bluuebunny/crossref_metadata_2025 huggingface dataset:
ANTIHYPERTENSIVE DRUGS AND BARORECEPTOR REFLEX CONTROL OF HEART RATE AND BLOOD PRESSURE
Authors: BERDEAUX A. , GIUDICELLI J.F.
Published: August 2009

Summary—The arterial baroreceptor reflex (BR; aortic and carotid sinus BR) and the cardiopulmonary BR are the most important reflexes acting as buffer systems for the maintenance of arterial pressure around a fixed physiologic value. They act as permanent inhibitory systems on the central cardiovascular structures and they can be either activated or deactivated by using selective techniques. During chronic hypertension there are structural alterations of the peripheral and/or central components of the BR that become «reset», with a shift in the function curve relating BR activity to blood pressure (BP) in the direction of higher pressure values. As a consequence of the hypertension‐induced resetting phenomenon, both the threshold pressure and sensitivity of BR are disturbed. However, if BR resetting during hypertension clearly decreases the sensitivity of BR control of heart rate (HR), BR control of peripheral resistance and arterial pressure as a whole is preserved and even increased when hypertension develops. Thus, this apparent discrepancy between BR control of HR and BP during hypertension demonstrates that evaluation of an antihypertensive therapy on reflex control of HR alone cannot predict what will happen to BR control of the whole cardiovascular system. Regarding BR control of HR, in contrast to the classical arteriolar vasodilators such as hydralazine and its derivatives, the majority of the modern antihypertensive drugs do not evoke reflex tachycardia in response to lowering of BP in normotensive or hypertensive subjects. Although the intrinsic pharmacologic mechanisms of action of these drugs on BR may be quite different (e.g., α,‐or β‐adrenoreceptor blocking agents, converting enzyme inhibitors, certain calcium‐channel blockers of the phenyldihydropyridine group, and so on), they all shift in a parallel manner the set‐point of the BR response curve towards lower pressures, with no change in HR or R‐R interval. Generally, this resetting phenomenon occurs after several weeks or months of antihypertensive therapy, but it can also occur acutely (e.g.after IV injection) after administration of drugs such as prazosin or ketanserin. Finally, antihypertensive agents such as clonidine and methyldopa can simultaneously reset the BR and increase its sensitivity, thus leading to almost complete restoration of control of HR response despite the concomitant decrease in BP.

Regarding BR control of blood pressure, only captopril and especially celiprolol (a β1‐adrenoreceptor blocking drug with vasodilating properties) are able to restore almost normal BR control of arterial pressure.
CALCIUM ANTAGONISTS, A NEW CLASS OF ANTIHYPERTENSIVE AGENTS
Authors: SCHWARTZ J.
Published: August 2009

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

In any case, calcium antagonists are potent antihypertensive agents, but in clinical practice they have limitations. A second generation of dihydropyridines may provide a higher degree of therapeutic selectivity.
DRUG PHARMACOKINETICS IN THE OBESE
Authors: CHEYMOL G.
Published: August 2009

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

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

Dose‐adjustment of hydrophilic drugs is assessed according to the ideal weight of the individual obese subject; with lipophilic drugs the loading dose can be fixed according to the total weight; calculation of the maintenance dose depends on possible changes in the total clearance.
HEMODYNAMIC, RENAL, AND ENDOCRINE EFFECTS OF 4‐ H INFUSIONS OF HUMAN ATRIAL NATRIURETIC PEPTIDE IN NORMAL VOLUNTEERS
Authors: BIDIVILLE J. , WAEBER G. , PORCHET M. , NUSSBERGER J. , BIOLLAZ J. , GOMEZ H. , CALLAHAN L. , WAEBER B. , BRUNNER H.R.
Published: August 2009

Summary— A synthetic human atrial natriuretic peptide of 26 aminoacids [human (3–28)ANP or hANP] was infused into normal male volunteers. Six subjects were infused for 4 h at 1‐wk intervals with either hANP at the rate of 0.5 or 1.0 μg/min or its vehicle in a single‐blind randomized order. Human (3–28)ANP at the dose of 0.5 μg/min raised immunoreactive plasma ANP levels from 104 ± 17 to 221 ± 24 pg/ml (mean ± SEM), but it induced no significant change in blood pressure, heart rate, effective renal plasma flow, glomerular filtration rate, or renal electrolyte excretion. At the rate of 1.0 μg/min, human (3–28)ANP increased immunoreactive plasma ANP levels from 89 ± 12 to 454 ± 30 pg/ml. It reduced effective renal plasma flow from 523 ± 40 to 453 ± 38 ml/min (P<0.05 vs. vehicle), but left glomerular filtration rate unchanged. Natriuresis rose from 207±52 to 501±69 μmol/min (P<0.05 vs. vehicle) and urinary magnesium excretion from 3.6±0.5 to 5.6±0.5 μmol/min (P<0.01 vs. vehicle). The excretion rate of the other electrolytes, blood pressure, and heart rate were not significantly modified. At both doses, human (3–28)ANP tended to suppress the activity of the renin‐angiotensin‐aldosterone system. In 3 additional volunteers, the skin blood flow response to human (3–28)ANP, infused for 4 h at the rate of 1.0μg/min, was studied by means of a laser‐doppler flowmeter. The skin blood flow rose during the first 2 h of pep‐tide administration, then fell progressively to values below baseline. After the infusion was discontinued, it remained depressed for more than 2 h. Thus, in normal volunteers, human (3–28)ANP at the dose of 1.0 μg/min produced results similar to those obtained previously with rat (3–28)ANP. It enhanced natriuresis without changing the glomerular filtration rate while effective renal plasma flow fell. It also induced a transient vasodilation of the skin vascular bed.
PHARMACOKINETICS OF DEXTROMORAMIDE IN SURGICAL PATIENTS
Authors: PAGANI I. , BARZAGHI N. , CREMA F. , PERUCCA E. , EGO D. , ROVEI V.
Published: August 2009

