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2016 ; 374
(20
): 1922-31
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Danazol Treatment for Telomere Diseases
#MMPMID27192671
Townsley DM
; Dumitriu B
; Liu D
; Biancotto A
; Weinstein B
; Chen C
; Hardy N
; Mihalek AD
; Lingala S
; Kim YJ
; Yao J
; Jones E
; Gochuico BR
; Heller T
; Wu CO
; Calado RT
; Scheinberg P
; Young NS
N Engl J Med
2016[May]; 374
(20
): 1922-31
PMID27192671
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BACKGROUND: Genetic defects in telomere maintenance and repair cause bone marrow
failure, liver cirrhosis, and pulmonary fibrosis, and they increase
susceptibility to cancer. Historically, androgens have been useful as treatment
for marrow failure syndromes. In tissue culture and animal models, sex hormones
regulate expression of the telomerase gene. METHODS: In a phase 1-2 prospective
study involving patients with telomere diseases, we administered the synthetic
sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months.
The goal of treatment was the attenuation of accelerated telomere attrition, and
the primary efficacy end point was a 20% reduction in the annual rate of telomere
attrition measured at 24 months. The occurrence of toxic effects of treatment was
the primary safety end point. Hematologic response to treatment at various time
points was the secondary efficacy end point. RESULTS: After 27 patients were
enrolled, the study was halted early, because telomere attrition was reduced in
all 12 patients who could be evaluated for the primary end point; in the
intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval
[CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the
patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared
with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory
analyses, similar increases were observed at 6 months (16 of 21 patients; mean
increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean
increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of
24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients
(83%) who could be evaluated at 24 months. Known adverse effects of
danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less
occurred in 41% and 33% of the patients, respectively. CONCLUSIONS: In our study,
treatment with danazol led to telomere elongation in patients with telomere
diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov
number, NCT01441037.).
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