RESUMEN
BACKGROUND & AIM: The CYP2D6 -1584C>G polymorphism (rs1080985) has been identified as a major factor for CYP2D6 expression and function, with the mutant -1584G promoter type being consistently associated with significantly greater expression than -1584C. It may therefore be associated with ultrarapid metabolism. The objective of the present study was to explore the relationship between the CYP2D6 -1584C>G polymorphism and the debrisoquine metabolic ratio in healthy volunteers in order to evaluate its potential impact on the ultrarapid CYP2D6 hydroxylation capacity. MATERIALS & METHODS: The CYP2D6 -1584C>G polymorphism was analyzed in 320 unrelated healthy individuals who were previously phenotyped for debrisoquine hydroxylation. RESULTS: The metabolic ratio (log10 mean ± standard deviation) of individuals with the -1584G allele was lower than that of individuals with the -1584C allele for carriers of one active CYP2D6 gene (-0.13 ± 0.33 and 0.17 ± 0.52, respectively; p < 0.05) or two active CYP2D6 genes (-0.32 ± 0.39 and -0.20 ± 0.44, respectively; p < 0.05). CONCLUSION: The presence of the -1584G allele in the promoter region of the CYP2D6 gene was related to a high CYP2D6 hydroxylation capacity.
Asunto(s)
Citocromo P-450 CYP2D6/genética , Debrisoquina/uso terapéutico , Hidroxilación/genética , Alelos , Regulación de la Expresión Génica/efectos de los fármacos , Genotipo , Voluntarios Sanos , Heterocigoto , Humanos , Hidroxilación/efectos de los fármacos , Polimorfismo Genético , Regiones Promotoras GenéticasRESUMEN
The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.
Asunto(s)
Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Catecolaminas/sangre , Clonidina/uso terapéutico , Debrisoquina/uso terapéutico , Modelos Animales de Enfermedad , Vías Eferentes/fisiopatología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/mortalidad , Riñón/inervación , Fallo Renal Crónico/epidemiología , Monoaminooxidasa/deficiencia , Monoaminooxidasa/metabolismo , Fibras Nerviosas/fisiología , Óxido Nítrico/fisiología , Norepinefrina/uso terapéuticoRESUMEN
BACKGROUND: We have previously shown that flurbiprofen metabolism to 4'-hydroxyflurbiprofen provides an in vivo measure of cytochrome P450 (CYP) 2C9 activity. This study evaluated the possibility of incorporating flurbiprofen into the current 5-drug Pittsburgh cocktail. METHODS: In a randomized, 3-way, Latin-square, crossover-design study, 24 healthy subjects (mean age [+/-SD], 47.8 +/- 15.1 years) received flurbiprofen (50 mg) and the Pittsburgh 5-drug cocktail (100 mg caffeine, 100 mg mephenytoin, 10 mg debrisoquin [INN, debrisoquine], 250 mg chlorzoxazone, and 100 mg dapsone) separately and in combination on 3 occasions over a period of 5 weeks. Urine was collected from 0 to 8 hours, and plasma was obtained at 4 and 8 hours after drug administration. Parent drug and metabolite concentrations were measured to determine phenotypic indices for each of the metabolizing enzymes. RESULTS: The geometric mean ratio and 90% confidence interval of the phenotypic indices were included within the 80% to 125% bioequivalence range for each of the probe drugs. There were no statistically significant differences between the phenotypic indices determined after administration of the 5-drug and 6-drug cocktails. However, there was a small but statistically significant increase (7.5%, P = .03) in the 8-hour urinary flurbiprofen recovery ratio after administration of the 6-drug cocktail compared with that after administration of flurbiprofen alone. The 6-drug cocktail was well tolerated. CONCLUSION: The results of this study show that caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (N-acetyltransferase 2), debrisoquin (CYP2D6), flurbiprofen (CYP2C9), and mephenytoin (CYP2C19) can be simultaneously administered in low doses without metabolic interaction.
