bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of prostaglandin E2 and indomethacin on the renal corticomedullary solute gradient in the rat
Authors: Haylor J , Lote C J
Published: April 2011

The renal corticomedullary solute gradient and the urinary excretion of fluid and solute were determined during a saline infusion in anaesthetized and conscious rats. In the anaesthetized group the influence of PGE2 (100 ng min−1) given by a local renal infusion was investigated. In the conscious group (where prostaglandin synthesis does not contribute to renal blood flow) the effect of indomethacin (i.v. 10 mg kg−1) was determined. Following PGE2 infusion the corticomedullary gradient for sodium was depressed, equalizing the sodium concentration between the papilla tip and the final urine. Sodium output and urine flow were elevated, but both urinary and gradient changes could be dissociated from any increase in renal blood flow, assessed by PAH clearance. Following treatment with the prostaglandin synthetase inhibitor indomethacin in the conscious rat, the corticomedullary osmotic gradient was elevated while the urine flow was reduced. This increase in the gradient produced by indomethacin was, however, found to be independent of the decrease in urine flow. The results of the present experiments are consistent with the hypothesis that prostaglandin synthesis helps to determine the renal corticomedullary osmotic gradient, and does so by a mechanism unlikely to involve changes in renal blood flow or tubular flow rate: a permeability hypothesis is proposed.
Analysis of the permeation and mechanical characteristics of some aqueous-based film coating systems
Authors: Okhamafe Augustine O , York Peter
Published: April 2011

The moisture permeability and mechanical properties of some aqueous-based free films have been evaluated using sorption-desorption and stress-strain techniques, respectively. These properties for blends of two film-formers—hydroxypropyl methylcellulose and polyvinyl alcohol—have been compared with those of hydroxypropyl methylcellulose films plasticized with polyethylene glycols. The polyethylene glycols generally increased the moisture permeability of hydroxypropyl methylcellulose films while polyvinyl alcohol decreased it. Both polyvinyl alcohol and the polyethylene glycols lowered tensile strength at break and Young’s modulus but the effects of the polyethylene glycols were more pronounced. These results are discussed in terms of structural interactions between film components. All film systems evaluated, except that containing hydroxypropyl methylcellulose alone, exhibited a degree of anisotropy, a phenomenon with potentially adverse consequences in tablet film coating.
The deamination of n-pentylamine by monoamine oxidase and a semicarbazide-sensitive amine oxidase of rat heart
Authors: Guffroy Christian , Fowler Christopher J , Benedetti Margherita Strolin
Published: April 2011

n-Pentylamine is deaminated by homogenates of rat heart. Clorgyline inhibition curves at 10 and 100 μM n-pentylamine indicated that this substrate was deaminated by MAO-A, -B and a clorgyline-resistant amine oxidase sensitive to inhibition by semicarbazide. These results have been compared with two other commonly used monoamine substrates, β-phenethylamine and benzylamine.
Dilazep: an inhibitor of adenosine uptake with intrinsic calcium antagonistic properties
Authors: Tonini M , Perucca E , Manzo L , Marcoli M , D'Angelo L , Saltarelli P , Onori L
Published: April 2011

Concentrations of dilazep which were ineffective in altering the muscular tone of the guinea-pig taenia caeci (0·03, 0·3 μM) or the phasic mechanical activity of the rabbit proximal ileum (0·03 μM) markedly potentiated the inhibitory action of adenosine on both these parameters. Dilazep, 0·3 μM or greater, dose-dependently inhibited the mechanical activity of the proximal ileum. This inhibitory action was probably mediated by more than one mechanism, as shown by the fact that theophylline (50,100 μM) antagonized the effect at lower dilazep concentrations (up to 3 μM) leaving essentially unchanged the response to higher concentrations (6, 10 μM). Similarly, the responses to low doses of dilazep were reduced after desensitization of the organ to adenosine, whilst the responses to higher doses were unaffected by this procedure. In a Ca2+-free, high-K+ medium, dilazep (1-10 μM) caused a parallel shift to the right of the Ca2+-induced contractions of the guinea-pig taenia caeci. Adenosine showed only slight Ca2+-antagonistic properties within the mM range of concentrations. These findings suggest that, at the higher concentrations tested, dilazep exhibits Ca2+-antagonistic properties unrelated to its adenosine-mediated mode of action.
The role of disintegrants in hard-gelatin capsules
Authors: Botzolakis J E , Augsburger L L
Published: April 2011

