RESUMEN
INTRODUCTION: Serotonin (HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) are commonly used as first line treatment of major depressive disorders (MDD). As compared to tricyclic antidepressants, they have proved similar efficacy and better tolerability. Milnacipran (MLN) (Ixel) and venlafaxine (VLF) (Effexor) are two SNRIs pharmacologically differing by their NA/HT ratio of potency: 1:1 and 1:30, respectively. OBJECTIVES: To investigate the efficacy and safety/tolerability of MLN and VLF administered at flexible doses (100, 150 or 200 mg/day) for 24 weeks (including 4 weeks of up-titration) in the outpatient treatment of adults with moderate-to-severe MDD. DESIGN: Multicentre, randomised, double blind, 2-parallel-arm, 24-week exploratory trial conducted in France by 50 psychiatrists. DIAGNOSIS AND MAIN INCLUSION CRITERIA: Male or female outpatients, aged 18 to 70, meeting the DSM-IV-TR and related MINI criteria for recurrent, unipolar, moderate-to-severe MDD, with neither psychotic features nor severe suicidal risk. A Montgomery-Asberg depression rating scale (MADRS) score> or =23 was required at inclusion. TREATMENT SCHEDULE: Patients were randomised to receive either MLN or VLF (1:1 ratio) for 24 weeks in double-blind conditions. Regardless of the treatment received, the following dosing schedule was applied: during the initial 4-week up-titration phase, the dosage was progressively increased from 25 mg/day (qd administration) to 150 mg/day (bid administration). At week 4, the dosage was either maintained at 150 mg/day, or adapted to 100 or 200 mg/day, based on the investigator's clinical judgement. At any time during the 20 following treatment weeks, the dose could be lowered for safety concerns until a minimal threshold of 100 mg/day. From Week 24, the dosage was decreased by 50mg/day every five days. After randomisation, eight assessment visits were organised at 2, 4, 6, 8, 12, 18, 24 weeks, and at study end (after the 5-15 days of down-titration and 10 days free of treatment). Efficacy evaluation ratings included the MADRS and global disease severity (CGI-S) total scores. Rates of MADRS response (reduction of initial score> or =50%) and remission (score< or =10) were calculated at Week 8 and Week 24 in the full analysis set as well as in the subgroups of patients with depressive disorder of severe DSM-IV intensity and with a MINI evaluation of suicidal risk (rated as required 'moderate' at the worst). STATISTICAL ANALYSIS: Standard distribution statistics (including mean and standard deviation [S.D.]) of scores and their changes from baseline, were calculated using the observed-case (OC) approach at all assessment times for the MADRS score, and the last-observation-carried-forward (LOCF) at 8 and 24 weeks for both MADRS and CGI-S scores. MADRS response and remission rates at 8 and 24 weeks were calculated using the LOCF approach by normal approximation of the binomial distribution. Bilateral exploratory statistical tests at 5% significance level were performed for results at 8 and 24 weeks of: (i) MADRS score changes from baseline, based on the score progress at each visit (mixed model for repeated measurements [MMRM]), and (ii) global MADRS response and remission rates (Chi(2)). RESULTS AND PATIENTS: A total of 195 patients were randomly assigned MLN (n=97) or VLF (n=98) and 134 (68.7%: 61.9%/MLN and 75.5%/VLF) completed the trial. At the end of the up-titration, patients received 100 mg/day (11.4%/MLN, 10%/VLF), 150 mg/day (30.4%/MLN, 43.8%/VLF), or 200 mg/day (58.2%/MLN, 46.3%/VLF). Totals of 177 patients (90/MLN and 87/VLF) and 181 patients (90/MLN and 91/VLF) were analysed for efficacy and safety, respectively. Treatment groups were similar for