bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for adaptive self‐superparasitism in the dryinid parasitoid Haplogonatopus atratus when conspecifics are present
Authors: Yamada Yoshihiro Y. , Sugaura Kazuma
Published: October 2003

Self‐superparasitism – ovipositing in or on a host that was previously parasitized by the same individual – had generally been considered maladaptive for solitary parasitoids. Recently, however, some researchers have suggested that self‐superparasitized hosts produce higher fitness returns per host than singly parasitized hosts when these hosts are parasitized by conspecifics. The present study is the first to verify this possibility in the parasitoid Haplogonatopus atratus. Fitness returns from the first and second ovipositions under triple parasitism were compared with those from the first oviposition under double parasitism. Fitness returns were assessed in terms of survival rate, adult size, and developmental time. No differences were found between the two groups in adult size and developmental time. When the interval between the second and third ovipositions was 1 h, the total survival rate of the first and second comers under triple parasitism was higher than the survival rate of the first comer under double parasitism, and as high as the total survival rate of two first comers under double parasitism. This suggests that the value of self‐parasitized hosts is as high as that of unparasitized hosts. When the second‐to‐third interval of triple parasitism was 24 h, self‐superparasitism produced no fitness returns. Moreover, fitness returns from ovipositing into self‐superparasitized hosts were similar to those from ovipositing into singly parasitized hosts.
State‐dependent risk‐taking by predators in systems with defended prey
Authors: Sherratt Thomas N.
Published: October 2003

Even defended prey items may contain nutrients that can sustain predators in times of energetic need. Conversely, a well‐fed predator might be expected to avoid attacking prey items that have a chance of being defended, particularly if there is an abundance of familiar palatable prey to support it. To further understand the implications of optimal state‐dependent foraging behaviour by predators in systems that contain defended prey, I developed a stochastic dynamic programming model. This state‐dependent approach formally accounts for the trade‐off between avoiding starvation and minimising harm from attacking defended prey. It predicts that the mean attack probability of predators on defended models and their undefended mimics should decline in a sigmoidal fashion with increasing availability of alternative undefended prey, and that the foraging decisions of predators should in general be relatively insensitive to the probability that a potentially defended prey item is indeed defended. Some implications of these predictions are that conspicuous warning signals are more likely to evolve in systems that contain an abundance of alternative undefended prey, and that imperfect mimicry will provide almost complete protection to the mimic when predators are readily supported by alternative food sources. Somewhat surprisingly, increasing the density of nutritious undefended mimics while keeping the densities of all other prey types constant tended to decrease the attack rates of predators on encounter with mimics and their defended models. This increase in dietary conservatism arose because in these cases there would be more prey available to sustain the predator if it ever found itself critically low in energy.
Experimental evidence that aboveground predators are sustained by underground detritivores
Authors: Miyashita Tadashi , Takada Mayura , Shimazaki Aya
Published: October 2003

Detrital infusion into grazing food web is considered to be important in terrestrial communities, but there is hardly any experimental evidence showing that generalist predators aboveground are sustained by belowground detritivores. We established two types of experimental plots in the forest floor, one with sheets on the ground to prevent the emergence of belowground arthropods and the other without sheet, to test the hypotheses that 1) reduced input of detrital arthropods decreases the abundance and species richness of web spiders (major generalist predators in terrestrial ecosystems) and 2) lower number of spiders increases the abundance of herbivorous arthropods. We found that spiders were less abundant in plots where the emergence of detrital arthropods was reduced, while the abundance of herbivores did not significantly increase in these plots. These results provide empirical evidence that organisms moving from underground to aboveground may be important for the maintenance of aboveground predators, although the cascading effect of predator abundance on the grazing food chain was not detected in the present study.
Effects of repeated damage and fertilization on palatability of Vaccinium myrtillus to grey sided voles, Clethrionomys rufocanus
Authors: Strengbom Joachim , Olofsson Johan , Witzell Johanna , Dahlgren Jonas
Published: October 2003

In this study we examined the responses of the dominant understorey plant species, Vaccinium myrtillus, in a Swedish boreal forest to nitrogen applications and repeated damage by clipping. Four years of clipping V. myrtillus reduced its abundance, regardless of whether the clipping was combined with fertilization or not. The treatments also induced changes in growth form and concentration of phenolic compounds in the shoots. Repeated damage to the shrub caused reductions in both the length and diameter of the shoots, while fertilization alone increased their diameter. Fertilization also decreased the concentration of condensed tannins in shoots of V. myrtillus, while clipping had no significant effect in this respect. Condensed tannin concentrations were higher in shoots given the combined fertilization and clipping treatment than in shoots that were fertilized but not clipped. The effect on tannins is in accordance with the predictions of the CNB‐hypothesis. Among the seven individual phenolic compounds analysed only one, a cinnamic acid derivate, showed a significant effect of the treatments. Repeated damage resulted in decreased concentration of this phenolic acid. In addition there was a tendency towards treatment effects on both nitrogen and carbon concentration of the V. myrtillus shoots, but none of these effects were statistically significant. The treatment‐induced changes in V. myrtillus also affected the food preferences of grey‐sided voles (Clethrionomys rufocanus), resulting in the following order of preference among the treatments: 1) fertilization and clipping, 2) fertilization, 3) control and 4) clipping. Not only biochemical changes, but also changes in growth form were found to influence the preferences, as the voles avoided the smallest shoots. This size‐dependent feeding may partly explain the observed differences in their preferences. Thus, induced changes in growth form need to be considered when conclusions about changes in herbivores’ preference are made.
N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine is a product of melatonin oxidation in rats
Authors: Rozov Stanislav V. , Filatova Elena V. , Orlov Alexandr A. , Volkova Anvara V. , Zhloba Alexand R.A. , Blashko Eduard L. , Pozdeyev Nikita V.
Published: October 2003

