Patent Publication Number: US-2019183894-A1

Title: Method of treatment of diabetic foot ulcers

Description:
FIELD OF THE INVENTION 
     The present invention is related to a method of treating, preventing and maintaining diabetic foot ulcers using sildenafil maleate. 
     BACKGROUND OF THE INVENTION 
     Diabetes is a chronic disease where the body is unable to control blood glucose due to defects in insulin secretion, insulin action or both. Diabetes may lead to a number of complications, resulting from damage exerted by hyperglycemia (blood glucose increase above normal levels) to organs and systems, especially to nerves and blood vessels. 
     One of the more frequent diabetes complications is diabetic foot, which may be defined as a set of syndromes where the presence of neuropathy, ischemia and infection causes tissue alterations or ulcers secondary to microtraumas. 
     Diabetic foot ulcers are chronic and complex wounds which use to be a result from one or more simultaneously caused risk factors. A risk factor is peripheral neuropathy, defined as a loss of protective sensitivity such as pain and autonomic dysfunction. 
     Other risk factors are peripheral arterial disease, increased levels of glycosylated hemoglobin, decrease of visual acuity, record of ulcer or amputation and onychomycosis. External trauma is an instrumental component for ulcer development having as main origin the use of unsuitable footwear. 
     It is less frequent that peripheral vascular disease is the precipitating event of diabetic foot ulcers; however, it plays an essential role in wound healing and in gangrene development; it is a contributing factor for half of amputations. Although the instrumental or triggering event of ulcer is frequently external trauma, the peripheral vascular disease is the underlying basis of physiopathology of this diabetic foot complication. Even when ulcer pathogenesis is neuropathy, a vascular etiology has been proposed for neuropathy. 
     Diabetic ulcers show amputation of affected limbs as a main problem; being demonstrated that 85% of lower limb amputations in diabetic patients are preceded by ulcerations, which allow entry of infectious agents, thus causing progressive tissue necrosis with minimum wound healing in the presence of ischemic media. 
     Amputation rate in diabetic patients is 15 times higher compared to general population. Moreover, it has been noticed that in 58% of patients who have suffered any amputation resulting from diabetic ulcers, there will be a new amputation in their opposite lower limb within the following 3 to 5 years; while mortality within 2 years after the first amputation is of 20 to 50%. 
     There are several types and grades of diabetic ulcers depending on foot damage. Ulcers are commonly located on foot sole and rarely above foot. There is not any universally accepted classification encompassing assessment criteria of diabetic foot lesions; however, the most common classification is Wagner scale which assesses ulcer depth together with the presence of gangrene and perfusion loss by using six grades (0-5). Table 1, shows the classification according to Wagner scale. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Classification of diabetic foot ulcers according to 
               
               
                 Wagner scale. 
               
            
           
           
               
               
               
            
               
                 Grade 
                 Lesion 
                 Characteristics 
               
               
                   
               
               
                 0 
                 None. Foot in 
                 Callus, hallux, mallet toes 
               
               
                   
                 risk 
               
               
                 1 
                 Surface ulcers 
                 Destruction of full skin 
               
               
                   
                   
                 thickness 
               
               
                 2 
                 Deep ulcer 
                 Penetrates skin, fat and 
               
               
                   
                   
                 ligaments without affecting 
               
               
                   
                   
                 bone, infected 
               
               
                 3 
                 Deep ulcers plus 
                 Extensive and deep, secretion, 
               
               
                   
                 abscess 
                 bad odor 
               
               
                   
                 (osteomyelitis) 
               
               
                 4 
                 Limited gangrene 
                 Necrosis in a section of the 
               
               
                   
                   
                 foot 
               
               
                 5 
                 Extended gangrene 
                 Whole foot affected, systemic 
               
               
                   
                   
                 effects 
               
               
                   
               
            
           
         
       
     
