bluuebunny/crossref_metadata_2025 huggingface dataset:
COMPARATIVE PHARMACOKINETICS OF d‐ AND l‐ALPHAMETHYLDOPA IN PLASMA, AQUEOUS HUMOR, AND CEREBROSPINAL FLUID IN RABBITS
Authors: AUCLAIR E. , LAUDE D. , WAINER I. W. , CHAOULOFF F. , ELGHOZI J.L.
Published: August 2009

Summary—The 2 stereoisomers of alphamethyldopa (αMD) were separately injected IV at 3 different doses (3, 10, 30 mg/kg) in anesthetized rabbits. Samples of plasma, aqueous humor (AH), and cerebrospinal fluid (CSF) were collected over a 300‐min period. The concentration of the aminoacid (AA) was determined by liquid chromatography and electrochemical detection. Parameters obtained from kinetic analyses of the plasma concentrations were close to the values reported in other species. Linear elimination kinetics were observed in the dose range studied. A marked dose‐dependent entry of αMD was observed in AH. A stereospecific active transport of αMD was evidenced in the AH since the concentration of the l‐isomer reached values above the plasma levels. CSF entry of the AA was small when compared to AH kinetics. A limited passive diffusion of the AA in the brain could account for this phenomenon. However, greater availability of the l‐stereoisomer was still observed in CSF. These αMD kinetic analyses illustrate the adaptation of AH and CSF removal procedures to the pharmacokinetic studies of the brain and ocular entry of AA isomers.
SPONTANEOUS AND OUABAIN‐INDUCED EFLUX OF CATECHOLAMINES AND DIHYDROXYPHENYLGLYCOL IN TWO CANINE BLOOD VESSELS
Authors: BRANCO D. , OSSWALD W.
Published: August 2009

Summary— The spontaneous efflux of endogenous noradrenaline, dopamine, dihydroxyphenylglycol (DOPEG) from adrenergic nerve endings of 2 canine blood vessels (the mesenteric artery and the saphenous vein) were studied during 8 successive incubation periods of 15 min each. Extraneuronal uptake and 0‐methylation were minimized by the presence of adequate concentrations of tropolone and hydrocortisone.

Both vessels had an efflux characterized by a decline in the 3 catechols, which was most marked for noradrenaline; the mesenteric artery lost larger amounts than the saphenous vein. Ouabain caused a large increase in the efflux of noradrenaline and dopamine and a reduction of DOPEG efflux. Cocaine had only a modest effect, more evident in the case of the mesenteric artery, increasing noradrenaline and reducing DOPEG effluxes. The combination of ouabain and cocaine had no additive effects, and the effects of ouabain were even reduced (on some parameters) by cocaine.

Accordingly, the noradrenaline: DOPEG ratio was markedly increased by ouabain, but not by cocaine; cocaine significantly reduced the effects of ouabain. The ratio dopamine: noradrenaline was decreased by cocaine and by ouabain. Comparison of tissue content and efflux allowed us to conclude that apparently no significant de novo synthesis of noradrenaline occurred during the incubation period.

We conclude that a fast and early component of spontaneous efflux is due to loss from the neurons and that its greater magnitude in the mesenteric artery may be due to differences in neuronal [Na+] and/or to differences in neuronal membrane adenosine triphosphatase activity. The results also suggest that neuronal reuptake plays only a minor role in the handling of spontaneously released noradrenaline.
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.
EFFECTS OF PROMETHAZINE ON ISCHEMIC AND REPERFUSION ARRHYTHMIAS IN RAT HEART
Authors: ROCHETTE L. , YAO‐KOUAME J. , BRALET J. , OPIE L.H.
Published: August 2009

Summary—The effects of the H1‐receptor antagonists promethazine, mepyramine, and chlorpheniramine on ischemic and reperfusion arrhythmias were studied in the isolated perfused rat heart. Promethazine reduced both ischemic and reperfusion arrhythmias (2times 10‐6M‐7.5times 10‐6M). Mepyramine and chlorpheniramine decreased these arrhythmias but at concentrations about 10 times higher. The H2‐blockers cimetidine and ranitidine had no antiarrhythmic effect. Promethazine also: (i) increased release of noradrenaline by the heart; and (ii) increased coronary flow in the reperfusion period and in some mildly ischemic zones. It is proposed that promethazine exerts most of its antiarrhythmic effects by a nonspecific mechanism, possibly membrane stabilization; in addition, enhanced coronary flow may play a role.
COMPARATIVE EFFECTS OF ACEBUTOLOL AND LABETALOL ON PERIPHERAL HEMODYNAMICS IN HEALTHY VOLUNTEERS
Authors: WURM M. , KANTELIP J.P. , DUCHENE‐MARULLAZ P.
Published: August 2009

Summary—

During a 28‐day treatment period, 10 healthy volunteers in a cross‐over, double‐blind study received at random 200 mg of either acebutolol or labetalol twice a day. Each treatment period was followed by administration of a placebo over an equal length of time.

Only acebutolol reduced heart rate measured in the supine position significantly at rest, whereas acebutolol and labetalol reduced it significantly after exercise on the treadmill.

Only acebutolol lowered humeral pressure at rest but not after exercise. Neither drug produced a change in blood pressure in the ankle or in the first toe at rest or after exercise.

Blood flow measured by plethysmography was increased by labetalol in the calf by comparison with placebo and in the first toe by comparison with placebo and acebutolol.

