Composition for the treatment of this form may be accompanied shape rubromycosis feet and hands

 

(57) Abstract:

The composition contains the following components, wt.%: a mixture of 4-nitro - and 6-nitro-5,7-dichlorobenzophenone when the ratio of these components 30 : 70 0,30-0,60; polyethylene glycol 400 of 79.65-79,80; polyethylene glycol 1500 16,95-17,10; dimethylsulfoxide 2,80. The composition for external treatment of this form may be accompanied shape rubromycosis feet and hands, caused by the fungus Trichophyton rubrum, at the same time has a fungicidal effect and the effect of normalizing the process of keratinization. 2 Il., 9 table.

The invention relates to medicine and can be used in the treatment of this form may be accompanied shape rubromycosis feet and hands, caused by the pathogenic fungus Trichophyton rubrum.

The treatment of fungal infections of the feet smooth skin presents great difficulties in individuals with impaired process of keratinization, endocrine disorders (hypercortisolism, diabetes mellitus, hypothyroidism, an imbalance of sex hormones), in such chronic diseases as tuberculosis, blood diseases, cancer. Thus, in patients with ichthyosis, keratoderma mycosis of the feet are logged in almost half of cases (C. M. Rukavishnikova, And. Sokolin, C. I. Kuklin. Treatment and prevention Mick is cherished the presence of background peeling hyperkeratosis of varying severity.

Known widely used for local treatment of rubromycosis feet and hands 1). Sulfur-salicylic ointment (precipitated sulfur -1,5 g; salicylic acid 0.9 g; vaseline to 30.0 g) and 2-5% tincture of iodine (b.p. Kashkin, N. D. Cheglakov. Guide to medical Mycology. M.: Medicine, 1978. -324 S.; kN.: Drug therapy in dermatology. Ed. by C. N. Mordovtsev's, H. B. Caselevel. Alma-ATA, 1994.- 89 C.). 2). The nitrofungin-solution containing 2-chloro-4-NITROPHENOL-1.0 g, triethylene glycol - 10,0 g, alcohol 50% to 100.0 g (M. D. Mashkovsky. Medicines, 1993, M.: Medicine. -S. 435; Reference Vidal, 1997. Drugs in Russia). The active ingredient of the nitrofungin is 2-chloro-4-NITROPHENOL. Used with the defeat of athlete interdigital folds stop 2-3 times a day. The duration of treatment is 4-6 weeks. Nitrofungin in structure and purpose is the prototype of the proposed structure, however, is quite frequent complication after external application is skin irritation. Therefore, the drug is currently in clinical practice. 3). Econazole - nitrate 1% or Peveril in a 1% cream and gel (C. M. Leshchenko. Peveril in the treatment of fungal infections. Journal of dermatology and venereology. 1995.-N 4.-S. 28-29). Drug used hyperbola layer of the epidermis.

Usually external treatment of rubromycosis feet and hands consists of 2 stages: the preparatory and main. The preparatory phase aims at the removal of scales and hyperkeratosis in this form may be accompanied shape with the help of the sulfur-salicylic ointment, detachment by A. milk-salicylic ointment, salicylic collodion. The main stage of treatment includes external use of antimycotic imported drugs (mikoseptin, nitrofungin, clotrimazole, terbinafine, and others). All of these drugs require long-term and repeated use and do not always provide a high therapeutic effect.

Drugs for external treatment of this form may be accompanied shape rubromycosis hands and feet at the same time have a fungicidal effect and the effect of normalizing the process of keratinization, in clinical medical practice.

