bluuebunny/crossref_metadata_2025 huggingface dataset:
Representing the Lives of Women with Learning Difficulties: Ethical Dilemmas in the Research Process
Authors: Brigham Lindsay
Published: August 2009

This paper describes a small scale project, carried out in 1995 in North Tyneside Further Education College, with a group of five young women with learning difficulties, between the ages of 18 and 20. The aim of the project was to create a women‐only ‘space’ within the college context, and to use a combination of strategies, i.e. group discussions, one to one interviews and art work, to enable these young women to articulate their personal life stories, present concerns and aspirations for the future. The outcome of the project was the collective production of a booklet; a record of the conversations, discussions and art work produced over a six‐week period (Brigham, 1995). The aim of this paper is to engage in a retrospective reflection upon the ethical dilemmas embedded in the research process and the tensions inherent in representing the lives of these young women.
Words and Numbers
Authors: Dumbleton Paul
Published: August 2009

People currently described as having disabilities have not always been described or construed in this way. Debates about, and changes in, terminology characterise professional debates in this field and are important to the self advocacy movement. This paper explores the grammar of terminology, and links it to the concerns of professionals in their attempts to describe and classify people. It traces the narrowing of the focus of attention from the whole person, to an aspect of the person — the mind, intelligence or the facility for learning. Finally, it questions whether these changes are as progressive as is often assumed.
Participation in Research by People with Learning Disability: Origins and Issues
Authors: Kiernan Chris
Published: August 2009

‘Traditional’ research with people with learning disability is very much research on rather than research with people. New models or paradigms of research place the ‘subjects’ of research in control of the research process as ‘co‐researchers’. Applying new paradigms to research with people with learning disability yields benefits, but there are a number of limitations, both practical and theoretical, which limit their value. The editorial seeks to outline the main ideas behind ‘new paradigm’ research, and to introduce some of the issues which it raises for research with people with learning disability.
Satisfaction for All: A Framework for Assessing Life Satisfaction for All People with Learning Disabilities
Authors: Money Delia , Collins Graham
Published: August 2009

Most services for people with learning disabilities are accessed by service users with varying learning disabilities and communication needs. This article presents a framework for assessing life satisfaction for all people with learning disabilities. The framework is designed to be an all‐inclusive service evaluation strategy, which embraces all service users, regardless of their abilities. It is a practical tool, for inter‐disciplinary use, providing a starting point for service development. The survey is broadly divided into three sections, dependent on service user communication skills. These sections are described and examples discussed. The article concludes with future implications and recommendations for surveying the life satisfaction of people with learning disabilities.
A Comparative Review of Primary Health Care Models for People with Learning Disabilities: Towards the Provision of Seamless Health Care
Authors: Martin David M. , Roy Ashok
Published: August 2009

The various health care needs of people with learning disabilities continue to present major challenges to providers of primary health care. At the same time there is a growing body of evidence which demonstrates that the health needs of people with learning disabilities can be well met by offering full health checks. This review looks at the way in which (in recent years) various providers of primary and specialist services have attempted to meet the primary health care needs of the client group. The benefits of a number of models of pro‐active primary health care are scrutinised. User and carer involvement (inclusion), specialist health service involvement, accessibility, comprehensiveness and effectiveness are compared and contrasted.
A Right to Sexuality?
Authors: Lesseliers Joan
Published: August 2009

In discourses on the sexuality of people with learning disabilities, there is one voice that goes unheard: that of people with learning disabilities themselves. Hence the motivation for the study described here. The author went to ask people with learning disabilities to enquire about the way they perceive their relationships and their sexuality, what they think of these topics and what is important to them in this respect. There is one major constant in all this information: that the circumstances of people's lives shape their perceptions of sexuality and relationships. Many service facilities have too many structural and organisational problems to allow relationships between service users, let alone value them. Professionals should be creative in finding ways to minimise the structural pressures exerted by the service facilities on the personal needs and wishes of people with learning disabilities.
Sex Therapy in a Couple with Learning Disabilities
Authors: Bell Dorothy M. , Toplis Laura , Espie Colin A.
Published: August 2009

Despite greater emphasis in the last decade on sex education programmes for young people who have learning disabilities, there are few reports of sexual counselling or sex therapy. This case study discusses a married couple who had been married for seven months and who had been together for the previous year. Sexual intercourse had only been achieved on two occasions. This was too low in frequency for both partners. No other problems, such as lack of time in foreplay or insufficient enjoyment of the act itself was mentioned, at this time, by either partner. On the two occasions of sexual intercourse, both partners stated that they had reached orgasm. There were no indications of any difficulties in either partner's sexual history (such as abuse), and their knowledge of sexual matters met the standards of routine education packages for people with learning disabilities. A number of standard measures were amended and used to assess current functioning and to chart progress. For treatment, an approach in two phases was used.
Validation Study of Genetic Associations with Coronary Artery Disease on Chromosome 3q13‐21 and Potential Effect Modification by Smoking
Authors: Horne Benjamin D. , Hauser Elizabeth R. , Wang Liyong , Muhlestein Joseph B. , Anderson Jeffrey L. , Carlquist John F. , Shah Svati H. , Kraus William E.
Published: August 2009

