bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of drug dissolution rate enhancement from β-cyclodextrin-drug systems
Authors: CORRIGAN O I , STANLEY C T
Published: April 2011

The influence of β-cyclodextrin on the physicochemical properties of bendrofluazide, chlorothiazide, hydrochlorothiazide and hydroflumethiazide was investigated using solubility, X-ray powder diffraction, differential scanning calorimetry (DSC) and intrinsic dissolution rate methods. The solubility of each drug was enhanced in the presence of β-cyclodextrin, the effect being greatest with bendrofluazide. X-ray diffraction data on equimolar freeze dried systems indicated the formation of a solid state inclusion complex only in the case of bendrofluazide. The relative increase in initial dissolution rate of drug from freeze dried systems varied from sixty fold for bendrofluazide to three fold for hydroflumethiazide. The observed dissolution rates were intermediate between those predicted by the classical two component soluble complex model and a carrier controlled model. It was concluded that the enhanced drug dissolution rates, which are above those predicted by the soluble complex model, are due to an extension of carrier phase dissolution control to higher drug weight fractions than predicted by the soluble complex model and that this was a consequence of the disparate solubilities of the carrier and drug.
Involvement of presynaptic dopamine receptors in the antihypertensive response to 2-NN-dimetnylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene(M-7)
Authors: CLAPHAM J C , HAMILTON T C
Published: April 2011

M-7, 1 and 3 mg kg−1 s.c., elicits an antihypertensive response and bradycardia in conscious spontaneously hypertensive rats (SHR) and causes inhibition of stimulation-evoked pressor responses and tachycardia in pithed SHR. Metoclopramide (30 mg kg−1 i.p.), but not piperoxan (5 mg kg−1 i.p.), abolishes the antihypertensive effect and inhibition of stimulation-evoked pressor responses produced by M-7 (1 mg kg−1 s.c.) in SHR. Conversely, piperoxan, but not metoclopramide, reduces the bradycardia and inhibition of stimulation-evoked tachycardia produced by M-7. Metoclopramide (30 mg kg−1 i.p.) did not affect the cardiovascular responses elicited by intracerebroventricular administration of either clonidine (1 μg) or M-7 (3 μg). These results suggest that the antihypertensive effect of M-7 may be mediated by stimulation of presynaptic dopamine receptors on sympathetic nerves to the vasculature and is independent of the bradycardia, which is probably due to stimulation of presynaptic α2-adrenoceptors on cardiac sympathetic nerve endings.
Renal handling of indomethacin and its relationship with the secretory pathway of prostaglandins
Authors: MELENDEZ ESTELA , REYES JOSE L
Published: April 2011

The uptake of prostaglandin E2, one of the main renal prostaglandins and of p-aminohippurate, an indicator of the anion organic transport, by slices of kidney cortex from adult female rats was studied in the presence and in the absence of indomethacin. The drug's inhibitory effect on the uptake of prostaglandin E2 was observed both after in vivo administration as well as when it was present in the bathing media. The effect was more pronounced when the drug was given in vivo and in addition, was present in the bath. [14C]PAH uptake was inhibited by indomethacin in a dose-related pattern and the kinetic analysis of this effect is indicative of a competitive inhibition. As expected, uptake of PAH by medullary slices was not affected by the presence of either indomethacin of PGE2. Indomethacin was more potent in inhibiting PGE2 uptake than PAH uptake.
The kinetics of solubilization of single component non-polar oils by a non-ionic surfactant
Authors: CARROLL B J , O'ROURKE B G C , WARD A J I
Published: April 2011

The kinetics of solubilization of two non-polar oils (hexadecane and 2,6,10,15,19,23 hexamethyl tetracosane) by a pure non-ionic surfactant (n-dodecyl hexaethylene glycol ether) have been investigated using a recently developed technique. A linear dependence of rate upon surfactant concentration above the cmc and a rapid increase in rate at temperatures close to the cloud point were observed. A previously developed theoretical description of the process has been expanded to account for the observation that the rates for the oils in given systems are not in the exact ratio of the equilibrium capacities of the system for the respective oils. If the effects of changes in aggregation number and shape of the micelle/solubilizate complex are considered, the absolute values of the measured and theoretical rates are in good agreement. Furthermore, the activation energies are nearly equal for the two solubilizates, a result which is in accord with theory. The micelle relaxation time τ2 is practically independent of surfactant concentration.
The relationship between chemical structure and the in vivo metabolism of an homologous series of n-alkyl carbamates
Authors: SARGENT NICHOLAS S E , WOOD STUART G , UPSHALL DAVID G , BRIDGES JAMES W
Published: April 2011

The metabolism and pharmacokinetics of carbonyl [14C] labelled ethyl, n-butyl, n-hexyl and n-octyl carbamates has been examined in rats after oral and intravenous administration. Hydrolysis of the carbamate group was a major metabolic fate, particularly of the more water soluble carbamates. Conversely, with increasing lipophilicity increasing amounts of ω-1 oxidation products were found both in plasma and urine. The plasma pharmacokinetic data could not be explained by a simple bi-exponential model, ethyl carbamate in particular showing unexpectedly persistent blood levels. A model has been proposed to explain the pharmacokinetic data for ethyl, n-butyl, n-hexyl and n-octyl carbamates. The essential features of this model are that carbamate is thought not to be in equilibrium between the peripheral and central compartment and that hydrolytic metabolism takes place in the peripheral compartment while oxidative metabolism to urinary metabolites occurs in the central compartment.
Tensile strength and compression of coated pharmaceutical powders
Authors: Malamataris S , Pilpel N
Published: April 2011