Abstract: The product of melatonin oxidation, N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine (AFMK), was synthesized and a method for its determination in biological samples was developed. High performance liquid chromatography (HPLC) with fluorescence detection provided good sensitivity and selectivity. Wavelengths of 350 and 480 nm were used for excitation and emission, respectively. Serum and retinal homogenates were extracted with chloroform prior to analysis by HPLC. Endogenous AFMK was detected in the retina of rats but the serum concentration of this melatonin metabolite was below the detection limit of the method for measurement. Retinal AFMK concentration was higher during the dark phase of the light/dark cycle, when the retinal melatonin content is maximal. Intraperitoneal administration of melatonin significantly increased serum and retinal AFMK levels. Formation of AFMK from melatonin was also confirmed by in vivo microdialysis with the probe implanted into the brain lateral ventricle. The study shows that AFMK is indeed a product of melatonin oxidation in vivo. The possible physiological significance of melatonin oxidation metabolic pathway is discussed.
Melatonin protects against myocardial doxorubicin toxicity in rats: role of physiological concentrations
Authors: Sahna Engin , Parlakpinar Hakan , Ozer Mehmet K. , Ozturk Feral , Ozugurlu Fikret , Acet Ahmet
Published: October 2003

Abstract: Doxorubicin (Dox) is a widely used antineoplastic drug. Oxygen radical‐induced injury of membrane lipids is considered to be the most important factor responsible for the development of Dox‐induced cardiotoxicity. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce Dox‐induced cardiac damage. However, the physiological role of melatonin in the prevention of this damage is unknown. We investigated physiological and pharmacological effects of melatonin on Dox‐induced changes in the levels of malondialdehyde (MDA), a lipid peroxidation product, and morphological changes in heart. Rats were pinealectomized (Px) or sham‐operated (control) 2 months before the studies. Melatonin was administered [4 mg/kg, intraperitoneally (i.p.)] 1 hr before or 24 hr after the administration of a single dose of Dox (20 mg/kg, i.p.) and continued for 2 days. The levels of MDA Dox was found to be significantly higher in the Px rats (55.9 ± 0.6 nmol/g tissue) than intact control animals (42.6 ± 0.4). Dox administration to Px and non‐Px rats significantly increased the MDA levels. Pre‐ and post‐treatment with melatonin in both Px and intact rats significantly reduced MDA levels. Morphological changes parallelled the MDA alterations. These findings strongly suggest that both physiological and pharmacological concentrations of melatonin are important in protecting the heart from Dox‐induced damage in rats. It would seem valuable to test melatonin in clinical trials for prevention of possible heart damage associated with Dox.
Melatonin protects against pro‐oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite
Authors: Teixeira Adriana , Morfim Marcos P. , de Cordova Clarissa A. S. , Charão Carla C. T. , de Lima Vânia R. , Creczynski‐Pasa Tânia B.
Published: October 2003

Abstract: We have investigated the action of melatonin against lipid peroxidation in membranes including brain homogenates (BH), brain and liver microsomes (MIC), and phosphatidylcholine (PC) liposomes, as well as its effect on the activity of pro‐oxidant enzymes such as constitutive neuronal nitric oxide synthase (cnNOS), xanthine oxidase (XO) and myeloperoxidase (MPO). The liposomes were reconstituted by a dialysis method, lipid peroxidation was monitored using the thiobarbituric reactive substances (TBARS) method and enzyme activities were measured spectrophotometrically. The ascorbyl and hydroxyl free radicals were generated by the reaction of ascorbic acid + FeSO4 and H2O2 + FeCl2, respectively, and peroxynitrite using a mixture of NaNO2 in an alkaline medium. Melatonin protected against lipid peroxidation induced by distinct reactive oxygen species (ROS) in all membranes tested although with different potency, in the following order BH < MIC < PC. The K0.5 for enzyme inhibition by melatonin was determined for nNOS (2.0 ± 0.1 mm), for XO (0.8 ± 0.1 mm) and for MPO (0.063 ± 0.003 mm), the latter one with high affinity. Melatonin showed a weak effect as a nitrogen monoxide (NO) scavenger in the presence of sodium nitroprusside (NO donor) and low reactivity with 1,1–diphenyl‐2‐picryl hydrazyl (DPPH). These results demonstrate the antioxidant action of melatonin, principally that related to the activity of pro‐oxidant enzymes such as XO and MPO.
Protective effect of indoleamines on in vitro ascorbate‐Fe2+dependent lipid peroxidation of rod outer segment membranes of bovine retina
Authors: Guajardo Margarita H. , Terrasa Ana M. , Catalá Angel
Published: October 2003

