bluuebunny/crossref_metadata_2025 huggingface dataset:
Intractable Eye Pain: Indication for Triptans
Authors: May A , Gamulescu MA , Bogdahn U , Lohmann CP
Published: March 2003

Management of pain is difficult in many eye diseases. Particularly in patients undergoing surgical procedures, postoperative intractable pain is a major concern and severely influences the patient's comfort. We present 13 patients (eight male, five female, mean age 36 years) in whom sumatriptan, a highly selective 5-HT1B/1D agonist that is normally used as a specific anti-migraine drug, was used for the treatment of pain following photorefractive keratectomy (PRK). In two patients both eyes were operated on different days, resulting in a total of 15 operated eyes. A positive clinical response was achieved in all patients. In particular, in four patients, who received a second dose prophylactically 4 h following the first dose and before the recurrence of pain, we achieved excellent efficacy and stable control of pain. Further controlled studies are needed to investigate the usefulness of 5-HT1B/1D agonists in painful eye conditions.
Spatial Contrast Sensitivity of Migraine Patients Without Aura
Authors: Benedek K , Tajti J , Janáky M , Vécsei L , Benedek G
Published: March 2003

Visual disturbances are frequent symptoms in migraine. Since there is a possibility of separate damage in the magno- or parvo-cellular visual pathway in migraine patients, we performed a study including the measurement of static and dynamic spatial contrast sensitivity on 15 patients suffering from migraine without aura under photopic and scotopic conditions. Fifteen healthy volunteers without primary headache served as controls. The results revealed a marked decrease in contrast sensitivity at low spatial frequencies in the migraine patients. Spatial contrast sensitivity demonstrated some lateralization, as the sensitivity to low spatial frequencies obtained through separate eyes showed significantly larger side-differences in migraine patients than in control subjects. These findings suggest that the mechanisms responsible for vision at low spatial frequencies are impaired in migraine patients. This might indicate impaired function of the magnocellular pathways in this condition.
Wilfred Harris' Early Description of Cluster Headache
Authors: Boes CJ , Capobianco DJ , Matharu MS , Goadsby PJ
Published: March 2003

Wilfred Harris was a London neurologist with a significant interest in the treatment of neuralgia. Harris' descriptions of what he called migrainous neuralgia were the first recorded of cluster headache in the English medical literature. He was probably one of the first to describe the cluster phenomenon itself and the effectiveness of ergotamine in treating acute attacks of cluster headache. His seminal contributions to the clinical and therapeutic spectrum of cluster headache are reviewed.
Tinted Spectacles and Visually Sensitive Migraine
Authors: Wilkins AJ , Patel R , Adjamian P , Evans BJW
Published: March 2003

A double-masked randomized controlled study with cross-over design compared the effectiveness of precision ophthalmic tints in the prevention of headache in migraine sufferers. Seventeen patients chose the colour of light that optimally reduced perceptual distortion of text and maximized clarity and comfort. They were later given glasses with spectral filters providing optimal colour under conventional white lighting ('optimal' tint) or glasses that provided a slightly different colour ('control' tint). The tints were supplied in random order, each for 6 weeks, separated by an interval of at least 2 weeks with no tints. Headache diaries showed that the frequency of headaches was marginally lower when the ‘optimal’ tint was worn, compared with the ‘control’. The trial extends to adults with migraine, the results of a previous double-masked study demonstrating, in children with reading difficulty, beneficial effects of precision tints in reducing symptom frequency. In the present study, however, the effects are suggestive rather than conclusive.
Hereditary Haemochromatosis in Two Cousins with Cluster Headache
Authors: Stovner LJ , Hagen K , Waage A , Bjerve KS
Published: March 2003

A 60-year-old woman with secondary chronic cluster headache had increased serum ferritin and serum transferrin saturation and was homozygous for the C282Y mutation in the HFE gene, which is indicative of hereditary haemochromatosis. Treatment with venesection that normalized her iron stores led to a radical improvement of her headache complaints that had been daily for several years. Later, the headache returned to some degree in spite of normal serum ferritin levels. Her cousin, a 33-year-old man who had had episodic cluster headache for several years, also had increased transferrin saturation and was compound heterozygous for two mutations, a genotype known to be associated with a slightly increased frequency of haemochromatosis. This is the first report of a headache disorder in a patient with hereditary haemochromatosis. The coexistence of the two disorders may be a mere coincidence, but the temporary improvement of headache from depletion of iron stores may indicate a causal relation, possibly mediated by iron deposits in pain-modulating centres in the brainstem.
Survey on the Use of Complementary and Alternative Medicine Among Patients with Headache Syndromes
Authors: von Peter S , Ting W , Scrivani S , Korkin E , Okvat H , Gross M , Oz C , Balmaceda C
Published: March 2003