Labetalol lowered peripheral resistance significantly in comparison with placebo in the calf and first toe. Acebutolol tended to lower the resistance insignificantly in the calf but to increase resistance in the first toe.
ALGEBRAIC POTENTIAL OF THE HILL EQUATION AS AN ALTERNATIVE TOOL FOR PLOTTING DOSE (OR TIME)/EFFECTS RELATIONSHIPS IN TOXICOLOGY: A THEORETICAL STUDY
Authors: BOUNIAS M.
Published: August 2009

Summary— Use of the Hill equation in plotting the results of toxicological experiments offers the following advantages:

In dose/effect relationships, the maximum response RM can be accurately determined by means of a described new noniterative algebraic method, from both hyperbolic and sigmoidal responses expressed in natural (nontransformed) units. The Hill coefficient (n) and the dose giving 50% (f50) or X% (fx) of RM, as well as their SD, are accurately deduced.

In time‐course experiments with sigmoidal shape, an additional set of parameters, readily available from the former basic 3, makes it possible to avoid arbitrary choices, such as the time at which a percentage or mortality is considered. The slopes of the tangents at the inflexion point (maximum rate of response) and at half‐maximum effect, then the coordinates of these points and the horizontal intercept of the tangent at inflexion point (as an index of initial lag‐phase) will give increasing and decreasing functions of doses, respectively, depending on RM, f50, and (n).

The processes described first allow the classical parameters LD50 (or LDx) and LT50 (or LTx: X%‐lethality time) to be calculated with high algebraic accuracy, in addition to RM and (n), both of which are of great interest in the general case of ligand‐receptor interactions. Thus, the deduced set of additional indexes, not readily available from classical “Probits‐type” transformations, eliminates the mortgage of subjective operations.
BOPINDOLOL: LONG‐TERM EFFECTS ON BLOOD PRESSURE, RENAL FUNCTION, PLASMA RENIN ACTIVITY, AND PLASMA ALDOSTERONE IN MILD‐TO‐MODERATE ESSENTIAL HYPERTENSION
Authors: SHOHAT J. , MODAN M. , ROSENFELD J.B.
Published: August 2009

Summary— Bopindolol was given to hypertensive patients in a single daily dose ranging from 1 to 4 mg. In 86.7% of the patients diastolic blood pressure was reduced by 10 mmHg or more, or lowered to below 90 mmHg, already during the first 4 wk of treatment. Inulin clearance decreased by 10%; PAH and creatinine clearance, blood urea nitrogen, and serum creatinine were unchanged.
EFFECT OF NIFEDIPINE ON THYROTROPIN, PROLACTIN, AND THYROID HORMONE RELEASE IN MAN: A PLACEBO‐CONTROLLED STUDY
Authors: VALENSI P. , PERRET G. , VASSY R. , UZZAN B. , NICOLAS P. , ATTALI J.R.
Published: August 2009

Summary—Nifedipine (10 mgtid) or placebo was administered in a randomized double‐blind trial for 1 wk to 2 groups of 10 mildly hypertensive euthyroid patients. Hormonal concentrations (thyrotropin [TSH], prolactin [PRL], thyroxin, triiodothyronine, and reverse triiodothyronine) before and during a TRH test were assessed in the 2 groups before (D0) and after (D7) each treatment. Parameters of the TRH test were determined (peak values, area under the curve [AUC], release [Kr], and elimination [Ke] rate constants) and their D7:D0 ratios were compared in the 2 groups. The TSH (peak values and Kr) and PRL (peak values and AUC) responses to TRH were significantly decreased in the nifedipine group compared to the placebo group. Neither basal nor TRH‐stimulated thyroid hormone levels were modified. These results confirm experimental data but seem to be clinically irrelevant.
PHARMACOLOGICAL MODULATION OF NEUROGENIC INFLAMMATION
Authors: SCHUMANN H.H. , LANGNER A. , RATHSACK R. , BEKEMEIER H. , HIRSCHELMANN R.
Published: August 2009

Summary— A neurogenic inflammation was induced by electrical stimulation of the exposed saphenous or sciatic nerve of male rats. The increase in paw weight of the stimulated leg was used as parameter for degree of inflammation. The content of substance P decreased significantly in the skin supplied by the antidromic stimulated nerves. Substances were tested whose effectivity in neurogenic inflammation is as yet unknown. Inhibition of the angiotensin converting enzyme by the inhibitor captopril did not yield an indirect reference for a causative role of substance P in neurogenic inflammation. The activity of catecholamines refers to the possible importance of blood vessel and/or cyclic nucleotide level alteration in this special type of inflammation.
EFFECT OF DOPAMINE, IBOPAMINE, AND EPININE ON α‐ AND β‐ADRENOCEPTORS IN CANINE PULMONARY CIRCULATION
Authors: SHEBUSKI R.J. , SMITH J.M. , RUFFOLO R.
Published: August 2009

