Combination of fulvic acid for treatment of various conditions and diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the field of medicine, namely to pharmacology, and describes a composition, containing fulvic acid or its salt and an antifungal compound, selected from fluconazole and amphotericin B. In accordance with the first version of the implementation the composition contains about 10 ml/kg of a solution of from about 0.25% to about 1% (wt/vol) fulvic acid or its salt and of about 10 mg/kg fluconazole. In accordance with the second version of the implementation the composition contains 0.25% (wt/vol) of the solution of fulvic acid or its salt and from about 0.06 mg/l to about 0.5 mg/l of amphotericin B.

EFFECT: invention can be used in a method of treating a fungal infection of the human or animal body, the method includes the introduction to an object, requiring it, of a therapeutically effective quantity of the composition.

11 cl, 1 dwg, 10 tbl, 3 ex

 

BACKGROUND of INVENTION

This invention relates to fullaway acid in combination with one or more antifungal compounds for use in therapeutic treatment or prevention of various conditions in the body of the animal or human.

Fulvic acid is one of the substances that are formed during the decomposition of organic substances in the environment. It is soluble in water under all pH conditions and, mainly, has a lower molecular size and weight and lower the color intensity than humic acids, which are also produced during the process of decay.

Despite the fact that fulvic acid occurs naturally at low levels in soil and water, it is difficult to isolate. The known process in order to get followww acid for use in medical application through control wet oxidation of coal, as described in US Patent No. 4912256. The use of such fullaway acid for the treatment of inflammation, acne, eczema, bacterial, fungal and viral infections was previously disclosed in International patent publication WO 00/19999. In addition, US Patent Nos. 4999202 and 5204368 disclose compositions that contain followww acid, salt or derivative, which have bacteriostatic or bactericidal is waista and are suitable for use as a disinfectant.

Produced from coal fulvic acids contain high concentrations of heavy metals, such as aluminum, mercury, cadmium, chromium and lead, which should be avoided in pharmaceutical preparations. The composition of fullaway acid, which is derived from a carbohydrate source (CHD-FA) by wet oxidation, has been previously disclosed in International patent publication WO 2007/125492. This CHD-FA is, in particular, use for pharmaceutical use, as it has a low content of heavy metals.

BRIEF description of the INVENTION

In accordance with the first embodiment of the invention, there is provided the combination of fullaway acid or salt of ester or its derivative and an antifungal compound selected from fluconazole and amphotericin b C.

Fulvic acid, salt, ester or derivative may have any pH from acid to alkaline. For example, the pH fullaway acid can be raised by converting the acid salt such as a salt of potassium or sodium. This can be achieved by adding a suitable hydroxide to fullaway acid. As a rule, fulvic acid is in the form of acids or salts.

Preferably, fulvic acid is a derived carbohydrate (CHD-FA) produced by the method described in WO 2007/125492. In particular, CHD-FA which may be derived from a saccharide. As a rule, CHD-FA has a molecular weight which does not exceed 20000 daltons, and a low content of such elements as aluminum, mercury, cadmium and chromium. CHD-FA is produced by exposure of carbohydrate wet oxidation and then processing the obtained reaction product to remove substantially all the acid components with a molecular mass of which exceeds 20000 daltons.

Fluconazole is a known antifungal agent and is described, for example, in Paragraph 4122 of the Merck Index, 14thEd. Fluconazole can be used in the form of ester, and it should be understood that the term "fluconazole" that is used here and in the formula include esters and other suitable pharmaceutical forms of fluconazole.

Amphotericin b is also known antifungal agent and is described, for example, in Paragraph 585 of the Merck Index, 14thEd.

Surprisingly it was found that the combination of fullaway acid and fluconazole was effective when it was applied against fungi that are resistant to fluconazole. In particular, the combination of fullaway acid and fluconazole is effective when it is applied against fluconazole-resistant Candida spp.

Amphotericin b, as surprisingly it was found, was effective at a lower, non-toxic dose when used against fungal different the varieties in combination with fulvic acid.

In one form of the invention the combination comprises from about 10 ml/kg of a solution of from about 0.25% to about 1% of fullaway acid or salt of ester or its derivative and about 10 mg/kg of fluconazole.

Amphotericin b may be present in combination in an effective dose, which is non-toxic to the subject. More particularly, the combination contains approximately 0.25% of fullaway acid and from about 0.06 mg/l to about 0.5 mg/l amphotericin b C.