The objective was to determine headache patients' knowledge, prevalence of use and perceived effectiveness of complementary and alternative medicine. Seventy-three patients with headache syndromes attending a head and neck pain clinic were interviewed using a standardized questionnaire. Alternative medical therapies were used by 85% of surveyed patients for the relief of their head pain. In 60%, the therapies were perceived to have a benefit. Almost 100% of the patients were familiar with one or more of the presented alternative treatments. Eighty-eight per cent perceived at least one of the complementary treatments to be an effective remedy for headache pain. Exposure to and interest in alternative treatments are common among patients with headache syndromes, despite the lack of scientific evidence of benefit and assessments of risks for many of the treatments. Neurologists and general physicians should be aware of the increasing role of alternative medicine in the healthcare system. There is still an urgent need for objective, integrative and critical research with regard to complementary and alternative medicine.
5-Hydroxytryptamine1B/1D and 5-Hydroxytryptamine1FReceptors Inhibit Capsaicin-Induced C-Fos Immunoreactivity Within Mouse Trigeminal Nucleus Caudalis
Authors: Mitsikostas DD , del Rio M Sanchez , Waeber C
Published: March 2003

In order to investigate the c-fos response within the trigeminal nucleus caudalis (Sp5C) after noxious meningeal stimulation, capsaicin (0.25, 0.5, 1 and 5 nmol) was administered intracisternally in urethane (1 g/kg) and α-chloralose (20 mg/kg) anaesthetized male mice. Capsaicin induced a robust and dose-dependent c-fos-like immunoreactivity ( c-fos LI) within Sp5C. C- fos LI was observed within laminae I and II of the entire brain stem from the area postrema to C2 level, being maximum at the decussatio pyramidum level. The area postrema, solitary tract, medullary and lateral reticular nuclei were also labelled. The 5-hydroxytryptamine1B/1D/1F receptor agonist sumatriptan (0.01, 0.1, 1 and 10 mg/kg), administered intraperitoneally 15 min before capsaicin stimulation (1 nmol), decreased the c-fos response within Sp5C, but not within solitary tract. The novel specific 5-hydroxytryptamine1F agonist LY 344864 (0.1 and 1 mg/kg, i.p.) significantly decreased the c-fos LI within the Sp5C as well. These findings suggest that intracisternally administered capsaicin activates the trigeminovascular system and that the pain neuro-transmission can be modulated by 5-hydroxytryptamine1B/1D/1F receptors in mice. Thus, the availability of this model in mice, taken together with the possibility of altering the expression of specific genes in this species, may help to investigate further the importance of distinct proteins in the neurotransmission of cephalic pain.
Migraine: Preventive Treatment
Authors: Silberstein SD , Goadsby PJ
Published: March 2003

Migraine is a common episodic headache disorder. A comprehensive headache treatment plan includes acute attack treatment to relieve pain and impairment and long-term preventive therapy to reduce attack frequency, severity, and duration. Circumstances that might warrant preventive treatment include: (i) migraine that significantly interferes with the patient's daily routine despite acute treatment; (ii) failure, contraindication to, or troublesome side-effects from acute medications; (iii) overuse of acute medications; (iv) special circumstances, such as hemiplegic migraine; (v) very frequent headaches (more than two a week); or (vi) patient preference. Start the drug at a low dose. Give each treatment an adequate trial. Avoid interfering, overused, and contraindicated drugs. Re-evaluate therapy. Be sure that a woman of childbearing potential is aware of any potential risks. Involve patients in their care to maximize compliance. Consider co-morbidity. Choose a drug based on its proven efficacy, the patient's preferences and headache profile, the drug's side-effects, and the presence or absence of coexisting or co-morbid disease. Drugs that have documented high efficacy and mild to moderate adverse events (AEs) include b-blockers, amitripty-line, and divalproex. Drugs that have lower documented efficacy and mild to moderate AEs include selective serotonin reuptake inhibitors (SSRIs), calcium channel antagonists, gabapentin, topiramate, riboflavin, and non-steroidal anti-inflammatory drugs.
Effects of Sumatriptan on Cerebral Blood Flow Under Normo- and Hypercapnia in Rats
Authors: Fukuda M , Suzuki N , Maruyama S , Dobashi K , Kitamura A , Sakai F
Published: March 2003

To investigate further the pharmacological mechanism of an anti-migraine drug, sumatriptan, a 5-HT1B/1D receptor agonist, we studied its effect on the cerebral circulation in seven anaesthetized rats, particularly during hypercapnia. After injection of 0.6 or 6.0 μg/kg sumatriptan succinate, no significant change in cerebral blood flow (CBF) was observed either in the striatum or in the parietal cortex. The increase in CBF both in the parietal cortex and the striatum during 5% CO2 inhalation was significantly less when sumatriptan succinate 6.0 μg/kg was injected. Sumatriptan appeared to have a vasoconstrictor effect on the relaxed vessels by CO2 inhalation. This mechanism might be attributable to vasoconstriction through activation of 5-HT1B receptors located in the vascular smooth muscle rather than 5-HT1B receptors in the vascular adventitia.
Reproducibility and Feasibility of Neurophysiological Assessment of the Sensory Trigeminal System for Future Application To Paroxysmal Headaches
Authors: van Vliet JA , Vein AA , le Cessie S , Ferrari MD , van Dijk JG
Published: March 2003

