bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects
Authors: Aruna D. , Naidu M. U. R. 
Published: September 2006

Aims Ginkgo biloba is available as an over‐the‐counter drug and reported to cause haemorrhage when coadministered with other antiplatelet agents. We set out to study the interactions of G. biloba with cilostazol and clopidogrel.MethodsA randomized, open‐label, crossover study of 10 healthy male volunteers. The dosage schedules were 120 mg G. biloba, 240 mg G. biloba, 100 mg cilostazol, 200 mg cilostazol, 75 mg clopidogrel, 150 mg clopidogrel, 120 mg G. biloba+ 100 mg cilostazol and 120 mg G. biloba+ 75 mg clopidogrel. Platelet aggregation, platelet count, bleeding time and clotting time were measured 0 and 6 h after drug administration. Platelet aggregation was performed using a dual channel aggregometer, by the turbimetric technique using adenosine diphosphate 5 µmol and 10 µmol, and collagen 1 µg ml−1.ResultsPlatelet inhibition with the combination of G. biloba and clopidogrel or cilostazol was not statistically significant compared with individual doses of drugs, with all the three aggregants. There was significant (P < 0.05) potentiation of prolongation of bleeding time with the combination of cilostazol and G. biloba compared with individual doses of both the drugs. There was no significant change in clotting time and platelet count.ConclusionsCoadministration of G. biloba either with cilostazol or clopidogrel did not enhance antiplatelet activity compared with individual agents. Ginkgo biloba potentiated the bleeding time prolongation effect of cilostazol. There was no significant correlation between prolongation of bleeding time and inhibition of platelet aggregation.
Lack of a pharmacokinetic interaction between steady‐state roflumilast and single‐dose midazolam in healthy subjects
Authors: Nassr Nassr , Lahu Gezim , Von Richter Oliver , Reutter Felix , Knoerzer Dietrich , Zech Karl , Erb Katharina A. , Schug Barbara , Blume Henning , Hermann Robert 
Published: September 2006

What is already known about this subject• Cytochrome P450 (CYP) 3A4 plays a prominent role in the metabolism of many drugs, which in turn implies, that changes in the activity of this enzyme caused by, for example, co‐administered drugs, might result in clinically significant drug interactions.• Roflumilast, a targeted PDE4 inhibitor in clinical development for the treatment of COPD and asthma, is partly metabolized by CYP3A4, and thus may have the potential to inhibit its activity.What this study adds• The results of this study show that therapeutic steady‐state concentrations of roflumilast and its active metabolite roflumilast N‐oxide do not alter the disposition of the CYP3A substrate midazolam.• Therefore, roflumilast treatment has a low susceptibility to alter the clearance of drugs metabolized by CYP3A4.AimsThe aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites.MethodsIn an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 µg once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart).ResultsA comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast.ConclusionsTherapeutic steady state concentrations of roflumilast and its N‐oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.
cDNA cloning and substrate specificity of equine tryptase, a possible mediator in equine heaves
Authors: Dacre K. J. , McAleese S. M. , Knight P. , McGorum B. C. , Pemberton A.D. 
Published: October 2006

SummaryBackground
Mast cell mediators are believed to play a central role in inflammatory lung disorders such as human allergic and occupational asthma. Equine heaves is characterized by reversible neutrophilic airway inflammation and airway obstruction, primarily due to bronchospasm and mucus hypersecretion, following exposure of susceptible horses to organic stable dusts. As such, heaves shares many similarities with human occupational dust‐induced asthma and therefore it is proposed that mast cells may also be implicated in the pathogenesis of heaves. Tryptase, a mast cell‐specific proteinase, can be used as an indicator of biological mast cell activity.Objective
The aim of this study was to determine the cDNA sequence of equine tryptase and to investigate its substrate specificity in order to rationalize its enzymatic activity.Methods
RT‐PCR cloning was used to sequence equine tryptase. Substrate specificity of equine tryptase was investigated using arginine and lysine containing substrates.Results
The cDNA and deduced amino acid (Aa) sequences for equine tryptase shared strong identity with other tryptases. Unusually for a trypsin‐like proteinase however, equine tryptase has alanine at residue 216, rather than glycine, which confers increased arginine substrate specificity in vitro and may restrict fibrinogenolysis in vivo.Conclusion
Cloning and sequencing of the mast cell proteinase equine tryptase will allow molecular probing of its expression in the lung of control and heaves‐affected horses. Further work is warranted to determine the biological relevance of the unique alanine 216 substitution in the molecular sequence of the equine tryptase substrate‐binding pocket.
Temporal and spatial variability in growth and condition of dab (Limanda limanda) and sprat (Sprattus sprattus) larvae in the Irish Sea
Authors: LEE ORLA , DANILOWICZ BRET S. , DICKEY‐COLLAS MARK 
Published: September 2006

