Impact of Poly-Herbal Formulation (PHF) on the Outcome of Diabetic Foot Ulcer (DFU) with Osteomyelitis

80

Impact of Poly-Herbal Formulation (PHF) on the Outcome of Diabetic Foot Ulcer (DFU) with

Osteomyelitis

Sudharshan Reddy Dachani¹, Satya Sai Devulapally², Shiva Krishna Devulapally³, Srinivasa Chary Devulapally⁴, Prasanna Mohana Bhaskaran⁵ ,Yasodha Krishna Janapati⁶ ,Tamatam Sunilkumar

Reddy⁷, Shanker Kalakotla⁸*

Abstract

Cellulitis is a bacterial infection involving the deeper layers of skin, fat and the soft tissues underneath. A 46-year- old male presented to the diabetic clinic with complaints of left foot pain, erythema and foul-smelling discharge from a non-healing ulcer of the left great toe with swelling of the great toe, tenderness, local warmth and malaise.

Cellulitis extending more than 2cm around the ulcer. The patient had a non-healing ulcer of insidious onset on the left great toe for 6 months. The co-morbidities in this patient include poorly controlled diabetes mellitus type-2 (HbA1c = 8.9%) of 12 years duration with renal impairment, neurological deficit after a Cerebrovascular accident (CVA) 6 years back, Tuberculosis 4 years back and he had been using alcohol regularly. Cultures revealed Staphylococcus aureus and Streptococcus pyogenes. Cellulitis was diagnosed in left leg and foot, abscess in the plantar aspect of the left foot. The left foot X-ray showed Osteolytic lesions of proximal phalanx of great toe with adjacent soft tissue swelling. The patient was treated with Poly Herbal Formulation (PHF)- Re Cell Heal 500 mg capsules (PRANATHI HERBALS; License No. T-2265/Ayur/; Letter No 2884/ DA/2018) orally (p.o) two times a day (b.i.d) for 5 months in addition to the topical application of Wound check ointment (Letter No 4964/DA/2018) (b.i.d) with adequate wound care by saline dressing. Marked clinical improvement was observed, decreasing erythema, swelling, pain, healing of the DFU and complete restoration of foot functionality. Glycemic control was achieved and well controlled during the period of treatment. Recent scientific evidences and trials conducted on Re Cell Heal reveals that the product is a traditional and alternative medicine in the treatment of Cellulitis, Osteomyelitis and Diabetic related foot infections. The product holds good in assuring patient safety and efficacy without any side effects.

Keywords: Cellulitis, Diabetic Foot Ulcer, Osteomyelitis, Staphylococcus aureus, Wound Healing, Re Cell Heal and Wound check Ointment.

DOI Number:10.4704/nq.2022.20.14.NQ88011 Neuro Quantology 2022; 20(14):80-85 1. Introduction

Diabetic foot ulceration (DFU) is a devastating complication of type 2 Diabetes Mellitus (T2DM) and is a major cause of morbidity and mortality. In recent years, diabetic foot ulcer has grown to reach pandemic proportions. It is a serious health problem that imposes a huge global economic burden. Every 20 seconds, a lower limb is amputated somewhere in the world because of diabetes, with 85% of these amputations caused by ulceration.

Osteomyelitis is one of the most common expressions (pathological consequence) of diabetic foot infection, being present approximately in 10–15% of moderate and in 50% of severe infectious process (Lipsky BA et.

Al, 2006). ‘Osteomyelitis’ (OM) is derived from three Greek words: osteon, myelos, and itis. It refers (conferred the meaning of) to the inflammation or infection of the bone and bone marrow. Osteomyelitis occurs after a soft tissue infection in the DFU area that spreads into the bone (10-20%), involving the cortex first and then the marrow. DFU and consequently osteomyelitis has been established as important risk factors for minor or major lower-extremity amputation (Lipsky BA et al, 2021) Patients with T2DM are prone to develop osteomyelitis in their feet especially when they have a foot ulcer. The transmission of infection from soft tissue to marrow indicates that cortical infection will precede marrow involvement.

81 Thus, virtually all patients with suspected OM

present with cortical involvement and features of chronic OM (Jeffcoate WJ and Lipsky BA, 2004).

The most important contributing factors in diabetic foot ulcerations are (Ghasemali Khorasani, 2008)

i. The compromised blood flow in the vessels of the legs and feet due to the plaques that builds up in the arteries - Peripheral Arterial disease-PAD.

ii. The sensory loss in the feet which is common in DM-Peripheral neuropathy, will lead to formation of sores either due to minor trauma or due to pressure effects (Trophic ulcer). Sores that are left untreated are dangerous for those with diabetes.