It is known that 4-nitro-5,7-dichlorobenzofuroxane (1) and 6-nitro-5,7-dichlorobenzofuroxane (II)

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it has fungicidal activity (L. M. Yusupov, G. C. Young, B. I. Buzykin, I. F. Pashov, N. N. Anisimov, P. Chernin, Century Century Polidoro, S. I. Sviridov, F. C. Levinson. "4-nitro and 6-nitro - 5,7-dichlorobenzophenone having fungicidal action. Pathé is-5,7-dichlorobenzophenone (II) (I. F. Pashov, L. M. Yusupov, B. I. Buzykin, So Century. Gareyev, J. C. Young, V. I. Kuklin, O. C. Turbine, R. W. Shaymardanov, B. C. Ugryumov, A. H. Ravil. "Fungicidal composition". RF patent N 94018860/15 from 25.05.1994. Publ. Bull. 1996. N 11), used to treat ringworm animal. Fungicidal composition contains a mixture of 4-nitro and 6-nitro-5,7 - dichlorobenzophenone (Doctor), emulsifier (surfactant) and the diluent (B) in the following ratios, wt.%: D. C. 0,25-1,00; SAS 0,50-2,00; P - the rest. As emulsifiers used nonionic surface-active substances (surfactants): OP 7, OP-10, monoalkylphenols esters of glycol-based polymetacrylate; neonol sodium alkylpolyoxyethylene, stearic-6-polyethylene-glycol monostearate. The treatment of animals suffering from trichophytosis and microsporia, compositions in concentrations of nutrient content in them 0,50-1,00% resulted in complete recovery of the animals.

A method of obtaining a mixture of 4-nitro and 6-nitro-5,7 - dichlorobenzophenone by mechanical mixing (J. C. Young, B. I. Buzykin, L. M. Yusupov, I. F. fashow. "Fungicidal composition". RF patent N 2076803 from 22.04.1992. Bull. Fig. 1997. -N 10. -S. 126) and chemical method (a method of obtaining a mixture of 4-nitro and 6-nitro-5,7-dichlorobenzophenone having fungicidal, bactericidal, with the X. Khisamutdinov, P., Belyaev, B. C. Ugryumov, A. 3. Ravil, N. N. Anisimov, R. Yusupov. RF patent N 2051913 from 22.04.1992. publ. Bull. 1996, N 1).

Data on the treatment of parasitic diseases of human skin, namely when this form may be accompanied form of rubromycosis feet and hands means based on the 4-nitro and 6-nitro-5,7-dichlorobenzophenone (I and II) in the literature are missing.

The objective of the invention is to develop a fungicidal composition for topical treatment of this form may be accompanied by a form of rubromycosis of the hands and feet caused by pathogenic fungus Trichophyton rubrum.

The problem is solved in that the fungicidal composition for topical treatment of this form may be accompanied by a form of rubromycosis of the hands and feet contain a mixture of 4-nitro and 6-nitro-5,7-dichlorobenzophenone (D. C. III), polyethylene glycol (PEG) 400 and 1500, dimethylsulphoxide (DMSO) in the following ratios, wt.%, are given in table. 1.

For a better understanding of the invention examples are shown below:

EXAMPLE 1. Preparation of a mixture of 4-nitro and 6-nitro-5,7 - dichlorobenzophenone (D,Century III) III prepared by mechanical mixing of the components of the 4-nitro and 6-nitro-5,7-dichlorobenzophenone (I) and 6-nitro-5,7-dichlorobenzoate is,5%.

Dissolve 0.5 g III 2.8 ml of dimethylsulfoxide. Then portions with thorough stirring, pre-molten core - the mixture of PEG-400 - 79,7, and PEG-1500 - 17,0,

Similarly prepared ointments with other composition components.

EXAMPLE 3. The study of antifungal activity of 0.5% microcannulas ointment.

Cup method to study the antifungal activity ointment microcannulas based on the ability of ointment to exert fungicidal action on a culture of the fungus Trichophyton rubrum, planted on a solid nutrient medium.

Used bacteriological method for evaluating the ability of III to release from ointments (A. I. Andreev. Obtaining and study of new veterinary medicinal forms furagin, furazolidone and furatsilina. Abstract. dis. Kida. M. , 1973. -26 C.). In the molten and cooled down to 40-42oC on Wednesday Saburo pour in 1 ml thick suspension cultures of the fungus Trichophyton rubrum in physiological solution, the mixture is mixed well and poured on 30 ml in Petri dishes. Solidification of agar on its surface is placed a glass cylinder with 0.5 g of the test ointment. The size of zones of inhibition of growth of the fungus is judged on the ability of the ointment to the release of the drug.