Asunto(s)
Estudios Cruzados , Flurbiprofeno/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Cafeína/metabolismo , Cafeína/farmacología , Cafeína/uso terapéutico , Clorzoxazona/metabolismo , Clorzoxazona/farmacología , Clorzoxazona/uso terapéutico , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Dapsona/metabolismo , Dapsona/farmacología , Dapsona/uso terapéutico , Debrisoquina/metabolismo , Debrisoquina/farmacología , Debrisoquina/uso terapéutico , Quimioterapia Combinada , Femenino , Flurbiprofeno/metabolismo , Flurbiprofeno/uso terapéutico , Genotipo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Mefenitoína/metabolismo , Mefenitoína/farmacología , Mefenitoína/uso terapéutico , Persona de Mediana EdadRESUMEN
Debrisoquine (D), an antihypertensive drug metabolized to 4-hydroxydebrisoquine (4-OHD) by CYP2D6, is commonly used as an in vivo probe of CYP2D6 activity and can be used to phenotype individuals as either extensive (EMs) or poor metabolizers (PMs) of such drugs as beta-adrenergic blockers, tricyclic antidepressants, and class 1C antiarrhythmics. This report describes reversed-phase HPLC systems by which D and 4-OHD or S-(+) and R-(-)-4-OHD in urine are more selectively quantified without the need for derivatization techniques. We also studied the urinary excretion of R-(-)- and S-(+)-4-hydroxydebrisoquine in EM hypertensive patients in order to determine weather 4-OHD formation exhibits enantioselectivity. Twelve patients with mild to severe essential hypertension were admitted to the study. They received a single tablet of Declinax containing 10 mg debrisoquine sulfate. All the urine excreted during the following 8 h was collected. The debrisoquine metabolic ratio (DMR) was calculated as % of dose excreted as D/% of dose excreted as 4-OHD and the debrisoquine recovery ratio (DRR) was calculated as % of dose excreted as 4-OHD/% of dose excreted as D+4-OHD. Debrisoquine and its metabolite were determined in urine by HPLC using a reversed-phase Select B LiChrospher column, a mobile phase of 0.25 N acetate buffer, pH 5-acetonitrile (9:1, v/v) and a fluorescence detector. The limit of quantitation was determined to be 25.0 ng/ml for D and 18.75 ng/ml for 4-OHD. Intra- and inter-day relative standard deviations (RSDs) were less than 10%. All hypertensive patients studied showed a DMR of less than 12.6 or a DRR higher than 0.12 and were classified as EMs. Direct enantioselective separation on chiral stationary phase involved resolution of S-(+)-4-OHD and R-(-)-4-OHD on a Chiralcel OD-R column with a mobile phase of 0.125 N sodium perchlorate, pH 5-acetonitrile-methanol (85:12:3, v/v/v). The quantitation limit of each enantiomer was 3.75 ng/ml of urine. Intra- and inter-day RSDs were less than 10% for each enantiomer. A high degree of enantioselectivity in the 4-hydroxylation of D favouring the S-(+) enantiomer was observed, resulting in R-(-)-4-OHD not detected in the urine of the EM hypertensive patients studied.
Asunto(s)
Antihipertensivos/orina , Cromatografía Líquida de Alta Presión , Debrisoquina/orina , Hipertensión/orina , Adulto , Anciano , Antihipertensivos/metabolismo , Antihipertensivos/uso terapéutico , Brasil , Calibración , Cromatografía Líquida de Alta Presión/métodos , Debrisoquina/análogos & derivados , Debrisoquina/metabolismo , Debrisoquina/uso terapéutico , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etnología , Masculino , Persona de Mediana Edad , Conformación Molecular , Fenotipo , Reproducibilidad de los Resultados , Población BlancaRESUMEN
Lung cancer, the most prevalent cancer in the western world, is predominantly caused by smoking and thus perceived as a "self-inflicted" disease. Nevertheless, only 20% of smokers develop lung cancer. This review examines the concept of high-risk populations and screening. It looks at developments in the molecular epidemiology of the disease that shed new light on genetic changes that may predispose individuals to malignancy. Improvements in existing drug therapy are discussed as well as important new therapeutic developments, including antigrowth factors (antagonists G and D), antimetastatic agents (matrix metalloproteinase inhibitors), and natural products, arising from a greater understanding of signal transduction pathways and the process of cell metastasis.
