bluuebunny/crossref_metadata_2025 huggingface dataset:
IS MONITORING PLASMA LEVELS OF NETILMICIN NECESSARY IN NEONATES?
Authors: AUTRET E. , LAUGIER J. , BRETEAU M. , LIONNET C. , FURET Y.
Published: August 2009

Summary— Thirty‐two neonates were treated with netilmicin 3 mg/kg every 12 h by IV infusion for 30 min for suspected infections, colonization, or proven infections. Pharmacokinetic studies were performed in order to define the situations in which monitoring of plasma levels would be appropriate.

Mean plasma levels were within the therapeutic range and did not differ in fullterms and preterms. In the 4 children who had 2 successive pharmacokinetic studies, plasma levels were increased between H1 and H5 at the second evaluation due to netilmicin accumulation.

Plasma half‐life was longer in proven infections and seemed to decrease in preterms with increased gestational age.

These results suggest that the dosage schedule should be left inchanged, but that administration time should be reduced from 30 to 20 min and that peak and trough plasma levels should be measured only in proven infections, in very premature babies (gestational age < 33 wk), and during netilmicin treatment longer than 5 d.
PHARMACOKINETICS OF LIDOCAINE AND BUPIVACAINE IN RETROBULBAR AND FACIAL BLOCK
Authors: LE NORMAND Y. , DE DIEULEVEULT C. , ATHOUEL A. , QUEINNEC M.C. , DE VILLEPOIX C. , LAROUSSE C.
Published: August 2009

Summary— Analgesia can be obtained during ophthalmic surgery by regional anesthesia using local anesthetic agents. As in other indications, neurological complications may occur, especially because the site of injection is close to the central nervous system. In order to evaluate the risk of retrobulbar and facial block obtained after 40 mg lidocaine and 20 mg bupivacaine injection, pharmacokinetics of both drugs was evaluated in plasma obtained from 11 patients. In addition, 3 cerebrospinal fluid samples were analyzed.

Maximal plasma concentration was 0.73 ± 0.33 μg.ml‐1 for lidocaine and 0.19 ± 0.06/ng‐ml‐1 for bupivacaine, obtained 24.7 ± 23.0 min and 12.0 ± 3.7 min after the end of injection, respectively. CSF/plasma ratio was in the range 0.05–0.26 for lidocaine and 0.56– 1.33 for bupivacaine.

In all patients, regional anesthesia was sufficient to perform surgery without any other analgesic drug. No sign of cardiovascular or respiratory toxicity was observed during the study.
IN VITRODESENSITIZATION OF β‐ADRENOCEPTORS IN GUINEA PIG TRACHEA: INTERACTIONS BETWEEN β‐ADRENOCEPTOR AGONISTS AND INFLUENCE OF ADENOSINE AND OTHER DRUGS
Authors: MATRAN R. , NALINE E. , ADVENIER C. , DUROUX P.
Published: August 2009

Summary—The aim of this study was to investigate quantitatively the action of and the interaction between beta‐adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 times 10−5M) or acetylcholine (5×10−5M) and concentration‐response (C/R) curves for various beta‐adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta‐adrenoceptor agonist (autodesensitization), with other beta‐adrenoceptor agonists (cross‐desensitization), or with a beta‐adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 ± 0.06 (N= 5) for salbutamol (10−5M), 0.78 ± 0.09 (N= 5) for fenoterol (10−6M), 0.30 ± 0.04 (N= 9) for isoprenaline (10−5M), and 0.33 ± 0.05 (N= 5) for adrenaline (10−5M). Our studies of cross‐desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10−5M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 ± 0.08,N= 5) and salbutamol (0.62 ± 0.05,N= 5) than for adrenaline (0.35 ± 0.07,N= 5) and isoprenaline itself (0.30 ± 0.05,N= 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10−8M) reduced it significantly, although to a negligible extent. Adenosine (3 times 10−4M) did not shift the C/R curve to isoprenaline by itself, but incubation of trachea! strips with adenosine and isoprenaline caused a significantly greater shift of C/R curves to isoprenaline (0.30 ± 0.04) than incubation with isoprenaline alone (0.20 ± 0.04) (P< 0.05,N= 5). These experiments suggest that adenosine may have increased the uncoupling and/or down‐regulation phenomena induced by isoprenaline, or modified adenylate cyclase‐cAMP activity.
CONTRACTILE RESPONSES TO HYPOXIA OF ISOLATED RINGS FROM THE LEFT BRANCH OF RABBIT PULMONARY ARTERY
Authors: BONNET P. , ARGIBAY J.A. , GARNIER D.
Published: August 2009

Summary— Contractile responses of left extrapulmonary artery segments with either intact or damaged endothelium were examined with changes in PO2 at constant pH. Hypoxia consistently reduced noradrenaline‐induced contractions. This hypoxia‐induced relaxation was sometimes followed by a contraction and a second relaxation. Hypoxia‐induced relaxations were also obtained if precontraction was elicited with KC1 (40 mM), but no triphasic response was observed. Relaxations faded away with time and only contractions were then observed. Relaxations were more considerable in rings from young animals and, although always present, decreased with the age of the animal. Endothelium damage reduced hypoxia‐induced relaxations. Indomethacin, a potent blocker of cyclooxygenase, increased hypoxia‐induced contraction and reduced relaxation in segments with intact endothelium. Without endothelium the indomethacin effect was less significant. It is concluded that the response to hypoxia of the pulmonary artery is similar to that of systemic vessels. Endothelium seems to play a modulatory role in the hypoxia‐induced response in extrapulmonary artery. Prostaglandin metabolism seems to play a minor role in this modulation.
COMPARATIVE EVALUATION OF SCAVENGER PROPERTIES OF EXIFONE, PIRACETAM AND VINBURNINE
Authors: BENTUE‐FERRER D. , PHILOUZE V. , PAPE D. , REYMANN J.M. , ALLAIN H. , VAN DEN DRIESSCHE J.
Published: August 2009