Summary—Dopamine has been widely utilized in the treatment of acute congestive heart failure. Ibopamine, the diisobutyrate ester ofN‐methyldopamine (epinine), is a novel inotropic agent that, unlike dopamine, is orally active. In clinical studies at doses that produce favorable hemodynamic responses, ibopamine and dopamine can evoke a slight and transient increase in pulmonary artery pressure and pulmonary capillary wedge pressure, an effect that is no longer apparent 1 h after administration. We have previously demonstrated in anesthetized dogs that this effect is due to stimulation of α‐adrenoceptors in the pulmonary circulation by dopamine and ibopamine, as well as by the active form of ibopamine, epinine. The aim of the present investigation was to determine how dopamine, ibopamine, and epinine interact with β‐adrenoceptors in the canine pulmonary circulation, since this activity may serve to offset the α‐adrenoceptor‐mediated pulmonary vasoconstrictor responses. Intraarterial injection of dopamine, ibopamine, and epinine resulted in dose‐dependent pulmonary vasoconstrictor responses with a maximum increase of approximately 50–60% above resting pulmonary vascular tone. When animals were pretreated with propranolol (1 mg/kg iv) to block β‐adrenoceptors, pulmonary vasoconstrictor responses to dopamine were unchanged, whereas pulmonary vasopressor responses to ibopamine and epinine were significantly potentiated, especially for epinine. Upon intraduodenal administration of a therapeutically effective dose of ibopamine (i.e.36 mg/kg) to normal dogs, virtually no pulmonary pressor response was observed. However, administration of this same dose of ibopamine to dogs pretreated with propranolol (1 mg/kg iv) resulted in a marked pulmonary pressor response. These data indicate that epinine, and therefore the parent compound ibopamine, have the capacity to stimulate β2‐adrenoceptors in the pulmonary circulation to a far greater degree than dopamine, and that this activity serves to offset, at least in part, the α‐adrenoceptor‐mediated pulmonary vasoconstriction that occurs in response to ibopamine.
PANCREATIC SECRETORY AND TROPHIC RESPONSE TO CAERULEIN IN RATS: EFFECT OF PROGLUMIDE AND LORGLUMIDE
Authors: VARGA G. , PAPP M. , SCARPIGNATO C.
Published: August 2009

Summary—The effect of proglumide and lorglumide, two CCK‐receptor antagonists, on caerulein‐induced pancreatic secretion and growth was studied in the rat. In anaesthetised animals, caerulein (1 μg/kg) significantly increased the volume of pancreatic juice and protein output. Lorglumide (5 and 10 mg/kg), administered intraperitoneally 15 min before stimulation, reduced peptide‐induced pancreatic exocrine secretion. By contrast, proglumide (100 and 400 mg/kg) was completely ineffective. In experiments dealing with the trophic effect of caerulein, both drugs were administered alone or combined with the peptide (1 μ/g/kg) 3 times daily for 5 d. Saline‐treated rats served as controls. At the end of the experiment, rats were sacrificed, and growth and composition of pancreatic tissue were determined. Pretreatment of the animals with either proglumide or lorglumide did not affect pancreatic size and composition. Caerulein increased the weight of the pancreas, the total pancreatic protein, trypsin, amylase, and DNA content. After pretreatment with proglumide, all these parameters were not significantly different from those obtained with caerulein alone. In contrast, when lorglumide was given together with caerulein, it significantly reduced caerulein‐induced pancreatic growth and decreased enzymatic protein content of the gland. These results show that lorglumide is a much more potent and effective CCK‐receptor antagonist than proglumide. Its ability to antagonize the pancreatic secretory and trophic action of a CCK‐analogue (i.e. caerulein) supports the view that these physiological actions of CCK are mediated through an interaction of the hormone with specific receptors.
PLASMA CATECHOLAMINES AND ADRENOCEPTORS AFTER CHRONIC SINOAORTIC DENERVATION IN DOGS
Authors: VALET P. , DAMASE‐MICHEL C. , MONTASTRUC J.‐L. , MONTASTRUC P.
Published: August 2009

Summary—Chronic sinoaortic denervation (SAD) performed by section of both carotid and aortic nerves induced a significant and sustained increase in blood pressure and heart rate in conscious dogs; under our experimental conditions, the values of systolic blood pressure and heart rate were never lower than 190 mmHg and 120 beats/min, respectively. The present long‐term study (8 mo) investigated the time‐course of plasma catecholamine levels and circulating blood cell adrenoceptor (leukocyte beta2and platelet alpha2) number. Catecholamine plasma levels were highly correlated with the variations of leukocyte beta adrenoceptors (measured by [125I]cyanopindolol binding and characterized as a beta2receptor in dogs). These two parameters followed a biphasic pattern after SAD: during the first 2 mo, significant increases in noradrenaline and adrenaline levels were associated with a decrease in leukocyte beta2adrenoceptor number; from the 4th month, they slowly returned to normal values, although blood pressure remained elevated. By contrast, platelet alpha2adrenoceptor number (measured by [3H]yohimbine binding) did not follow this pattern since it remained lower than before SAD during the whole experiment. Finally, the development (but not the maintenance) of SAD‐induced hypertension is associated with an increase in sympathetic tone. Only leukocyte beta2(and not platelet alpha2) adrenoceptors are directly regulated by the endogenous levels of catecholamines.
SK&F 89124, A POTENT AND SELECTIVE AGONIST AT PREJUNCTIONAL DOPAMINE RECEPTORS
Authors: HIEBLE J.P. , SULPIZIO A.C. , SARAU H.M. , FLAIM K.E. , BLUMBERG A.L. , McCAFFERTY J.P. , ZEID R.L.
Published: August 2009

Summary—SK&F 89124 (4‐[2‐(N,N‐di‐n‐propylamino)ethyl]‐7‐hydroxy‐2(3H) indolone) can be considered as a derivative ofN,N‐di‐n‐propyldopamine (DPDA) in which themeta‐hydroxyl is replaced by a cyclic amide function. SK&F 89124 is at least one order of magnitude more potent than DPDA as an agonist at peripheral inhibitory prejunctional dopamine receptors (DA2receptors) in the isolated perfused rabbit ear artery. A potent agonist action of SK&F 89124 at the DA2receptor can also be demonstrated by inhibition of radioactive overflow from prelabelled canine coronary artery or saphenous vein, and in the anesthetized dog as an inhibition of the tachycardia induced by cardioaccelerator nerve stimulation or the increase in hind‐limb perfusion pressure induced by stimulation of the lumbar sympathetic chain. SK&F 89124 is a potent inhibitor of the binding of [3H]spiroperidol to D2receptors in bovine pituitary homogenates.

