Reviewable on-line scientific magazine “Caucasus Medical Herald” ISSN E1987-80, N21, January 2010

Shalva Mardi, Med. Dr., Prof. et al.

MAGIC – MARDIL MEDICINE FOR THE TREATMENT OF BENIGN, VIRAL, PREMALIGNANT AND NONMETASTASIZING MALIGNANT SKIN and VISIBLE MUCOUS MEMBRANE TUMOR LESIONS

(THE GLOBAL SOLUTION OF THE SKIN CANCER EPIDEMICS)

Mardil medicine is novel topical intravital fixatory, immunomodulatory and antiangiogenic agent, the inhibitor of growth of hyperplastic, metaplastic and malignant neoplastic cells due to its:
a. angiocoagulation, dehydratation – intravitalfixation and selective devitalisation of neoplastic cells,
b. induction of cytokines (interferons, IL – 10, IL – 12),
c. promotion of endothelial cell apoptosis,
d. anti-proliferative, anti-infective and anti-virale actions.

Mardil medicine promote the activation of toll-like receptor – 7 ( TLR-7) associated signal transduction in dendratic cells and blood mononuclear cells.
Mardil is a new strategy for elimination of neoplastic disease associated with intensive pathologycal proliferation and neovascularization without any kind of toxcity and side effects, with excellent tolerability and curability.

Mardil chemically is SELENIUM COMPOUND
of ALIPHATIC HALOCARBOXYLIC ACID COMPLEX of HYDRATE.

GENERAL CHEMICAL FORMULA:

{SeZ (CH(3-n)XnCH(2-m) – xm COOH)y}.

Where: n = 0 – 5
m = 0 – 2
X = F, Cl, Br, J, or a combinatiom thereof
y = 1 – 4
k = 1 – 4
z = 1 – 3
and the carboxylic group can exist either in the free ( COOH), or in the ionized
( COO- ) forms.

The final pharmaceutical product is lipophilic molecules, such as halocarboxylic acid comlex, with a highly polar group that have a tendency to form liposomes or vesicles, in aqueous solutions. Therefore, they can stabilize the complexes with transition metals against hydrolysis, by hiding the metal ions inside the liposomic structures.
The final product of selenium complexes… (MARDIL) is brown colored, transparent, slightly viscous, liquid substances. The product has acidity approx. pH = 2,1-2,5, LD50 – approx. 2024 – 2343 mg/kg ( rat ). The concentration of selenium in the product depends on the type of starting chemical ingredients and can be about 500 – 1000 mg / liter ( the daily dose for human is between 100 – 150 micrograms ). Chemically and biologically the product is very stable for many years when stored between 1 and 1500 C in closed brown glass containers. The medication is practically non-toxic, its action is strongly localized, not absorbed into the organism and has no systemic, teratogenic, embryotoxic or carcinogenic properties. Mardil has neither significant side effects nor contraindication for use.