     Treatment of diabetic foot ulcers has a main objective of closing the wound; preferably, ulcers should be treated in a preliminary step in order to allow an early cure. The treatment consists of: 
     a) Optimum diabetes control: keeping or reaching ideal weight; keeping fasting blood glucose levels from 80 to 100 mg/dL and when going to bed from 100 to 140 mg/dL; keeping A1c glycosylated hemoglobin lower than 6%; blood pressure 120/80 mmHg; total cholesterol lower than 200 mg/dL; HDL-cholesterol higher than 35 mg/dL; LDL-cholesterol lower than 100 mg/dL 
     b) Efficient care of wounds: tissue debridement, inflammation control, humidity equilibrium (selection of optimum dressing) 
     c) Control of infections: use of antimicrobial agents 
     d) Strategies to release pressure 
     e) Restoration of blood flow 
     In brief, treatment of diabetic foot in addition to metabolic control and associated risk factors, consists of improving circulation and easing ulcer healing within the less possible time, decreasing treatment costs, as well as psychological and social impact. 
     It has been demonstrated that between 40 to 85% of amputations may be prevented, which enhances the significance of identifying risk factors, search and use of preventive measures, as well as improvement to available treatments. 
     Nowadays, cilostazol (50 mg and 100 mg) is used as a supplement of diabetic foot treatment, which is a cellular phosphodiesterase III specific inhibitor, having a vasodilator effect, improving circulation; however, it shows side effects such as postural hypotension, sickness, flatulence, palpitations and less frequently, tachyarrhytmias and angina. 
     Epidermal Growth Factor (EGF) is also used parenterally, intralesionally and around lesion to promote lesion healing and decrease the risk for amputations; however, it has been noticed that patients present pain, burning sensation, chills and fever, derived from application of such medicament. 
     The prior art has disclosed the use of 5-type phosphodiesterase (PDE5) inhibitors, an enzyme which acts specifically over cyclic guanosine monophosphate (cGMP), such as sildenafil, in treatment of ulcers and wounds, as well as prevention, reduction and reversion of damage to blood vessels caused by diabetes. 
     Document WO2002015893A2 discloses a method of treatment of chronic venous ulcers, chronic arterial ulcers, chronic decubitus and acute wounds with a cGMP PDE5 inhibitor. WO2011019399A1 describes a method for preventing, reducing or reverting one or more deleterious effects in a blood vessel with a phosphodiesterase inhibitor (PDE), wherein the deleterious effect may be caused by diabetes mellitus. 
     Document WO2001051042A2 is targeted to the use of cGMP PDE5 inhibitors, particularly, is targeted to the use of sildenafil in treatment of diabetic foot ulcers. On the other hand, WO2002002118A1 discloses a method of treatment and prevention of diabetic foot ulcer formation comprising treating to said patient with an effective amount of a pharmaceutical composition comprising a cGMP PDE5 inhibitor or a derivative or salt thereof. Said document also discloses a method for manufacturing a therapeutic agent of diabetic foot ulcer comprising sildenafil. 
     However, above mentioned documents, specifically document WO2001051042A2, which might be considered the closest state of the art, does not specify any dose or dosage regime of sildenafil which is useful, efficient and safe for treatment, prevention and maintenance of diabetic foot ulcers. 
     Moreover, none of the documents makes specific reference to sildenafil maleate, which shows several advantages such as a faster absorption and therefore, a faster action than sildenafil citrate. 
     SUMMARY OF THE INVENTION 
     The present invention describes the treatment, prevention and maintenance of diabetic foot using a 5-type phosphodiesterase (PDE5) inhibitor, specifically the use of sildenafil maleate. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As described in present invention, the “prevention” considers administration of treatment before development of any ulcer, in order to decrease a probability of ulcer development. On the other hand, the term “maintenance” refers to blood flow conservation after disappearance of involved lesions (healing). 
     As used in present invention, the term “conventional treatment” considers ambulatory wound care, application of antibiotics when needed, use of membranes and healing creams. 
     “Adverse events” are referred to unfavorable incidents, unexpected facts or undesirable therapeutic accidents and attributable to applied medicament or treatment. 
     The magnitude of health issue representing the care of diabetes patients, leads to medical staff to maximize available resources and emphasize in prevention of complications of such disease. Ulcers and amputations of lower limbs represent a serious issue in this group of patients. In spite of using all available means nowadays, healing time of foot ulcers in diabetic patients is long, demanding high social, psychological and economic costs, therefore other alternatives need to be searched allowing a faster and more effective cure. 
     The present invention provides a method of treatment, prevention and maintenance of diabetic foot ulcers, involving administration of sildenafil maleate, which is a 5-phosphodiesterase inhibitor drug and accordingly favors vasodilation. This component, in 10-mg daily dose has demonstrated an improvement in macro and microcirculation, accelerating granulation and healing of ulcers in diabetic foot patients, decreasing the probabilities of amputation of the affected limb, reducing treatment costs and improving patient&#39;s quality of life. Its administration is by oral route and sildenafil maleate does not show side effects unlike other medicaments used in such pathologies. 
     Sildenafil maleate is bioequivalent with sildenafil citrate; however, sildenafil maleate molecule is smaller and has a lower molecular weight, resulting in a faster absorption. Maximum sildenafil maleate concentration is reached after 60 minutes of its oral administration in fasting subjects; when ingested during a high fat content meal, maximum peak may be delayed 60 minutes. 
     Other advantage of sildenafil maleate is that the drug is widely distributed in tissues (distribution volume in 105-L stationary media); circulates together with its main metabolite N-demethyl sildenafil, mostly bound to plasma proteins. 
     Surprisingly, the inventors found that treatment with sildenafil maleate not only decreases the average time for ulcer cure in patients with diabetic foot, but further prevents development thereof and maintains blood flow, decreasing the possibility of appearance of future ulcers and amputations. 
     Specifically, sildenafil maleate exerted a vasodilator action over microcirculation, leading to a more effective granulation and healing. 
     EXAMPLES 
     Examples shown below have the sole purpose of illustrating and demonstrating some embodiments of the invention. Exemplary embodiments shall not be considered limitative of the present invention. As it may be acknowledged by any one skilled in the art, modifications and variations to embodiments herein described may be carried out without altering the essence of the invention. 
     Example 1 
     In order to assess the effect of sildenafil maleate in treatment of diabetic foot ulcers, a 12-week open-label longitudinal study was conducted to compare the conventional treatment and the conventional treatment with simultaneous administration of sildenafil maleate. 
     Sildenafil Maleate Formulation 
     A coated tablet containing a low dose of sildenafil maleate was prepared and further being stable for two years (Table 2). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Composition of coated sildenafil tablets. 
               