Abstract: Rod outer segment membranes (ROS) are highly vulnerable to autooxidation because of their high content of long chain polyunsaturated fatty acids (PUFAs). Melatonin and N‐acetylserotonin are indoleamines synthesized in the pineal gland, retina and other tissues. These compounds are free radical scavengers and indirect antioxidants because of their stimulatory effect on antioxidative enzymes. We compared the in vitro protective effect of melatonin and N‐acetylserotonin on the ascorbate‐Fe2+ induced lipid peroxidation of PUFAs located in ROS membranes. This process was measured by chemiluminescence and fatty acid composition of total lipids of ROS. We assayed increasing concentrations of melatonin (0–10 mm) and N‐acetylserotonin (0–2 mm). In both cases the total cpm originated from light emission (chemiluminescence) was found to be lower in those membranes incubated in the presence of either melatonin or N‐acetylserotonin; this decreased proportional to the concentration of the indole. Thus, 10 mm melatonin and 2 mm N‐acetylserotonin produced a reduction of 51 ± 6 and 100% in the total chemiluminescene (lipid peroxidation), respectively. We also noticed a PUFAs protection: the docosahexaenoic acid content decreased considerably when the membranes were submitted to oxidative damage. This reduction was from 37.6 ± 2.1% in the native membranes to 6.2 ± 0.8% in those which were peroxidized. These changes were less pronounced in treated ROS membranes; as an example in the presence of 10 mm melatonin or 2 mm N‐acetylserotonin we observed a content preservation of 22:6 n‐3 (23.6 ± 1.2 and 39.1 ± 1.2% respectively). The concentration of each compound required to inhibit 50% of the lipid peroxidation (IC50) was 9.82 mm for melatonin and 0.43 mm for N‐acetylserotonin, respectively. N‐acetylserotonin shows a protective effect about 20 times higher than that of melatonin.
Protective effect of melatonin against fractionated irradiation‐induced epiphyseal injury in a weanling rat model
Authors: Yavuz Melek N. , Aydin Yavuz A. , Ulku Cunay , Sener Muhittin , Yaris Ersin , Kosucu Polat , Karslioglu Ihsan
Published: October 2003

Abstract: The effects of melatonin, a free‐radical scavenger and a general antioxidant, on radiation‐induced growth plate injury have not been studied previously. The purpose of this study was to determine the potential benefits of sparing longitudinal bone growth by fractionated radiotherapy alone compared with pretreatment with melatonin that provides differential radioprotection of normal cells. Weanling 4‐wk‐old (75–100 g) male Sprague–Dawley rats were randomly assigned to one of three groups: Group R received fractionated radiation alone (n = 8); groups M5 (n = 8) and M15 (n = 7) received 5 or 15 mg/kg melatonin prior to fractionated radiation, respectively. The distal femur and proximal tibia in the right leg of each animal were exposed to a therapeutic X‐irradiation dose (25 Gy total in three fractions) with the contralateral left leg as the non‐irradiated control. Melatonin was administered intraperitoneally to the animals 30 min before radiation exposure. Six weeks after treatment, the rats were killed and the lower limbs disarticulated, skeletonized, radiographed, and bone growth was calculated based on measurement of the bone lengths. Fractionated radiation resulted in a mean percent overall limb growth loss of 41.2 ± 9.5 and a mean percent overall limb discrepancy of 11.2 ± 2.2. The administration of 5 or 15 mg/kg melatonin before each of the three fractions of radiotherapy reduced the mean percent overall limb growth loss to 33.9 ± 5.8 and 32.2 ± 4.5, respectively, and the mean percent overall limb discrepancy to 9.4 ± 1.6 and 8.9 ± 1.1, respectively; these values were significantly different compared with irradiation alone (range: P = 0.01–0.04). When compared with Group R, the growth arrest recovered by 5 or 15 mg/kg melatonin was 19.7 and 24.1% for the tibia, 7 and 18.6% for the femur, and 17.7 and 21.8% for the total limb, respectively. These results support further investigation of melatonin in combination with fractionation for potential use in growing children requiring radiotherapy to the extremity for malignant tumors.
Expression of β Chemokines in Explants and Trophoblasts from Early and Term Human Placentae
Authors: MOUSSA MARLÉNE , MOGNETTI BARBARA , DUBANCHET SYLVIE , MENU ELISABETH , CHAOUAT GÉRARD , MENU ELISABETH , BARRE‐SINOUSSI FRANÇOISE , MOGNETTI BARBARA , ROQUES PIERRE , DORMONT DOMINIQUE
Published: October 2003

PROBLEM: Implantation of human embryo requires expression of inflammatory cytokines and local attraction of T cells and natural killer (NK) cells. Chemokines are chemoattractants for these cells in classical inflammation. We speculated that they could also be involved in implantation.  METHOD OF STUDY: We assessed by enzyme‐linked immunosorbent assay (ELISA), reverse transcriptase‐polymerase chain reaction (RT‐PCR) and immunohistochemistry the presence of three classical β chemokines Macrophage Inflammatory Protein 1 (MIP1)α, MIP1β and Regulated upon activation, normal T cells expressed and secreted (RANTES) in cultures of placental villi or isolated trophoblasts derived from human first trimester and term placenta.  RESULTS: Explant culture assays were positive for these three chemokines, with important quantitative variations between individuals. Half of the highly purified trophoblasts cultures were found by ELISA and RT‐PCR to secrete in vitro MIP1α and MIP1β. RANTES was never detected by ELISA in trophoblasts cultures, albeit we could detect a low amount of messenger RNA. Immunohistochemistry experiments show that Hofbauer cells and the trophoblast layer are a secretion site of MIP1β in term placenta, and that cytotrophoblasts are able to secrete this chemokine in early placenta.  CONCLUSION: Human placenta is a site of secretion of chemokines that could be involved in establishment of pregnancy.
Autologous Endometrial Coculture in Patients with In Vitro‐Fertilization (IVF) Failure: Correlations of Outcome with Leukemia Inhibiting Factor (LIF) Production1
Authors: SPANDORFER S.D. , NAVARRO J. , LEVY D. , BLACK A.R. , LIU H.‐C. , VEECK L. , WITKIN S.S. , ROSENWAKS Z.
Published: October 2003