Summary— The involvement of radical reactions in the ageing process, physiological as well as pathological, is well demonstrated. It is accepted that alloxan cyto‐toxicity is linked to a production of hydroxylated free radicals and that a substance preventing the development of alloxanic diabetes possesses scavenger properties. The objective of this work was to demonstrate, in this model, the anti‐radical effect of 3 molecules recommended in the treatment of cerebral insufficiency and a reference substance (+)‐catechin. We observed a protective action with catechin (P<0.05) at the highest dose (100 mg/kg). PEG alone was moderately active but comparison of PEG‐alloxan and PEG‐exifone‐alloxan showed a highly significant difference (P<0.001) at the two highest doses (60 and 120 mg/kg). Piracetam (200 and 400 mg/kg) and vinburnine (7.5 and 15 mg/kg) were inactive. Under these experimental conditions, exifone demonstrated remarkable anti‐radical properties.
THE EFFECT OF 5‘‐N‐ETHYLCARBOXAMIDEADENOSINE ON THE ISOLATED HEMIDIAPHRAGM OF THE RAT DURING DIRECT AND INDIRECT ELECTRICAL STIMULATION
Authors: PROSTRAN M. , VARAGIć V. M.
Published: August 2009

Summary—Similar to adenosine and some of its derivatives, 5′‐N‐ethylcarboxamideadenosine (NECA) produced a biphasic effect on the isolated hemidiaphragm of the rat: a potentiation of the isometric contraction during direct electrical stimulation (in the presence of dipyridamole), and a depression during indirect electrical stimulation, and particularly so in a partially curarized preparation. The potentiating effect is presumed to be due to activation of the cAMP system, probably through A2receptor sites, although a differentiation of the receptor subtype could not be made with aminophylline and XAC. Inhibition is most probably due to a depressant action of NECA on the acetylcholine release from the motor nerve terminals. These results accord with our previous findings, suggesting that adenosine may be part of a buffer system which participates in balancing the excitatory and inhibitory influences on skeletal muscle contraction.
A NEW EX VIVO METHOD FOR THE STUDY OF NASAL DROPS ON CILIARY FUNCTION
Authors: LEVRIER J. , MOLON‐NOBLOT S. , DUVAL D. , LLOYD K.G.
Published: August 2009

Summary— Any pharmaceutical nasal preparation should respect the physiological function of the mucociliary transport system and should undergo testing to this effect. An experimental protocol has been developed using the guinea pig in order to assess the effects of commercial nasal drop preparations on mucociliary function. The method presented here consists of applying in vivo the test solution on the nasal respiratory epithelium. After a specified contact time and following rapid sacrifice of the animal, the mucosa is removed; the beating frequency of the cilia is then recorded ex vivo by micro‐photo‐oscillography.

The method is sensitive to compounds known to diminish mucociliary function as sodium mercurothiolate inhibits ciliary movement of the nasal epithelium ex vivo. This inhibition of ciliary movement is long‐lasting, although reversible.

This method can be used to test the action of intranasally administered pharmaceutical preparations on mucociliary function. Commercially available solutions of the nasal vasoconstrictors tymazoline, fenoxazoline or oxymetazoline do not alter ciliary movement ex vivo at dose levels equal to or greater than those clinically utilized. ATP significantly enhances nasal ciliary frequency in instances where a low basal rate occurred.

Thus, this method can be used for the testing of the maintenance of nasal ciliary function in the presence of compounds and preparations which will be applied into the nostrils. The advantages over previous techniques include a closer approach to the therapeutic utilization and the maintained physiological conditions of the mucosa during drug administration.
α‐ADRENOCEPTOR PROPERTIES IN RAT STRAINS SENSITIVE OR RESISTANT TO SALT‐INDUCED HYPERTENSION
Authors: ATTARI A. EL , QING W. , BEN‐ISHAY D. , PARINI A. , DAUSSE J.‐P.
Published: August 2009

Summary—Cerebral and renal α‐adrenoceptors are implicated in the control of sympathetic activity and of sodium reabsorption respectively. In addition, sodium ions play an important role in the regulation of either α‐adrenoceptor densities and affinities for adrenergic agonists. In the present study, α‐adrenoceptor properties were investigated in genetically predetermined salt‐sensitive and salt‐resistant Dahl and Sabra rats.

Cerebral α2‐adrenoceptor densities were higher in salt‐resistant than in salt‐sensitive Dahl and Sabra rats. In contrast, renal α2‐adrenoceptor density was higher in salt‐sensitive than in salt‐resistant rats. No difference in cerebral and renal α1‐adrenoceptor densities was observed between Dahl and Sabra substrains. Noradrenaline content in cerebral and renal cortex were also similar in both these rat substrains.

