Composition containing gamma interferon for treatment of prurigo

Abstract: As a remedy for prurigo, IFN-γ is administered systemically, preferably intravenously and still preferably via drip infusion, in a daily dose of from 250,000 JRU to 4,000,000 JRU preferably once a day or in several portions depending on the conditions of the patient and side effects. The administration method and dose can be changed depending on the conditions, age, etc., of the patient. IFN-γ is highly effective in the treatment of prurigo. The action of IFN-γ to normalize the imbalance in peripheral lymphocytes is suggested as the mechanism for the efficacy of IFN-γ in the treatment of prurigo.

Description: This invention relates to a pharmaceutical agent for treating prurigo which comprises γ-interferon as the active ingredient. Skin diseases include inflammatory skin diseases based on hypersensitive reactions, for example, contact dermatitis, atopic dermatitis, urticaria, etc., caused by allergic reactions. It has been known that these diseases can be effectively treated by external application of preparations containing an adrenocortical hormone or nonsteroidal preparations as well as oral administration of antihistaminic agents or antiallergic agents. In contrast, no effective method has been established so far for treating prurigo, a kind of an inflammatory skin disease. Prurigo is characterized by anthemas with serious itchiness (relatively hard and large erythematous papules or nodes, i.e., so-called prurigo nodes) scattering mainly on the trunk and the extensor side of the limbs. A number of causes for prurigo have been known including local factors such as insect bite as well as systemic factors such as pregnancy or those due to underlying diseases such as renal insufficiency, hepatopathy, gout, Hodgkin's disease, leukemia, visceral cancer, diabetes and polycythemia. When scratched and broken, anthemas undergo various states, for example, infiltration, thickening, lichenification, etc. However, anthemas never fuse with each other and the skin area between lesions usually remains intact. Depending on the progress, prurigo is classified into three types, i.e., acute, subacute and chronic ones. In acute prurigo, somewhat large urticarial papules appear solely or plurally and scatter in the form of serious papules or small nodes. Different from eczematous lesions fusing together, papules are separately located and cause serious itching. Subacute prurigo is frequently observed in middle age women. In this case, papules are symmetrically distributed usually on the trunk and the extensor side of the limbs and sometimes on the face and head. In chronic prurigo, anthemas, which are relatively exudative in the acute stage, show a tendency to grow with the progress of the disease and thus gradually become large and hard, solid or horny nodes. These nodes are distributed solely, aggregatively or generally, on the trunk and the extensor side of the limbs, but in particular, they are frequently localized to the lower legs. Even in the chronic stage, individual papules never fuse with each other and the area of the skin between lesions usually remains intact. In the treatment of prurigo, it is a primary requirement to cure the basal disease, if it can be clearly identified. Thus, it is sometimes observed that itching and anthemas are ameliorated with the progress of the treatment of the basal disease. However, this applies to only certain cases of prurigo and it is necessary in practice to symptomatically treat patients by medicines. In pharmacotherapy, antihistaminic agents or antiallergic agents are used to subside itching. However, no satisfactory result has been achieved in spite of attempts to vary the dosage or alter a drug. Also, it has been a common practice to use external preparations containing an adrenocortical hormone. Sometimes, attempts have been made to systemically apply an adrenocortical hormone. In such a case, however, special attention should have been paid to the side effects. As discussed above, no effective methods for treating prurigo has been established so far, and thus, there is a strong demand to develop a novel therapeutic method for treating it. Accordingly, the present invention aims at providing a medicine which is effective in the treatment of prurigo. On the other hand, various biological activities of interferon have been clarified since discovered as a repressor of virus replication produced by cells. On the basis of these activities, studies have been made in order to apply interferon to clinical trials. Regarding skin diseases, it has been revealed that interferon is effective against atopic dermatitis, herpesvirus infection, cutaneous T-cell lymphoma, etc. However, no one has reported hitherto on the efficacy of interferon against prurigo or its clinical use. The present invention for the production of a pharmaceutical agent for treating by