The CATHGEN study reported associations of chromosome 3q13‐21 genes (KALRN, MYLK, CDGAP, and GATA2) with early‐onset coronary artery disease (CAD). This study attempted to independently validate those associations. Eleven single nucleotide polymorphisms (SNPs) were examined (rs10934490, rs16834817, rs6810298, rs9289231, rs12637456, rs1444768, rs1444754, rs4234218, rs2335052, rs3803, rs2713604) in patients (N = 1618) from the Intermountain Heart Collaborative Study (IHCS). Given the higher smoking prevalence in CATHGEN than IHCS (41% vs. 11% in controls, 74% vs. 29% in cases), smoking stratification and genotype‐smoking interactions were evaluated. Suggestive association was found for GATA2 (rs2713604, p = 0.057, OR = 1.2). Among smokers, associations were found in CDGAP (rs10934490, p = 0.019, OR = 1.6) and KALRN (rs12637456, p = 0.011, OR = 2.0) and suggestive association was found in MYLK (rs16834871, p = 0.051, OR = 1.8, adjusting for gender). No SNP association was found among non‐smokers, but smoking/SNP interactions were detected for CDGAP (rs10934491, p = 0.017) and KALRN (rs12637456, p = 0.010). Similar differences in SNP effects by smoking status were observed on re‐analysis of CATHGEN. CAD associations were suggestive for GATA2 and among smokers significant post hoc associations were found in KALRN, MYLK, and CDGAP. Genetic risk conferred by some of these genes may be modified by smoking. Future CAD association studies of these and other genes should evaluate effect modification by smoking.
Chronic antiepileptic monotherapy, bone metabolism, and body composition in non‐institutionalized children
Authors: RAUCHENZAUNER MARKUS , GRIESMACHER ANDREA , TATARCZYK TOBIAS , HABERLANDT EDDA , STRASAK ALEXANDER , ZIMMERHACKL LOTHAR‐BERND , FALKENSAMMER GERDA , LUEF GERHARD , HÖGLER WOLFGANG
Published: August 2009

Aim  The aim of this study was to determine the influence of chronic monotherapy with antiepileptic drugs (AEDs) on vitamin D levels, bone metabolism, and body composition.

Method  Eighty‐five children (38 males, 47 females; mean age 12y 5mo, SD 3y 4mo) were treated with valproate and 40 children (28 males, 12 females; mean age 11y 10mo, SD 3y) were treated with other AEDs (lamotrigine, sulthiame, or oxcarbazepine), comprising the non‐valproate group. Forty‐one healthy children (29 males 12 females; mean age 12y 1mo, SD 3y 5mo) served as a comparison group. Height, weight, body impedance analysis, 25‐hydroxyvitamin D, calcium, phosphate, two bone resorption markers (receptor activator of nuclear factor κB ligand [RANKL] and tartrate‐resistant acid phosphatase 5b [TRAP5b]), osteoprotegerin, and leptin were measured.

Results  No child was vitamin D deficient as defined by a 25‐hydroxyvitamin D (25OHD) level of less than 25nmol/l (<10ng/ml). Leptin, body fat, weight standard deviation score (SDS), and body mass index (BMI) SDS were all significantly higher (each p<0.001) in valproate‐treated children than in the non‐valproate group, as were calcium (p=0.027) and RANKL (p=0.007) concentrations. Similarly, leptin was significantly higher in the valproate group than in control participants (p<0.001), as were body fat (p=0.023), weight SDS (p=0.046), BMI SDS (p=0.047), calcium (p<0.001), and RANKL (p<0.001), whereas TRAP5b concentrations were significantly lower in the valproate‐treated group (p=0.002). Furthermore, calcium and RANKL levels were significantly higher in the non‐valproate group than in comparison participants (p<0.001 and p=0.016 respectively).

Interpretation  Non‐enzyme‐inducing or minimal enzyme‐inducing AED monotherapy does not cause vitamin D deficiency in otherwise healthy children with epilepsy. Valproate therapy is associated with increases in weight, body fat, and leptin concentration, as well as with a bone metabolic profile that resembles slightly increased parathyroid hormone action.
EFFECT OF CLONIDINE ON ADRENAL MEDULLA CATECHOLAMINE LEVELS IN RATS
Authors: GAILLARD G. , TRAN M.A. , ROSTIN M. , SALVAYRE R. , MONTASTRUC J.L.
Published: August 2009

Summary— The effects of clonidine on adrenal medulla catecholamines levels were studied in normotensive rats. Intraperitoneal injections (50, 100 μ/kg) of clonidine caused a dose‐dependent decrease in adrenaline content of the gland. This effect was suppressed by denervation of the adrenal medulla, i.e. unilateral section of splanchnic fibers performed 5 days before. These results demonstrate that clonidine decreases the catecholamine content of the adrenal medulla only through a central action. They suggest that the adrenal medulla is involved in the hypotensive effect of clonidine.
EFFECT OF SIZE AND DOSAGE STRENGTH ON THE BIOVAILABILITY OF TWO DILTIAZEM FORMULATIONS DURING REPEATED ADMINISTRATIONS IN HUMANS
Authors: CAMPISTRON G. , ROSTIN M. , COULAIS Y. , CAILLARD C. , ZARROUK G. , FRANCES J. , THIERCELLIN J.F. , MONTASTRUC J.L. , HOUIN G.
Published: August 2009

Summary— In angina pectoris, diltiazem is usually prescribed as two 60 mg tablets in the morning and two 60 mg tablets in the evening. In the course of the pharmaceutical development of this drug, it was therefore planned to study an experimental formulation containing 120 mg of diltiazem. On the basis of dissolution tests in vitro, a bioavailability study was initiated to compare the 120 mg experimental formulation to the standard 60 mg tablet. The study was conducted in 12 healthy volunteers who received the 2 treatments (one 120 mg tablet bid for 7 days versus two 60 mg standard tablets bid for 7 days) according to a cross‐over design. Blood and urine samples were analysed by HPLC method with a UV spec‐trophotometric detection (sensitivity: 5 ng/ml). Analysis of variance did not show any significant difference between the two formulations for the following parameters: maximum plasma levels observed at steady‐state, area under the curves and unchanged urinary diltiazem. From these results the extent of absorption of the 120 mg experimental formulation can be considered as bioequivalent to the administration of 2 tablets of the 60 mg commercialy available diltiazem formulation. The time to peak, however, was delayed in 75% of the subjects with the 120 mg diltiazem tablet, showing that the surface area of the pharmaceutical preparation is of primary importance for drug dissolution and rate of absorption.
EFFECTS OF KETANSERIN ON CARDIOVASCULAR, SYMPATHO‐ADRENAL AND ENDOCRINE SYSTEMS DURING PHYSICAL EXERCISE IN MAN
Authors: DEFER G. , GUEZENNEC C.Y. , FRAITAG B. , LHOSTE F.
Published: August 2009