In the presence of a non-healing ulcer, the invading pathogens cause a wide range of infections involving skin and deeper structures.

The spectrum ranges from cellulitis, abscess, Osteomyelitis and wet gangrene. The most common pathogens associated with Osteomyelitis reflects the one found in soft tissue infections, rarely mono-microbial and more often polymicrobial.

Microbial Spectrum of Osteomyelitis:

No Organism Prevalence

1 Staphylococcus aureus Upto 50%

2 Staphylococcus epidermidis Upto 40%

3 Enterobacteriaceae Upto 40%

S.aureus, S.epidermidis and Enterobacteriaceae are the most commonly detected bacteria in

Diabetic Foot Organisms (Lipsky BA et al, 2004, Lipsky BA, Aragón-Sánchez J, 2016) and Strains of Staphylococcus aureus isolated from clinically non‐infected ulcers have been shown to have a lower virulence potential than from ulcers that are infected (Sotto A et al, 2008). Methicillin‐

susceptible S. aureus (MSSA) with a tropism for bone has emerged as the main staphylococcal pathogen in outbreaks of Diabetic Foot Osteomyelitis (DFO).

Staphylococcus aureus (including both methicillin-sensitive and methicillin-resistant strains) is present in 50% or more of patients with DFO. Osteomyelitis (OM) can affect any bone but most frequently the forefoot (90%), followed by the midfoot (5%) and the hind foot (5%). The other factors predisposing to OM are degree of peripheral neuropathy, vascular supply, extent of soft-tissue and bone destruction, degree of systemic illness, and patient’s co-morbidities (Lipsky BA, 2004).

Infected wounds usually show purulent secretions or at least two signs of inflammation (swelling, erythema, blood serum secretion or simply blood with or without bone fragments) (Eneroth M, Larsson J and Apelqvist J, 1999). An early and accurate diagnosis is required to ensure an effective treatment and reduce the risk of minor and major amputation (Bonham P, 2001)

Aerobic Gram-positive cocci (such as Staphyl- ococcus aureus, S. epidermidis, streptococci), and especially S. aureus, are the most commonly detected bacteria in DF infections, followed by Gram negative rods (such as Enterobacteriaceae). Methicillin-resistant Staphylococcus aureus (MRSA) plays an increasing role in DF infections nowadays

*Corresponding author: Kalakotla Shanker

Address: *Department of Pharmacognosy & Phyto-Pharmacy, JSS College of Pharmacy, JSSA cademy of Higher Education &

Research, Ooty, Nilgiris, Tamil Nadu, India.Email: drshanker@jssuni.edu.in

1Department of Pharmacy Practice & Pharmacology, College of Pharmacy, P.O. Box-33, Shaqra University-11911, Al-Dawadmi Campus-17412, Kingdom of Saudi Arabia (KSA)

2Pranathi Herbals, H.NO:2-91,Shivalayam Street, Adavidevulapally (V & M), Nalgonda Dist- 508207, Telangana Sate, India.

3Pranathi Herbals, H.NO: 2-91, Shivalayam Street, Adavidevulapally (V & M), Nalgonda Dist- 508207, Telangana Sate, India.

4Department of Microbiology, College of Medicine, Shaqra University (Al-Dawadmi Campus),Al-Dawadmi, Kingdom of Saudi Arabia-11961

5Department of Microbiology, College of Medicine, Shaqra University (Al-Dawadmi Campus), Al-Dawadmi, Kingdom of Saudi Arabia-11961

6School of Pharmacy and Health Sciences, United States International University Africa, P.O Box:14634-00800 Nairobi, Kenya.

7Department of Pharmacognosy & Phyto-Pharmacy, JSS College of Pharmacy, JSSA cademy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.

8Department of Pharmacognosy & Phyto-Pharmacy, JSS College of Pharmacy, JSSA cademy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.Email: drshanker@jssuni.edu.in

Relevant conflicts of interest/financial disclosures: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Received: Accepted:

82 (Amado A et al, 2010).

2. Case Study

2.1. Case Presentation

A 46-year-old male presented to the diabetic clinic with painful, erythematous swollen left foot with a non-healing sore with foul smelling discharge in the left great toe for the past six months. The patient had three trophic ulcers of insidious onset for the past 6 months over the plantar aspect of the left foot. Osteolytic destruction of proximal phalanx of left great toe adjacent soft tissue swelling (Fig:1a &1b).