High concentrations of SK&F 89124 do not activate the adenylate cyclase D1receptor in rat caudate homogenates, nor produce activation of α2‐adrenoceptors or H2‐histamine receptors in the guinea pig atrium. Although some α1‐adrenoceptor mediated vasoconstriction is produced in the rabbit ear artery and rabbit aorta, the concentrations required are several orders of magnitude higher than those active at the DA2receptor. From these data it is evident that this structural modification can increase both the potency and selectivity of DPDA as a DA2receptor agonist. The potency and selectivity of SK&F 89124 make this agent a useful tool for determination of the functional role of the DA2receptor.
ROLE OF ENDOTHELIUM ON PHENYLEPHRINE‐TRIGGERED CONTRACTILE EVENTS IN AORTA OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: AUGUET M. , DELAFLOTTE S. , PIROTZKY E. , CLOSTRE F. , BRAQUET P.
Published: August 2009

Summary—The ability of basal release of endothelium derived relaxing factor (EDRF) to alter contractile events in phenylephrine (PE)‐triggered contraction was tested on ring segments of the thoracic aorta removed from spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY). In normal medium, PE (1 μM) elicited similar whole contractions in endothelium denuded arteries of SHR and WKY. The presence of endothelium only reduced the WKY response. On aorta incubated in a Ca2+free‐medium, PE (1 μM) induced an initial phasic contraction due to intracellular Ca2+release. This was followed by a tonic contraction after Ca2+(2.5 mM) was restored to the bath. This sustained contraction was dependent on extracellular calcium influx. Identical phasic and tonic contractions were observed in endothelium denuded rings of SHR and WKY. However, the presence of endothelium only reduced the sustained contraction of WKY arteries. When experiments were carried out in medium containing D600 (1 μM), the presence of endothelium diminished the whole contraction of both SHR and WKY rings whereas the sustained but not the phasic contraction of WKY was also inhibited. This inhibitory effect of endothelium on WKY sustained contraction was significantly higher in the presence of D600. The calcium antagonist reduced both the whole and the tonic contractions of all preparations but was ineffective on the phasic one. The D600 inhibitory action on the sustained contraction was more prononced in denuded SHR rings than in the corresponding WKY arteries. Thus it is concluded that there is a basal influence of endothelium in both SHR and WKY. Under our conditions, the endothelial function inhibited the extracellular Ca2+influx and especially the part of Ca2+influx insensitive to D600. This part of Ca2+influx is diminished in SHR and thus the efficacy of endothelium products (e.g.EDRF) is reduced in this strain.
EFFECT OF APOMORPHINE ON ADRENAL MEDULLARY CATECHOLAMINE LEVELS
Authors: MONTASTRUC J.L. , GAILLARD G. , RASCOL O. , TRAN M.A. , MONTASTRUC P.
Published: August 2009

Summary—The effects of the dopamine receptor agonist, apomorphine, on the total catecholamine content of the adrenal medulla were studied in normotensive rats. Apomorphine (3, 15, 30 mg/kg SC) induced a dose‐dependent decrease in catecholamine content of the adrenal gland. The action of apomorphine was suppressed by previous treatment with the non specific dopamine receptor antagonist, haloperidol (9 mg/kg 1P), or the D2 antagonist domperidone (2 mg/kg 1P), but not by the D1 antagonist SCH 23390 (1 mg/kg 1P). The apomorphine‐induced decrease in adrenal catecholamine concentration was suppressed by denervation of the adrenal medulla,i.e.unilateral section of splanchnic fibers performed 5 days before. These results show that, under our experimental conditions, the effect of apomorphine is due to the activation of D2 dopamine receptors probably located on splanchnic nerve endings and suggest the existence of a peripheral D2 dopaminergic system which modulates adrenal medullary catecholamine content.
ACTIVATORS AND INACTIVATORS OF CALCIUM CHANNELS: EFFECTS IN THE CENTRAL NERVOUS SYSTEM
Authors: SPEDDINGS M. , KILPATRICK A.T. , ALPS B.J.
Published: August 2009

Summary—The interactions of calcium antagonists or channel activators with the different classes of calcium channel are reviewed with particular emphasis on interactions with neuronal tissue; reasons for the failure of calcium antagonists to inhibit neurotransmitter release under normal circumstances are outlined. Calcium antagonists may be protective in several pathological situations and the possibilities of protection against ischaemic damage in the central nervous system are evaluated.
ARTERIAL BARORECEPTOR REFLEX AND CALCIUM ANTAGONISTS
Authors: BERDEAUX A.
Published: August 2009

Summary—The tachycardia elicited by decreases in aortic pressure produced by various calcium antagonists, regardless of their chemical structures, is not always simply related to the reduction in pressure. Several experimental and clinical experiments have clearly demonstrated that some of these compounds interfer with the baroreceptor reflex control of heart rate. The voltage‐dependent calcium channel blockade induced by these antagonists is probably not involved in the baroreceptor mechanotransduction, but central modulation of the baroreceptor reflex is probably an important site for action of these drugs at therapeutic levels. During chronic treatment of hypertension with calcium antagonists, a resetting of the reflex occurred with parallel shift of the set‐point and of the baroreceptor reflex‐response curve towards lower pressures, thus explaining the lack of change in heart rate despite a permanent reduction in blood pressure under these conditions. However, these effects of calcium antagonists on the baroreceptor reflex do not provide evidence that such interactions could play a role in their antihypertensive action during chronic therapy.
CHARACTERISTICS OF THE DOPAMINE RECEPTORS INVOLVED IN THE ANORECTIC EFFECTS OF APOMORPHINE IN MICE
Authors: DUTERTE‐BOUCHER D. , NAUDIN B. , COSTENTIN J.
Published: August 2009

Summary—In food‐deprived mice apomorphine injected SC induced a brief (15–30 min) dose‐dependent (30– 150 μg/kg) reduction in food intake. This effect occurred in naive mice as well as in mice habituated to a food deprivation procedure. The anorectic effect of apomorphine (150 μg/kg SC) was antagonized by sulpiride (ID50= 8.6 mg/kg) and by haloperidol (ID50= 66 μg/kg) but domperidone was ineffective (250 μg/kg). Mice submitted to a semi‐chronic (6 d) blockade of dopamine receptors by haloperidol or injected intracerebroventricularly with 125 μg 6‐hydroxydopamine 21 d before testing failed to develop a hypersensitivity to the anorectic effect of apomorphine (60 μg/kg).