As the distribution of pain in primary headaches suggests involvement of the trigeminal sensory pathways, trigeminal somatosensory evoked potentials (TSEP) and blink reflexes (BR) may provide important information about their functional integrity. Functional differences between symptomatic and non-symptomatic sides and between measurements during and outside attacks may be particularly informative. These tests should therefore be reproducible and should require a suitable number of patients for future studies in patients with primary, paroxysmal headaches. We performed TSEP and BR twice in 22 healthy volunteers, in order to calculate sample sizes based on reproducibility data. This is, to our knowledge, the first study investigating the reproducibility of TSEP and BR measurements. Latencies of TSEP and BR are appropriate for future studies, as their reproducibility allows practical sample sizes (less than 25 subjects). Duration, amplitude and area parameters of the BR responses were less appropriate for longitudinal studies.
Familial Cyclic Vomiting Syndrome
Authors: Haan J , Kors EE , Ferrari MD
Published: March 2003

A family is described in which four members suffer from cycling vomiting syndrome (CVS), without additional symptoms. So far, only a few CVS families have been described in literature, and most patients belonging to these families had other symptoms in addition to CVS. We conclude that ‘pure’ CVS may also be a hereditary disorder. Its relation to migraine will be discussed.
The Effectiveness of Spinal Manipulation for the Treatment of Headache Disorders: A Systematic Review of Randomized Clinical Trials
Authors: Astin JA , Ernst E
Published: March 2003

To carry out a systematic review of the literature examining the effectiveness of spinal manipulation for the treatment of headache disorders, computerized literature searches were carried out in Medline, Embase, Amed and CISCOM. Studies were included only if they were randomized trials of (any type of) spinal manipulation for (any type of) headache in human patients in which spinal manipulation was compared either to no treatment, usual medical care, a ‘sham’ intervention, or to some other active treatment. Two investigators independently extracted data on study design, sample size and characteristics, type of intervention, type of control/comparison, direction and nature of the outcome(s). Methodological quality of the trials was also assessed using the Jadad scale. Eight trials were identified that met our inclusion criteria. Three examined tension-type headaches, three migraine, one ‘cervicogenic’ headache, and one ‘spondylogenic’ chronic headache. In two studies, patients receiving spinal manipulation showed comparable improvements in migraine and tension headaches compared to drug treatment. In the 4 studies employing some ‘sham’ interventions (e.g. laser light therapy), results were less conclusive with 2 studies showing a benefit for manipulation and 2 studies failing to find such an effect. Considerable methodological limitations were observed in most trials, the principal one being inadequate control for nonspecific (placebo) effects. Despite claims that spinal manipulation is an effective treatment for headache, the data available to date do not support such definitive conclusions. It is unclear to what extent the observed treatment effects can be explained by manipulation or by nonspecific factors (e.g. of personal attention, patient expectation). Whether manipulation produces any long-term changes in these conditions is also uncertain. Future studies should address these two crucial questions and overcome the methodological limitations of previous trials.
Determinants of Migraine-Specific Quality of Life
Authors: Santanello NC , Davies G , Allen C , Kramer M , Lipton R
Published: March 2003

This paper reports an analysis of two randomized controlled trials of rizatriptan, in which the 24-h Migraine Quality of Life Questionnaire© was used to assess migraine-specific quality of life in patients receiving acute treatment. The objective of the analysis was to determine which clinical effects of a migraine medication, as measured by traditional clinical trial endpoints, contribute to a better short-term health-related quality of life. The results demonstrate that patients who experience complete pain relief and are able to function at their normal ability within 2 h and experience no headache recurrence have the highest migraine-specific quality of life scores. Patients who were satisfied with medication at 2 h had higher migraine-specific quality of life scores than those who were not satisfied. In conclusion, migraine therapy that provides rapid, complete, and sustained pain relief, with restoration of functional ability, has the most beneficial impact on short-term health-related quality of life for migraineurs.
Ergot and Triptan Overuse in Austria - an Evaluation of Clinical Data and Cost
Authors: Lampl C , Buzath A , Yazdi K , Sandor PS
Published: March 2003

