Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan
Autor: | Mara Ferrandi, Daniele Cusi, Tzung-Dau Wang, Patrizia Ferrari, Roberto Bigazzi, Jan A. Staessen, Lit Fui Lau, Kang Ling Wang, Chern En Chiang, Giuseppe A. Scioli, Giuseppe Bianchi, Nicola Glorioso, Li Xiaoyi, Chiara Lanzani, Silvio Cavuto, Paolo Manunta, Lorena Citterio |
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Přispěvatelé: | Citterio, L., Bianchi, G., Scioli, G. A., Glorioso, N., Bigazzi, R., Cusi, D., Staessen, J. A., Cavuto, S., Ferrandi, M., Lanzani, C., Li, X., Lau, L. -F., Chiang, C. -E., Wang, T. -D., Wang, K. -L., Ferrari, P., Manunta, P. |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Male Blood Pressure 030204 cardiovascular system & hematology 0302 clinical medicine Clinical endpoint Pharmacology & Pharmacy Ouabain Genetics & Heredity Genetics Disease genetics Middle Aged Asians Losartan ADD1 Cardiovascular diseases Treatment Outcome Italy ADD3 Hypertension Molecular Medicine Female Life Sciences & Biomedicine medicine.drug Adult Taiwan Predictive markers White People Article 03 medical and health sciences Asian People Double-Blind Method medicine Humans Androstanols Genetic Testing OSBP Antihypertensive Agents Genetic association study Pharmacology Science & Technology Genetic heterogeneity business.industry Whites Gene Expression Profiling 030104 developmental biology Blood pressure Pharmacogenetics Pharmacogenomics business |
Zdroj: | The Pharmacogenomics Journal |
Popis: | We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10–11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6–19.0), P = 0.038 and 13.4 (25.4–2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10–11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians. |
Databáze: | OpenAIRE |
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