The clinical Investigations

The 6938 patients were recruited prospectively from different clinics, hospitals and private practices under common approved protocol – case records treated with <<Mardil>> from December 1994 to April 2005 with short and long term follow-up. Clinical results of
treatment are presented in Tables 1-11. It must be underlined that all the necessary pretreatment physicals, X-ray, biopsy and other laboratory analysis of the patients with suspected malignancies were previously carried out in different medical institutions, where they have ben insured, to detect and fix any regional or distant metastatic process, to avoid any additional private expenses. In 2001-2004, we undertook tracing and reexamination of all patients treated or retreated with <<Mardil>> medicine during 4-8 years prior to this review. For follow-up evaluation, only 4778 (68.8%) from 6938 treated patients were selected. Short term clinical results for all treated patients were equal.
The 4778 patients with long-term follow-up suffered from 45,474 tumor lesions. From these, 6,524 were local post-treatment recurrences (after surgery, X-ray, laser,
photo-, chemo-, immuno-manipulations, etc.). The 4,021 patients had more than one tumor lesion. In 894 cases (benign and malignant), lesions were proved microscopically. 411 patients suffered with more than 100 nonmalignant and malignant skin lesions. In many cases, all tumor lesions were treated in one session without any anesthesia or special conditions. Only in cases of Recklinghausen Disease – Miltiple form of peripheral Neurofibromatosis the Patients were treated in 2 and more session, when Number of skin tumor lesions were more than 100.
The goal of follow-up of treated patients with skin tumors was the detection of local recurrences or asymptomatic regional and distant metastases, as well as the development of new primary lesions. There is no support of a specific follow-up interval, but it was made at least 3 times per year, depending on the type of treated tumors and other risk factors: family history of melanoma, patient anxiety or ability to recognize signs and symptoms of disease.
Most of the patients treated for pigmented tumors are under the supervision of their regional physicians, responsible for routine physical and labor examinations. All the cases of histologically proved malignant melanomas may lack several of the known differentiation markers of melanocytes, including Protein–1 (TRP-1), S-100 and HMB-45. It must be underlined that all biopsy specimens were taken immediately only after topical application of a <<Mardil>> medicine on the pathological tissue, i.e., after fool devitalization and intravital fixation, with special radio-electrocauterization, to avoid any risk for lymphohematogenic dissemination of malignant cells.

