title: Topical nitrates potentiate the effect of botulinum toxin in the treatment of patients with refractory anal fissure.
abstract: BACKGROUND
  Anal fissure is perpetuated by high sphincter pressures and secondary local ischaemia. Pharmacological approaches include topical nitrates and botulinum toxin (BT) which act to reduce anal pressure. BT lowers anal pressure by preventing acetylcholine release from nerve terminals while topical nitrates act by donating nitric oxide (NO). The aims of the present study were to compare the therapeutic effect and lowering action on internal anal sphincter pressure of BT injection and local application of isosorbide dinitrate (ID) compared with BT given alone, in patients with chronic anal fissure (CAF) refractory to treatment with ID.
  
  
  METHODS
  Thirty consecutive patients with CAF who did not respond to previous topical ID treatments were randomly assigned to receive one of the following treatments: group A, injection of BT (20 U into the internal anal sphincter) and subsequent daily applications of ID (2.5 mg three times daily for three months); and group B, BT injection only (20 U). If at the end of six weeks following BT injection no improvement was seen in group B, ID was added. A series of anal pressure measurements, including resting basal pressure and resting pressure following topical ID (1.25, 2.5, and 3.75 mg), was carried out both before and two weeks after 20 U of BT injection into the internal anal sphincter. At the end of the trial, patients were followed up for an average period of 10 months.
  
  
  RESULTS
  At six weeks the fissure healing rate was significantly higher in group A patients (10/15 (66%)) compared with group B (3/15 (20%)) (p=0.025). At eight and 12 weeks, no significant differences were seen: 11/15 (73%) v 11/15 (73%) and 9/15 (60%) v 10/15 (66%), group A v group B, respectively. Maximum anal resting pressure (MARP) was significantly lower two weeks after BT injection than baseline MARP (90 (4) v 110 (5) mm Hg; p<0.001). A significantly greater reduction in MARP following local application of ID was achieved after BT injection compared with that achieved before BT injection (p=0.037)
  
  
  CONCLUSIONS
  (1) Combined BT injection and local application of ID in patients with CAF who failed previous treatment with ID was more effective than BT alone. This treatment modality appears to be safe and promising. (2) ID application induced a greater reduction in MARP following BT injection compared with ID application before BT injection. The improved potency of ID on MARP after BT injection suggests a primary cholinergic tonus dominance in some patients and not, as previously claimed, anal sphincter insensitivity to nitrates.
authors.affiliation: Department of Gastroenterology, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Lysy
authors.forename: Y
authors.initials: Y
authors.lastname: Israelit-Yatzkan
authors.forename: M
authors.initials: M
authors.lastname: Sestiery-Ittah
authors.forename: S
authors.initials: S
authors.lastname: Weksler-Zangen
authors.forename: D
authors.initials: D
authors.lastname: Keret
authors.forename: E
authors.initials: E
authors.lastname: Goldin
mesh_terms: D000328:Adult; D000368:Aged; D019274:Botulinum Toxins, Type A / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005401:Fissure in Ano / Q000188:drug therapy*; D006801:Humans; D007548:Isosorbide Dinitrate / Q000627:therapeutic use*; D008297:Male; D008365:Manometry; D008875:Middle Aged; D009465:Neuromuscular Agents / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D009465:Neuromuscular Agents; D014665:Vasodilator Agents; D019274:Botulinum Toxins, Type A; D007548:Isosorbide Dinitrate