Method for improving therapeutic efficacy of curcuminoids and analogues thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method of increasing the therapeutic efficacy of curcuminoids and analogues thereof. The cosmetic method for uniform skin tanning for patients suffering psoriasis without hyperpigmentation comprising administering curcumine or its derivatives orally in a combination with exposure to ultraviolet under certain conditions. The cosmetic method for uniform skin tanning for patients suffering vitiligo without hyperpigmentation comprising administering curcumine or its derivatives orally in a combination with exposure to ultraviolet under certain conditions. Using the pharmaceutical composition comprising curcumin and its analogues applicable in treating psoriasis of a moderate to severe degree of severity in a combination with visible exposure under certain conditions.

EFFECT: methods are effective for uniform skin tanning and psoriasis treatment.

6 cl, 5 ex

 

The technical FIELD

The present invention describes a method for improving therapeutic efficacy of compositions containing curcuminoid and their analogues, with the systemic administration of these compounds. The method differs in that the patient is irradiated with a certain amount of visible and ultraviolet radiation simultaneously with the introduction of the composition.

The present invention also describes an apparatus for phototherapy, which emit radiation in the visible part of the spectrum to the surface area of more than 0.20 m2if the radiation intensity of more than 2 mW/cm2and when dermatologically and/or proliferative diseases.

PRIOR art

Curcumin and its therapeutic analogues: it was shown that the rhizomes of turmeric extracts, curcuminoid (demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin), prodrugs and metabolites exhibit various pharmacological activities, for example, antioxidant and antiproliferative properties, induce apoptosis, etc. On the basis of the results obtained in vitro, it is proposed to use curcumin as a potential drug for the treatment of pathologies known in the existing art, for example, psoriasis, cancer, inflammation, vitiligo, etc.

But curcumin and its equivalent who have a very low bioavailability. In article Br J Cancer. 2004 Mar 8; 90 (5):1011-5 says that after the introduction of curcumin were found only trace amounts of its metabolites in liver tissue and was not detected by the curcumin. Therefore, curcuminoid deprived efficiency in vivo or their effectiveness is greatly reduced in comparison with the activity detected in vitro. In article, J Am Acad Dermatol. 2008 Apr;58(4):625-31 this observation is confirmed (published after the priority date). In this document it is reported that a phase II, uncontrolled trial in patients older than 18 years, which was introduced in 4.5 g of curcuminoids/day, was interrupted for the reason that only 17% of patients responded to treatment by reducing psoriatic plaques by 75%.

According to article Amand et al Biochem Pharmacol. 2008 Aug 19. [electronic publication before printing] (published after the priority date), the experts in this field are interested in finding ways to improve the effectiveness of compositions containing curcumin, in vivo and in discovery sverhsoznaniya". Were found techniques such as structural modification that improves the absorption of curcumin (EP1837030), new herbal formulations (WO/2008/030308) and the introduction of high doses in combination with other active ingredients (US 5925376, WO03088986).

Phototherapy is an effective tool for the treatment of various diseases, for example, proliferative and/or der is ecologicheskih pathologies (psoriasis, cancer), acne, and jaundice. Effect of phototherapy is based on the structural changes caused by irradiation.

Phototherapy is used to treat jaundice in newborns. In order to break down bilirubin, the body of the newborn, the surface area is 0.20 m2, is irradiated with visible light, preferably with a wavelength of maximum emission of 550 nm, and the intensity of the radiation is close to 40 W/m2.

Actinic light (wavelength of maximum emission is 420 nm) is used to treat acne, which is based on its bactericidal properties. The surface area irradiated by these lamps is less than 400 cm2.

Photochemotherapy, simultaneous introduction of psoralens and ultraviolet irradiation of light is a popular treatment of psoriasis moderate or severe, but such treatment has many secondary effects: hyperpigmentation, hepatotoxicity, hypersensitivity reactions and the need to carefully pick up the doses.

It was shown that aminolevulinic acid in combination with blue light is effective in the treatment of actinic keratosis. Thus, article J Invest Dermatol. 2002 Jul; 119(1):77-83 described system introduction aminolevulinic acid (oral) in combination with irradiation of visible light PR is the density of the dose of 1-20 j/cm 2(led with wavelength of maximum emission 417 nm) for the treatment of psoriasis, but the effectiveness is limited and this treatment cannot be used when the psoriasis is moderate or severe. The results show that out of 15 plaques size of 1.5×1.5 cm (34 cm2) the state of the plaques has improved only 42% compared with the baseline.

In in vitro tests, and the local introduction formed during irradiation in situ photoradical or products responsible for the pharmacological activity, unstable. After systemic injections fotosensibiliziruyuschimi tools, photosensitization may not develop immediately; first, the drug needs to be metabolized, and then it should be activated by light. In short, the effectiveness of phototherapy cannot be predicted a priori, since it depends on the bioavailability introduced drugs and pharmacological activity of the products formed during irradiation.

In the specific example with curcumin, the current level of technology it is known to possess the very low bioavailability and, in addition, it is known that curcuminoid decompose under the action of visible and ultraviolet light, as in solution and in the solid state. The main product of decomposition is cyklinowanie curcumin, which obrazets is by removal of two hydrogen atoms.

