bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between plasma leptin concentrations and the distribution of body fat in crossbred steers
Authors: YAMADA Tomoya , KAWAKAMI Shin‐Ichi , NAKANISHI Naoto
Published: December 2004

The objective of the present study was to examine the relationship between plasma leptin levels and fat distribution in crossbred steers. Twenty‐four crossbred steers (Japanese Black × Holstein) were used in this study. Six steers belonged to the growing phase (11 months of age), and 18 steers to the finishing phase (from 21 to 28 months of age). Plasma leptin levels correlated positively with body fat weight (r = 0.807, P < 0.01), body fat percentage (r = 0.802, P < 0.01), visceral fat weight (r = 0.807, P < 0.01), visceral fat percentage (r = 0.780, P < 0.01), subcutaneous fat weight (r = 0.745, P < 0.01), subcutaneous fat percentage (r = 0.734, P < 0.01), intermuscular fat weight (r = 0.793, P < 0.01), intermuscular fat percentage (0.775, P < 0.01), renal fat weight (r = 0.694, P < 0.01), renal fat percentage (r = 0.642, P < 0.01), subcutaneous fat thickness (r = 0.755, P < 0.01), intermuscular fat thickness (r = 0.721, P < 0.01), beef marbling score (r = 0.706, P < 0.01) and the crude fat content of Musculus longissimus thoracis (r = 0.592, P < 0.01). The location of fat deposits did not affect the correlation values. However, when steers were divided into growing (n = 6) and finishing (n = 18) groups, there was no significant correlation between plasma leptin levels and the carcass characteristics related to fat deposition (fat weight, fat percentage, carcass traits) in either group. These results suggest that plasma leptin levels in crossbred steers positively correlate with body fat content and carcass traits when these parameters vary widely.
Effect of oral administration of L‐pipecolic acid on food intake in chicks and mice
Authors: TAKAGI Tomo , ANDO Ryuichi , OHGUSHI Atsushi , NAKANISHI Tomonori , HUSSAIN‐YUSUF Hazizul , ONODERA Ryoji , SATO Hiroyuki , DENBOW D. Michael , FURUSE Mitsuhiro
Published: December 2004

It has been demonstrated that L‐pipecolic acid (L‐PA), a major metabolic intermediate of L‐lysine (L‐Lys) in the brain, is involved in the functioning of the γ‐aminobutyric acid‐ergic system. Previous study has shown that intracerebroventricular injection of L‐PA suppressed feeding and induced sleep‐like behavior in neonatal chicks. The present study examines whether the action of L‐PA was induced by gavage in both chicks and mice. Oral administration of L‐PA significantly inhibited food intake at 2 h after treatment in neonatal chicks, although no significant effect of L‐Lys was detected. In mice, oral L‐PA suppressed food intake compared to the control after 2 h of treatment. It was concluded that L‐PA was effective for suppression of food intake after oral administration in both avian and mammalian species.
Inhibitory effect of dietary anacardic acid supplementation on cecal lesion formation following chicken coccidial infection
Authors: TOYOMIZU Masaaki , NAKAI Yutaka , NAKATSU Tetsuo , AKIBA Yukio
Published: December 2004

Two experiments were conducted to determine the effects on male chicken performance of anacardic acid and cashew nut shell oil as feed supplements during an experimental coccidial infection. Seven‐day‐old chicks wer e fed a corn‐soybean diet containing anacardic acid at 0, 0.4 or 0.8% (Experiment 1), or cashew nut shell oil at 0, 0.1, 0.2 or 0.4% (Experiment 2) for 10 days. On the third day of each experiment, half of the birds fed each diet were individually inoculated orally with 2 × 103 or 5 × 104 (Experiment 1) and 1 × 104 or 1 × 105 (Experiment 2) Eimeria tenella oocysts. In Experiment 1, body weight gain and cecal length decreased significantly according to the level of oocyst inoculation, while oocyst production per cecum (log value) and cecal lesion score significantly increased. Dietary anacardic acid supplementation had no effect on these parameters except for that of lesion score, which was improved (i.e. decreased) by anacardic acid supplementation of 0.8% at the inoculation level of 2 × 103 oocysts, and of 0.4 and 0.8% for the higher inoculation (5 × 104 oocysts). Results of Experiment 2 also showed that cashew nut shell oil affected neither cecal length nor oocyst production per cecum (log value) at either of the inoculation levels, but the lesion score was improved by cashew nut shell oil supplementation at 0.2 and 0.4% in the diet at the inoculation level of 1 × 104 oocysts and at 0.4% for the higher inoculation. The present study provides the first evidence of the reducing effects of anacardic acid and cashew nut shell oil on the severity of cecal lesions in chickens during an experimental coccidial infection.
Changes of histochemical profiles of myofibers in pectoralis and supracoracoideus fasciculi induced by breeding for large or small body size in Japanese quails
Authors: IWAMOTO Hisao , GOTOH Takafumi , TABATA Shoji , NISHIMURA Shotaro , OKAMOTO Satoru
Published: December 2004

