Pharmacokinetics of cefradine, sulfamethoxazole and trimethoprim and their metabolites in a patient with peritonitis undergoing continuous ambulatory peritoneal dialysis

Cefradine and co-trimoxazole pharmacokinetics were studied in a patient with peritonitis that complicated continuous ambulatory peritoneal dialysis (CAPD). Concentrations in the plasma reached after oral administration of 500 mg cefradine four times daily and 400/80 mg co-trimoxazole four times daily were for cefradine 100g/ml, for trimethoprim 15g/ml, and for sulfamethoxazole 100/ml, respectively. In the dialysate concentrations were reached of 35–70/ml cefradine, 2–5/ml trimethoprim and 8–17g/ml sulfamethoxazole. The values for sulfamethoxazole are regarded too low to be clinically effective. Half-lives protein binding values and CAPD clearances are presented. Low CAPD clearances were obtained during the night and high values during the day. The dosage yielded too high plasma trimethoprim concentrations, while sulfamethoxazole dialysate concentrations were too low. It seems questionable therefore whether co-trimoxazole can be used orally for the treatment of CAPD peritonitis.     

Bedeutung der N- und α-Methylierung für die Affinität von Brenzcatechinaminen zu den adrenergischen Receptoren

Summary 1. N-methylation of dopamine yielding epinine means potentiation of the -adrenergic pressor action in the cat. It is only N-methylation which renders dopamine to a direct acting -sympathomimetic amine: the positive inotropic effect of epinine on the isolated electrically driven guinea pig auricle remained uninfluenced by pretreatment of the animals with reserpine, whereas the dose-response curve of dopamine was shifted to the right.The blood pressure lowering effect of epinine after phenoxybenzamine was—in contrast to that of dopamine—abolished by pronethalol.—N-methylation of noradrenaline doubled the affinity for the -receptors of the heart.2. Also by -methylation dopamine gains affinity to the adrenergic -receptors (heart and vessels): d--methyldopamine, an exclusively directly acting catecholamine, had a 40 times stronger inotropic action than dopamine on reserpinized auricles; the action of l--methyldopamine, a mainly indirectly acting amine, was only 4 times stronger than dopamine.-methylnoradrenaline, although having the same inotropic activity as noradrenaline, had a 10 times stronger depressor action than noradrenaline in the cat pretreated with phenoxybenzamine.By -methylation, the -adrenergic pressor effect of dopamine as well as that of noradrenaline was enhanced only in the range of lower doses since the dose-response curves of the -methylated compounds were generally less steep than those of the non-methylated catecholamines, indicating a lower intrinsic activity of the -methylated derivatives.3. The N- and -methylated catecholamines -methylepinine and -methyladrenaline resp. were blood pressure lowering agents per se, because both methylgroups additively enhanced the affinity to the vascular -receptors. -methylepinine was the most potent -sympathomimetic on the heart in the dopamine series (dopamine < d--methyldopamine epinine < dl--methylepinine). However, in the noradrenaline series the twofold methylated compound -methyladrenaline had the lowest positive inotropic action (d(–)-adrenaline > d(–)-noradrenaline (–)erythro--methylnoradrenaline > (–) erythro--methyladrenaline).4. From the results the following conclusions are drawn: The N- as well as the -methyl-group exerts and +I-effect on the ammonium group. Thereby, protonation will be increased which leads to an enhanced affinity of the resp. catecholamine to the adrenergic - and -receptor. Since the -CH₃ group—dependant upon its steric configuration—also causes a steric hindrance at the receptor site, the increase in affinity due to the +I-effect is partially neutralized. By that the lower intrinsic affinity of the -methylated compounds as indicated by the different slope of their pressor dose-response curves, is also readily explained. Furtheron it is intelligible why -methylation enhanced the -adrenergic activity in the less potent dopamine series (preponderance of the +I-effect), whereas it lowered the affinity to the cardiac -receptors in the noradrenaline series (preponderance of the steric hindrance).5. Although -methyladrenaline was the least potent -sympathomimetic of the noradrenaline series in the guinea pig heart, it was the most potent compound in lowering the cat's blood pressure. Therefore, it seems to be questionable whether the cardiac and the vascular -receptors and/or the mechanisms by which they induce the pharmacodynamic actions are identical.