Austria is one of the countries, in which ergots are still the most commonly used acute anti- migraine drugs. Overuse and chronification is a clinical problem for ergots, but also for the recently developed triptans. In a retrospective study for the year 1999 we evaluated clinical data from all Austrian neurological hospitals including cost of withdrawal as well as the estimated cost for ergots and triptans on the pharmaceutical retail market. We identified a total of 96 patients that underwent withdrawal, all of whom because of ergot overuse, and some with considerable long-term side-effects. The cost of withdrawal (more than €300 000) together with direct cost of medication amounted to more than €1 million. In contrast, cost of medication for triptans was €2.8 million for the same year, without any cost for withdrawal. If only cost aspects were to be considered in the prescription of acute anti-migraine drugs, our data would suggest to choose ergots rather than triptans. However, as scientific evidence is clearly in favour of triptans, decision making for the prescribing clinicians is more complex and will primarily focus on optimizing patient care, but also depend on the respective socio-economic situation.
Efficacy and Tolerability in Migraine Prophylaxis of Flunarizine in Reduced Doses: A Comparison with Propranolol 160 Mg Daily
Authors: Diener HC , Matias-Guiu J , Hartung E , Pfaffenrath V , Ludin HP , Nappi G , de Beukelaar F ,   on behalf of the Study Group
Published: March 2003

This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d. = FLU 10 mg and 5 mg o.d. = FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events ( n = 58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol ( P< 0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol ( P< 0.001) and showed a trend for noninferiority of FLU5 and propranolol ( P = 0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.
The health log: developing a health monitoring tool for people with learning disabilities within a community support agency
Authors: Curtice Lisa , Long Linda
Published: March 2003

The health log developed by Sense Scotland is a confidential hand‐held record of personal health information. It aims to assist the individual with complex communication difficulties to achieve improvements in health and well‐being. A secondary aim is to provide good information for healthcare professionals. The present paper describes the development of the log as part of a process to identify and respond to health needs as an integral part of person‐centred planning within a community support agency. Changes to the log, training, and plans for sharing and disseminating information about health management have been developed in response to feedback from staff. There is a need to increase awareness of the shared responsibility to promote good health throughout the networks of support providers in the community, to develop health monitoring systems to share information between health and social care providers, and to exchange good practice.
Makaton peer tutoring evaluation: 10 years on
Authors: Hooper Helen , Walker Margaret
Published: March 2003

The present paper describes an audit of the work of 164 Makaton peer tutors working in 23 establishments in England, Scotland and Wales. Questionnaires were sent to managers, Makaton peer tutors and facilitators (i.e. day centre staff, speech and language therapists, and teachers). The purpose of this study was to examine the effect of the Makaton peer tutoring scheme on the communication skills of all those involved. In addition, information was obtained from all participants about how the scheme had affected them, and what they thought had contributed to its success or failure. Sixteen establishments reported that the scheme had not only contributed to an increase in communication and the effectiveness of interaction, but that it had also resulted in an increase in self‐esteem, confidence and assertiveness. Out of those establishments which had stopped using the Makaton peer tutoring scheme, the loss of the facilitator was the most common cause.
Attention deficit hyperactivity disorder and mild learning disabilities: a case study
Authors: Young Susan , Newland John
Published: March 2003

The pervasive use of ‘challenging behaviour’ as an explanatory concept has precluded the development of alternative ways of construing the actions of people with learning disabilities. Moreover, possession of a challenging behaviour label has facilitated the segregation of individuals into specialist service provision. The present case study illustrates how an inclusive account can be developed using concepts from mainstream psychological activity. The development of alternative accounts also has implications for the design of interventions. It is argued that the process of developing alternative accounts may ultimately result in the redundancy of ‘challenging behaviour’ as an explanatory concept.
Thermodynamic study of capillary pressure curves based on free energy minimization
Authors: Deng Y. , Lake L. W.
Published: March 2003

This paper presents a new method for pore level network simulation of the distribution of two immiscible phases in a permeable medium. The method requires that the Helmholtz free energy of the system — the medium and the two phases contained within the pore space — be a minimum at all saturation states. We describe the method here and show some typical results from a computer algorithm that implements it. The results include (i) an explanation of the ‘scanning’ behaviour of capillary pressure curves based wholly on the free energy minimization, (ii) predictions of capillary pressure at arbitrary wetting states, including negative capillary pressures, and (iii) illustrations of how the minimized free energy changes along the scanning curves. The method also predicts the known dependency of the capillary pressure on the pore size distribution and interfacial tension. The current work is restricted to two‐dimensional networks, but the free energy minimization appears to be generalizable to three dimensions and to more than two fluid phases. Moreover, functions generated through the minimization, specifically contact areas between the medium surface and the phases, appear to have applications predicting other multiphase petrophysical properties.
The geological methane budget at Continental Margins and its influence on climate change
Authors: Judd A. G. , Hovland M. , Dimitrov L. I. , García Gil S. , Jukes V.
Published: March 2003

