A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

[Hormonal assessment in a woman with acne and alopecia]. / Bilan hormonal chez une femme présentant une acné ou une alopécie.

Acne, androgenogenetic alopecia, hyperseborrhea and hirsutism may result from hyperandrogenism in women. This may be peripheral "idiopathic" hyperandrogenism due to cutaneous metabolism of steroids, but in some cases hyperandrogenism is due to abnormal production or input of steroids with androgenic activity (hyperplasia, endocrine tumors, cysts, consumption of progestogens or other hormones with androgenic activity, menopause...). An assessment is useful only in cases of acne or alopecia if they are accompanied by other signs of peripheral hyperandrogenism and/or disturbed menstruation. The treatment is based on the administration of an anti-androgen (in France, usually cyproterone acetate), combined with other local or systemic treatments for the problem, depending on the age, dermatological signs and context.

Therapeutic alternatives for the hirsute woman.

A retrospective analysis of 21 hirsute women seen at a gynaecological endocrine clinic revealed a high incidence of infertility, menstrual irregularities and abnormal androgen profile. Polycystic ovarian syndrome (PCOS) was the underlying abnormality in the majority of cases. Cyproterone acetate (CPA) with ethinyl oestradiol in a reverse sequential regime was more effective and better tolerated but much more expensive than the combination of spironolactone and the oral contraceptive pill (OCP).

[Assessment of the effectiveness of Androcur in the treatment of precocious puberty]. / Otsenka éffektivnosti primeneniia Androkura pri lechenii prezhdevremennogo polovogo razvitiia.

The data are provided on the continuous use of Androcur in the treatment of genuine precocious puberty in children. The drug produced a beneficial effect in 100% of cases in respect to suppression of the secondary sexual characters, menstrual function in girls, and behavior normalization in boys. During treatment, the improvement of the growth prognosis was negligible. Stabilization of the processes of osseous maturation requires administration of the maximal drug doses, which may suppress glucocorticoid function of the adrenals. This fact should be taken into account during treatment, particularly on its discontinuation. The treatment should be discontinued according to the schedule similar to that applied in glucocorticoid discontinuation.

The clinical and endocrine assessment of three different antiandrogen regimens combined with a very long-acting gonadotrophin-releasing hormone analogue.

Tumor flare is reported in up to 40% of patients treated with gonadotrophin-releasing hormone analogues for prostate cancer. In order to investigate the optimal way to eliminate tumor flare, we have treated patients with one of three different antiandrogen regimens used in combination with gonadotrophin-releasing hormone (GnRH) agonist. The early results of this study are presented here. Thirty patients with advanced symptomatic disease were randomized to receive either cyproterone acetate 50 or 100 mg three times daily or flutamide 250 mg three times daily given for 1 week before and during the first month of GnRH agonist treatment. The endocrine profiles of these patients were compared with those of historic controls treated with depot agonist alone. Three patients treated with low-dose cyproterone acetate and one with flutamide developed a transient exacerbation of their disease. No patients treated with the higher-dose cyproterone acetate regimen developed tumor flare. No patients treated with cyproterone acetate had an increase in serum testosterone above baseline following depot GnRH agonist implantation. All patients treated with flutamide had increases in serum testosterone, but this did not significantly increase further with implantation. This study suggests that all patients receiving GnRH agonist treatment should be pretreated with cyproterone acetate 100 mg three times daily for 1 week before implantation and for the first treatment month.

Objective assessment of treatment response in hirsutism.

A simple photographic technique was used to assess the objective response of hirsute women to treatment with cyproterone acetate (CA). The skin in front of the left ear was shaved and photographs taken immediately and after 1 week, and hair growth per week estimated by averaging the length of 20 hairs in the magnified photographs. The precision, repeatability and patient acceptance of the method were found to be satisfactory. Basal hair growth rates were 2.28 +/- 0.4 mm/week (mean +/- SD, n = 34) and showed a significant correlation with hirsutism scores derived from a standard physician-rated scale. During therapy with CA the mean (+/- SD) improvement in hair growth rate was 19 +/- 13%, whereas physician-rated hirsutism scores improved by 33 +/- 20%. The reduction in hair growth rate showed no significant correlation with improvement assessed using subjective rating by either physician or patient. The greater improvement in physician-rated scores compared with hair growth rate assessment suggests that hair shaft width, colour and other factors may be as important as hair length when assessing treatment response.

Radical economic surgery and antiandrogenic therapy in management of prostatic cancer.

The treatment of early stage prostatic cancer with retropubic radical prostatectomy, pelvic lymphadenectomy and antiandrogenic therapy is reported. Out of 22 patients operated in the past 9 years, none died because of the tumor and metastases appeared in 1 patient only. The latter showed a microscopic seminal vesicle invasion and was considered as a P3 stage. Excluding impotence which is generally the rule, urinary incontinence was the most common complication: it was complete in 1 case but successfully treated surgically and mild in 6 cases without, however, requiring surgical intervention or collection device.

Epididymal and testicular enzymes as monitors for assessment of male antifertility drugs.

PIP: Since the synthesis and maturational processes of sperm are associated with characteristic alterations in different marker enzyme activities in testes and epididymis, it is possible to monitor these enzymes to investigate whether 3 antispermatogenic agents, WIN 18 446, alpha-chlorohydrin (AC), and cyproterone acetate (CA), have any characteristic effects on biochemical events associated with spermatogenesis and maturation of sperm; acid, neutral, and alkaline proteinases, particulate and soluble arylamidases, and sialidase were studied after treatment with 1 of the 3 agents in male albino rats (CIBA strain) by measuring these enzyme levels in rat testicular and epididymal tissues. After WIN treatment, sialidase activity as well as sialic acid content increased in the testis, whereas no such effect occurred in the epididymis at any dose. At low dose, AC (10 mg/kg/day for 7 days) and CA (50 mg/kg/day for 10 days) decreased the sialic acid content and the sialidase activity in the epididymis, whereas the sialic acid and sialidase activity in the testis remained unchanged. At higher dose levels, AC (25 mg) and CA (50 mg) both affected the tissues significantly, i.e., enhancing sialidase activity and lowering sialic acid content. Therefore, the effect of CA and AC is more prominent on the maturational phenomena than the testicular spermatogenesis. AC and CA deserve further investigation for use as a male contraceptive. The relationship between proteinase, sialidase, and arylamidase activities and different phases of spermatogenesis and maturation was established by these test results.^ieng

An assessment of (1) cyproterone acetate and (2) ethinyl oestradiol and lynoestrenol (Minilyn) in the treatment of idiopathic hirsutism.

The administration of cyproterone acetate can be effective in the treatment of 'idiopathic' hirsutism. In 5 similarly affected patients treated with ethinyloestradiol and lynoestrenol (Minilyn) the rate of hair growth was reduced in only two, even though the serum total testosterone was reduced in each instance.