Über einen Teil der Ergebnisse wurde auf der 7. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft in Mainz, 24.–27. April 1966, berichtet (Palm, Langeneckert u. Holtz, 1966).     

Investigations differentiating the mechanism of specific bradycardic agents from that of calcium channel blockers

Summary The effects of two specific bradycardic agents, falipamil (AQ-A 39) and the alinidine-congener STH 2148 2-[N-(cyclopropylmethyl)-N-(2,6-dibromophenyl)amino]2-imidazoline, on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated in comparison to that of the calcium channel blocker verapamil. Addition of falipamil (10 g/ml) to a maximally rate lowering concentration of STH 2148 (30 g/ml) exerted no further bradycardic effect. In contrast, verapamil (0.1 g/ml) added to either STH 2148 (30 gg/ml) or a maximally effective concentration of falipamil (30 gg/ml) resulted in a further, significant reduction of sinus rate. The results are compatible with the idea of a common mechanism of the two specific bradycardic agents, different from that of calcium channel blockers. Send offprint requests to W. Kobinger at the above address     

A method to estimate the potency of the μ-component of an opioid having mixedμ-, andκ- and/orδ-agonist activities

The SC administration of either typical-agonists such as morphine, pethidine, fentanyl and levorphanol or a mixed- and-agonist like [d-Ala²,d-Leu⁵]-enkephalin to 10-day-old rats produced loss of righting reflex. Additionally, the loss of righting reflex induced by these opioid agonists was antagonized by naloxone, an opioid antagonist having a preference for-receptors, but by neither nor-binaltorphimine nor naltrindole, a specific- or-antagonist, respectively, indicating that the loss of righting reflex was produced by the interaction of an opioid with-receptors. Moreover, the potency of each opioid agonist relative to that of morphine estimated by the present in vivo method was similar to that determined by the traditional in vitro isolated preparation. In contrast to-agonists, neither typical-agonists such as U-50, 488H, ketocyclazocine, pentazocine and butorphanol, nor a selective-agonist like [d-Pen²,d-Pen⁵]-enkephalin affected the righting reflex of 10-day-old rats, indicating that-agonists, but neither- nor-agonists, produced the naloxone-reversible loss of righting reflex in infant rats. By employing the present in vivo method to estimate the-agonist activity of an opioid with mixed agonist activities, it was indicated that the-agonist activity of ethylketocyclazocine, which had been employed as a representative-agonist, was essentially the same as that of morphine, a representative-agonist.     

Effects of (R)-α-methylhistamine and scopolamine on spatial learning in the rat assessed using a water maze

The effects of (R)--methylhistamine ((R)--MeHA, a selective H₃-receptor agonist) and scopolamine (SCOP, a muscarinic antagonist) were investigated on spatial learning and memory in the rat (Hooded Lister) using a water maze (WM). (R)--MeHA treatment (6.3 and 10 mg/kg IP) had no apparent effect on spatial learning but did result in enhanced spatial recall at the higher dose, assessed by a transfer (probe) test after training. In contrast, SCOP (0.5 mg/kg IP) induced a learning and memory deficit measured both during and after training. In animals treated with (R)--MeHA and SCOP, (R)--MeHA partially (6.3 mg/kg) and completely (10 mg/kg) reversed the SCOP-induced deficit during the training phase, while in the post-training transfer test, (R)--MeHA (10 mg/kg) significantly reduced the SCOP-induced memory deficit. None of the treatments described resulted in impaired visual acuity as demonstrated by a raised platform test. These results are consistent with a role for histamine in cognitive processes and suggest a possible interaction between central histamine and cholinergic mechanisms associated with rodent spatial learning and memory.     