Psoriasis is a chronic disease and its etiology is not fully clear. Clinically, psoriasis is characterized by the presence of foci or erythematous plaques, which have a dark red color, crisp edges and often covered with scales arising from changes in cell proliferation, which is different genetic and immunological mechanisms. Thus, psoriasis can be considered as a proliferative disease.

The severity of psoriasis is determined using the PASI index (an index of severity of psoriasis), BSA (body surface area of) and PGA (General therapeutic assessment). According to the PGA, psoriasis can be divided into the following types:

- Mild or moderate psoriasis: the foci are controlled with the help of local treatment; BSA < 10%, PASI < 10,

- Moderate psoriasis: it is still possible to control the disease with the help of local treatment; BSA > 10%, PASI of 10 or higher

- With psoriasis severity from moderate to severe: local treatment can not control the disease; BSA > 10%, PASI 10-20; very thick lesions in areas that are difficult to treat,

- Severe psoriasis: for the control of the disease requires systemic treatment; BSA > 20% or PASI > 20; significant very thick local damage with BSA > 10%.

Currently there is no model of psoriasis on animals that mo is but could use to assess the effectiveness of drugs in vivo for the treatment of psoriasis. It is necessary to test the effectiveness of drugs on people who suffer from psoriasis or in animal models by studying the inhibition of proliferation of tumors, for example, cell proliferation cell line A431 (epidermal cells carcinoma).

For evaluation of therapeutic efficacy of drugs used PASI - objective index to assess the severity of psoriasis. The main criteria EMEA suggests that patients should be considered responsible for treatment, if a reduction in PASI of at least 75% from baseline.

Drug Efalizumab, recently approved for the treatment of psoriasis, has some efficacy. 12 weeks of research 22-35% of patients reached PASI-75 (improvement of 75%).

Photochemotherapy only aminolevulinic acid and visible light showed improvement in psoriatic plaques by 42% compared with the baseline. According to the criteria EMEA, this method of treatment has not been effective, in particular, in the treatment of psoriasis with severity from mild to severe.

Patients with psoriasis tend to hide their pockets, and often refuse local treatment, because it stains the clothes. In accordance with the results of the survey, which was conducted by the European Federation of societies of patients with psoriasis, among those suffering from psoriasis who have a high level of dissatisfaction with the effectiveness of such treatments for this disease and refusal of treatment.

In EP1133992 described photosensitizing action of visible and ultraviolet light on curcuminoid, input in the form of extracts for topical application for the treatment of psoriasis. The cream described in EP1133992, should be applied before irradiation, but patients refuse treatment, since extracts of turmeric stained and dirty clothes. Psoriasis with severity from mild to severe, which affected more than 10% of the surface area of the body that cannot be treated topically because patients do not respond to drugs, administered through the local path.

The results obtained using the local introduction, cannot be extrapolated to the system introduction as described for aminolevulinic acid.

Another type currently used therapy is photodynamic therapy. Enter drug and irradiate the patient from the pulse light source which has a high radiation intensity approximately equal to 300 mW/cm2. The light is directed to small areas of the surface within a short period of time, when the density of the dose of 100 j/cm2but the use of this method causes pain patients.

Best present invention correspond to the following devices for phototherapy:

- UV cab emitted intensity) the treatment of ultraviolet light 2-30 mW/cm 2over the entire area of the surface of the body of the patient, but without the emission of visible light

devices that emit visible light, which is irradiated with a small surface area of approximately 500 cm2but always less than 10% of the surface area of an adult body

Gas - discharge lamps that emit light with wavelengths in the range of 400-550 nm and which can be installed in the UV booths, for example, Phillips TLK 40 W/03 or TLK 140 W/03, and these lamps are used in printing and for lighting aquariums.

There are also filters that selectively absorb light of a certain wavelength and transmit radiation in the range of 400-430 nm.

Considering the fact that at the present time there is no drug which is effective in phototherapy visible light, an expert in this field will not combine technical specifications of the equipment described above, in order to create an apparatus for phototherapy, which emits visible light with an intensity greater than 2 mW/cm2on the surface, the area of which exceeds 0.2 m2.

The OBJECTIVE of the INVENTION

Solved by the invention the problem is to improve therapeutic efficacy of curcuminoids and their therapeutic equivalents when their systemic administration.

Found by the authors this is the first invention, the solution lies in the combination of systemic injections of curcuminoids dosed exposure to visible and ultraviolet light.

The solution found by the authors of the present invention have reduced PASI more than 75%of that achieved at least 80% of patients with a probability of over 80% after irradiation or ultraviolet light or visible light at a density dose 1-18 j/cm2that, therefore, meet the performance criteria EMEA.

In contrast to article J Am Acad Dermatol. 2008 Apr;58(4):625-31, in which he reported that with the introduction of curcuminoids at doses of 4.5 g/day, they did not demonstrate efficacy in the treatment of psoriasis, the combination of curcuminoids or with ultraviolet or visible light is an effective, all patients achieved a reduction in PASI 75% and no patient refused treatment. In the middle of the test, on the fourth week (after 8 sessions of phototherapy), 50% of patients achieved a PASI reduction of more than 75% relative to the baseline. In the middle of testing the efficiency exceeded the efficacy of Efalizumab after 12 weeks of treatment and was not observed secondary effects.