In accordance with an additional embodiment of the invention, there is provided a pharmaceutical composition which contains a combination, which is described above as active ingredients.

The pharmaceutical composition may be in a form that is suitable for oral administration or topical application, or any other suitable form of application. For example, the pharmaceutical composition may be formed into a liquid, tablet, capsule, cream or ointment.

In accordance with an additional aspect of the invention, there is provided a combination or pharmaceutical composition described above for use in a method of treatment or prevention of a disease or condition of the body of the animal or human. The method may include oral, topical, or any other suitable form of application.

Man or alive is Noah, which will be treated, can be immunosuppressive or with reduced immune response.

Disease or condition can be caused by resistant to the effects of drugs of fungi.

A disease or condition can be caused by yeast. Preferably, the disease or condition is caused by Candida spp.

The disease or condition may be caused by Aspergillus spp or Zygomycetes.

In accordance with the additional object, the invention provides the use of combinations described above in the manufacture of pharmaceutical compositions for the treatment or prevention of a disease or condition of the body of the animal or human.

The pharmaceutical composition may be in a form that is suitable for oral administration or topical application, or any other suitable form of application. For example, the pharmaceutical composition may be formed into a liquid, tablet, capsule, cream or ointment.

BRIEF DESCRIPTION of DRAWINGS

The drawing shows the renal tissue of later complication infection of Candida albicans in mice treated with various concentrations of CHD-FA alone or in combination with fluconazole.

A DETAILED DESCRIPTION of the INVENTION

The stability of a drug is a big problem for the treatment of diseases and conditions which is caused by fungal media those which have occurred with the use of fluconazole to treat Candida infection and the use of amphotericin b in the treatment of Aspergillus. In particular, the use of amphotericin b in the treatment of Aspergillus infections is not daguerreotypes, as the dose required for inhibition of Aspergillus, is toxic to the object (3 mg/l).

In addition, opportunistic fungal infections that occur in patients with reduced immune response or immunosuppressive patients, are hard to control anti-fungal media.

Thus, the necessary treatment strategy in these patients, particularly cancer patients who receive drugs against cancer and other patients on any medications that cause weakening of the immune response.

Three studies were conducted in order to evaluate the antifungal characteristics of fullaway acid against certain organisms. Fulvic acid used in these studies was such that here described, and produced by the method described in WO 2007/125492, and referred to here in the future CHD-FA. In short, fulvic acid was obtained from carbohydrates, particularly sugar. CHD-FA has a molecular weight that does not exceed 20000 daltons, and a low content, i.e. less than 30 parts per million of the element is in, such as aluminum, mercury, cadmium, chromium, lead, silver, arsenic and beryllium. CHD-FA was produced by exposure of carbohydrate wet oxidation and then processing the obtained reaction product to remove substantially all the acid components with a molecular mass of which exceeds 20000 daltons.

In the first study of kidney burdened Candida albicans were identified as indicator of the effectiveness of increasing concentrations of CHD-FA alone or in combination with antifungal compound, fluconazole. The results showed that fulvic acid significantly enhances the activity of fluconazole against Candida albicans.

In the second study the effectiveness of fullaway acid alone or in combination with antifungal compound amphotericin b against Aspergillus or zygomycetes was determined by quantifying the number of colonies on the plates grown with living tissues.

In the third study, efficacy of fluconazole in combination with fullaway acid against a strain of drug-resistant Candida spp was determined by quantifying the number of colonies on the plates grown with living tissues.

All the solutions are given as percent weight per unit volume.

The following examples are given with only the purpose of illustration and should not be considered as limiting the invention in any way.

EXAMPLE 1 - In vivo efficacy of CHD-FA against Candida

1.1. The PHYSICAL PROPERTIES of a NEW ANTIBIOTIC AGENT MODULATION of RESISTANCE, ALSO KNOWN AS FULVIC ACID SECONDARY CARBOHYDRATE (CHD-FA)

CHD-FA was resuspendable as a 4% solution. The solution was stored at room temperature in the dark from the time of delivery. 4% solution of CHD-FA was yellow/brown, slightly viscous solution with a strong odour and a pH of 2.1 at 25°C.

1.2. METHODS

1.2.1 Regulatory research

All experiments on animals were performed in accordance with the License of the Ministry of internal Affairs of great Britain 40/3101 Invasive Fungal Disease (Licence Holder Dr. Peter Warn) and with the approval of the local ethical Committee. All experiments were performed by the technical staff who has completed parts 1, 2 and 3 courses personal licence course of the Ministry of internal Affairs and is the current holder of the personal licence. All experiments were performed in a special apparatus Biohazard 2 within Biological Service Unit the University of Manchester (this place is a holder of Certificate of Appointment).