Summary— Blood pressure, heart rate, oxygen consumption, plasma concentrations of catecholamines, renin, aldosterone and lactate were measured in 6 normotensive volunteers during a randomized crossover study of oral ketanserin (20 mg × 7) and placebo; measurements were made at rest and during maximal dynamic exercise on a bicycle ergometer. At rest ketanserin reduced blood pressure without modifying heart rate or plasma noradrelanine and adrenaline. Duration of exercise and blood lactate levels did not differ between the ketanserin and the control group. During exercise only systolic blood pressure was significantly decreased on ketanserin at maximal work rate whereas heart rate did not change. Plasma noradrenaline was significantly increased and plasma aldosterone significantly decreased during exercise in ketanserin‐treated subjects whereas plasma renin activity and plasma adrenaline remained unchanged. Finally, under ketanserin oxygen concumption during exercise was reduced. The results suggest that ketanserin might interfere with the sympathetic nervous system and aldosterone secretion in man.
EFFECTS OF FOUR ANGIOTENSIN I CONVERTING ENZYME INHIBITORS ON REGIONAL MYOCARDIAL BLOOD FLOW AND ISCHEMIC INJURY DURING CORONARY ARTERY OCCLUSION IN DOGS
Authors: BERDEAUX A. , BONHENRY C. , GIUDICELLI J.F.
Published: August 2009

Summary—The effects of 4 angiotensin I converting enzyme inhibitors (ACEI), captopril, enalapril, ramipril, and trandolapril, were investigated on regional myocardial blood flow (RMBF, radioactive microspheres) distribution in ischemic and nonischemic zones and on ST‐segment elevation in ischemic zones during intermittent coronary artery occlusion in anesthetized dogs.

The 4 ACEI inhibited plasma ACE activity to an almost similar extent. All similarly reduced systemic blood pressure, an effect related to a decrease in systemic vascular resistance. Heart rate and myocardial contractility were not affected, but myocardial oxygen consumption presumably decreased because of the reduction in afterload. RMBF and their distribution (between epicardial and endocardial layers and between nonischemic and ischemic zones) were not modified by ACEI. Coronary vascular resistance was slightly decreased in nonischemic zones. ACEI had no effect on ST‐segment elevation in ischemic zones. Thus, in this experimental model, all ACEI exhibited the same profile, inducing no change in RMBF and affording no protection against ischemic injury.
[3]PIRENZEPINE BINDING IN RAT CORPUS STRIATUM DECREASES AFTER HEMITRANSECTION OF THE NIGRO‐STRIATAL PATHWAY
Authors: PITTALUGA A. , VERSACE P. , MARCHI M. , RAITERI M.
Published: August 2009

Summary—The localization and pharmacologic characterization of muscarinic receptors possibly regulating the release of dopamine (DA) in rat corpus striatum were investigated byin vitrobinding with [3H]pirenzepine ([3H]PZ) after hemitransection of the nigro‐striatal pathway. DA levels in the corpus striatum ipsilateral to the lesion were substantially reduced by 66% compared with the unlesioned side after 8 days. The uptake of [3H]DA was also diminished by 63%. A significant decrease in the specific binding of [3H]PZ of 42% was seen in the corpus striatum ipsilateral to the lesion. The data indicate a loss of binding sites, whereas the lesion caused no change in the affinity constant for the muscarinic antagonist. The results support those previously obtained in studies of the muscarinic modulation of [3H]DA release from striatal synaptosomes and favor the idea that at least part of the muscarinic receptors regulating striatal DA release are localized on the nigro‐striatal axon terminals and belong to the pirenzepine‐sensitive subtype.
EFFECT OF SOME TRICYCLIC AND NONTRICYCLIC ANTIDEPRESSANTS ON [3H]IMIPRAMINE BINDING AND SEROTONIN UPTAKE IN RAT CEREBRAL CORTEX AFTER PROLONGED TREATMENT
Authors: BRUNELLO N. , RIVA M. , VOLTERRA A. , RACAGNI G.
Published: August 2009

Summary—Chronic administration of different antidepressant drugs reduced the number of [3H]imipramine ([3H]IMI) binding sites in rat cerebral cortex. In the same experimental conditions, fluvoxamine and dothiepin, as well as desmethylimipramine, induced an increase in the maximal velocity of high affinity serotonin (5HT) uptake in cortical slices, whereas citalopram and viloxazine were ineffective in this regard.

Our results indicate that even if 5HT uptake and [3H]IMI binding sites are located on the same nerve terminals, they are differently modulated. Increased Vmaxof the 5HT uptake process could be due to a rebound phenomenon after withdrawal from drugs that acutely inhibit 5HT uptake. The effect on [3H]IMI sites might be explained through either the agonist properties of the drugs towards these sites or the involvement of mechanisms still unknown.
1,25‐DIHYDROXYCHOLECALCIFEROL INDUCES AN INCREASE IN PGE1 ‐ AND FORSKOLIN‐STIMULATED CYCLIC‐AMP PRODUCTION IN T47D HUMAN BREAST CANCER CELL LINE
Authors: DE CREMOUX P. , CALVO F. , COST H. , GAUVILLE C. , LAGIER G. , ABITA J.P. , LECHAT P.
Published: August 2009