In preferred embodiments, the implementation of therapeutic equivalents of curcumin for the treatment of psoriasis are turmeric extracts (hydroalcoholic extracts with a concentration of curcuminoids 12% or alcoholic extracts with a concentration of curcuminoids 90%).

In another preferred embodiment, the curcumin administered m the sham parenteral (administered intraperitoneally), in order to inhibit tumor growth in combination with irradiation of visible light, but only the use of curcumin or only light did not inhibit tumor growth.

The combination of visible and/or ultraviolet light with curcuminoids provides a synergistic effect which can be used for the treatment of all pathologies, in respect of which curcumin may be a potential activity. However, visible light is preferred because the systemic use of curcuminoids or cash equivalents makes possible the introduction of a medicinal product with a basic meal, and not two hours before irradiation.

Oral administration of curcumin, curcuminoids, their metabolites or their prodrugs with concomitant irradiation of visible and UV light allows you to avoid problems that are typically associated with photochemotherapy. With the systemic administration of curcumin and its analogues and simultaneous irradiation:

therapeutic efficacy of curcumin improves in vivo and the efficiency is achieved, exceeding the efficiency of the approved methods of treatment,

- with the introduction of curcuminoids there is no need to find the dose or to carry out the irradiation, if you are using visible light,

- clothes of the patients do not get dirty, improves emotional state of patients, and improve personal relationships PAC is having treatment

- when using visible light in combination with UV, patients tan evenly and without hyperpigmentation

- admissible treatment of pediatric patients, since there has been no adverse reactions

after phototherapy patients do not need protection from light, normalized levels of transaminases and the product in combination with irradiation is not hepatotoxic, after irradiation eliminates the use of corticoids and antihistamines or at least this need is reduced,

- adherence is simplified, and the patient does not refuse the treatment, you can increase the radiation dose received per session phototherapy to reduce the number of sessions of phototherapy, reduces the time required for bleaching psoriatic lesions,

- when using visible light does not occur secondary effects caused by the accumulation of ultraviolet light, while maintaining therapeutic efficacy.

In another aspect of the problem to be solved in the present invention is to create a device for phototherapy for the treatment of proliferative diseases, in particular, for the treatment of psoriasis with severity from mild to severe. Found by the authors of the present invention is phototherapeutic the mini-system, which differs in that it emits visible light on the surface, the area of which exceeds 0.2 m2and the radiation intensity exceeds 2 mW/cm2. In a preferred embodiment, the wavelength of maximum emission is 420 nm, the light source based on LEDs and optional device may be a source of ultraviolet light in order to stimulate the development of good pigmentation and a healthy tan.

The application of this analogy of the system together with the system by the introduction of curcumin or therapeutic equivalents has a higher efficiency than currently used UV cabin.

DETAILED description of the INVENTION

therapeutic efficacy of curcuminoids, in the form of curcumin, alcoholic extracts of turmeric (90% curcuminoid) or hydro-alcoholic extracts of turmeric (12% curcuminoid) in vivo increases with their systemic administration in combination with exposure to visible and UV light (315-550 nm).

Alternatively, the effectiveness of other therapeutic equivalents or analogs of curcuminoids, known from the existing art, for example, described in the article Anand et al Biochem Pharmacol. 2008 Aug 19. [electronic publication before printing], rhizomes of turmeric or cyklinowanie of curcumin in vivo increases under the action of spots the existing exposure to visible and ultraviolet light.

After oral administration of curcuminoids, the combination of visible light and curcuminoids shows the same efficacy in psoriasis with severity from moderate to severe, as the combination with UV light.

In the model on mice irradiated mice visible light in combination with intraperitoneally the introduction of curcumin was given a 70% inhibition of cell proliferation in squamous cell carcinomas of the person (A431). The combination of visible and ultraviolet light with systemically introduced curcuminoids will be effective in the treatment of tumors of any type, for example, epidermal tumors, tumors of the esophagus, duodenum, colon, breast, liver, kidney or prostate. In the case of visible light, you can use any radiation intensity and any type of light source, for example, non-coherent, polarized, pulsed laser light source, which is explained by the absence of secondary effects. In a preferred method, the radiation intensity is in the range 2-300 mW/cm2and more preferably the radiation intensity, which is in the range of 2-30 mW/cm2can be used for irradiation at the dose densities of 1 to 18 j/cm2.

The combination of curcuminoids and visible and ultraviolet light is therapeutically effective when more Naskidashvili compared to dosages, known from the existing art, for example, oral 1 mg/kg/day for psoriasis or administered intraperitoneally at 50 mg/kg/day for inhibition of tumor models in mice.

In research in vitiligo, the combination of curcuminoids with UV light in treated patients was caused pigmentation without burning. The combination of curcuminoids and visible light + UV light makes possible the development of uniform pigmentation in all patients treated curcuminoids and visible light.

Thus, it is possible to develop formulations containing at least curcuminoid, or their equivalents, together with excipients suitable for systemic injections, and optionally other active ingredients.