EXAMPLE 4. Treatment of this form may be accompanied shape rubromycosis feet and hands of 0.5% microcannulas ointment.

The treatment is carried out on 2 groups of patients with be accompanied by the form of rubromycosis feet and hands for 20 people each.

Treatment of patients of group I spend 0.5% of microcannulas ointment. For a comparative study of the effectiveness of external treatment this form may be accompanied shape rubromycosis skin of the hands and feet treatment patients of the control group II of the sulfur-salicylic ointment, which is used in clinical practice and in this case is the prototype for the purpose.

All the patients before the treatment a full mycological examination, including direct microsporia pathological material in a 20% solution of KOH and planting on Wednesday, Saburo, etiological confirmation fungal nature of the disease. All patients observed the typical clinical picture of the disease, characterized by mellotronen peeling, especially pronounced in the folds of the skin, hyperkeratosis varying degrees vyrazhennoy times a day with subsequent fixation under the bandage. Clinical and laboratory monitoring of the results of treatment on the 3rd, 7th and 14th days of treatment. Then see patients within 6 months.

Dynamic observation showed that in the process of external treatment was observed following the dynamics of clinical manifestations: mellotronen peeling in the folds of the skin of the palms and soles was not observed for 3 days; thinning be accompanied layer in the lesions to 7 days from the start external treatment; lamellar peeling on the plantar and Palmar surfaces of the hands and feet disappeared for 7 days from the start of therapy. To 7 days observed a reduction of hyperkeratosis and 10 days clinical symptoms of hyperkeratosis disappear. After 14 days of topical treatment is not carried out. On the 21st day from start of treatment to control inspection: any of the observed to the treatment of clinical signs of disease (reddish-Senusret coloring, scaling and hyperkeratosis) were observed. Direct microsporia pathological material in a 20% solution of KOH and planting on Wednesday Saburo gave a negative result (Fig. 2).

In General blood and urine tests before and after treatment was statistically significant changes were observed (table. 2).

When studying level choicesi significant difference was not detected (table. 3).

Treatment of patients of group II conduct of the sulfur-salicylic ointment. Methods of treatment of patients with a similar group I: sulfur, salicylic ointment put on the affected areas of the hands and feet under the bandage once a day. Treatment is the same 2 weeks.

Dynamic observation showed that the scaling and hyperkeratosis decrease by the end of the 14-day course of topical treatment while maintaining the lesions of erythema. Microscopic examination of pathological material in 20% KOH were negative, but with repeated clinical and laboratory studies on the 21st day after the start of treatment, i.e. one week after the end of treatment, 6 patients (30%) were microscopically detected elements mushrooms. In General blood and urine tests and similar biochemical analyses serum significant differences before and after treatment were not identified. Thus, in the comparative study of the effectiveness of external therapy of this form may be accompanied shape rubromycosis of the hands and feet of 0.5% microcannulas and sulfur-salicylic ointment revealed that the positive dynamics of clinical manifestations (desquamation, hyperkeratosis and erythema) is significantly expressed in the treatment of patients 0,5% microcannulas ointment. At the 21 day 100%, in the treatment of sulfur-salicylic ointment - 70%.

According to the results of our data 0,5% microcinema ointment has a distinct advantage over used to treat this form may be accompanied shape rubromycosis of the hands and feet of the sulfur-salicylic ointment effect more pronounced fungicidal action and simultaneous normalization of keratinization.

EXAMPLE 5. Toxicological studies of a mixture of 4-nitro and 6-nitro-5,7-dichlorobenzophenone (D. C., III).

I. Studies of toxicity when injected into the stomach.

Single administration III in the stomach determine the toxicity parameters and study the symptoms of acute poisoning. Acute toxicity study on white rats weighing 170-200 g Mixture III is introduced into the stomach in the form of an aqueous suspension. As emulsifiers used OP-7 or OP-10. Animals of the control group is injected in the appropriate quantities of the emulsion containing only the emulsifier. Take into account the following indicators: appearance and behavior of animals, condition of coat and visible mucous membranes, towards the stern, mobility, rhythm and breathing frequency, time of occurrence and the nature of intoxication, its severity, reversibility, time of death of the animals or their withdrawest maximum tolerated dose - WDC; the dose which causes the death of 50% of the animals-LD50and absolutely lethal dose LD100, LD50and its confidence limits calculated by the method of Litchfield and Wilcoxon signed (M. L. Belenky. Elements of quantitative evaluation of the pharmacological effect. L., 1963.-153 C.). The research results are summarized in table. 4.

