E. Darracott Vaughan

The effect of finasteride in men with benign prostatic hyperplasia

Background Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. Methods In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. Results As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. Conclusions The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases.

Abstract The antihypertensive effect and mechanism of propranolol were studied in 47 hypertensive patients classified according to high, normal, or low plasma renin activity. The drug was uniformly effective in 13 patients with high renin activity and malignant, renovascular, or essential hypertension, producing a mean fall in diastolic pressure of 30 mm of mercury. In 22 with normal renin, propranolol reduced mean diastolic pressure by 20 mm of mercury, but individual responses were less consistent. In contrast, the drug was uniformly ineffective in the 12 patients with low-renin essential hypertension. In all three groups, the action of propranolol closely correlated with both the control renin levels and the degree of renin suppression produced. Propranolol usually suppressed aldosterone secretion but to a lesser extent than it did renin, perhaps because of a hyperkalemic effect of the drug. These special effects of propranolol in renin-dependent hypertensions point to the possibility of an associated ...

Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse

Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M‐VAC regimen), significant tumor regression occurred in 72% ± 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% ± 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2‐year and 3‐year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non‐TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T < pathologic [P] restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3–4Mo patients who achieved CR versus 33% of 100 with No‐+M+ lesions. Toxicity was significant with 4 (3%) drug‐related deaths, 25% incidence of nadir sepsis, 58% ⩾ 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens. Cancer 64:2448–2458, 1989.

Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs

Auriculin is a potent vasoactive and natriuretic peptide that was recently isolated and purified from rat atrial tissue. Since this peptide could be of great importance for renal, cardiovascular, and volume homeostasis, its functional properties have been characterized in dogs. The effects of synthetic auriculin on renal function, mean blood pressure, plasma renin activity, renin secretory rate, and plasma aldosterone levels were determined. Auriculin was administered intravenously as a prime (1.0 microgram/kg body weight) and constant infusion (0.1 microgram per minute/kg body weight for one hour) to five anesthetized dogs. In addition, two conscious dogs were used to verify some of the results obtained in anesthetized dogs. Auriculin decreased mean blood pressure from 134 +/- 5 to 122 +/- 4 mm Hg (p less than 0.05, paired t test) and increased glomerular filtration rate (25.5 +/- 2.7 to 32.4 +/- 4.1 ml per minute per kidney, p less than 0.05), diuresis (0.21 +/- 0.03 to 1.06 +/- 0.14 ml per minute per kidney, p less than 0.05), natriuresis (38 +/- 0.6 to 187 +/- 35 mueq per minute per kidney, p less than 0.05), and kaliuresis (14.8 +/- 1.6 to 35.7 +/- 6.3 mueq per minute per kidney, p less than 0.05). These effects were sustained throughout the infusion of auriculin and were entirely reversible. Renal plasma flow increased transiently for one to two minutes, and then returned to or below control levels. Urine osmolality decreased by 40 percent (p less than 0.05) whereas free water clearance remained unchanged (p less than 0.05). Auriculin reversibly decreased plasma renin activity (11.6 +/- 2.3 to 3.6 +/- 1.2 ng/ml per hour, p less than 0.05), renin secretory rate (895 +/- 313 to 255 +/- 28 ng per hour per minute, p less than 0.05), and plasma aldosterone levels (8.4 +/- 1.6 to 3.6 +/- 0.7 ng/dl, p less than 0.05), whereas plasma cortisol levels remained unchanged. These results demonstrate that auriculin has a unique combination of functional properties, increasing glomerular filtration rate, diuresis, and natriuresis, without a sustained increase in total renal blood flow, and lowering blood pressure, plasma renin levels, renin secretory rate, and plasma aldosterone levels. These properties suggest an important potential role for atrial natriuretic peptides in the regulation of renal function, extracellular volume, and blood pressure.

Percutaneous Transluminal Renal Angioplasty in Renovascular Hypertension Due to Atheroma or Fibromuscular Dysplasia

We attempted percutaneous transluminal renal angioplasty in 89 patients with hypertension and renal-artery stenosis (including 51 with atheromatous and 31 with fibromuscular stenoses) who were then followed for an average of 16 months (range, 4 to 40). Angioplasty was technically successful in 87 per cent of the fibromuscular stenoses and in 57 per cent of the unilateral atheromatous stenoses but in only 10 per cent of the bilateral atheromatous stenoses. After successful angioplasty, blood pressure was reduced to normal or improved in 93 per cent of the patients with fibromuscular dysplasia and in 84 per cent of the patients with atheromatous disease. Angiographic follow-up at an average of 21.8 months in 15 patients showed persistent relief of the stenoses and a 12 per cent average increase in kidney size. Renal angioplasty is effective for long-term control of hypertension in patients with renal-artery stenosis due to fibromuscular dysplasia or unilateral non-ostial atheroma.