topical or systemical administration of a therapeutically effective amount of a substance having γ-interferon activity either alone or in combination with at least one drug selected from among antihistaminic agents, adrenocortical hormones and antiallergic agents relates to the use prurigo. The present invention further for the production of a pharmaceutical agent for treating of a substance having γ-interferon activity either alone or in combination with at least one drug selected from among antihistaminic agents, adrenocortical hormones and antiallergic agents relates to the use prurigo associated with an imbalance between Th1 cells and Th2 cells in the peripheral helper T cells, to thereby normalize the balance and ameliorate the symptoms of prurigo. The present invention further for the production of a pharmaceutical agent for treating of a substance having γ-interferon activity either alone or in combination with at least one drug selected from among antihistaminic agents, adrenocortical hormones and antiallergic agents relates to the use prurigo progressed from an auto-sensitized dermatitis to thereby ameliorate the symptoms of prurigo. The present invention furthermore relates to the use of a substance having γ-interferon activity for the production of a pharmaceutical agent for treating prurigo which comprises admixing a substance having γ-interferon activity, either alone or together with at least one drug selected from among antihistaminic agents, adrenal cortical hormones and antiallergic agents, with a pharmaceutically acceptable excipient and/or carrier. The present invention further relates to use of a substance having γ-interferon activity for the production of a pharmaceutical agent for treating prurigo containing a substance having γ-interferon activity in an amount of 375,000 IU to 6.000.000 IU (250,000 JRU to 4,000,000 JRU per dose JRU: Japan Reference Unit, the antiviral activity of γ-interferon is expressed with JRU in Japan, for example, see BIOTHERAPY 3(4) p. 828, 1989), which comprises admixing a substance having γ-interferon activity, either alone or together with at least one drug selected from among antihistaminic agents, adrenocortical hormones and antiallergic agents, with a pharmaceutically acceptable excipient and/or carrier. Fig. 1 is a graph which shows the efficacy of IFN-γ in Clinical Example 1 (◆) and Clinical Example 2 () wherein the abscissa represents period (days) of IFN-γ administration, while the ordinate represents severity score. The present inventors have tried to clinically apply γ-interferon (IFN-γ) to prurigo. Namely, IFN-γ was administered to patients with prurigo. Then the severity of the symptom (hereinafter referred to as the severity score) was determined as the sum of the itching score evaluated in 4 grades and the anthema score similarly evaluated in 4 grades. Thus the efficacy of γ-interferon was evaluated on the basis of the change in the severity before and after the administration. The itching and anthema were evaluated in accordance with the following criteria. Criteria for symptoms Score Itching Anthema 3 serious erythematous and high rise 2 moderate erythematous and moderate rise 1 light erythematous but flat 0 none pigmentation alone As a result, the present inventors have clarified that a substance having IFN-γ activity is remarkably effective in the treatment of intractable prurigo and thus completed an agent for treating prurigo comprising a substance having IFN-γ activity as the active ingredient. Although the substance having IFN-γ activity to be used in the present invention may be either natural IFN-γ or those obtained by means of recombinant technology, IFN-γ of recombinant type is preferred in view of the stability of supply. For example, a commercially available IFN-γ preparation such as Biogamma ™ which is an IFN-γ preparation marketed from Suntory Ltd. (Osaka, Japan) as a medicament for mycosis fungoides. Alternatively, a variant type of IFN-γ may be constructed by deleting, inserting or replacing one or more amino acids thereof, so long as the effectiveness of the present invention is not significantly changed. Examples of such IFN-γ variants include one from which 4 amino acids at the N-terminal (Cys-Tyr-Cys-Gln) have been deleted [Japanese Patent Publication (Kokoku) No. Hei 7-45516], those from which amino acids at the C-terminal have been deleted by processing [for example, a variant with the deletion of 11 amino acids at the C-terminal described in Japanese Patent Laid Open (Kokai) No. Sho 60-84298], one in which the ninth amino acid Lys has been replaced by Gln [Japanese Patent Publication (Kokoku) No. Hei 7-45515], etc. When used as a medicament for prurigo, IFN-γ is administered systemically, preferably intravenously and still preferably via intravenous dripping, in a dose of from 375,000 to 6.000.000 IU/day (50,000 to 4,000,000 JRU/day) preferably once or in several portions