bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long‐acting formulation in healthy volunteers
Authors: Verloes R , Deleu S , Niemeijer N , Crauwels H , Meyvisch P , Williams P 
Published: May 2015

ObjectivesThis phase I healthy volunteer study (NCT01031589) was carried out to investigate the safety/tolerability and pharmacokinetics of a rilpivirine (RPV; TMC278) long‐acting (LA) formulation after single and multiple intramuscular (IM) injections.MethodsIn the first part of the study, which had an open‐label design, a single RPV LA IM injection (300 mg/mL) of 300 (n = 6) or 600 (n = 5) mg was given to the volunteers. In the second part of the study, which had a double‐blind, randomized, placebo‐controlled design, three RPV LA IM injections (one every 4 weeks) at 1200/600/600 mg (n = 6) or placebo (n = 2) were given. Safety and local tolerability were monitored. RPV plasma concentrations were analysed up to 28 days after injection or until they were < 20 ng/mL.ResultsGrade 1/2 RPV‐related adverse events in the 300, 600 and 1200/600/600 mg groups were: rash (zero, one and one subject, respectively, the last of whom discontinued participation in the study); musculoskeletal stiffness (three, zero and zero subjects, respectively); injection site reactions (one, two and two subjects, respectively). After one injection of 300, 600 or 1200 mg RPV LA, the mean (standard deviation) maximum plasma concentration was 39 (25), 48 (13) and 140 (16) ng/mL, and the mean (standard deviation) area under the concentration–time curve (28 days) was 17 090 (8907), 25 240 (8184) and 55 350 (13 550) ng h/mL, respectively. RPV pharmacokinetics were largely comparable after the 1200 mg loading dose and both 600 mg injections of RPV LA. The mean (standard deviation) RPV plasma concentration across the 28‐day dosing interval after the last injection in the 1200/600/600 mg group was 79 (19) ng/mL.ConclusionsSingle and multiple IM injections of RPV LA demonstrated favourable local/systemic tolerability in healthy volunteers. RPV pharmacokinetics suggested that clinically relevant plasma concentrations can be achieved with this LA formulation.
Preparation and characterisation of films from xylose‐glycosylated peanut protein isolate powder
Authors: Lin Wei‐Jing , Liu Hong‐Zhi , Shi Ai‐Min , Liu Li , Adhikari Benu , Wang Qiang 
Published: May 2015

SummaryThis work aimed at producing and characterising xylose‐glycosylated peanut protein isolate (PPI‐X) films by dissolving PPI‐X powder in water at ambient temperature and further plasticising with glycerol. The effect of powder dissolution temperature (20–100 °C) and glycerol concentration (15.0–45.0%, w/w) on mechanical properties and integrity of these films was quantified. The results showed that the powder dissolution temperature had no significant effect on the mechanical and water resistance properties of PPI‐X films within the temperature range tested. With increasing concentration of glycerol, the tensile strength and water resistance of PPI‐X films decreased and elongation increased. The films produced by dissolving the PPI‐X powder at 20 °C and plasticising with 25.0% glycerol had comparable mechanical properties and better water resistance compared to some other plant protein films plasticising with glycerol. The results suggested that PPI‐X films could potentially be used as biodegradable packaging materials.
Relationship of carrot sensory crispness with acoustic signal characteristics
Authors: Liu Yang , Huang Bi‐Zhu , Sun Yong‐Hai , Chen Fang‐Yuan , Yang Liu , Mao Qian , Liu Jing‐Sheng , Zheng Ming‐Zhu 
Published: May 2015

SummaryThe purpose of this study was to investigate the relationships of carrot sensory crispness with acoustic signal characteristics and microstructure after storage under common shelf conditions. The results showed that carrot sensory crispness declined significantly after the 14th day of storage, and the sensory score reduction was nearly up to 42% after the 28th day of storage. The carrot sensory crispness was positively related to both the waveform index (r = 0.785, P < 0.01) and sound intensity (r = 0.732, P < 0.01) of the acoustic signals in the time domain. Hilbert–Huang transform is a useful method for the observation of frequency changes in the time domain. The overall frequency bands were distributed around 200–2000 Hz through the Hilbert spectra. Rupture did not occur until the 14th day (crispness declined significantly) of storage through the scanning electron microscopy images of microstructure, and the crispness declined gradually with the increase of rupture.
Hemoglobin H identification by high‐performance liquid chromatography in confirmed hemoglobin H disease
Authors: Turley E. , McFarlane A. , Halchuk L. , Verhovsek M. 
Published: May 2015

