DARU, Journal of Pharmaceutical Sciences
Volume:16 Issue: 1, Spring 2008

Foot ulcers are one of the main complications in diabetes mellitus, with a 15% life time risk in all diabetic patients. The problem and features are infection, ulceration, or gangrene. Neuropathy, poor circulation, and susceptibility to infection are the three major contributors to the development of diabetic foot; which when present, foot deformities or minor trauma can readily lead to ulceration and infection. Not all diabetic foots are preventable, but appropriate preventive measures can dramatically reduce their occurrences. Awareness of physicians about foot problems in diabetic patients, clinical examination and Para clinical assessment, regular foot examination, patient education, simple hygienic practices and provision of appropriate footwear combined with prompt treatment of minor injuries can decrease ulcer occurrence by 50%. Many different methods have been proposed and their goal is to accelerate the wound healing. These treatments other than standard therapy include local use of epidermal growth factor, vacuum-compression therapy (VCT), hyperbaric oxygen and peripheral Stem cell injection. Since all these treatments have a partial effect in ulcer improvement and amputation rate; so more effective treatments are essential.A novel drug for treatment of this complication is an herbal extract, ANGIPARSTM, which has been studied in all steps of clinical trial. This new treatment by topical, oral and intravenous routs has had beneficial effects in the treatment of diabetic foot ulcer after one month. Angiogenesis is one of the considered mechanisms of action of this drug. Results of these clinical trials showed that this treatment can be superior to other treatments.

Semelil (ANGIPARSTM), an herbal formulation containing Melilotus officinalis extract, is a novel compound being developed for treatment of chronic wounds, particularly diabetic foot ulcers. The purpose of this study was to investigate toxicological, pharmacological, and pathomorphological effects of I.M. and I.P. administration of Semelil in animals.The acute toxicity parameters of Semelil diluted in normal saline (1:10 or 1:5) were determined after a single injection into BALB/c mice and Wistar rats in two steps. First, the LD50 was approximately assessed and then the precise lethal dose indices were estimated by the probit-analysis method. Specific single-dose effects of Semelil were monitored for clinical signs of toxicity, including general state of the animals, changes in their behavior, hematological and biochemical parameters for 14 days after drug administration. Then, subacute-chronic toxicity was evaluated in rats treated with Semelil for 3 months. In acute toxicity study, the calculated LD50 for drug diluted at 1:5 was in the range of 44-52 ml/kg. The adverse effects at drug doses close to the LD50 included depressed mood, narcosis, and sleep. No adverse pharmacological or toxicological effects of the drug diluted at 1:10 and administered in the single-dose (25-50 ml/kg body wt.) or chronically (daily doses of 0.07 and 0.21 ml/kg body wt.) were noted. Thus, the animal studies demonstrated a favorable safety profile for the phytotherapeutic Semelil.

Semelil (ANGIPARSTM), a novel herbal-based compound containing extract of Melilotus officinalis, was formulated for treatment of chronic wounds, especially diabetic foot ulcer. The purpose of this study was to investigate safety and toxicity effects of intramuscular administration of Semelil in dogs. Preliminary one-month study with Semelil was performed on 8 male and female dogs divided into 2 groups, test and control, four animals each. Semelil was administered intramuscularlyat a dose of 0.07 ml/kg body wt. once a day to the animals of the test group, while the control group received sterile saline. During experiments, general state of the animals including the dynamics of body weight changes, appetite, motor activity and behavior, hair condition, ECG parameters, rectal temperature of animals and data of hematological and biochemical tests were monitored for signs of toxicity and side-effects. Finally, morphology and histology analyses were performed using standard methods.No adverse health or toxicity effects were observed through the course of the study. No damaging consequences of Semelil injections on the functional state of main organs of the experimental animals were found. This observation gave a good evidence of a favorable safety profile compatible with potential therapeutic use of Semelil.