α-Adrenoceptor activity of arylalkylimidazoles is improved byα-methylation and impaired byα-hydroxylation

Summary To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on the-adrenoceptor activity of arylalkylimidazole derivatives, the cardiovascular effects of the molecules were studied in anaesthetized and pithed rats. The compounds studied were 4(5)-substituted imidazole derivatives with a methano, ethano or etheno bridge between the imidazole and the 2-, 2,3- or 2,6-methyl substituted phenyl rings. The hypotensive and bradycardic activities of the molecules in the anaesthetized rat were always reduced by-hydroxylation and usually augmented by-methylation of the bridge between the imidazole and phenyl rings. Hydroxylation was associated with a consistent, marked decrease in vasopressor and sympatho-inhibitory activity in the cardiovascular system of the pithed rat, but a methyl moiety as a bulky substituent in the-position of the alkyl bridge did not decrease but even caused an increase in-adrenoceptor activity in this test system. The detrimental effect of-hydroxylation of the compounds at ₁- and ₂-adrenoceptors supports the notion that the interaction of the imidazoles at-adrenoceptor is different from that of the classical, noradrenaline-like phenethylamines. The results also suggest that the alkyl bridge between the phenyl and imidazole rings of the imidazoles may contribute directly to the binding process.     

Antitumor Agents 126. Novel 4β-Substituted Anilino Derivatives of 3′,4′ -O,O-Didemethylpodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II

A series of derivatives of 3,4 0,0-didemethylpodophyllotoxin have been synthesized and evaluated for their inhibitor activity against neoplastic cell growth (KB) and against human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results show that the compounds possessing a 4-anilino moiety either unsubstituted or substituted at the para (F, COOCH₃, COCH₃, CN, CH₂CN, NO₂) or meta (OH) positions or with an ethylenedioxy moiety showed the same or greater activity than etoposide in causing cellular protein-linked DNA breakage and in inhibiting DNA topoisomerase II. However, compared to the corresponding 4-0-demethyl analogues, the 3,4-O,O-didemethyl compounds have a similar potency in inhibition of DNA topoisomerase II but are less active in causing cellular protein-linked DNA breakage. Complete correlation between the three biological activities–cytotoxicity, inhibition of DNA topoisomerase II, and induction of protein-linked DNA breakage–was also not observed. This supports the possibility that the biological determinants of action among these compounds may be different.     

Über die Bedeutung des Noradrenalingehaltes im Fettgewebe für die Mobilisierung unveresterter Fettsäuren

Zusammenfassung 1. Versuche an Ratten haben ergeben, daß der Anstieg unveresterter Fettsäuren (UFS) im Plasma nach subcutaner Injektion von Tyramin bzw. Metaraminol durch Freisetzung von Noradrenalin im Fettgewebe zustande kommt. Diese Wirkung ließ sich durch Vorbehandlung mit Cocain fast vollständig verhindern. Die lipolytische Wirkung injizierten Noradrenalins wurde jedoch durch Cocain verstärkt.2. Der Noradrenalingehalt des Fettgewebes war von entscheidender Bedeutung für das Ausmaß der durch Tyramin bzw. Metaraminol verursachten UFS-Mobilisierung: Verarmung des Fettgewebes an Noradrenalin durch Vorbehandlung der Tiere mit dem Reserpinanalogen Syrosingopin verhinderte die durch Tyramin bzw. Metaraminol ausgelöste UFS-Mobilisierung; Erhöhung des Noradrenalingehaltes im Fettgewebe durch Blockierung der Monoaminoxydase mit Nialamid oder Pargylin verstärkte die lipolytische Wirkung von Metaraminol, ohne diejenige injizierten Noradrenalins zu beeinflussen.3. Durch Vorbehandlung der Tiere mit -Methyl-Dopa bzw. -Methyl-m-Tyrosin ließ sich das Fettgewebe ebenfalls an Noradrenalin verarmen; Metabolite dieser Aminosäuren, -Methyl-Noradrenalin (Corbasil) bzw. -Methyl--Hydroxy-m-Tyramin (Metaraminol), konnten im Fettgewebe nachgewiesen werden. Die lipolytische Wirkung des Tyramins wurde durch Vorbehandlung mit -Methyl-m-Tyrosin aufgehoben, blieb jedoch nach Vorbehandlung mit -Methyl-Dopa unbeeinflußt. Behandelte man die Tiere zuerst mit -Methyl-m-Tyrosin und dann mit -Methyl-Dopa, so wurde Tyramin wieder wirksam. An Ratten, die mit -Methyl-Dopa vorbehandelt worden waren, verhinderten erst 10–20fach höhere Dosen von Syrosingopin die lipolytische Wirkung des Tyramins. In vitro war das aus -Methyl-Dopa entstehende -Methyl-Noradrenalin genauso stark lipolytisch wirksam wie Noradrenalin; -Methyldopamin war wirksamer als Dopamin. Demgegenüber war das aus -Methyl-m-Tyrosin entstehende Metaraminol mehr als 1000mal schwächer wirksam als Noradrenalin. -Methyl-m-Tyramin und Tyramin waren in vitro unwirksam. — Offenbar ist -Methyl-Noradrenalin, im Gegensatz zu Metaraminol, nicht nur ein materieller, sondern auch ein funktioneller Ersatz des verdrängten Noradrenalins im Fettgewebe.4. Der durch mehrstündige Kälteeinwirkung verursachte Anstieg der UFS im Plasma ist zum überwiegenden Teil nerval-noradrenergisch bedingt: er ließ sich durch Erhöhung des Noradrenalingehaltes im Fettgewebe (Nialamid, Pargylin) verstärken und durch Verarmung des Fettgewebes an Noradrenalin (Syrosingopin) stark abschwächen. Operative Entfernung des Nebennierenmarks (Demedullierung) verhinderte den UFS-Anstieg bei Kälte nicht. Demgegenüber ist die hyperglykämische Wirkung der Kälte überwiegend hormonal-adrenergisch bedingt, denn sie ließ sich durch Vorbehandlung mit Syrosingopin nicht verhindern, aber durch Demedullierung aufheben.