The histochemical profiles of myofibers in Musculus pectoralis (PT) and M. supracoracoideus (SC) fasciculi were compared among Japanese quail strains with large, normal and small body sizes. In male and female adults, both the PT and SC muscles had attained a 2.5–2.7‐fold weight gain in the large strain and conversely a 0.43–0.50‐fold change in the small strain relative to those of the normal size. The muscles were composed of fasciculi with a central cluster of type IIA fibers surrounded by a peripheral layer of type IIB fibers. In the large strain, the cross sectional area (CSA) of the fasciculus and CSA of the fibers in each type were significantly enlarged compared with those in the normal size, with the exception of the fasciculus in the deep region of the male PT muscle. The hypertrophied type IIA fibers in the large strain showed considerable variation in nicotinamide adenine dinucleotide dehydrogenase activity, some of which might represent a transitional form into type IIB fibers. In the small strain, the fasciculus CSA did not significantly differ from that of the normal size except for the PT surface region of the male. However, fiber atrophy was observed in type IIB fibers of the PT surface region in both sexes, and type IIA fibers of the PT deep region and SC muscle in the small strain male quails. The relative fiber type composition of a fasciculus in each region showed only a slight change across the strains. These results indicate that breast muscle hypertrophy in the large strain could be based mainly on fasciculus and fiber hypertrophy, but muscle atrophy in the small strain is not induced by fasciculus and fiber atrophy.
Comparison of collagen content, distribution and architecture among the pectoralis, iliotibialis lateralis and puboischiofemoralis muscles with different myofiber composition in Silky cocks
Authors: NAKAMURA Yoshi‐Nori , IWAMOTO Hisao , TABATA Shoji , ONO Yoshitaka , SHIBA Nobuya , NISHIMURA Shotaro
Published: December 2004

The total amount of collagen, the relative distributions of types I and III collagens in perimysium and endomysium, and the collagen fiber architecture were compared among the pectoralis (PT), iliotibialis lateralis (ITL) and puboischiofemoralis (PIF) muscles in Silky cocks. All of the myofibers in the PT muscle were type IIB, the myofibers in the ITL muscle were divided into type IIA, 41.7% and IIB, 58.3%, and the PIF muscle was composed of type I, 24.6%; IIA, 64.6%; and transitional, 10.8%. The total amount of collagen differed significantly among the PT (2.92 mg/g), PIF (4.20 mg/g) and ITL (8.06 mg/g) material, where only the PIF was a whole muscle with epimysium. On the image analysis of the immunohistochemical preparations, the percentage area of perimysial collagen to the total area in each type differed significantly among the PIF, PT and ITL muscles, where it was 26.8, 50.0 and 74.4% for the type I collagen and 27.4, 32.9 and 61.7% for the type III collagen, respectively. In the scanning electron micrography of the perimysium in macerated preparations, thick bundles of collagen fibers were observed in the ITL muscle, thinner but broad platelets in the PT muscle, and a coarse tissue of thinner collagen fibers in the PIF muscle. However, the endomysial fabric of collagen fibrils was similar among the muscles. Small, transverse collagen fibers, which branched off from the thicker perimysia, occupied narrow interendomysial spaces and separated the primary myofiber fasciculi. The results indicate that the ITL muscle, localized in the distorted and overextended part of the leg and subject to strong external forces, had highly developed perimysial collagen fiber bundles, but the ITL endomysial collagen architecture was similar to that of the PT and PIF muscles.
Effect of atropine and pyridostigmine on growth hormone response to GH‐releasing peptide‐2 and GH‐releasing hormone in swine
Authors: NOU Vonika , TOMOSHI Kyouko , INOUE Hiroaki , KUWAYAMA Hideto , HIDARI Hisashi
Published: December 2004

To investigate the effects of high and low somatostatinergic tone on GH‐releasing peptide‐2 (GHRP‐2) and GH‐releasing hormone (GHRH)‐induced growth hormone (GH) secretion in swine, we examined GHRP‐2‐ and GHRH‐induced GH secretion after pretreatment with atropine or pyridostigmine. Pretreatment of swine with atropine (80 µg/kg bodyweight (BW), intravenous (i.v.)) 15 min before i.v. administration of saline, GHRP‐2 (30 µg/kg BW), GHRH (1 µg/kg BW) or a combination of GHRP‐2 and GHRH, reduced plasma GH area under the curve (P < 0.05), completely blocked GH response to GHRH, and attenuated GH response to GHRP‐2 and GHRH combined (P < 0.05), without affecting GH response to GHRP‐2 only. A synergistic effect of GHRP‐2 and GHRH was not observed. In contrast, pretreatment of swine with pyridostigmine (100 µg/kg BW, i.v.), under the same pretreatment conditions as above, increased plasma GH concentration (P < 0.01), augmented GH response to GHRP‐2 (P < 0.05), and GHRP‐2 and GHRH combined (P < 0.05), but did not affect GH response to GHRH. These results suggest that the cholinergic muscarinic agents atropine and pyridostigmine modulate the GH response to GHRP‐2 and GHRH, and that GHRP‐2 acts antagonistically on the inhibitory effect of somatostatin in swine.
Immunohistochemical detection of pituitary transcription factor‐1 in paraffin sections of bovine adenohypophysis after wet heat‐induced antigen retrieval
Authors: MATSUZAKI Masatoshi , SATO Takahiro , WATANABE Kouichi , SHIBA Nobuya , TSUNEISHI Eisaku , YAMAGUCHI Takahiro
Published: December 2004