After creating a medicinal product which has the ability to increase its effectiveness in the introduction, which is accompanied by the irradiation of visible light, the professional in this field will be able to develop any phototherapy system, which includes means for emitting visible light with wavelengths 400-550 nm with the intensity of the radiation, greater than 2 mW/cm2on the surface, the area of which exceeds 0.20 m2. You can use light sources that include, for example, gas discharge lamps, LEDs, polarized the laser sources or solar radiation, past the filter.

Among the discharge lamps emitting light in the wavelength range 400-550 nm at the wavelength of maximum emission of 420 nm, Phillips presents TLK 40W/03 and Phillips TLK 140W/03. Their dimensions are 60×4 cm and 140×4 cm, respectively. Ten lamps Phillips TLK 40W/03, located at a distance of 45 cm, emit 5500 LC, that is, have a radiation intensity of 3 mW/cm2. Therefore, when reducing the distance between the light source and the irradiated surface will increase the intensity of the radiation. Source with a radiation intensity of 3 mW/cm220 minutes of radiation will provide a dose density of 3×20×60/1000 j/cm2= 3,6 j/cm2. These lamps can be easily installed in existing phototherapy booths that use a discharge lamp ultraviolet light.

The development of led technology allows to obtain radiation with higher relative luminous efficiency in a very narrow range of wavelengths emitted by the light (± 5 nm), which can be used for phototherapy. In article, J Invest Dermatol. 2002 Jul;119(1): 77-83 described the use of led panels for irradiation of the surface 30 cm2when the intensity of the radiation 9-11 mW/cm2however , the distance between the source and psoriatic plaque was not specified. Reducing the distance between the source and the irradiation of emoi surface will increase the intensity and decrease the exposed surface area. Irradiating from a distance of 5 cm can be achieved emission intensity of 30 mW/cm2when using modern commercial LEDs.

Similarly, increasing the number of led panels increases the irradiated surface. In order to treat psoriasis with severity from moderate to severe, you can use 60 panels by size 12×25 cm, similar to the panels described in article J Invest Dermatol. 2002 Jul;119(1):77-83, which will irradiate the entire surface of the body of an adult if the radiation intensity of 30 mW/cm2from a distance of 5 cm

It should be noted that a small spectral variations in emission or in the angles of incidence will affect radiometric measurements.

EXAMPLES

I. Effect of oral introduced hydroalcoholic extract of Curcuma longa in combination with UV light for psoriasis with the severity from moderate to severe

A pilot clinical trial was designed to treat patients diagnosed with psoriatic plaques moderate or severe and other treatments, for example, cyclosporine, psoralens/UFA or corticosteroids, previously not give the proper result. Research options:

- Number of patients: 22.

- Duration of test: 8 weeks // 16 sessions of irradiation with ultraviolet light.

- Drug therap the I: 24 mg of curcuminoids, in the form of a hydroalcoholic extract of Curcuma longa with the concentration of curcuminoids 12%. Excipients used in the composition: cellulose, magnesium stearate, corn starch, sodium starch glycolate, potassium phosphate, and silicon dioxide. pH one tablet dispersed in water (5% wt./vol.), was 5.

Extract of turmeric was obtained in accordance with the following process: extraction of Curcuma longa rhizomes ethanol, evaporating the solvent and quantitative determination of the content of curcuminoids in terms of curcumin; extraction of rhizomes from the previous stage with water and evaporation of the solvent; the resulting extracts were mixed and the obtained extract with a concentration of curcuminoids 10-15%.

- Scheme of administration: 3 tablets/day before meals (72 mg curcuminoids/day).

- Source: cabin PUVA COMBI LIGHT with 32 lamps Philips UVA 100 W (range 315-400 nm, maximum emission 365 nm).

- Irradiated surface: the entire surface of the naked body except the genitals, approximately 2 m2.

- Dose density: 2 sessions of phototherapy in the week. The initial dose density was 2.5 j/cm2. The density of the dose was increased by 0.5 to 1 j/cm2until he reached a slight reddening of the skin, and then with every session, it was increased by 2 j/cm2until he reached 16 j/cm2. The exposure time to achieve the PLO the particular dose of 16 j/cm 2approximately 30 minutes.

Funds emergency care:

- Softening composition containing vitamin B3, to relieve symptoms of skin manifestations.

- Desloratadin when bouts of itching.

Patients had skin types I, II, III, IV phototype. The average weight was 70 kg

The decrease in PASI for different visits V1-V16 (2 visits per week) is described in the following table. Patients who achieved PASI reduction of more than 90%left the study.

The decrease in PASI

For example, patients 1, 2, 3, and 9 received the following doses:

Patient1239Patient1239
PhototypeIIIIIIIVPhototypeIIIIIIIV
Visit 12,5 2,52,52,5Visit 1015,51615,515
Visit 23,53,53,53,5Visit 1116161615,5
Visit 34,54,54,54Visit 1216161616
Visit 45,55,55,55Visit 1316161616
Visit 55,57,56,56 Visit 1416161616
Visit 67,59,58,58Visit 1516161616
Visit 79,511,510,510Visit 1616161616
Visit 811,513,512,512
Visit 913,515,514,514

22 the patient has reached the density of the radiation dose of 16 j/cm2and the total dose density was approximately 170-180 j/cm2. No patient refused treatment and radiation was well tolerated without severe phototoxic reactions. Only one patient received the tablet desloratadine 5 mg

After the 7th session of phototherapy in patients appeared healthy tan without spots or hyperpigmentation. Hyperpigmentation has not appeared in any patient.

