title: Effects of escin on indinavir crystallization time in the urine of patients with HIV-I infection: a multicenter, randomized, open-label, controlled, four-period crossover trial.
abstract: BACKGROUND
  The combination of indinavir, a protease inhibitor, and reverse-transcriptase inhibitors is widely used in the treatment of HIV-1 infection. However, precipitation of indinavir crystals in the renal tubular lumen due to the drug's aqueous insolubility may result in characteristic symptoms of flank pain or classic renal colic. An in vitro study has shown that addition of escin to synthetic urine containing indinavir delayed the crystallization time of indinavir.
  
  
  OBJECTIVE
  This study examined the efficacy and tolerability of the addition of escin to highly active antiretroviral therapy containing indinavir to delay the crystallization time of indinavir in urine.
  
  
  METHODS
  This was a multicenter, randomized, open-label, controlled, 4-period crossover trial in which each period lasted 4 weeks. HIV-1-infected adults receiving treatment with indinavir plus 2 nucleoside analogue reverse-transcriptase inhibitors in whom plasma viral loads had been undetectable (HIV-1 RNA <200 copies/mL) for at least 6 months were randomly assigned to 1 of 2 groups based on the timing of the initiation of escin. Group I received escin during the second and third treatment periods, and group II received escin during the first and fourth treatment periods. The primary end point was the in vitro crystallization time of indinavir in 24-hour urine specimens, determined at the end of each 4-week period. Tolerability was assessed based on the number of patients with a rebound in plasma viral load and on the numbers of clinically and biologically relevant adverse events (including those requiring discontinuation of treatment). Clinical and laboratory evaluations were performed throughout each 4-week period.
  
  
  RESULTS
  Fifty HIV-1-infected patients were enrolled, 47 were randomized to treatment (40 [85.1%] men, 7 [14.9%] women; median [interquartile range] age, 36 [34-45] years), and 30 completed the study. Urine pH and plasma and urine indinavir concentrations were unaffected by the addition of escin to antiretroviral treatment. The mean time to the onset of crystallization was 14.7 minutes with escin (95% Cl, 11.8-17.5) and 9.9 minutes without it (95% Cl, 6.7-13.1). Therefore, the addition of escin increased the mean crystallization time by 5.5 minutes (95% Cl, 1.5-9.5; P = 0.008), representing the overall capacity of study treatment to inhibit indinavir crystallization in the urine. Three of 47 patients had mild gastrointestinal symptoms associated with escin treatment. No episodes of nephrolithiasis were recorded during the study or after the completion of study treatment.
  
  
  CONCLUSIONS
  The results of this prospective clinical trial of the effect of escin on indinavir crystallization time support the possibility that indinavir-associated nephrolithiasis may be prevented by means other than overhydration. Further research is needed in greater numbers of patients over longer follow-up times.
authors.affiliation: Laboratory of Renal Lithiasis Research, Faculty of Sciences, University of the Balearic Islands, Ctra. Valldemossa, km 7.5, 07122 Palma de Mallorca, Spain. lgrases@uib.es
authors.forename: Felix
authors.initials: F
authors.lastname: Grases
authors.forename: Ramón
authors.initials: R
authors.lastname: García-González
authors.forename: Enrique
authors.initials: E
authors.lastname: Redondo
authors.forename: Antonia
authors.initials: A
authors.lastname: Costa-Bauzá
authors.forename: Bartolomé M
authors.initials: BM
authors.lastname: Simonet
authors.forename: Raquel P
authors.initials: RP
authors.lastname: Sartini
authors.forename: Antoni
authors.initials: A
authors.lastname: Bassa
authors.forename: Carmen
authors.initials: C
authors.lastname: Gallegos
authors.forename: Antoni
authors.initials: A
authors.lastname: Payeras
authors.forename: Dulce
authors.initials: D
authors.lastname: Saro
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Martinez
authors.forename: Carmen
authors.initials: C
authors.lastname: Cifuentes
authors.forename: Francisco
authors.initials: F
authors.lastname: Homar
authors.forename: José A
authors.initials: JA
authors.lastname: Murillo
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernández
authors.forename: Melchor
authors.initials: M
authors.lastname: Riera
authors.forename: Antonio
authors.initials: A
authors.lastname: Conte
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D003460:Crystallization; D004928:Escin / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D017320:HIV Protease Inhibitors / Q000627:therapeutic use* / Q000652:urine; D015497:HIV-1; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019469:Indinavir / Q000627:therapeutic use* / Q000652:urine; D007684:Kidney Tubules / Q000187:drug effects*; D008297:Male; D008875:Middle Aged
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir; D004928:Escin