RESUMEN
Trandolapril is the prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It has been proposed that its active metabolite, trandolaprilat, is mainly excreted in bile, but this has not been clearly demonstrated. Recently it has been reported that temocaprilat, an active metabolite of the ACE inhibitor temocapril, is effectively excreted in bile via an ATP-dependent active transporter (canalicular multispecific organic anion transporter: cMOAT). To investigate whether trandolaprilat has the pharmacological ability to affect the cMOAT system in a manner similar to temocaprilat. The lipophilicity of trandolaprilat and temocaprilat was measured to determine the n-octanol-water partition coefficients. The dose-dependent inhibition of the up-take of [3H]-estradiol-17beta-D-glucuronide and [3H]-2,4-dinitrophenyl-S-glutathione, which are good substrates for cMOAT, in canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley rats was determined in the presence of trandolaprilat and temocaprilat. The partition coefficient of trandolaprilat (log Po/w - 1.1) was about 30 times higher than that of temocaprilat (log Po/w - 2.5). The uptake of [3H]-estradiol-17beta-D-glucuronide and [3H]-2,4-dinitrophenyl-S-glutathione was dose-dependently inhibited by the presence of temocaprilat, but trandolaprilat had no effect on the transport of [3H]-estradiol-17beta-D-glucuronide or [3H]-2,4-dinitrophenyl-S-glutathione into CMVs even at concentrations as high as 200 microM. It could be concluded that trandolaprilat has a higher lipophilicity than temocaprilat. But the hepatobiliary excretion system via cMOAT may not contribute to the excretion of trandolaprilat in bile.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Bilis/metabolismo , Estradiol/análogos & derivados , Glutatión/análogos & derivados , Indoles/farmacocinética , Proteínas de Transporte de Membrana , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Adenosina Trifosfato/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Canalículos Biliares/metabolismo , Estradiol/farmacocinética , Glutatión/farmacocinética , Indoles/química , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Ratas , Ratas Sprague-Dawley , Tiazepinas/química , Tiazepinas/farmacocinética , Vesículas Transportadoras/metabolismo , TritioRESUMEN
Many investigators have reported that angiotensin-converting enzyme (ACE) inhibitors have antiproteinuric effects and retard the progression of renal impairment in diabetic patients. On the other hand, those effects of ACE inhibitors have not been well established in patients with essential hypertension. This study was conducted to prospectively evaluate whether an ACE inhibitor, temocapril, could modify the urinary microalbumin excretion rate (UAE) in hypertensive outpatients who had no signs of renal impairment. To compare the long-term effect of temocapril with that of a diuretic on UAE, hypertensive patients treated with a diuretic (trichlormethiazide) were enrolled in a prospective study if they had normal serum creatinine levels and no overt proteinuria during a 3-month screening period. A urinary microalbumin-to-urinary-creatinine ratio (mg albumin/mmol Cr) was used as an estimate of UAE. Patients visited the hospital monthly to determine blood pressure (BP) and UAE. After baseline observation during the treatment with the diuretic, the subjects were randomly divided into two groups. In group A, the diuretic was switched to temocapril, 2 to 4 mg once daily for 12 months. In group B, the subjects continued to receive the diuretic for an additional 12 months. Seventy-six outpatients (41 men and 35 women; mean age, 59.0+/-1.4 years) with essential hypertension entered the study. The effects of temocapril on BP appeared to be clinically similar to those of the trichlormethiazide, but the use of temocapril significantly decreased UAE. In group A (n=37), UAE decreased significantly (p<0.01) from the baseline value of 4.19+/-0.37 mg albumin/mmol Cr to 2.47+/-0.29 and 2.68+/-0.28 mg albumin/mmol Cr at the 6th and 12th month of temocapril therapy, respectively. In contrast, in group B (n=39) UAE was unchanged (baseline, 4.16+/-0.63 mg albumin/mmol Cr; 6 months, 4.92+/-0.72; 12 months, 4.71+/-0.74). These results indicate that long-term therapy with temocapril may be superior in reducing UAE than is diuretic therapy in patients with essential hypertension who had no signs of renal impairment.