SummaryIntroductionAmong hemoglobin (Hb) H disease cases diagnosed by DNA testing in our hemoglobinopathy laboratory, we have noted instances of unreported Hb H from high‐performance liquid chromatography (HPLC) results of referring laboratories.MethodsTo characterize these issues, we identified all cases of genotypic Hb H disease diagnosed in our laboratory. HPLC chromatograms were reviewed to determine the presence and retention time of the Hb H peak.ResultsHemoglobin H was not reported in 24.2% of patients (23 of 95) with genotypic Hb H disease. The characteristic prerun peak of Hb H was present on review of all eight Variant or Variant II β‐thalassemia short‐program chromatograms. Elevated Hb F (≥3%) was reported in 14 cases. The Hb H peak was found in the Hb F window in 11 dual program cases. The incorrect identification of Hb H as elevated Hb F resulted in two testing referrals for ‘δβ‐thalassemia’.ConclusionsHemoglobin H may go unreported due to failure to examine for or recognize its peak on Variant or Variant II β‐thalassemia short‐program chromatograms. Elution of Hb H in the Hb F window resulted in misidentification of Hb H for Hb F and may indicate a Variant II HbA2/HbA1C program software error. Our findings highlight the need for careful chromatogram inspection and clinical correlation in the diagnosis of Hb H disease.
The formation and release of metaraminol during exposure to warm or cold environments
Authors: JOHNSON G. E. , PUGSLEY T. A. 
Published: May 2015

Rats were injected intraperitoneally with alpha‐methyl‐m‐tyrosine (400 mg/kg) and placed at either 27° C or 4° C. The levels of alpha‐methyl‐m‐tyramine, metaraminol and noradrenaline were determined in heart tissue after 1, 4 and 12 hr of treatment. The excretion of metaraminol, alpha‐methyl‐m‐tyramine, noradrenaline, adrenaline and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) was also estimated in both treated and control rats.
Cold exposure increased both the formation and excretion of metaraminol. Hearts removed from the cold‐stressed rats 4 hr after injection contained significantly more metaraminol than hearts taken from animals maintained in the warm environment. Twelve hours after treatment, no metaraminol remained in the hearts of cold‐exposed rats, whereas significant quantities of the amine still remained in the hearts of rats kept at 27° C. These results support the false transmitter concept advanced for metaraminol as they demonstrate that in vivo sympathetic stimulation can increase both the formation and release of metaraminol.
Alpha‐methyl‐m‐tyrosine produced a greater fall in cardiac noradrenaline in the rats kept at 27° C. Whereas an approximate mole‐for‐mole replacement of metaraminol for noradrenaline existed at 27° C, no such relationships existed at 4° C. Twelve hours after treatment the hearts of cold‐stressed rats contained no metaraminol and only 40% of control noradrenaline levels. These results do not support the necessity for a mole‐for‐mole replacement of noradrenaline with metaraminol to produce a catecholamine loss.
Alpha‐methyl‐m‐tyrosine depressed the noradrenaline excretion for at least 24 hr in the cold‐stressed rats. Excretion of 3‐methoxy‐4‐hydroxyphenylglycol was also lower in the treated rats between 0 and 12 hr in the cold but rose abruptly between 12 and 24 hr to exceed the quantity excreted by the control animals. This increase suggests an increase in noradrenaline synthesis, which may be related to the depletion of metaraminol from the body.
The results of this paper support the postulate that metaraminol may function as a false transmitter. They do not agree with the concept that the loss of noradrenaline from tissue sites is dependent upon a mole‐for‐mole replacement with metaraminol.
The actions of caerulein on the smooth muscle of the gastrointestinal tract and the gall bladder
Authors: BERTACCINI G. , DE CARO G. , ENDEAN R. , ERSPAMER V. , IMPICCIATORE M. 
Published: May 2015