PROBLEM: To determine if LIF produced by autologous endometrial co‐culture (ECC) was associated with outcome in 46 patients with a history of multiple IVF failures.  METHOD OF STUDY: The conditioned media (CM) from ECC cells exposed or non‐exposed to human embryos was analyzed for LIF.  RESULTS: Exposure or non‐exposure to an embryo did not result in differing levels of LIF in the CM. LIF levels were significantly greater in the CM than in the serum controls (LIF was not found in the serum controls). Embryos grown on ECC demonstrated a significant improvement in number of blastomeres and fragmentation when compared to embryos grown in conventional media without ECC (6.7±1.3 vs. 5.6±1.2 blastomeres and 17.6%±9.3 vs. 26.4%±9.8 fragmentation; P<0.05). When LIF levels were detectable in the CM, the embryos grown in ECC were of improved quality as compared to the embryos grown only in conventional media and demonstrated a non‐significant increase in pregnancy rates (60 vs. 48%, P=0.50).  CONCLUSIONS: We have demonstrated a significant improvement in embryo quality with ECC. The cells in the ECC express LIF. The presence of LIF in the CM was associated with embryonic development and clinical pregnancy.
Protective Vaccination Against Genital Herpes Simplex Virus Type 2 (HSV‐2) Infection in Mice is Associated with a Rapid Induction of Local IFN‐γ‐Dependent RANTES Production Following a Vaginal Viral Challenge
Authors: HARANDI ALI M. , HOLMGREN JAN , ERIKSSON KRISTINA , SVENNERHOLM BO
Published: October 2003

PROBLEM: To investigate the production of the CC chemokines RANTES, MCP‐1, and MIP‐1α in the vaginal mucosa following HSV‐2 challenge in vaccinated and unvaccinated mice.  METHOD OF STUDY: The concentrations of the chemokines were determined in the vagina of HSV‐2‐vaccinated as well as unvaccinated mice after HSV‐2 challenge using a PERFEXT method combined with ELISA.  RESULTS: HSV‐2 infection did not induce any measurable levels of MIP‐1α, whereas high levels of RANTES and MCP‐1 were detected in unvaccinated animals at 48 hr post challenge. The vaccinated mice developed a more rapid induction of RANTES, but not of MCP‐1, appearing as early as 24 hr post challenge. The local induction of RANTES production was preceded by a vaginal IFN‐γ response. Furthermore, vaccinated IFN‐γ−/− mice did not produce any enhanced levels of RANTES following HSV‐2 challenge.  CONCLUSIONS: The protective immune response against genital HSV‐2 infection is associated with a rapid induction of local IFN‐γ‐dependent RANTES production.
Hydrodynamic Interactions Between Rolling Leukocytes In Vivo
Authors: KING MICHAEL R. , KIM MICHAEL B. , SARELIUS INGRID H. , HAMMER DANIEL A.
Published: October 2003

Objective: The aim of this study was to characterize the hydrodynamic interactions between rolling and free‐stream leukocytes in an in vivo model of selectin‐mediated rolling, and to identify those physical mechanisms that influence the dynamics of transient adhesion with the walls of postcapillary venules.

Methods: Postcapillary venules of diameter 22–37 µm in the cheek pouch of anesthetized hamsters were visualized using intravital microscopy, with selectin‐mediated rolling occurring in response to surgical preparation.

Results: Rolling velocity was found to be a strong function of the center‐to‐center separation with the nearest cell, and also was found to correlate strongly with the number of nearby cells. These effects are shown to be beyond that attributable to variations along the length of the vessel. Adherent leukocytes were observed to provide a nucleation site, precipitating further adhesion events of free‐stream cells.

Conclusions: The dynamics of the transient adhesion of leukocytes to the vessel wall in postcapillary venules is strongly dependent on the local concentration of adherent leukocytes, due to the complex hydrodynamics induced by their presence. The results are shown to agree well with theoretical considerations of the flow field induced by multiple nearby cells, suggesting a need for the future exploration of multicellular effects in the microcirculation.
Early Hepatic Microvascular Injury in Response to Acetaminophen Toxicity
Authors: ITO YOSHIYA , BETHEA NANCY W. , ABRIL EDWARD R. , MCCUSKEY ROBERT S.
Published: October 2003

Objective: The hepatic toxic response to acetaminophen (APAP) is characterized by centrilobular (CL) necrosis preceded by hepatic microvascular injury and congestion. The present study was conducted to examine changes in liver microcirculation after APAP dosing.

Methods: Male C57Bl/6 mice were treated with APAP (600 mg/kg body weight) by oral gavage. The livers of anesthetized mice were examined using established in vivo microscopic methods at 0, 0.5, 1, 2, 4, 6, 12 hours after APAP.