            
           
           
               
               
               
            
               
                   
                 Component 
                 Amount 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Sildenafil maleate (equivalent to 
                 13.2 
                 mg 
               
               
                   
                 10 mg base) 
               
               
                   
                 Tribasic calcium phosphate 
                 40.0 
                 mg 
               
               
                   
                 Lactose 
                 60.2 
                 mg 
               
               
                   
                 Corn starch 
                 40.0 
                 mg 
               
               
                   
                 Croscarmellose sodium 
                 8.0 
                 mg 
               
               
                   
                 Microcrystalline cellulose (Avicel 
                 12.0 
                 mg 
               
               
                   
                 pH 101) 
               
               
                   
                 Polyvinylpyrrolidone (PVP K-30) 
                 10.0 
                 mg 
               
               
                   
                 Magnesium stearate 
                 4.0 
                 mg 
               
               
                   
                 Sodium glycolate starch 
                 12.0 
                 mg 
               
               
                   
                 Opadry Pink YS-1-1477 (Red No. 27 D&amp;C 
                 7.55 
                 mg 
               
               
                   
                 lacquer aluminum, blue No. 2 FD&amp;C 
               
               
                   
                 lacquer aluminum, hypromellose, 
               
               
                   
                 titanium dioxide, polyethylene 
               
               
                   
                 glycol, polysorbate 80) 
               
               
                   
                 Methylene chloride 
                 0.02096 
                 mL 
               
               
                   
                   
               
            
           
         
       
     
     Sampling 
     Diabetic patients with grade 2 and grade 3 ulcers were selected, according to Wagner classification and complying with the following inclusion and exclusion criteria: 
     Inclusion Criteria:
         Male or female patients with type-2 Diabetes Mellitus   Age younger than 80 years   Grade-2 or -3 foot or leg ulcer, of any origin according to Wagner classification, without compromising tendons nor bone, with a progression time not higher than 3 months.   Presence or absence of localized infection   Without peripheral vascular obstruction       

     Exclusion Criteria
         Type-1 Diabetes Mellitus patients   Grade-4 foot or leg ulcer according to Wagner classification or foot or knuckle necrosis   Peripheral vascular obstruction (ankle/arm index lower than 0.3)   Patients with creatinine higher than 1.2 mg/dL or blood urea nitrogen (BUN) higher than 50   Transaminases 2 times above baseline   Microalbuminuria higher than 100       

     Study Variables 
     During patient recruitment, the variables reported in Table 3 were studied. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Study variables 
               
            
           
           
               
               
               
            
               
                   
                 SPECIFIC VARIABLE 
                 CATEGORY-SCALE 
               
               
                   
                   
               
               
                   
                 Ulcer presence 
                 Yes/No 
               
               
                   
                 Ulcer location 
                 Forefoot, heel, toes, leg, etc. 
               