Sodium ions markedly increased cerebral and renal high‐affinity α2‐adrenoceptor densities in salt‐sensitive but not in salt‐resistant rats. Cerebral and renal α1‐adrenoceptor densities were unchanged in salt‐sensitive and salt‐resistant substrains of Dahl and Sabra rats. In addition, sodium ions reduced the affinity of adrenaline for renal α2‐adrenoceptors in salt‐sensitive rats but not in salt‐resistant rats.

We can conclude that there exist genetically determined differences in the densities and properties of cerebral and renal α2‐adrenoceptors between salt‐sensitive and salt‐resistant rat strains. Abnormal densities of α2‐adrenoceptors may play a primary role in the role in the development of hypertension in salt‐sensitive animals. These results also suggest an association between absence of sodium regulation of α2‐adrenoceptors and resistance to salt‐induced hypertension. The absence of sodium regulation in salt‐resistant rats may be linked either to a particular receptor conformation or to an abnormal structure of the receptor system. This property may represent a genetically‐mediated change responsible for the resistance to the development of salt‐induced hypertension.
NORADRENALINE RELEASE IN HUMAN CORPUS CAVERNOSUM AND ITS MODULATIONVIAPRESYNAPTIC α2‐ADRENOCEPTORS
Authors: MOLDERINGS G.J. , GÖTHERT M. , VAN AHLEN H. , PORST H.
Published: August 2009

Summary—Strips of human corpus cavernosum were incubated with3H‐noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. The electrically (0.66 Hz) evoked tritium overflow was abolished by tetrodotoxin or omission of Ca2+from the superfusion fluid. The α2‐adrenoceptor agonist B‐HT 920 (6‐allyl‐2‐amino‐5, 6, 7, 8–4H‐thiazolo‐5,4‐d‐azepine), inhibited the evoked overflow, whereas the α1‐adrenoceptor agonist, methoxamine, was ineffective. The α2‐adrenoceptor antagonist, rauwolscine, facilitated the evoked tritium overflow. It is concluded that the stimulation‐evoked release of noradrenaline from the sympathetic nerve fibres of the human corpus cavernosum is modulated via presynaptic α2‐adrenoceptors.
PHARMACOKINETICS OF METAPRAMINE AND ITS DEMETHYLATED METABOLITES IN PLASMA AND BRAIN OF MICE
Authors: BOUGEROLLE A.M. , CHABARD J.L. , ESCHALIER A. , AUMAITRE O. , FIALIP J. , DORDAIN G. , PETIT J. , BERGER J.A.
Published: August 2009

Summary—Previous studies on pharmacokinetic parameters of tricyclic antidepressants (TCAs) in rodents have shown different results from those obtained for the same drugs in man. The kinetics of metapramine (META) and its major demethylated metabolites (METs) were studied in the SWISS CD 1 mouse after acute administration in order to establish the pharmacokinetic parameters in plasma and brain. The plasma half‐life (T1/2) was very short (87 min) compared with the half‐life (7 h) in man. The metabolism of META was intensive as was the transfer of META and its metabolites into the brain. The kinetic profiles of the substances were quite similar both in plasma and in brain, namely a bicompartment open model. META was rapidly absorbed (Tmax=10 min) into and quickly eliminated (T1/2=40 min) from the brain.

These parameters were used to schedule sampling (blood and brain) at the appropriate time after acute administration of increased doses.

The administered doses were significantly correlated to firstly the plasma or brain levels of META, secondly the plasma levels of the main monodemethylated metabolite (MET I), and thirdly the plasma or brain levels of META + METs.

Finally, the evolution of plasma and brain levels of the substances was studied after repeated injections (i.e. every 40 min) and confirmed the high affinity of META and its metabolites for the brain regions.
MODEL‐INDEPENDENT PHARMACOKINETICS OF COLCHICINE AFTER ORAL ADMINISTRATION TO HEALTHY VOLUNTEERS
Authors: GIRRE C. , THOMAS G. , SCHERRMANN J.M. , CROUZETTE J. , FOURNIER P.E.
Published: August 2009

Summary— The pharmacokinetics of colchicine were studied after oral administration of three doses (0.5, 1.0 and 1.5 mg) to nine healthy male volunteers according to randomized cross‐over design. Plasma and urine samples were collected during 48 h after ingestion, and assayed for colchicine levels by a specific and highly sensitive radio‐immunoassay. Pharmacokinetic parameters t1/2β, AUC, MRT, CIT/F, CIR, Vd area/F) were calculated by model‐independent methods and compared across doses by multiway analysis of variance. Terminal half‐life (15.5–19.2 h), mean residence time (15.7–20.3 h), oral systemic (32.2–40.3 l/h) and renal (3.9–4.7 l/h) clearances, and oral volume of distribution (11.4–14.9 l/kg) did not differ significantly between doses, whereas the area under the concentration‐time curve was proportional to dose. Our results show that:

within the dose range studied (0.5–1.5 mg), the pharmacokinetics of colchicine are linear;

monitoring colchicine levels up to 48 hours yields much larger estimates of terminal half‐life and volume of distribution than previously reported from considerably shorter studies.
Sex differences in salicylic acid metabolism in streptozotocin induced diabetes in rats
Authors: Emudianughe TS
Published: August 2009