Liver enzymes were within normal limits, and hepatotoxicity was not identified. Observed an increase in the red series.

At the end of the trial the patients were satisfied with the treatment and noted that their self-esteem and personal relationships have improved.

These results indicate the possibility of using curcumin, curcuminoids, their metabolites or prodrugs as sunscreen filters against visible and ultraviolet radiation. That is, hyperpigmentation did not occur in patients with skin III and IV types, as well as in patients with fair skin had no freckles and redness.

In the middle of the test after four weeks and only 8 sessions of phototherapy, 50% of patients achieved a PASI reduction of more than 75%. Efficiency in the middle of the test was similar to the efficacy of the drug e is alsuma 12 weeks and without secondary effects.

All patients achieved a PASI reduction of 80%.

II. The influence of oral introduced hydroalcoholic extract of Curcuma longa in combination with visible light for psoriasis with the severity from moderate to severe

Research options:

- Number of patients: 10.

- Duration of test: 8 weeks // 16 sessions of phototherapy visible light.

- Drug therapy: 24 mg of curcuminoids in the form of a hydroalcoholic extract of Curcuma longa with the concentration of curcuminoids 12%. Excipients used in the composition: cellulose, magnesium stearate, corn starch, sodium starch glycolate, potassium phosphate, and silicon dioxide. pH one tablet dispersed in water (5% wt./vol.), was 5. The turmeric extract was also obtained, as in the previous test.

- Scheme of administration: 3 tablets/day before meal (72 mg curcuminoids/day).

- Light source: lamp Phillips TLK 40W/03 giving 5500 Lux visible light 100×40 W, the range of 400-550 nm, the maximum emission of 420 nm.

- Irradiated surface: 100×60×4 cm = 2.4 m2the surface of the naked body.

- Dose density: 2 sessions of phototherapy in the week. Emitted dose density was 18 j/cm2, irradiation duration 1 hour and 40 minutes.

Funds emergency care:

- Softening composition containing vitamin B3, to relieve symptoms of skin manifestations.

- Desloratadin PR the attacks of itching.

Participating in the study patients had skin II and III of the phototype. The average weight was 70 kg

The decrease in PASI for different visits VT-V16 (2 visits per week) are detailed in the following table. Patients who achieved PASI reduction of more than 90%left the study.

The decrease in PASI

no visitPatient
12345678910
V12317483040423725030
V225405442355049 541242
V331386361445765462557
V439507762476969662666
V547708070477581723973
V656788368697983 724567
V745788569697886774867
V868798970758887795978
V965869278799391836583
V107082808585 7385
V1179858485807686
V1279848791848095
V137987858784
V148281868884is the
V158589888886
V168590898887

The obtained results indicate that the irradiation of visible light was achieved the same efficiency as when irradiated with ultraviolet light. All patients achieved a PASI reduction of more than 80% in less than 8 weeks of treatment.

Patients received treatment and was not necessary to enter antigistaminny tools and corticosteroids.

III. The influence of oral ingested alcoholic extract of Curcuma longa in combination with visible light for psoriasis with the severity from moderate to severe

A clinical trial was performed on 4 patients, whose average age was 48 years, mean weight was 68 kg, and have had diagnostic the van with psoriasis severity from mild to severe.

As a diagnostic criterion used PASI psoriatic plaques on the back or tummy with a surface area of 30-35 cm2.

Spent the irradiation led lamp with the wavelength of maximum emission of 420 nm. Irradiation was carried out from a distance of 5 cm when the radiation intensity of 30 mW/cm2through the surface 40 cm2.

After attending screening for the removal of the electrocardiogram and the analytical determination of the indicators selected patients, each patient was chosen the most significant plaque with a surface area of 30-35 cm2.

On the day the patients took one capsule containing 280 mg of curcuminoids, in terms of alcohol extract with a concentration of curcuminoids 90%. The selected plaque began to irradiate a week after the beginning of treatment with turmeric extract and continued to be exposed to the phototherapy sessions twice a week. The initial density of the dose was 2 j/cm2and gradually increased up to 16 j/cm2.

Four patients achieved a PASI reduction of irradiated plaques more than 90% relative to the baseline after 8 weeks.

IV. The influence of oral introduced hydroalcoholic extract of Curcuma longa in combination with UV light for vitiligo

Six patients diagnosed with vitiligo received 3 tablets water-alcohol extra is that turmeric per day (72 mg curcuminoids/day) and irradiation in the UV cabin (range 315-400 nm, the maximum emission 365 nm). The initial dose density was 1 j/cm2and increased at 2 j/cm2up to 7 j/cm2. The last sessions of irradiation was carried out at the density dose of 8 j/cm2.

- 1 patient. Generalized vitiligo with a large focus on the face. 8 sessions of phototherapy. Quickly formed a tan without burning and redness.

- The patient 2. Vitiligo with lesions on the hands, chin and legs. 8 sessions of phototherapy hands at a density dose of 12 j/cm2. Pigmentation areas appeared on the edges of some lesions of vitiligo.