Pituitary transcription factor‐1 (Pit‐1) is a tissue‐specific transcription factor responsible for somatotroph (GH cell) development and growth hormone (GH) gene activation. To investigate the expression of Pit‐1 protein in bovine adenohypophysis, antigen retrieval conditions for detection of Pit‐1 were optimized in paraffin sections of bovine pituitary. We then localized Pit‐1 and GH employing a double‐immunohistochemical staining method and compared the distribution and proportion of adenohypophyseal cells containing Pit‐1 and GH between Japanese Black (Blk) and Holstein (Hol) steers. Autoclave heating pretreatment of sections in Dako Target Retrieval Solution for 20–30 min enabled reliable detection of the distinct nuclear immunostaining of Pit‐1. However, heat treatment in phosphate buffered saline or citrate buffer gave only a weak signal with increased background staining and false positive immunoreactions in the cytoplasm. Pituitary transcription factor‐1 was abundantly expressed in the bovine anterior pituitary and the number of Pit‐1 immunoreactive cells did not differ between the breeds. The proportion of GH cells relative to Pit‐1 immunoreactive cells was smaller in Blk than Hol steers, suggesting an intrinsic breed difference in cellular composition of bovine adenohypophysis. The immunohistochemical technique described will facilitate further investigation of the role played by Pit‐1 in the regulation of GH cell development and function in cattle.
Improvement of the emulsifying properties of porcine sarcoplasmic proteins with a low‐molecular weight surfactant by the two‐step emulsification method
Authors: MIYAGUCHI Yuji , HAYASHI Yuki , NAGAYAMA Kiyomi
Published: December 2004

The emulsifying properties of porcine sarcoplasmic protein (SP) with or without low‐molecular weight surfactants were examined. The emulsifying activity (EA) of SP was weaker than that of sodium caseinate (CA), blood plasma (BP) and whey protein isolates at a protein concentration of 0.5–3%. Sodium chloride decreased the EA of SP. The EA of SP was about one quarter that of CA in the presence of 3% sodium chloride. As homogenization time increased, the EAs of SP and BP decreased. The EA of SP was not influenced by sucrose stearate ester (SE) with a hydrophilic‐lipophilic balance (HLB) value of 16 (SE‐16) but was decreased by those with HLB values of 5 and 1. Low‐molecular weight surfactants such as SE‐16, Tween 80 and sodium cholate improved the EA of SP with the two‐step emulsification method: corn oil was previously emulsified with the surfactant before addition of SP and homogenization. In the case of the addition of SE‐16 as primary emulsifier, the EA was about twice as high as that of SP alone. The same effect was shown in the emulsions formed by CA and soy protein isolate. These results indicate that the emulsifying properties of meat protein would be improved by the addition of a low‐molecular weight surfactant in a two‐step emulsification.
Regulator protein that potentially triggers the transcription of the H+‐ATPase operon in a ruminal bacterium, Streptococcus bovis
Authors: OHKAWARA Sou , ASANUMA Narito , HINO Tsuneo
Published: December 2004

In order to seek regulator proteins that are involved in the transcription of the H+‐ATPase operon (atp) in Streptococcus bovis, a transcriptional promoter region of the atp was identified. DNase I footprinting revealed the presence of S. bovis cellular protein that binds to the promoter region. In vitro transcription analysis indicated that the cellular protein triggers atp‐mRNA synthesis. In vitro atp‐mRNA synthesis increased six‐fold on changing the culture pH from 7.0 to 4.5, suggesting that the potential regulator protein increases in response to low pH.
Estimation of additive, maternal and non‐additive genetic effects of preweaning growth traits in a multibreed beef cattle project
Authors: ABDEL‐AZIZ Mahmoud , SCHOEMAN Stephan Johannes , JORDAAN Gail F.
Published: December 2004

Data from purebred and crossbred calves, consisting of Afrikaner (AF), Charolais (CH), Simmental (ST) and Hereford and Aberdeen Angus combined (HA), were analyzed to estimate breed additive effects, breed maternal effects, average individual heterosis and average maternal heterosis. The traits studied were birthweight (BW), weaning weight (WW) and preweaning average daily gain (ADG) (kg). A multiple regression procedure was used for the estimation of these genetic effects and for predictions for breed crosses that were not included in the data set. Crosses containing higher proportions of CH or ST were heavier at birth and weaning than the other crosses and purebreds. The direct effects of BW were negative and significant (P < 0.05), except that of the CH, which was the highest. The regression coefficients were −24.87, −18.16, −22.80 and −27.02 for AF, CH, ST and HA, respectively. The maternal effects were not significant. Both average individual and average maternal heterosis regression coefficients were also not significant for BW. Regression coefficients of both direct and maternal effects for WW were not significant and were characterized by large standard errors. Average individual heterosis and average maternal heterosis regression coefficients were, however, significant (P < 0.01) and the values were 5.34 and 2.19, respectively. A similar pattern was observed for ADG, except for the regression coefficients of the maternal effects, which were significant, with larger estimates for AF and ST reflecting their superior mothering ability. The values were 0.01, 0.13, 0.13, 0.03; −0.82, −0.85, −0.85, −0.81; 0.03 and 0.01 for direct effects and maternal effects of AF, CH, ST and HA; and average individual heterosis and average maternal heterosis, respectively. Means and standard errors of purebreds and their F1 crosses not included in the dataset were predicted.
Viability of maternally heat‐stressed mouse zygotes in vivo and in vitro
Authors: OZAWA Manabu , YAMASAKI Yukiko , HIRABAYASHI Miho , KANAI Yukio
Published: December 2004