AbstractVariability in the high mortality rate during early life stages is considered to be one of the principal determinants of year‐class variability in fish stocks. The influence of water column stability on the spatial distribution of fish larvae and their prey is widely acknowledged. Water column stability may also impact growth through the early life history of fishes, and consequently alter the probability of survival to maturity by limiting susceptibility to predation and starvation. As a test of this concept, the variability in condition and growth of dab (Limanda limanda) and sprat (Sprattus sprattus) larvae was investigated in relation to seasonal stratification of the water column in the north‐western Irish Sea. RNA/DNA ratios and otolith microincrement analysis were used to estimate nutritional status and recent growth rates of larvae captured on four cruises in May and June of 1998 and 1999. Dab and sprat larvae were less abundant in 1999 and were in poorer condition with lower growth rates than in 1998. Dab larvae of <13 mm also exhibited spatial variability with higher RNA/DNA ratios at the seasonal tidal‐mixing front compared with stratified and mixed water masses. However, the growth and nutritional status of sprat larvae was uncorrelated to water column stability, meaning the more favourable feeding conditions generally associated with the stratified pool and tidal‐mixing front in the Irish Sea were not reflected in the growth and condition of these larvae. This suggests that the link between stability, production and larval growth is more complicated than inferred by some previous studies. The existence of spatio‐temporal heterogeneity in the growth and condition of these larvae has implications for larval survival and the recruitment success of these species in the Irish Sea.
Effects of floods on fish assemblages in an intermittent prairie stream
Authors: FRANSSEN NATHAN R. , GIDO KEITH B. , GUY CHRISTOPHER S. , TRIPE JEFF A. , SHRANK SALLY J. , STRAKOSH TIMOTHY R. , BERTRAND KATIE N. , FRANSSEN COURTNEY M. , PITTS KRISTEN L. , PAUKERT CRAIG P. 
Published: October 2006

Summary1. Floods are major disturbances to stream ecosystems that can kill or displace organisms and modify habitats. Many studies have reported changes in fish assemblages after a single flood, but few studies have evaluated the importance of timing and intensity of floods on long‐term fish assemblage dynamics.2. We used a 10‐year dataset to evaluate the effects of floods on fishes in Kings Creek, an intermittent prairie stream in north‐eastern, Kansas, U.S.A. Samples were collected seasonally at two perennial headwater sites (1995–2005) and one perennial downstream flowing site (1997–2005) allowing us to evaluate the effects of floods at different locations within a watershed. In addition, four surveys during 2003 and 2004 sampled 3–5 km of stream between the long‐term study sites to evaluate the use of intermittent reaches of this stream.3. Because of higher discharge and bed scouring at the downstream site, we predicted that the fish assemblage would have lowered species richness and abundance following floods. In contrast, we expected increased species richness and abundance at headwater sites because floods increase stream connectivity and create the potential for colonisation from downstream reaches.4. Akaike Information Criteria (AIC) was used to select among candidate regression models that predicted species richness and abundance based on Julian date, time since floods, season and physical habitat at each site. At the downstream site, AIC weightings suggested Julian date was the best predictor of fish assemblage structure, but no model explained >16% of the variation in species richness or community structure. Variation explained by Julian date was primarily attributed to a long‐term pattern of declining abundance of common species. At the headwater sites, there was not a single candidate model selected to predict total species abundance and assemblage structure. AIC weightings suggested variation in assemblage structure was associated with either Julian date or local habitat characteristics.5. Fishes rapidly colonised isolated or dry habitats following floods. This was evidenced by the occurrence of fishes in intermittent reaches and the positive association between maximum daily discharge and colonisation events at both headwater sites.6. Our study suggests floods allow dispersal into intermittent habitats with little or no downstream displacement of fishes. Movement of fishes among habitats during flooding highlights the importance of maintaining connectivity of stream networks of low to medium order prairie streams.
Optimising enzymatic maceration in pretreatment of carrot juice concentrate by response surface methodology
Authors: Sun Ying , Wang Zhengfu , Wu Jihong , Chen Fang , Liao Xiaojun , Hu Xiaosong 
Published: September 2006