- The patient 3. Widespread vitiligo associated with fibromyalgia and thyroid disorder. 8 sessions of phototherapy. A good tan. Watched the process of restoration of pigmentation on the neck.

- The patient 4. Widespread vitiligo. 8 sessions of phototherapy. The hypothyroidism. Increase of tan without burning. Pigmentation appeared on the belly.

- The patient 5. Widespread vitiligo with large lesions on the face. 8 sessions of phototherapy. A good tan without burning. The appearance of pigmentation on the face and neck.

Patient 6. Widespread vitiligo with large spots on the face. 8 sessions of phototherapy. A good tan. Vitiligo in the joints. The presence of pigmentation on his elbows.

V. Influence intraperitoneal injection of curcumin in the inhibition of tumor growth in mice

<> Naked Nude mice (NMRI) (5-6 weeks of age, 20-24 g) in the left and right flanks were injected subcutaneously injection of 5×106cells A431 (epidermal carcinoma person). Mice were fed sterile conditions. The animals were fed sterilized food ad libitum. Animals were sterilized by ketamine/xylazine. For the treatment of 5 mg of curcumin was first dissolved in 50 μl of ethanol, and optionally diluted in 2 ml of 1% methylcellulose and sterilized. On the day the mouse was administered intraperitoneally received 200 μl of the specified solution or solution of methylcellulose. 50 mg of curcuminoids/kg / day.

One group of mice (curcumin and methylcellulose) after injection were irradiated for 20 minutes with light 5500 LC. Was used for irradiation of 10 lamps Phillips TLK 4 0W/03 (length 60 cm H 4 cm in diameter), with a distance of 45 cm Lamps emit wave lengths in the range of 400-550 nm with maximum at 420 nm.

The control group received methylcellulose and curcumin, the animals were protected from light for 1 hour after injection. Tumor size was measured at the beginning of the experiment and after 10-12 days; subsequently, the volume and weight of tumors were determined twice a week. At the end of the experiment, after 29 days, the animals were anestesiology and squashed.

The results indicate that only in the group that was treated with curcumin and light manifested a significant difference in the inhibition of tumor growth compared on the Yu with the control group. On day 12 of mice treated with curcumin and light, the average tumor volume was reduced by 70% compared to control mice. In the group of mice treated with curcumin without light, tumor volume was not significantly less (p=0,16), i.e. visible light increased the efficiency of curcuminoids in vivo.

1. Cosmetic method for uniform tanning of human skin for patients with psoriasis without hyperpigmentation, including the introduction of curcumin or its derivatives, where the dose is 1 mg/kg per day, which is administered orally in combination with exposure to ultraviolet radiation in the range from 315 to 400 nm at a density of doses from 1 to 18 j/cm2.

2. Cosmetic method for uniform tanning of human skin for patients suffering from vitiligo without hyperpigmentation, including the introduction of curcumin or its derivatives, where the dose of 72 mg/day, which is administered orally in combination with exposure to ultraviolet radiation in the range from 315 to 400 nm at a density of doses from 1 to 8 j/cm2.

3. The use of pharmaceutical compositions containing curcumin or its analogue for use in the treatment of psoriasis with severity from moderate to severe in combination with visible radiation with a wavelength of emission from 400 to 550 nm, where
a. curcumin is administered orally;
b. minimum dose of curcumin sostav the em 1 mg/kg / day;
c. psoriatic plaques of a patient exposed to radiation with a dose of 2.5 - 16 j/cm2twice a week;
d. stages a) and b) are repeated until such time as the cumulative exposure dose is 170-180 j/cm2.

4. The use according to claim 3, characterized in that the dose of curcumin is 72 mg/day.

5. The use according to claim 3, characterized in that the dose of curcumin is 280 mg/day and the maximum wavelength of the emission radiation is 420 nm.

6. The use according to claim 3 or 4, characterized in that the radiation is exposed to the whole human body.



 

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SUBSTANCE: present invention relates to organic chemistry and specifically to novel morpholinopurine derivatives of general formula

,

or a pharmaceutically acceptable salt thereof, where R1 and R2, each independent of each other, denote a C1-C6 alkyl group or a hydrogen atom, R3a and R3b, each independent of each other, denote a C1-C6 alkyl group which can contain three substitutes selected from a group A, or a hydrogen atom, R4 denotes a C1-C6 alkyl group or a hydrogen atom, Ra denotes a group of formula -Y-R , where Y denotes a single bond or a C1-C6 alkylene group, R5 is a C1-C6 alkyl group which can contain one, two or three substitutes selected from group A, a tetrahydrofuranyl group, a pyrrolidinyl group which contains one substitute selected from a group D, and Rb and Rc, each independent of each other, denote a C1-C6 alkyl group which contains one substitute selected from a group E, or a hydrogen atom, or Rb and Rc, together with a nitrogen atom to which they are bonded, for a 5-7-member alicyclic nitrogen-containing heterocyclic group, which is pierazine, morpholine, pyrrolidine, piperidine, homopiperazine, which can contain one, two or three substitutes selected from group E; group A: halogen atom, hydroxy group, C3-C8 cycloalkyl group and oxy group; group D: C1-C6 alkylsulphonyl group; and group E: hydroxy group, formyl group, C1-C6 alkyl group, which can contain one substitute selected from said group A, diC1-C6 alkylamino group, C1-C6 alkylsulphonylamino group, C1-C6alkylsulphonyl C1-C6 alkylamino group, C1-C6 alkylsulphonylamino C1-C6alkyl group, C1-C6alkylcarbonyl group, which can contain one substitute selected from said group A, C1-C6 alkylsulphonyl group, C1-C6 alkylamino C1-C6 alkylcarbonyl group, diC1-C6 alkylamino C1-C6alkylcarbonyl group, which can contain one substitute selected from said group A, diC1-C6 alkylaminocarbonyl group, phenylsulphonyl group and hateroaryl C1-C6 alkylcarbonyl group, where the heteroaryl is imidazolyl. The invention also relates to a pharmaceutical composition, an inhibitor of phosphatidylinositol-3-kinase (PI3K), an inhibitor of mammalian target of rapamycin (mTOR) based on the compound of formula (1a), a method of treating cancer and use of the compound of formula (1a).