Asunto(s)
Albuminuria , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/orina , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Tiazepinas/uso terapéutico , Triclormetiazida/uso terapéutico , Creatinina/orina , Diuréticos , Humanos , Factores de TiempoRESUMEN
We report a case of a 23-year-old Japanese woman who had severe hyperparathyroidism associated with chronic renal failure before the start of dialysis treatment. Her chief complaints were swelling and pain in both shoulders. Laboratory examination revealed renal failure (BUN 134 mg/dl, serum Cr 7.3 mg/dl), severe normocytic normochromic anemia (hemoglobin 4.3 g/dl), hypercalcemia (11.8 mg/dl), and hyperphosphatemia (9.7 mg/dl). Serum PTH levels were extremely increased (intact PTH >1,000 pg/ml: normal range 10-50 pg/ml). X-ray examination of the skull and shoulders showed a salt and pepper appearance, and cauliflower-like deformity of the distal end of both clavicles, respectively. Accelerated ectopic calcification was observed in the costal cartilages, internal carotid arteries, and splenic arteries. Ultrasonographic examination revealed enlargement of the four parathyroid glands. Thallium-technetium subtraction scintigraphy of the parathyroid glands showed increased uptake into the upper two. Renal needle biopsy revealed severe impairment of the interstitium and tubules with much milder changes in glomeruli. The etiology of the renal failure could not be identified. Hemodialysis, total parathyroidectomy and auto-transplantation into the forearm were immediately performed. The pathological diagnosis was chief cell hyperplasia of the parathyroid glands. Based on the presence of chronic renal failure, remarkable hyperphosphatemia with mild hypercalcemia, an unusually high level of serum PTH, and accelerated ectopic calcification, the patient was diagnosed to have severe secondary hyperparathyroidism caused by chronic renal failure with major impairment of the renal interstitium and tubules.
Asunto(s)
Hipercalcemia/diagnóstico , Hiperparatiroidismo/diagnóstico , Fallo Renal Crónico/diagnóstico , Adulto , Anemia/complicaciones , Anemia/diagnóstico , Biopsia con Aguja , Femenino , Humanos , Hipercalcemia/complicaciones , Hiperparatiroidismo/complicaciones , Hiperparatiroidismo/cirugía , Riñón/patología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/cirugía , Glomérulos Renales/patología , Trasplante de Riñón , Túbulos Renales/patología , Glándulas Paratiroides/patología , Hormona Paratiroidea/sangre , Paratiroidectomía , Fosfatos/sangreRESUMEN
We studied the effects of chronic blockade of the renin-angiotensin system on hypertension and cardiac left ventricular hypertrophy (LVH) in Dahl salt-sensitive (DS) rats given a high-salt or low-salt diet. [Experiment 1] Twelve-week-old male DS rats were fed an 8% NaCl diet and received the angiotensin II receptor (AT1) antagonist, candesartan (3 mg/kg/d), the angiotensin converting enzyme inhibitor enalapril (30 mg/kg/d), or vehicle for 6 wk after 3 wk of 8% salt-loading. Neither candesartan nor enalapril with concomitant high salt-loading attenuated the blood pressure (BP) elevation. LVH was also not attenuated significantly by these treatments. [Experiment 2] After 8 wk of 8% salt-loading, the rats were given a 0.3% NaCl diet and concurrently received candesartan, enalapril, or vehicle for 5 wk. Switching from the high-salt to low-salt diet significantly decreased BP and left ventricular mass in the vehicle-treated animals. Both candesartan and enalapril normalized BP during salt-depletion; the blockade of the renin-angiotensin system produced an additive reduction in LVH. These findings suggest that sodium intake and hemodynamic load, but not the renin-angiotensin system, may be major determinants of the development of LVH in DS rats.
