Novel applications of Cold Atmospheric Plasma for the treatment of Plaque Psoriasis

 

Mukesh Chandra Sharma1, Mukul Sharma1,2*

1School of Pharmacy, Devi Ahilaya Vishwavidyalaya, Indore (M.P.)

2Faculty of Pharmacy, Medi-Caps University, Indore (M.P.)

*Corresponding Author E-mail: mukulscsharma@gmail.com, mukul.sharma@medicaps.ac.in

 

ABSTRACT:

Plasma is the fourth state of matter other than solid, liquid and gases. About 99 percent of mixture of free positive negative charges, neutral particles and photons. The plasma exists in two forms: hot plasma and cold plasma. Hot plasma is used in metallurgical operations while cold plasma is used in medical, skin psoriasis treatment, food agricultural, preservation and waste water treatment. Many clinical studies prove the effectiveness of cold plasma in dermatological disease management. Recent researches have established that combined use of cold plasma and nano-formulations is helpful in delivery of poorly water-soluble drugs. Plaque psoriasis is an autoimmune disorder in which silvery, thick, dead layer of skin shades off and cause inflammation, sometimes bleeding. It occurs in 3-4 percent of total world population. Scientific studies have proved that nano-scale particles permeate easily and interact with immune cells like lnterleukin-16, cytokines and TNF-alfa during inflammation and autoimmune disorders. As a result of which, thick layer of keratinocytes is produced and formation of TNF-alfa and interleukin is inhibited which are the causes of Plaque psoriasis. Since conventional medication has only been helpful in managing it, researches have been carried out using various techniques like phototherapy, use of UVA, UVB, IPL (Intense Pulsed Light), PDL (Pulsed Dye Light), LASER and low-level LASER light etc. but their excess exposure causes risk of skin cancer. Other therapies like use of nanometric Liposomes, Niosomes and their combination therapy are some novel clinical techniques for combating symptoms but are still in clinical trial. Since, Plasma therapy is non irritating and stops the triggering mechanism of inflammation, hence the use of nanotechnological topical formulation in combination with plasma therapy has the potential to become possible treatment of Plaque Psoriasis in future.

 

KEYWORDS: Novel drugs, Plaque Psoriasis, Phototherapy, Inflammation, Nanotechnology, Cold Plasma.

 

 


INTRODUCTION: 

Plasma is the fourth state of matter and this concept was given by Langmuir in 1944. It is expected that about 90% visible part of our universe is plasma.  It has been reported that plasma can kill bacteria, promote wound healing and induce apoptosis of tumour cells. There are wide applications of plasma medicines in dermatitis and wound healing activity. Cold plasma therapy stops the immunological responses, reverse the mechanism and stop inflammatory responses produced during diseased condition.

 

 

Many therapies claim for the management of skin disorders but are effective only on constant usage, disease may get worse once therapy is stopped. Psoriasis is one of them which negatively affects life of people emotionally, psychologically and sociologically. Approximately 30% of patients have disease onset before age of 18 years. Psoriasis is a chronic immune-mediated inflammatory skin disease in which γ δ T cells play an important role. It is reported that Plasma therapy might inhibit the triggers mechanism and their effects are long lasting, safe, non-toxic, safe to use and cause no scars on patient’s body. The life cycle of human skin completes within 28 to 44 days but many factors like age, stress, hormonal effect, trauma, inflammation or diseased condition of Psoriasis, the cell cycle completes in 3-4 days and forms scaly silver patch which shades rapidly1.

 

Psoriasis causes inflammation process in skin and joints in most of the patient2. Psoriasis is a non-communicable skin disease with no clear cause or cure. Advanced technologies have evolved in late 2000.  For that time, it was used for cosmetic purpose of many vascular lesions, unwanted hair, and pigmented lesions. These are non-LASER high intensity light radiation that make use of a high output flashlamp which produce a broad wavelength output of non-coherent light in the range of 500-1200nm wavelength. In many of the new devices, Xenon gas is filled in a chamber and light pulse is generated using electricity. The working basis of the IPL rests on the principle of selective photo-thermolysis, in which thermal radiation damage is confined to chosen epidermal and/or dermal pigmented targets at the cellular or tissue structural levels3.