per day depending on observed side effects, if any. The dose may be varied depending on the conditions and age of the patient, and various other factors. It is also possible to use an antipyretic analgesic agent together with IFN-γ so as to inhibit a fever which might be caused as the side effect of the administration of IFN-γ. Furthermore, IFN-γ can be used together with antihistaminic agents, adrenocortical hormones, antiallergic agents, etc., or PUVA therapy which have been employed in the symptomatical treatment of prurigo. The mechanism of how IFN-γ exerts its efficacy in the treatment of prurigo has not been clarified as the cause of prurigo is still unknown. However, as the Clinical Examples will reveal, it is assumed that IFN-γ normalizes the balance in peripheral lymphocytes to thereby cure prurigo. Peripheral helper T cells are classified into Th1 cells and Th2 cells depending on the patterns of the cytokines produced thereby. Thus, Th1 cells produce interleukin-2 (IL-2) and IFN-γ, while Th2 cells produce IL-4, IL-5 and IL-10. In normal state, the populations of the two types of T cells are balanced in such a manner that Th1 cells control Th2 cells by way of IFN-γ whereas Th2 cells control Th1 cells by IL-10. It is considered that imbalancing in these cells for some reason induces various diseases including prurigo. For example, as the following 3 cases will manifest, Th2 cells are dominative over Th1 cells at least in a number of patients with intractable prurigo. It is expected that this imbalance can be normalized and thus the symptoms can be ameliorated by giving IFN-γ to such a patient in order to suppress the action of Th2 cells. In Clinical Example 1, the administration of IFN-γ actually resulted in a decrease in messenger RNA (mRNA) of IL-4 which is a cytokine produced by Th2 cells. This supports the mechanism proposed above. In addition, chronic prurigo frequently progresses from an auto-sensitizing dermatitis and IFN-γ is effective against this type of prurigo too. In fact, the patient of Clinical Example 2 showed the clinical symptoms of auto-sensitizing dermatitis at the early stage, which supports the above suggestion. To demonstrate the efficacy of IFN-γ against prurigo, the following 3 Clinical Examples will be given. However, it is to be understood that the present invention is not limited thereto. Clinical Example 1: Treatment of patient with prurigo by IFN-γ (Case 1) Subject Female aged 48. Major complaint Systemic itching anthema. Previous disease Nothing to report. Family history Nothing to report. History and progress of present illness: Since autumn in 1992, erythematous papules appeared on the limbs and spread throughout the body. The symptoms could not be subsided by the oral administration of an antihistaminic agent and the external application of an adrenocortical hormone under the direction of a neighboring doctor. On February 7, 1994, the patient had a medicinal examination at the dermatology of the Hospital of Hamamatsu University School of Medicine. Then she was hospitalized for 40 days following February 8, 1994 and for 30 days following June 21, 1994 and treated with the oral administration of an antiallergic agent, the external application of an adrenocortical hormone and PUVA therapy. Although the anthemas ameliorated to a certain extent each time she left the hospital, the symptoms worsened soon after the beginning of the regular outpatient treatment. Since December 14, 1994, she was hospitalized a third time and the oral administration of an antiallergic agent and the external application of an adrenocortical hormone were continued. Since the anthemas and itching did not subside, an IFN-γ preparation Biogamma was administered via intravenous drip infusion since December 22. The dose of Biogamma was 375,000 IU/day (250,000 JRU/day) on the first day and then increased to 750,000 IU/day (500,000 JRU/day) on the next day (December 23). Then the administration was continued in this dose for 6 days. The severity score was lowered from 6 (before the administration) to 3 (day 3). On day 7 of the administration, the itching felt by the patient was reduced to 1/3 to 2/3 and the anthemas were flattened with pigmentation. Thus the severity score was lowered to 2, showing obvious amelioration. On day 14 of the administration, the severity score was 1 and thus further amelioration was observed (Fig. 1). The eosinocyte level was lowered from 24% (leukocyte count: 2,400/mm 3 , before the administration) to 19% (leukocyte count: 5,000/mm 3 , day 7 of the administration). Subsequently, Biogamma was continuously administered 3 to 5 days per week at a dose of 375,000 IU/day (500,000 JRU/day) until February 13, 1995. Since the anthemas and itching could be thus controlled, the patent was discharged from the hospital on February 18 followed by outpatient treatment. Although a fever as the known side effect of Biogamma was observed, it