Mammalian preimplantation embryos are susceptible to heat stress. This present study examined how maternal heat stress affects the development of mouse zygotes in vivo and in vitro. In Experiment 1, zygotes collected from female mice that were heat‐stressed for 12 h on day 1 of pregnancy were cultured in vitro. Maternally heat‐stressed zygotes developed normally to the two‐cell stage, but the majority of embryos failed to develop into morulae or blastocysts. In Experiment 2, pregnant mice were heat‐stressed on day 1 or from day 1 to day 3 of pregnancy. The number of living fetuses on day 14 of pregnancy was lower in heat‐stressed mice than in non‐stressed mice, but the difference was significant only in successively heat‐stressed mice. These results demonstrate that maternally heat‐stressed zygotes have reduced in vitro viability, but this phenomenon does not necessarily lead to embryo loss in the maternal environment.
Relationship between parity and mineral status in dairy cows during the periparturient period
Authors: KUME Shin‐ichi , NONAKA Kazuhisa , OSHITA Tomoko
Published: December 2004

Data from 65 cows were collected to clarify the relationship between parity and mineral status in Holstein cows during the periparturient period. Milk fever occurred in a second‐ and a fourth‐lactation cow at parturition. Bodyweight of cows decreased immediately after parturition, and the decreased weights of cows from 1 to 6 days after parturition ranged from 11 to 27 kg. Milk yield of multiparous cows was higher than that of primiparous cows, but Ca and P concentrations in colostrum were not affected by the parity. Plasma glucose of primiparous cows was higher than that of multiparous cows, and plasma nonesterified fatty acids of fourth‐and‐more‐lactation cows at parturition was highest. Plasma Ca concentration of cows at parturition decreased with advancing parity, and plasma inorganic P concentration of third‐and‐more‐lactation cows was lowest at parturition. Plasma parathyroid hormone of fourth‐and‐more‐lactation cows at parturition was highest, but plasma hydroxyproline and alkaline phosphatase was lowest. These results suggest that the large transfer of Ca and P to colostrum is a factor in the development of milk fever in third‐and‐more‐lactation cows.
Effect of follicle‐stimulating hormone on ZPC protein secretion by quail granulosa layer
Authors: SASANAMI Tomohiro , ATSUMI Ena , MORI Makoto
Published: December 2004

In avian species, ZPC, a glycoprotein of the inner layer of the vitelline membrane, is synthesized in the granulosa cells of developing follicles. We have previously reported that follicle‐stimulating hormone (FSH) is one of the factors that stimulate ZPC production in quails. In the present study, we examined the effect of FSH on ZPC secretion, and the mode of ZPC secretion from pieces of granulosa layer. Western blot analysis demonstrated that, in the absence of FSH, the intensity of ZPC bands in the medium faded after 6 h of incubation. The addition of FSH caused an increase in intensity of ZPC bands when incubated for more than 6 h. The ZPC secretion during the first 6 h of incubation was depressed by the addition of either cycloheximide or actinomycin D. These results show that the ZPC found in the medium during short‐term incubation is newly synthesized protein and is secreted from the granulosa cells by the constitutive secretory pathway.
TGF‐β and TNF‐α stimulate MMP‐9 production in murine epidermal keratinocytes
Authors: FUJISAWA Chie , INADA Noriko , MOCHIZUKI Rika , ARAI Katsuhiko , UEHARA Kohkichi
Published: December 2004

Matrix metalloproteinases 2 and 9 (MMP‐2 and ‐9) are zinc‐dependent metalloenzymes and have gelatin‐degrading activity. Both MMP are known to be secreted by many types of cells and play important roles in several biological changes including tissue remodeling and wound healing. In the present study, a primary culture of murine epidermal keratinocytes was prepared and effects of transforming growth factor‐β (TGF‐β), tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ) on expression of MMP‐2 and MMP‐9 by the keratinocytes was examined. Gelatin zymography revealed that murine epidermal keratinocytes secreted proenzyme forms of MMP‐2 and MMP‐9, but the active forms of both MMP were hardly detectable, indicating that in vitro autoactivation of these proenzymes did not occur. Both TGF‐β and TNF‐α stimulated MMP‐9 production in a dose‐dependent manner, but the MMP‐2 level was not changed. Interferon‐γ hardly affected production of MMP‐2 or MMP‐9. Ribonuclease protection assay demonstrated that TNF‐α increased the level of MMP‐9 mRNA 6‐fold compared to the control, whereas TGF‐β slightly up‐regulated it. These results suggest that expression of MMP‐9 could be regulated by several cytokines in murine epidermal keratinocytes.
DNA polymorphism in the chicken growth hormone gene: Association with egg production
Authors: KANSAKU Norio , NAKADA Asako , OKABAYASHI Hisato , GUÉMENÉ Daniel , KUHNLEIN Urs , ZADWORNY David , SHIMADA Kiyoshi
Published: December 2004

Restriction fragment length polymorphic markers in the chicken growth hormone (GH) gene were tested for their association with egg production traits. Alleles of GH were determined in 3 non‐inbred strains from different genetic bases. The frequency of PS1 (+) allele in the three strains was very low in contrast to the layer strain previously reported. Results of the present study indicate that the frequency of PS (+) is related to egg production and that the PS1 (+) allele may be used as a genetic marker for selection in egg production.
A computer model for the measurement of compliance using a dual tracer technique‘pa
Authors: Shine D. , McDonald J.
Published: December 2004

Aims We aimed to determine whether simultaneous use of two tracer compounds with long and differing elimination half‐lives may permit more precise recognition of percent compliance and discrimination among remote, intermediate, and recent patterns of daily dosing.

