WO2009031916A1

WO2009031916A1 - Vip antagonists in the form of an agent for treating psoriasis

Info

Publication number: WO2009031916A1
Application number: PCT/RU2008/000043
Authority: WO
Inventors: Ilya Davidovich Ionov
Original assignee: Ilya Davidovich Ionov
Priority date: 2007-09-05
Filing date: 2008-01-28
Publication date: 2009-03-12
Also published as: RU2007133287A

Abstract

The invention relates to medicine, in particular to the treatment of skin disease psoriasis. The inventive antipsoriatic agent is used for local application to the injured skin and comprises at least one antagonist of vasoactive intestinal (poly)peptide selected from a group comprising : VIP(6-28); VIP(10-28);[LyS(I), Pro(2,5), Arg(3,4), Tyr(6)]-VIP; [D-p-Cl-Phe(6), Leu(17)]-VIP; [Acetyl-His(l), D-Phe(2), Lys(15), Arg(16), Leu(27)]-VIP(l-7)/GRF(8-27)-NH2; [Myristoyl-His(l),Lys(12,27,28), Gly(29,30), Thr(31)]- VIP-NH2; [Acetyl-His(l),D-Phe(2),Lys(15),Arg(16),Leu(17)]-VIP; neurotensin(6-11)VIP(7-28); [Acetyl-ffis(l), D-Phe(2), Phe(4-Cl)(6), Har(9),Tyr(Me)(10), Abu(15), Nle(27), D-Arg(28), Har(29)]GRF(l-29)-NH2; [Acetyl-His(l), D-Phe(2), Phe(4-CI)(6), Lys(15), Arg(16), Lys(20), Tyr(22), Nle(27), D-Arg(28),Har(29)]GRF(1-29)-NH2; [Acetyl-His(1), D-Phe(2), Lys(15), Leu(17)]VIP(3-7)/GRF(8-27); [Acetyl-His(1), D-Phe(2), Lys(15), Arg(16)]VIP(3-7)/GHF(8-27)-NH2; [Acetyl-Tyr(l), D-Phe(2)]-GRF(l-29)-NH2; [N-stearyl, norleucine17]VIPhybrid; Leu-Met-Tyr-Pro-Thr-Tyr-Leu-Lys; [D-Phe2[VIP; PACAP(6-27); PACAP(6-38). The treatment by means of the inventive agent brings about a permanent therapeutic effect.

Description

VIF antagonists as a treatment for psoriasis

The invention relates to medicine, dermatology, in particular, to methods for treating psoriasis.

A known method of treating psoriasis [EP 1556020 (A2), A61K 31/00] by applying to the affected area of the skin a preparation containing blockers of the “peptide related to the calcitonin gene” [English. Calcitopip Gepe-Relat Repertide, CGRP)]. Data on the intensity of the therapeutic effect caused by this method, and on the duration of this effect are not given.

There is also known a method for the treatment of psoriasis by intravenous administration of the peptide T (testide T) [AST Derm Vpegheol. 1991; 71: 479-83]. Peptide T is an octapeptide of the structure Ala-Ser-Thg-Thg-Thr-Asp-Tug-Thr. This substance is similar in structure to the physiological factor "vasoactive intestinal peptides" (English. Vasoactive testosteride, synonymous with Vasoactive testosterone, VIP) [FEBS Lite. 1987; 211: 17-22], although it does not have the ability to either stimulate VIP receptors or block them [Pertides 1988, 9: 425-8; BIOSI Rp. 1994.14: 251-7]. The disadvantage of this method is the limited therapeutic effect. So, after 28 days of substance administration, the area of skin areas affected by psoriatic rashes decreased by less than 50%.

Closest to the proposed election on the technical nature is the method of treatment of psoriasis with the drug “antipsiotic” [B.H. Morodtsev et al. Psoriasis. Chisinau, Shtiintsa, 1991], which is an ointment of the following composition:

Trichlorotriethylamine - 1 part,

Medical Vaseline, 40,000 or 100,000 parts.

The disadvantage of this method is that the clinical effect is observed only in some patients and lasts basically no longer than 2-3 months.