Summary—The metabolism of salicylic acid was studied in male and female streptozotocin‐induced diabetic Wistar rats. Results obtained showed that in both sexes there was a significant increase in urinary excretion of salicyluric acid in diabetic rats when compared to controls (P≤0.001). Within the diabetic groups, there was a significant increase in the urinary excretion of salicyluric acid in the female in comparison to the male rats (P≤0.01). A statistically significant increase was observed in urinary excretion of salicyl‐glucuronic acid in diabetic female compared to control female rats (P≤0.01) while comparison of diabetic male to control male showed a significant decrease in urinary excretion of salicyl‐glucuronic acid (P≤0.01). Comparison of the diabetic female and male groups showed a high statistically significant difference in urinary excretion of salicyl‐glucuronic acid. The diabetic ration,iediabetic/control was significantly higher in female than in male rats with respect to salicyl‐glucuronic acid (P≤0.001) and total urinary excretion (P≤0.01). The diabetic ratio may likely reflect the true significance of the roles played by the two metabolic pathways. The results suggest sex differences in the metabolism of salicylic acid; this may also be the case in other disease states.
Effect of bromocriptine on neurogenic vasoconstriction in the isolated autoperfused hindquarters of the rat
Authors: Roquebert J. , Alaoui K. , Morán A.
Published: August 2009

Summary—The effects of local administration of bromocriptine were studied in the isolated autoperfused hindquarters of the rat, and compared to the actions of apomorphine and pergolide. Local injection of bromocriptine (1 μg kg−1) (into the hindquarters) did not alter perfusion pressure, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains at all frequencies used (0.5–10 Hz;5 ms;35 V). Bromocriptine (1 μg kg−1) did not alter the increases in perfusion pressure induced by local administration of noradrenaline. The effects of local administration of apomorphine (1 μg kg−1) and pergolide (1 μg kg−1) were similar to that of bromocriptine. The inhibitory effect by bromocriptine, apomorphine and pergolide of the stimulation‐evoked pressor responses was completely antagonized by intravenous administration of the dopamine receptor antagonist sulpiride (0.3 mg kg−1) but was not by the α2‐adrenoceptor antagonist yohimbine (1 mg kg−1). In this dose, yohimbine antagonized the inhibitory effect of the α‐adrenoceptor agonist clonidine (1 μg kg−1). The inhibitory effect of clonidine was not altered by sulpiride but was antagonized by yohimbine. The results indicate that bromocriptine like apomorphine and pergolide inhibit neurally‐induced pressor responses in the autoperfused hindquarters of the rat by stimulation of presynaptic dopamine receptors. Stimulation of these receptors leading to a fall in noradrenaline release and consequently of vasomotor tone, might at least in part explain the vasodilatator effects of bromocriptine in the rat.
Pharmacological aspects of chiral nonsteroidal anti‐inflammatory drugs
Authors: Muller N. , Payan E. , Lapicque F. , Bannwarth B. , Netter P.
Published: August 2009

Summary—Most NSAIDs are chiral molecules: they exist under 2 configurations of non‐superimposable mirror images which are termed enantiomers or optical isomers or optical antipodes. Direct or indirect (resolution) methods are used to separate this equal mixture of compounds. Some of the enantiomers of the NSAIDs are able to undergo chiral inversion from the inactiveR(‐) to the activeS(+) form. The pharmacokinetics in terms of absorption, distribution, metabolism, protein binding and elimination may be different for the 2 enantiomers, leading to interindividual variability in clinical response and drug toxicity.
Predictive value of phase I studies: relevant criteria
Authors: Sassard J. , Pozet N. , Bernard N. , Ferry N. , Cuisinaud G.
Published: August 2009

Summary— Phase I studies cannot predict the therapeutic efficacy of a new drug. However, they can lead to important information concerning: i), the undesirable effects and their mechanisms of occurrence; and ii), the pharmacokinetics and the metabolism of the drug as well as their possible alterations in renal or hepatic diseases. When considering the therapeutic effects, 3 cases have to be considered which are, in order of decreasing predictive value: i), when a direct relationship is expected between the drug concentration in the body and its therapeutic effects (eg, antibiotics); ii), when the drug has a known molecular or cellular target which is directly involved in the pathophysiology of the disease (eg, renin inhibitors); and iii), when the drug does not have a known target or is directed toward a precise target which is not directly involved in the disease. In all these cases, a phase I study in healthy volunteers should be able to describe, at least qualitatively, the pharmacodynamic effects of the drug which are relevant to its therapeutic goal.
Which experimental design for phase I clinical trials? Proposal for an investigational approach
Authors: Durieu I. , Girard P. , Boissel JP
Published: August 2009

Summary— The choice of a protocol for the first administration to man of a new drug remains an unresolved problem for the researcher. There are few studies concerning dose‐ranging experiments in phase I to determine the threshold and plateau doses of a new drug in a population. A simulation approach may help in evaluating different protocols, by considering how they could be optimized, and by selecting the best protocol for a given case.
Sequential design and analysis of dose finding studies in patients with life threatening disease
Authors: O'Quigley J.
Published: August 2009

Summary— We describe a recently developed approach to the design and analysis of dose finding studies in patients with life‐threatening disease. Such patients may be terminally ill and, although interest is focussed on cancer, the methodology is more generally applicable. Of major interest is the identification of a dose with a given targeted toxicity level. Experimentation is carried out at a level for which all current available evidence, ie any information available before beginning the study, typically used in determining dose levels, together with information accumulated in the course of the study, indicates the best estimate of the target level. At the end of the study it is possible to obtain a statistical estimate of the probability of toxicity at the chosen level. Note that such estimation is not possible after a dose finding study carried out along traditional lines.
The place of simultaneous pharmacokinetic pharmacodynamic modeling in new drug development: trends and perspectives*
Authors: Girard P. , Nony P. , Boissel JP
Published: August 2009

