title: Treatment of chronic anal fissure by application of L-arginine gel: a phase II study in 15 patients.
abstract: OBJECTIVE
  Local application of exogenous nitric oxide donors, such as isosorbide dinitrate and glyceryl trinitrate, promotes fissure healing by reducing anal resting pressure and improving anodermal blood flow. The major drawback of these nitric oxide donors is headache. The overall incidence of this side effect is approximately 40 percent. Recently we have shown in healthy volunteers that L-arginine, being an intrinsic precursor of nitric oxide, reduces anal resting pressure without headache as a side effect. The aim of the present study was to evaluate the effect of L-arginine on anal resting pressure, anodermal blood flow, and fissure healing in patients with chronic anal fissure.
  
  
  METHODS
  Fifteen patients with a chronic anal fissure were included in the present study. Before entering the study 10 patients were unsuccessfully treated by local application of isosorbide dinitrate. Six of these patients experienced severe headache during treatment with isosorbide dinitrate. All patients were treated for at least 12 weeks by local application of a gel containing L-arginine 400 mg/ml five times a day. In patients with a persistent fissure, treatment was continued until 18 weeks. Anal manometry and laser Doppler flowmetry of the anoderm were performed before treatment, 20 minutes after local application of the first dose, and after 12 weeks of treatment. A visual analog scale was used to assess fissure-related pain and headache.
  
  
  RESULTS
  One patient dropped out after one day of treatment, and one was excluded because of violation of the study protocol. After 12 weeks of treatment complete fissure healing was observed in 3 of 13 (23 percent) patients, and after 18 weeks the healing rate was 8 of 13 (62 percent) patients. None of the 13 patients experienced typical nitric oxide-induced headache. The pressure recordings showed a significant reduction of maximum anal resting pressure (mean +/- SD): pretreatment 89 +/- 17 mmHg; 20 minutes after application of the first dose 67 +/- 17 mmHg; 12 weeks after treatment 74 +/- 14 mmHg (P < 0.005). Recordings of anodermal blood flow showed a significant increase in flow: pretreatment 0.36 +/- 0.25 volts; 20 minutes after application of the first dose 0.59 +/- 0.27; 12 weeks after treatment 0.64 +/- 0.33 (P < 0.005).
  
  
  CONCLUSIONS
  Local application of L-arginine promotes fissure healing without headache as a side effect, and L-arginine is effective even in patients not responding to isosorbide dinitrate treatment.
authors.affiliation: Colorectal Research Group, Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Gosselink
authors.forename: M
authors.initials: M
authors.lastname: Darby
authors.forename: D D E
authors.initials: DD
authors.lastname: Zimmerman
authors.forename: H J
authors.initials: HJ
authors.lastname: Gruss
authors.forename: W R
authors.initials: WR
authors.lastname: Schouten
mesh_terms: D000287:Administration, Topical; D000328:Adult; D001003:Anal Canal / Q000098:blood supply; D001120:Arginine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D005260:Female; D005401:Fissure in Ano / Q000188:drug therapy*; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008365:Manometry; D008875:Middle Aged; D011312:Pressure; D012039:Regional Blood Flow; D016896:Treatment Outcome; D014945:Wound Healing
chemical_list: D001120:Arginine