 

Cold atmospheric plasma (CAP) has been evolved as novel technology to directly treat cells and tissue during therapy4. Various drug delivery systems including use of topical corticosteroids, vitamin D analogues, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin and combination therapies are used in psoriasis. Anti-interleukin-12 agents have been successfully used for the treatment of psoriatic adults found in literature5,6. Long-lived endothelial cell retraction is induced by inflammatory mediators, such as tumour necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1), released from injured cells7. Phototherapy is a good treatment for plaque Psoriasis. At present, broad-band UVB. narrow-band UVB. psoralen and UVA (PUVA) combination are the effective treatment of Psoriasis. The nano formulations provided enhancement of solubility, bioavailability, protection from toxicity, enhancement of pharmacological activity, reduction in dose enhancement of stability, improved tissue macrophages distribution, sustained delivery and protection from physical and chemical degradation8.

 

Research Envisaged:

As per data procured from PubMed and Science direct, more than 1200 research articles are published in various national and international journals and clinical experiments are done. Few review articles and very few are the patents in the field of psoriasis treatment. There is a need of development of novel therapies, topical therapy and change in existing treatment in psoriasis.

 

Figure 1. Research envisaged for Plaque psoriasis


 

Table 1. Existing Patents in Plasma Therapy for the psoriasis treatment

Title

Highlights

Inventor

Patent No.

Year

Cold atmospheric plasma treatment of actinic keratosis and non- melanoma skin cancer 9

CAP for the treatment of therapy-refractory Actinic Keratosis.

Wirtz, Michelle Zürich

WO 2018/069549

2018

Cold plasma treatment devices and associated methods10

A compact cold plasma device using 65 to 120 ⁰F with a magnet-free configuration, using radiofrequency with controller unit.

Gregory A. Watson. Robert M. Hummel. Marc C. Jacofsky. David J. Jacofsky

US9384947B2

2016

System and methods of cold plasma therapy11

Device which uses cold plasma to treat cancerous tumors which uses endoscopic tube instead of syringe. An exhaust tube can be provided to remove gas introduced into the body cavity by the cold plasma jet.

Michael Keidar,  Charanjeet Guron, Barry Trink

US20140378892A1

2014

Cold plasma associated methods and devices12

A cold plasma mask application device for delivery of a cold plasma used to treat acne as well as complex facial wounds, melanoma and other cancers of the face, rosacea and psoriasis.

Watson Gregory, Magnolia Ave, Sanford, Cave Creek, Jacofsky, Marc. C. N, Central Ave, Phoenix, Jacofsky, David. J, Williams Rd, Peoria.

WO 2013/040473 Al

2013

Cold plasma treatment of materials13

A low temperature plasma is used to treat the surfaces of polymeric materials and textile fibres to improve properties using cold plasma.

Richard W. Baird, William G. Baird. Spartanburg.

US3870610A

1975

 

Existing technology in Plaque Psoriasis:

Treatment of Plaque Psoriasis is based on the control of symptoms. Topical, systemic therapies as well as phototherapy are available for this. In practice, a combination of these methods is often used. Available treatment usually goes life long and is irritating since there is a rare chance of any patient to get cured completely from this disease. Novel therapies came in existence for the treatment of psoriatic patients recently, which are listed below:

 

Cold Atmospheric Plasma:

The plasma exists in two forms hot plasma and cold plasma. Hot plasma is used in metallurgical operations while cold plasma used in medical, food agricultural, preservation and waste water treatment. Many clinical studies have proven the effectiveness of Cold plasma in dermatological disease aliments and medical field14. Cold plasma has been found to active cellular responses and distinct mechanisms in the body and even target cancer cells without affecting healthy ones15. Cold plasma is the fourth states of matter and an ionized gas that has recently been extensively studied by researchers as a possible therapy in dentistry, oncology and skin disorders. Several different gases can be used to produce Cold Atmospheric Plasma such as Helium, Argon, Nitrogen, Helium and air16. Furthermore, it has been demonstrated that Cold Atmospheric Plasma induces apoptosis, necrosis, cell detachment and senescence by disrupting the S phase of cell cycle. This unique finding opens up avenues for potential therapy in ailments17,18.

