Comparison of the diagnostic accuracy of di-22:6-bis(monoacylglycerol)phosphate and other urinary phospholipids for drug-induced phospholipidosis or tissue injury in the rat.

Cationic amphiphilic drugs and aminoglycoside antibiotics can induce phospholipidosis (PLD), an abnormal accumulation of phospholipids in lysosome-derived vesicles, in preclinical studies. The incidence of PLD in patients and its clinical relevance are difficult to assess without noninvasive biomarkers. Di-docosahexaenoyl bis(monoacylglycerol)phosphate (di-22:6-BMP) is a phospholipid that is enriched in lysosomal membranes and a proposed urinary biomarker of drug-induced PLD. The specificity of di-22:6-BMP for PLD was compared to other phospholipid species that can increase in urine with nephrotoxicity. Using liquid chromatography coupled to mass spectrometry, 12 phospholipids were assayed in the urine of rats treated with drugs that induced PLD or caused renal or skeletal muscle injury. In receiver operating curve analyses, urinary di-22:6-BMP was a significantly better predictor of PLD and the least predictive of tissue injury of the phospholipids assayed. The data provide evidence supporting the use of di-22:6-BMP as a urinary biomarker of PLD in rats.

Drug-induced steatohepatitis.

Drugs rarely cause steatohepatitis, but amiodarone, perhexiline, and DH, have unequivocally been found to independently induce the histologic picture of alcoholic liver disease or NASH. All three agents have similar pathogenetic mechanisms of hepatotoxicity, targeting mitochondrial ATP production and fatty acid catabolism. Other drugs that occasionally cause steatohepatitis, most importantly steroid hormones, likely exacerbate the pathogenetic mechanisms leading to NASH. Similar to NASH, lipid peroxidation resulting from mitochondrial injury may account for all of the histologic findings in drug-induced steatohepatitis. Further research should determine the mechanisms by which drug-induced steatosis, a benign lesion, evolves to steatohepatitis and progressive fibrosis.

Stricture of the anterior urethra following estrogen therapy in patients with prostatic cancer.

A high incidence of urethral strictures was noted in patients with prostatic cancer who were treated by antiandrogen therapy. Retrograde urethrograms showed urethral stricture in 24 of 42 patients (57%) after or during the therapy, despite the fact that no stricture was found before initiation of therapy. The stricture was long and the entire penile urethra was narrowed, associated with more severely constricted portions. All of the patients with urethral stricture had received estrogens, while none of the patients who had undergone castration alone or had not received any therapy showed a stricture. The strictures disappeared after the cessation of estrogen administration. These results indicate that estrogen administration induces stricture in the male anterior urethra. It is suggested that large amounts of estrogen cause atrophy and fibrosis of the spongy and cavernous bodies of the penis, depriving the urethra of its normal elasticity, which results in urethral stricture. The stricture is one of the complications of estrogen therapy for cancer of the prostate.

Drug-induced chronic hepatic disease.

A number of chronic hepatic lesions can result from adverse reactions to medicinal agents. Such lesions include a form of chronic active hepatitis; hepatic steatosis, phoepholipidosis and granulomatosis; several vascular lesions; two types of noncirrhotic portal hypertension; several types of cirrhosis and several neoplasms.

[The effect of hexestrol on the breast in climacteric women (author's transl)]. / Die Wirkung von Hexöstrol auf die Brust klimakterischer Frauen.

In 176 women hexestrol was substituted during 12 month or longer after ovarectomy and hysterectomy. Changes of the breast were watched by mammography and plate-thermography during hexestrol treatment. Also blood cagulation was examined. No differencies were found between these women and 179 women of a control group. In the authors opinion the substitution of hexestrol is justified further on in climacteric periods.

Children sea-blue histiocytosis (2 cases) compared with phospholipidosis induced by 4-4' DET (4-4' p (diethylamino-2-ethoxy phenyl) 3-4 hexane) in rat.

Two cases of children with liver and spleen enlargement are reported. Sea-blue histiocytes and Pick cells were found in both cases in liver, spleen, bone marrow and blood. Further more, lysobisphodphatidic acids were identified in phospholipid analysis of liver biopsies and cultived liver cells. Absence of neurologic involvement at 14 and 18 years fo age suggest a Crocker type C of Niemann-Pick disease, i.e. a not yet well defined entity. Resemblance of these morphological and biochemical abnormalities with certain cases of drug poisoning (especially the well-known intoxication by 4-4' DET) is discussed on the basis of results from experimental studies with this drug in the rat.