Summary— The pharmacokinetics of the narcotic analgesic dextromoramide was investigated by means of a specific GC‐MS method in 9 patients who were given a single oral dose of the drug (7.5 mg) together with an anticholinergic before undergoing minor orthopedic surgery. Dextromoramide was rapidly absorbed from the gastrointestinal tract, with peak plasma levels between 68 and 177 μ/L usually achieved within 0.5‐4.0 h after dosing. In 5 patients, the decline of plasma concentrations after the peak followed a biphasic pattern, with half‐lives of 0.4‐1.6 h for the first phase and 6.3–21.8 h for the terminal phase. In the remaining patients, no clear‐cut biphasic pattern was seen and half‐lives calculated over the period between 4 h and 10 h after administration ranged from 1.5 to 4.7 h. Apparent clearance and volume of distribution values ranged from 0.06 to 0.36 l.h−1.kg−1 and from 0.6 to 2.4 l.kg−1, respectively. Less than 0.06% of the dose was excreted unchanged in urine within 8 h of administration. The concentration of the drug in a CSF sample collected 1 h after dosing was below the limit of detection (2 μ/L) in all subjects.
HIGH AFFINITY ACCEPTOR SITES IN GUINEA PIG BRAIN FOR [3H]52770 RP, A PAF ANTAGONIST
Authors: LEVY C. , BAUDOUY N. , BRUN V. , GOZE O. , ZUNDEL J.L. , BLANCHARD J.C. , LADURON P.M.
Published: August 2009

Summary—[3H]52770 RP, a PAF antagonist, was found to bind with high affinity and in a reversible manner on specific and saturable binding sites in guinea pig cortical membranes. Scatchard analysis revealed the presence of one class of binding sites with an equilibrium dissociation constant of 0.38 nM and a Bmaxof 1190 fmol/mg protein. However, these binding sites did not correspond to the PAF receptors described with this ligand in platelet plasma membranes; indeed, PAF and its analogs were unable to displace [3H]52770 RP binding in guinea pig brain. Therefore, one may conclude that [3H]52770 RP in guinea pig brain labels acceptor or recognition sites, rather than true receptor sites.
COMPARATIVE HEMODYNAMIC STUDY OF A NEW AMINOSTEROID: LND‐623 WITH ITS 20α‐ISOMER: LND‐369, AND WITH DIGOXIN AND DIGOXIGENIN‐RHAMNOSIDE IN THE ANESTHETIZED DOG
Authors: WEISSENBURGER J. , HECKLE J. , BIOUR M. , POIRIER J.M. , JARREAU F.X. , JAILLON P. , CHEYMOL G.
Published: August 2009

Summary—Hemodynamic effects of LND‐623, a new aminosteroid lacking the C17 lactone ring and the C14 hydroxyl group common to the natural glycosides, were studied in the pentobarbital‐anesthetized dog and compared to those of its 20α‐isomer LND‐369 and of digoxin and digoxigenin‐rhamnoside (DRh). Twenty‐four mongrel dogs were divided into 4 groups. Group I received either LND‐623 or saline on study day 1 and the other drug or saline 1 wk later. Saline was replaced by digoxin in group II, digoxigenin‐rhamnoside in group III, and LND‐369 in group IV. All drugs except LND‐369 were infused as 3.10−1mol.kg−1.min−1over 20 minutes. LND‐369 was infused at twice the dose.

LND‐623 increased left ventricular dP/dt for at least 3 h with a peak at end‐infusion or 15 min later, accompanied by a transient vasopressor effect. LND‐369 induced, at twice the dose, an inotropic effect of comparable magnitude but of shorter duration. Inversely, it provoked a more marked and prolonged vasopressor effect than its 20β‐isomer, LND‐623. Maximal digoxin inotropic effect occurred later but was of comparable magnitude to that induced by LND‐623. Its vasopressor effects reached a plateau rapidly and remained sustained until min 200. Digoxigenin‐rhamnoside inotropic but not vasopressor effects are weaker than those of LND‐623.

It is concluded that LND‐623, although lacking the most common structural features of the natural cardiac glycosides, provoked rapid and sustained inotropic activities with transient vasopressor effects. These time‐course effects differ from digoxin, and these differences are unrelated to their sugar‐moiety characteristics. LND‐623 inotropic effect is twice as potent as its 20α‐isomer.
PLASMA MEMBRANE LIPIDS MODULATE THE RESPONSE TO WATER DEPRIVATION IN RAT KIDNEY
Authors: MOURELLE M. , REYES J.L. , MELÉNDEZ E.
Published: August 2009

Summary— The lipid composition of biological membranes determines many of the cellular responses to stimuli such as hormones and drugs. It is known that the neonate has differences in renal function compared to the adult individual, which determine the characteristics of pharmacokinetics and pharma‐codynamics at this age. We studied the lipid composition of renal plasma membranes, the renal response to water deprivation, and the activity of plasma membrane gamma‐glutamyl transpeptidase (GGTP) in newborn, 21‐d‐old, and adult rat. It was found that the cholesterol/phospholipid (CH/PL) ratio of new‐born membranes was significantly higher than that of membranes from 21‐d‐old and adult rats, which were similar. These findings paralleled low ability to concentrate urine in the newborn and higher sensitivity of the neonatal kidney to water deprivation. Kidney membranes from 21‐d‐old and adult rats showed similar lipid composition, and the response to water deprivation was also similar. The changes observed in GGTP activity at different ages varied with the cholesterol content of kidney plasma membranes.