Summary— The effect of 1, 25‐dihydroxycholecalciferol [1, 25(OH)2 D3], the active form of vitamin D3, on cell growth, clonogenicity, and cyclic adenosine monophosphate (cAMP) production was examined in human breast cancer cell line T47D. 1,25(OH)2 D3 markedly inhibited proliferation of T47D cells in a time‐ and concentration‐dependent manner. 1,25(OH)2 D3 5 times 10−7 reduced to 70% [3H]thymidine incorporation into DNA. Specific high affinity nuclear receptors for 1,25(OH)2 D3 were present in this cell line. The cAMP produced by T47D cells was measured during 10 min stimulation by effectors (prostaglandin E1 or forskolin). Without effector, T47D cells produced similar amounts of cAMP in control and 1,25(OH)2 D3‐treated cells. After 3 days in the presence of 1,25(OH)2 D3, cAMP production was significantly increased compared to control cells when stimulated by 10−4 M prostaglandin E1 or 5 times 10−7 M forskolin (3.2‐ and 2.4‐fold increase, respectively). This cAMP increase was concentration dependent within the same range that inhibited cell growth and clonogenicity. These results suggest that 1,25(OH)2 D3 may indirectly affect cAMP production by modulating the target cell response to stimulatory agents of cAMP production.
THE EFFECTS OF AGEING ON AMINOPYRINE AND CAFFEINE BREATH TESTS IN THE RAT
Authors: FEELY J. , KELLEHER P. , ODUMOSU A.
Published: August 2009

Summary—The influence of ageing on demethylation of14C‐aminopyrine (AP) and14C‐caffeine (Caf) in Wistar littermate rats was studied serially using the14CO2‐breath test. In both sexes, the elimination half‐life (t1/2) of14C‐AP fell from a mean of approximately 75 min when weaned at 17 days to 45 min at maturity (49 days); thereaftert1/2 became prolonged, being most prolonged (82 min) in elderly male rats (210 days). Similarly,t1/2 of14C‐Caf was also prolonged with ageing. These studies using in vivo and longitudinal techniques indicate the importance of ageing on hepatic demethylation.
RO 13–6438 IN CONGESTIVE HEART FAILURE: DOSE‐RESPONSE RELATIONSHIP AFTER 3 SINGLE DOSES
Authors: KOMAJDA M. , LECHAT P. , ELKIK F. , GROSGOGEAT Y.
Published: August 2009

Summary—The dose‐response for the new cardiotonic agent RO 13–6438 was studied in 6 patients with grade III or IV congestive heart failure. Oral doses of 10, 20, or 30 mg of RO 13–6438 were administered on 3 consecutive days in accordance with a double‐blind, randomized cross‐over pattern. Hemodynamic changes, which were dose‐dependent, included an increase in cardiac index combined with decreases in pulmonary capillary wedge pressure and systemic and pulmonary arterial pressures. Heart rate remained unchanged. The area under the plasma RO 13–6438 concentration time curve and the peak plasma concentration were dose‐related. At each measurement, the log concentration of RO 13–6438 correlated with the percent changes in both cardiac index and capillary wedge pressure recorded at that time.
RAPID GAS‐CHROMATOGRAPHIC ASSAY OF BUPIVACAINE IN PLASMA
Authors: LE NORMAND Y. , ATHOUEL A. , BLANLOEIL Y. , DE VILLEPOIX C. , MELCHIOR J.‐C. , KERGUERIS M.‐F. , BOURIN M. , LAROUSSE C.
Published: August 2009

Summary— A method for estimating bupivacaine concentration in human plasma by capillary gas‐chromatography using solid injection and nitrogen‐specific detection is described. Etidocaine, another anilidetype local anesthetic was used as internal standard and added to the sample before single‐step extraction with diethylether. This method demonstrates high sensitivity (6 ng/ml plasma) and combines selectivity, rapidity, and simplicity. Results of this procedure correlate well with those obtained by an HPLC method.
RANDOMIZED, DOUBLE‐BLIND TRIAL OF EXIFONE VERSUS COGNITIVE PROBLEMS IN PARKINSON'S DISEASE
Authors: ALLAIN H. , DENMAT J. , BENTUE‐FERRER D. , MILON D. , PIGNOL P. , REYMANN J.M. , PAPE D. , SABOURAUD O. , VAN DEN DRIESSCHE J.
Published: August 2009

Summary— Exifone is a novel substance of the benzophenone group that possesses potent scavenging properties. Initial findings demonstrate beneficial effects on age‐related cognitive disorders. In this double‐blind clinical trial versus placebo, the efficacy of 2 dosages (600 and 1200 mg/d) was evaluated with regard to Parkinson's disease (PD)‐related cognitive disorders, for which there is increasing suspicion of a free‐radicals origin. Despite disparities between the treatment groups as assessed by validated scales and subtests, and a considerable placebo effect on main parameters, both dose levels of exifone produced statistically significant improvement of the cognitive items most commonly impaired by PD: immediate recall, naming of objects presented, spatiotemporal orientation, and calculation. These properties suggest a new slot for exifone in the range of therapeutics available.
ROLE OF EXTRACELLULAR CALCIUM IN THE EFFECTS OF SUBSTANCE P AND NEUROKININ A ON GUINEA PIG TRACHEA AND HUMAN BRONCHUS
Authors: MATRAN R. , NALINE E. , ADVENIER C. , LOCKHART A. , TRICOT J.F. , REGOLI D.
Published: August 2009

Summary—Whether the influux of calcium through voltage‐operated channels is involved in the stimulatory effects of substance P and neurokinin A in aiways smooth muscle is not yet firmly established. This question was addressed in the present study using guinea pig trachea and human bronchi suspended in normal or calcium‐free Krebs solution and tested with inhibitors of calcium channels.

In calcium‐free Krebs solution, the myotropic effects of substance P (10−7M), neurokinin A (3.10−8M), acetylcholine (2.10−5M), and histamine (2.10−5M) were reduced by 27–57%, while those of potassium chloride and tetraethylammonium were practically abolished.

