CZ2002729A3 - Use of dexrazoxane, product containing dexrazoxane, method for treating psoriasis and process for preparing a medicament therefor - Google Patents

Abstract

The use for the manufacture of a medicament for treating psoriasis of dexrazoxane, the d-isomer of 1,2-bis(3,5-dioxopiperazin-1-yl)-propane, or a physiologically acceptable salt thereof.

Description

Use of dexrazoxane, a product comprising dexrazoxane, a method of treating psoriasis, and a method of making a medicament

Technical field

The present invention relates to pharmaceutical compositions based on 1,2-bis (3,5-dioxopiperazin-1-yl) propane and pharmaceutically acceptable salts thereof.

1,2-Bis (3,5-dioxopiperazin-1-yl) propane has the formula

and may exist in the d-isomeric form, the 1-isomeric form, and the racemic dl-form.

BACKGROUND OF THE INVENTION

The racemic dl-form of 1,2-bis (3,5-dioxopiperazin-1-yl) propane is known as razoxane. Compounds of this type belong to the family of bis-dioxopiperazines which have been known for a long time, especially as antitumor agents. This class of compounds, their use and preparation are described in, for example, GB-1 234 936, GB-1 374 979, EP-A1 256 137, EP-A1 230 474, EP-A2 014 327 and EP-A1 125 475.

Bis-dioxopiperazines are lipophilic derivatives of EDTA (ethylenediaminotetraacetic acid), a compound known as a chelating agent. Bis-dioxopiperazines show inhibitory activity for topoisomerase II, which is probably responsible for the antitumor activity of these drugs. As bifunctional alkylating agents, these drugs cause mitosis to stop during G2 phase or early prophase of the cell cycle. The D-optical isomer of razoxane is known as dexrazoxane. In current clinical practice, dexrazoxane is used to prevent doxorubicin-induced heart disease in patients with metastatic breast cancer.

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Dexrazoxane is commercially available as the hydrochloride salt from Chiron, Inc under the registered trademark Cardioxane. Discussions on the chemical, biological, and clinical aspects of dexrazoxane and other bis-dioxopiperazines can be found in Current Medicinal Chemistry (1998) 5, 1-28. GB 1 234 935 is one of the oldest publications on bis-dioxopiperazines and describes their preparation by cyclizing the corresponding tetracarboxamidomethyl derivatives by heating with polyphosphoric acid. The therapeutic spectrum of these drugs includes certain forms of cancer, including leukemia, and certain non-malignant forms of proliferative disease.

Two main processes have been described for the preparation of dexrazoxane (U.S. Pat. No. 3,941,790). In the first process, 1,2-diaminopropanetetraacetic acid and formamide are heated together to form a cyclic product. In the second process, the corresponding tetraamide derivative of the aforementioned tetracic acid is heated in polyphosphoric acid or phenol, which also leads to the cyclization of the compound (see the aforementioned patent GB 1 234 935).

Other methods for the preparation of dexrazoxane are known, such as U.S. Pat. No. 4,764,614 or EP-A-0 330 381.

The preparation of a freeze-dried dexrazoxane-containing composition that is stable and less sensitive to light is described in detail in U.S. Patent 5,760,039.

Psoriasis is a chronic skin disease characterized by scaling and inflammation. The cause of psoriasis is unknown, but recent research suggests that it is probably an autoimmune disease. Psoriasis is a serious and unpleasant condition for which there is no cure and not all treatments are effective in any individual.

Psoriasis can be very painful, but pain is not the only problem. Patients also suffer mentally. It causes a physical limitation, mutilation and lengthy day-to-day treatment always takes a lot of time. Embarrassment, discontent, fear and depression are common. In extreme cases, the loss of self-esteem leads to complete sideline of society. There are various forms of temporary relief, but they work with varying degrees of success. Treatment and medication administration are often time-consuming and expensive, but one thing is certain: symptoms may appear and disappear, but almost always reappear. It is a lifelong disease.

Psoriasis is treated using an approach, which is sometimes called the "1-2-3" approach. Step 1 is local treatment, step 2 is phototherapy and step 3 is systemic treatment. Presently, drugs prescribed for systemic treatment are the immunosuppressive agents methotrexate and cyclosporin, hydroxyurea and retinoids.

Methotrexate and cyclosporin have unpleasant and potentially dangerous side effects. In addition, all these treatments leave patients with periodically recurring psoriasis, and since different patients respond differently to different treatments, it would be very welcome to have additional weapons in the treatment arsenal.