Although a single apomorphine injection (5 mg/kg) induced tolerance to the hypothermic effect of a second apomorphine injection of 150 μg/kg, it did not modify the anorectic effect. Repeated apomorphine injection (5times5 mg/kg) resulted in a slight but significant reduction in apomorphine‐induced anorexia. A similarly significant reduction was not observed in mice submitted to repeated injections of dexamphetamine (5times5 mg/kg).
RENIN INHIBITION: IMMUNOLOGICAL PROCEDURES AND RENIN INHIBITOR PEPTIDES
Authors: CORVOL P. , MENARD J.
Published: August 2009

Summary— Renin inhibitors represent an alternative to angiotensin‐converting enzyme inhibitors (ACEI) for the treatment of hypertension. They inhibit the renin‐angiotensin system at its first and rate limiting step, the renin‐angiotensinogen reaction. Passive administration of angiotensinogen or renin antibodies lowers blood pressure in primates to the same extent as ACEI. Chronic active immunization against renin decreases blood pressure markedly in normotensive marmosets. Renin can be inhibited by peptides derived from its prosegment. The design of compounds based on pepstatin and on angiotensinogen sequence has led to very potent and specific human renin inhibitors. Such inhibitors are active by the IV route in primates but still lack of good oral activity.
PHARMACOKINETICS AND EFFECTS ON EXERCISE HEART RATE OF PK 11195 (52028 RP), AN ANTAGONIST OF PERIPHERAL BENZODIAZEPINE RECEPTORS, IN HEALTHY VOLUNTEERS
Authors: FERRY A. , JAILLON P. , LECOCQ B. , LECOCQ V. , JOZEFCZAK C.
Published: August 2009

Summary—PK 11195 (or 52028 RP; 1‐(2‐chlorophenyl)‐N‐methyl‐N‐(1‐methylpropyl)‐3‐isoquinoline carboxamide), an antagonist of the peripheral‐type benzodiazepine receptors which are coupled to calcium channels, was administered to 10 healthy volunteers in order to study the pharmacokinetics and cardiovascular effects of the drug. PK 11195 was randomly administered intravenously (10 mg) and orally in three single dosages (100, 200 and 400 mg). Placebo was only given orally. Heart rate and blood pressure were recorded at rest and during exercise tests which were performed at 0, 1, 3, 6 and 24 h after dosing on each study day.

Summary—The results showed that after IV administration, PK 11195 was rapidly distributed in two or three open compartments. Its elimination T1/2was short (3.7 ± 3.0 h) with high interindividual variability. After oral ingestion the pharmacokinetics of PK 11195 were linear over the range of 100–400 mg single oral doses with a stable absolute bioavailability (33%). T1/2elimination was prolonged (7–12 h) and the presence of secondary increases in plasma concentration at 8–10 h and 22–24 h after drug absorption may have been related to enterohepatic cycling. No unchanged PK 11195 could be detected in urine. PK 11195 did not significantly modify heart rate and blood pressure at rest or during exercise and was well tolerated by the subjects. These data suggest a high inter‐individual variability in PK 11195 disposition with extensive metabolism in normal exercising volunteers.
EFFECTS OF ACUTE AND CHRONIC ADMINISTRATION OF TWO ANTIBIOTICS, AZTREONAM AND GENTAMICIN, ALONE OR IN COMBINATION, ON “OPEN‐FIELD TEST” IN MICE
Authors: DE ANGELIS L.
Published: August 2009

Summary— A study aimed at investigating the behavioural effects of aztreonam and gentamicin, given separately or in combination, was carried out in mice. Animals were randomly assigned to two test conditions: acute and chronic treatment. Those receiving acute treatment had a single IP injection 60 min before the test. Those receiving chronic treatment had IP injections once daily for 5 successive days prior to the test.

Behavioural patterns (ambulation, rearing, grooming and defecation) were assessed using the “open‐field” test. The results indicate that, both after single and multiple dosing, aztreonam (10, 40 and 80 mg/kg IP) and/or gentamicin (10 mg/kg IP) do produce changes in the behaviour of animals. A rate increasing effect for certain behaviours (rearing, grooming and defecation) and a reduction in other behaviours (ambulation) seems to occur.
Kinetic analysis of the binding of nomegestrol acetate to the progesterone receptors in rat uterus by competition studies
Authors: Botella J. , Duc I. , Delansorne R. , Paris J. , Lahlou B.
Published: August 2009