Results: The levels of hepatic transaminases (i.e., alanine aminotransferase [ALT] and aspartate transaminase) increased minimally for up to 2 hours. Thereafter, their levels were significantly and progressively increased. The numbers of swollen sinusoidal endothelial cells (SECs) in periportal regions were increased (3.5‐fold) from 0.5 to 6 hours, and those in CL regions were increased (4.0‐fold) at 0.5 and 1 hour. The intensity of in vivo staining for formaldehyde‐treated serum albumin, which is a specific ligand for SECs, was reduced from 2 to 12 hours. Erythrocytes infiltrated into the space of Disse as early as 2 hours, and the area occupied by these cells was markedly increased at 6 hours. Sinusoidal perfusion was reduced from 1 through 12 hours, with a nadir (35% decrease) at 4 and 6 hours. Phagocytic Kupffer cell activity was significantly elevated from 0.5 through 12 hours. Although gadolinium chloride minimized the changes in sinusoidal blood flow and reduced ALT levels 6 hours after APAP, it failed to inhibit endothelial swelling, extravasation of erythrocytes, and CL parenchymal necrosis.

Conclusions: These results confirm that APAP‐induced SEC injury precedes hepatocellular injury, supporting the hypothesis that SECs are an early and direct target for APAP toxicity. These findings also suggest that reduced sinusoidal perfusion and increased Kupffer cell activity contribute to the development of APAP‐induced liver injury.
Does menthol attenuate the effect of bupropion among African American smokers?
Authors: Okuyemi Kolawole S. , Ahluwalia Jasjit S. , Ebersole‐Robinson Maiko , Catley Delwyn , Mayo Matthew S. , Resnicow Ken
Published: October 2003

Background  African Americans have higher tobacco‐related morbidity and mortality and are more likely to smoke menthol cigarettes than their white counterparts. This study examined differences between African American menthol and non‐menthol smokers in smoking characteristics and cessation.

Methods  The study sample consisted of 600 African American smokers enrolled in a clinical trial that assessed the efficacy of sustained‐release bupropion for smoking cessation. Menthol (n = 471) and non‐menthol (n = 129) smokers were compared on smoking‐related characteristics and abstinence rates at 6 weeks and 6 months.

Results  Menthol smokers were younger (41.2 versus 52.9 years), more likely to be female (73.7% versus 56.6%) and more likely to smoke their first cigarette within 30 minutes of waking up (81.7% versus 69.8%) compared to non‐menthol smokers (all P < 0.01). Cigarette taste (50% versus 40%, P = 0.054) was rated non‐significantly higher by menthol smokers. Seven‐day point‐prevalence abstinence from smoking at 6 weeks were 28% and 42% (P = 0.006) and at 6 months were 21% and 27% (P = 0.21) for menthol and non‐menthol smokers, respectively. At 6 weeks follow‐up, stepwise logistic regression revealed that among those younger than 50 years, non‐menthol smokers were more likely to quit smoking (odds ratio = 2.0; 95% CI = 1.03–3.95) as were those who received bupropion (odds ratio = 2.12; 95% CI = 1.32–3.39).

Conclusion  African American menthol smokers had lower smoking cessation rates after 6 weeks of treatment with bupropion‐SR, thereby putting menthol smokers at greater risk from the health effects of smoking. Lower overall cessation rates among African Americans menthol smokers may partially explain ethnic differences in smoking‐related disease risks.
Changes in alcohol consumption following a reduction in the price of spirits: a natural experiment in Switzerland
Authors: Heeb Jean‐Luc , Gmel Gerhard , Zurbrügg Christoph , Kuo Meichun , Rehm Jürgen
Published: October 2003

Aims  To discover what changes in alcohol consumption had occurred in subgroups defined by age, sex, volume of drinking and drinking occasions, following a reduction in the price of spirits in Switzerland in July 1999.

Design  Quasi‐experimental. Longitudinal general‐population survey with baseline 3 months before and follow‐up 3 months after price change.

Participants  Probabilistic telephone sample of 1347 individuals with at least monthly consumption on average in the previous 6 months at both interviews. The response rate at baseline was 74,8% and the attrition rate from baseline to follow‐up 20.2%.

Measurements  Alcohol consumption was assessed by means of a beverage‐specific graduated‐frequency measure. High volume of drinking was defined as 40 + g/day for men and 20 + g/day for women. Binge drinking was defined as six + drinks on an occasion for men and four + drinks for women.

Findings  Spirits consumption increased significantly (by 28.6%) in the total sample, and specifically in young males and in individuals who were low‐volume drinkers at baseline. Consumption of alcohol overall, or of wine or beer, did not change significantly. No indication of effects of substitution was found.

Conclusions  Spirits consumption showed price‐responsiveness in the early postintervention period. This finding is of particular interest, as (a) the increase in spirits consumption took place at a time of generally declining consumption of alcohol in Switzerland; and (b) in contrast to the findings of most studies, the intervention, namely price reduction, increased availability.
Smoking reduction promotes smoking cessation: results from a double blind, randomized, placebo‐controlled trial of nicotine gum with 2‐year follow‐up
Authors: Wennike Poul , Danielsson Tobias , Landfeldt Björn , Westin Åke , Tønnesen Philip
Published: October 2003

Aim  To test the effect of nicotine gum and placebo in smokers not motivated or not able to quit smoking with regard to smoking reduction and smoking cessation.