Asunto(s)
Hipertrofia Ventricular Izquierda/patología , Sistema Renina-Angiotensina/efectos de los fármacos , Sodio en la Dieta/farmacología , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Bencimidazoles/farmacología , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Dieta , Hipertrofia Ventricular Izquierda/etiología , Ratas , Ratas Endogámicas , Renina/sangre , Tetrazoles/farmacología , Factores de TiempoRESUMEN
The present study was conducted to prospectively evaluate whether a new ACE inhibitor, temocapril, could modify urinary microalbumin excretion rate (UAE) in a group of hypertensive outpatients who had no evidence of renal impairment. Sixty-three outpatients (32 men and 31 women; mean age, 59.9 +/- 1.5 yr) with essential hypertension entered the study, all having been treated for at least 6 mo with dihydropyridine calcium-channel blockers (CCBs: nitrendipine, nisoldipine, or amlodipine). Their blood pressures (BPs) had been controlled to adequate levels with the CCBs. None had overt proteinuria (determined by Albustix) or abnormal serum creatinine levels. After 3 mo of baseline observation under the previous treatment, the subjects were randomly divided into two groups. In group A (n = 31), the previously used CCBs were switched to temocapril, 2 to 4 mg once daily for 12 mo, and BP was controlled at a level equivalent to that during CCB treatment. In group B (n = 32), the subjects were maintained on their previous treatment for a further 12 mo. The effect of temocapril on BP appeared to be clinically similar to that of the previously used CCBs, but it significantly decreased UAE as compared with the previous therapy. In group A, UAE decreased significantly (p < 0.01) from the baseline value of 38.9 +/- 5.1 mg/g creatinine (Cr) to 22.2 +/- 4.2 and 25.3 +/- 5.6 mg/g Cr at the 6th and 12th months of temocapril therapy, respectively. In contrast, in group B UAE was unchanged (baseline 39.8 +/- 6.6 mg/g Cr; 6 mo, 44.6 +/- 6.8; 12 mo, 45.9 +/- 7.7). In group A, 17 of 31 patients (54.8%) had abnormal UAE levels (> or = 29.5 mg/g Cr) during previous therapy with CCBs, but 6 mo after switching to temocapril 25 of these patients (80.6%) had normal UAE (< 29.5 mg/g Cr). In group B, 15 of 32 patients (46.9%) had abnormal UAE levels during the observation period, and these abnormal UAE levels remained unchanged; 17 of the 32 patients (53.1%) had abnormal UAE levels after a further 6 mo of continued CCBs therapy. We conclude that long-term therapy with temocapril may provide renal protection by reducing UAE even in hypertensive patients with no evidence of renal impairment.
Asunto(s)
Albuminuria/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Hipertensión/tratamiento farmacológico , Tiazepinas/uso terapéutico , Albuminuria/complicaciones , Albuminuria/orina , Análisis de Varianza , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Presión Sanguínea/efectos de los fármacos , Tos/inducido químicamente , Creatinina/sangre , Exantema/inducido químicamente , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/orina , Masculino , Persona de Mediana Edad , Pacientes Desistentes del Tratamiento , Estudios Prospectivos , Tiazepinas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Ácido Úrico/sangreRESUMEN
BACKGROUND: Intravascular ultrasound (IVUS) imaging, a new modality, may be feasible and useful for the assessment of atherosclerotic renal arteries. However, comparison between in vivo and in vitro studies to confirm pathological changes corresponding with IVUS findings obtained from renal arteries was not fully evaluated. METHODS: We evaluated ultrasound images of 18 post-mortem human renal arteries and cross-sectional IVUS images of main renal arteries in five patients with renal artery stenosis (RAS) or essential hypertension. RESULTS: In vitro studies have shown that renal-artery images had three layers when the arteries had fibrous intimal thickening and medial hypertrophy. Renal arteries, in which the fibrous intima was not well developed, showed circumferentially homogeneous bright echoes. In patients with atherosclerotic RAS and essential hypertension, IVUS images showed hyperechoic areas in the renal arterial walls, probably due to atherosclerosis. Typical three-layered ultrasound appearance was not easily seen during in vivo studies. CONCLUSION: Our findings suggest that hyperechoic images can be a diagnostic clue of atherosclerosis However, in vitro results do not always correspond exactly to in vivo findings, and caution is needed when findings from in vitro IVUS imaging studies are applied to in vivo studies.