baseline characteristics except a higher proportion of MLN patients with a severe depressive episode (63.3% versus 54%). RESULTS AND EFFICACY: MADRS score (mean [S.D.] initial score: 31 [4.5]) progressively decreased all along the treatment course and similarly in both groups (Week 8-OC : -18.8 [7.7]/MLN and -18.6 [7.3]/VLF, p(MMRM)=0.95 ; Week 24-OC : -23.1 [7.8]/MLN and -22.4 [7.3]/VLF, p(MMRM)=0.37 ). At week 8-LOCF, MADRS response rates were similar in both groups (64.4%/MLN, 65.5%/VLF, p(chi2)=0.88) as well as remission rates (42.2%/MLN, 42.5%/VLF p(chi2)=0.97). At week 24 they remained non clinically and statistically different between groups (response rates: 70%/MLN, 77%/VLF, p(chi2)=0.29; remission rates: 52.2%/MLN, 62.1%/VLF, p(chi2)=0.19). In both "severe depressive episode" and "MINI mild or moderate suicidal risk" subgroups (n=104 and 75, respectively), response and remission rates were non clinically different at both time points, however in the "MINI mild-to-moderate suicidal risk" subgroup, MLN tended to be more rapidly active (remission rate at week 8-LOCF: 44.7%/MLN, 35.1%/VLF). The changes in CGI-S were also indicative of a significant improvement of the global illness severity with both treatments. RESULTS AND SAFETY/TOLERABILITY: The tolerability profile of both drugs was in line with their pharmacological activity. About 70% of patients in both groups experienced at least one adverse event (AE). In both groups, the most common AEs were nausea, dizziness, headache and hyperhidrosis, and, in the male patients, genito-urinary problems: orgasmic disorders (VLF only) and dysuria (MLN only). These AEs were mostly responsible for definitive treatment discontinuation for tolerability concerns. None of the 6 serious adverse events (SAEs) on MLN and 4 of the 8 SAEs on VLF were related to the test drug. CONCLUSION: MLN and VLF at flexible doses up to 200 mg/day globally exhibited similar efficacy and tolerability profiles in the long-term treatment of adults with MDD.
Asunto(s)
Antidepresivos/administración & dosificación , Ciclohexanoles/administración & dosificación , Ciclopropanos/administración & dosificación , Trastorno Depresivo Mayor/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Adulto , Anciano , Atención Ambulatoria , Antidepresivos/efectos adversos , Ciclohexanoles/efectos adversos , Ciclopropanos/efectos adversos , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Milnaciprán , Inventario de Personalidad , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Suicidio/psicología , Clorhidrato de Venlafaxina , Adulto Joven , Prevención del SuicidioRESUMEN
A double-blind, randomized trial was conducted to determine the influence of topical steroid therapy on atopic skin flora. The bacteriological and clinical effects of desonide (Locapred), compared with those of its excipient, were studied in 40 children. Clinical scoring and bacteriological sampling were performed before the start of the trial and after 7 days of once-daily topical treatment. Before treatment, no differences in clinical score or Staphylococcus aureus colonization were noted between the two groups. After treatment, the clinical score improved (P < 0.001) in the desonide group, and S. aureus density decreased dramatically (P < 0.001). In the excipient group, no significant differences in clinical score or S. aureus density were noted. A comparison of the two groups demonstrated statistically significant differences with regard to clinical score (P < 0.001) and S. aureus density (P < 0.05). These results show the efficacy of topical corticosteroid treatment alone on S. aureus colonization in atopic skin, and confirm the critical role of inflammation in bacterial colonization.