Summary— The potential applications in drug development of pharmacokinetic‐pharmacodynamic modeling are numerous: optimal medication regimen, design of galenic forms, identification of specific effects of metabolites and enantiomers. Nevertheless, this methodology is presently under‐used, as appears from an analysis of the literature. We examine this point as well as progress in both non‐invasive pharmacodynamic measurement and specific experimental design that could lead to a future extension of PK‐PD in toxicology and phase I drug development.
Estimate of the number and of the temporal sequence of measurements in a kinetic experiment
Authors: Gomeni R.
Published: August 2009

Summary— The optimal choice of the number and the temporal sequence of measurements is that which minimizes the expected error on the parameters of the model later used to fit the observations. Practical constraints regarding the feasibility of a given temporal distribution of measurements, cost‐benefit ratio as well as prior knowledge about the parameters and their variability in the selected population must be integrated in the decisional process. A non‐linear integer programming procedure is used to find reasonable solutions to this problem.
Are phase I studies without drug level determination acceptable?
Authors: Morselli PL
Published: August 2009

Summary— Among the main objectives of phase I studies, the definition of the safety profile of the new drug, its pharmacodynamic profile and the relationship between doses, concentrations and effects can be cited. The definition of these correlations is of paramount importance not only for a correct choice of the dose and dosing intervals in patients, but also for a more rational evaluation of the possible risk/benefit ratio at a clinical level. It is hence evident that drug level determination is a “necessary” step during phase I studies in volunteers. These concepts are discussed, with particular emphasis on the possible acceptability of phase I studies without drug level determination.
Do we need highly sensitive analytical techniques in phase I?
Authors: Singlas E.
Published: August 2009

Summary— Pharmacokinetic studies constitute part of phase I clinical trials. Initiation of dosage regimen in phase II and III clinical trials depends on drug pharmacokinetics and the choice of dosing interval relies on the elimination rate constant. Consequently, inaccurate determination of these parameters can lead to unexpected drug levels and side‐effects in patients and can delay the clinical development of the drug.
Measurement of free drug in phase I: is it useful?
Authors: Barré J. , Riant P. , Tillement JP
Published: August 2009

Summary— Early investigation of protein binding of a new drug is mandatory. The following questions have to be answered: is unbound fraction constant over tested concentrations? Which proteins are involved? What are the binding parameters? Can the drug compete with other therapeutic agents for the binding sites or in other words can drug displacements be predicted? What is the interindividual variability in protein binding? Is the binding stereoselective? All this information is necessary in predicting the pharmacokinetic behaviour of the drug and in assisting in the design of future pharmacokinetic protocols in phases II and III. The use of free drug concentration should also be considered when comparing the bioavailability of regular vs sustained release dosage forms of drugs exhibiting concentration‐dependent binding and when studying concentration‐effect relationships.
Good clinical practices in phase I studies
Authors: Decousus H. , Perpoint B. , Mismetti P. , Ollagnier M. , Queneau P.
Published: August 2009

Summary— In France, official guidelines for good clinical practices in clinical trials were issued in 1987. In December 1988, a law was passed that fixed the requirements for carrying out experiments in healthy subjects. It will be completed by official guidelines for the structures in which experiments on healthy subjects (and patients as well, when the investigation would not benefit the health of the patients) may be conducted. Hence a battery of recent legal instructions precisely state what good clinical practices are in the setting of phase I studies. Of particular importance are: subject recruitement and selection methods and procedures; specific competence of the investigator, in particular to interpret the pre‐trial data; necessary and sufficient facilities to guarantee the subjects' safety; careful quality control to check all laboratory procedures; necessity of written standard operating procedures.
Selection of healthy volunteers for phase I studies
Authors: Sibille M.
Published: August 2009

Summary— Healthy volunteers selection is one of the foundations for phase I results. Safety for volunteers, quality of data and reliability for study results depend on healthy volunteers selection. The selection aim is not to choose normal subjects but to exclude every people with diseases or risk factors which could result in increased danger for themselves or confuse the interpretation of study results. The selection procedure needs to define a list of relevant disease to be excluded depending on phase I objectives (tolerability, pharmacokinetic, pharmacodynamic). The choice of diseases is based on frequency, potential risk for the subjects or for the study. The selection is mainly a clinical process but because of asymptomatic diseases a laboratory screening is necessary and useful. This laboratory screening requires that a basic common list of relevant tests be determined and an appropriate method of cut‐off point determination based on an evaluation of the risk of disease. According to the drug or the objective of the study adaptation of the procedure must be carried out. The percentage of erroneous inclusion of subjects is the best validation criterion for selection. The use of such a selection methodology by the author's group in Lyon results in a 50% exclusion for 494 first seen subjects with only 1% erroneous inclusion and 6% exclusion for laboratory test anomalies.
Healthy volunteers data bank: where and how?
Authors: Jaillon P.
Published: August 2009