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Summary 1. Experiments in rats disclosed that the increase of plasma free fatty acis (FFA) following the injection of tyramine and metaraminol resp. is predominantly mediated by the liberation of endogenous norepinephrine in adipose tissue since it was markedly reduced by pretreatment with cocaine and abolished after depletion of stored norepinephrine by syrosingopine. On the other hand, pretreatment with monoamine oxidase inhibitors (nialamid, pargyline) which increased the norepinephrine content of adipose tissue by nearly 100% enhanced the lipolytic action of metaraminol without affecting that of injected norepinephrine.2. The norepinephrine content of adipose tissue was also reduced after pretreatment with -methyl-dopa and -methyl-tyrosine resp. In these animals -methyl-norepinephrine (Corbasil) and -methyl--hydroxy-m-tyramine (metaraminol) resp. were shown to be present in adipose tissue. However, the tyramine induced increase of plasma FFA was not affected by pretreatment with -methyl-dopa but was abolished by -methyl-m-tyrosine. In -methyl-m-tyrosine treated animals the lipolytic response to tyramine was restored by additional treatment with -methyl-dopa. In syrosingopine treated animals the injection of -methyl-dopa also restored the lipolytic response to tyramine. In -methyl-dopa treated animals 10–20 fold higher doses of syrosingopine were necessary to prevent the tyramine induced lipolysis.3. The lipolytic activities of various sympathomimetic amines were studied in isolated epididymal fat pads. Epinephrine, -methyl-epinephrine and -methyl-norepinephrine had the same or slightly less potency of norepinephrine. -methyl-dopamine and octopamine were approximately 100 timesless potent, dopamine and metaraminol more than 1000 times less potent than norepinephrine. Tyramine and -methyl-m-tyramine were ineffective. — It is concluded that after pretreatment with -methyl-dopa -methyl-norepinephrine serves as a false but rather efficient transmitter substance in adipose tissue.4. The mobilization of FFA during cold exposure is mediated predominantly by an increased activity of sympathetic nerves since the effect was enhanced by pretreatment with monoamine oxidase inhibitors (nialamid, pargyline) and markedly reduced by pretreatment with the reserpine analogue syrosingopine or ganglionic blockade (chlorisondamine). Adrenal demedullation did not prevent the increase of plasma FFA during cold exposure. In contrast, hyperglycemia in cold exposed rats is predominantly mediated by hypersecretion of epinephrine from the adrenal medulla since it was not affected by pretreatment with syrosingopine but abolished by adrenal demedullation.