Asunto(s)
Neoplasias Pulmonares/genética , Antihipertensivos/uso terapéutico , Antineoplásicos/uso terapéutico , Debrisoquina/uso terapéutico , Matriz Extracelular/enzimología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Metaloendopeptidasas/antagonistas & inhibidores , Oligopéptidos/farmacología , Péptidos/farmacología , Lesiones Precancerosas/genéticaRESUMEN
Acute administration of haloperidol (0.2 mg/kg) produced many more side effects in normal controls than in unmedicated schizophrenic patients. Prior to the neuroleptic challenge, both groups were on the peripheral monoamine oxidase inhibitor, debrisoquin, for at least 1 week, in order to enhance the relative contribution of CNS catecholamine metabolites to those measured in both plasma and urine. The patient group had higher plasma levels of methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) and higher urinary MHPG output than controls, but there were no effects of haloperidol challenge, compared to placebo challenge. In both groups there were significant declines in plasma HVA levels from 8:30 AM to 12 NOON. These declines were unaffected by the haloperidol challenge. Explanations for the marked differences in behavioral effects of haloperidol on patients and controls include the possibility that dopamine receptor numbers were increased in the brains of the schizophrenic patients.
Asunto(s)
Antipsicóticos/farmacología , Debrisoquina/farmacología , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Debrisoquina/efectos adversos , Debrisoquina/uso terapéutico , Dopamina/metabolismo , Haloperidol/efectos adversos , Haloperidol/farmacología , Haloperidol/uso terapéutico , Ácido Homovanílico/sangre , Ácido Homovanílico/metabolismo , Ácido Homovanílico/orina , Humanos , Masculino , Metoxihidroxifenilglicol/sangre , Metoxihidroxifenilglicol/metabolismo , Metoxihidroxifenilglicol/orina , Placebos , Plasma/química , Plasma/metabolismo , Esquizofrenia/metabolismoRESUMEN
The pharmacokinetics of a single oral dose of the neuroleptic drug zuclopenthixol (10 or 6 mg) was studied in 6 extensive and 6 poor metabolizers of debrisoquine. The peak plasma concentrations of zuclopenthixol did not differ between the phenotypes, whereas the plasma elimination half-life was significantly longer in poor than in extensive metabolizers (29.9 +/- 6.6 vs 17.6 +/- 6.9 h). Accordingly, the total oral plasma clearance was lower in poor than in extensive metabolizers (0.78 +/- 0.27 vs 2.12 +/- 0.65 1/h/kg). Ten of the volunteers had previously participated in a similar study in which the kinetics of perphenazine, another neuroleptic drug, were studied in poor and in extensive metabolizers of debrisoquine. There was a significant correlation between the oral clearance of perphenazine and that of zuclopenthixol among these 10 subjects. The study indicates that the disposition of zuclopenthixol, as well as that of perphenazine, is related to the genetically determined capacity to hydroxylate debrisoquine. The significance of this polymorphism for the clinical use of neuroleptics is discussed.