Asunto(s)
Arteriosclerosis/diagnóstico por imagen , Arteria Renal/diagnóstico por imagen , Ultrasonografía Intervencional , Adolescente , Anciano , Arteriosclerosis/patología , Femenino , Humanos , Hipertensión/diagnóstico por imagen , Hipertensión/patología , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Arteria Renal/patología , Obstrucción de la Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/patologíaRESUMEN
This study was conducted to examine whether imidaprilat, an active diacid of the angiotensin-converting enzyme (ACE) inhibitor imidapril, preferentially inhibits angiotensin I degradation rather than bradykinin degradation, and whether imidapril is less active than other ACE inhibitors in inducing cough in patients with hypertension. The effect of imidaprilat on the inhibition of pressor response to angiotensin I and augmentation of depressor response to bradykinin was compared with that of enalaprilat and captopril in anesthetized rats. To determine the incidence of cough associated with imidapril, patients with a history of ACE inhibitor-induced dry cough were enrolled in a randomized, open-labeled, crossover trial with two 6-week periods to be treated with imidapril or amlodipine, a calcium-channel blocker. The recurrence of cough was assessed during both treatments. In the animal study, there were no significant differences in the ratio of inhibition of pressor response to angiotensin I and the augmentation of depressor response to bradykinin among the ACE inhibitors. In the cough-challenge trial, a total of 60 patients with hypertension were enrolled in the study. Cough and cough related symptoms recurred in 98.3% of the patients (59/ 60) during imidapril therapy. In contrast, only two patients reported cough during treatment with amlodipine. These results indicate that imidapril has no selectivity in inhibiting angiotensin I- and bradykinin-degradation in rats, and that clinically it is not different from other ACE inhibitors in inducing cough in patients with hypertension.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Tos/inducido químicamente , Hipertensión/tratamiento farmacológico , Imidazoles/uso terapéutico , Imidazolidinas , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Animales , Presión Sanguínea/efectos de los fármacos , Bradiquinina/efectos de los fármacos , Bradiquinina/metabolismo , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Ratas , Ratas WistarRESUMEN
Angiotensin-converting enzyme (ACE) inhibitors now have an accepted place in the treatment of hypertension and congestive heart failure. With the discovery and development of captopril, several other ACE inhibitors have been synthesized and introduced for clinical use. All ACE inhibitors bind to zinc ions located in the active site of the ACE molecule. ACE inhibitors can be classified according to the ligand of the zinc ion of ACE, into 3 different structural types: (1) the first type such as captopril has a sulphhydryl moiety as the ligand; (2) the second type such as enalapril uses a carboxyl moiety as the ligand; (3) the third type such as fosinopril uses neither a sulphhydryl nor carboxyl group, but a phosphinic acid as the zinc binding moiety. ACE inhibitors can also be classified according to the excretion route of their active moiety, into 2 different excretion route types:(1) excreated mainly through the kidney such as captopril, enalaprilat, lisinopril, benazeprilat, imdaprilat, trandraprilat, etc.; (2) excreated both in the bile and urine such as fosinoprilat, temocaprilat, zofenoprilat etc. ACE inhibitors have clinically beneficial effects not only for patients with either hypertension or congestive heart failure, but also can be used to prevent the progression of renal dysfunction induced by hypertension and diabetes mellitus.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enfermedad Coronaria/complicaciones , Humanos , Hipertensión/complicaciones , Enfermedades Renales/complicaciones , Enfermedades Renales/prevención & control , Peptidil-Dipeptidasa A , Sistema Renina-AngiotensinaRESUMEN
Fosinopril is a phosphorus-containing ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It is hydrolysed mainly in the gastrointestinal mucosa and liver to the active diacid, fosinoprilat, which has unique pharmacological properties. The majority of the active moieties of other ACE inhibitors are excreted in the urine. This means that an adjustment in either the dosage and/or the administration interval is needed in patients with moderate to severe renal dysfunction, in order to reduce drug accumulation and the possibility of an excessive decrease in blood pressure or other adverse effects. On the other hand, fosinoprilat is excreted both in urine and bile (as with temocaprilat, zofenoprilat and spiraprilat), and thus an adjustment of dosage and/or administration interval may be unnecessary in