1.2.2 Model animal

Mice that were used in this study, specimens of mice male CD1 (crossed unrelated individuals, which is very similar to house mice), and provided by Charles River (Margate UK) and were free of specific pathogenic organisms (16-18 g upon delivery). All mice had a weight of 20-22 g during immunosuppression.

Mice were housed in individually ventilated cages (CPI), supplied air, filtered through the HEPA filter. Sterile litter with aspen chips were supplied in pre-treated in an autoclave boxes. Sterile water was provided at the discretion of using disposable packages of actions. Regular meals mouse was provided at the discretion (the food was humidified in a mess, when mice were demonstrated symptoms of sepsis).

Mice were tested over a 12-hour cycle of day and night at 22±1°C, relative humidity of 55-60% and a background noise <60 decibels.

Animals were treated with the use or 30 g available 'insulin' Monojects (for intravenous (iv) or intraperitoneal (ip) injection), or 19 g of reusable needles.

All animals were immunosupression a single dose of 200 mg/kg cyclophosphamide (Pharmacia) by intraperitoneal (ip) for 3 days before infection. This results in a deep state of neutropenia, which lasts 3-4 days after infection.

1.2.3 the Duration of the experiment

The experiment was continued up to 53 hours after infection.

1.2.4 the Number of groups of animals

In the combined study animals were treated in groups of 4 mice per treatment group.

1.2.5 ZAR the position

Mice were infected with 0.2 ml suspension FA7070 in PBS+0.05% transition 80, containing 1.5×105blastoconidia/ml, that is 3.0×104yeasts on the mouse. After infection, all mice were observed at least 4 times daily. Animals who had exceeded the level of danger of the experiment, were humane way euthanized.

1.2.6 Antifungal treatment

Mice were treated 5 hours after infection than any of:

a) 0.125 ml of 2% CHD-FA, which was introduced by forced feeding (introduction mouse 25 g during treatment). CHD-FA was introduced twice a day (total of 6 of doses administered).

b) 0.125 ml of 0.5% CHD-FA, which was introduced by forced feeding (introduction mouse 25 g during treatment). CHD-FA was introduced twice a day (total of 6 of doses administered).

c) 10 mg/kg of fluconazole, which was injected in 5% glucose (0.25 ml)

d) Combination therapy 0.125 ml of 2% CHD-FA, which was introduced twice a day orally or 10 mg/kg of fluconazole, which was injected in 5% glucose.

e) Combination therapy 0.125 ml of 0.5% CHD-FA, which was introduced twice a day orally or 10 mg/kg of fluconazole, which was injected in 5% glucose.

f) 0.5 mg/kg of amphotericin b (dissolved in 5% glucose), which was introduced by intraperitoneal way.

(g) Mice, which is s treated with an inert substance, was given 0.125 ml of 0.9% saline by forced feeding, which was introduced twice a day, and 0.25 ml of 5% glucose was administered intravenously.

1.2.7 the End of the experiment on animals

After 53 hours after infection, all animals were euthanized with application procedures application 1. All animals were weighed; the kidneys were immediately removed and homogenized in chilled to zero sterile phosphate-buffered saline. Kidney homogenates were in the proportion cultivated on agar Saburo with dextrose and incubated at 37°C for up to 4 days and colonies were counted.

1.2.8 Statistical Analysis

Data from burdened cultures were analyzed by means of the criterion of the Kruskal-Wallis test using direct statistics.

1.3 RESULTS

1.3.1 Renal complication

Summary renal encumbrances detailed on the drawing 1.

In this study, there were no side effects noted after treatment of CHD-FA, and the study was completed in 53 hours after infection due to severe infections in the group that was treated with an inert substance.

1.3.2. Statistical Analysis

1.4 SHORT DESCRIPTION

Experiments were established using 0.125 ml of force skormin the th 2% and 0.5% CHD-FA twice a day (equivalent to 1% increase and a 0.25% increase CHD-FA, which was introduced at 10 ml/kg).

5 ml/kg of 2% or 0.5% CHD-FA (equivalent to 10 ml/kg at 1% and 0.25% CHD-FA) was well tolerated in mice.