In 1976, D. J. Atherton (Lancet, ii, 1296, 1976) first proposed the use of racemic razoxane (IRF-159) for the treatment of psoriasis. A review of the therapeutic use of razoxane in psoriasis can be found in the British Journal of Dermatology (1980), 102, 307. The drug has relatively good efficacy and is well tolerated, but some unpleasant side effects and some toxicity have been reported. Therefore, drug administration was only recommended under strictly controlled conditions. Horton and Wells (British Journal of Dermatology (1983), 109, 696-673) again reported relatively good success in razoxane treatment, but in a significant number of patients treatment was discontinued due to relatively serious side effects. The most commonly observed side effect was an abnormally low number of neutrophils in the blood, a potentially lethal loss of neutrophil leukocytes (a subset of leukocytes) reported to occur in a number of patients, even at low doses that are not even sufficient to control psoriasis. Other side effects were hair loss, nausea, diarrhea, nasal bleeding, foot ulcers, lethargy, headaches, and the occurrence of scaly skin tumors resulting from epithelial lining.

Due to these and other complications arising from long-term administration, razoxane treatment has not been further developed and is currently not recommended for the treatment of psoriasis. Therefore, the prior art known about razoxane has been such that it cannot be used safely and effectively for the treatment of psoriasis.

SUMMARY OF THE INVENTION

It has now surprisingly been shown that the optical d-isomer of 1,2-bis (3,5-dioxopiperazin-1-yl) propane, dexrazoxane alone, can be used safely and effectively for the treatment of psoriasis. Indeed, our studies show that in some patients the results of treatment are truly remarkable, when there is relief from fearless psoriasis for a period of at least one year. No serious side effects have been reported in clinical trials yet, with most patients not developing neutropenia and no cases of vomiting, nausea or diarrhea have been reported.

According to the present invention, the novel pharmaceutical composition for treating psoriasis comprises as active ingredient dexrazoxane or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier and / or excipient.

The invention also includes a method of treating psoriasis in a patient, comprising administering a therapeutically effective amount of dexrazoxane, the d-isomer of 1,2-bis (3,5-dioxopiperazin-1-yl) propane, a compound of formula

or a pharmaceutically acceptable salt thereof.

The invention is further described with reference to the accompanying Figure 1, which is a graphical representation of the mean value (n = 7) of psoriasis range and difficulty index (PAI) during a treatment protocol having three cycles of dexrazoxane administration.

The method of treatment may comprise administering dexrazoxane by injection or infusion (or other route of internal administration) at a daily dose of, for example, between 250 mg and 1750 mg, and in one suitable protocol comprises administering dexrazoxane in increasing doses, e.g. eg 5 days, a second daily dose in the second period up to eg 5 days and a third daily dose in the third period up to eg 5 days. The initial, second and third periods may be separated from one another and preferably are one or two days long; one of the initial, second and third periods does not require any treatment protocols. The first daily dose is usually from 250 mg to 750 mg (e.g. 500 mg), the second daily dose is usually from 750 mg to 1250 mg (e.g. 1000 mg), and the third daily dose is usually from 1250 mg to 1750 mg (e.g. 1500 mg).

In any case, the most preferred protocols for internal, e.g., parenteral, administration of dexrazoxane include administration of dexrazoxane at intervals such as, for example, dexrazoxane. Ftft with an interval between the administration periods of 5 to 20 days, more usually 8 to 16 days, and most preferably 10 to 14 days, eg 12 days. As indicated, the period of administration may last two consecutive days, with dexrazoxane being administered in each of them. Alternatively, a one-day administration period or an administration period longer than two days may be used, in which case dexrazoxane may be administered on all or some of these days. Particularly preferred protocols comprise three separate periods of administration, for example two days long and / or 12 day intervals; thus, the protocol may consist of three cycles, as shown in the figure

1. Protocols for administration may be repeated as necessary, for example after a period of a month to a year or more. Parenteral administration may be by infusion or injection, and the dexrazoxane is usually (but not exclusively) administered as a salt.

The dosage may be varied, for example increased, during treatment. In particular, the dosage may be increased after the first period of administration in the protocol described in the preceding paragraph if the initial patient response is insufficient. Suitably, an adult is administered a dose of from 250 mg to 750 mg each day during a two-day initial administration period, after which the dose may be maintained at the same level or increased (e.g. to 750 mg to 1250 mg). After the second administration period, the dose in the third administration period may be maintained at the same level or, if necessary, increased (or even reduced). It is desirable, but not necessary, that the dosage is varied in steps of 500 mg.