SummaryIn this paper, enzyme preparation for carrot pulp maceration was screened out and enzymatic maceration processing condition of the carrot pulp was optimised by response surface methodology for carrot juice concentrate. Pectinex Smash XXL was the best commercial enzyme preparation than Pectinex Ultra SP‐L, Pectinase FNP‐1 and cellulose FNC‐1 employed in the carrot juice processing in the study. The effect of enzyme concentration and incubation time and their complex interaction on juice β‐carotene content, juice yield and viscosity in the maceration process was studied by using experiments of central composite rotatable design. The results indicated that under the optimal conditions that the enzyme concentration was 100 mL t−1 and incubation time was 80 min, the juice β‐carotene content was ≥54.2 mg kg−1, the juice yield ≥63.5% and the juice viscosity ≤2.1 mPa S.
Sensitive and Specific Radioreceptor Assay for Calcitonin Gene‐Related Peptide
Authors: Wimalawansa Sunil J. 
Published: September 2006

AbstractCalcitonin gene‐related peptide is a 37‐amino‐acid neuropeptide which has a direct action on the heart and is an extremely potent vasodilator. Immunoreactive calcitonin gene‐related peptide is present in plasma, cerebrospinal fluid and in other tissues. We have previously established the specific binding characteristics of this neuropeptide to the cerebellar membranes. This paper describes a sensitive, rapid and specific radioreceptor assay for the measurement of receptor‐active calcitonin gene‐related peptide in tissues and in plasma extracts using cerebellar membrane preparations as the binding agent. This assay should prove a valuable tool in studies of the physiology of this vasoactive neuropeptide and of its involvement in disease.
Role of Anterior Peri‐Third Ventricular Structures in the Regulation of Supraoptic Neuronal Activity and Neurohypophysical Hormone Secretion in the Rat
Authors: Leng G. , Blackburn R. E. , Dyball R. E. J. , Russell J. A. 
Published: September 2006

AbstractNeurohypophysical hormone release, and the electrical activity of single neurons of the supraoptic nucleus, were monitored in urethane‐anaesthetized rats. Immediately after electrolytic lesions of the region anterior and ventral to the third ventricle (AV3V region), supraoptic neurons showed little spontaneous activity and their responses to ip injection of hypertonic saline were severely impaired; corresponding deficits were found in the secretion of both oxytocin and vasopressin. Similar deficits in oxytocin secretion were also found in rats following electrolytic lesions which destroyed all or part of the subfornical organ; however the effects of the lesions were not additive: rats with lesions of both the AV3V region and the subfornical organ region showed a similar degree of impairment of osmotically stimulated oxytocin secretion to rats with lesions of either site alone. Such deficits might occur either as a result of destruction of osmoresponsive projections to the magnocellular nuclei, or as a result of destruction of an afferent input which is essential for the full expression of the innate osmosensitivity of supraoptic neurons. To test the latter possibility, supraoptic neurons in AV3V‐lesioned rats were activated by continuous application of glutamate, and then tested with ip injection of hypertonic saline. Five of seven cells tested responded significantly to the hyperosmotic stimulus, though the responses were significantly weaker than observed in sham‐lesioned rats. We suggest that the innate osmosensitivity of supraoptic neurons does contribute to their responses to systemic osmotic stimulation, but that expression of this innate osmosensitivity requires inputs from the AV3V region and/or the subfornical organ, some of which may also be osmoresponsive. Electrical stimulus pulses applied to the AV3V region influenced the electrical activity of most supraoptic neurons strongly: the predominant response was a short‐latency, short‐duration inhibition followed by long‐latency, long‐duration excitation. Whereas intracerebroventricular administration of the angiotensin II antagonist saralasin reduced spontaneous or osmotically induced activity of supraoptic neurons, the neuronal responses to AV3V stimulation were impaired only with relatively high doses of saralasin. We conclude that angiotensin ll‐sensitive neurons are an important component of the afferent pathways that sustain the excitability of supraoptic neurons, but that angiotensin is probably not the major transmitter of the projection from the AV3V region to the supraoptic nucleus.
Nα‐Acetyl‐Vasopressin‐ and Nα‐Acetyl‐Oxytocin‐Like Substances: Isolation and Characterization in the Rat Neurointermediate Pituitary and Presence in the Brain
Authors: Liu Bin , Burbach J. Peter H. 
Published: September 2006

