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| 번호 | 제목 | 등록일 | 조회수 |
|---|---|---|---|
| 77 | Topical L-Arginine Gel Lowers Resting Anal Pressure [2002년 10월 DCR] | 2011-11-17 | 3830 |
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Possible Treatment for Anal Fissure
N. Griffin, M.R.C.S.,* D. D. E. Zimmerman, M.D.,† J. W. Briel, Ph.D., † H.-J. Gruss, M.D.,‡ M. Jonas, F.R.C.S.,* A. G. Acheson, F.R.C.S.,* K. Neal,* J. H. Scholefield, Ch.M.,* W. R. Schouten, Ph.D.†
From the *Departments of Surgery and Epidemiology, Queen’s Medical Centre, Nottingham, United Kingdom, the †Department of Surgery, University Hospital Dijkzigt, Rotterdam, the Netherlands, and ‡Norgine GmbH, Marburg, Germany.
PURPOSE: Exogenous nitric oxide donors, such as glyceryl trinitrate, have been used as treatment for anal fissures; however, headaches develop in 60 percent of patients. Nitric oxide produced from the cellular metabolism of Larginine mediates relaxation of the internal anal sphincter. This study investigated whether topical L-arginine gel reduces maximum anal resting pressure in volunteers.
METHOD: In a two-center study, volunteers received a single topical dose of L-arginine or placebo (AquagelTM). Anal manometry was performed for two hours after application of 400 mg of L-arginine gel or placebo gel to the anal verge in 25 volunteers. Side effects were recorded after single application and also after repeated dosing for three days.
RESULTS: L-Arginine reduced maximum anal resting pressure by 46 percent from a median of 65 cm of water to a minimal value of 35 cm of water (P < 0.001, Wilcoxon’s signed-rank test). The difference between L-arginine and placebo using repeated-measures testing was significant at P < 0.005. No side effects occurred with either gel; in particular, no episodes of headache were recorded. CONCLUSION: Topical L-arginine gel significantly lowers maximum anal resting pressure; its onset of action is rapid, and duration is at least two hours (P < 0.01). L-arginine may have therapeutic potential, but further evaluation is needed before it can be used as a possible alternative treatment for chronic anal fissure.
Chronic anal fissure is characterized by a linear ulcer usually in the posterior midline, often associated
with hypertonia of the internal anal sphincter muscle. The cause of anal fissure is uncertain, but it is most likely ischemic in nature with anodermal blood flow being lower in these patients. The standard in the treatment of this condition is lateral sphincterotomy; however, the risk of incontinence (from 5 to 30 percent6) has led to the development of nonsurgical therapies. Topical 0.2 percent glyceryl trinitrate (GTN) acts as a nitric oxide donor and has been shown to reduce anal resting pressure (ARP), with a corresponding improvement in anodermal blood flow and healing of the fissure in up to 70 percent of cases. The incidence of headaches occurs in up to 60 percent of patient on GTN therapy for fissures; this causes noncompliance and consequent treatment failure in up to 30 percent of patients. L-arginine acts as a substrate for nitric oxide synthase in the production of nitric oxide, and previous
in vivo work in rats has shown it to be effective in relaxation of the internal anal sphincter. The present study evaluates the effect of a single dose of topical L-arginine (the substrate for nitric oxide synthase) on maximum anal resting pressure (MARP) in volunteers and the incidence of side effects after repeated dosing to assess whether it may have potential as a new treatment for anal fissure. DISCUSSION
This study had two important findings. First, topical application of a single dose of L-arginine (400 mg/ml) to the anal verge causes a significant fall in the MARP. The results on the subset of volunteers involved at one center (Rotterdam, the Netherlands) have been previously reported by the authors. The fall in MARP was of rapid onset (within 5 minutes) and sustained for longer than two hours. The nature of the pressure drop for arginine is thought to be mediated through the action of nitric oxide synthase. The placebo gel caused a smaller, transient, and nonsignificant reduction in MARP which may be related to either the temperature or pH of the gel.
This study showed that after single and repeated dosing with topical L-arginine, no side effects were
demonstrated in volunteers. Since the effects of Larginine on sphincter tone is believed to be through the L-arginine–NO pathway, headaches might be expected, as is the case for topical GTN therapy. It is interesting to note that in studies where oral arginine has been given to volunteers and patients in the evaluation of esophageal and gallbladder physiology and interstitial cystitis11,12 (in doses ranging from 1.5 g to 30 g daily), no headaches were reported. Another explanation may be that L-arginine is working through a different mechanism altogether. If L-arginine can be shown to be free from side effects, especially headaches, this could have important
implications as a potential alternative treatment for anal fissure. It has been suggested that compliance can be an issue in patients prescribed topical GTN; one study showed a compliance rate of only 67 percent, with the side effect of headaches being a major contributing factor to noncompliance. The cure rate based on intention to treat may therefore be lower than expected because of patients not adhering to the treatment regime as prescribed; thus, arginine might provide better compliance than GTN. L-arginine serves as the substrate for the enzyme NO synthase (a heme-containing enzyme) to produce citrulline and nitric oxide. In-vitro studies have shown that nitric oxide is the principle inhibitory neurotransmitter in nonadrenergic, noncholinergic (NANC) mediated relaxation of gastrointestinal smooth muscle. Using immunocytochemistry, NO synthase has been found in a subpopulation of neurons in the
rectal myenteric ganglia in a variety of animal and human tissue. In-vivo studies using low-compliance, continuously perfused catheters to measure resting anal pressures in opossums have demonstrated that nitric oxide synthase inhibitor reverses the decrease in baseline pressure in response to either rectal distention or sacral nerve stimulation. The only in-vivo study investigating the effect of exogenous L-arginine on the internal anal sphincter showed that L-arginine (in concentrations ranging from 0.01 mg to 10 mg), when introduced into the rectum of gently restrained unanesthetized rats, caused a significant reduction in sphincter pressures (P < 0.05), with higher concentrations of arginine causing a more rapid fall in ARP and the maximal effect being reached at 30 minutes. |
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