Design  This randomized study evaluated nicotine gum versus placebo for up to 1 year in 411 healthy smokers highly motivated to reduce cigarette use. Smoking reduction was defined as self‐reported daily smoking less than 50% of baseline and any decrease (1 p.p.m. or more) in carbon monoxide.

Setting  Pulmonary department, Copenhagen, Denmark.

Findings  The overall success rate for sustained smoking reduction was significantly higher at all time‐points for active versus placebo gum (6.3% versus 0.5% after 24 months). Nicotine gum achieved significantly higher point prevalence cessation rates than placebo at 12 and 24 months [11.2% versus 3.9% (odds ratio = 3.1; 95% CI, 1.4–7.2 and 9.3% versus 3.4% (odds ratio = 2.9; 95% CI, 1.2–7.1), respectively]. There was a linear relationship between decrease in number of daily cigarettes and decrease in plasma cotinine, exhaled carbon monoxide and plasma thiocyanate, with significantly greater reduction in the nicotine gum group after 4 and 12 months (maximum treatment duration) but not after 24 months. The decrease in toxin intake was smaller than the decline in daily cigarette consumption, suggesting that compensatory smoking occurred.

Conclusions  Nicotine gum promoted cessation in this population of smokers unwilling to quit. Among reducers, the toxin intake correlated with reduced cigarette consumption although some compensatory smoking occurred.
Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine
Authors: GLEITER C. H. , FREUDENTHALER S. , DELABAR U. , ECKARDT K. U. , MÜHLBAUER B. , GUNDERT‐REMY U. , OSSWALD H.
Published: October 2003

1This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750 ml.

2Healthy male nonsmokers received i.v. in a parallel, randomized, single‐blind trial theophylline (loading dose 5 mg kg−1 over 20 min, followed by 0.5 mg kg−1 min−1), dipyridamole (0.21 mg kg−1 h−1) or placebo (0.9% NaCl) for 6 h following the phlebotomy. EPO concentrations were followed up to 72 h after phlebotomy.

3Following blood loss EPO concentrations increased during all treatments. The AUCEPO (0,72 h) were not statistically significantly different (theophylline: 398±30, dipyridamole: 301±15, placebo: 332±57 [mu ml−1 h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activitiy was significantly increased during theophylline infusion.

4In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.
Pharmacokinetics of inhaled drugs
Authors: LIPWORTH BRIAN J.
Published: October 2003

1A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively low levels of systemic absorption.

2Pharmacokinetic evaluation of drug absorption from the lungs provides an accurate and reproducible method for comparing different inhaler delivery systems, as well as for evaluating bioequivalence of generic drug formulations.

3The measurement of drug absorption from the lungs may also be applied to assess the effects of inhalation technique on drug delivery in vivo. For example with salbutamol delivered via a large volume spacer, lung bioavailability has been shown to be altered by factors such as the number of actuated puffs, inhalation‐actuation delay and washing procedure.

4Differences in drug delivery to the lungs between dry powder reservoir and pressurised metered‐dose aerosol devices translate directly into commensurate differences in clinical efficacy for delivery of both inhaled β2‐adrenoceptor agonists and corticosteroids.

5For inhaled corticosteroids, pharmacokinetic evaluation using oral charcoal to obviate alimentary absorption may be applied to quantify the relative gut and lung components of systemic bioavailability. In tandem with information on receptor potency and affinity, drug elimination and distribution, these data may help in part to explain observed differences between different inhaled corticosteroids in terms of their systemic bioactivity profiles.

6Studies are required to evaluate whether pharmacokinetic evaluation of lung absorption is a suitable way of quantifying delivery of nebulised aminoglycoside antibiotics, as for example in patients with cystic fibrosis.

7Pharmacokinetic evaluation appears to have an established role in the quantification of drug delivery to the lungs and provides important information which is complimentary to other techniques such as radiolabelled deposition. The next decade of research into pharmacokinetics of established and novel drugs and delivery systems is awaited with keen interest, and will hopefully provide a greater understanding into ways of optimising the benefit‐risk ratio for inhaled drugs.
Pharmacokinetics of the individual enantiomers of vigabatrin in neonates with uncontrolled seizures
Authors: VAUZELLE‐KERVROËDAN F. , REY E. , PONS G. , D'ATHIS Ph. , CHIRON C. , DULAC O. , DUMAS C. , OLIVE G.
Published: October 2003

The antiepileptic drug vigabatrin (VGB) is a selective irreversible inhibitor of GABA‐transaminase. It is administered as a racemic R(−), S(+) mixture, but the pharmacological activity of vigabatrin resides in the S(+) enantiomer and the R(−) enantiomer is inactive. The pharmacokinetic parameters of the two enantiomers have been studied after administration of a single oral 125 mg dose of the racemate to six neonates. The mean values of Cmax and AUC of the S(+) enantiomer were significantly lower (Cmax : 14.0±4.3 mg l−1; AUC: 143±44 mg l−1 h) than those of the R(−) enantiomer (Cmax: 34.1±9.5 mg l−1; AUC: 231±88 mg l−1 h), whereas no significant difference in the time to reach Cmax (S(+): 2.1±1.1 h; R(−): 2.2±1 h) was observed between the two enantiomers. During chronic administration (125 mg twice daily over 4 days), there was no evidence of accumulation of either enantiomer.
Limited value of the urinary phenytoin metabolic ratio for the assessment of cytochrome P4502C9 activity in vivo
Authors: TASSANEEYAKUL WICHITTRA , BIRKETT DONALD J. , PASS MICHAEL C. , MINERS JOHN O.
Published: October 2003