               
                   
                 Wagner classification 
                 1, 2, 3, 4 
               
               
                   
                 Ulcer size 
                 Centimeters 
               
               
                   
                 Progression time 
                 Days 
               
               
                   
                 Previous Treatment 
                 Yes/No; time; type 
               
               
                   
                 Infection presence 
                 Yes/No 
               
               
                   
                 Use of antibiotics 
                 Yes/No; type; time 
               
               
                   
                 Healing 
                 Yes/No 
               
               
                   
                 Age 
                 Years 
               
               
                   
                 Gender 
                 F/M 
               
               
                   
                 Time with diabetes 
                 Years 
               
               
                   
                 DB Treatment 
                 Yes/No; type 
               
               
                   
                 Degree of metabolic 
                 Good: HbA1c lower than 7%; bad: 
               
               
                   
                 control 
                 control HbA1c higher than or 
               
               
                   
                   
                 equivalent to 7% 
               
               
                   
                 Education 
                 Elementary, high school, college, 
               
               
                   
                   
                 postgraduate, illiterate. 
               
               
                   
                 Income level 
                 High, medium, higher low, lower low 
               
               
                   
                 Vascular assessment 
                 Doppler of affected limb, presence 
               
               
                   
                   
                 of obstruction; obstruction location 
               
               
                   
                 Assessment of 
                 Neurological assessment LIFE 
               
               
                   
                 amputation risk 
                 protocol; diabetic neuropathy 
               
               
                   
                   
               
            
           
         
       
     
     Protocol 
     Patients who meet inclusion and exclusion criteria, who voluntarily accept to participate in the study and further signing a written consent, are randomly assigned to two study groups: 
     Group I: Conventional treatment 
     Group II: Conventional treatment with simultaneous administration of sildenafil maleate. 
     Patients are required to perform wound treatment and to register lesion progression. 
     Visit 1
         Signature of written consent   Physical examination   Petition of clinical lab examinations: complete blood count, glycosilated hemoglobin (HbA1c), total colesterol, total lipids, triglycerides, HDL-colesterol, urea, creatinine, microalbumina, aspartate aminotransferase (TGO), alanine aminotransferase (TGP), reactive, ultra-sensitive C-protein (PCR-u), urine test, pre and postprandial glycemia, lesion culture when required.   Conventional healing of lesion   Arterial Doppler request of affected limb   Provide treatment with antibiotics when necessary       

     Visit 2 (1 to 3 Days after Visit 1)
         Interpretation of lab examination and Doppler study   Clinical/physical lesion examination   Patient inclusion/exclusion decision into the study   Random assignment of study groups   Registration of lesion characteristics (lesion photographs)   Assessment of metabolic control       

     Visit 3 (1 to 3 Days after Visit 2)
         Registration of lesion progression (lesion photographs)   Assessment of patient&#39;s metabolic control   Delivery of corresponding medicaments (antibiotics and sildenafil maleate as applicable)   Registration de adverse events       

     Visit 4 Until Week 12 of Study (2 to 3 Times Per Week)
         Registration of lesion progression (lesion photographs)   Registration de adverse events   Assessment of metabolic control       

     Visit 5 (1 to 5 Days after Final Visit)
         Registration of lesion progression (lesion photographs)   Registration of adverse events   Compliance with study medication intake   Education for future lesion prevention       

     Foot Assessment 
     Foot assessment of diabetic patient includes 4 components: vascular, neuropathic, orthopedic and infectious components; the presence of these components may define the prognosis for lesion progression. Assessment is carried out based on criteria described in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Foot Assessment 
               
            
           
           
               
               
               
            
               
                   
                 Component 
                 Assessment 
               
               
                   
                   
               
               
                   
                 Neuropathy 
                 Head of metatarsal bone 1, 2, 3 and 5 and 
               
               
                   
                   
                 first toe of foot are assessed with a 10 g 
               
               
                   
                   
                 Semmens Weinsten monofilament. It is 
               
               
                   
                   
                 positively determined if patient does not 
               
               
                   
                   
                 perceive the monofilament in more than 
               
               
                   
                   
                 one site. 
               