II. Toxicity studies when applied to the skin.

With a single application of mixture III on the skin determine the parameters of toxicity and symptoms of acute poisoning. On pre-clipped area of the skin of rats (on the back) 2x2 cm apply the mixture III in doses of 500 to 5000 mg/kg observation of the clinical status of animals should be performed within 14 days. The results are shown in table. 4.

Local action III is examined for white rats weighing 120-160 g techniques (Methods for determining the toxicity and hazards of chemicals. M.: Medicine, 1970.-344 C.). To study irritants mixture III experimental rats divided into 8 groups.

The first group of animals was applied once daily application of aqueous suspensions III in concentrations 0,25%; 0,50%; 1,00%; 5,00% on the outer surface of the auricle. The second group of animals aqueous suspension of the same concentration is wearing distilled water with surfactants. Treatment of rats of all groups should be performed within 10 days. After this time take blood from the tail to determine the number of erythrocytes and leukocytes in the camera Goryaeva, hemoglobin, leukocyte excretion by standard methods (Clinical laboratory diagnostics veterinary medicine. Reference edition. M: Agropromizdat, 1985. -287 C.). Take into account the following indicators: appearance at the point of application of hyperemia, edema, thickening of the skin folds and scratches. The data obtained is treated statistically (I. A. oivin. Pathphysiology, 1960. # 4. -S. 76-85). In the study of local action on the mucous membrane of the third aqueous suspension in the same concentrations contribute once in the conjunctival SAC of the rabbit in the amount of 1-2 drops for 7 days. When making pull the inner corner of the conjunctival SAC and then within one minute, press the lacrimal-nasal canal. Note the appearance and severity of hyperemia, edema, injection of the vessels of the sclera and cornea, measure the width of the pupil. Pay attention to the state of age. Assess the impact III on the mucous membrane of the nature of conjunctivitis (superficial, deep), keratitis.

Quantitative assessment of resorptive action is mow areas. Spend consideration for clinical signs of poisoning from different doses III. The research results are summarized in table. 5, 6 and 7.

III. The study of the allergenic properties. The study sensitizing properties carried out by the method (O., Alexeev, N. And. Shumsky. The study of the sensitizing properties in the experiment. In kN. Methods for determining the toxicity and hazards of chemicals. M.: Medicine, 1970. -S. 275-281) on white rats weighing 120-160 g, and rabbits weighing 2-2,5 kg Before experience evaluate primary irritant effect III rats by cutaneous applications in the form of aqueous suspensions at concentrations of 0.25%, 0,5%, 1% and 10%. In animals pre hair clip out on the site back 2x2 cm in rats, 5x5 cm in rabbits. Rats appliques make in the direction from the rear third of the back towards the head, the rabbits in the direction from the neck to the tail. The experimental rats divided in different quantities in 8 groups. The first three groups on the surface of the skin is applied and rubbed in once, respectively, 0,25%, 0,5%, 1% suspension within 15 days; the second three groups - twice a day during the same time. Control groups according to the same scheme used diluent (distilled water) with an emulsifier. All the animals put on the same skin area 10-30 at allow dose mixture III in the same concentrations.

Experienced rabbit clip out two skin area on both sides of the spine, treated with 70% alcohol and put a scarificator scratches. Then on one side put a 0.01% solution of histamine hydrochloride, and the other respectively of the investigated concentration of 0.25%, 0.5% and 1% suspension of the mixture III.

Monitor the condition of the skin of animals carried out in 30 min, 24 hour, 48 hour and 72 hour (take into account the emergence of eritem, infiltration, ulceration, necrosis of tissue. The research results are summarized in table. 6 and 7.