Asunto(s)
Dermatitis Atópica/microbiología , Desonida/uso terapéutico , Piel/microbiología , Staphylococcus aureus/aislamiento & purificación , Adolescente , Niño , Preescolar , Recuento de Colonia Microbiana , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Excipientes/uso terapéutico , Femenino , Humanos , Lactante , MasculinoRESUMEN
In earlier work, we demonstrated that 0.1 p. 100 topical tretinoin is clinically effective and well tolerated compared with placebo for the treatment of oral leukoplakia and oral keratosic or erythematous lichen planus. Here we aimed to complete this clinical protocol with histological and biochemical analyses comparing the biopsy specimens collected at inclusion and those collected after 4 months of treatment. Histological results were based on changes in keratinization observed between onset of treatment and 4 months treatment. Biochemical studies included the use of antibodies (anti-cytokeratins 10-11, anti-filaggrine) for the immunohistochemical evaluation of keratinization and 2-dimensional gel electrophoresis for measuring cytokeratins. In patients with lichen planus, histological changes during treatment showed that, in the 10 patients in the tretinoin group, keratinization disappeared in 6 and decreased significantly in 3. Immunohistochemistry revealed that cytokeratins 10-11 and filaggrin disappeared in 57 p. 100 of the patients treated with tretinoin versus 25 p. 100 in the patients given placebo. Bidimensional gel electrophoresis showed that cytokeratins 1, 2, 10 and 11 disappeared only in the tretinoin group (60 p. 100 of the cases). In patients with leukoplakia, histological changes during treatment showed that, in the tretinoin group, keratinization disappeared in 5 cases and decreased in 5 others. Immunohistochemistry revealed that cytokeratins 10-11 disappeared in 30 p. 100 of the patients treated with tretinoin versus 25 p. 100 in the placebo group. Bidimensional electrophoresis demonstrated that cytokeratins 1, 2, 10 and 11 disappeared in 43 p. 100 of the patients treated with tretinoin.
Asunto(s)
Queratinas/análisis , Leucoplasia Bucal/tratamiento farmacológico , Liquen Plano Oral/tratamiento farmacológico , Tretinoina/uso terapéutico , Administración Tópica , Electroforesis en Gel Bidimensional , Proteínas Filagrina , Humanos , Inmunohistoquímica , Leucoplasia Bucal/patología , Liquen Plano Oral/patología , Mucosa Bucal/efectos de los fármacos , Resultado del TratamientoRESUMEN
A randomized study was conducted to evaluate the effect of tretinoin and patient tolerance to treatment with topical applications in series of 20 cases of smoking-related or traumatic oral keratoses leukoplakia and of 20 cases of lichen planus. In each group, patients applied the topical ointment containing tretinoin (10 patients) or placebo (10 patients) twice daily. Clinical outcome was evaluated on the basis of the surface area of the lesion, measured monthly during treatment, as compared with the area observed at treatment onset. After 4 months treatment, there was a significant decrease in the surface area of the lesion in the patients with lichen planus (p < 0.02): 94 p. 100 in the tretinoin group versus 21.4 p. 100 in the placebo group. In patients with leukoplakias, there was also a very significant reduction in the surface area of the lesion after 4 months of treatment (p < 0.001): 80 p. 100 in the tretinoin group and 16 p. 100 in the placebo group. Tolerance to treatment was generally good despite a few complaints of quite temporary burning sensation at application rapidly resolutive.
Asunto(s)
Leucoplasia Bucal/tratamiento farmacológico , Liquen Plano Oral/tratamiento farmacológico , Tretinoina/uso terapéutico , Administración Tópica , Anciano , Método Doble Ciego , Evaluación de Medicamentos , Tolerancia a Medicamentos , Femenino , Humanos , Leucoplasia Bucal/patología , Liquen Plano Oral/patología , Masculino , Persona de Mediana Edad , Mucosa Bucal/efectos de los fármacos , Resultado del TratamientoRESUMEN
The aim of this study was to establish whether the criteria for the clinical effectiveness of steroids are correlated with the pharmacokinetics of prednisolone in children treated with prednisone during an attack of idiopathic nephrotic syndrome (INS). Thirteen patients with nephrosis were included. Prednisolone, prednisone and cortisol levels were measured using a specific high-performance liquid chromatography assay after an oral dose of 1 mg/kg body weight of prednisone taken at the onset of the disease. All the pharmacokinetic parameters, including the conversion of prednisone to prednisolone were similar to the data already published in children with INS. No correlation was found between the values of pharmacokinetic parameters and criteria of clinical effectiveness. Hypo-albuminaemia was significantly correlated with the area under the plasma-concentration curve but not with the elimination half-life of prednisolone. Moreover, the prednisolone elimination half-life correlated with the urinary excretion of 17-hydroxycorticosteroids achieved in the first 6 h. The present study suggests that routine measurements of prednisolone kinetics do not help when assessing the treatment of children with INS.