Calcium antagonists such as verapamil or nicardipine, when applied at concentrations of 10−8‐10−6M, inhibited the contractions produced by potassium chloride and tetraethylammonium, whereas higher concentrations (10−5‐10−4M) of both inhibitors were needed to reduce the effects of substance P, neurokinin A, acetylcholine, and histamine.

In neither preparation did the calcium agonist Bay K 8644 (10−6M) modify the effects of neurokinin A, substance P, acetylcholine, or histamine, but it potentiated potassium chloride's effect on human bronchi. We conclude that transmembrane calcium influx through voltage‐operated channels plays a minor role in the stimulatory effects of neurokinins in airways smooth muscle.
BINDING OF IMIPRAMINE TO PLATELET MEMBRANES IS REDUCED IN PANIC ATTACKS
Authors: MARAZZITI D. , ROTONDO A. , PLACIDI G.F. , PERUGI G. , CASSANO G.B. , PACIFICI G.M.
Published: August 2009

Summary—The binding of imipramine (IMI) to platelet membranes was investigated in 13 patients suffering from panic attacks (PA), in 5 patients affected by schizophrenic disorder (S), and in 11 healthy volunteers (V). From 6 volunteers, from 5 patients with panic attacks, and from all the schizophrenic patients, blood samples were collected in the spring, whereas from the others the samples were collected in the autumn. IMI binding was studied according to a protocol provided by the WHO. Binding parameters, the maximum binding capacity (Bmax), and the dissociation constant (Kd) were measured after construction of the Scatchard plot. The differences between V and PA and between V and S were tested by analysis of variance followed by at‐test. Overall and intragroup relationships between Bmaxor Kdand diagnosis and season were assessed by a 2‐way analysis of variance (ANOVA). Bmax(mean±SD) was 947±269 (V), 742±160 (PA), and 712±254 (S) fmol/mg protein. V was different from PA (P<0.04) and from S (P<0.01). Kd(mean±SD) was 1.41±0.6 (V), 1.15±0.6 (PA), and 0.79±0.20 (S) nM. V was different from S only (P<0.01). Our results show that panic attacks and schizophrenia decrease the binding capacity of IMI in platelets. In addition, we found a significant difference between patients and controls only for the samples taken in the spring. No statistically significant difference was detectable between the 2 groups in the autumn samples. This finding suggests that IMI binding may follow a seasonal rhythm in normal subjects, which is lacking in patients with panic attacks.
SPONTANEOUS TRANSMITTER RELEASE AT THE NEUROMUSCULAR JUNCTION
Authors: THESLEFF S.
Published: August 2009

Summary—The classical studies of Katz and co‐workers have shown that nerve impulses release quanta of acetylcholine at the neuromuscular junction. This release is regulated by presynaptic calcium and accounts for the trans‐synaptic transmission of nerve impulses. In resting conditions it gives rise to small spontaneous potentials,i.e.miniature endplate potentials. In addition these investigators described a spontaneous molecular leakage of acetylcholine from the motor nerve. I have studied a third type of acetylcholine release. It is a spontaneous intermittent secretion of acetylcholine which postsynaptically causes large, generally slow rising potentials. This release is unaffected by presynaptic calcium and is therefore not influenced by nerve activity. The acetylcholine responsible for these potentials comes from the same pool of transmitter as that liberated by nerve impulses. The observation that the release is blocked by drugs that prevent the accumulation of acetylcholine into synaptic vesicles indicates that the secretion originates from clusters of vesicles or large vesicle‐like structures in the nerve terminal. This type of release is present at a low frequency at normal neuromuscular junctions. It is markedly accelerated whenever the calcium‐dependent quantal release of acetylcholine is blocked or impaired. The drug 4‐aminoquinoline selectively stimulates this release. I speculate that this type of transmitter secretion is important for the development of synaptic connexions.
CALCIUM ANTAGONISTS, A NEW CLASS OF ANTIHYPERTENSIVE AGENTS*
Authors: SCHWARTZ J.
Published: August 2009

Summary—The mechanism of action of Ca++antagonists remains debatable. Not all voltage‐sensitive calcium channels have the same sensitivity to organic calcium blockers. Those in smooth muscle are clearly more sensitive than those in heart, and at least some of those in brain are not blocked at all. It is possible that in vascular smooth muscle, calcium antagonists act essentially on receptor‐operated channels.

In any case, calcium antagonists are potent antihypertensive agents, but in clinical practice they have limitations. A second generation of dihydropyridines may provide a higher degree of therapeutic selectivity.
EFFECTS OF INAKTIN ON CALCIUM METABOLISM IN THE RAT
Authors: HEITZ C. , STOCLET J.‐C.
Published: August 2009

Summary—Experiments were designed to investigate further the alterations in calcium metabolism caused by inaktin, a thiobarbiturate that impairs parathyroid hormone action in rats (1981). Treatment with an anesthetic dose of inaktin induced a drop in serum calcium without any variation in immunoreactive parathyroid hormone serum level and slowed body calcium turnover as studied with45Ca, but was without effect on blood pH or partial pressures of oxygen and carbon dioxide. In contrast, calcium metabolism in rats was unchanged after treatment with an anesthetic dose of pentothal, another thiobarbiturate anesthetic. The effect of inaktin on body calcium turnover was dose‐dependent and significant even at non‐anesthetic levels. A marked slowing of the fast phenomena accounting for the initial dilution of the tracer in the animal was observed, accompanied by a corresponding decrease in rapid45Ca uptake into bone, but not other tissues. These results show that inaktin slows calcium turnover, especially the fast renewal of calcium in bone. These effects were not correlated with anesthesia or immobilization, and we suggest that inaktin‐induced changes in calcium metabolism involve an impairment of hypocalcemia‐induced parathyroid hormone secretion, in addition to the impairment of parathyroid hormone effects previously reported. Furthermore, the present findings suggest that inaktin might be a useful tool for investigation of the rapid mobilization of bone calcium, which is as yet not well understood.
5‐HYDROXYTRYPTAMINE STIMULATES TWO DISTINCT ADENYLATE CYCLASE ACTIVITIES IN RAT BRAIN: HIGH‐AFFINITY ACTIVATION IS RELATED TO A 5‐HT1SUBTYPE DIFFERENT FROM 5‐HT1A, 5‐HT1B, AND 5‐HT1C
Authors: FAYOLLE C. , FILLION M.‐P. , BARONE P. , OUDAR P. , ROUSSELLE J.‐C. , FILLION G.
Published: August 2009