patients with moderate to severe renal dysfunction, as impaired renal function influences little of the pharmacokinetics of fosinoprilat. Furthermore, the available evidence suggests that the pharmacokinetic variables of fosinoprilat in patients receiving haemodialysis were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dose administration following dialysis may be unnecessary. The hypotensive effect of the combination of fosinopril and a diuretic is synergistic. Pharmacokinetic interactions with fosinopril are unlikely in patients receiving thiazide or loop diuretics. Fosinopril has beneficial effects for patients with hypertension and left ventricular hypertrophy because it produces an adequate reduction in blood pressure and reversal of left ventricular hypertrophy. There are a large number of studies of the pharmacokinetics of fosinopril. However studies of its pharmacokinetic drug interactions with other drugs are far fewer. Further investigations are needed in several clinical settings.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Antihipertensivos/farmacocinética , Fosinopril/farmacocinética , Absorción , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Interacciones Farmacológicas , Femenino , Fosinopril/farmacología , Fosinopril/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/metabolismo , Riñón/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología , Hígado/metabolismo , Hepatopatías/metabolismo , Hepatopatías/fisiopatología , Masculino , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/metabolismo , Diálisis Peritoneal Ambulatoria Continua , Diálisis RenalRESUMEN
The effects of long-term monotherapy with doxazosin, an alpha 1-blocker, or placebo on blood pressure (BP), glucose tolerance, and serum lipid levels were investigated prospectively in 43 hypertensive patients with impaired glucose tolerance. The levels of plasma glucose, serum lipids, fructosamine, and glycated hemoglobin A1c (Hb A1c) were determined before and during long-term (mean treatment period, 6.7 months) therapy with doxazosin (n = 23) or placebo (n = 20). A 75-g oral glucose tolerance test was performed before and during therapy. Significant decreases in both systolic and diastolic BP were maintained during doxazosin therapy; BP did not change in the placebo group. Neither fasting nor post-glucose-load venous plasma glucose levels were altered, and there was no significant change in the insulinogenic index in either group. Glucose intolerance was slightly improved with significant reductions in Hb A1c and fructosamine levels during doxazosin therapy. Serum total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels were significantly decreased, and high-density lipoprotein cholesterol levels were significantly increased in patients treated with doxazosin. Moreover, TC, LDL cholesterol, and apolipoprotein B levels were significantly decreased in patients with hypercholesterolemia (TC > or = 5.69 mmol/L). In contrast, there were no significant changes in Hb A1c, fructosamine, and lipid levels in the placebo group. These results suggest that long-term doxazosin therapy may improve glucose and lipid metabolism in hypertensive patients. Doxazosin appears useful as an antihypertensive agent for hypertensive patients with either impaired glucose metabolism or dyslipidemia.
Asunto(s)
Antihipertensivos/uso terapéutico , Doxazosina/uso terapéutico , Hipertensión/tratamiento farmacológico , Lípidos/sangre , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Aging and hypertension are known to be closely related with the pathogenesis and development of glomerulosclerosis. In this study, we examined the time course changes in the glomerulus associated with salt-induced hypertension using the inbred Dahl salt-sensitive rats. For this purpose, 5-week-old Dahl salt-sensitive rats (n=36) were fed either 4% NaCl diet (n=18) or 0.3% NaCl diet (n=18) up to 17 weeks of age. The high salt diet caused a dramatic increase in systolic blood pressure and also a dramatic renal hypertrophy as shown by a significant increase in the kidney weight. Histological examination revealed an age-dependent progression of glomerulosclerosis as documented by a quantitative scoring. This age-dependent progression was further accelerated by the co-existence of salt-induced hypertension in the high salt diet group. Northern blot analysis revealed an increase in the steady state mRNA levels of fibronectin, an important component of mesangial matrices, in the renal cortex, but not in the renal medulla, only in salt-loaded Dahl salt-sensitive rats. These findings indicate that salt-induced hypertension accelerates the age-dependent progression of glomerulosclerosis in Dahl salt-sensitive rats, and fibronectin may play a role in the pathogenesis, development, and progression of glomerulosclerosis associated with salt-induced hypertension.