THE RECOMENDED DOSE OF MARDIL – MEDICINE

The selenium compounds… of this invention are serve as a pharmaceutical product indicated only for topical use.
The recommended dose per lesion with a diameter 0.1 to 2.0 cm of the liquid form of this medicine is 0.01 to 0.2 ml . For multilesions the recommended dosage per one treatment session can be 0.2 to 2.00 cc.
SAFETY EVALUATIONS.
To assess safety patients returned to the clinic for designated visits for evaluation, photographs and documentation of treated lesion appearence, local skin reactions, vital sign measurements, adverse events, and concomitant medications.
All patients, after clinical examination and explanations signed an institutional board approved, written, informed conset document.
LOCAL SKIN REACTIONS.
A visual assessement and video-photo of the target tumor area was performed by the investigator at each clinic visit.
EFFICACY EVALUATIONS.
At the 3 – 6 – 12 weeks postreatment visit, the investigator made a clinical assessment to determine whether treated lesions was visible at the target site. Only in cases of suspected for malignancy of pigmented lesions was made a 3 – mm margin radioelectro excision and histopathologically examined for evidence of residual or recurrence tumor.
STATISTICAL EVALUTIONS.
After long-term follow-up investigations the statistical analisys was based on the intent – to – treat date set, which included all treated patients.
RESULTS
The analytical and statistical evaluation of treated patients are presented in Tables 1-11. The dates proved that the cure rate of treatment is about 98% during a 2-8 year follow-up period, local recurrence rate is approximately 2.8%. Any detection of regional and distant metastases or lethality depending on tumor lesions treated with <<Mardil>> medicine was not recorded. The treatment effect is not dependent on type of tumor (only in cases of <<Mozaik>> form of plantar and Palmar viral warts the clinical results in approximately 10% were not good), from range of age, skin color and sex. During the treatment period, a very short time of local allergic reaction, pain, itching and post-treatment period is possible in 5.8% of the cases, with the possible development of visible skin hypo-or hyperpigmentation, as well as scar and kelloid formation. Any systemic toxic effect needing additional medical care, was not recorded.
The <<Mardil>> medicine chemically and biologically is stable and has a very high curative action for the treatment of all kinds of viral, benign, premalignant and nonmetastasizing malignant skin and mucosa tumors and lesions.
The composition leads by local application to an immediate intravital fixation of the tissue with which it comes into contact. The extent of its effect is strictly limited to the treated area. The immediate effect is displayed in a white-yellowish to gray coloration of the treated area (downregulates the expression of proangiogenic factors, upregulatrs the expression of endogenius inhibitors, include endostanin, tumstanin, interferons, interleikins and thrombospondins, among other factors. The tissue devitalized in this way dries up and changes color to dark brown upon increasing mummification. The mummified scab detaches itself spontaneously after 2 to 3 weeks. The healing generally takes place without complications, especially without secondary infection, quickly and without leaving ugly scars or distortion of the surrounding tissue and the function of the treated organs (Fig. 1).
The dehidrated or mummified pathological tissue is useful for pathological or electron microscopical examination. The microscopic characteristics and structure of the devitalizated lesions are almost fully preserved and generally adequate for histological diagnosis. The reparative ability of the surrounding, healthy cells does not only remain preserved but leads to stimulation of immune response of granulocytes, lympho-cells and Langerhans cells, their activisation carry the antigen to the regional Lymph node. Thay are in connection with a proliferation of mesenchymal cells to fast regeneration and replacement of the tissue loss which occurs.
The MARDIL medicine in such situation works as an adjivant, supports the reaction induction of adaptive immune responds, similar as vaccination, protecting from the neoplastic prolapsus – recurrences. The normal vasculatore of surroding of notmal tissue remains unaffected because their endothelia are not proliferating.
After many years of clinical and pathomorphological investigations of novel pharmaceutical products – MARDIL medicine – it was established that its selective penetration and devitalizing action is limited only by affected anaplastic tissue with softer intercellular bridging and consequently firmly less compacted tissue structures than any surrounding normal tissue. Therefore, the devitalization effect of the MARDIL medicine is relatively more localized, selective, complete and the damage of surrounding normal tissue is almost absent or significantly less than with other methods of treatment.
It is our opinion that the MARDIL medicine is an effective stimulator for already depressed immunity, to decrease the influence of tumor-associated immunosuppression in the pathologically affected areas. Mardil can be used to suppres the progression of subclinical as well as clinically visible malignancy in the sun affected and damaged large regions of skin inducing DNA damage and a significant local reduction in endogenius inhibitors. So colled «precoursor lesions“, such as Aktinic keratosis, all type of atipical melanotic Nevi….. are already immunodepressed, their angiogenic and exhibit capillary densities greater than in surronding normal tissiu. The goal to cure entire region of at „risk lesions and tissue“ in order to prevent their progression to malignancy.
According our histo-citologycal-chemo-immuno- and electromicroscopical investigations it is possible, that MARDIL – medicine after topical application induces two broud response categories:
1. the Innate ( nonspecific ) immune response and
2. 2. the Adaptive ( specific, acquired ) immune response. During thies process forms selective tumor cells dehydration, devitalisation, intravital fixation – dry necrosis with producing of factor of TNF-a in mRNA, suggesting activation of a helper T – cell tipe –1, mediated response. Produced Interferon-a (IFN-a ), Interleukins ( EG, 1, 5, 6 and 8 ), as well as inflammatory chemoattractant proteins has significant activity against hyperplastic, metaplastic and anaplastic cells, what is possible to detect in all cases of treatment. The clinical apparenses of transitory form of intensive topical immunoreaction with hyperemie, hypertermie, edema, induration, but without of necrose, secondary infection, ulceration, needed additional medical manipulations, are desired and necessery defense response.
An innate immune response, according hundreds of scientific publications, is primarily a defense response, rapid, highly effective, activates the granulocytes, natural killer cells, micro- and macrophags, thier phagocytosis, producing cytokines, antineoplastic and antimicrobial peptids. The adaptive immune response, in contrast, is slower to activate, but is extremely specific, involving antigen – presenting devitalized tumor and memory cells: T- Lymphocytes and B – Lymphocytes.

