მკურნალობა უცხოეთში


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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