Geological methane, generated by microbial decay and the thermogenic breakdown of organic matter, migrates towards the surface (seabed) to be trapped in reservoirs, sequestered by gas hydrates or escape through natural gas seeps or mud volcanoes (via ebullition). The total annual geological contribution to the atmosphere is estimated as 16–40 Terragrammes (Tg) methane; much of this natural flux is ‘fossil’ in origin. Emissions are affected by surface conditions (particularly the extent of ice sheets and permafrost), eustatic sea‐level and ocean bottom‐water temperatures. However, the different reservoirs and pathways are affected in different ways. Consequently, geological sources provide both positive and negative feedback to global warming and global cooling. Gas hydrates are not the only geological contributors to feedback. It is suggested that, together, these geological sources and reservoirs influence the direction and speed of global climate change, and constrain the extremes of climate.
The use and abuse of frying oil
Authors: McSavage J. , Trevisan S.
Published: March 2003

The quality of frying oil discarded by a sample of catering establishments was assessed using a rapid test method, which measures the free fatty acid (FFA) concentration. Results show that none of the establishments used an objective assessment method; a lack of consistency between establishments, and many discarding oil where the FFA levels were above the recommended safe level. Analysis of used oil samples demonstrated, that the use of subjective methods lead, in the majority of cases, either to the abuse or underuse of the frying agent. The use of a simple, convenient‐to‐use, objective measurement is recommended.
Current environmental issues: a study of Sinai and Red Sea hotels
Authors: Kattara H. S. , Zeid A. W.
Published: March 2003

Environmental issues are now a concern in many industries including the food service and hospitality industries. This paper examines environmental issues in hotels in the newly developed tourist areas of the Sinai and Red Sea. Various environmental issues were studied including environmental practices, managers attitudes towards environmental issues, future environmental practices and anticipated hotel profitability resulting from applying environmental practices. Results show an opportunity to promote environmental practices in hotels and a high level of awareness and willingness of managers to preserve the environment.
Invasibility and diversity of plant communities:from patterns to processes
Authors: Lavorel S. , Prieur‐Richard A.‐H. , Grigulis K.
Published: March 2003

Research on the function of biodiversity has stimulated a renewed interest in the mechanisms underlying the invasibility of plant communities. Conflicting results provide evidence that observational correlative studies are a dead end if isolated from manipulative experiments. Using two studies in France, Portugal and Australia we illustrate how invasion research can move from pattern observation to the investigation of processes.

Artificial annual communities representing a factorial combination of one to three functional groups and one to six species per group were sown in Montpellier. Natural invasibility of the plots from the seed bank showed no strong relationship with functional or species richness. The survival of individuals of two congeneric exotic species (Conyza canadensis and C. bonariensis) introduced as seedlings did not relate to these simple diversity indices. On the other hand, their adult biomass did with a decrease in vegetative performance with increasing species richness but a decrease with increasing number of functional groups. Survival and biomass of invaders were strongly influenced by the identity of the resident functional groups.

In a study of the mechanisms underlying the demographic success of the pasture weed Echium plantagineum in Australia, germinations in mixtures with varying numbers, densities, and identities of co‐germinants showed no evidence that increasing diversity increased the competitive effect. Rather, significant reduction of recruitment resulted from increased densities.

These examples suggest that patterns and mechan‐ isms of community invasibility are likely to be far more subtle than people have acknowledged so far. Controlled experiments coupled with theoretical work are required to advance our understanding.
Alpha diversity of lianas in a tropical evergreen forest in the Anamalais, Western Ghats, India
Authors: Muthuramkumar S. , Parthasarathy N.
Published: March 2003

Abstract. Species richness, abundance, size‐class distribution, climbing mode and spatial patterns of lianas were investigated in a 30‐ha permanent plot of tropical evergreen forest at Varagalaiar in the Anamalais, Western Ghats, India. Each hectare was subdivided into 10 m × 10 m quadrats, in which all lianas ≥ 1 cm d.b.h. were measured, tagged and identified. The total liana density was 11, 200 individuals (373 ha–1) and species richness was 75 species, representing 66 genera and 37 families. The richness estimators employed for species and family accumulation curves after 100 times randomization of sample order, have stabilized the curves at 16th and 15th hectares, respectively. A greater proportion of lianas was twiners (55% of species and 44.4% of density) and root climbers (5% of species and 14% of density), and a few were tendril climbers, reflecting the late successional stage of the forest. In the size‐class distribution, 82% of abundance and 97% of species richness fell within 1–3 cm diameter threshold. The dominance of succulent diaspore type signifies the faunal dependence of lianas on vertebrate frugivores for dispersal. The diversity, population density and family composition of lianas of our site is compared with those of other tropical forests. The need for biomonitoring of this synusia in the permanent plot for forest functioning is emphasized.
Place prioritization for biodiversity reserve network design: a comparison of the SITES and ResNet software packages for coverage and efficiency
Authors: Kelley Chris , Garson Justin , Aggarwal Anshu , Sarkar Sahotra
Published: March 2003

