W. Vetter

Urinary free cortisol versus 17-hydroxycorticosteroids a comparative study of their diagnostic value in Cushing's syndrome

SummaryWe evaluated the usefulness of the basal urinary 24-h excretion rates of free cortisol versus 17-hydroxycorticosteroids in the diagnosis of Cushings syndrome. On an outpatient basis, both urinary free cortisol and 17-hydroxycorticosteroids levels were determined in 48 patients with Cushings syndrome, as well as in 95 obese and 94 healthy control persons of normal weight. Determination of the urinary free cortisol content allowed a clear-cut distinction between the patients with hypercortisolism and the controls, resulting in a sensitivity of 100% and specificity of 98% for the diagnosis of Cushings syndrome. The diagnostic accuracy of urinary free cortisol was distinctly superior to that of 17-hydroxycorticosteroids, which showed a wide overlap of values between the groups, with a sensitivity of 73% and a specificity of 94%. In conclusion, the measurement of basal urinary free cortisol provided an excellent diagnostic sensitivity and specificity in the assessment of adrenocortical function. This simple and accurate test thus seems to be particularly useful in the outpatient evaluation of patients with suspected Cushings syndrome.

Morning versus evening administration of nifedipine gastrointestinal therapeutic system in the management of essential hypertension

The nifedipine gastrointestinal therapeutic system (GITS) is a recently developed controlled-release formulation for once-a-day dosing. We evaluated the influence of morning versus evening administration of the drug in a randomized double-blind cross-over study including 15 essential hypertensives. Five patients had to be excluded from blood pressure analysis because of noncompliance (three cases) or intolerable side effects (two cases). To assess the exact duration of the antihypertensive efficacy noninvasive automatic ambulatory blood pressure monitoring was performed. After a placebo period patients were given 30 mg nifedipine GITS either at 1000 or 2200 hours. Twenty-four-hour systolic and diastolic blood pressure profiles documented a sustained antihypertensive effect of both nifedipine regimens throughout the whole period without affecting the circadian rhythm. Statistical analysis revealed no significant difference between morning and evening administration. Two patients stopped their medication because of intolerable side effects (fatigue and muscle cramps, respectively). Two more cases suffered from mild reversible headache which provoked no discontinuation of the drug. In conclusion our results document a sustained antihypertensive efficacy of 30 mg nifedipine GITS in patients with moderate essential hypertension. Time of administration has no impact on day- and nighttime blood pressure control.

Primary Aldosteronism: Diagnosis and Noninvasive Lateralization Procedures

In 72 patients with primary aldosteronism who were classified on the basis of adrenal pathology after adrenalectomy, analysis of routine clinical and laboratory data, of supine and upright plasma aldosterone, and of plasma renin activity were of limited value in differentiating patients with aldosterone-producing adenoma(s) (APA, n = 59) from those with idiopathic adrenal hyperplasia (IAH, n = 13). Normokalemic aldosteronism occurred in 6 patients (3 APA, 3 IAH). A correct classification of the adrenal lesion(s) was obtained in 80% of the patients by computed tomography and only in 69% by adrenal scintiscan. In addition, adrenal scintiscan was hampered by a relatively high rate of incorrect results independent of whether dexamethasone was used or not. Small adenomas (less than 1 cm) and more often adrenal hyperplasia may escape visualization by computed tomography.

Adrenalectomy in Primary Aldosteronism: A Long-Term Follow-Up Study

The effect of unilateral adrenalectomy in primary aldosteronism was analyzed in 38 patients with unilateral adenoma, 12 cases with idiopathic bilateral hyperplasia and 1 patient suffering from an aldosterone-producing carcinoma. Responses to surgery differed markedly. In all 38 adenoma cases plasma aldosterone dropped to normal levels and remained within normal range during a mean follow-up period of 75 +/- 12 months. 23 (61%) of these patients became normotensive without medication and thus could be classified as definitely cured. 34% (13 patients) improved (normotensive under medical treatment) and only 2 cases (5%) remained hypertensive despite sufficient medical treatment. In the hyperplasia group, however, the effect of adrenalectomy was disappointing. None of these subjects showed a long-lasting normalization of aldosterone secretion. A temporary remission for no more than 3-4 months was achieved in only 3 patients. In a fourth case with macronodular hyperplasia, primary aldosteronism relapsed after a 6-year period of normal blood pressure and aldosterone values. Therefore, 6 years after adrenalectomy no hyperplasia patient was definitely cured in contrast to 61% of the adenoma cases. The problems in the management of hypertension in adrenal hyperplasia are furthermore documented by a poorer blood pressure control despite antihypertensive medication and a high rate of vascular complications. During the follow-up, 3 of 12 hyperplasia patients experienced a cerebrovascular event and 1 a myocardial infarction.

Primary aldosteronism: treatment with trilostane.