Plain X-ray of the left foot (Fig: 1a and 1b) revealed the following:

1. Periosteal reaction or elevation.

2. Loss of bone cortex with bony erosion.

3. Focal loss of cortical trabecular pattern or marrow radiolucency.

4. Bone sclerosis, with erosion.

5. Presence of sequestrum: devitalized bone with radio dense appearance that has become separated from normal bone.

6. Presence of involucrum: a layer of new bone growth outside previously existing bone resulting from stripping off of the periosteum and new bone growing from the periosteum.

He went to a podiatrist who noticed thick, foul- smelling discharge coming from the toe and he referred to the diabetic clinic for further management. The patient had medical history of Type 2 DM for 12 years with co-existing renal impairment, and hypertension. He also gives history of being treated for DVT, CVA 6 years back, Tuberculosis 4 years back. He is a smoker and frequent alcohol user. Medications used Diabetes-Tab. Glimda-MV- 2 SR Glimepiride (2mg), Metformin (500 mg) + Voglibose (0.2 mg)] with Insulin preparation. Neuropathy – Tab.Neurokind-500 mcg, Hypertension treated with Tab. Atenlol-50 mg. For Tuberculosis-Anti- tubercular Treatment (ATT) –completed the treatment course. The patient was treated by

the previous physician for the DFU empirically with intravenous preparation of Piperacillin- tazobactum.

On Examination: Temp: 36.9°C Wt: 65 kg, Height: 5’4” BP: 150/100 mmHg, Pulse rate:

111/min, RR: 20/min,

Local Examination (Left Foot):

There were swelling and inflammation to the left foot and a foul-smelling discharge from the non-healing ulcer in the great toe (Fig: 2a). Dark blisters were noted with erythema tracking up the lateral aspect of the leg. There were three trophic ulcers over the plantar surface of the foot with maceration of the skin surrounding the ulcer and a serosanguinous drainage with foul smelling odor (Fig:2b). The patient had normal range of movements with diminished fine sensation. The patient had palpable feeble pulsations of posterior tibial and dorsalis pedis artery (Confirmed by Doppler study of the left foot) however the capillary refilling was normal.

Fig: 2a & 2b Foot Notes:

Fig: 2a: Non-healing ulcer over left great toe with secondary bacterial infection involving the soft tissue and the bone.

Fig: 2b: Trophic ulcers over the plantar aspect of left foot - Involving the soft tissues and the tendon.

Lab Investigations

A complete metabolic panel revealed a Fasting blood glucose level:209 mg/dL;HbA1c:

8.9%,The liver enzymes on admission SGOT

83 (AST): 37 U/L, SGPT (ALT): 29 U/L, ALP:120

IU/L, Blood Urea :51 mg/dL; Serum Creatinine:

1.7 mg/dL; Creatinine clearance: 30 ml/min, C reactive Protein (CRP) : 24 mg/L, A complete blood count revealed ; WBC 13.8 x 103/mm3-leukocytosis (increased Polym- orphs)- neutrophils 80% with 18% band forms. the patient had elevated serum inflammatory markers and elevated ESR: 35 mm/hr; Hb :8.1 g/dL; Platelet count: 5, 20,000 x 10³/Cumm. Serum Na⁺: 136 mEq/L; K⁺: 3.8 mEq/L; Cl^-: 97 mEq/L;

Cultures revealed Staphylococcus aureus (MRSA) and Streptococcus pyogenes.

Cellulitis was diagnosed in left leg and foot, abscess in plantar aspect of foot.

2.2. Management

After admission, the patient was prescribed wound check ointment along with Re Cell Heal capsules (Ayurvedic formulations) twice daily for Cellulitis and wound infection.

The patient continued Re Cell Heal treatment for 5 months. The wound over the left foot was debrided adequately and was provided with saline dressing on daily basis. After 5 months of intervention, inflammatory markers had returned to baseline. Clinically, the patient improved with restoration of adequate blood flow to his left lower limb (Confirmed by Doppler study of the left foot) and the ulcer has healed completely. Eventually 5 months after of treatment, the patient presented with complete healing of his Diabetic Foot Infection and restoration of his foot normal function. (Fig-3a

& 3b)

Fig-3a & 3 b Foot Notes:

Fig:3a: Non-healing ulcer over left great toe has completely healed.

Fig: 3b: Trophic ulcers over the plantar aspect of left foot have completely healed.