Summary— In order to improve safety for healthy volunteers to be included in phase I clinical trials, a national data bank will be set up and controlled by the French Ministry of Health. Each investigator responsible for an agreed phase I center will have a personal access code to the central computer in order to consult the national registry before including any healthy volunteer in a study. If the volunteer has already participated in a recent study, the investigator will find 2 important pieces of information in the data bank: the duration of the safety period following the preceding trial and during which the subject is not allowed to participate in another study; the total amount of money received by the subject during the last 12 months in grants for phase I studies; this amount will be limited by the Ministry of Health. This healthy volunteer data bank will decrease the risk of drug interaction and will improve safety in phase I trials. However, many practical and ethical problems remain to be solved.
Who is responsible for what?
Authors: Rouzioux JM
Published: August 2009

Summary— During the phase I trials, from the juridical point of view, the responsibilities are shared between the pharmaceutical company and the physician who manages the trial. The pharmaceutical company is responsible for the product, the choice of methodology and respect for the regulations. On the financial side, the company is liable for paying any damages. While the trial is being conducted, the physician is responsible both for the choice of the healthy volunteers and for their care.
Remuneration, freedom of choice, professional guinea pig
Authors: Demarez JP
Published: August 2009

Summary— The law of December 20, 1988 states that a participant in a clinical test without direct therapeutic benefit is not entitled to receive remuneration. Professionalism may be the strongest reason for participating. The law prohibits some participants from receiving an indemnity, not on the basis of healthy vs sick discrimination but when a situation of particular vulnerability or dependence has been established.
Specificity of the phase I trial for cytotoxic drugs in oncology
Authors: Armand JP , Klink‐Alakl M. , Recondo G. , de Forni M.
Published: August 2009

Summary— The phase I trial in oncology follows a very different methodology than in other areas of medicine. Its main objective is the identification of the maximal tolerated dose with short and middle range toxicity limits. In general the therapeutic index of anticancer drugs is narrow and the efficacy of drugs is closely associated with their toxic range: specially hematologic. This toxicity has to be well defined within its nature, its gravity, its dose relationship and its reversibility. It is usually correlated with pharmacokinetic. The cytotoxic agents have as their main target DNA and therefore the long term toxicity is poorly defined and seldom wellknown. The oncology phase I trial is always done in advanced cancer patients and in the great majority of cases after several therapeutic tentative having failed. It is never done in healthy volunteers. Patients have to be informed of the nature of the trial with the possibility of a therapeutic response as an associated objective.
Establishing a phase I unit: organisation
Authors: de Lauture D. , Kahan A. , Pinquier JL
Published: August 2009

Summary— The organisation of a phase I unit must take into account the safety, quality and scientific requirements of such studies. The clinical pharmacology unit demands a highly qualified staff, as well as intensive care equipment. The investigator, generally a clinical pharmacologist who coordinates the different tasks as a project leader, has often to initiate a fruitful collaboration with a specialised consultant staff in order to implement the studies.
Effects of dextronatrin on blood pressure, hematocrit, urinary sodium excretion and sympathetic nerve activity of rats
Authors: Flückiger JP , Deghenghi R. , Waeber B. , Immer HU , Nussberger J. , Brunner HR
Published: August 2009

Summary— The purpose of this investigation was to study in unanesthetized rats the blood pressure, renal and hematocrit responses to dextronatrin, a structural analogue of atrial natriuretic peptides (ANP). The peptide was infused intravenously for 20 min at doses of either 1 or 20 μg/min in binephrectomized rats as well as in rats with intact kidneys. The experiments were started 2 h after preparation of the rats under ether anesthesia. In binephrectomized rats, the small dose of dextronatrin lowered blood pressure and raised hematocrit. In those rats, the larger dose of the investigational peptide had no blood pressure lowering effect, but still increased hematocrit. Dextronatrin had no effect on heart rate, both in rats with and without kidneys. Dextronatrin given at the 1 μg/min dose to normal rats caused a significant increase in urinary Na excretion. The large dose, however, did not modify this parameter. The effect of dextronatrin (1 μg/min for 20 min) on splanchnic nerve activity was evaluated in other normal rats after a recovery period of 24 h from surgical procedure. Integrated nerve activity was found to significantly increase in parallel with heart rate while blood pressure was reduced. Taken together, these results show that a low dose of dextronatrin lowers blood pressure and induces an increase in urinary Na excretion and hematocrit. They also indicate that the blood pressure and renal effects of the peptide are abolished when a high dose is administered. In addition, it appears that the shift of fluid from the intra‐ to the extravascular compartment, reflected in binephrectomized rats by an increase in hematocrit, does not depend on the level of systemic blood pressure. Finally, the present observations suggest that the blood pressure lowering effect of dextronatrin is accompanied in the conscious rat by a stimulation of the sympathetic nervous system.
Action of neurotropin on cold‐induced pain in normal volunteers: a double‐blind placebo study
Authors: Thiebauld C. , Vandeput J. , Lintermans J. , Vandenbosch P.
Published: August 2009