Experiments were designed to investigate the efficacy of various disintegrants on hydrochlorothiazide dissolution from soluble (lactose) and insoluble (dicalcium phosphate) fillers at various lubricant concentrations and compression forces. Capsule fill weights as well as slug hardness appeared to be influenced by the addition of disintegrants. Disintegration times were not always in rank order agreement with dissolution data. Analysis of the dissolution data by 3-way analysis of variance revealed that all the main factors (disintegrant, compression force, lubricant and/or diluent) and their interactions were significant. The presence of interactions limits the conclusions to be drawn; however, an assessment of the averaged effect of each factor separately revealed several important relationships. A compression force effect was evident in most cases at the lower disintegrant concentration, and lower lubricant concentrations or a more soluble filler appeared to require lesser amounts of disintegrant. The magnitude and order of effectiveness of the disintegrants were altered when the filler system was changed from lactose to dicalcium phosphate.
The evaluation of an automatic system for filling liquids into hard gelatin capsules
Authors: McTaggart C , Wood R , Bedford K , Walker S E
Published: April 2011

A system is described in which an intermittent motion powder filling capsule machine is modified to fill liquids into hard gelatin capsules suitable for pilot scale or small production batches. The system is shown to be suitable for filling materials covering a wide range of viscosities and to give excellent fill weight uniformity which is largely independent of operating conditions. The process is clean and trouble-free.
Amorphous spray-dried hydroflumethiazide-polyvinylpyrrolidone systems: Physicochemical properties
Authors: Corrigan O I , Holohan E M
Published: April 2011

Hydroflumethiazide was spray-dried with polyvinylpyrrolidone (PVP) to produce products containing 0–30% PVP. These systems were amorphous and differed from previously prepared coprecipitates of similar composition. Differential scanning calorimetry (DSC) suggested that at low PVP weight fractions both amorphous drug and an amorphous drug-PVP complex can be present in spray-dried systems. The apparent solubility of hydroflumethiazide in spray-dried products increased with increasing PVP content reaching a plateau value approximately four times that of the pure crystalline drug. The estimated free energy and entropy of the spray-dried drug were greater than that of crystalline drug and also increased with increasing PVP content. Dissolution studies with compressed discs supported the apparent solubility data. The results suggest that amorphous phases having different orders of organization are formed in spray-dried systems with increasing PVP content.
Controlled release of radioprotective agents from matrix tablets—effect of preparative conditions on release rates
Authors: Benita S , Shani J , Abdulrazik M , Samuni A
Published: April 2011

Release rates of radioprotective agents from insoluble matrix tablets were measured as a function of ethylcellulose/stearic acid ratio and active ingredient concentration in the matrix. The influence of the compacting pressure applied during tablet formation on the release of these aminothiol compounds was also examined. The kinetic data conformed with the Higuchi square root equation and first order release. As both plots were linearly acceptable, a statistical method for release mechanism identification using the kinetic experimental results obtained without any further transformation was used. This non-linear regression search procedure accompanied by the χ2-square test has shown that aminothiol release from the matrix tablets definitely follows the Higuchi square root equation. Increasing the ethylcellulose amount in the matrix consequently improves the degree of wettability and leads to a faster rate of solvent penetration. This tends to release the aminothiols more rapidly from the matrix tablets. Solvent penetration, which also follows a square root of time relationship, is probably the rate-limiting factor in the release process. The linear increase in release rates of the aminothiols observed with ethylcellulose concentration is explained by a parallel increase in the porosity of the matrix tablets. Increase in the drug concentration in the tablet increases the cysteine hydrochloride release rate and decreases the cysteamine hydrochloride release rate. A similar effect was also observed by applying increasing compacting pressure during matrix tablet formation. It was suggested that these two experimental factors differently affect the internal structure of the matrix during the preparation process. In the presence of cysteine hydrochloride larger porosities and smaller tortuosities are produced in the matrix leading to an increase in release rate. On the other hand, in the presence of cysteamine hydrochloride smaller porosities and larger tortuosities are formed in the matrix leading to a decrease in the release rate with increasing aminothiol concentration and compacting pressure respectively.
Effect of chloroquine and some other antimalarials on the immune mechanism in experimental animals
Authors: Bhattacharya S K , Pillai C R , Mathur M , Sen P
Published: April 2011

The effects of chloroquine and some other antimalarials on the immune responses in experimental animals have been examined. Chloroquine and quinine caused significant decrease of serum anti−SRBC haemagglutination titre. Chloroquine lowered the serum IgM level and also reduced plaque−forming cells in the spleen of mice. The delayed−type hypersensitivity responses to SRBC and the passive cutaneous anaphylaxis were also diminished in rats treated with chloroquine. Thus, the immunosuppressant activity of chloroquine may explain its efficacy in various types of immune disorders.
Parallel bioassay of physalaemin and hylambatin on smooth muscle preparations and blood pressure
Authors: Erspamer G Falconieri , Mazzanti G , Yasuhara T , Nakajima T
Published: April 2011

Hylambatin, a novel tachykinin endecapeptide isolated from the skin of the African frog Hylambates maculatus, must be ascribed to the physalaemin subfamily. It differs structurally from all other known tachykinins mainly in having a methionine residue replacing the usual leucine residue at position 2 from the C―terminus. In parallel bioassay on a number of in―vitro and in―vivo test objects, hylambatin and physalaemin were nearly indistinguishable from each other, with few moderate quantitative differences.
Rheology of pharmaceutical granulations
Authors: Schildcrout Sigmund A
Published: April 2011