Semelil is a novel herbal-based compound formulated for treatment of bed sore and diabetic foot ulcer. The objective of the present preclinical study was to assess the mutagenicity and genotoxicity of Semelil in full compliance with the standard guidelines for testing chemicals. The potential genotoxicity of Semelil, as part of the safety evaluation process was assessed in three different in vitro and in vivo tests, including bacterial reverse mutation (Ames test), mammalian bone marrow chromosomal aberration, and rodent dominant lethal assays. Effects of Semelil was clearly negative at different doses in the Ames test. No statistically significant differences were observed between the levels of chromosomal aberrations in bone marrow cells of mice from the experimental and control groups. The rate of post-implantation losses and thus, the number of lethal mutations in germ cells at different stages of spermatogenesis in male mice treated with a single dose of Semelil did not statistically exceed the control rate. While on the basis of these observations, Semelil can be considered genotoxically safe, further investigations using other bio-assays for mutagenicity studies are warranted.

Background and the purpose of the study: In many cases of diabetic foot ulcer (DFU) management, wound healing is incomplete, and wound closure and epithelial junctional integrity are rarely achieved. Our aim was to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Semelil (ANGIPARSTM), a new herbal compound for wound treatment in a Phase I clinical trial. In this open label study, six male diabetic patients with a mean age of 57±7.6 years were treated with escalating intravenous doses of Semelil, which started at 2 cc/day to 13.5 cc/day for 28 days. Patients were assessed with a full physical exam; variables which analyzed included age, past history of diabetes and its duration, blood pressure, body temperature, weight, characteristics of DFU, Na, K, liver function test, Complete Blood Count and Differential(CBC & diff), serum amylase, HbA1c, PT, PTT, proteinuria, hematuria, and side effects were recorded. All the measurements were taken at the beginning of treatment, the end of week 2 and week 4. We also evaluated Semelil''s side effects at the end of weeks 4 and 8 after ending therapy.Results and major Up to the drug dose of 10 cc/day foot ulcer dramatically improved. We did not observe any clinical or laboratory side effects at this or lower dose levels in diabetic patients. With daily dose of 13.5 cc of Semelil we observed phlebitis at the infusion site, which was the only side effect. Therefore, in this study we determined the MTD of Semelil at 10 cc/day, and the only DLT was phlebitis in injection vein. The recommended dose of Semelil I.V. administration for Phase II studies was 4 cc/day.

Diabetes foot ulcers are a major predictor of future lower-extremity amputation in patients with diabetes. The animal studies have indicated that treatment with a new herbal extract named ANGIPARSTM improves healing of chronic ulcers. The main objective of the study was to evaluate the safety and healing rates of diabetic foot ulcers in patients treated with ANGIPARSTM. Ten diabetic patients (7 males and 3 females) were eligible for enrollment in this single arm before-after clinical trial. The target wound''s greatest length and width was measured at baseline. The target wound was photographed at baseline and then every two weeks. The wound area was determined by means of planimetry.The mean age of patients was 57± 2.3 years. The mean surface area of ulcers was 12.32±11 cm2, 9.55±9 cm2, and 6.96±6 cm2 at baseline, one month and two months of study, respectivly. Our results showed that the drug could reduce the wound size at least 50% during 8 weeks period. We found no adverse side effects in our patients. The main conclusion of the present study was to show the efficacy and safety of ANGIPARSTM as a novel therapy in diabetic foot ulcers.

Some diabetic foot ulcers, which are notoriously difficult to cure, are one of the most common health problems in diabetic patients. There are several surgical and medical options which already have been introduced for treatment of diabetic foot ulcers, so some patient will require amputation. The purpose of this study was to evaluate the efficacy of intravenous Semelil (ANGIPARSTM), a naive herbal extract to accelerate healing of diabetic foot ulcers. A multi-centric randomized controlled trial was conducted to evaluate intravenous Semelil for healing of diabetic foot ulcers. Sixteen diabetic patients were treated with intravenous Semelil, and nine other patients were treated with placebo as control group. Both groups were otherwise treated by wound debridement and irrigation with normal saline solution, systemic antibiotic therapy and daily wound dressing. Before and after intervention, the foot ulcer surface area was measured, by digital photography, mapping and planimetry. After 4 weeks, the mean foot ulcer surface area decreased from 479.93±379.75 mm2 to 198.93±143.75 mm2 in the intervention group (p = 0.000) and from 766.22±960.50 mm2 to 689.11±846.74 mm2 in the control group (p = 0.076). Average wound closure in the treatment group was significantly greater than placebo group (64% vs. 25%, p= 0.015). This herbal extract by intravenous rout in combination with conventional therapy is more effective than conventional therapy by itself probably without side effect. However, further studies are required in the future to confirm these results in larger population.

