title: A comparison of the natriuretic and kaliuretic effects of cicletanine and hydrochlorothiazide in prehypertensive and hypertensive humans.
abstract: OBJECTIVE
  The aim of this study was to compare the single-dose effects of thiazide-type diuretics cicletanine and hydrochlorothiazide (HCTZ), on natriuresis and kaliuresis in prehypertensive and treatment-naïve, stage 1 hypertensive patients and to explore the impact of GRK4 gene polymorphisms on thiazide-induced urinary electrolyte excretion.
  
  
  METHODS
  The study was a randomized, double-blind, placebo-controlled, three-period, four-treatment, balanced incomplete block, cross-over study in male patients assigned to treatment sequences consisting of placebo, cicletanine 50 mg, cicletanine 150 mg, and HCTZ 25 mg, doses used to treat hypertension. Cumulative urine samples were collected predosing and over 24 h after dosing in each period to compare urine electrolyte excretion profiles of potassium (UKV), sodium (UNaV), magnesium, calcium, phosphate, chloride, and pH among groups. Each treatment was administered to 18 different patients in each period, and an equal number of patients had less than and at least three GRK4 allele variants.
  
  
  RESULTS
  Compared with placebo, mean UKV was significantly increased with HCTZ 25 mg (12.7 mmol/day; P ≤ 0.001), cicletanine 50 mg (4.6 mmol/day; P = 0.026), and cicletanine 150 mg (5.5 mmol/day; P = 0.011), and mean UNaV was significantly increased with HCTZ 25 mg (102.2 mmol/day; P ≤ 0.001), cicletanine 50 mg (21.7 mmol/day; P = 0.005), and cicletanine 150 mg (57.9 mmol/day; P ≤ 0.001).
  
  
  CONCLUSIONS
  All treatments had more natriuresis, diuresis, and kaliuresis than placebo, and both doses of cicletanine had less kaliuresis than HCTZ. These findings suggest that cicletanine is a favorable and well tolerated option for the treatment of hypertension with an improved safety profile compared with HCTZ.
authors.affiliation: Charite Research Organization, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Wagner
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Malice
authors.forename: Erol
authors.initials: E
authors.lastname: Wiegert
authors.forename: Helen E
authors.initials: HE
authors.lastname: McGrath
authors.forename: John
authors.initials: J
authors.lastname: Gildea
authors.forename: Shabri
authors.initials: S
authors.lastname: Mitta
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Dyck
authors.forename: Inge
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: Christine McCrary
authors.initials: CM
authors.lastname: Sisk
authors.forename: Rose
authors.initials: R
authors.lastname: Fernandez
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Greenwalt
authors.forename: Chan
authors.initials: C
authors.lastname: Beals
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Irene
authors.initials: I
authors.lastname: Nunes
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000652:urine; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000652:urine*; D058246:Prehypertension / Q000188:drug therapy* / Q000235:genetics / Q000652:urine; D011725:Pyridines / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D011725:Pyridines; D006852:Hydrochlorothiazide; C038068:cicletanine; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; D011188:Potassium