The weights and percentages by weight of dexrazoxane specified in this application refer to dexrazoxane hydrochloride, i.e. refer to dexrazoxane in the form of the hydrochloride salt. If an alternative form is used, it is appropriate to adjust the dosage based on the relative molecular weights of the two forms.

Therefore, in one group of administration, dexrazoxane is administered intravenously or otherwise by injection or infusion. In current practice, solutions for injection or infusion are prepared by reconstituting lyophilized dexrazoxane just prior to administration. The lyophilisate is suitably packaged in an amount that corresponds to the dose to be used, and packages containing from 750 mg to 1250 mg or from 1250 mg to 1750 mg are all included in the invention. The invention also encompasses the use of dexrazoxane for the preparation of liquid dexrazoxane formulations in a form ready for use and administration of such liquid formulations (solutions).

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In another group of uses, dexrazoxane is administered topically, on or through the skin, i.e. in the form of an ointment, lotion or patch. Other methods include oral administration of dexrazoxane, for example in the form of tablets. The dexrazoxane may be administered in the form of a suppository. Alternatively, dexrazoxane may be administered as a topical preparation, for example, as an ointment, cream or gel. The dexrazoxane concentration is not critical. However, some topical preparations contain at least 0.1% by weight and more usually contain from 0.25% by weight, and in particular from 0.5% by weight to 5% by weight of dexrazoxane or more. One formulation group contains 1 to 2% by weight of dexrazoxane. The invention includes formulations adapted for topical administration to avoid oral or parenteral administration or administration by injection or infusion. Topical formulations are suitably packaged in tubes up to 100 g, with attached instructions on how to use them for the treatment of psoriasis.

Topical formulations may contain conventional carriers for testing purposes. By way of non-limiting example, the ointments may comprise water and one or more hydrophobic carriers selected from the group consisting of liquid paraffin, polyoxyethylene alkyl ether, propylene glycol and white petrolatum. The carrier compositions in creams are typically based on water and white petrolatum, in combination with glycerol and a plurality of minor ingredients, for example, one or more glycerin monostearate, PEG-glycerin monostearate, and cetyl stearyl alcohol. For example, gels may be prepared using isopropyl alcohol and water, and are suitably combined with minor components, for example, one or more glycerol and hydroxyethyl cellulose derivatives.

Dexrazoxane can be used in combination therapy, for example with non-steroidal anti-inflammatory drugs, a TNF inhibitor or a vitamin. The invention therefore encompasses products, particularly those containing topical formulations comprising dexrazoxane and an agent suitable for treating or alleviating psoriasis, as a combination agent which can be used in a simultaneous, separate or sequential method of treating psoriasis. The resulting product may be a topical formulation containing a combination of two or more active agents.

During the clinical trial, a rapid improvement in the symptoms associated with the disease was observed, even in particularly resistant cases in which psoriasis had been occurring for a long time. Itching diminished several hours after the first administration and virtually disappeared after the next dose. Scaling was suppressed, wetting disappeared, the thickness of the affected area was significantly reduced, and patients were relieved of joint pain.

Patients exhibited distinct subjective and objective reactions such as a 25-30% reduction in skin damage without suffering from known side effects of razoxane.

A preferred formulation is a sterile solution for injection or infusion, ointments, lotions, oral administration forms, patches and suppositories may also be used.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples: Clinical tests showing the efficacy of dexrazone:

Example 1:

This patient, a 55-year-old man, had a psoriasis of 20 years. The disease broke out after mental stress (loss of a close person) in the form of a rash on the scalp. From the very beginning of the disease, the patient was intensively treated with vitamins B ₁₂ , B ₆ , B ₂ and calcium. He was artificially induced elevated body temperature by injection of pyrogens, methotrexate, various ointments (eg, salycil ointment) under the supervision of a dermatologist at a specialized clinic. Despite the treatment, psoriasis rash spread to the torso, upper and lower limbs and was accompanied by a clear overall itching. The patient practically did not alleviate symptoms. Accompanying diseases were Grade II hypertension and chronic cholecystopancreatitis.

At the first examination, the patient complained of itching all over his body (resulting in insomnia) and pain in the large joints (mainly in the knees). The skin on the back, buttocks, chest and shoulders was covered with a red, spotty rash with a white coating (peeling). A similar but less intense rash was seen on the feet. The patient's general condition, haematological and biochemical profile were within normal range.