Summary— The analgesic action of neurotropin, a biological compound widely used in Japan with a record of very limited side‐effects, was tested in 8 Caucasian normal volunteers. For the pain test, the subjects were requested to immerse the right hand in ice‐cold water and to report the appearance of the following sensations: pain threshold (PThr) and tolerance to pain (PTol). Pain sensitivity range (PSR) was calculated by difference between PThr and PTol expressed in s from beginning of immersion. Neurotropin tablets or an indistinguishable inert placebo were administered according to a randomized double‐blind cross‐over design and their influence in the pain test was investigated during 2 daily sessions. The effects of both treatments were assessed by calculating the difference between initial and post‐medication values for each pain response parameter. Under placebo the means of all effects were found to be negative, reflecting the appearance of hyperalgesia under repetitive pain conditions, with neurotropin, the effects on PTol and PSR were positive and significantly different from those of placebo. These results are discussed in terms of possible mechanisms of action: neurotropin analgesic activity could be linked to its kinin release‐inhibiting properties or to a reduction in vaso‐constriction and hyperalgesia related to an effect on catecholamines.
Mechanism of action of doxepin in the treatment of chronic urticaria
Authors: Figueiredo A. , Ribeiro CA Fontes , Gonçalo M. , Almeida J. , Poiares‐Baptista A. , Teixeira F.
Published: August 2009

Summary— The present study examined 15 patients previously resistant to conventional antihistamines, in which doxepin at doses in the range of 50–75 mg/day was shown to be effective in treatment of chronic urticaria and without significant adverse side effects. However, some controversy remains about its mechanism of action in this particular disease. The aim of the present study was to examine the muscarinic, H1 and H2 blocking activity of doxepin. The following methods were used: a) gastric acid hypersecretion induced by histamine and carbachol in the pylorus‐ligated rat preparation; b) contractile dose‐response curves to histamine and carbachol in the guinea pig ileum; c) dimaprit‐stimulated guinea pig atrium in vitro. pA2 values were determined for atropine, mepyramine, cimetidine and doxepin. As regards histamine, doxepin (50 mg/kg, po) increased gastric pH and decreased secretion volume, gastric acid concentration and total acid output; with carbachol, doxepin weakly antagonized those values. In the ileum, doxepin competitively antagonized carbachol (pA2 = 7.08) and histamine (pA2 = 9.72); pA2 values for atropine and mepyramine against carbachol and histamine were 9.11 and 8.82, respectively. In the atria, the dose‐response curve to dimaprit was also competitively displaced by cimetidine (pA2 = 6.69) and doxepin (pA2 = 6.00). Doxepin displayed a very high affinity for H1 histaminic receptor, being 8‐fold more potent than mepyramine. Doxepin showed significant H2 blocking activity which was 5 times less potent than that of cimetidine. Doxepin competitively antagonized carbachol in the guinea pig ileum, and was 107 times less potent than atropine. The combined H1, H2 and muscarinic blocking activities of doxepin may contribute towards explaining its clinical efficacy in the treatment of chronic urticaria.
Bupivacaine free plasma levels in children after caudal anaesthesia: influence of pretreatment with diazepam?
Authors: Bruguerolle B. , Giaufre E. , Morisson‐Lacombe G. , Rousset‐Rouviere B. , Arnaud C.
Published: August 2009

Summary— Diazepam‐induced modifications in bupivacaine distribution have been noted in previously reported data investigating the influence of diazepam on bupivacaine plasma levels in children undergoing surgery under caudal block with a mixture of lignocaine and bupivacaine. Possible diazepam‐induced changes in protein binding were therefore examined in this study. Our data did not demonstrate significant modifications in bupivacaine protein binding when diazepam is used concomitantly.
Tissue distribution of dextromoramide in the rat
Authors: Kintz P. , Tracqui A. , Mangin P. , Lugnier AA , Chaumont AJ
Published: August 2009

Summary— The tissue distribution of dextromoramide was studied in rats after the intraperitoneal injection of 0.2 mg/kg of the drug. The pattern of distribution was similar at 15, 30, 60 and 90 min, with the highest concentrations being found in the liver and the myocardium, while other organs were not able to concentrate dextromoramide.
Pharmacokinetics of perindopril and its metabolites in healthy volunteers
Authors: Devissaguet JP , Ammoury N. , Devissaguet M. , Perret L.
Published: August 2009

Summary— Perindopril, an angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to its active diacid metabolite, perindoprilat and to a perindoprilat glucuronide. The pharmacokinetic parameters of perindopril, perindoprilat and perindoprilat glucuronide were evaluated after single administration to healthy volunteers (N = 12) of 8 mg of perindopril tert‐butylamine salt by oral route (treatment A), by intravenous route (bolus in 5 min, treatment B) and of an equimolar dose of perindoprilat (6.1 mg) by intravenous route (infusion over 2 h, treatment C). The treatments were administered as a randomised 3‐way cross‐over design. Plasma samples were collected up to 96 h and urines up to 120 h. Perindopril is rapidly absorbed with an oral bioavailability of 95% and is mainly eliminated by metabolic processes. The formation of perindoprilat is slow and about 20% of the available parent drug is transformed into this metabolite. Elimination profile of perindoprilat is biphasic, with a rapid renal excretion of the free fraction and a long terminal half‐life of the fraction bound to ACE. Perindoprilat glucuronide is mainly obtained from perindopril by a pre‐systemic first pass metabolism.
Inhibition by chlordiazepoxide of adenosine‐stimulated glucagon secretion
Authors: Chapal J. , Roye M. , Petit P. , Loubatières‐Mariani MM
Published: August 2009