In the intact conscious dog, caerulein causes emesis and evacuation of the bowel. The mean effective dose by the intravenous route is 0.4–0.5 μg/kg, and by the subcutaneous route 3–4 μg/kg.
The gall bladder in situ or as an isolated preparation is highly sensitive to caerulein. A few ng/kg injected intravenously are sufficient to stimulate the gall bladder in situ and less than 1 ng/kg per min is effective when infused intravenously. The isolated gall bladder is contracted by caerulein in concentrations as low as 0.03–2 ng/ml. Krebs solution. There is no tachyphylaxis but, generally, a good dose‐response relationship. Hence the gall bladder, especially that of the guinea‐pig, appears to be very suitable for the bioassay of caerulein and related peptides.
In situ, the musculature of the gastrointestinal tract is also highly sensitive to caerulein. Doses as low as 1–5 ng/kg, administered intravenously, have a spasmogenic action on jejunal loops of the dog, and slightly larger doses contract the small intestine of the cat. The stomach and the large intestine seem to be somewhat less sensitive to the polypeptide. Caerulein has a considerable spasmogenic action on the rat pylorus but relaxes the sphincter of Oddi of the guinea‐pig.
Isolated preparations of the gastrointestinal tract are relatively insensitive to caerulein and tachyphylaxis occurs readily.
Blockade with atropine produces different effects in different intestinal segments and in different animal species. The spasmogenic action of caerulein on the gall bladder is atropine‐resistant.
The effects of caerulein are similar to those of cholecystokinin‐pancreozymin in the organs tested in situ or as isolated preparations. Caerulein, however, is always more potent than cholecystokinin‐pancreozymin, even on a molar basis. Compared with caerulein, human gastrin I has negligible activity.
The possible use of caerulein in cholecystography is discussed.
The analgesic action of morphine‐N‐oxide
Authors: FENNESSY M. R. 
Published: May 2015

The analgesic activity of morphine‐N‐oxide in mice and rats has been investigated and compared with that of morphine.
Both morphine and morphine‐N‐oxide were more active when given subcutaneously than when given intraperitoneally.
Given subcutaneously, morphine was 11–22 times more potent than morphine‐N‐oxide and when given intraperitoneally it was 39–89 times more potent. The potencies depended on the test situation and the species of animal used.
In animals pretreated with amiphenazole or tacrine, the analgesic activities of morphine and morphine‐N‐oxide were increased. The potencies of these analgesic drugs given intraperitoneally were increased to a greater extent than were the potencies obtained by subcutaneous administration.
A possible explanation for the increase in analgesic potency of morphine‐N‐oxide produced by pretreatment with amiphenazole or tacrine may be that morphine‐N‐oxide is rapidly inactivated in the liver and this inactivation is impaired by amiphenazole and tacrine.
The ganglion‐stimulating effects of some amino‐acid esters
Authors: BRIMBLECOMBE R. W. , SUTTON JOAN V. 
Published: May 2015

The effects of some amino‐acid esters possessing both muscarinic and nicotinic activity have been investigated on the cat superior cervical ganglion. The compounds were applied to the ganglion in vivo by close intra‐arterial injection and responses were measured by contraction of the nictitating membrane or by recording post ganglionic compound action potentials.
The esters, like carbachol, produced effects which were blocked by hexamethonium and reduced by atropine. Pretreatment with an anticholinesterase agent had no effect on the response and the chronically denervated ganglion was, if anything, slightly more sensitive to the drugs.
Effects of standard muscarinic and nicotinic drugs were also studied and the results support the view that both muscarinic and nicotinic receptors are present in the ganglion.
From the results of this investigation it appears that the amino‐acid esters and carbachol produce their effects by interacting with post synaptic receptors in the ganglion. This is in contrast to other results in the literature which suggest that the receptors might be presynaptic. Further studies are required to resolve this difference.
The effect of antidepressants and “tranquillizers” on the response of mice to ethanol
Authors: MILNER G. 
Published: May 2015

The techniques and apparatus used for investigation of the interaction of various psychotropic drugs with ethanol in mice are described. The parameters measured were (a) length of loss of righting reflexes; (b) continuous coma; (c) subjects remaining in coma 12 hr after dosing; (d) changes in toxicity.
The following drugs were tested: amitriptyline, trimipramine, imipramine, nortriptyline, desipramine, thioridazine, phenelzine, methylphenidate, chlorpromazine, trifluoperazine, phenobarbitone, and diazepam. The total number of mice used was 3,140.
Imipramine caused no significant changes in the effects of ethanol. Methylphenidate and desipramine protected the mice against ethanol induced coma. All other drugs induced statistically significant potentiation of the depressant and toxic effects of ethanol in mice.
Late (delayed) deaths after a tricyclic antidepressant have been noted in animals and man.
It is suggested that the potentiation of alcohol by some psychotropic drugs may add to the hazards of drug overdosage and contribute to traffic accidents. Hence it is necessary to test all psychotropic drugs for interaction with alcohol.
The excretion and metabolism of oral 14C‐pyridostigmine in the rat
Authors: HUSAIN M. A. , ROBERTS J. B. , THOMAS B. H. , WILSON A. 
Published: May 2015