Methods We have derived, through computer modelling, the potential utility of digitoxin and phenobarbitone as simultaneous tracers. From kinetic data on these reliably measured compounds with long half‐lives we defined the percentage error below which this pair of tracers can be expected to discern the precise, and the approximate, pattern and number of daily doses taken over a month.

Results The longer the half‐lives of the tracers the greater the sensitivity of our model to percentage compliance. At extremely long half‐lives, relative to the period of dosing being monitored, sensitivity approaches 100% if measurement error is in the 1–2% range. The ratio of the half‐lives between the two tracers that is optimal for detection of percentage compliance is 0.2 to 0.8. The detection of pattern does not depend importantly either on the tracer half‐lives or on their ratio to each other. The greater the percentage compliance, the more accurately our two‐tracer model determines the pattern of dosing.

Conclusions Precise characterization of compliance using tracers must probably await the development of compounds with half‐lives measured in weeks or months. The probability of compliance of a given degree can be derived from our two‐tracer technique with best‐fit analysis such as we describe.
The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides
Authors: McDowell G. , Coutie W. , Shaw C. , Buchanan K. D. , Struthers A. D. , Nicholls D. P.
Published: December 2004

Aims Candoxatril is a specific neutral endopeptidase (NEP) 24.11 inhibitor, and previous work has documented the effect of NEP inhibition on atrial and brain natriuretic peptides (ANP, BNP). The aim of the present study was to ascertain the effect of NEP inhibition on circulating levels of vasoactive peptides.

Methods We studied seven patients with chronic heart failure who were randomized to receive candoxatril, candoxatril/captopril, captopril and placebo in a four way cross over, double‐blind pattern.

Results The mean circulating level of endothelin (ET) was increased 2 h after placebo (10 to 20 pg ml−1 ) and also calcitonin gene‐related peptide (CGRP) (27 to 51 pg ml−1 ), but ANP levels changed little during this time (73 to 75 pg ml−1 ). Following candoxatril, however, ET (10 to 39 pg ml−1, P<0.05), CGRP (34 to 99 pg ml−1, P<0.05) and ANP (72 to 108 pg ml−1, P<0.05) increased further. A similar result was observed following combined treatment with candoxatril and captopril.

Conclusions We conclude that neutral endopeptidase inhibition increases circulating plasma levels of ET and CGRP in addition to the natriuretic peptides.
Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole
Authors: Lefebvre Romain A. , Van Peer Achiel , Woestenborghs Robert
Published: December 2004

Aims The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied.

Methods Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration.

Results Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml−1 ) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml−1 h) and from 0 to infinity (17.4 to 48.2 ng ml−1 h), and the elimination half‐life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session.

Conclusions Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Twenty‐four hour plasma profile of sustained‐release isosorbide mononitrate in healthy volunteers and in patients with chronic stable angina. Two open label trials
Authors: Baxter T. , Eadie C. J.
Published: December 2004

Aims The plasma profile of a single dose of isosorbide mononitrate 25 mg (Elantan LA25) in healthy volunteers and in angina patients was examined.

Methods In volunteers and patients, blood samples for pharmacokinetics were obtained pre‐dosing and at intervals for 24 h after dosing.

Results This formulation exhibited rapid absorption and plasma levels were maintained at >100 ng ml−1 for up to 9 to 12 h.

Conclusions A comparison of the pharmacokinetics of Elantan® LA25 in volunteers and patients indicates that the profiles are similar.
Pharmacokinetics of vanadium in humans after intravenous administration of a vanadium containing albumin solution
Authors: Heinemann Günter , Fichtl Burckhard , Vogt Wolfgang
Published: December 2004

Aims
  Vanadium is currently undergoing clinical trials as an oral drug in patients with noninsulin‐dependent diabetes mellitus. Furthermore, vanadium occurs in elevated concentrations in the blood of patients receiving intravenous albumin solutions containing large amounts of the metal ion as an impurity. The present study was performed to examine the pharmacokinetics of vanadium in humans following a single intravenous (i.v.) dose of a commercial albumin solution containing a high amount of vanadium.

Methods
 The study was conducted in five healthy volunteer subjects who received intravenously 90 ml of a commercial 20% albumin infusion solution containing 47.6 µg vanadium as an impurity. Vanadium concentrations in serum and urine were determined by electrothermal atomic absorption spectrometry.

Results
  Vanadium serum concentrations after i.v. administration were measured for 31 days. The data could be fitted by a triexponential function corresponding formally to a three‐compartment model. There was an initial rapid decrease in serum concentrations with half‐lives of 1.2 and 26 h. This was followed by a long‐terminal half‐life time of 10 days. The terminal phase accounted for about 80% of the total area under the serum concentration‐time curve (AUC). The mean apparent volume of distribution of the central compartment was found to be 10 l. The volume of distribution at steady state was 54 l, and total clearance was 0.15 l h−1. Vanadium was mainly excreted by the kidneys. About 52% of the dose was recovered in the urine after 12 days.