Asunto(s)
Síndrome Nefrótico/tratamiento farmacológico , Prednisolona/farmacocinética , 17-Hidroxicorticoesteroides/orina , Enfermedad Aguda , Adolescente , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Niño , Preescolar , Creatinina/sangre , Resistencia a Medicamentos , Humanos , Hidrocortisona/sangre , Lactante , Síndrome Nefrótico/sangre , Síndrome Nefrótico/orina , Prednisolona/sangre , Prednisolona/uso terapéutico , Prednisona/sangre , Albúmina Sérica/metabolismoRESUMEN
The ability of flunarizine in inducing or worsening extrapyramidal symptoms is well documented. The relation with age or dose of such symptoms as their clinical characteristics remain controversial. We report 6 cases of extrapyramidal syndromes induced by flunarizine in five women and one man (mean age 71.5 +/- 5 years). The daily dose was 10 mg in five cases (as recommended by the marketing laboratory) and 20 mg in one patient. These observations allow to discuss the dose-dependent occurrence of this adverse reaction. In only three cases the reason for treatment was compatible with the official french indication. These side effects appeared after 7.0 +/- 1.6 months and disappeared after 2.2 +/- 0.5 months respectively. Flunarizine-induced extrapyramidal symptoms are mainly characterized by tremor (which was the main symptom in 4 cases and the only one in 2 cases).
Asunto(s)
Enfermedades de los Ganglios Basales/inducido químicamente , Flunarizina/efectos adversos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The pharmacodynamic parameters of a low molecular weight heparin (LMWH, CY 216) and their inter-individual variations were investigated. In a cross over study 100 anti-factor Xa IC U/kg were injected, one week apart, to 12 healthy volunteers by intravenous (IV) or subcutaneous (SC) route. The pharmacological effects were followed by performing activated partial thromboplastin time (APTT), thrombin clotting time (TCT) and a chromogenic anti-factor Xa assay. The main pharmacodynamic parameters were calculated from the anti-factor Xa activity disappearance curves. Five to ten min after IV injection, the APTT ranged between 56 and 98 sec (baseline 40 sec), the TCT between 28 and 99 sec (baseline 19 sec) and the anti-factor Xa activity between 1.58 and 2.28 IC U/ml. The anti-factor Xa activity half-life ranged between 1.5 and 2.9 h. After SC injection, there were no detectable APTT and TCT prolongations; the maximum anti-factor Xa activity ranged between 0.36 and 0.88 IC U/ml and the half life between 1.5 and 6.4 h. These results indicate that, as for standard heparin, there are large inter-individual variations in the anticoagulant responses to a given dose of CY 216 an observation which may have clinical implications.