Pyridostigmine labelled with carbon‐14 in the methyl group of the quaternary nitrogen has been used to investigate the excretion and metabolism of the drug after administration of single doses (500 μg) to the rat by stomach tube.
Pyridostigmine is slowly excreted in the urine; the maximum excretion occurs between 1–3 hr after administration. In 24 hr 42% of the dose is excreted in urine and 38.4% is present in faeces and intestinal contents.
The peak concentration of radioactivity in liver and blood occurs about 2 hr after administration.
About 75% of the radioactivity in urine is present as unchanged pyridostigmine, the remainder as metabolite.
The results are compared with those previously obtained after oral administration of neostigmine.
It is concluded that after oral administration the absorption of pyridostigmine is greater and the metabolism substantially less than that of neostigmine.
Interaction in the cerebral metabolism of the biogenic amines. Effects of phenelzine on the cerebral metabolism of the 5‐hydroxyindoles in dog brain
Authors: MOIR A. T. B. 
Published: May 2015

Summary
Chronic administration of phenelzine to dogs caused 5‐hydroxyindol‐3‐ylacetic acid (5‐HIAA) concentrations in c.s.f. from the lateral ventricle to be maintained at 50% of their normal values, but did not alter the concentrations of 5‐HIAA in c.s.f. from the cisterna magna.
Following 10 days treatment with phenelzine, the active transport of 5‐HIAA from c.s.f. which normally occurs in the region of the fourth ventricle, was inhibited. This transport system was also inhibited by the addition of phenylacetic acid, the acid metabolite of phenelzine, to the fluid perfusing the cerebral ventricles.
After 10–12 days treatment with phenelzine all regions of brain showed concentration increases to approximately 300% for 5‐HT and 150% for 5‐HIAA, but no alteration in the tryptophan concentration.
Intravenous administration of tryptophan to dogs pretreated with phenelzine caused large increases in the concentration of tryptophan in brain and body fluids but did not alter either the concentrations of 5‐hydroxytryptamine and 5‐HIAA in brain or of 5‐HIAA in c.s.f.
A model of the cerebral metabolism of 5‐hydroxytryptamine is proposed and the results are interpreted to mean that phenelzine has inhibitory actions, either directly or in some instances indirectly, on intracerebral tryptophan 5‐hydroxylase, monoamine oxidase and the transport of 5‐HIAA from both brain and c.s.f.
Intracellular pH in rat isolated superior cervical ganglia in relation to nicotine‐depolarization and nicotine‐uptake
Authors: BROWN D. A. , HALLIWELL J. V. 
Published: May 2015

Summary
The intracellular pH (pHi) of rat isolated superior cervical ganglia incubated in normal Krebs solution (pHo = 7·37) was estimated to be 7·33 from the uptake of a weak acid, 14C‐5,5‐dimethyloxazolidine‐2,4‐dione (DMO). Addition of 30 μm nicotine for 30 min reduced the DMO‐estimated pHi by 015 units to 7·18. This effect was prevented by hexamethonium (2·5 mm) or by depolarizing the ganglion with K+ (124 mm).
3H‐Nicotine (30 μm) was concentrated within the ganglia to an intracellular/extracellular concentration ratio (Ci/Co) of 5·54 in normal Krebs solution and 4·61 in 2·5 mm hexamethonium. This would suggest an intracellular pH of 6·54 and 6·63 respectively. In ganglia previously depolarized by K+ the corresponding values for Ci/Co were 402 (minus hexamethonium, estimated pHi 6·95) and 4·17 (plus hexamethonium, estimated pHi 6·94).
A multicompartment cell interior comprising an acid cytoplasm (pH˜6·6) and more alkaline nucleus and mitochondria is proposed to explain the difference between the values of pHi estimated from the uptake of DMO and nicotine. It is suggested that the fall in pHi during nicotine‐depolarization results from metabolic stimulation following Na+ entry.
ADRENOCEPTORS IN INTRACEREBRAL RESISTANCE VESSELS
Authors: MITCHELL G. , SCRIVEN D.R.L. , ROSENDORFF C. 
Published: May 2015