A study has been made of the tensile strength and compression of loosely packed beds of lactose, sodium chloride and calcium phosphate powders after they had been coated with small amounts of stearic acid, polyethylene glycols and polyvinylpyrrolidones. The properties of the systems were measured over a range of temperatures. Only when the coatings were continuous and durable did they produce reductions in both tensile strength and resistance to compression. Marked changes occurred in tensile strength at temperatures 20 ° — 40 °C below the conventional melting points of the coatings. The tensile strength results have been expressed in terms of the range and magnitude of the interparticle forces which depend on the surface free energy of the coated powders and on the Brinell hardness of the coating materials employed.
Presynaptic and postsynaptic sites of action of enhydrotoxin-a (EsNTx-a) isolated from Enhydrina schistosa venom
Authors: Gawade Shivaji P , Gaitonde Bhikaji B
Published: April 2011

Enhydrotoxin-a (EsNTx-a), one of the three toxins isolated from the venom of Enhydrina schistosa produced an irreversible blockade of indirect stimulation of rat phrenic nerve hemidiaphragm preparation in concentration of 0.5 to 1 μg ml−1. The response to direct stimulation was not affected over a 4 h period. The neuromuscular blockade produced by EsNTx-a was antagonized in so far as twitches evoked by indirect stimulation are concerned, when the preparation was treated with approximately double the concentration of purified sea snake antivenin. The tension of tetanic contractions, although depressed in amplitude by the toxin, was sustained. However, it was converted to a twitch-like response in toxin-antivenin treated preparations. In the presence of eserine (1 × 10−6 g ml−1), the twitch-like tetanus was dramatically restored in toxin-antivenin treated rat phrenic nerve hemidiaphragm preparations. Intracellular recordings showed that the frequency of spontaneous miniature end plate potentials (m.e.p.ps) recorded in EsNTx-a poisoned (1.24 × 10−6 g ml) rat phrenic nerve hemidiaphragm preparations decreased to zero, while the m.e.p.p. amplitude was decreased in the later phase of block. The evoked end plate potentials (e.p.p.) in EsNTx-a poisoned (1.24 × 10−1 g ml−1) preparations progressively diminished to zero. The antivenin molecules may have an easy access to bind to the toxin receptor complexes at the postsynaptic site while the presynaptic binding site by the toxin may be relatively inaccessible due to their being intracellular. The presynaptic effect of the toxin was revealed only when the postsynaptic effect was abolished.
Modulating effects of opioids, purine compounds, 5-hydroxytryptamine and prostaglandin E2 on cholinergic neurotransmission in a guinea-pig oesophagus preparation
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

The submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus was used to study the actions of morphine, opioid peptides, purine compounds, 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) on electrically-induced twitch contractions which are probably mediated by cholinergic nerve stimulation. The twitch contractions were inhibited by morphine (1–100 μM), methionine-enkephalin (1–100 μM) and β-endorphin (0.1–1 μM), but increased by adenosine (1–30 μM), adenosine 5′-triphosphate (1–30 μM), 5-HT (0.01–3 μM) and PGE2 (1–10 nM). The submaximal contraction induced by acetylcholine (12 or 20 nM) which is nearly equivalent to the twitch contractions was unaffected by morphine, methionine-enkephalin, β-endorphin and 5-HT, but augmented by purine compounds and PGE2. It is concluded that cholinergic neurotransmission in the submucous plexus-longitudinal muscularis mucosae of the guinea-pig oesophagus is inhibited by morphine and opioid peptides acting at prejunctional opiate receptors, and facilitated by 5-HT, purine compounds and PGE2 via prejunctional or postjunctional mechanisms.
The vibratory consolidation of particle size fractions of powders
Authors: Woodhead P J , Chapman S R , Newton J M
Published: April 2011

The use of controlled sinusoidal vibration as a means of consolidating packings of lactose within small containers has been examined. Vertical vibration was found significantly more effective and reproducible than horizontal vibration in terms of the degree of consolidation achieved. An optimum frequency range was identified within which the densification was greatest, and this range was largely independent of particle size for particle size fractions of mean volume diameters ranging from 15.6 to 155 μm. The consolidation increased with increasing vibration acceleration up to a level beyond which no further decrease in porosity resulted. Typical effective vibration conditions were characterized by amplitudes of an order of magnitude similar to the particle sizes studied. For particle size fractions of mean diameters 17·8, 37·5 and 80·8 μm, there is evidence that an optimum particle size range exists, within which energy requirements for consolidation are at a minimum.
Gastric blood flow responses to autonomic nerve stimulation and related pharmacological studies in rats
Authors: Yano S , Fujiwara A , Ozaki Y , Harada M
Published: April 2011

The effects of autonomic nerve stimulation on rat gastric blood flow (GBF) were studied using a cross thermocouple method. Stimulation of the periarterial nerve bundles along the left gastric artery produced a decrease in GBF which was antagonized by phenoxybenzamine (0·05 mg kg−1 i.v.), but not by propranolol (1 mg kg−1 i.v.). Stimulation of the vagus nerves elicited an increase in GBF, within a latency of 20 s, which was not apparently affected by atropine (0·15 and 1·5 mg kg−1 i.v.) but was completely blocked by hexamethonium (10 mg kg−1 i.v.). The GBF increase due to acetylcholine (0·25 μg rat−1 i.a.) was markedly blocked by atropine (0·15 mg kg−1 i.v.). Vagal stimulation also produced both the cholinergic excitation and non-cholinergic inhibition of gastric motility. The vagally induced GBF increase was little affected by any pretreatment with phentolamine, propranolol, indomethacin or aprotinin. These results suggest that sympathetic nerve stimulation decreases GBF through α-adrenoceptors and parasympathetic nerve stimulation increases GBF through a non-cholinergic mechanism in rats and that the GBF increase may result from a primary dilator effect of vagal stimulation on the blood vessels because of the immediate initiation of the response.
Pre-junctional α2-adrenoceptor activity of B-HT920
Authors: Mottram D R
Published: April 2011