The rheological transformations that take place when granulating fluid is added to pharmaceutical powders have been monitored by means of a laboratory scale (approx. 50 g amounts) torque rheometer. The three formulations studied, based on lactose, sulfadiazine, and benoxaprofen, had common characteristics in that each passed through a granulation peak of maximum torque. In the zone immediately before the peak the granules were growing, while after it the material had properties of a cohesive, viscoelastic mass. Therefore, the rheological state of the material under process is not specified by a single torque reading, but by the rheological history of the granulation.
The solubility of 17 β-oestradiol in aqueous polyethylene glycol 400
Authors: Groves M J , Bassett B , Sheth V
Published: April 2011

The solubility of 17 β-oestradiol (E2) in aqueous solutions of polyethylene glycol (PEG) 400 has been measured at 35 °C. Up to 80% w/w PEG the solubility data conform to a log linear equation In S = In Sw + fø where S is the E2 concentration in the water/cosolvent mixture, Sw is E2 solubility in water, f is the weight fraction of PEG 400 and ø is a parameter representing the solubilizing power of the cosolvent for the drug. Above 80% PEG the relationship becomes less convincing, with significant deviation from anticipated values. Reasons for these aberrations are discussed. It is suggested that conformational changes may be induced in the PEG by the addition of small quantities of water. Deviations noted for the melting point, viscosity and density data of PEG 400-water solutions may also confirm this suggestion.
A nuclear magnetic resonance (nmr) investigation of the micellar structure of a long-chain non-ionic surfactant
Authors: Elworthy P H , Patel M S
Published: April 2011

Peak integrals, peak widths at half-height (Δν1/2), spin-lattice relaxation times (T1), and chemical shifts (δ) of the alkyl and oxyethylene protons of CH3(CH2)21[OCH2CH2]27OH (C22E27) were measured in D2O at various temperatures. The peak integrals, Δν1/2, and δ values of the alkyl protons showed a large dependence on temperature below 313K, while the values for the oxyethylene protons were unaffected by temperature. These observations were explained by considering an intrusion of some oxyethylene groups into the hydrocarbon core of the micelle.
Characterization of β-adrenoceptors mediating relaxation of the guinea-pig ileum
Authors: Grassby Paul F , Broadley Kenneth J
Published: April 2011

Relaxation responses to sympathomimetic amines were recorded in potassium-contracted segments of guinea-pig ileum. Experiments were performed in the presence of phentolamine (5 times 10−6  m) to eliminate β-adrenoceptor-mediated effects. Metanephrine (10−5  m) and desmethylimipramine (5 times 10−7  m) were also present to prevent extraneuronal and neuronal uptake respectively. A potency order (-)-isoprenaline > (-)-noradrenaline > (-)-adrenaline was established, indicating a β1-adrenoceptor involvement for this relaxation. The potency of salbutamol (β2-selective) relative to isoprenaline in the ileum compared closely with its relative potency in isolated cardiac tissues (β1) but differed significantly from the value in lung parenchymal strips and vas deferens (β2). The pA2 values for antagonism of selective agonists (-)-noradrenaline (β1-selective) and fenoterol (β2-selective) by practolol (β1-selective) were identical, indicating a single β1-adrenoceptor population. The pA2 values for antagonism of these agonists by ICI 118,551 (β2-selective) were also identical and compatible with a β1-adrenoceptor population. Relaxation of the guinea-pig ileum is therefore mediated via a homogeneous population of β1-adrenoceptors.
Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic
Authors: Balsara J J , Gada V P , Nandal N V , Chandorkar A G
Published: April 2011

24 h pretreatment with molindone enhanced the behavioural effects of l-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats l-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite’s MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of l-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.
Plasto-elasticity and tableting of paracetamol, Avicel and other powders
Authors: Malamataris S , Baie S bin , Pilpel N
Published: April 2011

The plasto-elasticity of mixtures of paracetamol and Avicel powders and the tensile strengths of their tablets varied with the sizes of the particles and with the compositions of the mixtures. Tests made on these and other tablets showed that the logarithms of their strengths were inversely proportional to the ratios of the samples’ elastic recovery: plastic compression; they exhibited lamination or capping when this ratio was greater than 9.
Complexation of tetracylines with metal ions in relation to photosensitization
Authors: Riaz M , Pilpel N
Published: April 2011

It has been shown by spectroscopy and by a Photosensitive Index method, involving measurements of interfacial tension, that Cu2+ and Ni2+ form 2:1 complexes with oxytetracycline and 1:1 complexes with demethylchlortetracycline, Fe2+, Zn2+, Mg2+ and Ca2+ form weaker 1:1 complexes with both drugs. The possibility is discussed of using metal ions to reduce photosensitization by tetracyclines in-vivo.
The proinsulin content of commercial bovine insulin formulations
Authors: Sutcliffe N , Bristow A F
Published: April 2011