EFFECT: obtaining novel morpholinopurine derivatives, having useful biological properties.

42 cl, 19 tbl, 138 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula

,

using them as tubulin polymerisation inhibitors and PARP inhibitors, and also as an ingredient of pharmaceutical compositions containing the above compounds of formula (I), wherein R1, R2, R3, R4, R5, R6, R7 and Y have the values specified in the patent claim.

EFFECT: preparing intermediate compounds for preparing the compounds of formula (I) and a method for preparing the intermediate compounds.

16 cl, 3 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an acid addition salt of a compound of formula (1), formed by L-lactic acid. The compound (1) can be used as a Hsp90 inhibitor. Described are methods of producing a compound of formula (1), intermediate compounds used to produce a compound of formula (1) and methods of producing the intermediate compounds.

EFFECT: obtaining an acid addition salt of a compound of formula (1), formed by L-lactic acid.

10 cl, 22 dwg, 4 dwg, 22 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to oncology and radiology. The method involves the local radiation therapy sessions in a dynamic dose fractionation mode. Additionally, 3 times a week the local radiation therapy session is immediately followed by subtotal irradiation of the upper body from a suprasternal notch to a diaphragm. Thereafter, 21-28 days after the local radiation therapy completed, min. 4 cycles of the chemotherapy with each cycle combined with subtotal irradiation of the upper body from the suprasternal notch to the diaphragm 3 times a week.

EFFECT: method enables reducing a risk of developing a local recurrence of the tumour and metastases to 10,7% as compared to the previously known methods (15%), as well as a severity of complications with achieving the complete objective response to the treatment in 35,7% of the patients, and the partial response - in 46,42%.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and may be used for the purpose of the integrated treatment of the patients with II-IV breast cancer. That is ensured by administering cytostatic preparations after the one-stage chemotherapy, including: cyclophosphan (500 mg/m2) and doxorubicin (50 mg/m2) (the schedule AC) or cyclophosphan (500 mg/m2), doxorubicin (50 mg/m2) and fluorouracil (500 mg/m2) (the schedule FAC) intravenously. Besides, the preparation Panagen in the form of gastroenteric-coated tablets 30 mg/day is regularly divided over an active period of day that makes one tablet of the preparation Panagen for six times every two hours; the administration starts on the third day following the chemotherapy. The length of the administration of the preparation Panagen is 17 days and continued until the chemotherapeutic courses according to the above schedules completed.

EFFECT: method enables the higher clinical effectiveness in breast cancer that ensures preserving and stimulating granulocyte-macrophage and lymphocyte hematopoietic lineages that makes compensation for the negative effect of leukoreducing effect of the cytostatic preparations.

1 cl, 40 dwg

FIELD: biotechnologies.

SUBSTANCE: invention relates to compounds of general formula I, having cytostatic or cytotoxic activity, its pharmaceutically acceptable salts, tautomers or stereoisomers, a pharmaceutical composition on their basis. Compounds may be used for treatment of cancerous diseases. In the general formula I

Y is selected from the group comprising -CHRay- and -CHRay-CRby-CRcy-; each Ray, Rby and Rcy are independently selected from hydrogen and non-substitute C1-C12-alkyl; each R1, R2, R3, R4 and R5 are independently selected from hydrogen and non-substitute C1-C12-alkyl; R6 is selected from NR8R9 and OR10; A means , W means NR7; R7 means hydrogen; R8 means hydrogen; R10 means non-substitute C2-C12-alkenyl; each dotted line means unnecessary additional link, but when there is a triple link between atoms of carbon, to which R1 and R2 are attached, then R1 and R2 are absent, and when there is a triple link between carbon atoms, to which R3 and R4 are attached, then R3 and R4 are absent; R9 is selected from substitute C2-C12-alkenyl and substitute C4-C|2-alkenylyl, where substitutes are selected from the group, consisting of: halogen, OR', OCONHR' and OH, protected with a simple silyl ether; where R' means hydrogen; provided that whenever Y means -CHRay-CRby=CRcy- and there is a single or double link between atoms of carbon, to which R3 and R4 are attached, then R9 means substitute C4-C12-alkenylyl; and each R16, R17 and R18 are independently selected from hydrogen and ORa; each Ra is selected from hydrogen or non-substitute C1-C12-alkyl.