Relationships between the ratio of p‐hydroxyphenytoin (p‐HPPH), the major metabolite of phenytoin, to unchanged phenytoin excreted in urine (the urinary metabolic ratio or MR) were compared with a number of indices of the metabolic clearances of phenytoin and tolbutamide published previously for seventeen subjects separately administered these known cytochrome P4502C9 (CYP2C9) substrates. Significant correlations (rs=0.50–0.60, P<0.05) were observed between the phenytoin MR, derived from either 0–24 or 24–48 h urine collections, and inverse areas under the plasma unbound concentration‐time curves (measured over various time intervals) of phenytoin and with plasma unbound tolbutamide clearance. Significant correlations (rs =0.59–0.74) were also observed between the phenytoin MRs and metabolic unbound clearances for p‐hydroxyphenytoin formation. Despite the significant correlations, variability in tolbutamide and phenytoin metabolic clearance parameters tended to account for <50% of the variability in phenytoin MR. Correlations between the renal clearance of phenytoin and the phenytoin MRs suggest that variability in the renal clearance of unchanged drug limits the usefulness of the phenytoin MR for the investigation of factors influencing CYP2C9 activity in vivo.
A comparison of the post‐marketing safety of four selective serotonin re‐uptake inhibitors including the investigation of symptoms occurring on withdrawal
Authors: PRICE JOHN S. , WALLER PATRICK C. , WOOD SUSAN M. , MACKAY ANGUS V. P.
Published: October 2003

1We have addressed the question of whether there is a ‘serotonin withdrawal syndrome’ by analysis of spontaneous reports of suspected adverse drug reactions (ADRs) associated with four SSRIs. A comparison of the post‐marketing safety profiles of the four SSRIs has also been made.

2The UK database of ADRs was examined for reactions associated with fluoxetine, fluvoxamine, paroxetine and sertraline. The safety profiles of the four SSRIs were similar. However, withdrawal reactions with paroxetine constitute a greater proportion of reports (5.1%) than with the other SSRIs (0.06–0.9%). They have been reported more often with paroxetine (0.3 reports per thousand prescriptions) than with sertraline and fluvoxamine (0.03), and least often with fluoxetine (0.002).

3Descriptions of withdrawal reactions received and further details of 217 reports of withdrawal reaction with paroxetine obtained by mailing a questionnaire to the reporting doctor were examined. Withdrawal symptoms were diverse but most commonly comprised dizziness, paraesthesia, tremor, anxiety, nausea and palpitation. They usually occurred after 2 days and lasted for an average of 10 days. There was no evidence of a physical drug dependency syndrome.

4Symptoms different from the previous depressive illness occur after discontinuing an SSRI, and are reported most often with paroxetine. Paroxetine is the most pharmacologically specific of the SSRIs, but it is not clear whether the reactions constitute a ‘serotonin withdrawal syndrome’.
Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women
Authors: WALLE T. , FAGAN T. C. , WALLE U. K. , TOPMILLER M. J.
Published: October 2003

1 The metabolism of a single 80 mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE2) or in combination with norethindrone (OC).

2 Whereas the total clearance of propranolol (2713±404 ml min−1 (mean±s.e.mean)) was not significantly altered by either EE2 (3365±347 ml min−1) or the combined OC (2905±345 ml min−1), significant changes in all three primary metabolic pathways were observed.

3 The clearance through side‐chain oxidation decreased from 345±55 ml min−1 to 262±33 ml min−1 after EE2 (P<0.05). A similar reduction of cytochrome P450 metabolism by EE2 has been observed for other drugs.

4 The clearance through glucuronidation increased from 364±61 ml min−1 to 625±117 ml min−1 after EE2 (P<0.01). Similar stimulation of glucuronic acid conjugation by EE2 has also been observed for other drugs.

5 The clearance through ring oxidation increased from 697±109 ml min−1 to 1280±162 ml min−1 after EE2 (P<0.01). This observation appears to be a novel finding with EE2 and cytochrome P450 metabolism.

6 The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE2.
Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers
Authors: DEMOLIS J.‐L. , CHARRANSOL A. , FUNCK‐BRENTANO C. , JAILLON P.
Published: October 2003

1Sparfloxacin, a new fluoroquinolone, slightly increases the duration of the QT interval. Reverse rate‐dependence of QT interval prolongation has been shown for many agents that are known to prolong QT interval duration, and QT prolongation at slow heart rates may be a risk factor for torsades de pointes.

2A double‐blind, randomized, placebo controlled, crossover study was performed in 15 healthy volunteers to determine the effects of single oral doses of sparfloxacin (200 and 400 mg) on the QT interval at various heart rates.

312‐lead ECGs were recorded at rest and during exercise tests 5 h after sparfloxacin or placebo administration. QT intervals were calculated at predetermined RR intervals (1000, 800, 700, 600, 500 and 400 ms) after individual QT‐RR curve fitting.

4Sparfloxacin at both doses induced prolongation of the QT interval which was around 4% greater than placebo. No significant reverse rate‐dependence of QT interval prolongation was observed.