               
                   
                 Vascular 
                 Femoral, popliteal, pedal and tibial 
               
               
                   
                   
                 posterior pulses; forefinger, ankle, arm 
               
               
                   
                   
                 are assessed by palpation; Doppler of 
               
               
                   
                   
                 lower limbs. 
               
               
                   
                 Orthopedic 
                 Alteration of foot shape producing 
               
               
                   
                   
                 difficulty for using standard footwear 
               
               
                   
                   
                 (unmodified); it may include flat foot or 
               
               
                   
                   
                 high-arched foot, mallet toes, bunions, 
               
               
                   
                   
                 previous amputations. 
               
               
                   
                 Infectious 
                 Presence of infection signs which 
               
               
                   
                   
                 aggravates ulcer progression and requires 
               
               
                   
                   
                 the use of antibiotics; may be located or 
               
               
                   
                   
                 systemic. 
               
               
                   
                 History of 
                 Review of medical records; patient is 
               
               
                   
                 previous ulcer 
                 asked about. Previous lesions increase 
               
               
                   
                 and background 
                 the risk of complications. 
               
               
                   
                 Disability 
                 Physical: the patient cannot reach 
               
               
                   
                   
                 his/her feet. 
               
               
                   
                   
                 Visual: the patient does not see his/her 
               
               
                   
                   
                 feet sufficiently well in a safe manner 
               
               
                   
                   
                 to cut his/her nails. 
               
               
                   
                   
               
            
           
         
       
     
     Assessment of Amputation Risk 
     The risk of amputation is based on the presence of any neuropathic, vascular or orthopedic complication impeding or retarding a normal healing. 
     Low risk is considered when detected at least one pulse on each foot, there is no neuropathy, no deformity, no disability and absence of ulcer records. 
     On the other hand, when there is an ulcer or amputation record, absence of pulses and neuropathy or one of those above with deformity, a high risk is present. 
     Comorbidity 
     Comorbidity is a coexistence of two or more pathologies. On this regard, a number of epidemiological studies show that diabetes is associated with arterial hypertension (HTA), diabetic neuropathy, dyslipidemia (DISL), hypothyroidism, diabetic retinopathy, diabetic nephropathy, cardiopathy, depression, cerebral-vascular disease (ECV), and similar diseases. Comorbidity was determined based on medical records and clinical studies. 
     Wound Treatment and Follow Up 
     Wound treatment applied to all patients during each visit consists of cleaning with 9% saline and distilled water, using sterile material; ointment MEBO® (Moist exposed Burn Treatment) was locally applied and dressing with sterile gauze when needed. 
     Study medication was delivered in accordance with the previously established protocol; compliance with medication intake and presence of adverse events was verified. Medication was suspended in case of showing any adverse effect, even a mild event associated with study medicament (sildenafil maleate). 
     Results 
     Table 5 shows general results of patients belonging to study Group I (conventional treatment), while Table 6 shows results obtained from a study conducted on patients belonging to Group II (conventional treatment with simultaneous administration of sildenafil maleate). 
     100% of patients in Group II (conventional treatment with simultaneous administration of sildenafil maleate) obtained a satisfactory result (lesion healing); while only 85% of patients in Group I (conventional treatment) obtained a satisfactory result. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 General results of patients belonging to study Group I (Conventional treatment) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 WEEKS 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 OF 
               
               
                 PATIENT 
                   
                   
                 YEARS 
                   
                 METABOLIC 
                   
                 AFFECTED 
                 WAGNER 
                 AREA 
                 INFEC- 
                 TREAT- 
               
               
                 CODE 
                 SEX 
                 AGE 
                 W/DIABETES 
                 COMORBIDITY 
                 CONTROL 
                 FOOT 
                 ZONE 
                 CLASSIF 
                 (cm 2 ) 
                 TION 
                 MENT 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 V-I-01S 
                 F 
                 80 
                 30 
                 HTA-DYSL-EAC 
                 HG ORAL 
                 L 
                 MALEOLAR 
                 W-2 
                 4 
                 YES 
                 15 
               
               
                 V-I-02S 
                 F 
                 61 
                 42 
                 HTA-EAC 
                 INSULIN 
                 L 
                 HEEL 
                 W-3 
                 20 
                 YES 
                 16 
               
               
                 V-I-05S 
                 F 
                 78 
                 8 
                 HTA-EAC 
                 INSULIN 
                 R 
                 PLANTAR 
                 W-3 
                 3 
                 YES 
                 17 
               