Abstract. The place prioritization problem in conservation biology is that of establishing a sequentially prioritized list of places on the basis of biodiversity content. Such a list can then be used to select reserve networks that are designed to be fully representative of the biodiversity of an area as efficiently as possible (for instance, with minimum area or cost). The usual goal is the representation of all chosen biodiversity surrogates up to or beyond a required target, or to the greatest available extent. The purpose of this paper is to compare the respective performances of two place prioritization software packages, SITES and ResNet, on four datasets (distributions of termite genera in Namibia, breeding bird species in the Falkland Islands/Islas Malvinas, vertebrate species in Texas and flora and fauna species that are at risk in Québec), to determine their respective merits. The two software packages implement radically different algorithms: SITES is based on a simulated annealing procedure for finding (local) optima; ResNet uses an algorithm based on rarity and complementarity. This analysis indicates that the rarity‐complementarity based algorithm of ResNet surpasses the simulated annealing approach of SITES with respect to time and completeness. SITES, however, contains other features that are useful in conservation planning. Ways in which the two packages can be used together effectively are suggested.
Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism
Authors: Vemulapalli Subbarao , Kurowski Stan
Published: March 2003

The contribution of NO‐cGMP dependent pathway to phentolamine mesylate‐evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency‐related relaxation that was significantly attenuated by L‐NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation‐induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose‐dependently enhanced electrical field stimulation‐induced relaxation of the rabbit corpus cavernosum. Prazosin (30 μM) and yohimbine (30 μM) failed to affect phentolamine mesylate‐mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of α‐adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L‐NAME significantly‐attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of α‐adrenergic receptor blockade.
Comparison of the contractile responses of human coronary bypass grafts and monkey arteries to human urotensin‐II
Authors: Paysant J. , Rupin A. , Simonet S. , Fabiani J. N. , Verbeuren T. J.
Published: March 2003

Human urotensin‐II (hU‐II) is a cyclic peptide recently cloned in humans and present in human cardiac tissue and human arteries. The effects of hU‐II were studied on human coronary bypass grafts in vitro. In three out of eight human mammary arteries, and two out of three human radial arteries, hU‐II caused contraction; human saphenous veins did not respond to hU‐II. When it exists, the contraction slowly develops and has a low‐to‐moderate intensity. All radial arteries obtained from young healthy non‐human primates contracted strongly to hU‐II.
Cooling‐induced gastrointestinal smooth muscle contractions in the rat
Authors: Mustafa Seham M. D. , Thulesius Olav
Published: March 2003

The aim of this study was to assess the effect of cooling on smooth muscle contraction in various parts of the gastrointestinal tract (esophagus, stomach, duodenum, jejunum and colon) and to investigate the basic mechanism underlying cooling‐induced (CIC) tonic and rhythmic contractions. Recordings of isometric tension from smooth muscle strips of different parts of the rat gastrointestinal tract were performed using organ‐bath techniques, and stepwise cooling was applied. Cooling was tested before and after the addition of various standard agents interfering with known neurogenic (autonomic blockers, tetrodotoxin, capsaicin) and myogenic mechanims of contraction (calcium channel blockers, Sarcoplasmatic and Ca2+‐ATPase pump inhibitors). Step‐wise cooling (37 °C to 5 °C) of all gastrointestinal smooth muscle preparations induced reproducible graded tonic contractions, inversely proportional to temperature. CIC was most pronounced in the jejunum. Cooling abolished rhythmic smooth muscle activity. CIC was not dependent on a neural mechanism nor the release of neurotransmitters, but linked to translocation of calcium. It was reduced by incubation in Ca2+‐free solution. Blockage of the Ca2+‐ATPase pump, which inhibits the extrusion of calcium, plays a significant role in the process and enhances CIC. Cooling of gastrointestinal smooth muscle preparations induces graded myogenic contractions inversely proportional to the temperature. The mechanism is not dependent on local nervous control but related to a temperature‐sensitive process of calcium translocation.
Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers
Authors: Baltes Eugène , Coupez René , Giezek Hilde , Voss Gudrun , Meyerhoff Carsten , Benedetti Margherita Strolin
Published: March 2003

