type 2 diabetes ( t2d ) is a chronic disease with an increasing incidence worldwide .
it remains the leading cause of nontraumatic lower - extremity amputation [ 1 , 2 ] .
the annual incidence of diabetic foot ulcers varies between 1.9% and 2.2% , with a prevalence of 7.5% to 12% .
the risk of amputation is associated with the presence of sensory peripheral neuropathy , peripheral vascular disease , charcot joint , ulceration , and the presence of infection .
fifty - six percent of diabetic foot ulcers will develop infection and 20% of them will end up in a lower - extremity amputation .
a number of chemical mediators are involved in the tissue repair process such as cytokines and growth factors . within this complex process
, the transforming growth factor beta ( tgf- ) plays a key role regulating the development , differentiation , growth , and apoptosis of most cells .
tgf- in turn activates monocytes by increasing gene expression of proinflammatory cytokines such as interleukin 1 ( il-1 ) and tumor necrosis factor alpha ( tnf- ) .
. the natural substrates of mmps include major proteins of the extracellular matrix ( ecm ) such as collagen , elastin , and proteoglycans .
therapies including growth factors , bioengineered skin , tissue grafts , hyperbaric oxygen , negative pressure wound therapy , and other novel approaches to stimulating wound healing have demonstrated healing rates of around 40% in noninfected diabetic foot ulcers .
1-phenyl-5-methyl-2-[1h]-pyridone ( pirfenidone ) is a synthetic chemical molecule that acts as a selective cytokine regulator , providing its action by anti - inflammatory and specific antifibrotic properties .
pirfenidone acts as a modulator of tnf- , tgf- , fibroblast growth factor ( fgf ) , platelet derived growth factor ( pdgf ) , and vascular endothelial growth factor ( vegf ) , which are cytokines involved in the inflammatory - fibrotic process .
this results in a reduced expression of tgf- by a direct inhibition of furin , a proprotein convertase .
pirfenidone has shown utility in the treatment of patients with wounds , burns , and scars without serious adverse events .
topical pirfenidone may improve healing of diabetic foot ulcers and could be an option as an adjuvant therapy .
therefore , the aim of this study is to evaluate the effect of pirfenidone added to conventional treatment on noninfected diabetic foot ulcers assessing the rate of complete wound closure and the change in ulcer size .
the protocol was approved by the comite de etica en investigacion del instituto nacional de ciencias medicas y nutricion .
subjects who attended the diabetic foot clinic at the instituto nacional de ciencias medicas y nutricion salvador zubiran in mexico city were recruited .
grade 0 is a patient at risk or with a postulcerative diabetic foot without ulcer .
grade 1 is a full - thickness ulcer not involving tendon , capsule , or bone .
grade 2 is an ulcer that involves tendon or capsule , without abscess or osteomyelitis .
the inclusion criteria were the following : men and women with t2d , being older than 18 years of age , being with a diabetic foot ulcer grade wagner 1 or 2 , ulcer size 1  cm , and being with duration of at least 8 weeks .
the exclusion criteria included infected ulcers , presence of an ankle brachial index ( abi ) < 0.4 , ulcers due to a different cause such as venous insufficiency , inability to attend to the weekly evaluations , use of systemic or topical diabetic foot ulcer treatments , immunosuppressant treatment , connective tissue diseases , pregnancy , and lactation .
the elimination criteria were an attendance to < 75% of the evaluations , allergy to pirfenidone , development of ulcer infection , and occurrence of other serious diseases requiring hospitalization .
conventional treatment consisted of weekly ulcer cleansing with saline , debridement using a surgical blade , maintenance of a moist environment , and covering with sterile gauzes .
in addition , patients were instructed to perform daily cleansing with saline - moistened gauzes and offloading the affected extremity .
group 1 received conventional treatment in combination with topical pirfenidone for the first eight weeks and at the end of this period they were switched to conventional treatment only for the remaining 8 weeks .
group 2 received conventional treatment only for the first 8 weeks and at the end of this period they were switched to conventional treatment in combination with topical pirfenidone for another 8 weeks .
the body mass index was calculated as the weight in kilograms divided by the squared height in meters .
in addition , all ulcers were categorized using the classification of the international working group on the diabetic foot ( iwgdf ) , abbreviated with the acronym pedis , which stands for perfusion , extent ( size ) , depth ( tissue loss ) , infection , and sensation ( neuropathy ) . to evaluate the presence of lower - extremity vascular disease ,
the abi was calculated and classified as follows : normal from 0.9 to 1.3 , peripheral artery disease ( pad )  0.9 , and severe pad < 0.4 .
after debridement , the length and width of the ulcer were measured with a standard ruler , the maximal size was calculated in cm , and a photograph was taken .
biochemical parameters included complete blood cell count , erythrocyte sedimentation rate , c - reactive protein , glucose , creatinine , uric acid , total cholesterol , high density lipoprotein- ( hdl- ) cholesterol , low density lipoprotein- ( ldl- ) cholesterol , triglycerides , glycosylated hemoglobin , aspartate aminotransferase , alanine aminotransferase , and 24  h albuminuria .
patients were reinforced about offloading their affected extremities , and adherence to treatment was assessed by requesting the empty tubes .
finally , possible harm including burning , redness , itching , and hypergranulation was monitored by physical examination and questioning .
complete wound closure was defined as full epithelialization of the ulcer with absence of drainage .
percentage of closure was estimated by calculating the ulcer size in cm at visit 1 and at visit 8 .