The proinsulin-like immunoreactivity (PLI) content of traditional and highly purified bovine insulin preparations sold by three insulin manufacturers in the UK has been estimated by radioimmunoassay. We report the PLI content of 22 batches of traditional insulin products and 32 of highly purified insulin, marketed between March 1980 and March 1983. Estimates of the PLI content of traditional insulins ranged from 2290 to 48400 parts per million (ppm). In contrast the estimated PLI content of the highly purified insulins varied between less than 1 ppm and 1160 ppm, although more recent batches prepared by current methodology contained less than 10 ppm of PLI. We conclude that highly purified bovine insulin on sale in the UK may now be expected to contain less than 10 ppm of proinsulin-like immunoreactivity.
Diflunisal and blood acid base status in the rabbit
Authors: Smith J E , Bradshaw E G , Pleuvry B J
Published: April 2011

Both diflunisal and acetylsalicylic acid given orally caused respiratory alkalosis and metabolic acidosis. However the fall in standard bicarbonate was much less in diflunisal-treated rabbits and pH in these animals remained elevated for the duration of the experiment. Whilst the severity of the fall in arterialized venous PCO2 was a good indicator of the degree of acetylsalicylic acid intoxication this was not the case for diflunisal as fatalities occurred with trivial changes in PCO2. Diflunisal toxicity was associated with markedly elevated temperatures. This was not observed in acetylsalicylic acid-treated rabbits.
Hypotensive effects and biotransformation of nicorandil, a new antianginal agent, administered to rats by different routes: comparison with nitroglycerin and isosorbide dinitrate
Authors: Sakai Kazushige , Akima Michitaka , Hinohara Yoshikazu , Obatake Noriko
Published: April 2011

The effects of nicorandil, N-(2-hydroxyethyl)nicotinamide nitrate (ester), in reducing systemic blood pressure (SBP) in rats were studied in comparison with isosorbide dinitrate and nitroglycerin. The drugs were administered to pentobarbitone-anaesthetized rats by jugular vein (i.v.), portal vein (p.v.), intrajejunal (i.j.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Nicorandil was absorbed rapidly through all routes, and caused marked hypotension dose-dependently. With isosorbide dinitrate and nitroglycerin, unlike nicorandil, the p.v. dose required to induce a vasodepressor response was significantly greater than that required to cause a comparable response after i.v. administration. In non-recirculating rat liver perfusion experiments, nicorandil was reduced only 5–10% during a single passage through the liver, while nitroglycerin was reduced over 95%. In recirculating liver perfusion experiments, the progressive decrease of nicorandil in the blood recirculated was accompanied by a corresponding increase of SG-86, a denitrate compound of nicorandil (its main metabolite). Sixty min after dosing, nicorandil was decreased by approximately 73% of the initial nicorandil blood concentration and SG-86 was increased by approximately 70%. The extent of degradation of nicorandil in liver homogenates, examined by thin-layer chromatography, was in the following order: rat = guinea-pig > dog = monkey > pig. In these species a close inverse relationship is apparent between the rate of liver nicorandil degradation and hypotensive effects of nicorandil.
Quinidine-induced rise in ajmaline plasma concentration
Authors: Hori Ryohei , Okumura Katsuhiko , Inui Ken-Ichi , Yasuhara Masato , Yamada Kazushi , Sakurai Tsunetaro , Kawai Chuichi
Published: April 2011

A high-performance liquid chromatographic method is described for the simultaneous determination of ajmaline and quinidine in human plasma. With 0·5 ml plasma samples of ajmaline and quinidine, concentrations as low as 0·001 and 0·01 μg ml−1, respectively, could be detected and the technique could be used to investigate the effect of quinidine on the pharmacokinetics of ajmaline. Four healthy subjects were given oral ajmaline (50 mg) alone or in combination with quinidine sulphate (200 mg) on separate occasions. When ajmaline was administered alone, its plasma concentrations were less than 0·03 μg ml−1. Quinidine induced a marked increase to give a mean peak concentration of ajmaline which increased from 0·018 μg ml−1 after a single administration to 0·141 μg ml−1 in combination with quinidine. The area under the ajmaline concentration-time curves was increased 10 to 30-fold by the concurrent administration of quinidine. According to the one compartment open model, the absorption rate constant of ajmaline did not change appreciably, but the elimination rate constant was reduced to approximately 50% of the value in the absence of quinidine. The results indicate the existence of a significant interaction between oral ajmaline and quinidine.
Ha-117 and Ha-118 are potent dopamine receptor agonists
Authors: Ilhan Mustafa , Long John P , Cannon Joseph G
Published: April 2011