 

 

Figure 2. Cold plasma Technology (Image adopted from phys.org)19

 

Phototherapy:

A variety of light/lasers with different mechanisms of action have been developed for psoriasis including ultraviolet B (UVB), psoralen ultraviolet A (PUVA), pulsed dye laser (PDL). photodynamic therapy (PDT), intense pulsed light (IPL), light-emitting diodes (LED) all are used to treat lesions, including trunk, scalp, arms, legs, and partial nail psoriasis. Light/laser each has specific therapeutic and adverse effects. it is important to adequately choose the sources and parameters in management of psoriasis with different pathogenic sites. severities. and duration of the disorder. UV light is primarily used for stable Plaque psoriasis and PDL for topical psoriatic lesions with small area. both of which are safe and effective. Excessive exposure of UV may lead to cancer. Phototherapy has been widely used to treat stable psoriatic lesions. including trunk, scalp, arms and legs. and partial nail psoriasis. There is a chances of skin cancer when long time exposure sometimes darkening. blackness of skin and cause mutation. This therapy is long term up to 1 year sometimes it possesses no benefit. ReConnective therapy (RCT), the Narrow Band- UVB (NB-UVB) phototherapy is frequently used as main treatment of phototherapy in psoriasis is it can be given to any patient which includes pregnant women and children20,21,22.

 

Use of Ultraviolet-C:

Anti-psoriatic activity of Madhuca longifolia on rats using Peris Scientific model. Rats were exposed to the UVC light for 3 days and developed photodermatitis treated with standard and Madhuca longifolia (Ml) gel with various strength of 2.5% to 5% made. After few days, decrease in thickness of dead layer seen with respect to control was observed in groups treated with tazarotene and ML gel 2.5% and 5%. It was concluded that the maximum antiproliferative activity was observed with 5% ML gel as per study23,24.

 

Pulsed Dye LASER (PDL):

It is a source of high intensity monochromatic light that is used for the treatment of various skin disorder. for the treatment various parameters like wavelength. energy output and pulse characteristics affect the treatment. Various LASER is available but have different uses and different level of penetration power. In this, organic dye like rhodamine, fluorescein, coumarin, stilbene, umbelliferon, tetracene and malachite green are mixed in a solvent like water, glycerol, methanol, ethanol, hexane, cyclohexane and cyclodextrin which act as lasing medium. High energy light used as a source of light. In the same way high velocity of liquid circulated so that it helped to avoid triplet absorption and to decrease degradation of the dye. The light molecules excite the dye molecules which stimulate radiation. The wavelength of pulses at 585 to 595 nm and duration is 0.45-40ms. Sometimes it is used with the combination of radiofrequency to enhance their effect. As proven in studies that low doses of PDL treatment may reduce side effects during therapy. Some studies showed complications due to non-selectively diffused and absorbed by surrounding tissue and structures25.

 

Intense Pulsed Light (IPL):

The intense pulse light exposes to tissue with specific duration, controlled intensity which absorbs specific wavelength and treatment may possible. Th17 cells profoundly participate in the pathogenesis of certain skin disorders, in particular, psoriasis26. Tissues surrounding these targeted structures, including overlying or immediately neighbouring cells are spared, potentially reducing nonspecific. widespread thermal injury. The three main chromophores (haemoglobin, water, and melanin) in human skin all have broad absorption peaks of light energy. allowing them to be targeted by a range as well as a specific wavelength of light. Therefore, monochromaticity of the light beam is not a prerequisite for selective heating of target structures in human skin. The broad wavelength range discharged from an IPL device leads to the simultaneous emission of green, yellow, red and infrared wavelengths allowing the various chromophores to be targeted concurrently27.