These findings suggest participation of the lipid composition of kidney membranes in modulation of the renal response to water deprivation.
EFFECTS OF CICLETANINE ON HISTAMINE‐INDUCED CONTRACTIONS OF ISOLATED RABBIT MESENTERIC ARTERIES
Authors: EBEIGBE A.B. , CABANIE M. , GODFRAIND T.
Published: August 2009

Summary—The antagonism by cicletanine of contractile responses to histamine has been examinedin vitroon ring preparations of rabbit mesenteric arteries. Cicletanine (10‐8–10−6M) caused a parallel rightward shift of histamine concentration response curve, with a pA2value of 7.48 (slope = 0.89 ± 0.19, not significantly different from unity). Histamine‐induced contractions were nifedipine‐sensitive and associated with cicletanine‐sensitive increased45Ca uptake.

Endothelium removal resulted in enhanced contractile responses to histamine, but did not significantly modify cicletanine‐induced antagonism: KB(dissociation constant) values for cicletanine antagonism in the presence or absence of endothelium were: 3.7 (± 0.1)x 10−8M and 3.6 (± 0.3)x 10−8M, respectively.

Cicletanine (>10−4M) also significantly attenuated 10 mM caffeine‐induced contractions in rings exposed to Ca‐free 100 mM K+ depolarizing medium.

The results suggest that cicletanine‐induced antagonims of histamine H1receptor‐mediated contractions of rabbit mesenteric arteries is associated with interference with calcium entry as well as at high concentrations, release from intracellular stores.
BLOOD DISTRIBUTION OF TENOXICAM IN HUMANS: A PARTICULAR HSA DRUG INTERACTION
Authors: BREE F. , NGUYEN P. , URIEN S. , RIANT P. , ALBENGRES E. , FENNER H. , TILLEMENT J.P.
Published: August 2009

Summary—Blood binding of tenoxicam was studiedin vitroby equilibrium dialysis. Isolated human plasma proteins and blood cells were checked, and the distribution of the bound form was then calculated. The results showed that texoxicam is mainly bound to HSA and that binding percentages are not different when measured in plasma (98.4%) and in an HSA solution at physiological concentration (704 μM, 98.15%). In these conditions, within the range of 1–150μM, the tenoxicam binding percentage remained constant, evidence of a nonsaturable process.

When a lower HSA concentration (10 μM) was used, the binding parameters of the tenoxicam interaction were calculated by using the same equilibrium dialysis data, by 3 methods of analysis‐ a stoichiometric method and site‐oriented methods, fixing or not the number of HSA binding sites (n) as integer values. The best fit was observed with the first method, suggesting that two main interactions occurred. The site‐oriented method gave lesser fits, the better being observed whennwas not fixed. Its value, 1.77, suggest the possibility of two binding sites, one of them not preformed.

The effects of known markers of site I, warfarin and apazone, of site II, diazepam and ibuprofen and of palmitic acid showed that tenoxicam is bound simultaneously to both sites I and II. The binding capacity of site I for tenoxicam is enhanced by diazepam: as this compound alone is bound to site II, this result suggests that the two HSA binding sites are not independent.
EFFECTS OF ISOPROTERENOL AND PROPRANOLOL ON PHARMACOLOGICALLY INDUCED DEPRESSION OF INTRAVENTRICULAR CONDUCTION
Authors: LANG J. , TIMOUR Q. , LANCON J.P. , AUPETIT J.F. , BERTRIX L. , FAUCON G.
Published: August 2009

Summary—The cardiac adrenergic system is known to have practically no influence on conduction velocity in the ventricles under normal conditions. The effects of isoproterenol and propranolol were investigated on depression of intraventricular conduction induced by a class IC antiarrhythmic drug, cibenzoline, in anaesthetized, closed‐chest dogs. In addition to electrocardiogram for measurement of QRS duration in sinus rhythm, conduction time was measured in the ventricular contractile tissue between an electrode advanced to the apex and a pacing electrode near the base, at 400‐ and 200‐ms pacing periods. Effective refractory period (ERP) was measured concurrently according to the extrastimulus method. After intraventricular conduction had been slowed down by cibenzoline IV administered (loading dose of 3 mg/kg plus infusion of 0.2 mg/kg/min over 15 min), isoproterenol was infused or propranolol injected by the intravenous route also (0.5 mn/μg/kg/min over 5 min and 0.4 mg/kg, respectively).

When conduction time has been raised by 75/150% (depending on the pacing rate), isoproterenol appears to attenuate and propranolol to aggravate substantially the impairment of conduction, whereas the reduction undergone by ERP does not differ from usual. Thus, reentrant arrhythmias might be prevented by isoproterenol and triggered by propranolol. Intraventricular conduction, when depressed, therefore, is sensitive to adrenergic drugs, probably because of the enhanced influence of polarization of the fibres in the presence of a sodium conductance impairment.
MATURATION OF AFMU EXCRETION IN INFANTS
Authors: PONS G. , REY E. , CARRIER O. , RICHARD M.O. , MORAN C. , BADOUAL J. , OLIVE G.
Published: August 2009