Asunto(s)
Envejecimiento , Fibronectinas/genética , Glomerulonefritis/patología , Hipertensión/patología , Corteza Renal/patología , Riñón/patología , Animales , Expresión Génica , Hipertensión/inducido químicamente , Hipertrofia , Corteza Renal/metabolismo , ARN Mensajero/metabolismo , Ratas , Cloruro de Sodio Dietético/administración & dosificaciónRESUMEN
1. We investigated the effects of direct blockade of angiotensin II (AngII) by a potent, non-peptide angiotensin II toff 1 (AT1) receptor antagonist, TCV 116, on the development of cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats. 2. Six week old male Dahl salt-sensitive rats (n = 44) were fed a 4% salt diet and were simultaneously given various doses of TCV 116 orally for 7 weeks. Each control group received vehicle alone. 3. Dietary high salt intake elevated blood pressure continuously and caused left ventricular hypertrophy in rats treated with vehicle. TCV 116 had a minor effect on the rise in blood pressure. Left ventricular mass (left ventricular weight/body-weight) decreased slightly but not significantly, in rats treated with 3 mg/kg per day of TCV 116 (n = 8). Higher doses of TCV 116 (6 and 10 mg/kg per day; n = 8 each) did not show a decrease in left ventricular mass compared with the vehicle control. 4. These results suggest that AngII blockade has only minor effects on hypertension and on cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats and that the renin-angiotensin system may not contribute to the development of cardiac hypertrophy in Dahl salt-sensitive rats on a moderately high-salt diet.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertrofia Ventricular Izquierda/prevención & control , Profármacos/farmacología , Sodio en la Dieta/efectos adversos , Tetrazoles , Animales , Peso Corporal , Relación Dosis-Respuesta a Droga , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/etiología , Masculino , Distribución Aleatoria , RatasRESUMEN
We describe a rare case of ACE inhibitor-induced angioedema during long-term therapy in a 51-year-old male patient with essential hypertension; and this is the third case reported of this adverse reaction in Japan. The patient received enalapril for 66 months, and complained of a dry cough which was mild and tolerable. Recently, he noted tenderness of his mouth, face, swelling of lips and tongue for 3 to 4 h after taking his morning dose of enalapril. These symptoms abated spontaneously, so he continued taking the drugs. He again noted similar episodes of angioedema 29 days after the first experience. He had no further episodes of angioedema or dry cough after cessation of enalapril. This case of angioedema developed during long-term therapy with enalapril administered as 19,930 mg of enalapril maleate. We emphasize that angioedema may occur at any time during the use of enalapril.
Asunto(s)
Angioedema/inducido químicamente , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The effects of long-term monotherapy with cilazapril, an angiotensin-converting enzyme inhibitor, on blood pressure, glucose tolerance, and serum lipid profiles were prospectively investigated in 66 patients with hypertension: 23 with normal glucose tolerance and 43 with glucose intolerance (including 9 patients with non-insulin-dependent diabetes mellitus). The levels of plasma glucose, serum insulin, serum lipids, glycated hemoglobin A(lc) (Hb A(lc)), and fructosamine were determined before and during long-term (mean +/- SD, 26.2 +/- 1.2 weeks) therapy with cilazapril. A 75-g oral glucose tolerance test was performed before and during treatment. Significant reductions in both systolic and diastolic blood pressures in both patient groups were maintained during the study. Neither fasting nor post-glucose load venous plasma glucose levels were altered in either group of patients, and no patient with normal glucose tolerance developed diabetes mellitus during the study. There was no significant change in the insulinogenic index (delta serum insulin/delta venous plasma glucose at 30 minutes post-glucose load) in either group, and glucose intolerance was slightly improved with significant reductions (P < 0.01) in Hb A(lc) and fructosamine in the patient group with impaired glucose tolerance. Serum total cholesterol (TC), low-density lipoprotein cholesterol, and triglyceride levels were significantly (P < 0.01) decreased and high-density lipoprotein cholesterol levels increased in patients with hypercholesterolemia (TC levels > or = 5.69 mmol/L). These results suggest that long-term cilazapril therapy may improve glucose and lipid metabolism in hypertensive patients with impaired glucose tolerance. Cilazapril also appears to be useful as an antihypertensive agent for hypertensive patients with either impaired glucose tolerance or hypercholesterolemia.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Glucemia/metabolismo , Cilazapril/farmacología , Hipertensión/sangre , Lípidos/sangre , Inhibidores de la Enzima Convertidora de Angiotensina/sangre , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Cilazapril/sangre , Cilazapril/uso terapéutico , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Humanos , Hipercolesterolemia/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Masculino , Estudios ProspectivosRESUMEN
The pharmacokinetics and pharmacodynamics of nisoldipine (CAS 63675-72-9, isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate, Bay k 5552), a calcium antagonist, were investigated after administration of a single oral 10 mg dose and after 7 same doses on consecutive days to hypertensive patients with normal renal function (NRF) and those with mild to moderate renal dysfunction (impaired renal function, IRF). A significant decrease in blood pressure was observed after consecutive dosing of nisoldipine compared to baseline values over 24 h in both groups. There were no significant differences in plasma profiles of nisoldipine in both groups after either single or consecutive dosing. The plasma concentration-time profiles of the active metabolite, Bay r 9425, were similar to those of nisoldipine in both groups. The pharmacokinetic parameters of nisoldipine and its active metabolite in the NRF and IRF groups did not differ after the single and the consecutive dosing. In addition, there were neither prolongation of apparent elimination half-life (t1/2), nor increases in peak plasma levels (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) after consecutive dosing in both groups. Cumulative urinary excretion rates of the major metabolites, Bay s 4755 and Bay s 1869, did not differ significantly between the NRF and IRF groups in both single and consecutive studies. In the present study, mild flushing was observed in one patient with IRF. There was no deterioration in renal function during the study. These results suggest that nisoldipine may have a long-lasting antihypertensive effect during consecutive dosing and that it can be used in hypertensive patients regardless of presence of renal dysfunction.