Our Original Mothod of treatment, using MARDIL – already patented medicine, gives the possibility to avoid the dissemination of cancer cells in blood or lymph vessels and consequently, the very poor prognosis (66).
The advantages of the new preparation – MMMM – can be summarized as follows:
The treatment is limited to pathologically altered parts of tissue which should be removed.
The loss of tissue resulting from topical application can be restricted to a minimum.
The scar remaining in most cases is less visible than after any other kind of treatment.
The surrounding tissue is not damaged.
The treatment is generally painless.
The treatment can be carried out ambulatorily: the patient is subsequently not limited in his/her activities.
The treatment is of particular advantage if multiple lesions (for instance, in patients with multiple skin form of peripheral Neurofibromatosis- Recklinghausen disease) are present, or if prior operations or radiotherapy exclude renewed surgery or radiotherapy.
No one of type skin tumor or lesions are not resistent to the Mardil Medicine.
The treatment is MONOTHERAPY, not require multilpe visits to Medical Doctors, long time consuming and is not expensive.
The MARDIL medicine has the potential:
TO STOP, PREVENT, CURE AND SOLVE GLOBAL SKIN CANCER EPIDEMICS !!
to cure all of types of viral, benigne, premalignant and nonmetastasizing malignant tumors of the skin and visible mucosa membraneous tumors or lesions.
The pharmaceutical product of selenium compound halogenocarboxylacid complex hydrate has SIGNIFICALLY AND DEMONSTRATED SUPERIORITY in its antitumor activities compared with other existing significantly less effective methods: plastic surgery, Carbox dioxide, neodymium: yttrium-aluminium-garnet and other laser surgery, X-ray therapy, cryosurgery, longterm fotodinamyk therapy, thermoradiosurgery, chemosurgery, including Mohs’ methods (zinc chloride in combination of trichloroacetic acid), immunological (vaccine, interferons, Imiquomid – Aldora, Tazarotene, etc.), pharmaceutical preparations, including any cytostatics, antioxydants, metabolites ( Efudixe ), cyclooxygenase –2, retinoids as well as very popular Solcoderm, Solcogyn ( ISN Ltd, USA – Switzerland, Solcoderman – Basotherm AG, Germany, invented 30 years ago by S. Mardi, MD, prof. acad.
The common methods for the treatment of various skin tumors, namely electrocauterization, cryosurgery, radiotherapy, chemotherapy or plastic surgery, are not always necessary and fully satisfying. A procedure and sometimes necessary plastic surgical measures are particularly difficult near the eyes or in the nose region or not possible at all, especially in the case of multiple lesions and recurrences. In such cases, the MARDIL medicine can be employed when other treatment possibilities can no longer be applied (64).
After Mohs’ surgery, the following complications appear very often: bleaching, infection, ulceration, pain, allergical and exematic reactions, healing problems, hypertrophic and kelloidal painful scars, acquired use of topical or systemic steroids, antibiotics, antiseptics, anticoagulants and different kinds of tissue-stimulated creams, drugs, etc., with occlusive hydrophilic dressings and laminates (silicon/nylon mesh, collagen, fibrin, etc.).
Accordong the «Journal of the American Academy of Dermatology”, June 2005, volume 52, Number 6, Index ISSU 0190 – 9622, p.997 – 1002 after standarted exision of Cutaneous Sqw. cell carcinoma IN SITU !!! is reported to have a 5 –year r e c u r r e n c e rate 19%.
Between 270 patients with 270 skin tumors (Sqw. cell Carcinima IN SITU ), treated with Mohs micrigrafic surgery the overall 5 – year follow-up recurrence was 6,3%
( 2,5% for primary tomors and 9,1% for recorrent tomors).
For Mohs’ longterm, very expensive, strongly aggresive and destructive method, a lot of location of skin tumors are contraindicated due to the high risk of severe disfigurement, bony involvement, loss of vision (for example: area of orbit, nose, face) and even death may occurf
The Mardil is useful for the treatment-pilling of sun affected and photodamaged skin tissue, the Field of future „Cancerization“ subclinical Actinic keratosis) and transform in the normal skin tissue.
The main fields of use in medicine are suitable indications in dermatology, oncology, urology, cosmetic medicine, ophthalmology and gynecology.
The composition should only be applied superficially by the doctor or on his instructions and under his control by experienced medical staff, but on no account by the patients themselves.
If we take into account that our pharmaceutical product – the MARDIL medicine – is able to prevent and cure not only all types of skin tumors, but also visible mucosa membraneous lesions (66 clinical indications, Table 1) with a 98-99% cure rate, it can significantly reduce the letality the millions of people and safe the billions of US$. It means that if our invention is a reality, we should go back to cheapest and simple, but significantly more curative method of treatment from sophisticated technology, electronic and digital spheres, from concepts of multidisciplinary cares and very expensive and traumatic medical “service”.