Summary— The maturation of the N‐acetyltransferase‐dependent AFMU production from caffeine was studied during infancy. The group of children (N = 14) consisted of 4 premature newborn infants and ten 1–19 month‐old infants who received caffeine citrate solution for the treatment and prevention of apnea. Caffeine, AFMU, 1X and 9 other metabolites were measured in urine using HPLC. The AFMU/1X ratio did not vary significantly in this population with increasing age. In one of the infants serially studied, the AFMU/1X ratio increased dramatically between 6 and 12 months of age. This observation suggests that the maturation of N‐acetyltransferase activity is not completed before 1 year of age implying that acetylator status cannot reliably be determined before that age. Patients studied before 1 year of age whose AFMU/1X ratio was below 0.4 may be either true slow acetylators or still immature fast acetylators.
CENTRAL CARDIOVASCULAR EFFECTS OF DIHYDROPYRIDINES IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: LAURENT S. , BRISAC A.M. , CHAMPEROUX P. , LACOLLEY P. , HUGUET F. , LEGRAND M. , LUCET B. , TSOUCARIS D. , BRIAND V. , SCHMITT H.
Published: August 2009

Summary—Intracerebroventricular (i.c.v.) injections of dihydropyridine derivatives calcium channel agonist (BAY K8644) and antagonists (nifedipine, nicardipine, PN 200–110) induced opposite long‐lasting changes in blood pressure (BP) in pentobarbital anesthetized spontaneously hypertensive rats (SMR). I.c.v. nifedipine (NIF), nicardipine (NIC), and PN 200–110 decreased mean blood pressure dose‐dependently and stereoselec‐tively, (+) NIC and (+) PN being 8 and 3 times more potent than their (‐) isomers, respectively. The decrease in BP was due to a withdrawal of the sympathetic tone, since NIF‐ and NIC‐induced falls in BP were suppressed after either hexamethonium (HXM), 6 OHDA or bilateral adrenalectomy. I.c.v. BAY K8644 increased BP dose‐dependently. The i.c.v. BAY K8644‐induced hypertensive effect was inhibited: a), by NIF and (+) PN but not by (‐) PN, therefore probably occurring at central DHP sites; b), by HXM and reserpine, thus probably mediated by an increase in sympathetic tone; c), by i.c.v. methylatropine (MA) while i.v. MA and i.c.v. HXM had no inhibitory effect, thus probably involving central muscarinic sites. In SHR, NIC did not after the K+‐evoked ACh release but suppressed the BAY K8644‐induced increase in ACh release. In anesthetized normotensive control rats (WKY), neither i.c.v. NIF, NIC or BAY K8644 changed BP, nor did the latter after ACh release. Moreover, in conscious WKY, i.c.v. nicardipine increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data suggest that central DHP sites may be involved in the cholinergic transmission and may participate in genetic hypertensionviasympathetic tone.
CENTRAL CARDIOVASCULAR ACTIONS OF CALCIUM CHANNEL ANTAGONISTS IN DOGS
Authors: DAMASE‐MICHEL C. , MONTASTRUC J.L. , MONTASTRUC P.
Published: August 2009

Summary—Several pharmacological and clinical studies have suggested that calcium channel antagonists (CCA) can exert central actions. The aim of the present study was to investigate their putative central cardiovascular properties in dogs. In normotensive pentobarbital‐anesthetized dogs, intravenous (I.V.) nicardipine, — nifedipine — verapamil or diltiazem — induced a dose‐dependent decrease in systolic and diastolic blood pressures followed by tachycardia due to baroreflex activation. By contrast, central (in‐tracisternal: I.C.) administration of the same CCA (at doses ineffective by the I.V. route) induced an increase in both blood pressure and heart rate. Two kinds of neurogenic hypertensive sinoaortic dener‐vated (SAD) dogs were used to study whether the central sympathoexcitatory effects of CCA depend on the level of the sympathetic tone. In acute SAD dogs (where the sympathetic tone is nearly maximum), I.V. administration of nicardipine, nifedipine, verapamil or diltiazem significantly reduced the SAD‐induced increase in blood pressure and heart rate, thus demonstrating the sympathoinhibitory properties of CCA when sympathetic tone is maximum. In chronic SAD awake dogs (where the sympathetic tone is high but not maximum), I.V. nicardipine significantly decreased arterial blood pressure, but also induced both a marked tachycardia and a significant increase in plasma noradrenaline and adrenaline release. However, this direct central activation was not observed with verapamil I.V. under the same experimental conditions (chronic SAD awake dogs). The present data show that CCA could exert central cardiovascular actions in dogs. The positive chronotropic effects of CCA not only result from a baroreflex activation (following the decrease in blood pressure) but also from a direct centrally‐mediated effect on sympathetic tone. Moreover, the magnitude of this sympathoexcitatory effect seems to vary according to the CCA group (phenylalkylamines being less potent that dihydropyridines) and to depend on the level of sympathetic tone: CCA exert stimulant effects when the sympathetic tone is low (normal dogs) and depressor actions when it is high (SAD dogs).
NEUROPSYCHOLOGICAL PROFILES OF CALCIUM ANTAGONISTS
Authors: SOUBRIE P.
Published: August 2009

Summary—The present study aims at reviewing the preclinical evidence suggesting that calcium antagonists exert bio‐behavioural effects that may have some relevance to CNS pharmacology, and thus to psychiatry. We briefly address the question of whether calcium antagonists share the following profiles: anxiolytic, antidepressant, neuroleptic, anticonvulsant, analgesic and memory‐enhancing. This survey suggests that calcium antagonists and, more especially, dihydropyridine derivatives share all these profiles together. There are, however, important limitations in the interpretation of these preclinical data. Whether the various calcium antagonists may have varying profiles, and thus varying potential psychiatric applications, cannot be explored in depth as there are few comparative data on these drugs on a large variety of animal models. In addition, the doses of calcium antagonists reported to produce behavioural responses are generally higher than the doses sufficient to produce other pharmacodynamic actions. Thus, the possibility that these former responses could be secondary to these latter actions cannot be excluded.
THE EFFECTS OF CAPTOPRIL AND ENALAPRIL ON TISSUE LEVELS OF VARIOUS ELEMENTS IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: ALLAIN P. , LEBLONDEL G. , GRANRY J.C.
Published: August 2009