 

Use of UVA and UVB Rays:

Phototherapy with ultraviolet (UV) irradiation of wavelengths between 280 and 320nm (UVB) is a safe and effective treatment for a variety of inflammatory skin diseases. In addition to standard broad band UVB, narrow band phototherapy with fluorescent bulbs emitting near monochromatic UV between 310-315nm has become an important treatment for diseases such as psoriasis, atopic dermatitis or vitiligo. Other diseases respond favorably to narrow band UVB phototherapy. Number of potential indications for such phototherapy is continuously growing. The differential effects of narrow band UVB phototherapy in comparison to other UV phototherapies, as well as new and established indications for this treatment modality are reviewed8. Scientific literature reveled that effect of UV- A and B in 40 patients with Plaque psoriasis undergoing NB-UVB therapy. Researchers compared among three treatment regimens: NB-UVB alone as well as NB-UVB preceded by crude coal tar 3% on one side and petrolatum on the other side. Tar and petrolatum were topically applied thrice/day the day before NB-UVB exposure. There were significant (P<0.01) decreases in both PASI and PGA scores in all the groups1,21.

 

Use of Narrow band Ultra Violet B:

One of the research studies showed that use of narrow band UVB on 95 patients with Plaque-type psoriasis. The NB-UVB phototherapy was administrated 3 times a week for 6 months in a standardized fashion. Patients were asked to complete pre- and post-phototherapy Dermatology Life Quality Index (DLQI)3,29.

 

Combination of NBUVB plus Methotrexate:

Researcher revelled the efficacy of combined narrowband Ultraviolet-B (NBUVB) plus methotrexate (MTX) versus each one alone in the treatment of psoriasis. Psoriasis has many symptoms including arthritis, cardiovascular diseases, metabolic syndrome, inflammatory bowel disease and depression30. Combination of NBUVB plus MTX provided rapid improvement with less cumulative doses of both therapies compared with each one alone in the treatment of psoriasis.30,31

 

Nanoparticles:

Novel nanocarriers that deliver the drugs directly to the target cells. After application. these nanocarriers can penetrate through the stratum corneum into viable skin and accumulate at the target site. However, uptake does occur after damage and in certain diseased skin. Nano-particles are colloidal systems with particles varying in size therapeutically 10nm to 100nm are best suited, enhancement of solubility, bioavailability, protection from toxicity, enhancement of pharmacological activity, reduction in dose enhancement of stability, improved tissue macrophages distribution, sustained delivery and protection from physical and chemical degradation. Some other delivery system like nano-encapsulation vesicular delivery including nanoemulsion and nanocrystals, some lipid carriers like solid lipid nanoparticles, polymeric nanocapsules, nanostructured lipid carriers, micelles, carbon nanotubes, fullerenes and dendrimers24,32.

 

Nanogels:

Nanogels are very effective drug delivery in skin inflammatory diseases, a skin permeating nanogel system (SPN) have been developed that is composed of a surface of modified polymeric bilayer nanoparticles along with a gelling agent. In this SPN, Poly- (lactide-co-glycolic acid) and chitosan were used to prepare bilayer nanoparticles (NPS) and oleic acid (NPSO) was used to make modified surface. For nanogel formation, hydroxypropyl methyl cellulose (HPMC) and Carbopol with suitable viscosity.  Researches have showed the effective percutaneous delivery of drugs in case of skin diseases33. Development of a new formulation is majorly attributed to parameters such as solubility and stability of the drug at ambient temperature. Therefore, various approaches have been made in developing new formulations to improve the solubility and bioavailability of those drugs34.

 

Polymeric nanoparticles:

These are able to accumulate at inflamed regions in many diseases and thus enhance the therapeutic effects of several drugs in murine and rat colitis models. Therefore, they might offer a new targeting approach for the treatment of IBD. Although the mechanisms of accumulation in humans and animals should be comparable, a remaining challenge is the clinical proof of the efficacy of this targeting approach35.

 

Solid lipid nanoparticles:

SLNs are nano-sized lipid carriers possessing a profound hydrophobic lipid structure stabilized by a surfactant, thus, SLNs appear to be an intriguing strategy to the successful delivery of anti-psoriatic drugs via the epidermis, which seems to be the main site of psoriasis operation. Researchers have found the effectiveness and explored the capacity of the Triamcinolone acetonide loaded SLN method for successful trans epidermal psoriasis delivery36.

Curcumin Nanoparticles:

Many scientists worked on Curcumin and found special intrinsic feature that can target the intracellular enzymes, genome (DNA) and messengers (RNA). Curcumin from Curcuma longa regulates the intracellular signal pathways which control the growth of cancerous cell. Inflammation, invasion and apoptosis. These studies indicated that nanotechnology can formulate curcumin effectively. Curcumin is effective against various inflammatory cells. It was found that curcumin have better efficacy and bioavailability under in vivo conditions37.