5Oral administration of sparfloxacin appears unlikely to be associated with marked QT interval prolongation.
Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes
Authors: ZOMORODI K. , HOUSTON J. B.
Published: October 2003

1The metabolism of diazepam to its primary metabolites 3‐hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a Vmax /Kmratio of 0.50–7.26 μl min−1 mg −1 protein.

2Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a Ki of 201±89 μm was obtained for the 3HDZ pathway (Km/Ki ratio of 3.0±0.9).

3Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar Kis of 121±45 and 188±73 μm respectively (Km/Ki ratios of 5.2±2.3 and 3.3±1.5 respectively).

4These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam‐omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.
Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients
Authors: GIACCONE M. , BARTOLI A. , GATTI G. , MARCHISELLI R. , PISANI F. , LATELLA M.A. , PERUCCA E.
Published: October 2003

1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine.

2Compared with controls, epileptic patients showed markedly shorter ethosuximide half‐lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., P<0.001) and higher apparent oral clearance (CL/F) values (15.3±3.8 vs 9.2±1.9 ml kg−1 h−1, P<0.001). The apparent volume of distribution (V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1 l kg−1, P<0.05).

3These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity.

4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.
Pathophysiology of asthma
Authors: BARNES PETER J.
Published: October 2003

1Our understanding of asthma and its therapy has changed markedly over the last few years, particularly with the application of molecular and cell biology and the discovery of new and more specific pharmacological tools.

2Many inflammatory cells participate in the inflammatory process in asthma and mediate a complex mixture of mediators. Cytokines are of particular importance as mediators of chronic inflammation and the means by which cytokines amplify and perpetuate the inflammatory process is now emerging. Airway epithelial cells may be a particularly important source of cytokines and other mediators, such as nitric oxide and endothelin, and may be a major target cell for inhaled steroids, which are the most effective therapy for asthma currently available.

3The inflammatory process in asthma results not only in bronchoconstriction, but also plasma exudation, the activation of neural mechanisms, mucus secretion. The chronic inflammation may lead to structural changes, including an increase in airway smooth muscle and fibrosis, that are essentially irreversible. There is increasing evidence that transcription factors, such as NF‐κB, play a pivotal role in the expression of inflammatory genes in asthma and may be the major molecular target for glucocorticoids.
Racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration
Authors: SOWINSKI KEVIN M. , LIMA JOHN J. , BURLEW BRAD S. , MASSIE JAMES D. , JOHNSON JULIE A.
Published: October 2003

1Racial differences in propranolol enantiomer kinetics following oral dosing were previously documented in our laboratory. The purpose of this study was to more completely describe propranolol kinetics in black and white subjects with the goal of gaining a better understanding of the mechanism(s) responsible for racial differences in oral propranolol kinetics.

2Twelve white and 13 black healthy males were included in the study. Poor metabolizers of dextromethorphan and mephenytoin were excluded. Subjects took oral propranolol 80 mg every 8 h for 16 doses and received an intravenous dose of radiolabelled propranolol with the 16th dose. Serum and urine samples were collected for 24 h after the 16th dose. Serum concentrations of R‐ and S‐propranolol and urine concentrations of its three primary metabolites were determined by h.p.l.c.

3Apparent oral clearances of R‐ and S‐propranolol were higher (P<0.05) in blacks than whites (R‐propranolol: 5036±4175 ml min−1vs 2854±879 ml min−1; S‐propranolol 3255±1723 ml min−1vs 2125±510 ml min−1; blacks vs whites).

4R‐ and S‐propranolol clearances were higher in blacks than whites (R‐propranolol 1069±316 ml min−1vs 841±161 ml min−1; S‐propranolol 947±271 ml min−1vs 771±142 ml min−1; blacks vs whites, P<0.05).

5There were trends (P >0.05<0.10) toward higher side chain oxidation, 4‐hydroxylation and R‐propranolol glucuronidation in blacks compared with whites. Ethnic differences in the enantiomeric ratios of partial metabolic clearance values were not observed.

6We conclude the higher propranolol oral clearances in black subjects are explained by blacks having slightly higher hepatic metabolism via all three of its major metabolic pathways. Higher propranolol clearances among black subjects were also observed and we conclude this finding is explained largely by the higher hepatic metabolism, but also by slightly higher liver blood flow among black subjects.
Pharmacokinetics of bismuth and ranitidine following single doses of ranitidine bismuth citrate
Authors: KOCH K. M. , DAVIS I. M. , GOODING A. E. , YIN Y.
Published: October 2003

1The pharmacokinetics of bismuth and ranitidine derived from ranitidine bismuth citrate given in single oral doses ranging from 200 mg to 1600 mg were evaluated in healthy subjects.

2Bismuth was only minimally absorbed (<0.5% of the amount dosed) after administration of ranitidine bismuth citrate, and peak plasma concentrations never exceeded 33 ng ml−1 in any subject. Plasma concentrations and urinary recoveries of bismuth at doses up to and including 800 mg were relatively constant and not proportional to dose. Bismuth absorption was increased more than proportionally with the dose at 1600 mg.

3The pharmacokinetics of ranitidine after administration of ranitidine bismuth citrate were dose‐proportional and consistent with previous observations for ranitidine administered alone.

4Ranitidine bismuth citrate was well‐tolerated in single oral doses of up to 1600 mg.