In-vitro studies evaluated the presynaptic dopamine receptor activities of trans-N-propyl-7,9-dihydroxyoctahydrobenzo[f]quinoline (Ha-117) and trans-N-ethyl-7,9-dihydroxyoctahydrobenzo[f]quinoline (Ha-118) using isolated field-stimulated cat right atria. Ha-117 and Ha-118 were found to be potent dopamine receptor agonists since their effects were antagonized by haloperidol. Compounds were inactive on presynaptic α2-adrenoceptors using rat vas deferens and guinea-pig ileum. Results show that both resorcinol derivatives of octahydrobenzo[f]quinoline are potent dopamine receptor agonists without having presynaptic α2-adrenoceptor stimulating activity.
Microencapsulation of paracetamol using polyacrylate resins (Eudragit Retard), kinetics of drug release and evaluation of kinetic model
Authors: Benita Shimon , Hoffman Amnon , Donbrow Max
Published: April 2011

Methacrylate copolymers were used for microencapsulation of paracetamol by phase separation from chloroform with polyisobutylene 6% in cyclohexane. With polyisobutylene as an anti-aggregating agent, high quality microcapsules were obtained. Drug release appeared to fit both first order and Higuchi matrix model kinetics. However, on application of the differential rate treatment, the evidence supported the first order description, which was further supported by computed simulations of the models. Variation of production conditions showed that increasing the proportion of core material raised the microcapsule drug content and the release rate. Reduction of core particle size correlated with reduced coating thickness and faster release rate. The rate constants correlated with the estimated surface areas and wall thicknesses of the various batches. The data were used to estimate an apparent permeability constant for paracetamol in Eudragit RS microcapsules, which was constant and comparable with values found single core, non-aggregated microcapsules containing other similar drugs and different wall materials.
Nicotine binding to brain tissue from drug-naive and nicotine-treated rats
Authors: Benwell M E M , Balfour D J K
Published: April 2011

Two nicotine binding sites with dissociation constants for nicotine of approximately 3 nM and 12 μM respectively have been found in homogenates of rat hippocampus, hypothalamus, parietal cortex and mesencephalon, the greatest density of high affinity binding sites being in parietal cortex (30.0 ± 3.0 fmol (mg protein)−1), the lowest in hypothalamus (16.1 ± 1.0 fmol (mg protein)−1). The density of the low affinity sites (approx. 20 pmol (mg protein)−1) did not show any regional variation. Neither site was present in homogenates of medulla oblongata. The accumulation of radioactivity following the subcutaneous administration of [3H]nicotine (0.4 mg kg−1) was rapid, the highest concentrations being found in the brain regions with the highest density of high affinity binding sites. Medulla oblongata did not accumulate radioactivity above the concentration found in plasma. The chronic administration of nicotine (0.4 mg kg−1 s.c. daily for 39 days) had no significant effects on [3H]nicotine binding to brain tissue or its accumulation into brain following subcutaneous administration. It is concluded that nicotine readily passes from plasma into brain tissue and is accumulated in the areas containing high affinity binding sites for the compound. It is also concluded that the biochemical and behavioural effects reported previously in response to the chronic daily administration of nicotine do not depend upon changes in its uptake or binding by brain tissue.
α-Adrenergic agonist and antagonist activity of dihydroergotoxine in rats
Authors: Roquebert Jacques , Demichel Patricia
Published: April 2011

The α-adrenergic activity of dihydroergotoxine had been studied in both pithed and urethane or pentobarbitone anaesthetized rats. In anaesthetized rats, blood pressure effects varied with the anaesthetic agent: hypotension with urethane, hypertension with pentobarbitone. This latter pressor response was a peripheral effect. In pithed rats, the vasopressor response to dihydroergotoxine was reduced competitively by yohimbine, and noncompetitively by nifedipine, but not by prazosin or methysergide, showing that the vasoconstriction is mediated by α2-adrenoceptors. Dihydroergotoxine decreases the tachycardia elicited by stimulation of the cardioaccelerator nerves, this effect being antagonized by yohimbine. It also reduced the pressor response to (-)-phenylephrine. These results indicated that, on the peripheral vascular system of the rat, dihydroergotoxine acts as an α1-adrenoceptor blocker and an α2-adrenoceptor agonist.
Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: Relation to lipid solubility
Authors: Ochs Hermann R , Greenblatt David J , Abernethy Darrell R , Arendt Rainer M , Gerloff Joachim , Eichelkraut Wolfgang , Hahn Norbert
Published: April 2011

In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = −0.83 and −0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.
Evidence against VIP or substance P being the transmitter in non-cholinergic excitatory nerves supplying the guinea-pig bladder
Authors: Meldrum Lorna A , Burnstock Geoffrey
Published: April 2011

In the guinea-pig bladder, contractile responses to substance P (0.3 μM) and VIP (3 μM) were unaffected by P2-purinoceptor desensitization with α,β-methylene ATP (3 times 10−6M), while the responses to stimulation of the non-cholinergic excitatory nerves (4–16 Hz) were abolished. The evidence presented suggests that ATP or a related purine nucleotide, and not VIP or substance P, is responsible for the non-cholinergic excitatory component of the nerve-mediated response.
Dose-dependent effect of calcium and magnesium etidronate on salicylic acid absorption in the rat
Authors: Shrewsbury Robert P , Wurster Dale Eric , Dittert Lewis W
Published: April 2011