Summary—The action of a water soluble benzodiazepine, chlordiazepoxide (CDZ) on the stimulatory effect of adenosine on glucagon secretion from the isolated pancreas of the rat perfused in presence of 2.8 mM glucose was studied. CDZ 10−7and 10−6M had no effectper seon glucagon secretion under our experimental conditions. In contrast, CDZ 10−6M (but not 10−7M) markedly reduced the peak of glucagon secretion provoked by adenosine, 2‐chloroadenosine (1.65 times 10−6M) and by a stable analogue, 5′‐N‐ethylcarboxamidoadenosine or NECA (1.65 times 10−8M). This peripheral interaction between CDZ and adenosine seemed to be specific, since CDZ did not modify the peak of glucagon secretion induced by (‐)isoproterenol (10−8M). Our results demonstrate an inhibitory effect of CDZ on adenosine‐stimulated glucagon secretion.
Time‐related changes in serum perphenazine, striatal3H‐spiperone binding and regional brain acid metabolites of dopamine and 5‐hydroxy‐tryptamine after a single dose of perphenazine
Authors: Mjörndal T. , Persson SÅ
Published: August 2009

Summary—A single dose of perphenazine (5.0 mg/kg) was administered intraperitoneally to male Wistar rats. The time‐related alterations in serum levels of perphenazine, striatal3H‐spiperone bindingex vivoand the regional brain metabolism of dopamine and 5‐hydroxy‐tryptamine were studied. Low serum levels of perphenazine were observed together with increased Kdof3H‐spiperone. No significant changes in Bmaxwere observed. Since Kdof3H‐spiperone binding peaked several hours after the maximal serum levels of perphenazine, perphenazine in serum appeared not to directly reflect the events at the receptor level. The concentrations of 3,4‐dihydroxyphenylacetic acid (DOPAC) and 3‐methoxy, 4‐hydroxyphenylacetic acid (HVA) in the striatum were increased after perphenazine. They were maximal 1–3 h after the drug administration and showed positive correlations (correlation coefficient 0.93 and 0.80, respectively) with the serum levels of perphenazine. Increased levels of HVA were also observed both in the olfactory tubercle and in the frontal cortex. However, in the olfactory tubercle, administration of perphenazine did not significantly increase the DOPAC concentrations. In the olfactory tubercle 5‐hydroxyindoleacetic acid (5‐HIAA) was decreased 1–24 h after administration of perphenazine. In the striatum and in the frontal cortex only slight changes in 5‐HIAA were seen. Thus, in the olfactory tubercle 5‐hydroxytryptaminergic mechanisms could modulate the dopaminergic neurotransmission.
Failure of aerosolized endothelin (ET‐1) to induce bronchial hyperreactivity in the guinea pig
Authors: Lagente V. , Boichot E. , Mencia‐Huerta J. , Braquet P.
Published: August 2009

Summary— Aerosol administration of endothelin (ET‐1) has been shown to provoke a potent bronchoconstriction in the guinea pig. We investigated whether or not, aerosolized ET‐1 induces a bronchial hyperreactivity in the guinea pig. Aerosolized ET‐1 (10 μg/ml for 60 min) did not alter the dose‐response curve, established by successive aerosol administration of acetylcholine (ACh) 3–4 h and 18–24 h after challenge with the peptide. In a second protocol, aerosolized ET‐1 (10 μg/ml for 3 min) induced, in anaesthetized guinea pigs a bronchopulmonary response but did not alter the dose‐response curve to aerosolized ACh established 30 min after the challenge. These results suggest that ET‐1 may participate to the early, but not the late alteration of the bronchopulmonary tone observed during pathophysiological conditions.
Pharmacology of noradrenaline and neuropeptide tyrosine (NPY)‐mediated sympathetic cotransmission
Authors: Lundberg JM , Franco‐Cereceda A. , Hemsén A. , Lacroix JS , Pernow J.
Published: August 2009

Summary—Pharmacological and physiological aspects for neuropeptide Y (NPY) and noradrenaline (NA) cotransmission have been studied in the peripheral sympathetic nervous control of blood vessels, heart, spleen and vas deferens. NPY coexists with NA in large dense cored vesicles and is released compared to NA mainly upon high frequency stimulation or strong reflex sympathetic activation. NPY release is inhibitedviaprejunctional α‐2 adrenoceptors and adenosine receptors but facilitated by angiotensin II or β‐receptor activation. NPY exerts prejunctional inhibitory actions on both NA and NPY release, enhances the vasoconstrictor effect of NA and evokes potent, long‐lasting vasoconstriction. Specific receptor mechanisms for NPY exist at both the pre‐ and postjunctional levels; a large amidated C‐terminal portion of NPY is necessary for receptor binding, inhibition of cyclic AMP formation and vasoconstrictor effects. Denervation results in supersensitivity for both NA and NPY‐evoked vasoconstriction. Reserpine pretreatment is associated with depletion of NA as well as NPY; the effect on NPY is entirely dependent on an intact nerve activity. Reserpine treatment combined with preganglionic denervation depletes NA by 99% while NPY levels are maintained intact. The characteristic appearance of the nerve stimulation evoked vasoconstrictor response with a high correlation to NPY outflow after reserpine treatment, suggests that NPY may be involved as a transmitter in a variety of vascular beds. NPY‐synthesis in ganglia seems to be regulated by nicotinic receptor activity; secondary stimulation by eg reserpine stimulates and nicotine antagonists decrease NPY‐synthesis. Many classical pharmacological agents including guanethidine, clonidine, yohimbine, angiotensin II, nicotine and desipramine influence NPY release. A complex interplay therefore seems to occur at both the pre‐ and postjunctional levels of transmission for the classical transmitter NA and the coexisting peptide NPY, creating a great diversity of chemical signalling potential.