The effects of two inhibitors of angiotensin I converting enzyme, captopril and enalapril, on the concentrations of Na, K, Ca, Mg, Fe, S, P, Sr, Mn, Cu and Zn ions in blood, plasma, heart, skeletal muscle, liver and kidney of spontaneously hypertensive rats (SHR) were studied. Captopril and enalapril were given by the intraperitoneal route for 15 days, at 160 μmol/kg/d and 40 μmol/kg/d, respectively. Elements in tissues were determined by inductively coupled plasma emission spectrometry with a JY 48 instrument.

The common changes produced with the two drugs were: a decrease of Na in muscle (‐ 10%), a decrease of Ca in plasma and kidney (< — 10%) and a decrease of Mn in liver (‐ 15%). The main effects observed with only one of the two drugs were: an increase of Cu in plasma (+ 26%) with captopril, and increases of Sr in heart (+ 56%), muscle (+ 79%) and liver (+ 74%) with enalapril. Zinc concentration in tissues was not modified, except for an increase in liver with captopril (+ 13%) and a decrease in heart with enalapril (‐ 11%).
CYTOTOXIC EFFECTS OF TENIPOSIDE COMBINED WITH CIS‐DIAMMINE‐DICHLOROPLATINUM (II) ON THE IN VITRO LEWIS LUNG CARCINOMA MODEL: INFLUENCE OF THE TREATMENT SCHEDULE
Authors: BLANCY E. , CANAL P. , BERG D. , BUGAT R.
Published: August 2009

Summary— The interactions between cis‐diammine‐dichloroplatinum (CDDP) and teniposide (VM26) have been studied in vitro on a Lewis lung carcinoma culture in terms of span, order of exposure or time delay between both drugs. When the cells were simultaneously exposed to VM26 and CDDP for 24 h, a supra‐additive effect was observed (P < 0.001). When the cells were first incubated with VM26, the cytotoxicity was emphasized (P < 0.02), whereas after a prior exposure to CDDP, only an additive effect was noticed. For a short exposure to the drugs (1 h), we noticed an enhancement of the cytotoxic effect when the cells were first exposed to VM26, principally when the time delay between epipodophyllotoxin and CDDP was 0 or 1 h (P < 0.001). The sequence in which VM26 was given before CDDP induced a significant increase of the cytotoxic effect, whatever the span of exposure.
DISOPYRAMIDE‐INDUCED HYPOGLYCEMIA: CASE REPORT AND REVIEW OF THE LITERATURE
Authors: CACOUB P. , DERAY G. , BAUMELOU A. , GRIMALDI A. , SOUBRIE C. , JACOBS C.
Published: August 2009

Summary—Disopyramide is a group I antiarrhythmic drug which is mainly used for the treatment of ventricular and supraventricular rhythm disturbances. Commonest side effects result from disopyramide's anticholinergic activity. Other side effects such as hypoglycemia have been reported less frequently. We report one observation of disopyramide induced hypoglycemia, and a review of the literature is presented.

Including our observation, 14 cases (9 men and 5 women, aged from 41 to 88) have so far been reported. Doses of disopyramide ranged from 200 to 1 200 mg per day, administered from one day to one year. Symptomatology was mainly neurologic (12 patients) and two patients were clinically asymptomatic. The outcome was favorable in all but the 2 patients who died with persistent hypoglycemia after a single dose of 250 mg in one patient and after 400 mg daily during 4 days in the other (without stopping the drug). Renal function was markedly impaired in 9 patients, two of these patients being on a long term dialysis therapy. Blood levels of disopyramide were measured in 7 patients and ranged from 1 to 11.4 ng/ml. In five patients it was in the normal range (1–4 ng/ml). Three patients were rechallenged for disopyramide: hypoglycemia occured in all, without clinical symptoms in two of them. The main risk factors of disopyramide induced hypoglycemia are a preexisting chronic renal failure, advanced age, and malnutrition. In these patients normally non toxic disopyramide blood levels, as defined in normal subjects, seem to be inappropriately high. We suggest that in patients at risk, disopyramide blood levels should be maintained at the lower range of therapeutic level. The recommended daily dose is 400 mg/day. Thus, it appears appropriate not to exceed 2/3 of this dosage, and to be particularly caution when using this drug in patients at risk.
Alcohol and GABA: ethanol intake modifies hippocampal nipecotic acid binding in ethanol‐preferring and non‐preferring rats
Authors: Daoust M. , Saligaut C. , Moore N. , Lhuintre JP , Boismare F.
Published: August 2009