Table. 1 SUMMARY OF PATIENTS WITH DIFFERENT TYPES OF BENIGN SKIN TUMORS.

Skin benign tumors	№ of patients	№ of lesions	Sex		Skin		Follow-up in months		posttr. Scars in %
1. Seborrheic keratosis	452	3.824	302	150	184	268	6-51	34	3,4
2. Epidermal Nevus	196	528	112	84	134	62	13-74	52	12,1
3. Linear epidermal nevus (unius lateralis)	32	53	19	13	17	15	24-78	56	5,2
4. Nevus sebaceus of    Jadassohn	58	84	33	25	40	18	15-62	41	4,9
5. Intradermal Nevus	294	1053	157	137	188	106	3-86	59	6,7
6. Nevus pilosus	36	78	22	14	21	15	5-74	44	1,5
7. Skin tags and acrochordons	114	2188	76	38	70	44	5-96	71	1,8
8. Epidermal inclusion cysts	47	158	15	92	18	29	16-72	52	0,0
9. Sebaceous hyperplasia	95	884	30	65	55	40	8-64	47	0,1
10. Multiple syringomas	44	615	7	37	12	32	11-73	42	1,2
11. Clear cell acanthoma	110	214	73	37	71	39	14-62	38	13,1
12. Compound nevus	97	436	61	36	50	47	10-85	54	4,7
13. Halo Nevi	27	31	18	9	8	19	11-64	47	14,2
14. Spindle cell (Spitz) nevus        (epitheloid)	104	380	56	48	38	66	14-92	70	6,4
15. Giant Hairy Nevus	18	34	5	13	7	11	6-87	61	12,3
16. Blue Nevus	116	429	29	87	34	82	15-74	52	8,8
17. Nevus of    Ota	5	5	2	3	1	4	7-52	34	7,1
18. Dermatofibroma	88	202	34	54	38	50	12-76	48	3,6
19. Angiofibroma	129	156	81	48	49	80	8-72	44	1,0
20. Multiple cherry hemangioma	24	412	8	16	17	7	13-92	63	1,3
21. Pyogenic granuloma	44	67	31	13	19	25	8-84	51	0,9
22. Angiokeratoma	184	498	80	104	97	87	6-79	52	0,1
23. Lymphangioma	12	36	5	7	7	5	11-68	48	0,4
24. Junctional Nevus	106	112	61	45	40	66	13-88	51	12,2
25. Nevus Araneus (Spider telangiectasia)	23	106	13	10	16	7	6-75	46	0,1
26. Reclingausen   deases – Neurofibromatisis	28	1236	20	8	15	13	18-64	50	1,2
27.  Steroide  form   Hyperkeratosis  and   Papillomatosis	30	1158	12	18	21	9	9-76	53	2,4
28. Nevus flammeus (Port-wine stain)	8	8	6	2	3	5	13-82	42	0,2
29. Xanthelasma	103	397	30	73	66	37	5-90	61	1,9
Total	4624	15282

Table.  2.    SUMMARY  OF  PATIENTS  WITH  VIRAL  WARTS.

Viral warts	№ of patients	№ of Tumors	Sex		Skin		Follow-up in months
			Male	Female	Fair	Dark	Range	Mean
30. Verruca vulgaris	104	957	60	44	74	30	6-84	60
31. Verruca plana	52	1017	31	21	24	28	6-71	52
32. Verruca palmaris and plantaris	98	438	54	44	59	39	11-68	42
33. Condiloma acuminatum	78	241	60	18	54	24	6-91	59
34. Molluscum contagiosum	41	827	28	13	27	14	9-84	47
Total	373 (7,8%)	3480	233	140	238	135

Table 3.   SUMMARY OF PATIENTS WITH DIFFERENT TYPES OF PREMALIGNANT SKIN LESIONS.