An in-vitro study has been carried out on the pre-junctional α2-adrenoceptor activity of the thiazoloazepine derivative B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine) using isolated, field-stimulated rat vas deferens and guinea-pig ileum. The α2-selective agonists clonidine (an imidazoline derivative) and α-methyl noradrenaline (a β-phenethylamine derivative) were compared. Results show that B-HT 920 is a potent agonist on pre-junctional α2-adrenoceptors and is competitively antagonized by the selective α2-adrenoceptor antagonist yohimbine. The characteristics of the pharmacological responses obtained with B-HT920 indicate that it interacts with the receptor in an imidazoline-like, rather than a β-phenethylamine-like, manner.
Morphine concentrations in serum, brain and cerebrospinal fluid in the rat after intravenous administration of a single dose
Authors: Bolander Hans , Kourtopoulos Harry , Lundberg Sven , Persson Sven-Åke
Published: April 2011

Morphine has been determined in serum, cerebrospinal fluid (c.s.f.) and in five brain regions in the rat after a single intravenous dose, using high performance liquid chromatography with an electrochemical detector. In pure solution 50 pg morphine and 200 pg naloxone could be detected. Maximal concentrations of morphine were observed in serum and in most brain regions 5 min after administration of morphine. There was a rapid decline in morphine concentrations during the first 30 min, in serum and in all brain regions studied. The morphine concentration in the c.s.f. was constant for the first 30 min, but 30 min later there was a dramatic increase, suggesting that elimination through the c.s.f. could be an important way of eliminating morphine in the central nervous system.
Effect of dithiothreitol on agonist and antagonist actions in frog muscle
Authors: Bleehen Tirza , Clark Amanda L , Hobbiger F
Published: April 2011

The effects of the disulphide bond reducing agent dithiothreitol (DTT) in the frog rectus abdominis preparation have been investigated. DTT, 1 mM, reduced the potency of the monoquaternary agonists acetylcholine, carbachol and tetramethylammonium and the response to electrical field stimulation; the same applied to nicotine, but the action of edrophonium was unaffected and that of the bisquaternary agonist, decamethonium, was increased. The potency of tubocurarine and gallamine as antagonists was unaltered or slightly reduced by DTT when monoquaternary agonists were used and increased when decamethonium was used as agonist. All these effects of DTT were reversed by the oxidizing agent 5-5′dithiobis(2-nitrobenzoic acid) and can be explained by a reduction of a disulphide bond in the vicinity of the anionic site of the nicotinic cholinoceptor. Comparison between these results and published data indicate that there are species differences between nicotinic cholinoceptors at motor endplates. In the guinea-pig ileum preparation DTT reduced the potency of nicotine acting at ganglionic nicotinic cholinoceptors, but had no effect on the agonist response mediated via muscarinic cholinoceptors.
Ascorbic acid and membrane ageing: critical determinants of the in-vitro binding of [3]ADTN to rat striatal tissue
Authors: Bradbury A J , Costall B , Naylor R J
Published: April 2011

Tritiated(±)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene ([3H]ADTN), binding (0˙125-4˙0 nM) to rat striatal membranes was investigated using Tris-HCl buffer containing Na2EDTA, nialamide and varying concentrations of ascorbic acid. In the absence of ascorbic acid [3H]ADTN exhibited a high affinity (KD 1˙26 nm) saturable binding (Bmax 138 fmol mg−1 protein) (Scatchard analysis). This was not modified by 10−6 or 10−5  m ascorbic acid used immediately or 60 min after preparation. However, 10−4  m ascorbic acid added (within) 15 min after its preparation reduced the number of bindings sites and added 60 min after it also reduced affinity. Ascorbic acid 5.7 mm reduced affinity whether used within 15 min or 60 min of its preparation. When ascorbic acid 10−4  m was used within 15 min of preparation, and membranes were used immediately, the binding of 2 nm [3H]ADTN was specifically displaceable by nm or sub-nm concentrations of dopamine agonists and antagonists. However, when membranes were used 1–2 h after their preparation there was an increasing loss of the high affinity binding sites displaceable by sub-nm concentrations of (±)-ADTN. Thus, [3H]ADTN can be shown to exhibit high affinity stereoselective binding to rat striatal membranes when these are freshly prepared and the assay is performed using Tris-HCl buffer containing nialamide, Na2EDTA and 10−4  m ascorbic acid prepared within 15 min of use. The characteristics of this binding can be markedly modified if the concentration of ascorbic acid is increased, if its preparation time is extended, or if the membranes are allowed to ‘age’.
Work of friction and net work during compaction
Authors: Ragnarsson Gert , Sjögren John
Published: April 2011

Series of tablets were compressed in a reciprocating tablet machine with a gradually increasing die wall friction. The force needed on the upper punch to maintain the tablet dimensions constant increased with the die wall friction while the lower punch force decreased. The change in punch forces due to differences in die wall friction had no effect on the tablet strength. The net work of compaction should be constant under these circumstances. The net work calculated by subtracting the work of friction and the expansion work from the gross work input was constant when the frictional work was calculated according to one of the two equations proposed in the literature (Järvinen & Juslin 1974) while the other appears to give an overestimation of the work of friction.
Thermal behaviour and dissolution properties of phenylbutazone polymorphs
Authors: Tuladhar M D , Carless J E , Summers M P
Published: April 2011