did not cause any serious trouble and thus the administration could be continued. The expressions of β-actin, IL-2, IL-4 and IL-10 at the mRNA level in peripheral blood lymphocytes were examined by the RT-PCR method before the administration of IFN-γ and after the administration of 750,000 IU/day (500,000 JRU/day) of IFN-γ for 5 days. As a result, β-actin and IL-2 showed no change, while IL-4 and IL-10 showed respectively remarkable and moderate reduction. Change in mRNA for cytokines in peripheral blood lymphocyte in Clinical Example 1 mRNA Before administration of IFN-γ 5 days of administration β-actin +++ +++ IL-2 ++ ++ IL-4 ++ - IL-10 ++ + - : not observed + : slight ++: moderate +++: remarkable Thus it is considered that Th2 cells were dominative over Th1 cells and thus there was an imbalance of these cells in this patient but the administration of IFN-γ controlled Th2 cells to thereby ameliorate the anthemas and the subjective symptoms. Clinical Example 2: Treatment of patient with prurigo by IFN-γ (Case 2) Subject Male aged 65. Major complaint Systemic itching anthema. Previous disease Hypertension. Family history Nothing to report. History and progress of present illness: In January, 1995, erythematous papules with serious itching appeared throughout the body. 5 days before the initial consultation, the anthemas showed a tendency to worsen. Thus the patient was hospitalized at the dermatology of the Hospital of Hamamatsu University School of Medicine on May 10, 1995. On the date of the hospitalization, he was diagnosed as having prurigo due to the highly itchy erythematous papules scattered on the trunk and limbs. Neither intravenous injection of an antihistaminic agent (chlorpheniramine maleate), the oral administration of an antiallergic agent (oxatomide) nor the external application of an adrenocortical hormone (betamethasone valerate) achieved any therapeutic effect and the anthemas spread throughout the body. Thus, Biogamma was administered by intravenous drip infusion in a dose of 3,000,000 IU/day (2,000,000 JRU/day) for 10 days. As a result, the symptoms ameliorated and the severity score was reduced from 6 (before administration) to 3 (day 5 of the administration). On day 10, prurigo nodes were flattened with pigmentation and the itching was considerably relieved. Thus the severity score was lowered to 1, showing remarkable amelioration (Fig. 1). After the completion of the administration, no relapse was observed and the prurigo could be controlled simply by the external application of the adrenocortical hormone. The patient left the hospital on May 29, 1995. Although a fever as the known side effect of Biogamma was observed, it did not cause any serious trouble and thus the administration could be continued without problem. Although this patient indicated eosinophilia and hyper-IgE-immunoglobulinemia, the peripheral eosinocyte level was reduced from 11% (leukocyte count: 6,200/mm 3 , before the administration of IFN-γ) to 4% (leukocyte count: 6,700/mm 3 , after the administration) falling within the normal range. Clinical Example 3: Treatment of patient with prurigo by IFN-γ (Case 3) Subject Male aged 42. Major complaint Systemic itching anthema. Previous disease Cataract. Family history Nothing to report. History of present illness: The patient consulted the doctor for the first time 9 years ago. Itching anthemas appeared on the back and gradually spread throughout the body. Under the treatment by a neighborhood doctor, he sometimes got better but then had a relapse. He visited a general hospital and was diagnosed as having intractable prurigo 6 years ago. The oral administration and external application of an adrenocortical hormone and the PUVA therapy caused repeated improvement and worsening. Progress: From July 7 to July 31, 1995, Biogamma was administered in a dose of 3,000,000 IU/day (2,000,000 JRU/day) everyday. During the first week, the severity score was remarkably lowered from 3 to 1. From August 1 to September 30, Biogamma was administered in a dose of 3,000,000 IU/day (2,000,000 JRU/day) three times a week. As a result, the disease remained in a stable state. These Clinical Examples indicate that IFN-γ is highly effective for treating prurigo which is an intractable disease. Accordingly, the present invention makes it possible to provide a cure for prurigo against which no efficacious therapeutic method has been known so far. Formulation Examples The following Examples demonstrate the preparation of pharmaceutical compositions for treating prurigo which comprise IFN-γ as the active ingredient. Recombinant human IFN-γ 3×10 6 IU/vial (2×10 6 JRU/vial) Human serum albumin 1.00 mg/vial L-Cysteine hydrochloride 0.50 mg/vial glycine 20.0 mg/vial Citric acid 1.81 mg/vial Sodium monohydrogen phosphate 3.58 mg/vial The solution was adjusted to pH 4.1 - 4.8, sterilized by passing through a 0.22 µm membrane filter and lyophilized.