IV. The study of resorptive action.

The study of resorptive action of a mixture of III (Y. I. Kundiev. Methods study resorptive action of chemical substances. In the book: Methods for determining the toxicity and hazards of chemicals. M.: Medicine, 1970. -S. 275-281). The reaction of rats studied in concentrations of 0.25%; and 0.50% and 1.00% by hour exposure of rats tail in test tubes with suspension III at a temperature of 28oC. Tails control animals are placed in a test tube with water and surfactant. All tubes are in a water bath. About skin-resorptive effect III judged by daily monitoring the physiological condition of rats for 14 days.

V. Learning bride is a Finance test sub-chronic toxicity (Lim, R. K., Rink K. G., Qlass H. G. , Soaje-Echaque E. Arch. Intern. Pharm. Therapie. 1961, Vol. 130, NOS 3-4. -P. 336). The mixture in the third dose from a previously installed a single LD50(component 0,1) cause cutaneous animals of the experimental group the first 4 days. Then every subsequent 4 days, the dose (III increase in 1,5 times and put the animal. The duration of the experience of 244 days. By the end of the experience caused dose of 8.5 LD50. Evaluate the results of the study in relation to the average effective doses of acute and subacute actions. During the experience of watching animals, consider: status (agitation, depression), the nature and degree of activity and coordination, reaction of the animal to approximate, tactile and painful stimuli, the presence of tremor, convulsions, paresis, paralysis, discharge from the eyes, nose, skin discoloration, change in body weight, food anxiety.

See Toxicological studies have shown that a mixture of 4-nitro - and 6-nitro-5,7-dichlorobenzophenone (III) has the following parameters toxicity (table. 4).

When applied once on the skin to experimental rats a mixture of (III) at doses of 500, 1000, 2500 and 5000 mg/kg did not cause death of the animals.

The obtained data allow us to classify the studied mixture (III) to the third class umenie (GOST 12.1.007-76- "Harmful substances. Classification and General safety requirements").

As can be seen from the obtained data table. 5, the mixture of (III) at concentrations of 0.25%, 0.50% and 1.00 m% does not affect the skin irritant and does not alter the physiological condition of the rats.

The study of the allergenic properties of the mixture (III) showed the absence of contact dermatitis in rats from concentrations of 0.25 to 1.00%. The skin of the rats remained within 72 hours smooth and shiny. Indication of the strength of allergen exposure, in addition to local skin reactions, is a common reaction of the body, manifested in the increase in the number of eosinophils in the peripheral blood.

As can be seen from the table. 6 and 7, even 30% concentration of the mixture of (III) did not cause an increase in the number of eosinophils in peripheral blood and remained at the level benchmarks. The number of erythrocytes and leukocytes, hemoglobin remain within the normal range of control from the application of 5 and 10% concentrations III.

In the experiments on determination of reaction rabbits in response to 0,25-0,50% concentration of the mixture III was not observed reaction. After application of 1% concentration III after 24 hours there was little roller (compaction) during the scratches that after 24 hours it had disappeared.

Posted islamocracy III up to 1% may cause a minor reaction of the body.

As shown by the results on the study of resorptive action of the investigated mixture III at concentrations of 0.25, 0.50 and 1% did not have any toxic effect on the physiological condition of the animals. The leather tails are not marked swelling, redness, peeling, subcutaneous infiltration, destructive phenomena.

A single cutaneous application of a mixture of III even at a dose of 5000 mg/kg did not cause death in rats. Local action was characterized by redness, peeling skin and loss of hair.

In the experiments on determination of the cumulative properties of the mixture III when applied to skin, failed to cause the death of a single rat, although each animal received III total dose 3813 mg/kg

Thus, a mixture of 4-nitro and 6-nitro-5,7-dichlorobenzophenone III in the investigated concentrations and doses not have an irritating, allergenic, skin-resorptive and cumulative effect.

EXAMPLE 6. A study of genotoxic mixture of 4-nitro and 6-nitro-5,7-dichlorobenzophenone (nitroxane).

Evaluation of the mutagenic activity were carried out using the Ames test. The Ames test will provide an opportunity to investigate the mutagenicity as the source of the drug and its metabolites.

Metabolic preferably, derived from liver cells of rats pre-treated monooxygenase inducers of mixed fractions.

