (-)-isomer. It has been claimed by some workers that biological activity in certain other substituted phenylpropionic acids resides almost entirely in the (+)-isomer (Shen, 1967; Ham, Cirillo & others, 1972; Takeguchi & Sih, 1972; Tomlinson, Ringold & others, 1972; Greig & Griffin, 1975). The resolution of the drug was carried out with (-)-1phenethylamine (Adams, Cliffe & others, 1967; Brooks & Gilbert, 1974). The (+)-isomer is believed to have the S configuration (Wechter, Loughhead & others, 1974). The purpose of this study has been to determine the contribution that the isomers of ibuprofen make to the activity of the normal compound, which is a racemic mixture. Several groups of workers have shown that the ability of non-steroidal anti-inflammatory compounds to inhibit various prostaglandin synthetase systems in vifro bears a semi-quantitative relation to their ability to exert anti-inflammatory, analgesic and antipyretic actions in vivo (Ham & others, 1972; Takeguchi & Sih, 1972; Tomlinson & others, 1972; Flower, Gryglewski & others, 1972). Our own experience with selected members of the substituted phenylalkanoic acid series of anti-inflammatory compounds, using a bovine seminal vesicle microsomal preparation (BSVM) of prostaglandin synthetase in vitro, has shown that this relationship is extremely good. We have therefore examined the ability of ibuprofen and its isomers to inhi bit this prostaglandin synthetase system. The method and conditions of incubation used were identical to those of Tomlinson & others (1972) except that, because of the high potency of our enzyme preparation, we incubated substrate and enzyme for only 8 min instead of 1 h. We also introduced a 5-min preincubation period for drug and enzyme before adding [14C]arachidonate substrate to the reaction mixture. Enzyme inhibition by drugs was measured by a decrease in the formation of [14C]PGE,. The results in Table 1 indicate that the (+)-isomer was highly active but that very little activity occurred in the (-)-isomer. However, this large difference in potency between the two isomers was not found in vivo when they were compared simultaneously with the racemic substance in anti-inflammatory and analgesic tests. The experimental models used (Adams, McCullough & Nicholson, 1969) were ultraviolet erythema in the guinea-pig, acetylcholine-induced writhing in mice, and the pain threshold technique using the yeast-inflamed Table 1. isomers in a prostaglandin synthetase system in vitro. Inhibitory potencies of ibuprofen and its optical

The uptake and translocation of latex nanospheres and microspheres after oral administration to rats.

Abstract: Non-ionic and carboxylated fluorescent polystyrene microspheres (100, 500 nm, 1 and 3 microns in diameter), were fed by gavage (2.5% w/v; 1.25 mg kg-1) daily for 10 days to female Sprague Dawley rats. Peyer's patches, villi, liver, lymph nodes and spleen of animals fed the non-ionic microspheres from 100 nm to 1 micron showed unequivocal evidence of uptake and translocation of the particles. Heart, kidney and lung showed no evidence of the presence of microspheres. Carboxylated microspheres were taken up to a lesser degree than the non-ionised particles. Experiments with 125I radiolabelled 100 nm and 1 micron particles showed a higher uptake of the smaller particles, which were concentrated in GI tissue and liver. Particles were not distributed randomly in the tissues, but were concentrated at the serosal side of the Peyer's patches and could be seen traversing the mesentery lymph vessels towards the lymph nodes. The results demonstrate a need to re-examine the possibilities of particulate oral delivery, as well as the potential toxicity of ingested particulates.

Some physico-chemical factors in drug action.

Abstract: THERE are two facets to the problem of the biochemical and physical aspects of drug action: the influence of drugs on the body and the influence of the body on drugs. Although the present article is concerned mainly with the latter a few thoughts on the influence of drugs on biochemical mechanisms may not be out of place. This aspect of drug action is truly an enigma, which attempts to solve have yielded little success thus far. The mechanism of action of drugs is explainable at a gross physiological level only. This permits us to say, for example, that dibenamine blocks the action of noradrenaline at hypothetical receptor sites ; or that quinidine acts by slowing the conduction time or by increasing the refractory period of heart muscle. But the question of their precise biochemical mechanisms is unanswered*. The orthodox approach, repeated faithfully with almost every new therapeutic agent of importance, has been to determine its effect on one known enzyme system after another on the assumption that the response to the drug is caused by an interference with a known biochemical process. The almost constant failure to relate the effect of a drug on an enzyme system in vitro with its response in the body arouses suspicion that the present approach may be aimed at the wrong target. Physiologists have also experienced little success in connecting known biochemical events with the specialised functions of organs-the beating of the heart, the response of a nerve cell, or the gastric secretion of acid are good examples. Perhaps the present failure to relate biochemical reactions to physiological function or to drug action is an inevitable consequence of thinking in terms of the “universality” of tissue catalysts, itself a useful concept in biochemical speculation, but one which may have been carried too far. This idea implies that functional differences between organs like brain and kidney arise mainly from differences in the organisation and control of the same tissue catalysts. This is like saying that nature plays all her combinations with a pack of only fifty-two cards and that the difference between various kinds of cells is a reflection merely of the difference in the way the cards are dealt. It seems more plausible to explain the specialised functions of the brain and kidney in terms of biochemical reactions that have an unique role in each organ and that these are unlikely to be present in the unicellular organism. The