5 ml/kg of 2% or 0.5% CHD-FA (equivalent to 10 ml/kg at 1% and 0.25% CHD-FA) was effective in reducing kidney weights in mice infected with Candida albicans. Burden after treatment was significantly lower than in mice treated with an inert substance (~0.6 log10CFU/g reduction).

5 ml/kg of 2% or 0.5% CHD-FA (equivalent to 10 ml/kg at 1% and 0.25% CHD-FA) was added when used in combination with fluconazole. The combined reduction in the weight of the fabric was much higher than any treatment, used as monotherapy.

EXAMPLE 2 - In vitro efficacy of CHD-FA against Aspergillus and Zygomycetes

2.1 PHYSICAL properties of CHD-FA, ALSO KNOWN AS FULVIC ACID

CHD-FA was resuspendable as a 4% solution. The solutions were stored at room temperature in the dark from the date of delivery. 4% solution of CHD-FA was a yellow/brown slightly viscous solution with a strong odour and a pH of 2.1 at 25°C.

2.2 METHODS a Preliminary Experiment

2.2.1 Fungal Culture

The susceptibility tests were performed on the following crops, which are all species isolated from cases of human clinical disease.

(i)2 x Aspergillus fumigatus.

(ii) 2 x Aspergillus terreus - these varieties are moderately resistant in vitro and persistent in vivo to amphotericin b, which is typical to the species A. terreus.

(iii) 2 x Aspergillus flavus - these species have intermediate susceptibility in vitro and correspondingly depleted in vivo to amphotericin b (1 variant).

(iv) 2 x Aspergillus flavus - these species have intermediate susceptibility in vitro and correspondingly depleted in vivo to amphotericin b (1 variant).

(v) 2 x Absidia corymbifera - these varieties are susceptible in vitro and accordingly have a very depleted in vivo to amphotericin Century

(vi) 2 x Fusarium solani - these varieties are very resistant in vitro and therefore are not in vivo to amphotericin Century

Each culture was grown on agar Saburo at 37°C for 10 days, to ensure the purity and allow disputes to ripen.

2.2.2 Environment

RPMI-1640 (Sigma, Dorset, UK) was added to 2% glucose (Sigma) buffered with morpholinepropanesulfonic acid (pug), (Sigma) and adjusted to pH 7.0, was used as recommended in the Clinical Laboratory Standards document MA (Reference method for broth dilution antifungal susceptibility testing of conidia-forming filamentous fungi. Approved standard. Document M38-A. 2002a. NCCLS, Wayne, Penny is lvania 2002. NCCLS, Wayne, Pennsylvania, United States).

2.2.3 Preparation of inoculum

a) All of the mushrooms were kulturerbe in the atmospheric air at 35-37°C in a reducing environment (agar Saburo with dextrose) for 8-10 days before testing.

b) Inoculate suspensions were prepared from 8 days to 10 days of cultivation, grown on agar Saburo with dextrose at 37°C in vented flasks for growing living tissue, to avoid cross-contamination. Spores were collected by pouring surface, on which is grown, 25 ml of sterile physiological solution with phosphate buffer plus 0.05% Tween 80. The number of spores was adjusted using counting chambers.

c) the Inoculum was completely suspended by intense shaking on a vortex mixer for 15 seconds. The final density of spores in the tests MICK was between 0.5×104and 5×104CFU/ml, as evidenced by the quantitative counting of colonies. Non-pharmacological and cell-free controls were included (RPMI Medium, which is used in the plates was prepared or at 2 - or 4-final strength to provide a single dissolution supernatant and dissolved CHD-FA was added).

2.2.4 Test pathological conditions

Sterile plastic plates disposable steps for micrometrology with 96 plockton the diversified wells were used.

STEP 1 Add amphotericin b (mother solution prepared in 100% DMSO)

a) Column 1 of panel micrometrology was filled with 100 µl of sterile water, which contains four values of the final drug concentration (16 mg/l of amphotericin b).

b) Columns 2-12 were filled with 50 µl of distilled water.

(C) the Amount of 50 µl were taken from the wells in column 1 and doubly dissolved by passing them in column 2 multichannel pipette (±2% coefficient of variation). 50 ál of the samples were then removed from the column 2 and moved to column 3 and so on up to column 10. The last 50 ál of the dissolved drug is then released. Thus, each hole in columns 1-10 will contain 50 ál of water containing four values of the final concentrations of the antifungal drug.