Diagnosis and Treatment of Primary Hyperaldosteronism

Primary aldosteronism is characterized by hypertension, hypokalemia, and low plasma renin activity and is most commonly caused by an adrenal adenoma that produces aldosterone. The plasma aldosterone level of affected patients usually fails to increase when renin activity increases during either upright posture or infusion of angiotensin II; thus, aldosterone will be secreted independently from the renin-angiotensin system [1]. A less common cause of this syndrome is idiopathic hyperaldosteronism, characterized by nonadenomatous hyperplasia and low plasma renin activity, in which the adrenal gland usually responds to angiotensin II. However, this syndrome has considerable phenotypic heterogeneity, with diagnostic variants differing from the more typical forms by their responsiveness to angiotensin. For example, a subset of adrenal hyperplasia mimics an aldosteronoma because it is associated with angiotensin-independent aldosterone overproduction and can be cured by unilateral adrenalectomy [2]. Conversely, some adenomas respond to angiotensin; Tunny and colleagues [3] have correlated the magnitude of this aldosterone response with the proportion of glomerulosa cells present in the tumor. This biochemical diversity is also manifested by characteristic patterns of steroid metabolism. In adenomas, levels of C-18 methyl oxidation metabolites of cortisol (18-oxocortisol and 18-hydroxycortisol) exceed those in idiopathic hyperaldosteronism and were elevated in patients with hyperplasia who were cured by adrenalectomy [4, 5]. The presence of an adrenal adenoma that produces aldosterone is considered the major clinical characteristic distinguishing primary aldosteronism that is curable by surgery. Refinements of imaging techniques have facilitated the detection of subtle adrenal abnormalities early in the clinical course. Coordinated use of these diagnostic approaches should improve the ability to determine which patients are likely to be cured by adrenalectomy. However, several studies have shown that the chances for curing hypertension are less predictable than those for the related biochemical abnormalities. Accordingly, these studies showed that only 50% of patients with adenomas were normotensive 5 years after adrenalectomy and that older patients were more likely to require postoperative antihypertensive medications [6, 7]. The clinical and biochemical diversity of this syndrome has important implications regarding its pathophysiology and responsiveness to therapy. We sought to characterize patients with primary aldosteronism who are followed at The Cardiovascular Center at The New York Hospital-Cornell Medical Center to identify features that would predict favorable responses to treatment and to attempt to understand why adrenalectomy often fails to produce a sustained reduction in blood pressure. Methods Patients A retrospective analysis of the medical records at The Cardiovascular Center of The New York Hospital-Cornell Medical Center indicated that 82 patients with primary aldosteronism were evaluated from 1976 to 1991. This diagnosis was established by the following criteria: 1) hypertension; 2) elevated rates of urinary aldosterone excretion as determined by an established nomogram that relates 24-hour urinary sodium excretion with urinary aldosterone and plasma renin activity [8]; 3) low renin activity [in most patients]; and 4) hypokalemia that was either spontaneous or diuretic-induced and associated with inappropriate renal potassium loss (>40 mmol/d). Diagnoses Adenomas (n = 52) were diagnosed when an adrenal tumor was observed by contrast-enhanced computed tomographic (CT) scan. When possible, this was corroborated by lateralization of adrenal aldosterone secretion by adrenal vein sampling or evidence of functional autonomy, defined by a failure of the plasma aldosterone level to increase when the patient was in upright posture. An adenoma was confirmed surgically in 47 patients. Five patients had radiographic and biochemical features that indicated adenoma, but they refused surgery and were treated medically. Idiopathic hyperaldosteronism was diagnosed in 22 patients whose CT scans showed unilateral or bilateral adrenal hyperplasia without an adenoma. These patients were treated with antihypertensive medication. Eight additional patients with nonadenomatous hyperplasia had adrenalectomy because their preoperative evaluation suggested an adrenal adenoma; 3 of these 8 patients had adrenal sampling and lateralized aldosterone secretion. Biochemical Studies In 56 patients (34 with adenomas and 22 with hyperplasia), medications were withdrawn approximately 2 weeks (for spironolactone, at least 1 month) before hemodynamic, biochemical, and hormonal evaluation. Dietary intake of sodium and potassium was not controlled in most patients during their evaluation. Hormonal profiling was usually done when patients were hypokalemic, although some received potassium supplements. Demographic, blood