3. Discussion

In this era dominated by the emergence of multi-resistant organisms and limited options in the choice of newer antibiotics, the professionals involved in the treatment of these superbugs causing these menaces are in the hunt for some ancient healing methods by using traditional and alternative medicine in wound management. The intricacies involved in the pathogenesis of DFU and the long-term duration of treatment for the patients with DFU add more woes to the patients. The lifetime vulnerability of developing a diabetic foot ulcer is between 19%

and 34% (Michael Edmonds et al, 2021) Between 0.03% and 1.5% of patients with diabetic foot, require an amputation (Sudharshan Reddy Dachani et al, 2020).

Plants and their extracts swear evidence-based potential for the management and treatment of DFU through various clinical studies conducted around the globe (Vijay Viswanathan et al, 2011). Active constituents of ginger Gingerol (Anti-inflammatory and Anti-microbial activity), Zingerone (Anti-bacterial activity, Antiinfla- mmatory action and Antioxidant activity), Paradols: (Anti-microbial activity Anti-oxidant activity), Shogaol (anti-inflammatory and Anti- oxidant activity), Zerumbone (Anti-microbial, Anti-tumor activity and infectious diseases, rheumatism and swellings. Withania somnifera chemical constituents such as steroidal lactones, alkaloids, flavonoids, tannins, saponins somniferine, somniferine, somnine, with amine, pseudowithamine, withanmine and with- anmine. Shorea Robusta active principles terpenoids, flavonoids, carbohydrate, lignans, phenols and sterols. Euphorbia tirucalli contains terpenes, sterols alkaloids, cardiac glycosides, coumarins, flavonoids, saponins and tannins,

84 etc., Crocus sativus contained apocarotenoid

glycosides: crocin, picrocrocin, protocrocin, volatile oil, safranal, carotenoids: lycopene, alpha-, beta-, gamma-carotene; fatty oil and starch (Arshad H Rahmani and Salah M Aly ,2014)

1. Oral medication like Zingiber officinale, Withania somnifera, Shorea Robusta, Euphorbia tirucalli Latex, Crocus sativus, Swarna bhasma (Clax of gold) and Shankha Bhasma (Clax of conch) are clinically established and practiced drugs in the management of diabetes mellitus and also anti-oxidant, antimicrobial, analgesic, antipyretic, anti-rheumatism and anti- inflammatory actions which help in the prevention of wound infections (Gupta A and Singh S, 2014) W somnifera has long been used in traditional and Ayurvedic medicine to cure diabetes and obesity. Recent studies and observations have revealed that, flavanoids found in the roots of W. somnifera were able to reduce the high blood glucose level in experimental animals. It was also shown that cells to stimulate the release of insulin.

Moreover, it also works for the control of the infection, boosting the immunity, discharge of the pus from the infected wounds and swelling.

Zingiber officinale, Withania somnifera, Shorea Robusta, Crocus Sativusas a wound healing agent is proved and practiced since decades and its ingredients acts on the various stages of wound healing process thus reducing inflammation, promoting wound contraction, Epith- elialization, Granulation tissue formation and scar remodeling (Yaseen Khan Mohammad, Pundarikakshudu Kilambi 2015; Ghasemali Khorasani et al, 2008; Euler Nicolau Sauaia Filho et al, 2013; Thakur Vivek and Sharma Khemchand, 2017; Sudharshan Reddy Dachani, Satya Sai Devulapally and Shiva Krishna Devulapally et al., 2020). As we look towards a future where many of our current antibiotics may no longer work with the efficacy to which we have become accustomed, I think “Re Cell Heal capsules and Wound check ointment have the potential to serve as an alternative strategy to fill that gap,”

4. Conclusion

Diabetic foot Ulcer (DFU) disease treatment should be approached in a holistic manner. The key factors are strict glycemic control, infection control and patient rehabilitation through

appropriate counseling strategies. The goal of the treatment in DFU has got three dimensions like safety of the patient, mental health of the patient and the quality of life of the patient. The chronicity of the treatment exposes the patient to the toxic effects of the drugs. The re- exploration of our ancient medicinal treatments like using Ayurvedic ingredients certainly reduces the toxicity. The Re Cell Heal polyherbal formulation contains a number of beneficial natural ingredients, which are considered to harbor substantial anti-inflammatory and antimicrobial action, promote synthesis of collagen fibers and increase supply of vital nutrients (amino acids, vitamins and fatty acids) to the wound site. From the Ayurvedic prospective, to manage the problems of DFU, polyherbal formulation (Re Cell Heal capsules) and Wound check ointment will provide relief with less toxicity. Many herbal preparations with hypoglycemic and healing properties have a significant role when compared with their toxic synthetic counterparts.

5. Acknowledgments

The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work.

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