Conclusions
  This study provides data on vanadium pharmacokinetics in healthy humans.
Glutathione, glutathione‐dependent enzymes and antioxidant status in erythrocytes from children treated with high‐dose paracetamol
Authors: Kozer Eran , Evans Sandra , Barr Joseph , Greenberg Revital , Soriano Ingrid , Bulkowstein Mordechai , Petrov Irena , Chen‐Levi Zehava , Barzilay Bernard , Berkovitch Matitiahu
Published: December 2004

Aim
To investigate glutathione and antioxidant status changes in erythrocytes from febrile children receiving repeated supratherapeutic paracetamol doses.

Methods
Fifty‐one children aged 2 months to 10 years participated in the study. Three groups were studied: group 1 (n = 24) included afebrile children who did not receive paracetamol; and groups 2 (n = 13) and 3 (n = 14) included children who had fever above 38.5°C for more than 72 h. Patients in group 2 received paracetamol at a dose of 50 ± 15 (30–75) mg kg−1 day−1 and those in group 3 received paracetamol above the recommended therapeutic dose, ie 107 ± 28 (80–180) mg kg−1 day−1. A blood sample was taken for the measurement of liver transaminases, gammaglutamil transferase (GGT), reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S‐transferase (GST), superoxide dismutase (SOD) and antioxidant status.

Results
Aspartate aminotransferase activity in group 3 was higher than in the other groups (P = 0.027). GSH, SOD and antioxidant status were significantly lower in group 3 compared with groups 1 and 2 (mean differences: for GSH 3.41 µmol gHb−1, 95% confidence interval (CI) 2.10–4.72, and 2.15 µmol gHb−1, 95% CI 0.65–3.65, respectively; for SOD 856 U min−1 gHb−1, 95% CI 397–1316, and 556 U min−1 gHb−1, 95% CI 30–1082, respectively; and for antioxidant status 0.83 mmol l−1 plasma, 95% CI 0.30–1.36, and 0.63 mmol l−1 plasma, 95% CI 0.02–1.24, respectively). GR activity was significantly lower in groups 3 and 2 in comparison with group 1 (mean differences 3.44 U min−1 gHb−1, 95% CI 0.63–6.25, and 5.64 U min−1 gHb−1, 95% CI 2.90–8.38, respectively). Using multiple regression analysis, paracetamol dose was found to be the only independent variable affecting GR, GST and SOD activities (P = 0.007, 0.003 and 0.008, respectively).

Conclusions
In febrile children, treatment with repeated supratherapeutic doses of paracetamol is associated with reduced antioxidant status and erythrocyte glutathione concentrations. These significant changes may indicate an increased risk for hepatotoxicity and liver damage.
Who receives lipid‐lowering drugs: the effects of comorbidities and patient characteristics on treatment initiation
Authors: Yang Chen‐Chang , Jick Susan S. , Testa Marcia A.
Published: December 2004

Aims
  Little is known about the effects of comorbidities and patient characteristics on treatment initiation of lipid‐lowering drugs (LLDs), which can be helpful in the evaluation of the risks and benefits of LLDs.

Methods
  Baseline characteristics among subjects who received their first ever‐recorded LLD prescription in general practice between 1 January  1990 and 31 December  1997, and hyperlipidaemic patients without LLD therapy during the same period were obtained from the UK General Practice Research Database. Differences between patients who received and patients who did not receive LLDs, as well as patients who received different classes of LLDs were compared by fitting multivariate logistic regression models that adjusted for age, sex, body mass index, smoking status, and year of treatment initiation or hyperlipidaemia diagnosis.

Results
  We found that there were many differences in the baseline characteristics, such as number of general practitioner visits, diagnosis and severity of cardiovascular diseases, and concurrent medications, between the 25 331 patients who received and the 16 287 patients who did not receive LLDs. We also noted that patients with statin therapy had more prior hospitalization, more recent myocardial infarction/stroke, and more concurrent cardiovascular medications, than those patients who received other LLDs.

Conclusions
  Patients who received LLDs in primary care, especially patients with statin therapy, were more likely to be elderly and to have more concomitant severe cardiovascular comorbidities than those hyperlipidaemic patients who did not receive LLDs. Examining the medical records of individuals eligible for LLD therapy is an important first step in selectively targeting who will experience the greatest benefit to risk ratio for the treatment of hyperlipidaemia, and is an important step in avoiding confounding by indication when designing epidemiological studies comparing the risks and benefits of treatments for hyperlipidaemia.
Bronchodilator effects of intravenous olprinone, a phosphodiesterase 3 inhibitor, with and without aminophylline in asthmatic patients
Authors: Myou Shigeharu , Fujimura Masaki , Kamio Yumie , Hirose Tatsuki , Kita Toshiyuki , Tachibana Hideki , Ishiura Yoshihisa , Watanabe Kazuyoshi , Hashimoto Takuma , Nakao Shinji
Published: December 2004

Aims There is no evidence demonstrating the clinical usefulness of phosphodiesterase (PDE) inhibitors in the treatment of asthma, although PDE3 and 4 inhibitors have received much attention for the treatment of bronchial asthma. We compared the bronchodilator effects of intravenously administered olprinone, a selective PDE3 inhibitor, and aminophylline, a nonselective PDE inhibitor, both alone and concomitantly.