ANGIPARSTM is a new herbal extract which has been produced in oral, topical, and intravenous forms. The present article contains preliminary results of the study which was planned to evaluate the efficacy and safety of orally applied ANGIPARSTM and to compare it with the combination of oral and topical forms and also with conventional therapy in patients with diabetic ulcers of the lower extremities.Twenty one patients with diabetic foot ulcers were divided into 3 groups. The first group received 100 mg of oral ANGIPARSTM twice a day for 6 weeks in addition to conventional therapies. In the second group, ANGIPARSTM gel 3% was added to the oral form of the same product besides the conventional therapies for the same period of time. Finally, in the third group which was considered as control, only conventional therapies were performed. The patients were followed for 6 weeks. Parameters such as granulation tissue formation, skin epithelization, and wound surface areas changes were analyzed to determine the effectiveness of the compound in wounds healing. Furthermore, drug safety was assessed by monitoring adverse events and by clinical and laboratory evaluations.The study data showed significant differences between the intervention and control groups with respect to efficacy and tolerability. In each intervention group, primary wound healings occurred following 2 weeks. Complete wound healing which was greater than 70% improvement in wounds surface areas was achieved in 83% and 100% of group 1 and group 2 participants, respectively after 6 weeks. On the other hand, at the same period of time, only 22.2% of patients in control group revealed complete healing. Therefore, ANGIPARSTM had significant positive effect in increasing the incidence of complete wound closure compared with control group (p = 0.042). However, our evaluations indicated that adding topical treatment with 3% gel once a day to the oral therapy with the same product did not make significant difference in healing outcomes statistically (p = 0.769). Clinical and paraclinical evaluations did not show any adverse events during the study.This study showed that in diabetic foot ulcers, either treatment with oral ANGIPARSTM capsules (100mg) twice a day or combination therapy with oral and topical forms, in conjunction with good wound care significantly increased the incidence of complete wound closure. In addition, the application of this product was safe and did not make any unexpected adverse event.

The prevalence of pressure ulcers of the foot is a major health care problem in frail elderly patients. A pressure sore dramatically increases the cost of medical and nursing care, and effective treatment has always been an essential nursing concern. Management options for pressure ulcers include local wound care; surgical repair and, more recently, topical application of growth factors.The main goal of this study was to examine the effects of intravenous treatment of Semelil (ANGIPARSTM), a new herbal extract in patients with severe, noninfected pressure ulcers of the foot.As a randomized clinical trial, 18 patients with pressure ulcers were recruited from Vali-e-Asr hospital, Medical Sciences/ University of Tehran, Iran. Nine patients received intravenous Semelil (ANGIPARSTM) besides to conventional therapy and nine received only conventional treatment.At the baseline, the treatment and control groups did not differ across demographic variables, clinical characteristics, and functional measures. The mean surface areas of the ulcers were reduced 43.2 ± 57.4 cm2 (80.3%) and 2.8± 6.2 cm² (6.3%) in the treatment and control groups, respectively (p=0.000). The average reduction in pressure ulcer area at four weeks was statistically and clinically greater in the treatment group than in the control group So, intravenous Semelil (ANGIPARSTM) can be recommended as an effective treatment for patients with severe pressure ulcers.

Pressure ulcers are one of the major health care problems and results in a substantial amount of burden for both patients and health services. The aim of this study was to appraise effectiveness of topical Semelil (ANGIPARSTM), a naive herbal extract, in pressure ulcers As a randomized controlled clinical trial, 18 patients with pressure ulcers were recruited from Vali-e-Asr hospital, Medical Sciences/ University of Tehran, Iran. Nine patients received topical Semelil (ANGIPARSTM) during hospitalization and nine other patients received conventional treatment. Baseline characteristics of the topical and control groups did not differ across demographic, clinical and functional measures. The mean surface areas of the ulcers were reduced 48.2 ± 85.3 cm2 (78.3%) and 2.8± 6.2 cm² (6.3%) in the treatment and control groups, respectively (p=0.000).From the results of this study it may be concluded that the use of topical Semelil (ANGIPARSTM) with conventional treatment is more effective than those of only conventional treatment for patients with pressure ulcers.