AbstractPost‐translational modifications of vasopressin and oxytocin in pituitary and brain were investigated in view of recent evidence that oxytocin is partly Nα‐acetyfated in the bovine pineal gland. Two peptides were isolated from the neurointermediate lobe of the rat pituitary gland and characterized as Nα‐acetyl‐vasopressin and Nα‐acetyl‐oxytocin, based on chromatographic and immunological properties as well as the blocked N‐terminus. In the neurointermediate pituitary the acetylated forms represented approximately 1% of the vasopressin and oxytocin contents. These two peptides were also detected in some, but not all, investigated brain areas. The highest degree of acetylation was found in the pineal gland. In all regions acetylation of oxytocin was more abundant than that of vasopressin. The data indicate that acetylation of vasopressin and oxytocin generally occurs as a post‐translational modification. They support the concept that acetylation may represent a mechanism aimed to control bioactivity of the neurohypophyseal hormones.
The Carboxy‐Terminal Glycopeptide of the Vasopressin Precursor in the Guinea‐Pig: Release Studies Using a Specific and Sensitive Homologous Radioimmunoassay
Authors: Fairhall K. M. , Robinson I. C. A. F. 
Published: September 2006

AbstractThe glycopeptide corresponding to the C‐terminal portion of the vasopressin precursor (CPP)has been isolated from guinea‐pig posterior pituitary glands and used to generate a specific and sensitive radioimmunoassay. The antiserum is directed to the peptide rather than sugar moieties, and detects two components in pituitary extracts: CPP itself, and a biosynthetic intermediate (NP‐CPP) containing both neurophysin and CPP sequences. Release of CPP from neurointermediate lobes incubated in vitro was stimulated five‐fold by high K+ in a Ca2+ dependent manner: in vivo studies suggest that CPP is released under conditions stimulating vasopressin release. Chronic dehydration depleted neural lobe stores of CPP in parallel with other vasopressin‐related components, and plasma levels of CPP were raised from 68±18 to 320 + 89 fmol/ml (SEM, n = 6). In anaesthetized guinea‐pigs, intraperitoneal injections of increasingamounts of hypertonic saline increased plasma levels of CPP in a graded manner compared with isotonic saline injections. Acute haemorrhage also stimulated CPP release into plasma, and the half‐time of clearance of CPP after infusion to steady state levels in guinea‐pig plasma was 24 min. Cerebrospinal fluid withdrawn from the cisterna magna also contained detectable amounts of CPP (390 + 25 fmol/ml) suggesting that CPP is released from both hypophysical and extra‐hypophysical projections. This assay may now be used to study the biosynthesis, processing and release of endogenous CPP under different physiological conditions.
Ultradian Rhythm of Growth Hormone Secretion in Unrestrained, Conscious Male Rabbits: Role of Endogenous Somatostatint†
Authors: Minamitani Naoto , Chihara Kazuo , Kaji Hidesuke , Kodama Hitoshi , Kita Tetsuya , Fujita Takuo 
Published: September 2006