Summary— The characteristics of binding (Kinetic and equilibrium binding analysis) of nomegestrol acetate (NOM, 17 α‐acetoxy‐6 α‐methyl‐19‐nor‐pregna‐4.6‐diene‐3.20‐dione) to the progesterone receptor (PgR) in rat uterine cytosolic fraction were determined in comparison to progesterone (P), to fully appreciate the amplitude and specificity of the induced biological response. Since an appropriate radio‐labelled form of this steroid molecule was not available, competition studies were performed against the synthetic progestin: [3H]‐Organon 2058 ([3H]‐ORG). This allowed a direct comparison between the unlabelled forms of NOM and P, the kinetic constants of which were respectively: Inhibition constant (K_1): 22.8 and 34.3 nM; Association rate constant (k1): 0.39times103 and 0.21 times 103 M−1.s−1; Dissociation rate constant (k‐1): 1.81 times 10−5 and 2.16times10−5 s−1. These results are much more informative than the mere determination of relative binding affinities which only reflect the specificity of the PgR. It was concluded that NOM behaves like the natural hormone in the cytosol of rat uterus.
Effects of CRL 41034 on the adrenergic neuroeffector interaction in the canine saphenous vein
Authors: Boulanger C. , Flavahan NA , Katusic ZS , Komori K. , Vos AA , Vanhoutte PM
Published: August 2009

Summary—Experiments were designed to determine the effect of CRL 41034, a buflomedil analogue, on the adrenergic responsiveness of canine veins. Rings of saphenous vein (without endothelium) were suspended for isometric tension recording in modified Krebs‐Ringer bicarbonate solution at 37°C. CRL 41034 produced a concentration‐dependent inhibition of the contractions evoked by the alpha adrenergic agonists norepinephrine, phenylephrine and UK 14304 which was insensitive to the blockade of neuronal uptake by cocaine. CRL 41034 was more potent in inhibiting the concentration‐dependent contractions evoked by UK 14304 than those by phenylephrine and the antagonism it caused against the response to UK 14304 fulfilled the criteria for competitivity. CRL 41034, at 10−5M significantly depressed, and at 10−4M abolished the contractions induced by electrical stimulation of the adrenergic nerves and those evoked by the indirect sympathomimetic amine tyramine. Strips of canine saphenous vein were superfused after incubation with [3H] norepinephrine. During sympathetic nerve activation, CRL 41304 increased the stimulation‐evoked overflow of [3H] norepinephrine and 3‐methoxy‐4‐dihydroxyphenylglycol; in the presence of rauwolscine the compound only increased the stimulation‐evoked overflow of 3,4‐dihydroxyphenylglycol. These experiments suggest that the major vascular effects of CRL 41034 in canine veins are blockade of alpha2‐adrenoceptors on vascular smooth muscle, and inhibition of prejunctional alpha2‐adrenoceptors on adrenergic nerve endings.
Hemodynamic and cardiac effects of spiraprilat in normal and sodium depleted conscious dogs
Authors: Gérard JL , Pussard E. , Berdeaux A. , Giudicelli JF
Published: August 2009

Summary— The cardiac and hemodynamic effects of 3 doses (0.1, 0.3 and 1 mg/kg, iv) of spiraprilat, the diacid active metabolite of the new angiotensin I converting enzyme inhibitor spirapril, have been investigated and compared to those of saline in chronically implanted conscious dogs at rest. Under a normal sodium diet, spiraprilat, 1 mg/kg, induced significant (at least P<0.05) decreases in mean arterial pressure (MAP, −11%), total peripheral resistance (TPR, −21%), left ventricular end diastolic pressure (LVEDP, −15%) and increases in heart rate (HR, + 12%) and cardiac output (CO, + 16%) whereas dP/dtmax remained unchanged. Spiraprilat‐induced tachycardia was not modified by propranolol pre‐treatment but was abolished by previous administration of the propranolol‐N‐methylatropine combination. Spiraprilat, 0.1 mg/kg, did not affect any parameter, but spiraprilat, 0.3 mg/kg, showed intermediate effects. Finally, sodium depletion strongly potentiated spiraprilat effects on MAP, TPR, LVEDP, HR and CO. We conclude that: a), in conscious dogs under normal sodium diet, spiraprilat reduces TPR and MAP through peripheral vasodilating properties; b), spiraprilat‐induced tachycardia is mainly related to parasympathetic tone withdrawal, possibly in relation with high and low pressure baroreceptors deactivation; and c), sodium depletion considerably potentiates spiraprilat cardiac and hemodynamic effects.
Reduction of [3H]6‐nitroquipazine‐labelled 5‐hydroxytryptamine uptake sites in rat brain by 3,4‐methylenedioxymethamphetamine
Authors: Hashimoto K. , Goromaru T.
Published: August 2009

Summary—3,4‐Methylenedioxymethamphetamine (MDMA; Ecstasy) is a known neurotoxin to 5‐hydroxytryptamine (5‐HT; serotonin) nerve terminals. It has recently been demonstrated that [3H]6‐nitroquipazine is a new radioligand for studying the 5‐HT transport system in brain. Therefore, we examined the effects of repeated systemic administration (10 mg/kg ip, twice daily for 3 d) of MDMA on [3H]6‐nitroquipazine‐labelled 5‐HT uptake sites in rat brain. Marked reductions in the concentrations of 5‐HT and its major metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) were observed in the cerebral cortex 1 week after the last injection of MDMA. In addition, the density of [3H]6‐nitroquipazine‐labelled 5‐HT uptake sites was significantly decreased by MDMA. Furthermore, the reduction of 5‐HT and 5‐HIAA content and the density of [3H]6‐nitroquipazine‐labelled 5‐HT uptake sites by MDMA were significantly prevented by co‐administration of 6‐nitroquipazine (5 mg/kg), a very potent and selective 5‐HT uptake inhibitor. The present results indicate that the 5‐HT uptake carrier plays an important role in the neurotoxic action of MDMA.
Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers
Authors: Drouet‐Coassolo C. , Iliadis A. , Coassolo P. , Antoni M. , Cano JP
Published: August 2009

Summary— The pharmacokinetic behaviour of flunitrazepam and its main active metabolite, N‐desmethyl flunitrazepam, was investigated in 12 patients with liver disease (cirrhosis or hepatitis) compared to 6 healthy volunteers. A gas‐liquid chromatographic method allowing for simultaneous determination of flunitrazepam and N‐desmethyl flunitrazepam in plasma samples was developed. The accuracy and the precision near the quantification limit of ca. 1 ng/ml were better than 5%.