STEP 2 Add the CHD-FA

Royal solutions CHD-FA was content 4%, 2%, 1%, 0.5% and 0.25% of native connections.

100 µl of the dissolved CHD-FA was added to the panels of micrometrology so that the number And contained a final dilution of 2%, range 1% of range 0.5%, the number D of 0.25%, the number of E 0.125% and series F only solvent.

STEP 3 Add Aspergillus or Zygomycetes loads

50 µl of the dissolved spore suspension in 4 x RPMI was added to all cells. This produces wells containing 200 μl final volume (consisting of 50 μl of dissolved about everyblock substances, 100 µl of the dissolved CHD-FA or diluent, 50 ál of 4 X RPMI containing fungal spores).

STEP 4 Incubation plates

All plates were incubated at 37°C in air in a darkened incubator.

STEP 5 Read plates

Plates were read visually with the endpoint, which was taken as the lowest concentration of drug that inhibited growth by 50% relative to the same without medical supervision.

2.3. The results of the Preliminary experiment

2.3.1 MICK in relation to CHD-FA and Amphotericin b

MICK compared to single agents demonstrated that CHD-FA at 4%, 2% and 1% inhibited growth of Aspergillus and Zygomycetes for at least 24 hours. The values of MIC for CHD-FA and Amphotericin b are detailed in Table 2.

Table 2
The efficacy of CHD-FA against Aspergillus and zygomycetes
Type IDIsolate IDMICK (%) CHD-FAAmphotericin b MIC (mg/l)
A. fumigatus10.50.5
A. fumigatus2 0.50.25
A. terreus10.50.5
A. terreus20.51.0
A. flavus10.54.0

Type IDIsolate IDMICK (%) CHD-FAAmphotericin b MIC (mg/l)
A. flavus20.250.5
Absidia10.250.25
Absidia20.250.06
Fusarium10.252.0
Fusarium20.252.0

3.3.2 the MIC in relation to the combination of CHD-FA and Amphotericin b

MICK about what to wear to a combination of CHD-FA and amphotericin b are shown in table 3. They are notable for the fact that none of the combinations was not antagonistic, but the combination was very effective against the resistance of Aspergillus fumigatus, which is stable in vitro and in vivo to amphotericin Century

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Table 3
The efficiency of the combination of CHD-FA and amphotericin b against Aspergillus
Type IDCHD-FA dilutionMICK CHD-FAAmphotericin MICKThe combination of MICKEffect
A.0.5NoNo growthNo growthPossible synergy
fumigates0.25growthNo growthNo growth
heaviness0.125No0.06<0.06
1 growth
Growth
A.0.5NoNo growthNo growthNeither synergy nor antagonism
fumigates0.25growthNo growthNo growth
heaviness0.125No0.1250.125
2growth
Growth
A. terreus0.5NoNo growthNo growthNeither synergy and antagonism
heaviness0.25growthNo growthNo growth
10.125No0.250.25
growth
Growth
A. terreus0.5NoNo growthNo growthNeither synergy nor antagonism
heaviness0.25growthNo growthNo growth
20.125No0.1250.125
growth
Growth

Type IDCHD-FA dilutionMICK CHD-FAAmphotericin MICKThe combination of MICKEffect
A. flavus0.5NoNo growthNo growthThe combination of reduced MICK from resistant to highly susceptible
heaviness0.25growthNo growthNo growth
10.125No>4.0<0.06
growth
Growth
A. flavus0.5NoNo growthNo growthNeither synergy nor antagonism
heaviness0.25growthNo growthNo growth
20.125No0.250.5
growth
Growth

2.4. SHORT DESCRIPTION

- CHD-FA does not demonstrate antagonistic activity when used in combination with amphotericin b Aspergillus spp.

The combination of 0.25% CHD-FA with amphotericin b (0.06-0.5 mg/l) inhibited the growth of all ku is tour Aspergillus, tested regardless of amphotericin b MIC cultures.

EXAMPLE 3 - In vitro efficacy of combination of fluconazole and CHD-FA against Candida spp.

3.1 PHYSICAL properties of CHD-FA, ALSO KNOWN AS FULVIC ACID

CHD-FA was resuspendable as a 4% solution. The solutions were stored at room temperature in the dark with the date of posting. 4% solution of CHD-FA was a yellow/brown slightly viscous solution with a strong odour and a pH of 2.1 at 25°C.