Summary—3H‐nipecotic acid (3H‐NIP) binding to GABA uptake recognition sites was studied in the hippocampus of 3 groups of male, Long Evans rats: Group 1: ethanol‐naive rats (ENR); Group II: ethanol‐preferring rats (DR) and non‐preferring rats (NDR), which had consumed about 5 g.kg−1.d−1and 1 g−1.d−1of alcohol respectively in the form of a 12% ethanol solution prior to3H‐NIP binding analysis; Group III: DR and NDR who had had no access to ethanol for 21 d after the initial exposure of ethanol solution (28 d). Binding studies showed that ethanol drunk by both DR and NDR in Group II decreased3H‐NIP binding (Bmaxdecreased) with an enhancement of affinity (KDdecreased). In rats subjected to withdrawal of ethanol (Group III), affinity of3H‐NIP for GABA uptake sites was higher than in controls (Group I), but lower than in Group II, Bmaxin this group being higher than in the 2 other groups. In Group III,KDwas higher in DR than in NDR. These results showed that ethanol intake, in a free‐choice paradigm, altered3H‐NIP binding, and that differences in ethanol intake between DR and NDR were associated with differences in sensitivity of hippocampal GABA uptake sites. These differences in3H‐NIP binding could either precede ethanol intake, or be a direct result from it. The results, together with data from other laboratories suggest that: 1),3H‐NIP binding sites are involved in the regulation of ethanol intake; 2), 1 factor responsible for individual differences in ethanol response is reflected by the GABA uptake system.
Investigations of the antifibrillatory activity of flunarizine and lidoflazine in isolated hearts of rabbits and guinea pigs
Authors: Almotrefi AA
Published: August 2009

Summary—In Langendorff‐perfused rabbit hearts, ventricular fibrillation threshold (VFT) was measured by applying rectangular impulses of 3ms duration at a frequency of 20Hz. Perfusion with 0.2 and 0.4μM of flunarizine or 0.2μM of lidoflazine produced a significant rise in VFT. When the hearts were perfused with higher concentrations of either drug (0.8μM flunarizine, 0.4 and 0.8μM lidoflazine), VFT did not continue to increase in a dose‐dependent manner but rather a smaller increase in VFT than the previous dose was observed. Both drugs caused significant decrease in the spontaneous heart rate and amplitude of contraction of the isolated rabbit heart. In the Langendorff‐perfused guinea pig heart, perfusion with 0.8μM of flunarizine produced complete protection against ouabain‐induced ventricular fibrillation while 7 out of 7 and 1 out of 6 hearts fibrillated in the presence of 0.2 and 0.4 μM of the drug respectively. During perfusion with 0.2, 0.4 and 0.8 μM of lidoflazine the incidence of ventricular fibrillation was 3 out of 6, 1 out of 6 and 5 out of 7 hearts respectively. These results may indicate a limited effectiveness of these 2 calcium entry blockers against ventricular fibrillation.
Genetic polymorphisms of drug metabolism*
Authors: Meyer UA
Published: August 2009

Summary—The molecular mechanisms of 3 genetic polymorphisms of drug metabolism have been studied at the level of enzyme activity, enzyme protein and RNA/DNA. As regards debrisoquine/sparteine polymorphism, cytochrome P‐450IID6 was absent in livers of poor metabolizers; aberrant splicing of premRNA of P‐450IID6 may be responsible for this. Moreover, 3 mutant alleles of the P‐450IID6 locus on chromosome 22 associated with the poor metabolizer phenotype were identified by Southern analysis of leucocyte DNA. The presence of 2 identified mutant alleles allowed the prediction of the phenotype in ≅25% of poor metabolizers. The additional gene‐inactivating mutations which are operative in the remainder of poor metabolizers are now being studied. Regarding mephenytoin polymorphism, although the deficient reaction, S‐mephenytoin 4‘‐hydroxylation, has been well defined in human liver microsomes, the mechanism of this polymorphism remains unclear. All antibodies prepared to date against cytochrome P‐450 fractions with this activity recognize several structurally similar enzymes and several cDNAs related to these enzymes have been isolated and expressed in heterologous systems. However, which isozyme is affected by this polymorphism is not known. As regards N‐acetylation polymorphism,N‐acetyltransferases have been purified from human liver, specific antibodies prepared; it was observed that immunoreactiveN‐acetyltransferase is decreased or undetectable in liver of “slow acetylators”. Two genes that encode functionalN‐acetyltransferase were characterized. The product of one of these genes has identical activity and characteristics as the polymorphic liver enzyme. Cloned DNA from rapid and slow acetylator individuals has been analyzed to identify the structural or regulatory defect that causes deficientN‐acetyltransferase.
Influence of diuretics on brachial artery diameter and distensibility in hypertensive patients
Authors: Laurent S. , Lacolley PM , Cuche JL , Safar ME
Published: August 2009

Summary— Blood pressure, brachial artery diameter and pulse wave velocity were determined before and after diuretic treatment in 2 groups of hypertensive patients treated either by indapamide (2.5 mg per d) or by canreonate (50 mg per d). Brachial artery diameter, measured from pulsed Doppler flowmetry, and pulse wave velocity, evaluated from mechanography, did not alter significantly despite a significant blood pressure reduction. The study indicates that, in hypertensive patients of middle age, diuretics did not change brachial artery diameter and distensibility, whether the drug caused an increase or a decrease in plasma potassium levels.
Randomized double‐blind trial of injectable heptaminol for controlling spontaneous or bromocriptine‐induced orthostatic hypotension in parkinsonians
Authors: Milon D. , Allain H. , Reymann JM , Morel G. , Sabouraud O. , Van den Driessche J.
Published: August 2009