Asunto(s)
Inhibidores del Factor Xa , Heparina de Bajo-Peso-Molecular/farmacología , Adulto , Factor Xa/farmacocinética , Femenino , Heparina de Bajo-Peso-Molecular/administración & dosificación , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Tiempo de Tromboplastina Parcial , Tiempo de TrombinaRESUMEN
Dermatan sulfate (DS), a catalyst of the thrombin-heparin cofactor II interaction, has antithrombotic activity and is devoid of significant hemorrhagic risk in several animal models. We investigated the pharmacodynamic and pharmacokinetic properties of DS in humans. DS was injected in single bolus intravenous injections of four increasing doses (0.5, 1, 1.5, 2 mg/kg) to six healthy volunteers. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). There were dose-dependent prolongations of the APTT and TCT, and the anticoagulant activities disappeared in less than three hours. The pharmacokinetic parameters were calculated from the plasma concentrations of DS measured with a new chromogenic assay. The volume of distribution was approximately 1.8 times greater than the theoretical plasma volume and was independent of dose. In contrast, the clearance decreased with dose and the terminal half-life ranged from 0.45 +/- 0.08 hours at 0.5 mg/kg to 0.72 +/- 0.11 hours (mean +/- SD) at 2 mg/kg. The bioavailabilities of subcutaneous (SC) and intramuscular (IM) administration relative to those of intravenous administration were determined in 12 other volunteers. The respective bioavailabilities were 24.7% +/- 12.9% and 12.4% +/- 9.2% for SC and IM administration. There was no detectable change in the APTT and the TCT when the volunteers were injected with 1.5 mg/kg SC or IM. In addition, the pharmacokinetic parameters derived from plasma concentrations of DS showed considerable interindividual variations by the two later routes of administration. Peak concentrations were noted 2.7 +/- 1.3 hours after SC injection and 4.3 +/- 4.9 hours after IM injection. The average peak concentrations were 0.7 +/- 0.3 and 0.4 +/- 0.2 mg/L after SC and IM injections, respectively. The half-lives of DS were 7.9 +/- 6.5 hours (SC) and 6.3 +/- 7.4 hours (IM). No adverse reaction to DS was recorded during this study.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Condroitín/análogos & derivados , Dermatán Sulfato/farmacología , Adulto , Dermatán Sulfato/sangre , Dermatán Sulfato/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Tiempo de Tromboplastina Parcial , Tiempo de TrombinaRESUMEN
The involvement of cholinergic mechanisms in the central cardiovascular effects of a dihydropyridine, nicardipine, was investigated in pentobarbital-anaesthetized normotensive dogs. Nicardipine (1 microgram/kg) injected intracisternally (i.c.) induced a rise in both blood pressure and heart rate. This induced hypertension was suppressed by pretreatment with intravenous (i.v.) atropine or i.c. methylatropine but not i.v. methylatropine. I.c. methylatropine reduced nicardipine-induced tachycardia. These results demonstrate the involvement of cholinergic pathways in the central cardiovascular effects of i.c. nicardipine in dogs and suggest a functional interaction between dihydropyridine binding sites and cardiovascular cholinergic mechanisms in the brain.
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Sistema Cardiovascular/inervación , Hemodinámica/efectos de los fármacos , Nicardipino/farmacología , Receptores Colinérgicos/efectos de los fármacos , Animales , Atropina/farmacología , Derivados de Atropina/farmacología , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Perros , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Nicardipino/antagonistas & inhibidoresRESUMEN
The effects of clonidine on adrenal catecholamine (adrenaline and noradrenaline) secretion were investigated in chloralose-anaesthetized dogs. Intravenous administration of clonidine (10 and 20 micrograms kg-1) induced a decrease in both adrenal catecholamine secretion rates and cardiovascular parameters (blood pressure and heart rate). In contrast, a dose of 5 micrograms kg-1 was ineffective. Intracisternal clonidine (in a lower dose of 3 micrograms kg-1) also decreased adrenaline and noradrenaline release from the adrenal gland. Clonidine failed to modify adrenal catecholamine release evoked by electrical stimulation of the splanchnic nerve. These results demonstrate that clonidine decreases adrenaline release from the adrenal gland through a central and not a peripheral mechanism in dogs. This action might contribute to its antihypertensive effects.