Claims: A use of a substance having γ-interferon activity either alone or in combination with at least one drug selected from among antihistaminic agents, adrenocortical hormones and antiallergic agents for the production of a pharmaceutical agent for the treatment of prurigo wherein said agent is topically or systemically administrable. A use as claimed in claim 1, wherein said substance is obtained by recombinant technology. A use as claimed in claim 1 or 2, wherein said substance is γ-interferon. A use as claimed in claim 1 or 2, wherein said substance is a mutant of γ-interferon in which the N-terminal amino acid sequence Cys-Tyr-Cys-Gln of γ-interferon has been deleted. A use as claimed in claim 1 or 2, wherein said substance is a mutant of γ-interferon in which the 11 amino acids at the C-terminal of γ-interferon have been deleted. A use as claimed in claim 1 or 2, wherein said substance is a mutant of γ-interferon in which the ninth amino acid Lys in γ-interferon has been replaced by Gln. A use as claimed in any of claims 1 to 6, wherein said prurigo is one associated with an imbalance between Th1 cells and Th2 cells in peripheral helper T cells. A use as claimed in any of claims 1 to 7, wherein said prurigo is one progressed from auto-sensitizing dermatitis. A use as claimed in any of claims 1 to 8, wherein said agent is administrable by intravenous administration including drip infusion. A use as claimed in any of claims 1 to 9, wherein said substance having γ-interferon activity is administrable in a single or divided doses at 375.000 IU to 6.000.000 IU (250,000 JRU to 4,000,000 JRU) per day. A use as claimed in any of claims 1 to 10, wherein an antipyretic agent is employed so as to inhibit a fever which may be caused by the substance having γ-interferon activity. A use of a substance having γ-interferon activity for the production of a pharmaceutical agent for treating prurigo which comprises admixing a substance having γ-interferon activity, either alone or in combination with at least one drug selected from among antihistaminic agents, adrenal cortical hormones and antiallergic agents, with a pharmaceutically acceptable excipient or carrier. A use as claimed in claim 12, wherein said substance is obtained by recombinant technology. A use as claimed in claim 12 or 13, wherein said substance is γ-interferon. A use as claimed in claim 12 or 13, wherein said substance is a mutant of γ-interferon in which the N-terminal amino acid sequence Cys-Tyr-Cys-Gln of γ-interferon has been deleted. A use as claimed in claim 12 or 13, wherein said substance is a mutant of γ-interferon in which the 11 amino acids at the C-terminal of- γ-interferon have been deleted. A use as claimed in claim 12 or 13, wherein said substance is a mutant of γ-interferon in which the ninth amino acid Lys in γ-interferon has been replaced by Gln. A use as claimed in any of claims 12 to 17, wherein said prurigo is one associated with an imbalance between Th1 cells and Th2 cells in peripheral helper T cells. A use as claimed in any of claims 12 to 18, wherein said prurigo is one progressed from auto-sensitizing dermatitis. A use as claimed in any of claims 12 to 19, wherein said agent for treating prurigo is an intravenous preparation including a drip infusion. A use as claimed in any of claims 12 to 20, wherein said agent for prurigo contains a substance having γ-interferon activity in an amount from 375.000 IU to 6.000.000 IU (250,000 JRU to 4,000,000 JRU) per dose. A use as claimed in any of claims 12 to 21, wherein an antipyretic analgetic agent is employed so as to inhibit a fever which may be caused by the substance having γ-interferon activity.

Inventors: TAKIGAWA MASAHIRO, TOKURA YOSHIKI, TAKIGAWA, MASAHIRO, TOKURA, YOSHIKI
Applicants: SUNTORY LTD, SUNTORY LIMITED
Application year: 1996
Main classification: A61K38
IPC codes: A61P17, A61K38