Bhardwaj, R.; (2004) Neuromyogenic properties of the internal anal sphincter: Applications for the treatment of anal fissures. Doctoral thesis , University of London.

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Abstract

Pharmacological therapy of anal fissures reduces maximum resting pressure (MRP), allowing healing by promoting anodermal vascular perfusion. In this thesis the clinical and manometric responses to diltiazem and botulinum toxin and the therapeutic potential of indoramin and salbutamol were investigated. A porcine internal anal sphincter model was developed to validate the responses to pharmacological agents. Of 33 patients with anal fissures with higher MRP than in 20 controls [110 (77-227) vs. 88 (46-175) cmH2O, P 0.05], the fissures healed in 19 (58%) after a two-month course of diltiazem, [110 (77-195) vs. 81 (53-147) cmH2O, P 0.0001]. Those with unhealed fissures [111 (77-227) vs. 92 (56-136) cmH2O, P 0.01] received another course. At four months in 18 (75%) of 20 the fissures healed; 12 [114 (88-195) vs. 113 (51-142) cmH2O, P=0.07] that had healed initially and 6 [102 (77-227) vs. 109 (47-134) cmH2O, P=0.50] of 8 after a second course. At six months the fissures healed in 13 (90%) of 15 patients [110 (77-144) vs. 125 (53-161) cmH2O, P=0.63]. While 58% of fissures with high MRP healed with diltiazem, 42% did not despite reduction in MRP; a subgroup with normal MRP healed although MRP remained unchanged.A "no-needle" delivery, evaluated by injecting methylene blue in porcine anal sphincters allowed maximal instillation into the IAS at 60% to the horizontal axis, was employed to inject 25 Units botulinum toxin on either side of the fissure in 10 patients. At one week MRP [99 (71-185) vs. 81 (37-166) cmH2O, P 0.01] and pain scores [6 (3-8) vs. 4 (1-8), P 0.001] were reduced. At three months 5 (50%) fissures healed. Oral indoramin (20mg) reduced MRP at one hour in 10 volunteers [85 (46-136) vs. 63 (36-117) cmH2O, P 0.005] and 10 patients with anal fissures [131 (94-227) vs. 88 (57- 169) cmH2O, P 0.0001] and the reduction was sustained for three hours. The results were similar with oral salbutamol (4mg) [94 (47-175) vs. 65 (44-101) cmH2O, P 0.01] and [144 (97-194) vs. 101 (78-181) cmH2O, P 0.005]. Salbutamol caused tremors in 9 subjects and was not investigated further. In 8 volunteers topical indoramin in paraffin base (10mg, 20mg, 30mg and 40mg) applying each dose on different days, like placebo had no effect after one or three hours [P=NS, ANOVA]. Porcine IAS muscle tissue was morphologically similar to human tissue and maintained a spontaneous tone. Histamine and phenylephrine induced concentration-dependent contractions; isoprenaline induced relaxation. Glyceryl trinitrate (GTN) at a concentration of 2.2x10-4, 6.6x10-4 and 2.2x10-3 M caused mean relaxation of 14.9%, 28.7% and 35.3%. L-NAME (N(G)-nitro-L-arginine methyl ester) abolished acetylcholine mediated relaxation due to muscarinic relaxation with nitric oxide. Adenosine triphosphate-induced relaxation was enhanced by the purinoceptor antagonist suramin. Indoramin reduced phenylephrine induced contraction suggesting an effect on ?1 adrenoceptors. Prazosin reduced histamine induced IAS contraction. Nitric oxide was the predominant but not the sole neurotransmitter for inducing relaxation, as there was some relaxation on electrical field stimulation (EFS) after the addition of L-NAME. The EFS responses in hypertonic in vitro porcine IAS caused by phenylephrine, were investigated to explain failure of fissures to heal with agents that reduce sphincter tone. The residual tone, i.e. the level of tone after EFS in 10 IAS strips was proportional and correlated with the level of tone before EFS, (r2 = 0.90, P 0.001, d.f. =120) and after GTN [2.2x10-4, 6.6 x10-4, 2.2x10-3 M] and diltiazem [1x10-4 M] was also proportional to the tone before treatment [r2=0.95, d.f =21; r2=0.87, d.f =20; r2=0.72, d.f. =20; r2=0.90, d.f=25 respectively]. Hence fissures do not heal despite reduced MRP because the ischaemic threshold, above which there is inadequate perfusion of the anoderm is not reached.

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