Plasma levels of flunitrazepam were not significantly altered by hepatic failure, whereas plasma levels of N‐desmethyl flunitrazepam were lower in patients than in heathly subjects. Pharmacokinetic parameters did not differ significantly between healthy subjects and liver disease patients: the oral clearance was 3.5 ± 0.8, 3.5 ± 1.9 and 4.0 ± 1.2 ml/min/kg, respectively in healthy subjects, patients with hepatitis and patients with cirrhosis. The apparent elimination half‐life was 22 ± 5 h in healthy subjects, 25 ± 10 h in patients with hepatitis and 20 ± 6 h in patients with cirrhosis. However, the expected increase of the drug free fraction during liver disease could decrease the therapeutic and toxic ranges of flunitrazepam in these patients.
The effects of alprazolam, quazepam and diazepam on saccadic eye movements, parameters of psychomotor function and the EEG
Authors: Blom MW , Bartel PR , de Sommers K. , Van der Meyden CH , Becker PJ
Published: August 2009

Summary— The effects of a single oral dose of alprazolam (1 mg), quazepam (15 mg) and diazepam (10 mg) on the peak saccadic velocity (PSV) of saccadic eye movements (SEM), the Sternberg memory scanning and choice reaction time (SMS‐CRT), critical flicker fusion frequency (CFFF), spectral analysis of the EEG and a mood scale were assessed in 9 healthy volunteers in a double‐blind, placebo‐controlled crossover study. Alprazolam revealed greater sedative effects than diazepam in the above‐mentioned tests. Quazepam had the least sedative effect of the 3 drugs tested, showed a time lag at the onset of its effects and a more prolonged effect on psychomotor impairment than reported previously.
Tianeptine and its main metabolite. Disposition in chronic renal failure and haemodialysis
Authors: Salvadori C. , Merdjan H. , Brouard R. , Baumelou A. , Nicot G. , Friès D.
Published: August 2009

Summary— The disposition of the antidepressant tianeptine and its MC5 metabolite (pentanoic acid analogue of tianeptine) was studied following a single 12.5 mg oral dose of tianeptine sodium salt in 20 patients with chronic renal failure. In 12 patients (group I) having a creatinine clearance of less than 19 mlmin−1 the pharmacokinetics parameters for tianeptine and MC5 metabolite were determined and compared with those obtained in a matched control group (group II). The other 8 patients (group III) were functionally anephric and were studied during 1 dialysis to assess the haemodialysis clearances of tianeptine and MC5 metabolite. The comparison between groups I and II showed that renal failure did not appear to affect the disposition of parent tianeptine. However, the MC5 metabolite terminal half‐life was found to be increased in renal patients compared to controls (14.2 ± 9.3 h vs 4.9 ± 1.7 h). Due to a large interindividual variability the difference did not reach a significant level (P = 0.054). According to the antidepressant activity of the MC5 metabolite in pharmacological tests, the sustained rise in its plasma level suggests that a reduced daily dose should be administered and 12.5 mg of tianeptine should be given twice daily to patients with chronic renal failure. In patients from group III elimination of the compounds by haemodialysis was found to be low. The dialysis clearances were 3.9 ± 9.9 ml±min−1 and 19.2 ± 8.6 ml±min−1 for tianeptine and its MC5 metabolite respectively. This low dialysability has 2 clinical implications. Firstly, patients currently undergoing haemodialysis and treated by tianeptine could be given the drug without taking dialysis into account. Secondly, haemodialysis does not appear to be an effective method for tianeptine elimination in cases of overdosage.
Effect‐kinetic characterization of dimethindene maleate following oral administration (Fenistil, Tropfen)
Authors: Rehn D. , Geissler H. , Schuster O. , Lukas H. , Hennings G.
Published: August 2009

Summary— Dimethindene maleate is a well known H1‐receptor antagonist with strong affinity to the H1‐receptor. In order to evaluate the time course of its activity, dimethindene maleate was investigated in a histamine provocation model in man. Eight healthy male volunteers were treated either with 4 mg dimethindene maleate using a commercially available solution (Fenistil, Tropfen) or an identically appearing placebo solution (po) following a double‐blind, crossover study design. Intracutaneous histamine injections were administered at ‐ 1, 2, 5, 14, 17, 20, 23, 26 and 29 h following drug administration. Areas of flares and weals were measured 5, 10, 20, and 30 min following histamine provocation.

A strong inhibition of the development of flares and weals was observed to be more pronounced in flares than in weals. Baseline adjusted areas under the curve differ statistically significantly following verum and placebo treatment conditions (P = 0.0028). According to the time schedule of the study maximal effects were observed at time point 5 h. The mean residence times of the inhibitory effects were calculated to be ± 13 h compared to the mean residence times of dimethindene blood levels of ± 8 h indicating a non‐linear relationship between blood level and effect.
Methods of drug protein binding determinations
Authors: Sebille B.
Published: August 2009

Summary— The determination of drug binding to proteins is carried out by several different approaches based mainly on separation methods. The most popular of these is equilibrium dialysis, which requires membranes devoid of non‐specific adsorption to drugs. Ultrafiltration techniques have some advantage over dialysis due to shorter measurement times and the possibility of evaluation of the free drug under circumstances corresponding to physiological conditions. Now there is an increasing use of chromatographic techniques for fundamental studies on determination of binding parameters (number of sites, affinity constant). Different procedures can be chosen depending upon the biological materials available. They are based on the presence of the interacting species in the eluent, avoiding any chemical grafting.
A comparative study of cyproheptadine and DL carnitine on psychomotor performance and memory in healthy volunteers
Authors: Hakkou F. , Jaouen C. , Iraki L.
Published: August 2009