Disodium etidronate affected salicylic acid absorption from the rat small intestine, in-situ, when instilled into a jejunal segment for different exposure times before the salicylic acid absorption was measured. At low etidronate concentrations and short exposure times, the salicylic acid absorption rate was significantly increased compared with saline controls. At high etidronate concentrations and longer exposure times, the absorption rate was reduced. Etidronate precomplexed with calcium or magnesium ions at low concentrations still enhanced salicylic acid absorption but at high concentrations absorption of salicylic acid was close to saline controls. Intestinal mucosa exposed to high etidronate concentrations showed a progressive structural destruction but with the complexes, there was no visible alteration. It is proposed that a solubilized etidronate complex, formed either in-situ or administered as such, is responsible for enhancing salicylic acid absorption. This effect is hidden at high etidronate concentrations because of the deterioration of the mucosal surface and at high complex concentrations because these decrease the absorbing surface area and increase the viscosity of the lumen contents.
Stress crack resistance of some pigmented and unpigmented tablet film coating systems
Authors: Okhamafe Augustine O , York P
Published: April 2011

Stress crack resistance parameters—tensile strength: Young's modulus ratio, relative surface energy, and toughness index—have been examined for unpigmented free films of hydroxypropyl methylcellulose containing polyvinyl alcohol, and polyethylene glycols 400 and 1000, as well as similar film systems pigmented with either talc or titanium dioxide. Incorporation of either polyvinyl alcohol or polyethylene glycols 400 and 1000 in hydroxypropyl methylcellulose film coatings eliminated the incidence of edge splitting in the coated tablets. Increase in pigment concentration generally led to a decrease in the crack resistance of pigmented films. There was a relation between the stress crack resistance of pigmented free films and the incidence of edge splitting of corresponding film coatings applied to aspirin tablets—generally, the higher the crack resistance the lower the incidence of edge splitting. A similar relationship applied to the unpigmented films only when the tensile strength: Young's modulus ratio was considered.
Extension of Johnson's equation of homogeneity of random mixtures
Authors: Egermann H
Published: April 2011

The volume-weighted/volume-number mean particle diameter of the ingredient is applied to the equation of Johnson (1972) as a measure of the mean particle size defining the degree of homogeneity of random mixtures. By introducing the volume shape factor, the applications of this equation are extended to ingredients of nonspherical particle shape.
Similarities in the release rates of different drugs from polyethylene glycol 6000 solid dispersions
Authors: Dubois Jean-Luc , Ford James L
Published: April 2011

The dissolution rates (mg min−1) of 10 drugs, solid dispersed by fusion in polyethylene glycol 6000 (PEG 6000) have been examined by rotating disc methodology. The dispersions generally displayed release rates which were linearly dependent upon the drug concentration (% drug) at high polymer content. However the range over which this linearity was encountered varied unduly, e.g. 0–2% for phenylbutazone and 0–15% for paracetamol. The slope of this line (mean value: 0.451 mg min−1 %−1) was statistically the same for nine of the drugs studied, the exception being griseofulvin which did not form a true solid dispersion but was a microcrystatline dispersion of the drug within the PEG. During fusion, chain scission of the PEG 6000 occurred in the presence of several drugs. PEG 6000 was incompatible with disulfiram, frusemide, chlorothiazide and chlorpropamide.
Intracisternal glycine activates the micturition reflex in urethane-anaesthetized rats
Authors: Maggi Alberto Carlo , Furio Martino , Santicioli Paolo , Meli Alberto
Published: April 2011

Intracisternal glycine, but not GABA, activates a series of neurogenic rhythmic contractions of the urinary bladder in urethane-anaesthetized rats. This effect of glycine was prevented by strychnine but not by bicuculline, indicating the involvement of specific glycinergic receptors. The effects of glycine were also prevented by either atropine or haloperidol suggesting an involvement of cholinergic and monoaminergic excitatory neurotransmission to the bladder.
The fate of pharmaceutical chemicals in the aquatic environment
Authors: Richardson Mervyn L , Bowron Judith M
Published: April 2011

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 μg 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.
A photometric analysis of tablet movement in a side-vented perforated drum (Accela-Cota)
Authors: Leaver T M , Shannon H D , Rowe R C
Published: April 2011