Five different polymorphic forms of phenylbutazone were prepared and characterized by differential scanning calorimetry (D.S.C.). Rapid heating rates produced single endothermic peaks due to melting but slower heating rates resulted in interconversion of three of the polymorphs to the more stable form. Interconversion on grinding the polymorphs was also observed. From equilibrium solubility and intrinsic dissolution rates it was concluded that the dissolution process could be described by the Berthoud model. The effect of some tablet excipients on the dissolution process is briefly reported.
Effects of ultraviolet light on lecithin monolayers in the presence of fluorescein dyes and tetracycline drugs
Authors: Riaz M , Pilpel N
Published: April 2011

A Langmuir trough was employed to measure the effects of u. v. irradiation on the force area characteristics of monolayer films of lecithin spread on aqueous solutions of some dyes and tetracycline drugs both in the absence and presence of Ca2+ and Ni2+. Irradiation caused photochemical reactions which resulted in the expansion of the films and the extent of reaction was measured by the Photosensitive Indices. The reaction with tetracyclines was inhibited by adding Cu2+ or Ni2+ to the substrate. The kinetic orders of the reactions are given.
Tensile strength and compression of coated pharmaceutical powders: tablets
Authors: Malamataris S , Pilpel N
Published: April 2011

A study has been made of the tensile strength and compression during tableting of lactose, sodium chloride and calcium phosphate powders after they had been coated with small amounts of stearic acid, polyethylene glycols and polyvinylpyrrolidones. The properties of the systems were measured over a range of temperatures. The tensile strength and the compression behaviour depended not only on the amount and type of the coating material but also on the homologous temperature of processing. The changes in tensile strength have been explained in terms of changes in interparticle separation, changes in interparticle forces and the formation of welded bonds by the coatings. The compression results have been analysed in terms of the Heckel and the Cooper & Eaton equations.
Assay of 6-thioguanine nucleotide, a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine, in human red blood cells
Authors: Lennard L , Maddocks J L
Published: April 2011

An assay for 6-thioguanine (6-TG) nucleotide, a major metabolite of the cytotoxic drugs azathioprine, 6-mercaptopurine and 6-thioguanine in human red blood cells (RBCs) has been developed. The metabolite was not detected in RBCs when azathioprine or 6-mercaptopurine was incubated with whole blood in-vitro. The assay for intracellular 6-TG nucleotide is specific and requires 8 times 108 RBCs (100 μl packed cells) for which the limit of sensitivity is 30 pmole 6-TG nucleotide. Pre-dose blood samples were obtained, 12 h after the last azathioprine dose, from 10 renal transplant recipients with stable functioning cadaver grafts on a total daily dose of 150 mg azathioprine. The mean 6-TG nucleotide concentration was 171 pmole/8 times 108 RBCs(s.d. = 84). The assay is also suitable for use in measuring 6-TG nucleotide in the RBCs of leukaemic children undergoing 6-mercaptopurine treatment.
Moment analysis for disposition kinetics of several cephalosporin antibiotics in rats
Authors: Yamaoka Kiyoshi , Nakagawa Terumichi , Uno Toyozo
Published: April 2011

Disposition kinetics of cefamandole, cefoperazone, cefotiam, cefmenoxime and cefmetazole following rapid intravenous injection into rats is investigated. The plasma concentrations of the antibiotics are determined by the high performance liquid chromatographic method, and the pharmacokinetic behaviours of the cephalosporins are evaluated by moment analysis which is a model-independent method. Analysis of variance (ANOVA) followed by the paired t-test reveals that cefmetazole and cefmenoxime have greater mean residence time (MRT) than cefotiam, cefamandole and cefoperazone, and that cefamandole and cefmetazole show larger steady-state volume of distribution (Vss) than the other cephalosporins. Cefamandole has the greatest total body clearance (40.2 ml kg−1 min−1) and cefmenoxime the smallest (7.72 ml kg−1 min−1).
Physicochemical characterization of the human nail: permeation pattern for water and the homologous alcohols and differences with respect to the stratum corneum
Authors: Walters Kenneth A , Flynn Gordon L , Marvel John R
Published: April 2011

In order to develop a basic concept of the permeability of the human nail plate and thus create a better understanding of the toxic potentials and therapeutic possibilities of substances applied to the nail, avulsed cadaver nails have been placed in specially constructed diffusion chambers and their permeation by water and the n-alkanols through dodecanol, all in high aqueous dilution, has been investigated. The permeability coefficient of water is 16.5 times 10−3 cm h−1 and that for methanol is 5.6 times 10−3 cm h−1. Ethanol’s permeability coefficient measured 5.8 times 10−3 cm h−1. Permeability coefficients decreased systematically thereafter to a low value of 0.27 times 10−3 cm h−1 at n-octanol. The middle chain length alkanols, n-pentanol through n-octanol, have similar permeability coefficients but n-decanol and n-dodecanol show higher rates of permeation. The data suggest that, as a membrane, the hydrated human nail plate behaves like a hydrogel of high ionic strength to the polar and semipolar alcohols. Declining permeability rates appear linked to decreased partitioning into the complex matrix of the plate as the compounds become hydrophobic. The results for n-decanol and n-dodecanol introduce the possibility that a parallel lipid pathway exists which favours the permeation of these exceedingly hydrophobic species.
Naltrexone metabolism and sustained release following administration of an insoluble complex to rhesus monkeys and guinea-pigs
Authors: MacGregor Thomas R , Drum Mary A , Harrigan Stephen E , Wiley James N , Reuning Richard H
Published: April 2011