Summary—5‐HT binding sites of the 5‐HT1type are heterogeneous and appear to comprise several subtypes (5‐HT1A, 5‐HT1Band 5‐HT1C); their physiological role is as yet unclear. The stimulation of adenylate cyclase induced by 5‐HT has been investigated in membrane fractions prepared from rat brain cortex.

Enzymatic activity was determined by measuring cAMP production with an HPLC technique. It was shown that 5‐HT stimulates adenylate cyclase activity with 2 activation constants (Kact): one shows a high apparent affinity (Kact= 0.8 nM) and the other a lower apparent affinity (Kact= 0.30 μM). The latter activity, induced by micromolar concentrations of 5‐HT, was inhibited by spiperone at concentrations that block 5‐HT1Abinding. 5‐Methoxytryptamine, bufotenin, and LSD also had a stimulatory biphasic effect on adenylate cyclase activity, whereas trifluoromethylphenylpiperazine, 5‐carboxyamidotryptamine, 8‐hydroxy‐(2‐di‐n‐propylamino)tetralin, RU 24969 had a monophasic effect. Enzyme activation by drugs acting in the micromolar range was inhibited by spiperone (1 μM), suggesting a link between this activation and 5‐HT1Asites.

On the other hand, the high‐affinity activation of the enzyme induced by 5‐HT, 5‐methoxytryptamine, bufotenin, LSD, and the activation induced by TFMPP were not inhibited by spiperone (1 μM), by propranolol (3 μM), or by mesulergine (0.1 μM), which selectively block 5‐HT1A, 5‐HT1B, and 5‐HT1Csites. Inhibition was produced by dihydroergotamine, methysergide, cinanserin, and mianserin, but not by naloxone, phenoxybenzamine, and phentolamine. Therefore, these activations seem related to 5‐HT1receptors but not to 5‐HT1A, 5‐HT1B, or 5‐HT1Csites.

Accordingly, binding of [3H]5‐HT to 5‐HT1‐like sites was examined in the presence of spiperone (1 μM) and propranolol (3 μM); in these conditions, a high‐affinity site (KD= 3.4 nM) was indeed revealed. The relative potencies of a series of drugs that stimulate or inhibit the activation of the adenylate cyclase with a high affinity and their ability to inhibit this binding of [3H]5‐HT showed a positive correlation, strongly suggesting a direct relation between this recognition site for 5‐HT and the production of a second messenger (cAMP). Moreover, this potential receptor is shown to be heterogeneously distributed within the brain, and was localized postsynaptically at serotonergic synapses.
DRUG PHARMACOKINETICS IN THE OBESE*
Authors: CHEYMOL G.
Published: August 2009

Summary—In the obese, modifications in body constitution (higher percentage of fat and lower percentage of lean tissue and water) can affect drug distribution in the tissues. For slightly liposoluble molecules (e.g., digoxin, antipyrine), the equilibrium distribution volume (V), total and per kilogram weight, is significantly less than that of control subjects. With lipophilic drugs (e.g., barbiturates, benzodiazepines), this parameter is significantly increased, explaining the prolongation of the plasma elimination half‐life. For drugs that are almost equally soluble in water and oil (methyl xanthines, aminoglycosides), the V is slightly increased in the obese.

The other main factors involved in drug diffusion in the tissues are binding to plasma and tissue proteins, and regional blood flow. In the obese the binding of drugs to albumin does not seem to be altered. A marked increase in plasma α‐glycoprotein acid and in propranolol binding has been reported in some studies; this has not been corroborated by other authors. Although the cardiac output and total blood volume are increased in the obese, the blood flow per gram of fat is less than in nonobese subjects. This could limit diffusion in the tissues of some lipophilic drugs. Studies on hepatic clearance of drugs are not available in the obese, but hepatic histological alterations have been described. In most publications concerning drugs with biotransformation as the principal elimination route, the total plasma clearance is not reduced. Up to the present, there are no reports of any impairment involving renal elimination of drugs in the obese.

Dose‐adjustment of hydrophilic drugs is assessed according to the ideal weight of the individual obese subject; with lipophilic drugs the loading dose can be fixed according to the total weight; calculation of the maintenance dose depends on possible changes in the total clearance.
LACK OF PRESYNAPTIC EFFECTS OF KETANSERIN ON CARDIAC NORADRENERGIC NERVE TERMINALS IN THE SHR
Authors: SCALBERT E. , RICHER C. , GIUDICELLI J.F.
Published: August 2009