Trilostane, an inhibitor of the 3 beta-hydroxysteroid dehydrogenase enzyme system of steroid biosynthesis, was applied to 18 patients with primary aldosteronism (9 patients with adrenal adenoma, 9 patients with bilateral adrenal hyperplasia) for 12 weeks. A marked decrease in plasma aldosterone was observed during therapy combined with a reduction in blood pressure and a rise in serum potassium levels. Except for slight diarrhea in 4 patients, which did not require cessation of trilostane medication, no further side effects were observed. Trilostane proved to be an effective inhibitor of aldosterone biosynthesis and was found useful in the treatment of primary aldosteronism both in patients with adrenal adenoma and in those with bilateral adrenal hyperplasia.

Primary aldosteronism: difference in clinical presentation and long-term follow-up between adenoma and bilateral hyperplasia of the adrenal glands

Since 1974 primary aldosteronism has been diagnosed in 71 patients in our outpatient clinic. Thirty-four patients had a unilateral aldosterone-producing adenoma, whereas bilateral adrenal hyperplasia was diagnosed in 37 patients. Although at the time of diagnosis the mean potassium values were lower and mean aldosterone levels were higher in patients with an adenoma, as compared to those with bilateral hyperplasia, these laboratory data did not allow us to differentiate between the two leading causes of primary aldosteronism in the individual patient due to pronounced overlap of laboratory values between the two groups. During the first few years, a successful differential diagnosis was made by adrenal phlebography and separate sampling of plasma aldosterone in both adrenal veins; later non-invasive imaging techniques such as computed tomography and radionuclide scanning were used. The best results were obtained in patients with adenoma who underwent adrenalectomy. Fifty-six percent of these patients were clinically and biochemically cured; 28% were improved and had normal blood pressure values during drug treatment. In contrast, patients with bilateral hyperplasia were treated pharmacologically, but only in half of the patients could normal blood pressure values be achieved. Two thirds of the male patients developed gynecomastia during spironolactone treatment. As expected, unilateral adrenalectomy was unsuccessful in the 7 patients with bilateral hyperplasia who underwent surgery. Our results confirm that surgical treatment of adrenal adenomas and drug treatment of bilateral hyperplasias are the appropriate therapy in primary aldosteronism. A differential diagnosis cannot be made on the basis of clinical and non-invasive laboratory data alone; imaging techniques have to be included in the diagnostic process. The long-term clinical outcome was more favorable in patients with an adrenal adenoma that can be removed surgically than in patients with idiopathic hyperplasia of both adrenal glands.

Comparison of casual, ambulatory and self-measured blood pressure in a study of nitrendipine vs bisoprolol

SummaryIn a double-blind, placebo-controlled study the antihypertensive efficacy and tolerability of a single morning dose of either 10 mg bisoprolol (n=26) or 20 mg nitrendipine (n=27) were investigated. Blood pressure was measured by three techniques: (1) Casual blood pressure 24 h after the dose; (2) ambulatory 24-h whole-day monitoring; and (3) self-recorded blood pressure in the morning 24 h after the dose (6–8 a.m.) and in the evening (6–8 p.m.). After 4 weeks of therapy bisoprolol had produced a highly significant reduction in blood pressure as assessed by casual, ambulatory day- and night-time monitoring, and self-measured morning and evening readings. Bisoprolol was significantly more effective than nitrendipine, which did not induce a significant reduction in the ambulatory night-time recordings. Whole-day ambulatory blood pressure profiles showed an antihypertensive effect of bisoprolol throughout the entire 24-h period. 24-h blood pressure curves after nitrendipine demonstrated a markedly shorter duration of action, with no reduction in early morning blood pressure. Adverse effects and tolerability of the two drugs were comparable. The average changes in systolic and diastolic blood pressure after bisoprolol and nitrendipine in 2-h periods of ambulatory monitoring (6–8 a.m. and 6–8 p.m.) and self-measured blood pressure (6–8 a.m. and 6–8 p.m.) showed a good agreement between ambulatory and self-measured blood pressure determinations with no significant difference between the methods.The results show that 24 h antihypertensive efficacy was more pronounced for bisoprolol than for nitrendipine at the doses studied. Further, self-measured blood pressures at home were suitable for accurate estimation of the 12-h and 24-h antihypertensive efficacy of the two drugs. The methodological findings of this study have important implications for further pharmacological trials investigating the duration of action of antihypertensive drugs.

Atenolol versus pindolol: side-effects in hypertension.

SummaryThis randomized crossover out-patient study was designed to compare the antihypertensive effects of atenolol and pindolol. After a wash-out period of two weeks in pretreated cases, 107 patients with essential hypertension were given either atenolol 100 mg once-daily or pindolol 20 mg slow release (SR) once-daily. Both atenolol and pindolol lowered blood pressure over the 24 week period. The diastolic blood pressure reduction was significantly greater (p<0.01) with atenolol than with pindolol. Before β-blocker therapy, many patients had already experienced side-effects such as fatigue, sleep disturbances and dreams. This probably relates to the high sensitivity of the analogue scale used to assess side-effects, and to the high incidence of such symptoms in untreated patients. As the study progressed there was a reduction in the frequency of fatigue (p<0.03) and dreams (p<0.05) in both groups, whereas sleep disturbances significantly increased under pindolol (p<0.05) but decreased under atenolol (p<0.05). The only important side-effect difference between the two β-blockers was the higher incidence of sleep disturbances with pindolol which may be due to the higher lipophilicity of this β-blocker.