               
                 V-I-06S 
                 M 
                 45 
                 6 
                 HTA-DYSL-EAC 
                 HG ORAL 
                 R 
                 AMP BED 
                 W-3 
                 8 
                 NO 
                 12 
               
               
                 V-I-07S 
                 M 
                 44 
                 20 
                 HTA-DYSL 
                 INSULIN 
                 L 
                 AMP BED 
                 W-3 
                 3 
                 YES 
               
               
                 V-I-08S 
                 M 
                 48 
                 5 
                 HTA-DYSL-AEV 
                 HG ORAL 
                 R 
                 EXTERNAL 
                 W-3 
                 10 
                 YES 
                 12 
               
               
                 V-I-09S 
                 M 
                 55 
                 19 
                 HTA-DYSL-EAC 
                 HG ORAL 
                 R 
                 1 ST  TOE 
                 W-2 
                 1 
                 NO 
                 13 
               
               
                 V-I-10S 
                 F 
                 60 
                 10 
                 HTA-DYSL 
                 HG ORAL 
                 L 
                 DORSOLATE 
                 W-2 
                 15 
                 YES 
                 15 
               
               
                 V-I-11S 
                 M 
                 82 
                 32 
                 HTA-DYSL 
                 HG ORAL 
                 R 
                 AMP BED 
                 W-3 
                 2 
                 YES 
                 15 
               
               
                 V-I-12S 
                 F 
                 58 
                 10 
                 HTA-DYSL 
                 HG ORAL 
                 R 
                 2ND, 3 RD  TOE 
                 W-2 
                 1 
                 YES 
                 4 
               
               
                 V-I-13S 
                 M 
                 73 
                 1 
                 HTA 
                 HG ORAL 
                 L 
                 AMP BED 
                 W-3 
                 1 
                 YES 
               
               
                 M-1-M 
                 F 
                 58 
                 10 
                 HTA 
                 INSULIN 
                 R 
                 KNUCKLE 
                 W-2 
                 2 
                 YES 
                 15 
               
               
                 M-2-M 
                 M 
                 60 
                 5 
                 HTA 
                 HG 
                 R 
                 HEEL 
                 W-2 
                 2 
                 NO 
                 13 
               
               
                 M-3-M 
                 M 
                 52 
                 18 
                 HTA 
                 INSULIN 
                 R 
                 PLANTAR R 
                 W-2 
                 2 
                 YES 
                 7 
               
               
                 M-4-M 
                 M 
                 55 
                 5 
                 OBESITY 
                 HG 
                 L 
                 1ER KNUCKLE 
                 W-2 
                 2 
                 YES 
                 7 
               
               
                 M-5-M 
                 F 
                 54 
                 3 
                 DYSL 
                 HG 
                 L 
                 HEEL 
                 W-2 
                 2 
                 YES 
                 8 
               
               
                 M-6-M 
                 F 
                 73 
                 10 
                 HTA 
                 INSULIN 
                 R 
                 LEG INT 
                 W-2 
                 2 
                 YES 
                 8 
               
               
                   
                   
                   
                   
                   
                   
                   
                 FACE 
               
               
                 M-7-M 
                 M 
                 65 
                 4 
                 DYSL 
                 HP 
                 L 
                 PLANTAR 
                 W-2 
                 2 
                 NO 
                 16 
               
               
                 M-8-M 
                 F 
                 61 
                 5 
                 OBESITY 
                 HG 
                 R 
                 LEG INT 
                 W-2 
                 4 
                 YES 
                 7 
               
               
                   
                   
                   
                   
                   
                   
                   
                 FACE 
               
               
                 M-9-M 
                 M 
                 58 
                 4 
                 DYSL 
                 HG 
                 L 
                 2 ND  TOE 
                 W-2 
                 2 
                 YES 
               
               
                 M-10-M 
                 M 
                 56 
                 10 
                 HTA 
                 INSULIN/HG 
                 L 
                 PLANTAR 
                 W-2 
                 2 
                 NO 
                 8 
               
               
                 M-11-M 
                 M 
                 71 
                 12 
                 HTA 
                 HG 
                 R 
                 1 ST  TOE 
                 W-2 
                 2 
                 NO 
                 3 
               
               
                 M-12-M 
                 M 
                 47 
                 10 
                 DYSL 
                 HG 
                 R 
                 KNUCKLE 
                 W-2 
                 2 
                 YES 
                 7 
               