Asunto(s)
Clopentixol/farmacocinética , Debrisoquina/metabolismo , Administración Oral , Adulto , Clopentixol/sangre , Clopentixol/uso terapéutico , Debrisoquina/uso terapéutico , Debrisoquina/orina , Femenino , Humanos , Hidroxilación , Masculino , Perfenazina/metabolismo , Perfenazina/uso terapéutico , Esquizofrenia/tratamiento farmacológicoRESUMEN
A possible modulating influence of noradrenergic activity on serum lipoproteins was assessed under placebo conditions and following 4 weeks of sympathetic neurone blockade with debrisoquine in 9 normal subjects, 11 patients with mild essential hypertension, 9 normotensive, and 9 hypertensive hemodialysis patients. Plasma norepinephrine (NE) did not differ significantly among groups on placebo and was consistently reduced (P less than 0.05-0.001) by sympathetic blockade. The latter also decreased (P less than 0.05-0.001) plasma total cholesterol (C) as well as low and very low density lipoprotein cholesterol (LDL + VLDL-C) in the three patient groups. In the two dialysis groups, basal levels of plasma triglycerides (Tg) were increased and high density lipoprotein cholesterol (HDL-C) was diminished (P less than 0.01-0.001); sympathetic blockade lowered Tg and raised HDL-C (P less than 0.01-0.001). In normal subjects, sympathetic blockade did not significantly modify plasma lipoproteins. In the three patient groups, significant correlations (r = 0.62 - 0.88; P less than 0.05 - less than 0.001) existed between (a) basal plasma NE and total C or LDL + VLDL-C and (b) debrisoquine-induced changes in NE and changes in total LDL + VLDL-C. These findings suggest that in essential hypertension as well as in hemodialysis patients, the atherogenic C fraction, represented by LDL + VLDL-C, may be modulated by the noradrenergic activity.
Asunto(s)
Arteriosclerosis/fisiopatología , Colesterol/sangre , Hipertensión/fisiopatología , Norepinefrina/fisiología , Sistema Nervioso Simpático/fisiopatología , Adulto , Presión Sanguínea/fisiología , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Ensayos Clínicos como Asunto , Debrisoquina/uso terapéutico , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión Renal/fisiopatología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Diálisis Renal , Método Simple CiegoAsunto(s)
Imipramina/metabolismo , Debrisoquina/efectos adversos , Debrisoquina/metabolismo , Debrisoquina/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/psicología , Femenino , Humanos , Imipramina/efectos adversos , Imipramina/uso terapéutico , Masculino , Mefenitoína/efectos adversos , Mefenitoína/metabolismo , Mefenitoína/uso terapéutico , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
Optimization of tricyclic antidepressant (TCA) therapy by dosage adjustments made in response to inappropriate concentrations in plasma or side effects can be extremely slow owing to the long half-lives of these drugs. I examine the practicality of alternative methods of arriving quickly and reliably at an adequate starting dosage. The clearance of a single test dose from plasma has been used to select individualized dosages before commencing therapy, but this takes several days and requires computer-assisted calculation of clearance. A simpler technique is to measure the concentration in a single timed plasma sample as an index of metabolism, and to infer the required dosage directly from a nomogram. Ideally, the nomograms should be interchangeable between patient populations and independent of the analytical method used, and the drug must have linear kinetics. Furthermore, TCAs are metabolized by common routes--demethylation and hydroxylation--so one might apply a single tolerance test for the entire class of drugs. Hydroxylation of TCAs can also be correlated with that of debrisoquine. The debrisoquine clearance test is non-invasive, faster, and analytically less demanding than TCA measurements. In the absence of rigid therapeutic ranges, tests that identify abnormally slow metabolizers may well be invaluable in preventing iatrogenic poisoning. Despite the usefulness of these methods in establishing effective initial dosages, their continued success depends upon good compliance, the maintenance of the patient's concurrent drug therapy, and a stable physical condition. In the non-ideal world, therefore, TDM cannot be dispensed with, but must be seen as an essential part of effective TCA treatment, based ultimately of course on sound clinical judgement.