On the first and second days of the treatment cycle, the patient received the first doses of 500 mg of cardioxane (dexrazoxane.HCI) daily by intravenous drip infusion. On day 15, the patient reported itching several hours after the first administration of cardioxan. Itching virtually disappeared after the next dose of cardioxan, ie 1000 mg administered on day 16. The patient has been found to reduce scaling, disappearance, and flushing. Oozing, relieving hypernia, smoothing out the rash and completely relieving joint pain.

The patient slept well for the first time in a long period of illness. The effect still persisted at the examination on days 29 and 30, when the patient received the last two injections of cardioxan, each containing 1500 mg of the substance.

At the last examination, on day 29, the patient found a smoothing of the rash, the disappearance of some injuries and the appearance of a normal skin area (up to 2 cm in diameter, especially on the lower limbs). An overall reduction in skin injuries of 25 to 30% was diagnosed. Itching, although it returned briefly approximately 1.5 weeks after the first two injections, did not reappear after the 3rd and 4th injections as well as joint pain. There were no adverse effects after any injection.

Example 2:

This patient, a 50-year-old man, has been suffering from general psoriasis since he was 25. The rash appeared first on the head and right upper limb and later extended to the torso and upper limbs. The patient was treated similarly to the one described in Example 1. In addition, he was treated with UV therapy, peloid compresses, hydrogen sulfide baths, but without sustained effect. The patient had no concomitant illness except physical weakness, arrhythmia and left ventricular hypertrophy. The skin on the back, in the area of the hips and shoulders was covered with interlocking, reddish pimples, blistering and peeling wounds. The rash on the breast and lower limbs was mostly red and less pronounced. Skin injuries covered about 50% of the body surface. The patient did not complain of itching.

The patient received 6 intravenous, drip injections with cardioxan according to the following scheme:

Day 1 and 2 after 500 mg of cardioxane,

15 and 16 days after 1000 mg of cardioxane,

Day 29 and 30 after 1500 mg of cardioxane.

At the 15 and 29 day examination, the patient found a slight improvement in redness on his back. The other wounds showed no change. No side effects were observed.

Φ Φ Φ Φ · φ · · · φ φ φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ • • φ φ φφφφ

Example 3:

This patient, a 37-year-old woman, had a 16-year history of the disease, which occurred after abortion and mental stress. Psoriasis rash appeared on the hair part of the head and neck and spread further to the body. The patient was given sunlight, but only with a temporary effect. The patient underwent 4 hospitalizations in which treatment with vitamins, calcium and various ointments was performed. After a period of intense stress due to the loss of a loved one, the patient relapsed sharply and redness injuries occurred, covering most of the body. The patient has also experienced periodic attacks of allergic asthmatic bronchitis in the past.

At the first examination on Day 1, the patient observed a continuous reddened papulous rash of psoriasis with peeling on the front of the abdomen (below the breast fold), groin, shoulders and cross, buttocks and lower extremities, severe itching and diffuse breathing (asthmatic) bronchitis). A marked increase in the number of eosinophilic leukocytes was also significant.

The patient received 6 intravenous, dripping injections of cardioxan according to the protocol given in Example 2. At examination on day 15, the patient reported complete disappearance of the itch on the 2nd or 3rd day after the first cardioxan injection. The lower half of the abdomen as well as the upper quadrants of the buttocks were practically free of rash. No adverse effects were noted after cardioxan injections except slight pain along the vein at the injection site.

At day 30 examination, the patient found a complete regression of about 80% of the rash, with residual depigmentation in the lumbar, sacrum and legs. Itching was still not felt. Despite the patient's current allergic condition, no adverse effects were reported.

Example 4:

In a clinical study, the efficacy and tolerability of dexrazoxane in patients with non-healing psoriasis was evaluated.

After examination, suitable patients were given, on two consecutive days, by intravenous infusion of 500 mg of Cardioxan®. They were examined 7 and 14 days after the first day of treatment. Patients received a second course of treatment, consisting of either 500 mg of Cardioxan® administered by intravenous infusion in two consecutive infusions. ························································································· (days 15 and 16) if complete response, or 1000 mg of Cardioxan® administered by intravenous infusion on two consecutive days (days 15 and 16) if an incomplete response occurred.

The third treatment cycle was administered after the same time interval (day 29 and 30). Patients who had a complete response received the same dose as in the second cycle, while one patient who showed no response received two doses of 1500 mg each.