               
                 M-13-M 
                 M 
                 63 
                 4 
                 HTA 
                 HG 
                 R 
                 REAR FACE 
                 W-2 
                 4 
                 YES 
                 11 
               
               
                 M-14-M 
                 F 
                 58 
                 13 
                 HTA 
                 INSULIN 
                 L 
                 HEEL 
                 W-3 
                 10 
                 YES 
               
               
                 M-15-M 
                 M 
                 49 
                 4 
                 HTA 
                 HG 
                 L 
                 PLANTAR 
                 W-2 
                 2 
                 YES 
                 7 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 General results of patients belonging to study Group II (Conventional treatment and 
               
               
                 sildenafil maleate) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 WEEKS 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 OF 
               
               
                 PATIENT 
                   
                   
                 YEARS 
                   
                 METABOLIC 
                   
                 AFFECTED 
                 WAGNER 
                 AREA 
                 INFEC- 
                 TREAT- 
               
               
                 CODE 
                 SEX 
                 AGE 
                 W/DIABETES 
                 COMORBIDITY 
                 CONTROL 
                 FOOT 
                 ZONE 
                 CLASSIF 
                 (cm 2 ) 
                 TION 
                 MENT 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 V-I-01M 
                 M 
                 61 
                 30 
                 HTA-ECV-DYSL 
                 INSULIN 
                 L 
                 AMP BED 
                 W-2 
                 2 
                 YES 
                 7 
               
               
                 V-I-02M 
                 F 
                 58 
                 10 
                 HTA-ICC 
                 ORAL HG 
                 R 
                 PLANTAR 
                 W-2 
                 4 
                 YES 
                 7 
               
               
                 V-I-03M 
                 M 
                 47 
                 3 
                 HTA-DYSL-OB 
                 ORAL HG 
                 R 
                 FOREFOOT 
                 W-2 
                 20 
                 YES 
                 15 
               
               
                 V-I-04M 
                 M 
                 85 
                 40 
                 HTA 
                 ORAL HG 
                 R 
                 METATAR 
                 W-2 
                 6 
                 YES 
                 11 
               
               
                 V-I-05M 
                 F 
                 45 
                 2 
                 HTA-EAC 
                 ORAL HG 
                 R 
                 AMP BED 
                 W-2 
                 5 
                 NO 
                 6 
               
               
                 V-I-06M 
                 F 
                 61 
                 42 
                 HTA-EAC 
                 INSULIN 
                 R 
                 HEEL 
                 W-2 
                 8 
                 NO 
                 7 
               
               
                 V-I-07M 
                 M 
                 55 
                 10 
                 HTA 
                 INSULIN 
                 L 
                 AMP BED 
                 W-2 
                 6 
                 YES 
                 4 
               
               
                 V-I-08M 
                 M 
                 60 
                 21 
                 HTA 
                 ORAL HG 
                 L 
                 PLANTAR 
                 W-2 
                 1 
                 NO 
                 7 
               
               
                 V-I-09M 
                 M 
                 53 
                 15 
                 EAC-DYSL 
                 ORAL HG 
                 L 
                 HEEL-FOOT 
                 W-3 
                 15 
                 YES 
                 13 
               
               
                 V-I-10M 
                 M 
                 63 
                 2 
                 DYSL 
                 ORAL HG 
                 R 
                 PLANTAR 
                 W-3 
                 20 
                 YES 
                 12 
               
               
                 V-I-12M 
                 F 
                 73 
                 7 
                 HTA 
                 ORAL HG 
                 R 
                 AMP BED 
                 W-2 
                 6 
                 NO 
                 9 
               
               
                 V-I-13M 
                 M 
                 57 
                 20 
                 EAC-DYSL 
                 ORAL HG 
                 L 
                 TAL-PL-DOR 
                 W-3 
                 20 
                 YES 
                 11 
               
               
                 V-I-14M 
                 M 
                 49 
                 10 
                 DYSL 
                 INSULIN 
                 L 
                 AMP BED 
                 W-2 
                 2 
                 YES 
                 9 
               
               
                 I-10-S 
                 M 
                 57 
                 15 
                 HTA 
                 HG 
                 R 
                 KNUCKLE 
                 W-2 
                 2 
                 YES 
                 4 
               
               
                 I-11-S 
                 M 
                 58 
                 10 
                 HTA 
                 HG 
                 L 
                 EXT FACE 
                 W-2 
                 3 
                 YES 
                 6 
               