 

Liposomes:

Many Investigators prepared Liposomal particles have concentric bilayer structure with excellent entrapment efficacy and effectively delivered both hydrophilic and hydrophobic drugs. It falls under the category of novel drug delivery system. Capsaicin (CAP)-containing Liposomes. Liposomes can vary in size, from 15 nm up to several µm and can have either a single layer (unilamellar) or multilayer (multilamellar) structure. Niosome and Emulsomes provide localized and controlled delivery and bypass the horny layer efficiently. CAP liposomes were prepared by the film hydration method. Skin retention studies of CAP from in vitro and in vivo experiments showed significantly higher accumulation of drug in the case of the Emul-gel formulation. Emul-gel dosage form had a potential approach and an effective therapy for Psoriasis in future38.

 

Niosomes:

Many scientists researched on Niosomes and found that spherical Niosomes exhibited the highest entrapment efficiency with appropriate nano-size and zeta potential improve its characteristics. Encapsulation of the drug inside the Niosomes make efficient and delivery is control over the period of time. Anti-psoriatic activity of the medicated nano Niosomes was proved ex vivo in HaCaT cells (a keratinocyte cell line)39.

 

Dendrimers:

These are organic chemical entities with a structure similar to a tree. The branch terminals provide a rich source of surface functionalities for nanoparticles. Their measurements are exceedingly small and have diameters of between 2 and 10nm. These are prepared by divergent and convergent method. Dendrimers are an exciting new form of macromolecular architecture and an important component for treating varieties of skin conditions in the nanotechnology-based cosmeceuticals market. L'Oreal, Unilever, and the Dow Chemical Company hold multiple patents for skin care, products for the application in psoriasis40.

 

 

Low-level light/LASER therapy (LLLT):

Researchers found that the near infrared (NIR) and visible red light with low energy showed promise for treating psoriasis. Low light intensity causes less side effects and high energy radiations. Various studies found that PDT-IPL had moderate effect on nail psoriasis41.

 

CONCLUSION:

The research work will explore new horizons for the development of clinically proven path for the Plaque Psoriasis and reduce the rate and extent of severity of disease using combination and multiple therapies. Many of the drugs showed synergistic effects in presence of light. Vitamin D3 and vitamin A analogues showed excellent safety, tolerability, use in combination therapy and effective treatment of Plaque Psoriasis compare other coal tar and other derivatives topically. Also, it will reduce of risk of carcinogenicity when used in combination with phototherapy (UVB) Plasma technology will add value to improve health and normalize healthy condition.  Combination Therapy will be efficient, non-irritating, non- immunogenic and improve patient health and cope up with psychological condition. Plasma therapy is one of the recent and newer approach to treat Psoriasis and under clinical trial phase. Phototherapy is an effective, safe, and accessible treatment without incurring any systemic side effects. In contrast to biological agents or other drugs are highly stable of Plaque psoriasis. The Psoriasis patient can experience discomfort with inflammation, infection, soreness and burning like symptoms.  Care for patients with Psoriasis requires not only treating skin lesions and joint involvement, but it is also very important to identify and manage common morbidity needs to develop novel drugs which are safe, effective, non-irritating and provide patient compliance and cure in future treatment. Many of the clinical studies proved that Plasma therapy may reduce all kinds of disorders caused by Psoriasis and this is the novel approach will be helpful to improve patient psychological conditions in stipulated time as compared to long term therapy and reduce extra side effects caused by use of topical corticosteroids.

 

ACKNOWLEDGEMENTS:

Authors would like to thank Dr. Rajesh Sharma Professor and Head, School of Pharmacy, Devi Ahilaya Vishwavidyalaya and Dr. Sanjay Jain, Dean, Faculty of Pharmacy, Medi-Caps University, Indore, Madhya Pradesh, India for providing support during the work.

 

CONFLICTS OF INTEREST:

The authors declare that there is no conflict of interest of any kind.

 

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Received on 01.02.2022            Modified on 03.05.2022

Accepted on 13.07.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(5):2543-2548.

DOI: 10.52711/0974-360X.2023.00418