A novel particle tracing technique has been used to study the effect of the normal process variables i.e. drum speed, drum loading and the presence/absence of mixing elements (baffles) on the movement of tablets in a side-vented perforated drum (24 in diameter Accela-Cota). The technique involves measuring the duration of light emission from a single luminous tablet using a photomultiplier mounted to scan the same area as a spray gun, and has enabled the quantification of both the time that the tablet spends on the surface per pass (surface time) and the time that the tablet spends within the bulk of the tablet bed (circulation time) over run lengths equating to the normal tablet coating cycle. The technique also allows the study of the uniformity of tablet appearances by means of circulation profiles. It was found that, while both the surface and circulation times decreased with increasing drum speed and loading, there was irregularity of tablet appearance especially at low drum speeds and in the absence of baffles.
Displacement of striatal 5-hydroxytryptamine by dopamine released from endogenous stores
Authors: Waldmeier P C
Published: April 2011

Combined treatment with amfonelic acid and neuroleptics caused a considerable loss of striatal, but not cortical 5-hydroxytryptamine (5-HT) in rats. This could be prevented by pretreatment with the specific 5-HT uptake inhibitor, citalopram. The results are best explained by the assumption that the combined treatment with amfonelic acid and neuroleptic had massively released dopamine into the synaptic cleft, and a part of this had been taken up into the 5-HT neurons by the 5-HT uptake mechanism and displaced the indoleamine.
Muscarinic cholinergic receptors in rabbit retina
Authors: Neal M J , Dawson C
Published: April 2011

Binding sites with high affinity and specificity for [3 H]-quinuclidinyl benzilate are present in rabbit retinal homogenates. Only one set of binding sites was detected with an apparent dissociation constant of 2.13 times 10−10 M and a density of 59.2 fmol mg−1 of protein. The pharmacological characteristics of specific binding were similar to those in the goldfish, chicken and cow.
Comparative evaluation of the effects of lidocaine (lignocaine) hydrochloride and salicylate on nervous and purkinje fibres
Authors: Mitolo-Chieppa D , Carratù M R , Dubois J M , Mugelli A , Amerini S , Conte-Camerino D , Siro-Brigiani G
Published: April 2011

Lidocaine hydrochloride and lidocaine salicylate (lisacaine) have been tested on the frog node of Ranvier, on the sheep cardiac Purkinje fibres and rat phrenic nerve-diaphragm. On the node of Ranvier both drugs produced the same degree of reduction of peak INa and steady-state potassium current and the same degree of shift of the steady-state inactivation curve for INa to more negative potential. Lisacaine took less time to reach the steady-state effect. On the cardiac Purkinje fibres both drugs decreased the action potential duration without any detectable difference; but their effects on V max (i.e. the maximum rate of depolarization) were different, that of lisacaine being faster. On the rat phrenic nerve-diaphragm both drugs produced the same percentage of reduction of the contractile response of diaphragm but, the action of lisacaine was faster. Therefore the lidocaine molecule with the salicylate anion while displaying the same anaesthetic effectiveness has a faster action than the hydrochloride.
The preparation and properties of niosomes—non-ionic surfactant vesicles
Authors: Baillie A J , Florence A T , Hume L R , Muirhead G T , Rogerson A
Published: April 2011

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.
Evidence for dopamine release and metabolism beyond the control of nerve impulses and dopamine receptors in rat substantia nigra
Authors: Nissbrandt H , Pileblad E , Carlsson A
Published: April 2011

In rat substantia nigra a biphasic disappearance curve of dopamine (DA) was seen after tyrosine hydroxylase inhibition by α-methyl-p-tyrosine (α-MT): the initial phase had a fast turnover and a half life of 0ṁ5 h and the later phase had an extremely slow turnover. In contrast to the effects in striatum, neither haloperidol nor apomorphine influenced α-MT-induced DA disappearance in the substantia nigra. Furthermore, inhibition of impulse flow by γ-butyrolactone prevented DA disappearance in striatum but not in the substantia nigra. Measurements of DA and 3-methoxytyramine following treatment with inhibitors of monoamine oxidase (pargyline) and catechol-O-methyl transferase (tropolone) indicated that O-methylation is a more important metabolic pathway in the substantia nigra than in the striatum. The data are interpreted to indicate that the release and metabolism of DA in the substantia nigra are largely beyond the control of nerve impulses and DA receptors. It is suggested that such an arrangement forms an important feature of autoreceptor-mediated feedback control of DA nerve cell activity.
The effect of the relationship between punch velocity and particle size on the compaction behaviour of materials with varying deformation mechanisms
Authors: Roberts R J , Rowe R C
Published: April 2011

The effect of punch velocity over the range 0.033–300 mm s−1 on the compaction properties of lactose, microcrystalline cellulose and a drug substance (a phthalazine derivative) for a range of particle sizes has been studied using the yield pressure derived from the Heckel relationship and a strain rate sensitivity index (SRS index), as the criteria to describe their behaviour. For lactose, a material which deforms by a mixed mechanism of particle fracture and plastic deformation at the contact points, the yield pressure increased and the SRS index decreased as particle size decreased, due to a reduction in the amount of fragmentation of the particles. For microcrystalline cellulose, a material which is known to deform plastically, the yield pressure and the SRS index were independent of particle size. For the phthalazine derivative the yield pressure increased as particle size decreased; however the SRS index reduced from 41% to zero, indicating that the deformation mechanism was changing from plastic flow to brittle behaviour. This decrease in the SRS index has been explained in terms of the relative amounts of strain-hardened material produced as milling severity increased, resulting in an increasing resistance to deformation and thus an apparent increase in brittle behaviour as particle size decreased.
Comparison of fluorescence polarization immunoassay and high performance liquid chromatography for the quantitative determination of phenytoin, phenobarbitone and carbamazepine in serum
Authors: Ashy Abdul Rahman , El-Sayed Yousry M , Islam Samira I
Published: April 2011