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Ausgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft (We272). Über einen Teil der Ergebnisse wurde auf Tagungen der Deutschen Pharmakologischen Gesellschaft berichtet (Stock u. Westermann 1962a, 1963a; Westermann u. Stock 1963, 1964) sowie in einer kurzen Mitteilung (Stock u. Westermann 1964).     

In-Vitro Dissolution Profile Comparison: Statistics and Analysis,Model Dependent Approach

Purpose. To develop and propose a model dependent approach for the in-vitro dissolution profiles comparison. Methods. Diltiazem hydrochloride tablet dissolution profiles were compared using a statistical approach based on a mathematical model. A similarity region (SR) was defined based on the intra- and inter-lot parameter variances of the final production size standard lots. Statistical distances between the test and reference lot parameter means were computed and normalized. A 90% confidence region (CR) was developed around the statistical distance. The confidence region was compared with the similarity region to assess the similarity or dis-similarity of the test and reference (REF) lot dissolution profiles. Two test lots, one with a minor modification (mm) the other with a major modification (MM), were evaluated. Results. Weibull was selected as the model function. A comparison of the confidence regions around the statistical distance of mm-REF and MM-REF with the similarity region, suggested that the dissolution profiles of the minor modification lot were similar and that of major modification lot were dis-similar to the reference lot. Conclusions. A model dependent approach was shown to be useful for the inter-lot in-vitro dissolution profiles comparison.     

Modification of Δ9-THC-actions by cannabinol and cannabidiol in the rat

Cannabinol (CBN) and Cannabidiol (CBD) were tested in several test procedures known to be altered by ⁹-tetrahydrocannabinol (THC) or crude cannabis preparations. They were inactive in doses up to 80 mg/kg in tests on animal motility, food and water intake, body temperature and catalepsy. In contrast, CBD enhanced the hexobarbitone sleeping time more pronounced than ⁹-THC whereas CBN increased the sleeping time only slightly. When administered in combination CBD prolonged all actions of THC, whereas CBN selectively blocked the effect of THC on hexobarbitone sleeping time. The enhancement by CBD is best explained by an inhibition of THC-metabolism.This paper was in part presented at the C.I.N.P., Copenhagen, 1972.Supported in part by a research grant of the Bundesminister für Jugend, Familie und Gesundheit.     

Interferon-γ in Starch Microparticles: Nitric Oxide-Generating Activity in Vitro and Antileishmanial Effect in Mice

Recombinant mouse interferon- (mu IFN-) was covalently coupled to polyacryl starch microparticles, a lysosomotropic drug carrier. The microparticle-bound mu IFN- was found to activate cultured macrophages for nitrite production and had an anti-leishmanial effect in mice. Low doses of mu IFN-, which had no effect in the free form, when bound to microparticles significantly reduced the load of Leishmania donovani in infected mice. Further, inducement of nitrite production in cultured macrophages by microparticle-bound mu IFN- required intact cell membrane receptors.     

Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines

Summary Diethyldithiocarbamate (DDTC) and other dithiocarbamates are currently receiving attention as potential adjuncts to traditional chemotherapy. In vitro studies with rodent cancer cell lines have consistently shown that DDTC concentrations of 0.1–1.0 g/ml are highly cytotoxic. Paradoxically, however, concentrations of 10–100 g/ml have been significantly less toxic.In the present study, such a biphasic pattern was reproduced when 3 rodent cell lines were exposed for 1 hour to 0.001 to 1000 g DDTC/ml. In contrast, in 7 human cell lines survival decreased steadily with increasing DDTC concentration (in the same dose range) without evidence of a biphasic pattern. These data might have implications for studies in which rodent cell lines are used to model the effects of dithiocarbamates in human tissues.     

Über Beziehungen zwischen proteolytischer Aktivität und blutcoagulierender sowie bradykinin-freisetzender Wirkung von Schlangengiften

Summary 1. Protein fractions with a different relation of proteolytic to coagulating activity were obtained by ammonium sulphate fractionation of the venom from Bothrops jararaca. The precipitate at 40% saturation possessed only feeble coagulating, but strong proteolytic activity (Protease), whereas there was feeble proteolytic and strong coagulating activity in the precipitate at 60% saturation (Koagulin).2. A substance which stimulated the intestine, probably bradykinin, was formed on incubation of Koagulin or Protease with plasma globulins. With Koagulin the formation was optimal atph 6,5 and increased with the duration of incubation; with Protease theph optimum was 8,0 and the gut stimulating activity decreased with prolonged incubation.3. The effects of the Koagulin- and the Protease fraction of the venom — the thrombin-like activity, the activation of prothrombin and the formation and destruction of bradykinin — were ascribed to different substrate-specific proteases.