Methods In 12 patients with mild stable asthma, we compared the acute bronchodilator effects of the following two drugs, alone and together using a double‐blind crossover design: intravenous administration of olprinone, 30 µg min−1; aminophylline, 2.25 mg min−1; and olprinone plus aminophylline over a total period of 150 min.

Results Mean maximal increase (95% confidence interval) in the FEV1 was 7.8% (2.4, 13.2), 17.1% (10.0, 24.2), 16.6% (11.2, 22.0), and 1.0% (−1.1, 3.1) during infusion of aminophylline, olprinone, aminophylline and olprinone, and saline, respectively. The magnitude of bronchodilatation produced by olprinone was greater than that by aminophylline. The combination of aminophylline and olprinone did not produce any greater bronchodilatation than olprinone alone. Olprinone alone or in combination with aminophylline lowered diastolic blood pressure, and increased heart rate.

Conclusions These results suggest that the intravenous administration of PDE3 inhibitors exhibits a bronchodilatory effect. There are no additive or synergistic effects of administration of olprinone and aminophylline at the same time.
Undertreatment of hypercholesterolaemia: a population‐based study
Authors: Mantel‐Teeuwisse A. K. , Verschuren W. M. M. , Klungel O. H. , Kromhout D. , Lindemans A. D. , Avorn J. , Porsius A. J. , De Boer A.
Published: December 2004

Aims  To assess the level of undertreatment of hypercholesterolaemia in the general population, taking intra‐person variability in serum cholesterol concentrations into account, and to identify determinants of undertreatment of hypercholesterolaemia.

Methods  In this cross‐sectional study, data from two population‐based surveys on cardiovascular disease risk factors conducted between 1987 and 1997 in the Netherlands were used. For all 64 757 respondents aged 20–59 years, treatment eligibility for lipid‐lowering drug use was established according to the Dutch Cholesterol Consensus. Multivariate logistic models were used to identify determinants of undertreatment.

Results  During the study period, 56.8% of the study population had undesirable cholesterol concentrations (serum total cholesterol> 5 mmol l−1) and 5.5% of those were eligible for pharmacological treatment based on their absolute risk of coronary heart disease. Of those eligible for pharmacological treatment, 16.3% were treated, and 19.6% of those treated had their serum total cholesterol concentration controlled. Only 3.2% of those eligible for pharmacological treatment were both treated and controlled. We identified several determinants for undertreatment, e.g. male gender and younger age for primary prevention and female gender and older age for secondary prevention. Treatment has improved slightly in more recent years.

Conclusions  Over 95% of the population eligible for the pharmacological treatment of hypercholesterolaemia was either untreated or was uncontrolled. To decrease undertreatment, identification of high‐risk patients should be increased. Those who are treated with lipid‐lowering medication could further benefit from more aggressive treatment, especially with statins.
Low blood selenium concentrations in schizophrenic patients on clozapine
Authors: Vaddadi K. S. , Soosai E. , Vaddadi G.
Published: December 2004

Aims
  To compare plasma and red‐cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders.

Methods
  Plasma and red‐cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations.

Results
  Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups.

Conclusions
  Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine‐treated patients may be important in the pathogenesis of life threatening cardiac side‐effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.
Development, implementation and cost‐effectiveness of a protocol for review of combination diuretic prescribing
Authors: Morgan Julie D. , Wright David J. , Chrystyn Henry , George Bethan , Booth Andrew C. , Shoesmith David J.
Published: December 2004

Aims
To determine the extent of inappropriate prescribing of combination diuretics and the cost implications of protocol implementation.

Methods
Pharmacist‐run medication review clinics in two general practices in Bradford, UK.

Results
Sixty‐one patients, mean ± s.d. age 75.8 ± 12.0 years, were reviewed. Thirty‐six met protocol criteria; 30 (49.2%) patients had their potassium‐sparing diuretics (PSDs) discontinued. Mean (95% confidence interval) reduction in serum potassium concentrations after intervention in these 30 patients was 0.26 (0.09, 0.43) mmol l−1 (P < 0.01). Twenty‐eight (93.3%) patients were within the reference range at follow‐up; none was below.

Conclusions
Of prescribed PSDs, 59% were found to be unnecessary. Using the developed protocol potentially improves drug safety and enables cost savings.
The pharmacokinetics of pioglitazone in patients with impaired renal function
Authors: Budde Klemens , Neumayer Hans‐Hellmut , Fritsche Lutz , Sulowicz Wladyslaw , Stompôr Tomasz , Eckland David
Published: December 2004

Aims To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M‐III and M‐IV with impaired renal function and normal renal function.

Methods In a phase‐I, open‐label, parallel‐group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min−1), nine patients with moderate renal impairment (creatinine clearance 30–60 ml min−1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min−1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M‐III and M‐IV were assessed for the first and last dose administered (day 1 and day 12, respectively).

Results Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M‐III and M‐IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration‐time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; −23%; confidence interval (CI) −57, 38), M‐III metabolite (13 394 vs 15 071, P = 0.841; −11%; CI −74, 194) and M‐IV metabolite (27 991 vs 49 856, P = 0.006; −44%; CI −62, −17). After repeated oral doses of pioglitazone, mean AUC values (µg.h l−1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; −40%; CI −57, −16), M‐III (3991 vs 7,289, P = 0.0009; −45%; CI −60, −25) and M‐IV (21 080 vs 25 706, P = 0.181; −18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups.