pressure, and biochemical data from 26 patients (18 with adenomas and 8 with idiopathic aldosteronism) who did not discontinue drug therapy before treatment were excluded from the statistical analysis of pretreatment diagnostic features. Assays for plasma renin activity [9], urinary and plasma aldosterone [10, 11], cortisol (Coat-A-Count Cortisol, Diagnostic Products Corporation, Los Angeles, California; 12), and atrial natriuretic peptide levels [13] have been described previously. In our laboratory, a plasma renin activity of 0.15 ng/mL per hour is at the lower limit of detection. We recently reported urinary excretion rates of 18-hydroxycortisol and 18-oxocortisol from 42 patients with primary aldosteronism [5]. We evaluated the clinical characteristics of a subset of these patients (15 with adenomas and 9 with hyperplasia) and include here the levels of these cortisol metabolites. A positive postural stimulation test result was defined by an ambulatory plasma aldosterone level that was either lower than the supine baseline level or that was increased less than 30% above that value [14]. For this test, plasma samples for aldosterone, renin, and cortisol were obtained from supine patients at 0800 h before they arose from their overnight recumbency, and again after 2 hours of ambulation. We excluded data from analysis if plasma cortisol and aldosterone levels simultaneously increased (for cortisol levels, an increase >30% greater than supine levels) because an increase in cortisol levels after 0800 h indicates a stress adrenocorticotropin hormone response that can also increase aldosterone secretion. We obtained adrenal vein aldosterone samples using percutaneous catheterization. Adrenal vein catheterization was considered successful when the plasma cortisol level from the adrenal vein was two times higher than the level from the inferior vena cava [15]. The mean plasma cortisol level for the adrenal vein was more than 10 times higher than that from the inferior vena cava (256 g/dL compared with 16 g/dL [difference, 240g/dL; CI of the difference, 320g/dL to 160g/dL; P < 0.001]). We defined lateralization of adrenal aldosterone secretion as a ratio of adrenal vein (aldosterone/cortisol levels)/inferior vena cava (aldosterone/cortisol levels) greater than 1.0 from the ipsilateral adrenal vein and 1.0 or less from the contralateral adrenal vein [16, 17]. Clinical Outcomes We considered hypertension to be cured when blood pressure decreased to 140/90 mm Hg or less after adrenalectomy and if postoperative antihypertensive medication was not required, to be improved when systolic pressure decreased by at least 10 mm Hg and diastolic pressure decreased by more than 5 mm Hg after adrenalectomy or medication, or to be not improved when the preceding criteria were not met after treatment. Statistical Analysis We used unpaired t-tests to compare baseline blood pressure and hormonal values between groups and used paired t-tests to compare treatment-related changes in these variables within groups. We calculated 95% confidence intervals for the differences in sample means. Chi-square analysis was used to evaluate differences in the numbers of patients in the diagnostic groups for demographic, blood pressure, and laboratory characteristics. Results Patient Characteristics Demographics Of the 82 patients with primary aldosteronism, 52 had adenomas and 30 had hyperplasia. Patients with adenomas were younger (46 years compared with 54 years [difference, 8 years; CI, 6 years to 10 years]). The sex and race distributions were similar in both groups. The 56 patients (34 with adenomas and 22 with nonadenomatous hyperplasia) who were studied after therapy with antihypertensive medication was discontinued were representative of all 82 patients with primary aldosteronism. Blood Pressure Patients with adenomas had higher mean systolic and diastolic blood pressures Table 1, although moderate to severe hypertension was common in both groups. After medical therapy was discontinued, systolic blood pressure was 175 mm Hg or greater in 66% of patients with adenomas but only in 15% of patients with hyperplasia (P < 0.001). Diastolic pressure was 114 mm Hg or greater in 50% of patients with adenomas and in 19% of those with hyperplasia (P = 0.09). Table 1. Blood Pressure and Laboratory Values before Treatment Renal Disease Baseline creatinine clearance was similar in both groups (1.88 mL/s for the adenoma group and 1.65 mL/s for the hyperplasia group; P = 0.18). Only one patient had an elevated serum creatinine level (>141.4 mol/L [1.6 mg/dL]). However, pathologic levels of proteinuria or microalbuminuria, defined as a daily protein excretion of greater than 0.2 g or an albumin excretion of greater than 0.03 g, were observed in more than 40% of patients in both groups. The most abundant proteinuria (1.5 g every 24 hours) occurred in the patient with adenoma who had the highest plasma renin activity (2.1 ng/mL per hour), although mean plasma renin activ