Summary—This study was performed in order to investigate the extent and severity of cyproheptadine effects on psychomotor performance, mood and memory functions and to compare them to the effects of DL carnitine, another appetite stimulant. Twelve healthy volunteers received 2 doses (at 800 am and 1200 am) of 6 mg cyproheptadine, 1600 mg DL carnitine and placebo on separate days at a weekly intervals. The study followed a double‐blind, latin‐square design. Assessment of dependent variables was performed 1 h after the first and 1 h and 5 h after the second administration of the drug. On each of these occasions, the following measurements were performed: choice reaction time (CRT), critical flicker fusion (CFF), digit symbol substitution test (DSST), short‐term memory (paired words association test), long‐term memory (picture test) and 100 mm visual analogue scales of subjective ratings (VAS). Cyproheptadine significantly impaired objective measures (CFF) and subjective ratings both at 1 h and 5 h after the second dosage. Compared with cyproheptadine, DL carnitine induced a slight improvement in psychomotor performance as assessed by CRT. None of the drugs had any effect on memory and on appetite at the doses studied. In conclusion, cyproheptadine at usual doses had a sedative effect, the intensity and duration of which implied a certain risk in performing daytime functionsegwhen driving, or manipulating machines. DL carnitine had no effect on vigilance.
Determination of cerebrospinal fluid production rate using a push‐pull perfusion procedure in the conscious rat
Authors: Baudrie V. , Roullet JB , Goureau Y. , Chaouloff F. , Elghozi JL
Published: August 2009

Summary—The inulin dilution technique was used to determine the cerebrospinal fluid (CSF) production rate by means of a push‐pull cannula implanted into a lateral ventricle. Artificial CSF containing trace amount of3H‐inulin was perfused for 2 h in conscious rats.3H‐inulin in the effluent reached a plateau level depending on the CSF production rate. The control lateroventricular CSF production was 0.98 μl/min. Production was reduced to 0.34 μl/min during a perfusion with acetazolamide (l mM), a carbonic anhydrase inhibitor.
Perspectives in antiviral chemotherapy
Authors: Huraux JM , Ingrand D. , Agut H.
Published: August 2009

Summary— The current progress in antiviral therapy is related to our better understanding of the viral multiplication, with potential targets for specific antiviral action at each step of the multiplication cycle inside the infected cell. Amantadine and Rimantadine are anti‐influenza A drugs interfering with the penetration and the release of the virus. Most of the other antiviral drugs which are clinically available have the same target in common, namely the viral DNA polymerase. This holds true for modified nucleosides such as Acycloguanosine (Acyclovir), DHPG, Adenine‐Arabinoside, Azidothymidine as well as pyrophosphate derivatives such as phosphonoformic acid. Unfortunately the antiviral chemotherapy must confront 3 obstacles: 1) a possible interference with the normal cellular metabolism, leading to residual cytotoxic side effects; 2) the genetic variability of the viruses, producing drug‐resistant mutants and 3) the inability of any antiviral chemotherapeutic agent known to date to eradicate latent viral infection. A new approach of the control of latent infection is suggested with anti sense oligonucleotides or hybridons.
Whether phenylephrine exerts inotropic effects through α‐ or β‐adrenoceptors depends upon the relative receptor populations
Authors: Chess‐Williams RG , Williamson KL , Broadley KJ
Published: August 2009

Summary—Phenylephrine produced concentration‐related positive inotropic responses in isolated left atria and papillary muscles of guinea‐pigs and rats. In rat tissues, these responses were unaffected by propranolol but antagonized by prazosin and therefore mediated via α1‐adrenoceptors. The α1‐adrenoceptor agonist methoxamine also exerted positive inotropic effects in these rat tissues. The maximum α‐adrenoceptor‐mediated effect of methoxamine (relative to the isoprenaline maximum) was greater than that of phenylephrine in left atria (in the presence of propranolol), whereas in papillary muscles phenylephrine exerted the greater maximum. In guinea‐pig papillary muscles, the response to phenylephrine was unaffected by prazosin but was antagonized by propranolol and therefore caused by stimulation of β‐adrenoceptors. Methoxamine had no effect in guinea‐pig papillary muscles. Guinea‐pig left atria produced biphasic concentration‐response curves for phenylephrine, the lower portion being antagonized by phentolamine and was therefore a‐adrenoceptor‐mediated, while the upper portion was antagonized by propranolol and therefore β‐adrenoceptor‐mediated. Methoxamine exerted a small inotropic response, the maximum of which was similar to that of the first component of the phenylephrine response. Phenylephrine was a partial agonist for the cardiac β‐adrenoceptor. The density of rat ventricular α‐adrenoceptors was 4 times greater than β‐adrenoceptor density, as measured by [3H]‐prazosin and [3H]‐dihydroalprenolol binding. This explains why the responses of rat papillary muscles were α‐adrenoceptor‐mediated. In contrast, the density of β‐adrenoceptor binding sites in guinea‐pig ventricles was 6 times greater than the α‐adrenoceptor density. This explains why the phenylephrine responses were β‐adrenoceptor‐mediated in guinea‐pig papillary muscles. In the left atria of guinea‐pigs, which displayed both α‐ and β‐adrenoceptor‐mediated responses, the densities of α‐ and β‐adrenoceptor binding sites were similar. Thus, phenylephrine exerts positive inotropic effects through α‐ or β‐adrenoceptors depending upon their relative densities.