According to modern concepts, the key role in the development of the psoriatic process is played by two neurotransmitters located in the skin: CGRP and “Station P” (EP 1 556 020 (A2), A61K31 / 00; Progr Vraip Res. 2004; 146: 433-7). In the light

SUBSTITUTE SHEET (RULE 26) of these representations, the antipsoriatic effect in antagonists of these neuropeptides seems highly probable. At the same time, the current level of technology does not give reason to assume antipsoriatic action in antagonists of such a neuropeptide as VIP. On the contrary, it seems reasonable to expect the activation of the psoriatic process under the influence of VIP antagonists. VIP got its name for its intense vasodilator effect (J Arrl Prussiol. 2004.97: 1291-8), and inhibition of vasodilator, as established using β-blockers, leads to exacerbation of psoriasis (J Am Acad Dermatol. 1988.19: 837- 41). In addition, in vit vit experiments it was found that the VTP antagonist enhances the proliferation of keratinocytes (J Ipvest Dermatol. 1992, 98: 421-7), i.e. able to have a direct stimulating effect on the psoriatic process. This effect was found in the VIP peptide (10-28) (a fragment of a VΙP molecule consisting of amino acid residues from 10th to 28th), which has the properties of an antagonist of VDP receptors (Рertides, 1986, 7: 849-54).

Thus, from the prior art, it is possible to predict the ability of VIP antagonists to increase the severity of the psoriatic process.

The objectives of the present invention are to increase the effectiveness of the treatment of psoriasis by increasing the duration of the recurrence periods, as well as expanding the arsenal of means of influencing the psoriatic process. The problem is solved using various VTP antagonists, which, contrary to the above forecast, in clinical conditions have antipsoriatic efficacy.

The duration of the effect caused by VJP antagonists significantly exceeds that for the prototype and is at least 3 years.

The method is as follows. A mixture is prepared consisting of at least one VIP antagonist in an effective concentration and one or more pharmaceutically acceptable excipients and carriers. The resulting mixture is applied to the affected area of the skin of a patient with psoriasis.

SUBSTITUTE SHEET (RULE 26) VIP peptide antagonists are used, which are derivatives of several neuropeptides: VIP, the “hormone releasing hormone factor”, the “hormone receptor receptor activating receptor” receptor receptor. and neurotensin (English. peurotepsip).

The VIP antagonist is selected from the group consisting of the following substances:

VIP (6-28);

VTP (10-28);

[Lys (l), Pro (2.5), Arg (3.4), Tyr (6)] - VIP;

[D-p-Cl-Phe (b), Leu (17)] - VIP;

[Acetyl-His (l), D-Phe (2), Lys (15), Arg (16), Leu (27)] - VTP (l-7) / GRF (8-27) -NH ₂ ;

[Myristoyl-His (l), Lys (12.27.28), Gly (29.30 x Thg (31)] VIP-NH ₂ ;

[Acetyl-His (1), D-Phe (2), Lys (15), Arg (16), Ley (17)] - VIP; neugotensin (6-l l) VIP (7-28);

[Acetyl-His (l), D-Phe (2), Phe (4-Cl) (6), Har (9), Tyr (Me) (10), Abu (15X Nle (27), D-Agg ( 28), Ha (29)] GRF (l-29) -NH ₂ ;

[Acetyl-His (l), D-Phe (2), Phe (4-Ciχб), Lys (15), Arg (16), Lys (20), Tyr (22), Nle (27), D-Arg (28), Har (29)] GRF (l-29) -NH ₂ ;

[Acetyl-His (l), D-Phe (2), Lys (15), Leu (17)] VIP (3-7) / GRF (8-27),

[Acetyl-His (l), D-Phe (2), Lys (15), Arg (16)] VTP (3-7) / GHF (8-27) -NH ₂ ; [Acetyl-Tyg (1), D-Phe (2)] - GRF (1 -29) -NH ₂ ;

[N-stearal, norleucinel7] VIPhybrid;

Leu-Met-Tur-Pro-Thr-Tur-Leu-Lus; p-Phe2 [VIP;

PACAP (6-27);

PACAP (b-Zδ).

These peptides have been found to have the ability to inhibit the process of exposure of VIP to sensitive tissues (Epidogologu. 1985, 116: 2643-9;

SUBSTITUTE SHEET (RULE 26) Am J Phusiol. 1986, 250: G553-7; J MoI Neurossi. 1994-1995.5: 231-9; J Phusiol. 1996, 493: 503-15; Pertids 2000, 21: 1543-8; Rros Natl Acad Sсi USA. 2000, 97: 1218-23; Br J Pharmacol. 2004, 143: 107-18; J Surg Res. 2007,141: 22-30), i.e. are antagonists of VIP.

Each of the above VIP antagonists was investigated by topical application to psoriasis on damaged skin. The drugs were applied twice a day, morning and evening.