3.2 METHODS a Preliminary experiment

3.2.1 Fungal culture

Tests for susceptibility were performed on 5 cultures of Candida albicans, which all represent a clinical culture (all with reduced susceptibility to fluconazole). Each culture was grown on agar Saburo at 37°C for 48 h in order to guarantee purity.

3.2.2 Environment

RPMI-1640 (Sigma, Dorset, UK), added to 2% glucose (Sigma), which is buffered with morpholinepropanesulfonic acid (pug), (Sigma) and adjusted to pH 7.0, was used as recommended in the European Committee on antimicrobial testing sensitivity (E. Dis. 7.1) (Rodriguez-Tudela, J. L, F. Barchiesi, J. Bille, E. Chryssanthou, M. Cuenca-Estrella, D. Denning, J. P. Donnelly, B. Dupont, W. Fegeler, C. Moore, M. Richardson, P. E. Verweij) and the Subcommittee on testing antifungal sensitivity (Subcommittee on Antifungal Susceptibility Testing (AFST) of the European Community To onicescu Microbiology and Infectious diseases of The European Society of Clinical Microbiology and Infectious Diseases) of the ESCMID European Committee for antimicrobial testing sensitivity (European Committee for Antimicrobial Susceptibility Testing) (EUCAST) 2003. The method of determining the minimum inhibitory concentration (MIC) by broth dilution fermentative yeast. Clinical Microbiology and infection (9:I-VIII).

3.2.3 Preparation of inoculum

All yeast fungi were cultivated in an air environment at 35-37°C for vosstanovitelnoi environment (dextrose agar Saburo) for 18-24 h before testing.

b) the Inoculum was prepared by selection of five different colonies from 18 to 24 h of cultivation and their suspension in 5 ml of sterile distilled water.

c) the Inoculum was completely suspended by intensive shaking in a vortex mixer for 15 seconds. The density of cells was adjusted to a density of 0.5 standard Macfarland by adding sterile distilled water and measuring the absorbance in a spectrophotometer at a wavelength of 530 nm. This gave a suspension of yeasts 1-5×106CFU/ml of the working suspension was prepared by further dilution of 1 to 10 in 4 X RPMI to obtain 1-5×105CFU/ml (RPMI Medium, which is used in the plates was prepared with 4-final voltage to provide 75% dissolution of one supernatant and diluted CHD-FA was added).

3.2.4 Test pathological conditions

Sterile the plastic plates disposable steps for micrometrology with 96 flat-bottomed wells were used.

STEP 1 Add fluconazole

a) Column 1 of panel micrometrology was filled with 100 µl of sterile water, which contains four values of the final drug concentrations (512 mg/l fluconazole).

b) Columns 2-12 were filled with 50 µl of distilled water.

c) the number of 50 µl were taken from the wells in column 1 and doubly dissolved by passing them in column 2 multichannel pipette (±2% coefficient of variation). 50 ál of the samples were then removed from the column 2 and moved to column 3 and so on up to column 10. The last 50 ál of the dissolved drug is then released. Thus, each hole in columns 1-10 will contain 50 ál of water containing four values of the final concentrations of the antifungal drug.

STEP 2 Add the CHD-FA

Royal solutions CHD-FA was content 4%, 2%, 1%, 0.5% and 0.25% native compound. 100 µl of the dissolved CHD-FA was added to the panels of micrometrology so that the number And contained a final dilution of 2%, range 1% of range 0.5%, the number of E 0.25%, series D 0.125% and series F only solvent.

STEP 3 Add Candida albicans

50 µl of the dissolved suspension of Candida albicans in 4 x RPMI was added to all cells. This produces wells containing 200 μl final volume (costsi of 50 μl dissolved fluconazole, 100 µl of the dissolved CHD-FA or diluent, 50 ál of 4 X RPMI, contain Asia Candida albicans).

STEP 4 Incubation plates

All plates were incubated at 37°C in air in a darkened incubator.

STEP 5 Read plates

Plates were read visually with the endpoint, which was taken as the lowest concentration of drug that inhibited growth by 50% relative to the same without medical supervision.

3.3.1 RESULTS of the Preliminary experiment

Initial tests showed that CHD-FA at 4%, 2% and 1% inhibited the growth of Candida albicans within at least 24 hours when combined with 1 X RPMI 1640 culture medium, growth at 0.5% CHD-FA occurs at similar levels to control the dissolution. Inhibition of growth (4%, 2% and 1%) was possible due to the strongly acidic pH. When the pH of CHD-FA (pH 2.1) could be detected by the lack of synergy or antagonism with fluconazole.

pH CHD-FA was adjusted to pH 7.0 using 10 M NaOH solution (ideal pH for activity of fluconazole). This has resulted in brown slightly viscous solution with a strong characteristic aroma. The susceptibility test was repeated as above.

