Ketoconazole (Nizoral), an oral broad spectrum antifungal agent, inhibits ergosterol synthesis in fungi and cholesterol synthesis in mammalian cells by inhibition of the 14-demethylation of lanosterol. After a blunted cortisol response to ACTH in normal men after ketoconazole has been shown by others we studied the influence of the antifungal agent on the cortisol secretion in a patient with a cortisol producing adrenal adenoma in vivo and in vitro. Repeated oral doses of ketoconazole (200 mg every 5 h over a period of 48 h) induced a reproducible clear-cut fall of serum cortisol levels under 2.5 micrograms/dl. The inhibitory effect of the cortisol secretion could be detected first 5 h after the first dose, 9 h after the last dose cortisol levels recovered. In addition the inhibitory effect of ketoconazole on cortisol secretion could be reproduced in vitro by incubating tissue slices of the excised adrenal tumor together with the antifungal agent in concentrations equivalent to therapeutic serum levels. These findings emphasize that patients with an autonomous cortisol production caused by an adrenal tumor are prone to dangerous hypoadrenalism if treated with ketoconazole.
Zusammenfassnng. Bei 42 Patienten mit nephrotischem Syndrom wurde die Protein-und Cholesterinausscheidung im 24 Stundenurin gemessen. Die gefundene positive Korrelation (r--0,76, p<0,01) zwischen Cholesterin und Protein im Urin w/ire vereinbar mit einer gesteigerten glomerul/iren Filtration yon Plasmalipoproteinen als Ursache der Lipidurie beim nephrotischen Syndrom. Sehliisselwarter: Nephrotisches Syndrom -Gesamtcholesterin im Urin Protein im UrinSummary. The excretion of protein and cholesterol in 24 h urine was measured in 42 patients with the nephrotic syndrome. The finding of a positive correlation (r = 0.76, p < 0.01) between urinary cholesterol and urinary protein would be compatible with an enhanced glomerular filtration of plasma lip•proteins as the cause of lipiduria in the nephrotic syndrome. Key words: Nephrotic syndrome -Urinary total cholesterol -Urinary proteinLipiduria is a commonly emphasized component of the nephrotic syndrome and refers usually to the birefringent or anisotropic crystals found in the urinary sediment of these patients. These anis•tropic bodies have the typical "Maltese cross" appearance when viewed with a polarizing microscope and cholesterol esters have been identified as the major components of these elements [6, 8, 91. A positive correlation between urinary cholesterol and urinary protein has been reported in several studies [1, 6] but could not be confirmed by others [2]. Most authors agree that an increased glomerular permeability to lip•protein is probably necessary before appreciable amounts of lipid appear in the urine [1][2][3][5][6][7][8][9].However, in all the said former studies urinary cholesterol was determined using nonspecific analytical procedures, mainly colorirnetric methods.Therefore, we studied with a specific gasliquid chromatographic method, whether a positive correlation would exist between urinary protein and urinary cholesterol in patients with the nephrotic syndrome. Offprint requests to: Dr. D. Jfingst (address see page I216)A nephrotic syndrome was defined as a clinical state in which there is a combination of •edema, proteinuria and hypoproteinaemia, irrespective of the aetiology or any other clinical features. This definition stresses the occasional clinical similarities of many unrelated diseases.Total urinary cholesterol was analyzed in 2 ml aliquots of 24 h urine. After extraction with 6 ml ethyl acetate for 30 rain in a rotating system, the urinary phase was removed. The ethyl acetate extract was purified with alkali (2 ml 0.1 N NaOH) and water washings and dried under a stream of nitrogen. The residue was dissolved in 0.1 ml of the internal standard solution (10 mg 4-androstene-3,17-dione/dI isooctane), followed by GLC on a 180 cm 1% XE 60 column, i.d. 2 ram, temperature const. 220 ° C. Quantitation was performed due to the peak height ratio, since alterations of cholesterol and 4-androstenedione concentrations gave a linear response. For the determination of total urinary cholesterol hydrolysis of the dried extract with 0
Urinary excretion of nonesterified (NEC) and total cholesterol (TC) has been investigated in 79 patients with prostatic adenoma (BPH) and 48 patients with carcinoma of the prostate. Normal range of NEC was determined in 62 healthy individuals and was found to be 0.26-2.2 mg/24 hours (2 SD) with a mean value of 0.76 mg/24 hours. TC ranged from 0.3-2.9 mg124 hours with a mean value of 0.92 mg/24 hours. In benign prostatic hyperplasia normal values for NEC and TC were determined in stages without residual urine. in prostatic cancer has been reported re~e n t l y .~* " It was concluded that both parameters are valuable in the diagnosis of the disease. A comparative evaluation of NEC and TC has not yet been undertaken; in addition, the performed studies did not show the value of these parameters in diagnosis of early clinical stages. Other known common conditions of urinary cholesterol hyperexcretion in males are pluripotential testicular neoplasms, diseases of kidney and urinary tract and benign prostatic h y p e r p l a~i a .~J~~'~,~* J~ In regard to the frequency of BPH in comparison to prostatic carcinoma, it was additionally necessary Accepted for publication March 15, 1978. to investigate whether elevated levels of urinary cholesterol were present in all clinical stages of BPH or only in patients with BPH and residual urine with indication for surgical treatment. MATERIALS A N D METHODSNonesterified and total urinary cholesterol were analyzed in 2 ml aliquots of 24-hour urine. After extraction with 6 ml ethyl acetate for 30 minutes in a rotating system, the urinary phase was removed. The ethyl acetate extract was purified with alkali (2 ml 0 . 1~ NaOH) and water washings and dried under a stream of nitrogen. The residue was dissolved with 0.1 ml of the internal standard solution (10 mg 4-androstene-3, 17-dione/dl isooctane), followed by GLC on a 180 cm 1 % XE 60 column, i.d. 2 mm, temp. const. 220 C. Quantitation was performed due to the peak height ratio, since alterations of cholesterol and 4-androstenedione concentration gave a linear response.
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