EFFECT: higher efficiency of compound application.

FIELD: biotechnologies.

SUBSTANCE: invention relates to new compounds of the formula I:

or its pharmaceutically acceptable salts, where values R1, R2, R3, R3', R4, R4', X2, X1, X3, X4, X5, R6, R7, R5', R6', R7', R14', R8, R9, R10, R11a, b, c are specified in the clause 1 of the formula.

EFFECT: compounds demonstrate antitumoral activity and may be used to produce a pharmaceutical composition for tumor treatment in a mammal.

14 cl, 18 dwg, 1 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and concerns a combined pharmaceutical composition for treating skin diseases. The composition contains betamethasone, preferentially betamethasone dipropionate, urea and at least one adjuvant. As adjuvants, the composition contains a hydrophobic component, an emulsifier, a preserving agent, a buffer agent, a non-aqueous solvent and water. A method for preparing the declared composition consists in the fact that the melted hydrophobic component, emulsifier and water are emulsified, and then betamethasone and the preserving agent are introduced at temperature below 60°C, homogenised and added with a prepared solution of urea and the buffer agent.

EFFECT: pharmaceutical composition is characterised by high pharmacological activity, stability, uniform distribution of the active ingredients.

7 cl, 8 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method relates to medicine, particularly to dermatology, and may be applied in treating guttate psoriasis. For this purpose, with underlying ointment therapy, the narrow-band medium-wave UV-radiation is applied at wave length 311 nm. That is preceded by prescribing Perfloxacin 400 mg twice a day for 5-7 days.

EFFECT: method enables reducing a number of procedures, reducing a dose of the medium-wave UV-radiation, ensuring the faster clinical effect and prolonging the remission, arresting a comorbidity, reducing a probability of side effects and complications.

2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of dermatology and represents application of 1-aminoalkylcyclohexane derivative, selected from neramexane and its pharmaceutically acceptable salts for treatment or prevention of inflammatory skin diseases, which represent acne, irritant dermatitis, impetigo and atopic dermatitis.

EFFECT: invention ensures extension of arsenal of medications for treatment of inflammatory skin diseases.

39 cl, 7 ex, 35 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an agent for neutralising toxic action of tumour necrosis factor on the basis of hydrated pyrido(4,3-b)indoles of formula (1), a pharmaceutical agent on the basis thereof, and a method of treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

EFFECT: preparing the agent for treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

13 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method relates to medicine, particularly to dermatology, and may be applied in treating psoriasis vulgaris. That is ensured by a therapy involving a combination of the hepatoprotector Phosphogliv and an external non-hormonal therapy. Phosphogliv is prescribed according to the schedule: 2.5 mg intravenously once a day for 10 days, then orally 1 capsule 3 times a day; and the non-hormonal preparation is Cinocap cream 3 times a day; the therapeutic course makes 4 weeks.

EFFECT: invention enables reducing a risk of complications and side effects and prolongs remission ensured by anti-inflammatory, hypolipidemic, immunomodulatory action of the prescribed preparations.

FIELD: medicine.

SUBSTANCE: what is presented is the use of xenon in the form of an agent for external therapy of chronic recurrent inflammatory dermatopathies prepared by extra pure grade xenon saturation of a fatty base.

EFFECT: what is shown is considerable reduction of an inflammatory reaction on the second therapeutic day in such polygenic chronic inflammatory diseases, as psoriasis, atopic dermatitis, acne, acne rosacea, eczema.

4 ex

FIELD: medicine.

SUBSTANCE: method relates to medicine, particularly to dermatology, and may be applied in treating psoriasis vulgaris. For this purpose, a patient is exposed to narrow-band medium-wave ultraviolet (UV therapy) at wave length 311 nm. It is combined with introducing liptonorm 10 mg once a day for 21-28 days. The UV therapeutic course makes 10 procedures.

EFFECT: method provides fast and prolonged clinical remission of the disease, as well as reduced side effects of the therapy due to the specified UV exposure mode and liptonorm introduction ensuring high photosensitising effect.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to solid forms of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulphonylethyl]-4-acetylaminoisoindoline-1,3-dione of formula (I) inhibiting TNF-α or PDE4 production that enables using them in treating psoriasis.

EFFECT: producing an agent for treating psoriasis.

36 cl, 14 tbl, 33 dwg, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition for local application containing fusidic acid within the range of 1 wt % to 5 wt % and mometasone within the range of 0.05 wt % to 2 wt % and a pharmaceutically acceptable carrier to be applied in treating or preventing inflammatory dermatoses caused by a secondary bacterial infection in a patient.

EFFECT: invention provides effective elimination of secondary bacterial infections in dermatologic injuries.

11 cl, 8 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to using phytoecdysone for preparing a composition for reducing abdominal fat in mammals. Using 20-hydroxyecdysone for preparing the composition for reducing abdominal fat in mammals with 20-hydroxyecdysone introduced as pure 20-hydroxyecdysone, or in the form of saponin-free quinoa extract.

EFFECT: presented 20-hydroxyecdysone effectively reduces abdominal fat in mammals.

8 cl, 5 dwg, 2 tbl, 3 ex

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