Pig Ear Skin as an In‐vitro Model for Human Skin Permeability

Abstract: Pig skin has been shown to have similar histological and physiological properties to human skin and has been suggested as a good model for human skin permeability. In this series of experiments, the in-vitro permeability of pig ear skin was compared with human (abdominal) skin and rat (dorsal) skin using both hydrophilic (water, mannitol, paraquat) and lipophilic (aldrin, carbaryl, fluazifop-butyl) penetrants. Pig skin was found to have a closer permeability character than rat skin to human skin, particularly for lipophilic penetrants. Electrical conductivity measurements across pig skin membranes showed that skin conductivity could be a useful method for assessing the integrity of membranes, particularly when used in conjunction with water permeability assessments.

Selectivity of neutrophil 5-lipoxygenase and cyclo-oxygenase inhibition by an anti-inflammatory flavonoid glycoside and related aglycone flavonoids.

Abstract: A newly described plant-derived flavonoid, hypolaetin-8-glucoside, which has anti-inflammatory and gastroprotective actions in-vivo, and its corresponding aglycone, hypolaetin, have been compared with 14 other flavonoids for inhibition of eicosanoid generation via the 5-lipoxygenase and cyclo-oxygenase pathways in elicited rat peritoneal leukocytes stimulated with calcium ionophore. Comparable results for the inhibitory profiles of the compounds were obtained using either radioimmunoassay of released eicosanoids or radio-TLC of metabolites formed from labelled arachidonate, but there were differences in absolute potency of the inhibitors. Hypolaetin-8-glucoside was a weak but selective inhibitor of 5-lipoxygenase (IC50 56 microM vs 5-lipoxygenase; greater than 1000 microM vs cyclo-oxygenase), whereas the aglycone hypolaetin was a more potent and selective 5-lipoxygenase inhibitor (IC50 4.5 microM vs 70 microM). Results with three other glycoside/aglycone pairs confirmed that addition of sugar residues greatly reduces inhibitory potency whilst retaining selectivity against 5-lipoxygenase. Analysis of 12 aglycone flavonoids showed that inhibitory potency and selectivity against 5-lipoxygenase is conferred by the presence of 3'4'-vicinal diol (catechol) in ring B as part of a 3,4-dihydroxycinnamoyl structure as proposed by others and by incorporation of additional hydroxyl substituents. In contrast, "cross-over" of inhibitory selectivity is observed in compounds containing few hydroxyl substituents (with none in ring B) which are selective against cyclo-oxygenase. These results are discussed in relation to possible mechanisms of hypolaetin-8-glucoside's protective actions and the concept that these inhibitory effects of flavonoids cannot be ascribed to a unitary free radical scavenging action.

Delay of castor oil diarrhoea in rats: a new way to evaluate inhibitors of prostaglandin biosynthesis

Abstract: Forty-four non-steroidal anti-inflammatory compounds were tested for possible effects on castor oil-induced diarrhoea in rats. A small but significant delay of intestinal evacuations was found with all compounds. Quantitatively, the oral doses required to delay diarrhoea beyond the first hour after castor oil challenge reflected the acute anti-inflammatory potency of the tested compounds. Qualitatively, the evolution of the effective doses with increasing delay was linear for potent inhibitors of prostaglandin biosynthesis. The evolution for less potent compounds was markedly different and suggested the earlier occurrence of non-specific drug effects. Suprofen, the most potent of the series of compounds, produced the 1 h delay at an oral dose of 1.11 mg kg-1; the ED50 increased linearly to 115 mg kg-1 for a 4 h delay. Compared with other compounds the activity pattern of suprofen was consistent with that of a very potent, short-acting inhibitor of prostaglandin biosynthesis, which maintains its specific action over a wide dose range. It is concluded that delay of castor oil-induced diarrhoea in rats allows a detailed characterization of aspirin-like compounds, and that inhibition of prostaglandin biosynthesis is insufficient to suppress the intestinal effects of the oil.

A rapid gas-liquid chromatographic method for the determination of cotinine and nicotine in biological fluids.

Abstract: A rapid method is described for the simultaneous measurement of nicotine and cotinine in biological fluids using capillary column gas-liquid chromatography. Using 100 microliters sample volume the lower limit of detection for both nicotine and cotinine was 100 pg mL-1, allowing the method to be used for the measurement of these compounds in both smokers and non-smokers. The extraction time is 3 min per sample, and by using multi-pipetting and vortexing systems 250 samples can be extracted per day. The average coefficient of variation over the nicotine range 1.0 to 100 ng mL-1 was 3.9% and for cotinine over the range 1.0 to 1000 ng mL-1 was 2.2%. Saliva cotinine concentrations were quantitatively related to passive exposure to parental smoking in a population study of 1118 non-smoking schoolchildren.