Under the supervision were 112 patients aged 15 to 64 years, of which 63 men and 49 women. All patients received one of the drugs in monotherapy. In the group of patients receiving the drugs, 78 patients suffered from common plaque psoriasis with lesions of more than 50% of the skin, 17 patients with teardrop-coin-like psoriasis, 5 patients with palm-plantar form of psoriasis, 7 patients with psoriasis with a pronounced exudative component, 5 patients with psoriatic erythroderma. A progressive stage of the disease was observed in 83 patients, stationary - in 29. The duration of the disease ranged from 6 months to 27 years.

All patients received a drug containing a VIP antagonist for 28 days.

Already on the 8th – 9th day of treatment, peeling ceased in patients; by the 15th day, swelling and hyperemia of the affected skin areas sharply decreased. By 45-50 days after the start of treatment, 106 patients had complete cleansing of the skin, which lasted at least 3 years. In 6 patients, treatment was not effective, all of these patients abused alcohol during the treatment process.

Example 1. Patient O., 48 years old. Upon receipt of a complaint of rashes throughout the body and periodic intolerable skin itching. Psychologically depressed. Has psoriasis for 12 years. Over the past 5 years, significant remissions were not observed, despite ongoing inpatient and outpatient treatment using various drugs, including hormonal ones. Objectively: on the trunk and extremities, extensive plaques covered with gray scales. On the periphery

SUBSTITUTE SHEET (RULE 26) of individual plaques, small papules of saturated red color are noted. The isomorphic Köbner reaction appears. Diagnosis: common psoriasis, plaque variety, progressive stage, autumn-winter form. For the purpose of treatment, a preparation containing Dp-Cl-Phe (b), Leu (17)] - VIP was applied to the affected areas of the skin. After 5 days, the patient noted a complete cessation of itching, peeling stopped on the 9th day of treatment. Starting from 13 days, puffiness and hyperemia of plaques began to decrease sharply, from 18 days in the area of foci areas of skin enlightenment began to appear. By the 50th day from the start of treatment, weak redness remained at the site of the plaques, in some cases slightly showing hyperpigmentation. By this moment, the patient had not noted any subjective manifestations of the disease. During the entire period of treatment, the patient was in good health. Treatment-induced remission lasts 3 years 8 months.

Example 2. Patient L., 53 years old. Upon receipt of a complaint of rashes throughout the body and severe itching, most pronounced in the anal area and in the armpit. He has psoriasis for 19 years. The disease began with small red spots on the extensor surfaces of the forearms, the spots subsequently spread throughout the trunk and extremities. In place of the spots, “geographic” plaques formed, intense skin itching appeared. The process escalates in the winter. Periodically received various medications, as well as physiotherapeutic and balneological treatment. Treatment gave a slight short-term effect. Objectively: more than 50% of the skin is affected by plaques covered with grayish-yellow scales. Some scaly layers are oyster-like. Plaques tend to peripheral growth. On the periphery of the plaques, the triad of signs is positive. Diagnosis: common psoriasis with an exudative component, progressive stage, autumn-winter form. For treatment, a preparation containing VTP (IO-28) was applied to the affected areas of the skin. After 7 days, peeling and itching were significantly reduced. By day 15, most of the plaques noticeably brightened. By day 18, puffiness of the skin disappeared, in place of plaques, slight redness, periodically short-term itching. By day 40, complete cleansing of the skin and the complete disappearance of unpleasant subjective sensations were noted. Wellness throughout the entire period of treatment is good.

SUBSTITUTE SHEET (RULE 26) It was observed within 3 years after the treatment, during this period, no new exacerbations were noted.

Example 3. Patient Yu. 39 years old. Upon receipt of a complaint of rashes on the palms, periodic severe itching in the area of rashes. Rashes appeared 1.5 years ago. The disease began with small red spots, in the area of which after 5-6 months itching, swelling and peeling began. The process escalates in the winter. He was periodically treated in the clinic and on his own, using drugs that he learned about from television advertising. The treatment did not give a significant effect. Objectively: on the palms of the spot are bright red in color, the skin is swollen, with a partially exfoliated stratum corneum. Diagnosis: psoriasis, palmar-plantar form, stationary stage. For the purpose of treatment, a preparation containing [Acetyl-His (l), D-Phe (2), Phe (4-Cl) (6), Lys (15), Agg (lb), Lys (20) was applied to damaged skin Tyr (22), Nle (27) ₅ D-Agg (28), Har (29)] - GRF (l-29) -NH2. After 7 days, peeling significantly decreased, itching decreased. By the 12th day, the spots began to noticeably lighten, by the 18th day, the swelling of the skin disappeared. By day 25, there was a slight redness at the site of the rash, periodically there was a slight short-term itching. By day 40, complete cleansing of the skin and the complete disappearance of unpleasant subjective sensations were noted. Wellness throughout the entire period of treatment is good. It was observed for 3 years 2 months after the treatment, with no new exacerbations noted.