The primary objective of the present study was to compare the absorption and disposition of levocetirizine, the eutomer of cetirizine, when administered alone (10 mg) or in presence of the distomer. An additional objective was also to investigate the configurational stability of levocetirizine in vivo in humans. The study was performed in a randomized, two‐way cross‐over, single‐dose design with a wash‐out phase of 7 days between the two periods. A total of 12 healthy male and 12 healthy female volunteers were included in the study. Bioequivalence can be concluded from the analysis of the pharmacokinetic parameters of levocetirizine when administered alone or as the racemate cetirizine. No chiral inversion occurs in humans when levocetirizine is administered, i.e. there is no formation of the distomer. When comparing the pharmacokinetic characteristics of levocetirizine and the distomer, the apparent volume of distribution of the eutomer is significantly smaller than that of the distomer (0.41 and 0.60 L/kg, respectively). For an H1‐antagonist a small distribution volume can be considered as a positive aspect, both in terms of efficacy and safety. Moreover the non‐renal clearance of levocetirizine is also significantly lower than that of the distomer (9.70 and 28.70 mL/min, respectively), which constitutes an additional positive aspect particularly as far as metabolism‐based drug interactions are concerned. The information collected in the present study on the pharmacokinetics of levocetirizine and the distomer provide additional reasons for eliminating the distomer and developing levocetirizine as an improvement on cetirizine.
Modulation of dopamine release in the guinea‐pig retina by Gi‐ but not by Gs‐ or Gq‐protein‐coupled receptors
Authors: Weber Bernd , Schlicker Eberhard
Published: March 2003

The modulation of dopamine release from the guinea‐pig retina was studied using maximally effective concentrations of 10 agonists acting on Gi‐, Gs‐ or Gq‐protein‐coupled receptors (PCRs). Retinal discs were preincubated with [3H]noradrenaline and superfused; tritium overflow was evoked electrically. The following compounds acting on Gi‐PCRs reduced the tritium overflow, which represents quasi‐physiological dopamine release under the experimental conditions of our study: the dopamine and α2‐adrenoceptor agonist B‐HT 920 by 95%, the muscarinic agonist oxotremorine by 96%, melatonin by 94%, the cannabinoid agonist WIN 55,212–2 by 71% and histamine by 66%. Tritium overflow was not affected by serotonin or by agonists acting on Gs‐PCRs (ACTH1‐24 and the β‐adrenoceptor agonist procaterol) and Gq‐PCRs (angiotensin II and bradykinin). The effects of B‐HT 920, oxotremorine and melatonin were studied in more detail using appropriate antagonists. The inhibitory effect of a submaximally active concentration of B‐HT 920 was counteracted by the dopamine D2/3 antagonist haloperidol but not affected by the α2‐adrenoceptor antagonist phentolamine. The muscarinic antagonist atropine shifted to the right the concentration‐response curve of oxotremorine (pA2 8.7) and the melatonin MT2 antagonist 4‐P‐PDOT produced a rightward shift of the concentration‐response curve of melatonin (pA2 10.6). Melatonin was also studied in superfused brain slices (from the guinea‐pig) preincubated with [3H]noradrenaline. The electrically evoked tritium overflow in cerebrocortical, hippocampal and hypothalamic slices (representing quasi‐physiological noradrenaline release) and in striatal slices (representing quasi‐physiological dopamine release) was not affected by melatonin at a concentration that causes the maximum effect in retinal discs. In conclusion, dopamine release in the guinea‐pig retina is inhibited via Gi‐PCRs including dopamine (D2/3), muscarinic and melatonin (MT2) receptors but not affected via any of the Gs‐ or Gq‐PCRs under study. Unlike in the retina, melatonin fails to inhibit monoamine release in four brain regions of the guinea‐pig.
Exposure of rat isolated stomach and rats in vivo to [14C]agmatine: accumulation in the stomach wall and distribution in various tissues
Authors: Molderings Gerhard J. , Heinen Anja , Menzel Sigrid , Göthert Manfred
Published: March 2003

The aims of the present study were: (i) to investigate the accumulation of radioactivity in the stomach wall after luminal exposure of the rat isolated stomach to[14C]agmatine and (ii) to determine the distribution of radioactivity in various tissues after oral administration of this radiolabelled polyamine to rats in vivo. In isolated rat stomach, [14C]agmatine was accumulated in part by an energy‐dependent uptake process that could be inhibited by phentolamine. These findings correspond to properties of the recently identified specific agmatine transporter in human glioma cells, suggesting that in rat stomach [14C]agmatine is taken up by such a carrier.

In in vivo experiments, rats received 0.5 μCi [14C]agmatine adsorbed to 5 g rat standard chow after a fasting period of 24 h. After oral ingestion of [14C]agmatine, radioactivity was recovered in all organs investigated as well as in blood and urine. Radioactivity also seemed to be secreted into the pancreaticobiliary fluid, as it was recovered in the luminal content of distal ileum and sigmoid colon. Accumulation of radioactivity in organs and distal gut luminal content was dose‐dependently decreased by simultaneous administration of putrescine.