the size at the end of each period was subtracted to the initial ulcer size ( week 1 and week 8) and the change was estimated and expressed as a percentage .
a sample size of 50 ulcers was calculated estimating a 25% change in ulcer size with pirfenidone treatment , with an alpha error of 5% ( z = 1.96 ) and a beta error of 10% ( power of 90% ) .
participants were randomly assigned in blocks to one of the two groups with the use of sealed envelopes using a random sequence numbers generator .
normal distributed variables were described as means and standard deviation . in the case of nonnormal distributed variables ,
differences between groups were evaluated with independent student 's t - tests or u mann - whitney tests , as appropriate .
forty patients with 55 ulcers were randomized to pirfenidone ( n = 20 ) or conventional ( n = 20 ) treatment .
participants ' characteristics were not different between the groups except for the body mass index , which was slightly higher in the group assigned to receive conventional treatment first ( 29 vs 25.3  kg / m , p = 0.048 ) .
we do not consider that this slight difference in the body mass index may have affected the results .
however , according to the abi classification , in group 1 there were more patients with pad and in group 2 there were more patients with noncompressible arteries .
we excluded patients with severe pad and do not consider that these differences affected the results .  
, 52.4% of the ulcers assigned to group 1 healed compared with 14.3% of group 2 ( p = 0.025 ) .
after the crossover , the remaining 22 ulcers switched treatments and 30.8% of ulcers that received pirfenidone ( during 8 to 16 weeks ) healed compared with none in the conventional only group ( p = 0.081 ) .
, the median percentage reduction in ulcer size was 100% [ 73100 ] in group 1 compared with a 57.5% [ 28.974 ] reduction in group 2 , p = 0.011 ( figure 2(a ) ) . at 16 weeks , the median percentage reduction was 93% [ 42.7100 ] in the pirfenidone group compared with a 21.8% [ 1677.5 ] size reduction in the conventional group , p = 0.050 ( figure 2(b ) ) . 

figure 3(a ) shows an ulcer assigned to group 1 and figure 3(b ) an ulcer assigned to group 2 .
no serious adverse events were observed during the course of the study in any treatment group .
one patient in group 2 developed hypergranulation during pirfenidone treatment which resolved spontaneously . in group 2 , a patient was diagnosed with thyroid carcinoma during conventional treatment and was eliminated from the study ( figure 1 and table 4 ) . during the first 8 weeks , 10 ulcers ( 8 patients ) developed osteomyelitis .
four ulcers ( 4 patients ) were in group 1 and 6 ulcers ( 4 patients ) in group 2 ; one of them had a supracondylar amputation .
this study demonstrates that pirfenidone added to conventional treatment is superior to conventional treatment alone .
treatment with pirfenidone decreased the size and increased the rate of complete healing of chronic noninfected diabetic foot ulcers . a greater number of ulcers achieved complete wound closure when receiving pirfenidone treatment .
pirfenidone enhanced successful healing in addition to the standard ulcer care . a key component of the intervention was the weekly ulcer debridement and offloading the affected foot .
debridement enables removal of devitalized and necrotic tissue and promotes the beginning of the healing process .
chronic diabetic foot ulcers represent a therapeutic challenge and their treatment involves debridement , frequent assessment , identification and treatment of infection , revascularization if indicated , and satisfactory offloading the foot .
analysis of the evidence regarding the effectiveness of interventions to enhance healing of chronic diabetic foot ulcers is difficult .
there is not strong evidence to choose a specific dressing or topical medication in preference to another .
products designed to improve wound biochemistry and cell biology to promote wound healing demonstrate an ulcer healing rate between 40% and 80% .
however , the evidence to support their use is not robust and further rigorously designed blinded trials are needed .
a crossover design was chosen because otherwise it would not have been possible to control variables that could influence significantly the healing process such as ulcer size , ulcer depth , glycemic control , physical activity , and weight .
in summary , this study demonstrates that the addition of topical pirfenidone to conventional treatment significantly improves the healing of chronic diabetic noninfected foot ulcers .
 only 30 percent of chronic diabetic foot ulcers heal after 20 weeks of standard treatment . 
 pirfenidone is a drug with biological , anti - inflammatory , and antifibrotic effects . 
 the aim of this study was to evaluate the effect of topical pirfenidone added to conventional treatment in noninfected chronic diabetic foot ulcers . 
 this was a randomized crossover study . 
 group 1 received topical pirfenidone plus conventional treatment for 8 weeks ; after this period , they were switched to receive conventional treatment only for 8 more weeks . in group 2 , 
 the order of the treatments was the opposite . 
 the end points were complete ulcer healing and size reduction . 
 final data were obtained from 35 ulcers in 24 patients . 
 fifty - two percent of ulcers treated with pirfenidone healed before 8 weeks versus 14.3% treated with conventional treatment only ( p = 0.025 ) . between 8 and 16 weeks , 
 30.8% ulcers that received pirfenidone healed versus 0% with conventional treatment ( p = 0.081 ) . by week 8 , the reduction in ulcer size was 100% [ 73100 ] with pirfenidone versus 57.5% with conventional treatment [ 28.974 ] ( p = 0.011 ) . by week 16 , the reduction was 93% [ 42.7100 ] with pirfenidone and 21.8% [ 877.5 ] with conventional treatment ( p = 0.050 ) . 
 the addition of topical pirfenidone to conventional treatment significantly improves the healing of chronic diabetic noninfected foot ulcers . 
1. Introduction
2. Material and Methods
3. Results
4. Discussion
5. Conclusion