Both the release and the metabolism of naltrexone have been evaluated after intramuscular administration of a sustained release [15,16-3H2]naltrexone aluminium tannate complex in guinea-pigs and rhesus monkeys. In both species, measurable excretion of radioactivity was obtained for < 50 days and complete recovery of the dose was obtained in the guinea-pig. The radioactivity excretion rate-time profile differed in the two species with guinea-pig yielding a continuously declining rate and monkey yielding a peak at 5 days. In selected monkey urine samples (days 4,17–20 and 49–52) subjected to t.l.c., evidence was obtained for the presence of naltrexone, β-naltrexol and 2-hydroxy-3-O-methyl-β-naltrexol, mostly as glucuronide and/or sulphate conjugates. The t.l.c. data also suggest that in monkey a naltrexone metabolite builds up relative to naltrexone over the 52 day release period.
Physical factors affecting microencapsulation by simple coacervation of gelatin
Authors: Siddiqui Ovais , Taylor Harry
Published: April 2011

Gelatin has been coacervated at 60 †C using sodium sulphate. Interfacial tensions between coacervate and supernatant liquid, coacervate and two oils (with and without one of two drugs, clofibrate and chlormethiazole) and supernatant liquid and the oils (± drug) have been measured by a drop volume technique, in the presence and absence of one of three surfactants, cetrimide, sodium lauryl sulphate and hexadecyltrimethylammonium lauryl sulphate (double salt). Spreading coefficients calculated from tensions indicate that coacervate should spread readily over oil droplets in presence of double salt, less readily with cetrimide and spreading is unlikely in the presence of sodium lauryl sulphate. The sign of the charge on coacervate droplets and oil droplets was identified under different conditions and showed coacervate droplets and oil droplets have opposite charges except in the presence of sodium lauryl sulphate. Microcapsules were prepared using cetrimide or ‘double salt’ as emulsifier and release of drug measured. Those prepared with ‘double salt’ released more slowly than those prepared with cetrimide.
Capsule filling studies using an mG2 production machine
Authors: Jolliffe I G , Newton J M
Published: April 2011

A production mG2 G36 machine has been employed to study the effects of compression on the capsule filling properties of four particle size fractions of lactose having a range of flow properties. The effect of the surface texture of the dosator nozzle bore on capsule filling is also investigated. Fine, cohesive powders gave uniform fill weights over a whole range of compression settings but as increasingly free-flowing powders were used, this range diminishes. For both types of powder, the upper limit on compression is set by compaction of powder which produces poor fill weights; coarse, free-flowing powders, which are less compressible, compact at lower compressions. Free-flowing powders, in particular, also require a minimum compression to be retained. Resurfaced nozzles produced improved capsule filling. One nozzle surface produced slightly more uniform fill weights and was unaffected by powder coating of the nozzle suggesting that an optimum surface texture exists for capsule filling. The results are similar to those obtained using the mG2 simulator and hence validate the latter’s use in studying production capsule filling.
Photosensitization by fluorescein dyes and tetracycline drugs at an oil/water interface
Authors: Riaz M , Pilpel N
Published: April 2011

Measurements were made of the changes that occur in the interfacial tension of isopropylbenzene when floating on water containing between 10−5 and 10−3 M of various fluorescein dyes and tetracycline drugs and irradiated for up to 240 min with ultraviolet light. Singlet oxygen was found to be an active intermediate in the reactions. The results are discussed in relation to adverse photosensitization in-vivo due to fluorescein dyes and tetracycline drugs.
The influence of deposition method on the packing uniformity of powder beds
Authors: Woodhead P J , Newton J M
Published: April 2011

A number of methods of preparing powder packings have been assessed in terms of the resulting variability of local porosity. Measurement of local porosity was carried out by a γ-ray attenuation technique. It was found that overall porosity and the distribution of local porosity were highly dependent on particle properties and deposition method. Some deposition methods tended to give rise to the alternate formation and collapse of temporary structures within a growing bed, and in such cases, relatively high variability of local porosity was detected. More uniform packings could be formed by deposition of powder in even layers. In many cases, a significant relationship between local porosity and position within a packing was established, the central areas generally being of lowest porosity. This was true of packings both of high and low overall variability of porosity.
Enhancement of rectal absorption of insulin using salicylates in dogs
Authors: Nishihata Toshiaki , Rytting J Howard , Kamada Akira , Higuchi Takeru , Routh Mack , Caldwell Larry
Published: April 2011

Sodium salicylate and 5-methoxysalicylate both increased the rectal absorption of insulin in dogs when co-administered with insulin in various formulations. Microenema formulations containing 4% gelatin showed the highest insulin biavailability of the formulations studied whereas microenemas (without gelatin) and suppository formulations were not as effective in enhancing the rectal absorption of insulin.
HI6 as an antidote to soman poisoning in rhesus monkey respiratory muscles in-vitro
Authors: Smith A P , Wolthuis O L
Published: April 2011