Captopril in various forms of severe therapy-resistant hypertension

SummaryIn this study 51 patients with severe hypertension (20 essential, 15 renovascular and 16 renalparenchymatous) resistant to a standardized triple therapy were treated with the oral converting enzyme inhibitor captopril. Mean treatment period was 8.6 in essential, 8.9 in renovascular and 9.9 months in renalparenchymatous hypertension.In each of the 3 groups a marked and sustained blood pressure reduction was observed promptly after introducing captopril. However, absolute fall in mean blood pressure as well as individual blood pressure response were more pronounced in renovascular than in essential and in renalparenchymatous hypertension demonstrating a higher blood pressure lowering activity of the converting enzyme inhibitor in the former.In addition, our results document that monotherapy with captopril was rather the exception than the rule. More than 90% of all patients required at least the addition of a diuretic and even a substantial percentage of patients needed as a third drug a betablocker (50% in essential, 38% in renalparenchymatous and 26% in renovascular hypertension).As expected renin activity increased under captopril whereas plasma aldosterone and converting enzyme activity decreased.Side-effects (skin rash, pruritus, supraventricular extrasystoles, tachycardia, water and fluid retention, Raynaud-phenomenon, incomplete and complete taste loss and leucopenia) occurred in 17.6% (n=9) of the 51 patients.Our results show that captopril is a potent blood pressure lowering agent in severe and therapy resistant hypertension. The vast majority of patients, however, required concomitant therapy with a diuretic and/or a betablocker. Finally, the frequency of drug induced side-effects necessitates a close and careful monitoring of all patients.ZusammenfassungIn der vorliegenden Studie wurden 51 Patienten mit schwerer, auf eine standardisierte Dreiertherapie resistente Hypertonie (20 mit essentieller, 15 mit renovaskulärer und 16 mit renalparenchymatöser Hypertonie) mit dem oralen Converting enzyme Inhibitor Captopril behandelt. Die mittlere Behandlungszeit betrug 8,6 Monate für Patienten mit essentieller, 8,9 Monate für solche mit renovaskulärer und 9,9 Monate für Fälle mit renalparenchymatöser Hypertonie.In allen 3 Patientengruppen konnte ein ausgeprägter und anhaltender Blutdruckabfall beobachtet werden. Allerdings war sowohl der absolute Blutdruckabfall als auch die individuelle Blutdruckantwort bei Patienten mit renovaskulärer Hypertonie ausgeprägter als bei solchen mit essentieller und renalparenchymatöser Hypertonie. Diese Ergebnisse weisen damit auf einen stärkeren antihypertensiven Effekt von Captopril bei Patienten mit renovaskulärer Hypertonie hin.Unsere Resultate zeigen weiter, daß eine Monotherapie mit Captopril eher die Ausnahme als die Regel war. So benötigten über 90% der Patienten zusätzliche Gabe eines Diuretikums und ein weiterer Anteil der Patienten darüberhinaus die Gabe eines Betablockers (50% der Patienten mit essentieller, 38% der Fälle mit renalparenchymatöser und 26% der Patienten mit renovaskulärer Hypertonie).Die Plasma-Renin-Aktivität stieg unter Captoprilbehandlung erwartungsgemäß an, während die Plasma-Aldosteron-Konzentration und die Converting enzyme Aktivität abfielen.In 17,6% (n=9) der 51 Patienten konnten Nebenwirkungen (Exanthem, Pruritus, supraventrikuläre Extrasystolen, Tachykardie, Wasser- und Flüssigkeitsretention, Raynaud-Phänomen, unvollständiger und vollständiger Geschmacksverlust und Leukopenie) beobachtet werden.Unsere Ergebnisse zeigen, daß Captopril bei schwerer therapieresistenter Hypertonie ein potentes Antihypertensivum ist. Dabei war bei unseren Patienten eine Monotherapie mit Captopril eher die Ausnahme als die Regel. So benötigten die meisten Patienten zusätzlich ein Diuretikum und/oder einen Betablocker. Allerdings erfordern die Nebenwirkungen des Medikaments eine engmaschige und genaue Überwachung aller Patienten.

Potentiation of vascular smooth muscle cell activity by Cyclosporin A

SummaryPretreatment of rat vascular smooth muscle cells with cyclosporin A caused concentration- and time-dependent enhancement of both angiotensin II- and platelet-derived growth factor-stimulated cellular functions, which may be related to a rise in vascular tone. In particular, cyclosporin A increased cytosolic free calcium, and augmented the agonist-induced formation of inositol polyphosphate. In addition, it markedly increased the sensitivity of the cells to platelet-derived growth factor-mediated stimulation of thymidine incorporation.The potentiation of vascular smooth muscle cell activity by cyclosporin A may be a novel mechanism by which it exerts an adverse vasoconstrictor effect.