The drug solution is prepared in dimethyl sulfoxide at standard concentrations (1, 10, 100, 1000 and 10000 µg/ml). A preliminary stage to assess mutagenicity is the determination of the toxicity of the drug in relation to testory strains to exclude the possibility of obtaining false-negative results.

In a test tube with 3 ml of cold 0.6% of mycopathologia agar (MPA) add 0.1 ml of bacterial suspension of the desired dilution and 0.1 ml of the substance in the tested concentration. The solution is stirred and layer on the bottom 2% nutrient agar in a Petri dish. In the negative control instead of matter add 0.1 ml of solvent. After 24 hour incubation at 37oC count the number of colonies in the experiment and control and calculate the percentage of survival or toxicity of the substance.

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To evaluate the mutagenicity of the drug in paleobotany of 0.6% top agar contribute 0.1 ml of bacterial suspension, 0.1 ml of tested compound, 0.5 ml of microsome activating mixture (MAC) containing cofactors, and in the case of evaluation of mutagenic activity of metabolites distilled water (incomplete MAC) for OTS who CLASS="ptx2">

Semisolid agar should cover the bottom surface of minimal agar smooth thin layer. A Cup of leave at room temperature for 30-40 min and after solidification is transferred in a thermostat at 37oC. experience also put negative and positive control.

In the negative control in the upper layer of agar together with a suspension of bacteria also add a complete (or incomplete) MAC and 0.1 ml of solvent. As positive controls using known drugs, for showing mutagenic effects in the same modifications experience with metabolic activation or without it.

Without metabolic activation usually use nitrozometilmochevinu (100 μg/ml) for TA 1535 and TA 100 and nitrosoguanidine (5 μg/ml) for TA 1538 and TA 98. With metabolic activation of cyclophosphamide (100 mg/ml) for TA 100; 2 aminofluorene (30 µg/ml) - AND TA 98. Analysis carried out after 48 h of incubation. Compare the number of colonies - revertants in the experiment and the control.

Used Salmonella typhimurium strains TA 98 and TA 100, taking into account respectively mutations Tina shift of the reading frame and replacement of base pairs. Metabolic activation simulating the transformation of compounds in mammals, carried/P> Each value represents the average of three replicates, with standard deviation does not exceed 5%.

Nitroxane at concentrations of 100 µg/bowls and 1000 µg/bowls completely inhibited the growth testinig bacteria, therefore, for further research in the Ames test we used the following concentration ranges: 0,1, 1, 10 ág/vial.

The results of studies of the drug on the mutagenic activity in the test Salmonella/microsome assay are presented in table. 9.

From the data presented in table. 9, it follows that the studied compound in this range of concentrations is not mutagenic activity in the Ames test without metabolic activation. However, metabolic activation in vitro microsome activating composition on the basis of microsome fractions of rat liver lead to an increase in genotoxic activity of the study drug. Nitroxane at a concentration of 10 µg/bowls causes almost 8-fold excess (7.84 times in strain TA 98 and 7.8 times in strain TA 100) above the spontaneous background mutation engine.

Thus, nitroxane is promutagens - shows a weak mutagenic effect in the presence of enzymes microsome fraction mammals.

Therefore, the composition of in in the Russian form of rubromycosis the hands and feet, not have an irritating, allergenic, skin-resorptive, cumulative and mutagenic action.

Composition for the treatment of this form may be accompanied shape rubromycosis feet and hands, caused by the fungus Trichophyton rubrum, containing the active substance - nitrosoaniline and a diluent, wherein the active substance composition contains a mixture of 4-nitro - and 6-nitro-5,7-dichlorobenzophenone when the ratio of these components 30 : 70 respectively, and the diluent is a mixture of polyethylene glycol and dimethyl sulfoxide, in the following ratio, wt.%:

This mixture of 4-nitro - and 6-nitro-5,7-dichlorobenzophenone - 0,30 - 0,60

The polyethylene glycol 400 - of 79.65 - 79,80

Polyethylene glycol 1500 - 16,95 - 17,10

Dimethyl sulfoxide - 2,80

 

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