AbstractThe profiles of growth hormone (GH) secretion were examined by obtaining serial blood samples every 15 min for a 5 to 24 h observation period from freely‐moving, conscious male rabbits chronically implanted with a right atrial cannula. The effects of restraint or surgical stress on GH secretion were also investigated in these animals. Four days after cannulation of the right atrium, plasma GH levels remained low without oscillation, during a 5 h observation period (1100 to 1600 h) with the mean (± SEM) value of 1.6±0.2 ng/ml. Individual rabbits exhibited a spontaneous, pulsatile GH secretion 7 days after the surgery. Mean 6 h GH levels were 5.6 ± 0.8 ng/ml at 7 days after the surgery, 6.3 ± 0.6 ng/ml at 14 days and 7.0 ± 1.2 ng/ml at 28 days. Therefore, the animals, 7 to 14 days after cannulation, were used to analyse the pulsatile pattern of GH secretion throughout 6 to 24 h. Two episodes of 45 min immobilization stress, separated by 75 min, caused a complete suppression of the spontaneous GH secretion (mean 6 h GH levels, 2.2 ± 0.1 ng/ml vs control, 5.0 ± 0.5 ng/ml, P<0.01). No surges appeared after the first restraint stress. In 14 non‐treated rabbits, plasma GH levels fluctuated in an episodic manner throughout the study with the peaks of 14.2 + 0.7 ng/ml, the nadirs of 2.6 ± 0.2 ng/ml and the peak to peak intervals of 2.20 ± 0.17 h. The iv administration of normal goat λ‐globulin (NGG) affected neither GH secretory patterns nor baseline levels of plasma GH. In contrast, the iv administration of anti‐sornatostatin goat λ‐globulin (ASG) caused a significant increase in the amplitude of plasma GH peaks (38.8±1.9 vs NGG‐treated, 13.7 ± 0.8 ng/ml, P<0.001) as well as the trough level (13.5 ± 0.6 vs NGG, 2.9 ± 0.1 ng/ml, P<0.001) during a 24 h observation period. Also, ASG treatment increased numbers of plasma GH peaks per day (18.8±2.7 vs NGG, 12.2 ± 0.8, P < 0.05) with concomitant shortening of the peak to peak interval (1.25 ± 0.10 vs NGG, 2.03±0.12h, P<0.01).These findings suggest: 1) that GH is episodically secreted throughout the day in conscious male rabbits, 2) that surgical and restraint stresses suppress the spontaneous GH secretion, and 3) that endogenous somatostatin might rather play a tonic inhibitory role in GH release in conscious male rabbits, since ASG treatment resulted in sustained marked increases of plasma GH levels irrespective of the stage in GH pulsatile rhythm.
Adrenergic and Noradrenergic Regulation of Pulsatile Luteinizing Hormone Release*
Authors: Gallo Robert V. , Bona‐Gallo Antonella , O'Sullivan David 
Published: September 2006

AbstractThe object of this study was to further define the roles of both norepinephrine (NE) and epinephrine (EPIN) in regulating pulsatile luteinizing hormone (LH) release in 4‐day ovariectomized rats, in particular to examine the effect of decreasing NE synthesis on pulsatile LH secretion in animals with already greatly depleted levels of brain EPIN. Rats were injected ip with vehicle or drug at ‐27, ‐20, ‐5 and ‐ 3 h relative to the onset of a 3‐h blood sampling period. Hypothalamic‐preoptic area (HPOA) levels of NE and EPIN were determined by high‐performance liquid chromatography. Compared to controls, FLA‐63 (25 mg/kg, a dopamine‐ß‐ hydroxylase inhibitor), given at ‐ 3 h, produced 50% and 22% declines in HPOA‐NE and EPIN, respectively, and reductions in pulse amplitude and frequency. LY134046 (50 mg/kg, a phenylethanolamine N‐methyltransferase inhibitor), given at ‐ 27, ‐ 20 and ‐ 5 h, or ‐27, ‐20, ‐5 and ‐3 h, produced no change in NE, 88% and 86% declines in EPIN, respectively, and reductions in pulse frequency only. Each LY134046 treatment protocol produced the same decline in EPIN and pulse frequency. Thus, EPIN levels were maximally decreased by three LY134046 injections. When rats were given LY134046 at ‐27, ‐20 and ‐5 h, and FLA‐63 at ‐3 h, compared to rats treated with LY134046 alone, there was no further decrease in HPOA‐EPIN (82% decline), a 46% decline in NE, a further reduction in pulse frequency and a reduction in pulse amplitude. This further suppression of LH release must be due to a reduction in HPOA‐NE levels since no further decrease in EPIN levels occurred. These data demonstrate within the same animal that NE and EPIN are both stimulatory to pulsatile LH release. NE stimulates the amplitude and frequency, and EPIN stimulates the frequency of pulsatile LH secretion.