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Durchgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Naloxone protein binding in adult and foetal plasma

Summary Binding of naloxone hydrochloride was determined at 37°C, by equilibrium dialysis against 0.067 M phosphate buffer, pH 7.4, in plasma obtained from 18 healthy adults, and 18 samples of umbilical cord venous (foetal) plasma. The percentage free fraction (% free) in plasma was independent of naloxone concentration (9 ng/ml to 2.5 µg/ml). Percent free naloxone in adult (x=54.0) was lower (p<0.01) than in foetal (x=61.5) plasma. In buffered solutions of purified HSA, %free naloxone (x=68.7) was independent of HSA concentration over the range 3.0 g/dl to 5.5 g/dl. Adult plasma concentrations of ₁-acid glycoprotein (₁-AGP) and -lipoprotein were higher (p<0.01) than foetal concentrations. Furthermore %free naloxone in foetal plasma decreased with the in-vitro addition of purified ₁-AGP. It is suggested that qualitative differences in adult and foetal albumin and quantitative differences in plasma levels of ₁-AGP and perhaps -lipoprotein are responsible for naloxone plasma binding differences between adults and the newborn.     

Disposition Kinetics of α-Tocopherol in Apolipoprotein B Knockout Mice

Purpose. We examined the effects of apolipoprotein B (apoB) on the disposition kinetics of -tocopherol by using apoB knockout mice. Methods. The concentrations of -tocopherol in plasma and tissues were measured by gas chromatography-mass spectrometry. Results. In apob (–/–) mice, the endogenous levels of -tocopherol in plasma and tissues (except liver) were significantly lower, and the liver concentration was significantly higher than those in wild-type mice. After single i.v. administration of -tocopherol (25 mg/kg), the area under the plasma concentration-time curve (AUC) and the distribution volume at steady state were significantly decreased, whereas the total clearance of -tocopherol was significantly increased in apob (–/–) vs. wild-type mice. -Tocopherol was highly distributed to the liver, compared with other tissues. After an oral administration of -tocopherol (100 mg/kg), the intestinal absorption of -tocopherol was very low in apoB knockout mice, as the value of AUC_0-32h for apob (–/–) mice (17.7 ± 8.3 g h/mL) was significantly less than that for apob (+/+) wild-type mice (96.5 ± 15.8 g h/mL, mean ± SD of five experiments, p < 0.01). The biliary excretion of -tocopherol was significantly greater in apob (+/–) mice than in apob (+/+) mice. Conclusions. These results show that apoB plays a role in hepatic secretion and intestinal absorption of -tocopherol.     

Viscoelastic Properties of Bioadhesive,Chlorhexidine-Containing Semi-Solids for Topical Application to the Oropharynx