Conclusions Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.
Genotyping of four genetic polymorphisms in the CYP1A2 gene in the Egyptian population
Authors: Hamdy Samar I. , Hiratsuka Masahiro , Narahara Kaori , Endo Naomi , El‐Enany Mervat , Moursi Nadia , Ahmed Mohammed S.‐E. , Mizugaki Michinao
Published: December 2004

Aims
The goal of this study was to determine the frequencies of CYP1A2*1C, *1D, *1E and *1F variants in the Egyptian population and compare frequencies with other populations.

Methods
Genotyping was performed in a total of 212 unrelated Egyptian subjects using polymerase chain reaction‐restriction fragment length polymorphism assay.

Results
The frequencies of CYP1A2*1C, *1D, *1E and *1F variants in the Egyptian population were 0.07, 0.40, 0.03 and 0.68, respectively. The Egyptians have a lower frequency of CYP1A2*1C, and CYP1A2*1E than the Japanese (0.07 vs 0.21 and 0.03 vs 0.08, respectively), while the frequencies of CYP1A2*1D and CYP1A2*1F did not differ significantly between the two groups. CYP1A2*1F (0.68) frequency in Egyptians was identical to that observed in Caucasians (0.68 among 236 German individuals).

Conclusions
The present study is the first to describe the frequencies of four known allelic variants of CYP1A2 among the Egyptian population. CYP1A2*1C and *1E occurred at frequencies significantly lower than that in Japanese, while similar frequencies were observed for CYP1A2*1D and *1F. The CYP1A2*1F frequency appeared to be identical to that of Caucasians. This does not exclude the possibility of the presence of new mutations relatively specific to the Egyptian population that have not been identified.
A placebo‐controlled pharmacodynamic and pharmacokinetic interaction study between tamsulosin and acenocoumarol
Authors: Rolan P. , Terpstra I. J. , Clarke C. , Mullins F. , Visser J. N.
Published: December 2004

Aim
To evaluate pharmacokinetic and pharmacodynamic interactions between tamsulosin and acenocoumarol.

Methods
Twelve healthy volunteers received tamsulosin 0.4 mg or placebo once daily for 9 days in a double‐blind, cross‐over study. On day 5 of each study period, a single 10‐mg oral dose of racemic acenocoumarol was administered.

Results
The ratios (point estimates (90% confidence intervals)) of values in the presence and absence of tamsulosin were: AUCPT 1.01 (0.98, 1.03); maximum prothrombin time (Ptmax) 0.99 (0.94, 1.05); AUC (R)‐acenocoumarol 1.02 (0.90, 1.16), and AUC (S)‐acenocoumarol 1.03 (0.89, 1.20). Both combinations, tamsulosin and placebo with acenocoumarol, were well‐tolerated.

Conclusions
Multiple doses of tamsulosin had no effect on the pharmacokinetics or pharmacodynamics of a single high dose of acenocoumarol.
Quality, efficacy and safety of complementary medicines: fashions, facts and the future. Part I. Regulation and quality
Authors: Barnes Joanne
Published: December 2004

This is the first of two papers which review issues concerning complementary medicines. The first reviews the extent of use of complementary medicines, and issues related to the regulation and pharmaceutical quality of these products; the second considers evidence for the efficacy of several well‐known complementary medicines, and discusses complementary‐medicines pharmacovigilance. The term complementary medicines describes a range of pharmaceutical‐type preparations, including herbal medicines, homoeopathic remedies, essential oils and dietary supplements, which mainly sit outside conventional medicine. The use of complementary medicines is a popular healthcare approach in the UK, and there are signs that the use of such products is continuing to increase. Patients and the public use complementary medicines for health maintenance, for the treatment or prevention of minor ailments, and also for serious, chronic illnesses. The pervasive use of complementary medicines raises several concerns. Many of these arise because most complementary medicines are not licensed as medicines, and therefore evidence of quality, efficacy and safety is not required before marketing. The regulatory framework for herbal medicines and dietary supplements is currently under review. A new system for registration of traditional herbal medicines will ensure that marketed products meet standards for quality and safety. At present, the pharmaceutical quality of many complementary medicines is a cause for concern.
Dose–response relationship and reproducibility of urinary salbutamol excretion during the first 30 min after an inhalation
Authors: Tomlinson H. S. , Corlett S. A. , Chrystyn H.
Published: December 2004

Aims  To determine the reproducibility and dose–response relationship for urinary salbutamol excretion post inhalation.

Methods  Fifteen volunteers inhaled either one, two, three, four or five doses of 100 µg salbutamol on separate days and then seven of these also repeated each of the one, three and five doses on five occasions. After each study dose urine was collected 30 min post inhalation.

Results  The mean (SD) 30 min urinary salbutamol after one, two, three, four and five doses was 2.61 (1.0.), 5.47 (1.59), 8.68 (2.73), 12.34 (3.96) and 15.99 (4.50) µg, respectively. Statistical analysis revealed a linear relationship (P < 0.001). Mean (SD) coefficient of variation after one, three and five doses was 10.5 (3.6), 10.1 (2.7) and 9.4 (2.3)%.

Conclusions  The 30 min salbutamol urinary excretion post inhalation pharmacokinetic method, to compare inhaled products, is linear with inhaled dose and reproducible.