Summary—Heptaminol is a molecule with experimental cardiovascular analeptic properties. In this double‐blindvsplacebo trial, the potency, so far unproven, of the injectable form of a 626 mg dose of heptaminol chlorhydrate on spontaneous or induced orthostatic hypotension (OH), was assessed. Nineteen patients were included in the study: 7 displayed spontaneous OH, and in the other 12 OH was induced by bromocriptine, as monitored 103 min/after an oral intake of 6.6 mg on average. Neither spontaneous nor induced OH were recorded in 32% of the Parkinsonian population registered, with no obvious distinctive characteristics. Potency tilt‐trials, performed 15, 30 and 45 min after parenteral administration of heptaminol, revealed a significant and expressive potency of the molecule on the systolic blood pressure after 15 min (P< 0.05). Clinical and biological tolerance was excellent. Low plasma renin activity and the absence of response to orthostatism indicated, in this population of Parkinsonian extrapyramidal syndromes, a loss in positive tonus likely to be of sympathetic origin. The anti‐hypotensive action of heptaminol does not seem to be related to any renal or even sympathetic interaction.
Phase I studies: what to measure?
Authors: Rosenkranz B.
Published: August 2009

Summary— Drug law require the assessment of quality, safety and efficacy of new compounds. In this context, phase I studies are performed in order to investigate their tolerability, pharmacodynamic effects and pharmacokinetics. For the assessment of safety aspects, standard clinical (eg blood pressure, heart rate, body temperature, ECG), laboratory data (eg checklist recommended by local clinical chemistry societies) and subjective rating scales (eg open or structured questionnaires) are the main parameters. Additional investigations may be included according to the results obtained in pharmacological and toxicological studies. The selection of appropriate measuring times is crucial. The maximum pharmacological effects in many cases are seen at the time of peak serum concentration, whereas in other cases they may be a delay (eg effect on coagulation factors, toxic granulocytopenia). For the assessment of the pharmacodynamic effects of a new drug, standardized procedures should be used which predict its therapeutic effect in patients. The main purposes of pharmacodynamic studies in healthy volunteers are: proof of efficacy and mechanism of action in man, dose finding, search for possible adverse events, for additional therapeutically relevant mechanisms or pharmacodynamic interactions. For all these studies, it is crucial to select the appropriate variables, the appropriate validated and non‐invasive method and the appropriate time points.
Can therapeutic efficacy be predicted from phase I data?
Authors: Thiercelin JF
Published: August 2009

Summary— The aim of phase I studies per se is to explore the tolerance of new compounds which have demonstrated a certain level of activity in animals at sufficiently low non‐toxic doses. In most cases, these studies are conducted in 2 steps in a limited number of healthy male volunteers: a single rising dose study followed by a repeated dose study in which the pharmacokinetic features of the drug are explored. In such a context, it would be quite presumptuous to ascertain the therapeutic efficacy of a drug from those initial human studies. At best, these trials can provide pharmacological and/or biological indications which are related to some degree to the expected efficacy of the drug: hypnotics, anticancer drugs, antibiotics, platelet antiaggregants, beta‐blockers, etc. In these examples it is recommended to design controlled study protocols so as to better investigate these potentially interesting signs of activity. In the majority of cases, however (psychoactive drugs, analgesic, anti‐inflammatory drugs, gastro‐intestinal compounds), phase I studies will unfortunately not provide much information regarding the expected therapeutic activity.
Concepts and usefulness of pharmacokinetic‐pharmacodynamic modelling
Authors: Holford NHG
Published: August 2009

Summary— The combined application of pharmacokinetic and pharmacodynamic models to concentration and effect observations can be used to predict the consequences of alternative dosing strategies. Efficient experimental design is intimately related to the models that may be employed for data analysis. This is especially important in phase I studies which provide the basis for decisions on future clinical trials.
With whom does the French drug industry want to work for phase I?
Authors: Bogaievsky Y.
Published: August 2009

Summary— Industry chooses phase I partners by evaluating quality versus cost. However, since December 20, 1988, in France only those centers, private or public, authorized by the French authorities can be chosen. However, ability to perform rapidly, reliability and worldwide acceptability of results will be considered in choosing the phase I partner.
Public hospitals and phase I
Authors: Nivet L. , Leclercq B.
Published: August 2009

Summary— The forthcoming opening of a phase I unit in a French public hospital ‐ the Louis Pradel Cardiovascular and Pneumological Hospital, Hospices Civils de Lyon ‐ presents an opportunity for its manager, Benoît Leclercq, to explain with both public hospitals and the phase I unit have a mutual interest in working together: the hospital facilities and staff ensure safety and quality, whereas the phase I structure improves the public hospital image and adds renewed dynamism.
Private hospital and phase I
Authors: Gallet M. , Nony P.
Published: August 2009

Summary— Since December 1988. French law has authorized phase I studies and the creation of phase I units within public or private hospitals. The scientific standards regarding private hospitals are not different from those in public hospitals. Practitioners who conduct clinical trials in private hospitals are well aware of good clinical practices and methodological constraints. Phase I units can be structured in private as well as within public hospitals. Finally, the question to be addressed is whether clinical pharmacology and scientific investigations in healthy volunteers should be integrated in the policy of private hospitals.
Private companies for phase I studies?
Authors: Lhoste F.
Published: August 2009

Summary— In France, the debate is still open regarding where phase I studies should take place. According to its strict definition, very few phase I studies are performed per year in our country. Because they are usually carried out on healthy volunteers, ethics and safety are intimately mixed in with such studies. Safety in these highly specific investigations is founded on 2 bases, first on the independence of the investigator and secondly on the laboratory environment. The economic independence and total lack of responsibility in this respect on the part of the investigator ensure that all ethical considerations including safety are focused on the personal interest of the volunteer who participates in the study.
Pyroglutamic acid improves the age associated memory impairment
Authors: Grioli S. , Lomeo C. , Quattropani MC , Spignoli G. , Villardita C.
Published: August 2009