Summary—The potential cardiac presynaptic effects of ketanserin (K) (0.01–3.00 mg/kg IV) were investigated in pithed SHR in 4 experimental conditions: (a) basal heart rate (HR); (b) HR increased by selective cardiac sympathetic stimulation (SS); (c) HR increased by aminophylline infusion; and (d) HR increased by SS and brought back to basal value by clonidine. Control groups were treated with saline. In the 4 types of experiments, K, starting from 0.3 mg/kg, induced almost identical and dose‐dependent decreases in HR (maximal reduction: 45 beats/(min at 3 mg/kg). Thus we conclude: (1) that K is devoid of any presynaptic facilitatory effect on norepinephrine release since it was unable to raise HR in experiment D; (2) that K is devoid of any presynaptic inhibitory effect on norepinephrine release since it lowered HR to the same extent in both experiments B (noradrenergic tachycardia) and (non‐noradrenergic tachycardia); and C (3) that the bradycardia which was induced by high doses of K (much above those required to block 5‐HT2and α1‐adrenergic receptors) and which was of similar magnitude in the 4 experimental conditions is probably due to a direct, nonspecific depressant effect of K on the sinus node.
NEUROTRANSMITTERS AND INTRAOCULAR PRESSURE*
Authors: LAPALUS P. , ELENA P.P.
Published: August 2009

Summary— The role of the ocular autonomic nervous system in IOP regulation has been well established. Pharmacological and autohistoradiographic studies confirmed the high density of beta2 and alpha2 receptors on ciliary processes and iris epithelium. Their respective pharmacological activation or blockade is discussed. The role of other ocular neurotransmitters is also complex, as shown by the paradoxical similar action of dopamine agonists and antagonists on IOP.

Concerning the cholinergic system, ocular muscarinic receptors are pharmacologically not well documented. Numerous other neurotransmitters may modulate IOP without necessarily leading to the development of new drugs. Drugs of the future will probably concentrate on dopaminergic agonists, cAMP‐stimulators such as forskolin, prostaglandins, and cannabinoids.
IMMUNOTOXICOLOGY IN 1987: PROBLEMS AND CHALLENGES
Authors: SPREAFICO F.
Published: August 2009

Summary—After the definition of immunotoxicology and of the main current domains of this recently recognized, multifaceted discipline, this article examines the health significance of xenobiotically induced immune abnormalities and considers the possible mechanisms through which damage to the immune system can occur. In the second part of this review, the current status of knowledge and the problems still open with regard to preclinical testing for nonallergic immunotoxicities are examined, and current views on the general strategy for such testing discussed.
PHARMACOKINETICS AND PHARMACODYNAMICS OF 2,4‐DIAMINOPYRIDINE IN THE CAT
Authors: BIESSELS P.T.M. , HOUWERTJES M.C. , SCAF A.H.J. , AGOSTON S. , HORN A.S.
Published: August 2009

Summary—The pharmacokinetics, antagonistic effects, and cardiovascular effects of 2,4‐diaminopyridine (2,4‐DAP) were studied in 7 anaesthetized cats. Cats received a pancuronium infusion at a constant rate to cause a 90% block of contraction of the anterior tibialis muscle, stimulated through the sciatic nerve. After steady state was reached, 2,4‐DAP (750 μg/kg IV) was administered. Plasma, urine, and bile were collected over 8 h and analyzed by means of an HPLC assay. Plasma concentrations decreased biexponen‐tially with half‐lives of 9.0± 5.7 min and 140 ± 36 min, respectively. The volume of the central compartment was 0.85 ± 0.27 L/kg, and the volume of distribution in the steady state was 3.1 ± 1.1 L/kg. Total plasma clearance was 18 ±5 ml/kg/min. Ninety percent of the administered dose was recovered in the urine and 0.1 percent in the bile in 8 h. The antagonism of the pancuronium‐induced steady‐state block was 98%±5%, with onset and duration of 3.5±2 min and 165±40 min, respectively.
RELAXATION OF RABBIT MIDDLE CEREBRAL ARTERIES IN VITRO BY H1 HISTAMINERGIC AGONISTS IS INHIBITED BY INDOMETHACIN AND TRANYLCYPROMINE
Authors: KIM L. EA , SERCOMBE R. , OUDART N.
Published: August 2009

Summary— The H1‐histaminergic agonists 2‐pyridylethylamine (2‐PEA) and 2‐methylhistamine relaxed potassium‐constricted, perfused, rabbit middle cerebral arteries at low concentrations (3times10−11 to 3 times 10−8M) and constricted them at high concentrations (3 times 10−7 to 3 times 10−4M). The relaxation and the contraction were not antagonized by propranolol (up to 3times 10−6M) given 30 min before, suggesting that beta‐adrenergic mechanisms were not involved. When 2‐PEA was tested on arteries constricted with uridine triphosphate (UTP), similar results were obtained. In the UTP‐constricted arteries, the 2‐PEA‐induced responses were competitively antagonized by 3times 10−9M mepyramine. Together with previous work (Ea Kim et al., 1986), these results are compatible with the hypothesis that H1‐receptors were responsible for both the relaxation and the contraction observed.

When either indomethacin (10−8, 3times 10−7, or 10−5M), dexamethasone (10−5M), or tranylcypromine (10−5 or 10−4M) were tested on the response to 2‐PEA or 2‐methylhistamine, these inhibitors suppressed the relaxation or reversed it to a contraction. Furthermore, they potentiated the contraction induced by these agonists. These results favour the hypothesis that the H1‐mediated relaxation in rabbit cerebral arteries may in part involve the release of prostaglandins, especially prostacyclin. The participation of such a prostanoid in histaminergic relaxation seems exclusively an H1‐mediated mechanism, since the relaxation induced by the H2‐agonist dimaprit (in the presence of mepyramine) was not antagonized by either indomethacin (3times 10−7M) or tranylcypromine (10−4M).
COMPARISON OF THROMBOLYTIC, FIBRINOLYTIC, AND FIBRINOGENOLYTIC PROPERTIES OF TISSUE PLASMINOGEN ACTIVATOR, STREPTOKINASE, SINGLE‐CHAIN UROKINASE, HIGH MOLECULAR WEIGHT AND LOW MOLECULAR WEIGHT UROKINASE IN HUMAN PLASMA IN VITRO
Authors: Samama M. , NGUYEN G. , DESNOYERS P. , LOURENCO D.M. , FRETAULT J. , HORELLOU M.H. , CONARD J. , SZWARCER E. , VERDY E. , VAHANIAN A.
Published: August 2009

Summary— Thrombolytic, fibrinolytic, and fibrinogenolytic properties of tissue plasminogen activator (t‐PA) from melanoma cells (mt‐PA), recombinant t‐PA (rt‐PA), streptokinase (SK), single‐chain urokinase plasminogen activator (scu‐PA), and high and low molecular weight urokinase (HMW UK, LMW UK) were compared in vitro by means of systems using human plasma.