Asunto(s)
Antidepresivos Tricíclicos/uso terapéutico , Monitoreo Fisiológico/métodos , Amitriptilina/farmacocinética , Amitriptilina/uso terapéutico , Antidepresivos Tricíclicos/sangre , Antidepresivos Tricíclicos/farmacocinética , Debrisoquina/farmacocinética , Debrisoquina/uso terapéutico , Semivida , Humanos , FenotipoRESUMEN
Plasma levels of the dopamine metabolite homovanillic acid (pHVA) may potentially reflect upon central dopamine activity. This study examines the effects of debrisoquin, haloperidol, and the two drugs combined on pHVA concentrations of schizophrenic patients. Debrisoquin is a drug that suppresses the peripheral formation of homovanillic acid without affecting the central formation. Acute haloperidol administration consistently increased pHVA concentrations in patients pretreated or not pretreated with debrisoquin, suggesting that this increment reflects haloperidol's central and not peripheral effects.
Asunto(s)
Debrisoquina/uso terapéutico , Haloperidol/uso terapéutico , Ácido Homovanílico/sangre , Isoquinolinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Quimioterapia Combinada , Humanos , Masculino , Esquizofrenia/sangre , Factores de TiempoRESUMEN
The total 24 hour urinary outputs of the catecholamines norepinephrine (NE), epinephrine (E), dopamine (DA) and the DA metabolite homovanillic acid (HVA) were measured in hypertensive fawn-hooded rats and compared to the ancestral strain of normotensive Wistar rats. The hypertensive fawn-hooded rats demonstrated significantly higher urinary outputs of the catecholamines NE and DA, and of the DA metabolite HVA. Following treatment with the antihypertensive, debrisoquin sulfate, the blood pressure of the fawn-hooded rats decreased until it approached the levels observed in normotensive Wistar rats. By inhibiting sympathetic nervous activity and monoamine oxidase, the debrisoquin treatment significantly decreased the output of DA, NE and HVA but not E. The data suggest the fawn-hooded rat is a model of neurogenic hypertension which is characterized by an increased sympathetic output.
Asunto(s)
Dopamina/orina , Hipertensión/orina , Norepinefrina/orina , Animales , Presión Sanguínea/efectos de los fármacos , Debrisoquina/uso terapéutico , Ácido Homovanílico/orina , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Ratas , Ratas Endogámicas , Especificidad de la EspecieRESUMEN
A 36-year-old man who had been an insulin-dependent diabetic for 27 years developed severe postural hypotension only when taking debrisoquine and a short-acting insulin. Hourly recordings of lying and standing blood pressure after an oral dose of debrisoquine in the presence and absence of short-acting insulin confirmed an interaction between the drugs causing symptoms of postural hypotension which may be confused with hypoglycaemia.
Asunto(s)
Antihipertensivos/uso terapéutico , Debrisoquina/uso terapéutico , Diabetes Mellitus Tipo 1/complicaciones , Hipertensión/complicaciones , Insulina/uso terapéutico , Isoquinolinas/uso terapéutico , Adulto , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Sinergismo Farmacológico , Humanos , Hipertensión/tratamiento farmacológico , MasculinoAsunto(s)
Debrisoquina/metabolismo , Isoquinolinas/metabolismo , Nortriptilina/uso terapéutico , Adulto , Amitriptilina/administración & dosificación , Amitriptilina/uso terapéutico , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/metabolismo , Antidepresivos Tricíclicos/uso terapéutico , Debrisoquina/administración & dosificación , Debrisoquina/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Quimioterapia Combinada , Femenino , Humanos , Hidroxilación , Litio/administración & dosificación , Litio/uso terapéutico , Nortriptilina/administración & dosificación , Nortriptilina/metabolismoRESUMEN
Thirty patients with uncomplicated essential hypertension were treated for an average of 44 months by 14 internists in private practice. All patients had previously participated in a controlled comparative trial of antihypertensive drugs carried out by the same physicians in their offices. During the long-term follow-up period, ie, after completion of the initial trial, the physicians administered antihypertensive therapy based on their best judgment; the drugs they most commonly prescribed were diuretics (80% of patients) and beta-blocking agents (60% of patients). Although 80% of the patients received at least two different antihypertensive agents, diastolic pressures fell below 96 mmHg in approximately 60% of the patients and below 90 mmHg in only a small fraction. Thus it appears that it is not easy for physicians in private practice to optimally reduce blood pressure levels in hypertensive patients despite the availability of numerous antihypertensive drugs. The tendency of practitioners to approximate blood pressure levels to multiples of 5 or even 10 mmHg may be partially responsible for the unsatisfactory results.
Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Debrisoquina/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Cuidados a Largo Plazo , Masculino , Mefrusida/uso terapéutico , Metildopa/uso terapéutico , Persona de Mediana Edad , Propranolol/uso terapéuticoRESUMEN
The influence of agents that inhibit sympathetic nerve activity on cardiovascular responsiveness as related to major pressor factors has been unclear. Therefore, these components were evaluated in 11 normal subjects and 13 patients with mild essential hypertension before and after 4 weeks of sympathetic neuron blockade with the agent debrisoquine. In these normal and mildly hypertensive subjects, sympathetic neuron blockade caused approximately similar decreases in urinary and supine or upright plasma norepinephrine (NE) levels (average changes in the two groups, -41% and -45%, respectively; p less than 0.05 to less than 0.005), the chronotropic dose of isoproterenol (-45% and -38%), and the NE pressor dose (-47% and -51%, p less than 0.01), while the relationship between NE-induced changes in blood pressure and concomitant plasma NE concentrations was displaced to the left (p less than 0.01). Supine heart rate was also lowered (-10% and -8%, p less than 0.05). Compared to the orthostatic variations during placebo conditions, mild postural decreases in blood pressure were apparent in both the normal and hypertensive groups (-8% and -7.5%). However, supine blood pressure was unchanged following debrisoquine treatment. Other parameters were also not consistently changed, such as total blood volume, exchangeable body sodium, urinary electrolytes, plasma epinephrine, renin, and angiotensin II (AII) levels, the pressor dose of infused AII, and the relationship between AII-induced changes in blood pressure and plasma AII measured before and during AII infusion. These findings demonstrate that the reduction in sympathetic outflow during sympathetic neuron blockade may elicit a hyperresponsiveness of alpha- and beta-adrenergic receptors that is equal in normal subjects and patients with mild essential hypertension.
Asunto(s)
Debrisoquina/uso terapéutico , Hipertensión/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Receptores Adrenérgicos/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Adulto , Anciano , Angiotensina II/metabolismo , Presión Sanguínea/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/metabolismo , Receptores Adrenérgicos/fisiología , Renina/sangreRESUMEN
The antihypertensive effect of debrisoquine (20 mg/day), methyldopa (100 mg/day) and propranolol (160 mg/day) was compared to that obtained with a placebo in a controlled trial carried out by a group of 14 internists. Forty-eight patients with uncomplicated essential hypertension were included. Mefruside (25 mg/day) was first given alone for 6 weeks ("open phase" of the trial) and to this diuretic was then added in double-blind fashion and randomized sequence a placebo or an active drug. Each of the 4 blind phases lasted 4 weeks. At the end of the "open phase", blood pressure in seated position averaged 168/111 +/- 19.6/13.5 mm Hg (mean +/- SD). A significant blood pressure decrease was observed after 4 weeks of treatment with the placebo as well as with the investigated compounds. With the placebo blood pressure was reduced to 158/102 +/- 19.6/13.5 mm Hg (p less than 0.001). The magnitude of the additional blood pressure decrease induced by the active drugs was relatively small and varied from 4 (debrisoquine) to 10 mm Hg (methyldopa, p less than 0.01) for the systolic and from 3 (debrisoquine, p less than 0.05) to 5 mm Hg (propranolol, p less than 0.05) for the diastolic. The percentage of patients with systolic pressure of less than or equal to 140 mm Hg and with diastolic pressure of less than 90 mm Hg during administration of either drug was not greater than 40 to 20% respectively. Propranolol appeared to be better tolerated than the other antihypertensive agents. These rather disappointing blood pressure results suggest that the efficacy of antihypertensive agents in private practice cannot be extrapolated from studies carried out in specialized hypertension clinics.