As was previously noted with the inherent CHD-FA, 4%, 2% and 1% solutions inhibited the growth of Candida albicans within at least 24 hours when combined with 1 X RPMI 1640 culture medium, growth at 0.5% CHD-FA occurs at similar levels to control the influencers effects on dissolution. Could be detected by the lack of synergy or antagonism with fluconazole.

MICK encumbrances Candida albicans with and without CHD-FA are listed in Table 4 (pH CHD-FA was adjusted to 7.0).

Table 4
The minimum inhibition concentration of fluconazole (mg/l), combined with CHD-FA
Candida Weight2% CHD-FA1% CHD-FA0.5% CHD-FA0.25% CHD-FA0.125% CHD-FASolvent
1No growthNo growth161616128
2No growthNo growth32161616
3No growthNo growth2161616
4No growthNo growth32323232
5No growthNo growth32321616

3.4 METHODS the Main experiment

3.4.1 Fungal culture

Tests for susceptibility were performed on 40 donor strains of Candida, among which 38 had reduced susceptibility to fluconazole. The group contained 25 C. albicans, 11 C. glabrata (all with reduced susceptibility to fluconazole) and 4 C. tropicalis (all with reduced susceptibility to fluconazole). Each culture was grown on agar Saburo at 37°C for 48 h to ensure purity.

3.4.2 Environment

As indicated in 3.2.2.

3.4.3 Preparation of inoculum

As outlined in 3.2.3.

3.4.4 Test pathological conditions

Sterile plastic plates disposable steps for micrometrology with 96 flat-bottomed wells were used.

STEP 1 Add fluconazole

a) Column 1 of panel micrometrology was filled with 100 µl of sterile water, which contains four values of the final drug concentrations (512 mg/l is luconazole).

b) Columns 2-12 were filled with 50 µl of distilled water.

c) the number of 50 µl were taken from the wells in column 1 and doubly dissolved by moving them in column 2 using a multichannel pipette (±2% coefficient of variation). 50 ál of the samples were then removed from the column 2 and moved to column 3 and so on up to column 10. The last 50 ál of the dissolved drug is then released. Thus, each hole in columns 1-10 will contain 50 ál of water containing four values of the final concentrations of the antifungal drug.

STEP 2 Add the CHD-FA

Royal solutions CHD-FA were produced with a content of 4%, 2% (1% and 0.5% for Candida parapsilosis and Candida krusei). 100 µl of the dissolved CHD-FA was added to the panels of micrometrology so that the rows contain the final solution.

For Candida albicans and tropicalis: 1st number of pairs 0.5% CHD-FA, 2-Noah the number of pairs of only the solvent.

For Candida glabrata: 1-St row of three 1% CHD-FA, 2-Noah series of three 0.5% CHD-FA, 3-rd row three, only the solvent.

For Candida parapsilosis and Candida krusei series included 2%, 1%, 0.5%, 0.25 and 0.125% CHD-FA and a series of solvent.

All of the above concentrations were mixed with a fixed concentration of fluconazole at 128, 32, 8, 2, 0.5 mg/l and a solvent for the assessment of synergy/antagonism.

STEP 3 Add Candida spp

50 µl of the dissolved suspension of Candida spp in 4 x RPMI was added to the all cells. This produces wells containing 200 μl final volume (costsi of 50 μl dissolved fluconazole, 100 µl of the dissolved CHD-FA or diluent, 50 ál of 4 X RPMI containing Candida).

STEP 4 Incubation plates

All plates were incubated at 37°C in air in a darkened incubator.

STEP 5 Read plates

Plates were read visually with the endpoint, which was taken as the lowest concentration of drug that inhibited growth by 50% relative to the same without medical supervision.

3.5. The RESULTS of the Main experiment

The results are summarized in Tables 5-10.

No Candida overgrowth did not occur during prolonged incubation (96 hours) at 37°C or room temperature.