The effects of tyramine and isoprenaline on hypothalamic blood flow (HBF) were measured in conscious rabbits.
Injections of small doses of tyramine caused an increase in HBF while larger doses caused a decrease in HBF.
Isoprenaline injections also produced an increase in HBF.
The vasodilatation induced by isoprenaline and the small dose of tyramine was blocked by propranolol.
The vasoconstriction induced by the larger doses of tyramine was abolished by phenoxybenzamine.
Chemical sympathectomy of the hypothalamus with 6‐hydroxydopamine and depletion of biogenic amines by reserpine also abolished tyramine‐induced vasoconstriction.
These results suggest the presence of α‐ and β‐adrenoceptors in cerebral resistance vessels, and that these receptors may be activated by released (endogenous) noradrenaline.
MODULATION BY ACETYLCHOLINE OF ADRENERGIC TRANSMISSION IN THE RABBIT EAR ARTERY
Authors: ALLEN G.S. , GLOVER A.B. , McCULLOCH M.W. , RAND M.J. , STORY D.F. 
Published: May 2015

Low concentrations of acetylcholine (4 × 10−11 and 1 × 10−10 M) increase the vasoconstrictor response of the isolated ear artery of the rabbit to stimulation of the periarterial sympathetic nerves. Higher concentrations (4 × 10−8 M and greater) decrease the response.
Low concentrations of acetylcholine (1 × 10−11 and 1 × 10−10 M) increase the stimulation‐induced efflux of radioactivity from artery segments previously incubated with [3H]‐noradrenaline. Higher concentrations (3 × 10−8 M and greater) decrease the efflux.
Neither atropine nor hexamethonium affects the facilitatory action of low concentrations of acetylcholine on adrenergic transmission in the rabbit ear artery.
Atropine antagonizes the inhibitory effect of higher concentrations of acetylcholine on adrenergic transmission.
INTERACTION OF COMPETITIVE ANTAGONISTS: THE ANTI‐CURARE ACTION OF HEXAMETHONIUM AND OTHER ANTAGONISTS AT THE SKELETAL NEUROMUSCULAR JUNCTION
Authors: BLACKMAN J.G. , GAULDIE R.W. , MILNE R.J. 
Published: May 2015

In the rat isolated diaphragm preparation hexamethonium and other low potency competitive antagonists of acetylcholine (ACh), including gallamine and hyoscine butylbromide, reverse block by the potent antagonists tubocurarine, pancuronium and alcuronium.
In the presence of tubocurarine, hexamethonium increases the amplitude of the end‐plate potential without increasing the quantal content. It enhances the response to ACh applied iontophoretically to the end‐plate but does not enhance the response to ACh applied in the bath.
The anti‐curare effect of hexamethonium is abolished in the diaphragm of the rat, guinea‐pig and mouse by inhibitors of acetylcholinesterase. The effect is not observed in the indirectly stimulated toad sartorius muscle.
The effect is explained if tubocurarine does not dissociate appreciably in the time taken for ACh to achieve high occupancy of receptors, so that a fraction of receptors is completely excluded from occupation by ACh. Equilibration with hexamethonium reduces the fraction excluded by tubocurarine and the transmitter now competes with hexamethonium for more receptors and produces a larger response.
On the basis of this explanation the half‐time for dissociation of tubocurarine must be about 1 millisecond. It follows that tubocurarine does not act competitively with ACh at synapses when transmitter action is sufficiently brief, and that its binding to the receptor is probably diffusion‐limited.
THE ACTIONS OF DIHYDROXYPHENYLALANINE AND DIHYDROXYPHENYLSERINE ON THE SLEEP‐WAKEFULNESS CYCLE OF THE RAT AFTER PERIPHERAL DECARBOXYLASE INHIBITION
Authors: ALTIER H. , MOLDES M. , MONTI J.M. 
Published: May 2015

The actions of dihydroxyphenylalanine (DOPA) and dihydroxyphenylserine (DOPS) were assessed on the sleep‐wakefulness cycle of male Wistar rats.
In comparative studies the extracerebral decarboxylase was inhibited with serinetrihydroxybenzylhydrazide (RO 4‐4602) before injection of DOPA or DOPS.
DOPA (80‐160 mg/kg, i.p.) with or without previous inhibition of the peripheral decarboxylase gave rise to an initial significant increase of slow wave activity, which may be related to a release of 5‐hydroxytryptamine.
During the subsequent 8 h sessions, DOPA significantly decreased slow wave sleep and rapid eye movement sleep (REM) and increased wakefulness.
DOPS (80‐160 mg/kg, i.p.) did not significantly modify the sleep‐wakefulness cycle apart from a decrease of the latency for the first REM episode after 160 mg/kg in the RO 4‐4602 pretreated animals.