SUBSTITUTE SHEET (RULE 26)

Claims

CLAIM

1. A medicine for the treatment of psoriasis, applied by local exposure to affected skin, characterized in that it contains at least one antagonist of a vasoactive intestinal (field) peptide in an effective concentration and one or more pharmaceutically acceptable excipients and carriers.

2. The drug according to claim 1, characterized in that the antagonist of the vasoactive intestinal (field) peptide is selected from the group including:

VIP (6-28);

VIP (10-28);

[Lys (l), Pro (2.5), Arg (3.4), Tyr (6)] - VIP;

[D-p-Cl-Phe (6), Leu (17)] - VIP;

[Aeetyi-His (l), D-Phe (2), Lys (15), Arg (16), Leu (27)] - VIP (l-7) / GRF (8-27) -NH ₂ ;

[Myristoyl-His (l), Lys (12.27.28), Gly (29.30), ThT (Sl)] VIP-NH ₂ ;

[Acetyl-His (1), D-Phe (2), Lys (15), Arg (16), Leu (17)] - VIP; neurotensin (6-l l) VIP (7-28);

[Acetyl-His (l), D-Phe (2), Phe (4-Ciχб), Har (9), Tyr (Me) (10), Abu (15), Nle (27), D-Agg (28 ), Har (29)] GRF (l-29) -NH ₂ ;

[Acetyl-His (l), D-Phe (2), Phe (4-Cl) (6), Lys (15), ATg (IO), Lys (20), Tyr (22), Nle (27), D-Arg (28), Hag (29)] GRF (l-29) -NH ₂ ;

[Acetyl-His (l), D-Phe (2), Lys (15), Leu (17)] VIP (3-7) / GRF (8-27);

[Acetyl-His (l), D-Phe (2), Lys (15), Arg (16) jVIP (3-7) / GHF (8-27) -NH ₂ ;

[Acetyl-Tyr (l), D-Phe (2)] - GRF (l-29) -NH ₂ ;

[N-stearal, noleucinel7] VIPhybrid;

Leu-Met-Tur-Pro-Thr-Tur-Leu-Lus;

[D-Phe2 [VIP;

PACAP (6-27);

PACAP (6-38).

SUBSTITUTE SHEET (RULE 26)

3. The use of antagonists of vasoactive intestinal (field) peptides from the group:

VSC6-28);

VIP (10-28);

[LyS (I), Pro (2.5), Arg (3.4), Tyr (6)] - VIP;

[D-p-Cl-Phe (b), Leu (17)] - VIP;

[Acetyl-His (l), D-Phe (2), Lys (15), Arg (16), Leu (27)] - VIP (l-7) / GRF (8-27) -NH ₂ ;

Pviyistoyl-His (l), Lys (12.27.28), Gly (29.30), ThT (Sl)] VIP-NH ₂ ;

[Acetyl-His (l), D-Phe (2), Lys (15), Arg (16), Leu (17)] - VIP; neurotensin (6-l l) VIP (7-28);

[Acetyl-His (l), D-Phe (2), Phe (4-CI) (6), Har (9), Tyr (Me) (10), Abu (15), Nle (27), D- Arg (28), Har (29)] GRF (l-29) -NH ₂ ;

[Acetyl-ffis (l), D-Phe (2), Phe (4-Cl) (6), Lys (15), Arg (16), Lys (20), Tyr (22), Nle (27), D-Arg (28), Hag (29)] GRF (l-29) -NH ₂ ;

[Acetyl-ffis (l), D-Phe (2), Lys (15), Leu (17)] VIP (3-7) / Giα ^g (8-27);

[Acetyl-His (l), D-Phe (2), Lys (15), Arg (16)] VIP (3-7yGHF (8-27) -NH ₂ ;

[Acetyl-Tyg (1), D-Phe (2)] - GRF (1 -29) -NH ₂ ;

[N-stearal, norleucinel7] VIPhybrid;

Leu-Met-Tur-Pro-Thr-Tur-Leu-Lus; p-Phe2 [VIP;

PACAP (6-27);

PACAP (6-38). for the manufacture of an antipsoriatic drug intended for local use.

SUBSTITUTE SHEET (RULE 26)