Purpose. This study examined the viscoelastic properties of bioadhesive, chlorhexidine-containing semi-solid formulations, designed for topical application to the oropharynx. Methods. Oscillatory rheometry was performed using a Carri-Med CSL²-100 rheometer at 20.0 ± 0.1° C in conjunction with parallel plate geometry (2 cm diameter, 0.5 mm sample thickness). Samples were subjected to a constant strain (6.5 × 10^–3 rad) and defined viscoelastic parameters, namely storage modulus (G), loss modulus (G), loss tangent (tan ) and dynamic viscosity (), measured over a defined frequency range (0.01-1.0 Hz). Results. As the oscillatory frequency was increased, G G of all formulations increased, whereas both and tan significantly decreased. The magnitude of increase of G and G as a function of frequency was relatively small, indicating that, in general, the formulations were non-cross-linked elastic systems. Increasing concentrations of HEC, PVP and PC significantly increased G, G, yet decreased tan observations that may be attributed to the physical state of each polymer in the formulations. Formulation elasticity increased (i.e. tan decreased) as a result of increased entanglement of polymeric chains of dissolved components (i.e. HEC and PVP) and the restrained extension of swollen, cross-linked chains of PC. Additionally, in formulations where the saturation solubility of PVP was exceeded and/or insufficient 'free-water' was available for maximal swelling of PC, formulation elasticity increased as a result of the increasing mass of dispersed solid particles of PVP and/or PC. Formulation increased due to the attendent effects of polymer chain entanglement and polymer state on overall formulation viscosity. Conclusions. Following application to the oropharynx, the formulations will behave as elastic systems. Thus, these formulations would be expected to offer advantageous clinical properties, e.g., prolonged drug release, increased bioadhesion. However, it is noteworthy that the final choice of formulation for clinical evaluation will involve a compromise between viscoelastic characteristics and acceptable textural properties, e.g. ease of product application. This study has shown the applicability of oscillatory rheometry for both the characterisation and selection of candidate, topical bioadhesive formulations for clinical evaluation.     

Clonidine induced intrahypothalamic stimulation of eating in rats

Intracerebral injection of 1 l volumes of solutions containing noradrenaline, clonidine, oxymetazoline and phentolamine were performed in the antero-lateral hypothalamus of the Wistar rat at the level of the pars infracommissuralis of the Stria terminalis.Intrahypothalamic clonidine in a dose as low as 1 g strongly increased food intake in satiated rats.Clonidine (4 g) was more potent than noradrenaline (12 g) but as potent as oxymetazoline (1.5 g).The clonidine induced eating response was completely blocked by the -sympatholytic drug phentolamine.The results emphasize the role of clonidine as an activator of noradrenaline receptors in the central nervous system.     

Viscoelasticity of Anionic Polymers and Their Mucociliary Transport on the Frog Palate

The influence of formulation variables on the rheology of polyanionic formulations and the relationships between viscoelastic properties and mucociliary transport rate were investigated. Polymeric samples were oscillated from 0.001 to 5 Hz using either a "cone and plate or a "coaxial cylinder measuring system. The mucociliary transport rates of polymeric samples were determined and compared movement of charcoal powder on the frog palate. For the linear polymeric solutions, sodium carboxymethylcellulose and sodium alginate, the elastic modulus (G) increased with increasing amplitudes during frequency scan. However, the G or viscous modulus (G) of partially cross-linked polyacrylic acid (cPAA) samples did not change significantly under oscillation. Both G and G of cPAA samples were significantly influenced by the amount of salt present in the formulation. The rheology of 2% (w/w) cPAA in 90:10 (w/w) propylene glycol:alcohol changed from a viscous fluid to a coarse suspension after neutralization. The pH increased gradually when the nonaqueous formulation reacted with water and the maximum dynamic moduli were obtained after incorporating 20% (w/w) water in the formulation. A negative correlation was found between the G of linear polyanionic samples and the relative transport rate. However, the lowest mucociliary transport rate was observed when the loss tangent (G/G) was around 0.4–0.5.     

Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application

Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and C_max) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 ghr/ml and the C_max values ranged from 0.04 to 2.17 g/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and C_max results in ranges of 0.001 to 0.473 ghr/ml, and 0.001 to 0.119 g/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and C_max corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.     

Influence of flupenthixol and flupenthixol-decanoate on methylphenidate and apomorphine-induced compulsive gnawing in mice

-Flupenthixol and -flupenthixol decanoate were tested in mice against methylphenidate-induced stereotyped gnaw-compulsions. The effect of both -flupenthixol, and -flupenthixol decanoate disappeared 2 days after administration.In addition, the influence of -flupenthixol and -flupenthixol decanoate on the apomorphine-induced behaviour in mice was followed over a period of 12 days. Under these conditions apomorphine-induced compulsive gnawing was seen on the days on which the methylphenidate antagonistic effect had subsided.The apomorphine-induced compulsive gnawing seen in -flupenthixol and -flupenthixol decanoate pretreated animals could be antagonized by additional small doses of -flupenthixol given 2 h before apomorphine. The interference of the neuroleptic drugs with dopaminergic receptors is discussed.