Premalignant Lesions	№ of patients	№ of tumors	Sex		Skin		Follow-up in months
			Male	Female	Fair	Dark	Range	Mean
35. Actinic keratosis	233	2612	181	52	199	34	5-78	52
36. Cutaneus horn	84	216	56	28	58	26	9-81	54
37. Bowens disease	51	327	32	19	37	14	6-94	42
38. Lentigo simplex and senilis	102	498	68	34	71	31	3-87	50
39. Lentigo maligna	102	232	66	36	71	31	14-92	68
40. Keratoacanthoma	84	114	62	22	59	25	7-83	51
41. Trychoepitheliomas	32	217	21	11	19	13	6-74	44
42. Multiple displastic Nevi	52	288	28	24	31	21	6-98	60
43. Arsenal keratosis	2	32	–	2	2	–	11-68	41
44. Juvinel pseudomelanoma	4	16	3	1	2	3	14-77	47
Total	746  (15,6 %)	455 (18 %)	180	96	184	281

Table 4.   SUMMARY OF  PATIENTS  WITH  NON-METASTASIZING  MALIGNANT SKIN  TUMORS

Malignant skin tumors	№ of patients	№ of tumors	Sex		Skin		Follow-up in months		Posttr.  Scars in %
			Male	Female	Fair	Dark	Range	Mean
45. Superficial basal cell carcinoma	148	315	88	60	111	37	3-98	67	3,7
46. Basal cell carcinoma	498	2024	301	197	318	180	3-81	53	8,1
47. Nodular basal cell carcinoma	102	381	73	29	60	480	6-78	47	11,2
48. Basal cell pigmented nevus syndrome-Basaliomas	18	190	11	7	13	5	8-92	43	6,2
49. Squamous cell carcinoma	98	422	68	30	59	1	33-90	44	14,3
50. Merkel-trabecular cell carcinoma	4	27	1	3	3	1	14-74	53	6,6
51. Nevus sebaceus of Jadassohn with basal cell carcinoma	47	144	29	18	33	14	6-80	48	1,4
52. Superficial spreading melanoma in situ and stage 1a	5	11	3	2	4	1	18-75	41	2,8
53. Nodullar malignant melanoma in situ and stage 1a	3	3	2	1	3	–	11-83	48	6,8
54. Kaposis hemorrhagic sarcoma (Early macular lesion, non-AIDS related)	15	157	8	7	11	4	13-67	35	1,4
55. Lentigo malignant melanoma	57	85	33	24	41	16	3-92	62	8,2
Total	1.052 (20,8%)	3759 (14,8%)

Table 5.    THE  VISIBLE   MUCOSA  LESIONS

Mucus membrane lesions (oral)	№ of patients	№ of tumors	Sex		Skin		Follow-up		Scars
			Male	Female	Fair	Dark	Range	Mean
56. Papillomas	98	306	44	54	35	63	8-84	56	0,1
57. Fibroepitheliomas	16	44	12	4	8	8	6-77	49	2,3
58. Hemangiomas	4	13	3	1	2	2	14-82	51	1,9
59. Hyperplastic or Hypertrophic Lesions	22	38	16	6	7/52	19/88	10-78	42	0,9
Total	140 (2,9%)	401 (1,6%)	75	65	52	88

Table 6.  AGE DISTRIBUTION OF PATIENTS. 

Range of Age	Number of patients
1-10	121
11-20	384
21-30	401`
31-40	1553
41-50	528
51-60	1101
61-70	1180
71-80	342
81-90	198
Total	4778

 Table 7.  LENGTH OF FOLLOW-UP.

Months	Patients
5
5-10	41
11-15	124
16-20	104
21-25	255
26-30	381
31-35	227
36-40	315
41-45	891
46-50	688
51-55	711
56-60	467
60	574
Total	4778

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