In conclusion, the present data are compatible with the view that agmatine can be absorbed in rat at least from the stomach and probably also from the gut by means of an energy‐dependent agmatine transport mechanism. Agmatine itself and/or its degradation products, which also have the potential to be pharmacologically active, are unevenly distributed between the organs. Putative secretion of radioactivity into the pancreaticobiliary fluid suggests the potential for an enterohepatic circulation of agmatine. In view of the high intraluminal concentration of agmatine in the stomach and distal gut and the operation of an agmatine transporter, it is rather likely that agmatine in the chyme of the gut represents an important source for agmatine detected in the tissues of the organism.
Safety pharmacology in the nonclinical assessment of new medicinal products: definition, place, interest and difficulties
Authors: Claude Jean‐Roger
Published: March 2003

Until the year 2000 there was no internationally‐accepted definition for the terms used in nonclinical pharmacology (primary, secondary pharmacodynamics, discovery, safety pharmacology, etc). Now, after ICH5 (San Diego, November 2000), a harmonisation of the nomenclature is adopted: safety pharmacology is defined as the studies that investigate the potential undesirable pharmacodynamic effects of a medicinal product on physiological functions in relationship to exposure. Consequently, safety pharmacology studies are a part of the safety assessment for a new product, in the same way than toxicological studies, and a basic battery of tests (core battery) has to be conducted prior to the first administration to humans.

Safety pharmacology studies are of peculiar interest: they show a good predictive potential for humans, they do not require a large number of laboratory animals, long‐term studies, large amount of products and they are more dynamic and more flexible than toxicological studies. Nevertheless, many difficulties occur for the implementation in industry, related to practical and/or scientific problems: location of the studies, routine activity for the pharmacologists, sometimes difficulties in the relationship between toxicologists and pharmacologists, adaptation to the GLP requirements, elaboration of an early relevant scientific programme, necessity to go to contract‐labs or to academic research for unusual or for up to date methods, etc.

To conclude, a retrospective timetable of the regulatory evolution for the last 10 years will be provided, as an illustration of the worldwide progress in the concept of `harmonisation' for the assessment of new medicinal products.
Integration of safety pharmacology endpoints into toxicology studies
Authors: Luft Jörg , Bode Gerd
Published: March 2003

In the ILSI Human Toxicity Program, human toxicity was identified with 94% in studies of 1 month or less duration. Safety pharmacology studies and 1 month toxicity studies are prerequisites of INDs. These studies contributed in 69% to the predictivity of human toxicity. Correlating data from pharmacology and toxicology data will therefore enhance the predictivity of human toxicity. The ILSI Human Toxicity Program also showed that non‐rodent toxicology studies were more predictive of human toxicity than rodents. Consequently, the usage of non‐rodents, especially dogs, produces data more relevant to the safety of humans. Integration of data from safety pharmacology and pharmacological endpoints from integrated toxicology studies, which cover a wide dose range, allow data interpretation also concerning chronic effects. Differences in relation to chronic exposure and species specific pharmacodynamic effects can be taken into consideration. In vivo data in pharmacology are taken from a larger number of species. Usually, pharmacokinetic data and histopathology are often lacking in pharmacology (e.g. guinea pig). Studies in a smaller number of species, which are incorporating pharmacology, pharmacodynamic and toxicology, allow also crossinterpretation with data from clinical chemistry, haematology and histopathology. Endpoints relating to behaviour (functional observation battery/FOB) and cardiovascular toxicity can be integrated into regulatory toxicology. Technical progress in non‐invasive methodology and refined measurements for pharmacological parameters and standardization of study design allow the incorporation into regulatory toxicity studies today. The limitations of conducting pharmacological measurements in regulatory toxicology studies are acknowledged. Safety pharmacology studies should complement toxicity studies in terms of choice of species and dose regimen. Ethical usage of animals, especially dogs or monkeys, can only be justified in the future, when more clinically relevant data can be gained from fewer in vivo studies. Multidisciplinary co‐operation between pharmacology, pharmacokinetics and toxicology will lead to refinements and reduction of in‐vivo studies when functional parameters are integrated into regulatory studies.
Pharmacogenetics and personalised medicine
Authors: Kalow Werner
Published: March 2003

ABSTRACT The traditional concern of pharmacogenetics was Mendelian (monogenic) variation, which visibly affected some drug responses. Pharmacogenetics was broadened by the observation that multifactorial genetic influences, in conjunction with environmental factors, usually determine drug responses. Variability of gene expression, a new theme of the science of genetics, also affects pharmacogenetics; for example, enhanced enzyme activity does not necessarily indicate a mutation, but may be the consequence of a drug‐induced enhancement of gene expression. Methodological advances permit the conversion of pharmacogenetics into the broad practice of pharmacogenomics; this improves the possibility of identifying genetic causes of common diseases, which means establishing new drug targets, thereby stimulating the search for new drugs. While the main medical effect of pharmacogenetics was an improvement of drug safety, pharmacogenomics is hoped to improve drug efficacy. On the way to personalized medicine, we may stepwise improve the chances of choosing the right drug for a patient by categorizing patients into genetically definable classes that have similar drug effects (as, for example, human races, or any population group carrying a particular set of genes). It is wise to expect that, even after we have reached the goal to establish personalized medicine, we will not have eliminated all uncertainties.