Asunto(s)
Hipertensión/metabolismo , Enfermedades Renales/metabolismo , Nisoldipino/farmacocinética , Presión Sanguínea/efectos de los fármacos , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Nisoldipino/efectos adversos , Nisoldipino/uso terapéutico , Diálisis RenalRESUMEN
OBJECTIVE: The pharmacokinetics of amikacin were studied in patients undergoing slow hemodialysis (HD). DESIGN: Slow HD was performed at the dialysate flow rate of 30 ml/min. After a single intravenous dose of amikacin 5 mg/kg, pharmacokinetic variables were calculated by fitting individual concentration-time curves to a two-compartment open model. PATIENTS: 6 critically ill patients with renal failure were entered into the study. RESULTS: The volume of distribution was 0.35 +/- 0.03 l/kg. Total body clearance was 35.1 +/- 2.3 ml/min with an elimination half-life of 10.5 h. During a 10.5 h session of slow HD, the serum amikacin concentration decreased from the peak level of 21.3 +/- 1.2 mg/l to 7.2 +/- 0.9 mg/l. CONCLUSION: Slow HD eliminate amikacin more efficiently than other types of slowly performed renal replacement therapy and had profound effects on the pharmacokinetics. Amikacin elimination by this approach should be taken into consideration for designing a dosage schedule during the treatment.
Asunto(s)
Amicacina/farmacocinética , Cuidados Críticos , Diálisis Renal/métodos , Insuficiencia Renal/metabolismo , Anciano , Amicacina/administración & dosificación , Esquema de Medicación , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Diálisis Renal/instrumentación , Insuficiencia Renal/terapia , Factores de TiempoAsunto(s)
Renina/sangre , Adolescente , Adulto , Secuencia de Aminoácidos , Humanos , Métodos , Datos de Secuencia MolecularRESUMEN
We studied the roles played by the renin-angiotensin system in inducing hypertension in nine patients with Cushing's syndrome (CS) resulting from adrenocortical adenoma, and compared them with those in patients with primary aldosteronism (PA), renovascular hypertension (RVH) and essential hypertension (EH). In the CS group, each parameter, including serum potassium, plasma renin activity, plasma aldosterone, deoxycorticosterone and corticosterone concentrations, is within the normal range. However, plasma renin activity in the CS group was lower than that in the RVH group but higher than that in the PA group, and plasma aldosterone concentration was lower than that in each RVH or PA group. These findings indicated that the CS group had a different type of hypertension from that in either RVH or PA, in which the renin angiotensin system or mineralocorticoids play an important role in hypertension. Meanwhile, captopril (50 mg) administration either with or without indomethacin pretreatment decreased the mean blood pressure in the CS group, although captopril failed to change it in the PA group or in normal subjects. Furthermore, the pressor response to exogenous angiotensin II in the CS group was higher than that in the RVH or EH group, but was not different from that in the PA group. Thus, the hypertension in patients with CS due to adrenocortical adenoma appears to be mediated through a change in the renin-angiotensin system in the form of exaggerated pressor responses to angiotensin II.