The Abbott TDx fluorescence polarization immunoassay (FPIA) system has been evaluated and compared with well-established high performance liquid chromatography (HPLC) for the determination of three anticonvulsant drugs: phenytoin, phenobarbitone and carbamazepine. These assays were evaluated for precision, calibration curve stability, specificity and accuracy. Within-run precision studies using control samples (n = 15) in the subtherapeutic, therapeutic, and toxic concentrations, resulted in coefficients of variation in the range of 1.79–3.99% (FPIA) and 1.16–2.52% (HPLC), respectively. Between-run precision ranged from 2.32–6.34% for FPIA and from 2.04–3.38% for HPLC. Comparison of 122 patient samples assayed with both methods indicated an extremely good analytical correlation (r = 0.96) for all three comparisons. The FPIA method offers significant advantages in calibration curve stability while maintaining accuracy and precision comparable with those of established HPLC procedures.
Dual effect of orally administered sennosides on large intestine transit and fluid absorption in the rat
Authors: Leng-Peschlow Elke
Published: April 2011

Quantity and consistency of the faecal output, large intestine transit time, and colonic net fluid absorption were investigated in rats after oral administration of sennosides A + B (12.5–200 mg kg−1). The release of normal faecal pellets was accelerated 3–4 h after drug administration; excretion of soft faeces was evident within 4–5 h and reached its maximum 5–7 h after administration. Large intestine transit time was dose- and time-dependently influenced by sennoside treatment. A highly significant reduction in transit time from more than 6 h in controls to 90 min for a 2 h pretreatment and a nearly maximal reduction to 30 min for a 4 h pretreatment was induced by a dose of 50 mg kg−1. Inhibition of net fluid absorption in the colon was maximal with the same dose, but clearly more pronounced after a 6 h pretreatment period than after a 4 h period. Since the increase in fluid volume due to net fluid secretion is delayed compared with the acceleration of large intestine transit, the early motility effect seems to be largely independent of the changes in absorption mechanisms. Therefore, the laxative effect of the sennosides consists of changes in colon motility as well as in colonic fluid absorption, but motility may be an earlier and more sensitive parameter than net absorption.
Fast-atom bombardment mass spectra of some pentapeptides related to natural enkephalins
Authors: Casy Alan F
Published: April 2011

The mass spectral features of four diastereoisomeric pairs of peptides related to the enkephalins recorded under fast-atom bombardment conditions are presented and shown to provide evidence of molecular weight and amino acid content and sequence.
Neither morphine nor clonidine influence the non-adrenergic, non-cholinergic inhibitory response in the rat gastric fundus
Authors: Lefebvre R A , Bogaert M G
Published: April 2011

Morphine and clonidine are among the few agents reported to modulate non-adrenergic, non-cholinergic (NANC) responses in different tissues. They were therefore tested for their effect on the NANC inhibitory response in the rat gastric fundus. Neither morphine (10−5 M), nor clonidine (10−5 M in the presence of prazosin 10−6 M to avoid its own relaxatory effect) modified the NANC response in the rat gastric fundus.
Differing potencies of muscle relaxants on rat and guinea-pig phrenic nerve diaphragm preparations
Authors: Bradshaw E G , Harper N J N , Pleuvry B J , Modla C Y
Published: April 2011

The sensitivities of two in-vitro preparations to neuromuscular blocking agents have been compared. The guinea-pig phrenic nerve diaphragm preparation proved to be more sensitive to vecuronium, atracurium and pancuronium than the equivalent preparation from the rat. Only tubocurarine had a similar potency on the preparations from both species. This would suggest that the guinea-pig diaphragm would be the most appropriate bioassay preparation if only small quantities of drug were available. Small differences in the cholinesterase content of the preparations was not thought to be a likely reason for the differences between the two preparations.
Effects of diltiazem on morphine-induced respiratory decline
Authors: Szikszay Margit , Snyder Frederick R , London Edythe D
Published: April 2011

The individual and combined effects of subcutaneous morphine and diltiazem, a calcium channel inhibitor, on arterial blood gases and pH were assessed in conscious Fischer-344 rats. Morphine (4mg kg−1) produced hypercapnia, hypoxia and slight acidosis, as compared with control values. Diltiazem (10 mg kg−1) alone did not affect these parameters; however, it significantly delayed the onset of the aforementioned effects of morphine.