This study was carried out to evaluate the rhesus monkey as a model for man with respect to oxime-induced acetylcholinesterase reactivation as a mechanism contributing to restoration of soman poisoned neuromuscular function. In-vitro neuromuscular blockade in intercostal and diaphragm muscle strips of rhesus monkeys was induced by exposing them for 2.5 or 15 min to the cholinesterase inhibitor soman. Subsequent treatment with the oxime HI6 produced only a partial reversal of this blockade. Only a minor part of the recovery obtained could be attributed to enzyme reactivation and suggested that this species responded in a manner closer to that reported in man than other animal species studied.
Different stereoselective inhibition of monoamine oxidase-B by the R- and S-enantiomers of MD 780236
Authors: Dostert P , Benedetti M Strolin , Guffroy C
Published: April 2011

MD 780236, a selective inhibitor of the B form of MAO behaves as an irreversible inhibitor in in-vitro conditions and mainly as a short-acting inhibitor in ex-vivo experiments. The enantiomer with the R absolute configuration (MD 240928) is fully reversible in ex-vivo conditions, whereas the S-enantiomer (MD 240931) has kept the irreversible component of the inhibition seen with MD 780236. The corresponding racemic alcohol derivative (MD 760548) is also a short-acting inhibitor of the B form of MAO; its S-enantiomer, which has an absolute configuration corresponding to that of MD 240928, has a selectivity towards the B form superior to that of the other enantiomer. The mechanism of the MAO inhibition by MD 780236 is discussed.
Enhanced effect of haloperidol and apomorphine after hypophysectomy: pharmacokinetic considerations
Authors: Lloyd K G , Bianchetti G , Worms P , Morselli P L
Published: April 2011

The behavioural effects of both apomorphine (stereotypies) and haloperidol (catalepsy and reversal of stereotypies) were significantly enhanced in hypophysectomized rats compared with sham-operated rats. Both the efficacy and duration of action were increased. Hypophysectomized animals had significantly greater brain haloperidol concentrations than did sham-operated animals. The data suggest that changes in brain drug concentrations following hypophysectomy at least partially explain the behavioural alterations seen in this test situation.
The metabolism and biosynthesis of (±)-o-octopamine and (±)-o-synephrine in the rat
Authors: James Michael I , Midgley John M , Williams Clyde M
Published: April 2011

The metabolism of (±)-o-octopamine and (±)-o-synephrine by rats was studied quantitatively by a gas chromatography-mass spectrometry-selected ion monitoring (g.c.-m.s.-s.i.m.) method using deuterated internal standards. When o-octopamine was injected intraperitoneally into rats four metabolites were excreted in the urine: (i) unconjugated o-hydroxymandelic acid (OHMA) (16%), (ii) unconjugated o-hydroxyphenylglycol (OHPG) (4·5%), (iii) an acid-hydrolysable conjugate of OHPG (28%) and (iv) unconjugated o-octopamine (10%). When o-synephrine benzoate was similarly administered six metabolites were excreted in urine: (i) unconjugated OHMA (13·5%), (ii) unconjugated OHPG (3·3%), (iii) an acid-hydrolysable conjugate of OHPG (15·6%), (iv) unconjugated o-synephrine (10%), (v) an acid-hydrolysable conjugate of o-synephrine (8·5%) and (vi) unconjugated o-octopamine (0·3%). Adult rats normally excreted OHMA (1·0 μg day−1) but OHPG, o-octopamine and o-synephrine could not be detected in urine. After the administration of a monoamine oxidase inhibitor, unconjugated o-octopamine (0·3 μg day−1) was excreted in urine but OHPG and o-synephrine could not be detected. o-Tyramine given to rats afforded urinary o-octopamine (75 ng day−1) and this was increased 10-rold upon co-administration of a monoamine oxidase inhibitor and o-tyramine.
Comparison of digoxin-induced cardiac toxicity in resistant and sensitive species
Authors: Weinhouse Elliott , Kaplanski Jacob , Posner John
Published: April 2011

We have examined the species-specific arrhythmogenic effects of digoxin in the rat (resistant species) and in the guinea-pig (sensitive species). 26 adult rats and 23 adult guinea-pigs were anaesthetized with pentobarbitone and injected subcutaneously with varying doses of digoxin. Electrocardiograms were monitored continuously for 4 1/2 h following digoxin administration. The arrhythmogenic dose (AD50) and lethal dose 50 under anaesthesia (LD50) were determined using the method of Litchfield & Wilcoxin. AD50 in rats was 13·0 ± 1·0 mg kg−1 (mean ± s.d.) compared with 0·60 ± 0·04 (P < 0·01) in the guinea-pig and LD50 was 30·0 ± 1·9 mg kg−1 in the rat compared with 0·60 ± 0·04 (P < 0·01) in the guinea-pig. The onset of arrhythmias was not dose-dependent in the rat but was clearly so in the guinea-pig; for example 102 ± 15 min (mean ± s.e.m.) following 0·5 mg kg−1, and 43 ± 2 mm following 1 mg kg−1. In the rat the onset of arrhythmias was 54·0 ± 11·5 min. Supraventricular arrhythmias (paroxysmal atrial tachycardia) appeared in 73% of rats compared with only 18% of guinea-pigs whereas ventricular arrhythmias (ventricular tachycardia), multiple premature ventricular contractions and or multifocal PVC’s occurred in 100% of guinea-pigs compared with only 32% of rats. All guinea-pigs that developed arrhythmias died whereas several rats recovered from supraventricular tachycardias. In conclusion, the guinea-pig is much more sensitive to digoxin toxicity than the rat, develops arrhythmias at much lower doses and these arrhythmias are much more likely to be ventricular in origin and cause fatality.
Influence of drug partition coefficient and pH value of sink solution on permeation from porous thick-walled ethyl cellulose microcapsules
Authors: Vidmar Vesna , Jalšenjak I
Published: April 2011