Table 5
The efficacy of CHD-FA (0.5%) in combination with fluconazole against Candida albicans
Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FA
C. Albicans1128No growth
28No growth
C. Albicans316No growth
C. Albicans44No growth
C. Albicans5128No growth
C. Albicans6>128No growth
C. Albicans7128No growth
C. Albicans8128No growth
C. Albicans964No growth
C. Albicans10128No growth
C. Albicans110.5N the t growth
C. Albicans1264No growth
C. Albicans130.5No growth
C. Albicans1432No growth
C. Albicans152No growth
C. Albicans1664No growth
C. Albicans17>128No growth
C. Albicans18>128No growth

Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FA
C. Albicans190.5C. Albicans20>128No growth
C. Albicans214No growth
C. Albicans222No growth
C. Albicans231No growth
C. Albicans241No growth
C. Albicans25>128No growth

Table 6
The efficacy of CHD-FA (0.5%) in combination with fluconazole against Candida glabrata
Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FA
C. glabrata1>128/td> >128
C. glabrata2>128>128
C. glabrata3>128>128
C. glabrata4>128>128
C. glabrata5>128Signs of growth
C. glabrata6>128>128
C. glabrata7>128>128
C. glabrata8>128>128
C. glabrata9>128>128
C. glabrata10>128>128
C. glabrata11 >128>128

Table 7
The efficacy of CHD-FA (1%) in combination with fluconazole against Candida glabrata
Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FA
C. Glabrata1>128No growth
C. Glabrata2>128No growth
C. Glabrata3>128No growth
C. Glabrata4>128No growth
C. Glabrata5>128No growth
C. Glabrata6>128No growth
C. Glabrata7>128No growth
C. Glabrata8>128No growth
C. Glabrata9>128No growth
C. Glabrata10>128No growth
C. Glabrata11>128No growth

Table 8
The efficacy of CHD-FA (0.5%) in combination with fluconazole against Candida tropicalis
Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FA
C. Tropicalis116No growth
C. Tropicalis2 >64No growth
C. Tropicalis316No growth
C. Tropicalis416No growth

Table 9
The efficacy of CHD-FA (0.5%) in combination with fluconazole against Candida parapsilosis
Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FACHD-FA (%) without fluconazole
C. parapsilosis18No growth0.25
C. parapsilosis22No growth0.5
C. parapsilosis38No growth0.5
C. parapsilosis48No growth0.5
C. parapsilosis58No growth0.5

Table 10
The efficacy of CHD-FA (0.5%) in combination with fluconazole against Candida krusei
Type IDIsolate IDFluconazole MIC (mg/l) aloneFluconazole MIC with 0.5% CHD-FACHD-FA (%) without fluconazole
C. krusei132No growth0.25
C. krusei232No growth0.5
C. krusei332No growth0.25
C. krusei4 32No growth0.5
C. krusei532No growth0.5

3.6 SHORT DESCRIPTION

- CHD-FA is equally effective as an antifungal agent in vitro as in the study with inherent pH 2.1 or buffered to pH 7.0.

- CHD-FA inhibits the growth of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida krusei when used in the form of 0.5% in vitro.

- CHD-FA inhibits the growth of Candida glabrata when used in the form of a 1% solution.

- Combination of 1% CHD-FA with fluconazole (0.25-128 mg/l) inhibited the growth of all tested isolates of Candida.

- CHD-FA is very effective against encumbrances C. krusei, which are inherently resistant to fluconazole.

1. A composition comprising a combination of:
(a) fullaway acid or its salts, and
(b) an antifungal compound selected from fluconazole and amphotericin b,
for use in a method of treatment of fungal infection of the human body or animal body, the method includes the introduction of the object in need, a therapeutically effective amount of the composition.

2. Composition under item 1, in which fulvic acid is a CHD-FA.

3. Composition under item 1, in which salt contains sodium salt or the lia.

4. The composition according to p. 1, containing about 10 ml/kg of a solution of from about 0.25% to about 1% (wt./about.) fullaway acid or a salt thereof and about 10 mg/kg of fluconazole.

5. The composition according to p. 1, containing 0.25% (wt./about.) solution fullaway acid or its salt and from about 0.06 mg/l to about 0.5 mg/l amphotericin b C.

6. Composition under item 1, in the form of liquids, tablets, capsules, or etc.

7. Composition under item 1, which is introduced by means of oral administration.

8. Composition under item 1, which is entered through a local application.

9. Composition under item 1, which is introduced in the form of a cream, ointment or liquid.

10. Composition under item 1, in which a fungal infection caused by resistant to the drug by the fungus.

11. Composition under item 1, in which the animal or person is immunosuppressive or immune-compromised.



 

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2 ex

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5 cl, 9 ex

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