Thrombolytic activities were tested on standard or labeled hanging clots. When compared on the basis of urokinase international units, t‐PA appeared to be slightly more active than scu‐PA and streptokinase, and about 10‐fold more active than both preparations of UK when they were diluted in plasma.

Fibrinolytic activity was evaluated by measuring the lysis time of recalcified plasma containing variable amounts of thrombolytic agents. t‐PA was shown to be twice as active as HMW UK, which was itself more active than LMW UK. When scu‐PA and both types of UK were compared on bovine fibrin plates, they showed similar fibrinolytic activity, but the t‐PA calibration curve was not parallel to those obtained with UK and scu‐PA.

Relative thrombolytic and fibrinogenolytic properties were studied for each thrombolytic agent. For similar thrombolytic activities, fibrinogenolysis provoked by scu‐PA was less marked than with t‐PA and with both UK, while SK showed the highest activity. Our results demonstrate that the thrombolytic/fibrinogenolytic ratio is much more favorable to t‐PA and scu‐PA than to both forms of UK. Another observation clearly shows that fibrinogenolysis can be induced in vitro in human plasma by high doses of t‐PA. This consequence may be important since the therapeutic use of t‐PA can be associated with high concentrations of t‐PA, and thus t‐PA infusion could lead in vivo to severe fibrinogen breakdown. In addition, the methodology described could be useful in standardizing comparison between different species of thrombolytic agents.
BRONCHOSPASMOLYTIC EFFECTS OF RU 42173
Authors: FICHELLE J. , NALINE E. , FRESLON J.L. , JOUQUEY S. , PLASSARD G. , THOMPSON M.A. , MILLER P. , ADVENIER C.
Published: August 2009

Summary— The bronchodilator properties of RU 42173, a new beta‐adrenergic stimulant with an original structure, as a cyclic analogue of an arylethanolamine, have been evaluated on different in vitro and in vivo models and compared with those of salbutamol and isoprenaline. RU 42173 equipotently inhibited histamine‐, acetylcholine‐, and KC1‐induced contractions in isolated guinea pig trachea or small bronchus and in isolated human bronchus. When administered to guinea pigs by the IV or aerosol route, RU 42173 dose‐dependently inhibited bronchospasm induced by histamine, acetylcholine, and methacholine. It also inhibited PAF‐induced bronchoconstriction and PAF‐induced hyperreactivity to histamine. Moreover, RU 42173 had a rapid onset and prolonged duration of action. The potency of RU 42173 was similar to that of salbutamol.
RENAL EFFECTS OF NIFEDIPINE IN HEALTHY NORMOTENSIVE VOLUNTEERS. EFFECTS OF DOSE, FORMULATION, DURATION OF TREATMENT, AND CHLOROTHIAZIDE COADMINISTRATION
Authors: ADEBAYO G.I. , COKER H.A.B. , FAGBURE F.
Published: August 2009

Summary—Renal effects of nifedipine were assessed in 3 groups of healthy normotensive volunteers. In the first group (N = 10), a single 20‐mg dose of the slow‐release formulation caused an increase in 8‐h sodium excretion (P<0.025) and urine volume (P<0.005). Natriuresis (P<0.05) and diuresis (P<0.05) were still evident after 1 wk of pretreatment, but were significantly attenuated (P<0.05), in each case, compared to levels after a single dose. Natriuresis and diuresis after 2 wk of intake were indistinguishable from control levels.

In another group of 8, a single 10 mg dose of the conventional formulation (capsule) effected natriuresis (P<0.01) and diuresis (P<0.001) similar to those associated with intake of a single 20‐mg dose of the slow‐release formulation. Natriuresis and diuresis associated with a 20‐mg single dose of the conventional formulation were not different from control but were less than those following intake of the 10‐mg dose (P<0.025 in each case).

In the third group of 6, nifedipine, though weaker than chlorothiazide, promoted natriuresis (P<0.025) and diuresis (P<0.025) of the thiazide without augmenting its kaliuresis. In all the groups, there were no changes in creatinine clearance, and nifedipine did not alter kaliuresis.

It is suggested that natriuretic and diuretic effects of nifedipine in healthy normotensive individuals are dependent on the dose employed, the formulation used, and the duration of treatment. Moreover, although the effects of nifedipine and chlorothiazide are possibly additive, the calcium channel blocker is a weaker natriuretic and diuretic agent than the thiazide.
QUANTITATIVE ANALYSIS OF SERUM METHOHEXITAL BY GLC USING CAPILLARY COLUMN AND NITROGEN‐SELECTIVE DETECTION
Authors: LE NORMAND Y. , DE VILLEPOIX C. , ATHOUEL A. , KERGUERIS M.F. , BOURIN M. , LAROUSSE C.
Published: August 2009

Summary— A gas chromatographic method for routine quantitation of methohexital in plasma samples is reported. One‐step extraction in organic phase, the use of a fused silica capillary column, and nitrogen‐selective detection permit simple, precise, and sensitive determination of methohexital in plasma. A linear relationship is described between peak height ratio and methohexital concentrations ranging from 0.125 to 50.0 μg/ml (r=0.998). The sensitivity limit of the assay was 6 ng/ml in plasma. No interfering peak was observed with numerous other drugs.

The procedure was successfully applied to the determination of pharmacokinetic parameters of methohexital after IV administration or continuous infusion in a child and an adult.