Asunto(s)
Médula Suprarrenal/metabolismo , Clonidina/farmacología , Médula Suprarrenal/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Catecolaminas/metabolismo , Cisterna Magna , Clonidina/administración & dosificación , Perros , Estimulación Eléctrica , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones , Inyecciones Intravenosas , Masculino , Nervios Esplácnicos/efectos de los fármacos , Nervios Esplácnicos/metabolismo , Nervios Esplácnicos/fisiologíaRESUMEN
An intensive survey of pharmacovigilance was carried out in a medical admission department over a 4-month period. Out of 2,017 admissions to hospital, 23 (1,1 p. 100) were motivated by adverse reactions to drugs. Questioning brought out allergy and multiple drug therapy as important factors. Lesions of the skin and mucosae predominated, notably after treatment with antibacterial and non-steroidal anti-inflammatory agents. The categories of drugs involved were, in decreasing order of frequency: cardiovascular (6/23), anti-bacterial (5/23), neuropsychiatric (4/23) and non-steroidal anti-inflammatory drugs (4/23). The fact that the patients had taken several products rendered evaluation difficult. Using imputability scales made it possible to reduce the cause-effect relationship in 26 p. 100 of the cases.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Estudios de Evaluación como Asunto , Vigilancia de Productos Comercializados , Servicio de Admisión en Hospital , Adolescente , Adulto , Anciano , Enfermedades Cardiovasculares/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades de la Piel/inducido químicamenteRESUMEN
In angina pectoris, diltiazem is usually prescribed as two 60 mg tablets in the morning and two 60 mg tablets in the evening. In the course of the pharmaceutical development of this drug, it was therefore planned to study an experimental formulation containing 120 mg of diltiazem. On the basis of dissolution tests in vitro, a bioavailability study was initiated to compare the 120 mg experimental formulation to the standard 60 mg tablet. The study was conducted in 12 healthy volunteers who received the 2 treatments (one 120 mg tablet bid for 7 days versus two 60 mg standard tablets bid for 7 days) according to a cross-over design. Blood and urine samples were analysed by HPLC method with a UV spectrophotometric detection (sensitivity: 5 ng/ml). Analysis of variance did not show any significant difference between the two formulations for the following parameters: maximum plasma levels observed at steady-state, area under the curves and unchanged urinary diltiazem. From these results the extent of absorption of the 120 mg experimental formulation can be considered as bioequivalent to the administration of 2 tablets of the 60 mg commercially available diltiazem formulation. The time to peak, however, was delayed in 75% of the subjects with the 120 mg diltiazem tablet, showing that the surface area of the pharmaceutical preparation is of primary importance for drug dissolution and rate of absorption.
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Diltiazem/administración & dosificación , Angina de Pecho/tratamiento farmacológico , Disponibilidad Biológica , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Diltiazem/farmacocinética , Esquema de Medicación , Humanos , ComprimidosRESUMEN
The effects of clonidine on adrenal medulla catecholamines levels were studied in normotensive rats. Intraperitoneal injections (50,100 micrograms/kg) of clonidine caused a dose-dependent decrease in adrenaline content of the gland. This effect was suppressed by denervation of the adrenal medulla, i.e. unilateral section of splanchnic fibers performed 5 days before. These results demonstrate that clonidine decreases the catecholamine content of the adrenal medulla only through a central action. They suggest that the adrenal medulla is involved in the hypotensive effect of clonidine.
Asunto(s)
Médula Suprarrenal/efectos de los fármacos , Catecolaminas/metabolismo , Clonidina/farmacología , Médula Suprarrenal/inervación , Médula Suprarrenal/metabolismo , Animales , Desnervación , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Endogámicas , Receptores Adrenérgicos alfa/metabolismoRESUMEN
The action of several dopamine agonists on blood pressure was investigated. In dogs, apomorphine induced a decrease in blood pressure and an increase in heart rate. These effects were suppressed by intravenous haloperidol or phentolamine. Intravenous but not intracisternal domperidone suppressed the hypotensive responses elicited by intravenous or intracisternal apomorphine. Furthermore, the hypotensive effect of bromocriptine or apomorphine was abolished in adrenal demedullated dogs. Apomorphine and bromocriptine decreased adrenal catecholamine levels. In men, the acute hypotensive property of apomorphine (but not the long term effect of bromocriptine) was suppressed by pretreatment with domperidone. In hypertensive Parkinsonians, bromocriptine reduced blood pressure, induced an increase in inulin clearance, a decrease in plasma creatinine concentration and in renal vascular resistances. These results suggest that dopamine agonists (like apomorphine or bromocriptine) reduce blood pressure through both a decrease in sympathetic tone and an improvement in renal function. However, the mechanism of the acute and long term hypotensive effects could be different only involving peripheral mechanisms after acute administration and both peripheral and central structure under chronic treatment. In addition, preliminary results suggesting the potential interest of dopamine antagonists in the management of orthostatic hypotension are discussed.