The permeation of barbitone sodium, benzoic acid, and salicylic acid from microcapsules into aqueous medium has been examined at different pH values. The apparent diffusion coefficients of drugs were linearly proportional to the ethyl cellulose/water partition coefficient of drugs, and the straight line parameters were dependent upon volume fractions of water-filled pores (i.e. capsule size), testifying to a previously proposed mechanism of drug permeation. The rate of drug permeation was also a function of the pH-value of the surrounding sink solution; the period of zero order release was longer at low pH because of the change of drug partition or solubility or both.
Motor inhibition induced by aporphine derivatives in the mouse
Authors: Bradbury Amanda J , Costall Brenda , Naylor Robert J , Neumeyer John L
Published: April 2011

The ability of some aporphine and benzylisoquinoline derivatives to inhibit mouse spontaneous locomotor activity at low doses, and at higher doses to have a reduced motor inhibitory effect, was used to determine whether motor inhibitory and facilitatory potentials could be dissociated, and the optimal structure required to cause these behavioural changes. Ability to displace [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro-naphthalene [3H]ADTN from its binding sites in rat striatal tissue was used as a broad measure of the abilities of the test compounds to bind to the ‘dopamine receptor’. The order of potency for ‘low dose’ inhibition of mouse spontaneous locomotion was (1) (-)N-n-propylnorapomorphine>(2) apomorphine > (3) (-)2,10,11-trihydroxy-N-n-propylnoraporphine > (4) (-)2,10,11-trihydroxyaporphine > (5) f-10,11-dihydroxy-N-(hydroxy-ethyl)noraporphine > (6) norapomorphine > (7) (±)10-hydroxy-N-n-propylnoraporphine > (8) 1-(3,4-dihydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroiso- quinoline. The latter two compounds were only weakly active and (±)8-hydroxy-N-n-propylnoraporphine and 1-(4-hydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroisoquinoline were inactive. The reduction in motor inhibitory effect as dose of agonist was increased (indicative of facilitation of locomotion) was only observed with compounds 1 and 2, other compounds (3 and 4) caused non-specific changes which interfered with motor performance or the doses required were so large as to render testing impractical (5,6,7 and 8). The potent motor inhibitory actions of compounds 1–4 were antagonized by pretreatment with spiperone but not with prazosin or yohimbine. Specific binding of 2·0nM [3H]ADTN was displaced by nanomolar concentrations of (±)-ADTN and aporphine derivatives. Isoapomorphine and the two benzylisoquinoline derivatives were ineffective at 10−6M. The optimal structure for those derivatives examined was shown in all tests to be (-)N-n-propylnorapomorphine.
Differential inhibition of α2-adrenoceptor-mediated pressor responses by (+)- and (-)-verapamil in pithed rats
Authors: van Meel Jacques C A , Qian Jiaqing , Timmermans Pieter B M W M , van Zwieten Pieter A
Published: April 2011

The inhibitory effects of (+)- and (-)-verapamil on the hypertensive responses brought about by the α2-adrenoceptor agonist B-HT 920 were investigated in pithed normotensive rats. (-)-Verapamil was found to be about 4 times more potent with respect to depressing α2-pressor responses compared with (+)-verapamil. To rule out the effect of ‘unspecific’ vasodilatation after the administration of the stereoisomers of verapamil, vasopressin was continuously infused into the carotid artery of pithed rats in a separate series of experiments. In the course of this vasopressin infusion, new inhibitory activities of the stereoisomers of verapamil on α2–adrenoceptor-mediated pressor responses were determined. Under these circumstances, the potency ratio of (-)- vs (+)-verapamil was about 7. With the aid of a radioligand binding assay using [3H]clonidine to identify α2–adrenoceptors, low affinities were measured for the stereoisomers of verapamil. A Ki = 6170 nM for (-)-verapamil and a Ki = 41700 nM for (+)-verapamil were calculated. The results indicate that the interaction between α2-adrenoceptor-mediated pressor responses and calcium entry blockers, such as verapamil, is a stereoselective event.
Mechanism of inhibition of contraction by cadmium in guinea-pig taenia coli
Authors: Nasu T , Koshiba H , Mase K , Ishida Y
Published: April 2011

Further evidence about the mechanism of the inhibition of contractions caused by cadmium ions (Cd2+) in guinea-pig taenia coli has been sought. Cd2+ at a concentration of 0·5 mM completely inhibited the high-K (40 mM)-induced contraction within 3–5 min. Cd2+ did not shift the Ca2+-induced concentration-response curve to the right in Ca2+-free K+ depolarized muscle, although it reduced the Ca2+ response size. The K+-induced increase in tissue calcium content and 45Ca uptake determined by the lanthanum method was significantly reduced in the presence of Cd2+ (0·5 mM) and the contractions of the glycerolated taenia coli were inhibited with increasing Cd2+ (0·001–0·5 mM). Muscle strips, incubated in a medium containing 0·5 mM Cd2+, accumulated greater amounts of cadmium than within the extracellular space. It is suggested that the inhibitory action on tension produced by Cd2+ in taenia coli may result from the interference of calcium permeability at the cell membrane. There is the possibility that Cd2+ acts on the contractile system of the muscle.
Binding of [3H]mianserin to bovine serum albumin, human serum albumin and α1-acid glycoprotein
Authors: Shami M R , Skellern G G , Whiting B
Published: April 2011