Summary— Pyroglutamic acid (PCA) was compared with placebo in a randomized, double blind trial for assessing its efficacy in treating memory deficits in 40 aged subjects. Twenty subjects were treated with PCA and 20 with placebo over a period of 60 d. Memory functions were evaluated at baseline and after 60 d of treatment by means of a battery made up of 6 memory tasks. The results suggest that PCA is effective in improving some verbal memory functions in subjects affected by age‐related memory decline.
Cardiovascular properties of LF 2.0254, a new potent vasoselective calcium channel blocker with a slow onset of action
Authors: Pruneau D. , Roy F. , Brown NL
Published: August 2009

Summary—The effects of LF 2.0254, a new 1,4‐dihydropyridine derivative, were studied in rabbit aorta stimulated by various contractile agents and in isolated guinea pig atria. LF 2.0254 inhibited in a time‐dependent fashion K+‐ and CA2+‐induced contractions of rabbit aorta with respective IC50of 2.7 nM and 1.7 nM. An action of LF 2.0254 at the voltage operated calcium channel was consistent with the finding that LF 2.0254 antagonized45Ca2+‐uptake induced by depolarisation of smooth muscle, and since contractile responses evoked by (‐) norepinephrine and the calcium ionophore A23187 were insensitive to the drug. In isolated paced left atria and spontaneously beating right atria of guinea pig, LF 2.0254 added for 60 min at 1 μM only slightly decreased the contractile force and beating rate. In anesthetized open‐thorax dogs, LF 2.0254 (1 to 100 μg/kg, iv) dose‐dependently lowered systemic blood pressure and increased cardiac output with a slower onset of action than nifedipine. LF 2.0254 and nifedipine decreased total peripheral, coronary, femoral and vertebral resistance. In marked contrast to nifedipine, LF 2.0254 induced only a slight decrease in left ventricular dP/dt. In conscious hypertensive dogs LF 2.0254 (0.1 and 0.3 mg/kgper or) decreased blood pressure and concomitantly increased heart rate and plasma renin activity. It is concluded that LF 2.0254 differs markedly from nifedipine in its more gradual onset of action and greater selectivity for the vasculature with respect to the myocardium.
Interaction of cholecystokinin and diazepam: effects on brain monoamines
Authors: Rybarczyk MC , Orosco M. , Rouch C. , Jacquot C. , Cohen Y.
Published: August 2009

Summary— An antagonism between cholecystokinin (CCK) peptides and benzodiazepines (BZD) has been described in various paradigms. We sought to determine whether CCK and BZD are also antagonistic in their effects on brain neurotransmitter levels in the rat. No effect on the noradrenergic system was induced in any brain area by CCK 8 S and diazepam alone or in combination. Administered alone, sulfated CCK octapeptide (CCK 8 S) (5 μg/kg ip) and diazepam (5 mg/kg ip) were found to decrease DOPAC levels in the cortex and to induce 5‐hydroxy‐tryptamine accumulation in the hippocampus. When administered together, these variations were no longer observed. However, a slight tendency by each substance to decrease 3‐methoxy‐tyramine levels in the striatum, became significant when given in association. The differences in CCK‐BZD interactions observed in the striatum, cortex and hippocampus suggest that different mechanisms of action are involved. The addition of the effects occuring in the striatum might involve a GABA‐ergic mechanism.
Selective agonists of tachykinin binding sites
Authors: Lavielle S. , Chassaing G. , Lœuillet D. , Convert O. , Torrens Y. , Beaujouan JC , Saffroy M. , Petitet F. , Bergström L. , Glowinski J.
Published: August 2009

Summary—Three types of binding sites for the mammalian tachykinins,ieSubstance P (SP) Neurokinin A (NKA) and Neurokinin B (NKB), have been found in both the central and peripheral nervous systems. Substance P binds to the NK‐1 subclass of binding site while NKA and NKB are less selective endogenous ligands, which preferentially interact with the NK‐2 and NK‐3 subclasses of binding sites, respectively. Complementary strategies, including 3‐dimensional structure analysis by NMR spectroscopy and structure‐activity relationships led to the design of selective agonists of these binding sites. [Pro9] SP, [Pro10] SP and the cyclic analogues [Cys3,6, Tyr8, Pro9] SP and [Cys3,6, Tyr8, Pro10] SP are selective NK‐1 agonists. [Lys5] NKA(4–10) is a water soluble NK‐2 potent agonist. Finally, [Pro7] NKB, which completely discriminates NK‐2 and NK‐3 binding sites, is a water‐soluble NK‐3 selective agonist.
Physiological basis for neuroimmunomodulation
Authors: Neveu PJ , Moal M Le
Published: August 2009

Summary— A large number of clinical and experimental observations indicate that immune responses may be modulated by the central nervous system (CNS). The immune system (IS) and CNS are known to communicate via the endocrine and the autonomic nervous systems. In this overview, we will focus on the immunomodulating role of neurotransmitters and neuropeptides. Immune cells appear to express membrane antigens similar to those of neural cells. Similarities re‐enforce analogies between CNS and IS cells. The concept that the CNS modulates immune functions implies that the immune system feeds back information to the CNS. In fact, interleukins have neuroendocrine functions whether they are produced at the periphery by immune cells or at the CNS level by glial cells. Finally, the possible endocrine functions of lymphocytes are described and it is suggested that a complete regulatory loop between immune and neuro‐endocrine systems exists. Studies in neuroimmunomodulation are of great importance from a theoretical point of view, the CNS‐IS interrelationships may not be considered only between the CNS and the periphery but also at the level of the immune micro‐environment which may be considered as an immune‐neuro‐endocrine complex.