               
                 I-12-S 
                 M 
                 39 
                 2 
                 HTA 
                 INSULIN 
                 R 
                 DORSAL 
                 W-2 
                 2 
                 YES 
                 3 
               
               
                 I-13-S 
                 M 
                 51 
                 5 
                 OBESITY 
                 INSULIN/HG 
                 R 
                 PLANTAR 
                 W-2 
                 1 
                 NO 
                 3 
               
               
                 I-14-S 
                 M 
                 57 
                 12 
                 HTA-DYSL 
                 INSULIN 
                 L 
                 3 RD  TOE 
                 W-3 
                 1 
                 YES 
                 7 
               
               
                 I-16-S 
                 M 
                 43 
                 3 
                 HTA 
                 HG 
                 R 
                 AMP BED 
                 W-2 
                 4 
                 YES 
                 4 
               
               
                 I-18-S 
                 F 
                 63 
                 20 
                 OBESITY 
                 INSULIN/HG 
                 R 
                 PLANTAR 
                 W-3 
                 5 
                 YES 
                 10 
               
               
                 I-19-S 
                 F 
                 43 
                 12 
                 HTA 
                 INSULIN/HG 
                 R 
                 PLANTAR 
                 W-2 
                 3 
                 YES 
                 8 
               
               
                 I-20-S 
                 F 
                 53 
                 7 
                 HTA-OBESITY 
                 HG 
                 R 
                 PLANTAR 
                 W-2 
                 4 
                 YES 
                 7 
               
               
                 I-21-S 
                 F 
                 76 
                 11 
                 HTA 
                 INSULIN 
                 L 
                 INT FACE 
                 W-3 
                 15 
                 YES 
                 16 
               
               
                 I-22-S 
                 M 
                 56 
                 5 
                 HTA 
                 HG 
                 L 
                 KNUCKLE 
                 W-2 
                 1 
                 YES 
                 11 
               
               
                 I-23-S 
                 M 
                 53 
                 12 
                 HTA 
                 INSULIN/HG 
                 R 
                 PLANTAR 
                 W-2 
                 4 
                 YES 
                 3 
               
               
                 I-24-S 
                 M 
                 79 
                 7 
                 HTA 
                 INSULIN 
                 R 
                 KNUCKLE 
                 W-2 
                 1 
                 YES 
                 4 
               
               
                   
               
            
           
         
       
     
     Healing Time 
     It was surprisingly found that regardless of the ulcer grade according to Wagner scale and the lesion area, patients treated with sildenafil maleate decreased the recovery time by about 20 days. 
     As appreciated from Tables 7 and 8, patients who showed grade 2 ulcers and treated with sildenafil maleate, though having 296 more of average area of lesion demonstrated a 20 days lower healing than the group with conventional treatment. In case of patients with grade 3 ulcer, the result is better than the group treated with sildenafil maleate, although such group duplicates the average area of lesion of the group with conventional treatment. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Area of lesions 
               
            
           
           
               
               
               
            
               
                   
                 Average of 
                 Average of 
               
               
                 Ulcer grade as per 
                 lesion area 
                 lesion area 
               
               
                 Wagner scale 
                 Group I (cm 2 ) 
                 Group II (cm 2 ) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 2 
                 2.94 
                 3.80 
               
               
                 3 
                 4.88 
                 12.67 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Healing time for grade 2 and 3 ulcers according to 
               
               
                 Wagner scale 
               
            
           
           
               
               
               
            
               
                 Ulcer grade 
                 Average healing 
                   
               
               
                 according to Wagner 
                 time 
                 Average healing time 
               
               
                 scale 
                 (Group I) 
                 (Group II) 
               
               
                   
               
               
                 2 
                 67 days 
                 47 days 
               
               
                 3 
                 101 days  
                 81 days 
               
               
                 2 and 3 
                 75 days 
                 55 days 
               
               
                   
               
            
           
         
       
     
     A total recovery was observed in the group of patients treated with sildenafil maleate and who further has previous amputations. However, 15% of patients with conventional treatment suffered amputations due to development of existing lesions and appearance of new ulcers. 
     Moreover, it was noticed that patients in Group II, whose treatment concluded previous to the 12 weeks provided in present study, kept an improvement in blood flow and generally in health status of lower limbs. 
     Adverse Events 
     Although sildenafil maleate is a vasodilator agent, patients belonging to Group II (treated with sildenafil maleate) and further presenting arterial hypertension (HTA), did not experience adverse events.