Scatchard plots which were curvilinear with negative slopes were obtained when the binding of [3H]mianserin to bovine serum albumin (BSA), human serum albumin (HSA), defatted human serum albumin (D-HSA) and α1-acid glycoprotein (α1-AGP) was studied with equilibrium dialysis with constant protein concentrations and various ligand concentrations. Binding parameters were estimated graphically and with a non-linear least-squares computer program, assuming two classes of independent binding sites. α1-AGP had the highest binding affinity (K) and binding capacity (nK). The binding parameters, n and K were not independent of protein concentration when the BSA concentration was varied. Linear atypical Scatchard plots with positive slopes were obtained when the protein concentration was varied for BSA, HSA and D-HSA, at a fixed ligand concentration.
Inhibitory effect of captopril on renal responses to frusemide in sodium-restricted rats
Authors: Chiu P J S , Brown A D , Barnett A
Published: April 2011

Indomethacin (10 mg kg−1 orally) caused a moderate inhibition of the renal responses to frusemide (30 mg kg−1 orally) only in Na+-deficient rats, suggesting that renal prostaglandins (PG) are necessary for optimal effects of frusemide during Na+ restriction. Captopril (1, 3 and 10 mg kg−1 orally) also inhibited frusemide-induced diuresis and natriuresis in Na+-deficient rats; the large effect of captopril at 10 mg kg−1 was accompanied by arterial hypotension. In normal rats, captopril did not disturb blood pressure or affect the renal effects of frusemide. By comparison, minoxidil (10 and 20 mg kg−1 orally) caused hypotension and reduced the natriuretic effects of frusemide in both normal and low-Na+ states. Since circulating angiotensin II (AII) is a stimulus for PG synthesis during Na+ restriction, it is suggested that captopril may impair the renal responses to frusemide through hormonal and haemodynamic changes resulting from inhibition of A II formation.
The influence of agitation intensity, particle size and pH of dissolution fluid on the in-vitro release of drug from hard gelatin capsules
Authors: Newton J M , Muhammad N A H
Published: April 2011

The influence of agitation intensity on the in-vitro release of controlled particle size fractions of acetylsalicylic acid from hard gelatin capsules into buffered dissolution fluids has been investigated employing a dissolution technique. The value of T50 decreased as the stirring rate increased from 120 to 320 rev min−1 for all particle size fractions and pH values. A further increase in the stirring rate had a limited effect on the value of T50 and the changes were particle size dependent. The influence of the drug solubility, induced by changing the pH of the dissolution fluid, was decreased by increased agitation. When the capsules were filled at bulk densities above the maximum tapped bulk density, the value of T50 was increased, the extent of increase being greater the smaller the particle size of the drug. The kinetics of the solution process were influenced by agitation intensity and particle packing.
Non-enhancement of sodium cromoglycate intestinal absorption by quaternary ammonium ions. An effect of salt on ion-pair formation?
Authors: Schurgers N , De Blaey C J , Tomlinson E
Published: April 2011

Studies on the nature of rat small intestine perfusates indicate that this environment is thermodynamically unfavourable for the production of ion pairs between cromoglycate and alkylbenzyldimethylammonium ions. This is suggested as being the reason why, unlike previously found for ocular absorption of cromoglycate, these quaternary ammonium ions do not alter cromoglycate intestinal absorption.
Structure elucidation of protriptyline photoirradiation products
Authors: Jones G E , Sharples D
Published: April 2011

Three photoirradiation products of the tricyclic antidepressant protriptyline have been isolated by preparative tlc and identified as the 10,11-epoxide, 10-hydroxy and 10,11-dihydrodiol derivatives of protriptyline by tlc, uv and mass spectroscopy.
Ethanol- and isoprenaline-induced responses in pig parenchymal lung tissue
Authors: Goldie R G , Ellis G M , Paterson J W
Published: April 2011

Ethanol (8·7–34·8 mm; 0·5–0·20% v/v) had no significant effect on spontaneously developed tension in pig lung parenchyma strips, although higher cumulative concentrations caused relaxation (at 34·8–174 mm) and contraction (at 348–1392 mm). Ethanol-induced effects were not caused by activation of adrenoceptors or of cholinoceptors, since blockade of these receptors did not alter those effects. Single low concentrations of ethanol (8·7–34·8 mm) which can occur in-vivo in man, caused increases in the relaxant potency of isoprenaline in pig lung strips, although the sizes of these increases varied widely. In addition, ethanol-induced potentiation of isoprenaline was not concentration-related. This effect was not caused by inhibition of isoprenaline uptake since [3H]isoprenaline transport was found not to be significantly altered in the presence of ethanol (8·7–34·8 mm).
Possible role of prostaglandins in post-tetanic potentiation at the nerve-muscle junction in the longitudinal muscle strip of guinea-pig ileum
Authors: Kadlec Ondřej , Mašek Karel , Růžička Vladimir , Šeferna Isidor
Published: April 2011

The effect of tetanic stimulation on the twitch responses of the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum to electrical stimulation was investigated in the presence of naloxone. Under this condition, or after the addition of PGE2, twitch contractions were maximal and no potentiation of twitches following tetanus was observed. In the presence of indomethacin (1 μmol litre−1) twitches were diminished and post-tetanic potentiation (PTP) was manifested. PTP was seen with indomethacin concentrations of 1 to 20 μmol litre−1 or after simultaneous addition of diphloretin phosphate (16 μmol litre−1). Thus it seems unlikely that the effect of prostaglandins released during tetanic stimulation would be of key importance for the manifestation of PTP. Rather it is thought that a decrease in the release of acetylcholine from motor nerve terminals, and consequently smaller twitches in the presence of indomethacin, offer favourable conditions for PTP.