Antihypertensive action of propranolol: Specific antirenin responses in high and normal renin forms of essential, renal, renovascular and malignant hypertension*

The antihypertensive effect of propranolol was evaluated in 96 patients with various forms of hypertension preclassified according to plasma renin activity considered in relation to urinary sodium excretion. In essential hypertension (no = 74) 74 percent of high-renin patients (14 of 19) exhibited striking blood pressure reductions and 66 percent of normal-renin patients (25 of 38) achieved diastolic pressures less than or equal to 95 mm Hg. In sharp contrast, propranolol was completely ineffective in 17 low-renin patients. In all 11 patients with unilateral renal artery or parenchymal disease propranolol also lowered blood pressure in proportion to control renin levels. The response was predictive of the antihypertensive benefit of surgery even in six “normal” renin patients. In eight patients with high-renin malignant hypertension, propranolol normalized renin, aldosterone and potassium levels and produced dramatic though often incomplete blood pressure correction. In one low-renin patient with the malignant syndrone propranolol was ineffective. Regardless of etiology, antihypertensive effectiveness of propranolol correlated with control renin levels and with the decrement in renin secretion. Thus, a simple biochemical measurement indexed against sodium excretion predicted antihypertensive drug responsiveness. These observations expose, for the first time, a role for renin in a major fraction of patients with essential hypertension. Renin-induced vasoconstriction appears to cause the hypertension in high renin and also in some normal renin patients in whom renin may be inappropriately high for sodium balance. The antihypertensive action of propranolol strikes at both vasoconstrictor and volume components of hypertension since inhibition of renin secretion naturally retards aldosterone secretion, thus preventing compensatory salt and water retention which often vitiates hypotensive therapy. Accordingly, propranolol added to either vasodilator or diuretic agents ought to improve hypotensive effect by curtailing reactive increases in renin and aldosterone: this should also reduce diuretic-induced potassium loss. Propranolol given alone may prove effective in a sizeable fraction of all hypertensive disorders and without inducing the dehydrated hyperreninemic state caused by diuretics. Therefore propranolol may prove to be an alternate first approach, except in lowrenin hypertensions where this type of therapy is ineffective and contraindicated.

The Effect of Finasteride in Men with Benign Prostatic Hyperplasia

BACKGROUND Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. METHODS In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. RESULTS As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. CONCLUSIONS The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Volume factor in low and normal renin essential hypertension: Treatment with either spironolactone or chlorthalidone

The blood pressure response to spironolactone or chlorthalidone was studied in 71 patients with essential hypertension exhibiting either low or normal plasma renin activity. The patients with low renin activity were more responsive to both of these diuretic agents, but neither drug was uniquely or uniformly effective in this group. Blood pressure became normal in only 57 percent of patients with reduced renin activity receiving spironolactone therapy, whereas 24 percent maintained a diastolic pressure greater than 105 mm Hg; 44 percent of them responded to chlorthalidone, but 31 percent did not. In patients with normal renin values the blood pressure was normalized in 36 percent by spironolactone and in 37.5 percent by chlorthalidone. Responses to spironolactone were usually manifested with a dose of 100 mg/day; an increased dose rarely had an additional antihypertensive effect. The similar effectiveness of both drugs in 27 patients treated sequentially with each agent suggests that volume depletion is a common mechanism of action. The sustained induced elevations of plasma renin activity and aldosterone excretion, and the chronic elevations of blood urea nitrogen induced by both agents, indicate that a persistent shift or loss of body sodium or water occurs during therapy. Thus, the antihypertensive action of either diuretic agent appears to result from a reduction of a possibly excessive sodium or volume content relative to capacity of the vascular bed. Patients failing to respond may have had inadequate volume depletion or a hypertensive state that was maintained by a relatively greater vasoconstrictor (renin) response for the degree of volume depletion induced by the drug. Altogether the data suggest that diuretic therapy with either spironolactone or a sulfonamide is primarily indicated in low renin essential hypertension. In patients with normal renin activity diuretic therapy could be reserved for those in whom beta adrenergic blockade proves inadequate. Such sequential single-drug antihypertensive therapy offers the potential for further characterization and understanding of hypertensive disorders while affording a simpler and more specific long-term drug regimen for some patients.

Renal Cell Carcinoma Extending into the Inferior Vena Cava: The Prognostic Significance of the Level of Vena Caval Involvement

The records of 24 patients with renal cell carcinoma involving the inferior vena cava who were free of metastatic disease at presentation were reviewed retrospectively. The over-all 2-year survival for the group was 45.8 per cent, with a mean survival of 38.9 months. When the group was analyzed according to the level of extension of the vena caval thrombus marked differences in the rate of survival and of incidence of local progression of disease were found. The 10 patients with an infrahepatic vena caval thrombus had a 2-year survival rate of 80 per cent and a mean survival of 61.4 months. Two patients (20 per cent) had extension of tumor into the perinephric fat and none had involvement of the regional lymph nodes. The 14 patients with a vena caval thrombus extending to the level of the hepatic veins or beyond had a 2-year survival rate of 21 per cent and a mean survival of 22.9 months. Tumor was present in the regional lymph nodes and/or perinephric fat in 9 of these patients (64 per cent). These results suggest that the level of vena caval involvement by tumor thrombus in patients with renal cell carcinoma has prognostic significance.