The primary efficacy indicator was the percentage of reduction in the area of psoriasis-affected skin and its intensity, as determined by a standardized assessment of PAHI (psoriasis area and S1 index).

Seven patients were included in the study and all of them underwent a two-week follow-up period. At baseline, the PASI score was between 23.1 and 44.1, with an average score of 31.9. Most patients showed a response to treatment, except one of them who was completely resistant to treatment. At the end of the third treatment cycle, PASI scores ranged between 3.4 and 29.7, with an average score of 11.4.

Eleven weeks after the start of treatment, the mean reduction in PAI was 65%, with a maximum reduction of 88% and one case was resistant. The tolerance to treatment was excellent and no serious adverse reactions were reported. In addition, Cardioxan® therapy resulted in better and quicker relief of symptoms associated with psoriasis arthritis compared to Cyclosporin A therapy (which is a standard drug in this indication and was previously used in the clinic).

The results are shown in Table 1 and shown graphically in Figure 1.

φ · φ • φ φ φ φ φ φ · φ · · φ · · ·

Table 1

Effect of Cardioxan treatment on PAHI (psoriasis area and SI index)

PASI score and patient / initial number visitation C. 1 / HH 2 / MR 3 / MZ 4 / PH 5 / PZ 6 / FJ 7 / DJ v1 23.1 43.6 29.8 27.0 29.1 44.1 26.6 v4 11.3 36.3 18.4 18.6 16.9 24.8 23.6 v7 7.7 23.1 11.6 13.5 9.9 20.3 23.0 v9 6.5 15.6 9.7 10.8 9.3 15.6 21.8 v10 6.5 12.3 7.1 12.0 7.8 15.6 28.5 v11 5.6 14.0 6.5 5.2 3.4 15.3 29.7

mean PASI score at baseline (n = 7): ξ = 31.9 average PASI score after 7 weeks (n = 7): ξ = 11.4 average PASI score reduction (n = 7): 65%

Of the seven patients treated, only one of them had mild, reversible leukopenia after approximately one week of treatment (approximately 3x10E9 cells per liter, classified as grade I). This neutropenia disappeared after another week and the numbers have been normal since then. All other patients had normal white blood cell counts. Toxicity assessments were performed according to the WHO criterion: grade 0 (non-toxic, baseline, counts more than 4x10E9), grade 1 (mild) to grade 4 (most severe). No cases of vomiting, nausea or diarrhea have been reported.

According to the most recent information, most patients are still in remission one month after the last injection. Three patients have not been completely cured, but the disease has such a mild manifestation that it can be easily treated with conventional therapies such as ointments. Previously, all these patients suffered greatly from their psoriasis, which was resistant to other treatments.

In another long-term study of three patients with resistant psoriasis, one patient is still relatively free of disability and symptoms after one year. This patient, who previously suffered from a difficult resistant psoriasis, can be treated with conventional softening agents

99 9 resources. Dexrazoxane therefore has the ability to provide remarkably long-term relief from resistant psoriasis and exhibits a low level of side effects.

Example 5

An infusion solution is prepared:

Cardioxan® is available in a 36 ml brown glass bottle. Each vial contains 500 mg of lyophilized active substance, dexrazoxane hydrochloride salt. For restoration, the contents of each vial are dissolved in 25 ml of sterile water for injection. The contents dissolve within a few minutes with gentle stirring. The pH of the resulting solution is about 1.6.

The solution should be further diluted for infusion. Sodium lactate UP (0.16 M) or Ringer's BP solution with lactate for infusion are preferred. Both solutions provide an infusion fluid with an acceptable pH.

Dilution of 4 vials of Cardioxan® (restoration) Solution Volume (ml) PH Total volume after dilution (ml) Sodium lactate UP (0.16 M) 500 4.66 600 300 4.47 400 100 ALIGN! 3.80 200 Ringer's BP solution with lactate 500 3.45 600 400 3.19 500 300 2.85 400 100 ALIGN! 2.14 200

Example 6:

The following tablets are prepared:

mg / tablet

Cardioxan® 100 mg

Avicel® (microcrystalline cellulose) 16 mg fc * starch hydroxypropylmethylcellulose magnesium stearate polyvinylpyrrolidone colloidal silicon dioxide mg 3 mg 1 mg 0.6 mg 0.3 mg • fcfcfc ·· fc fc fc · · · Fcfc · fcfcfc fc fcfcfc • fc 9999

Half of the total amount of hydroxypropyl methylcellulose, polyvinylpyrrolidone and sufficient water are mixed together and mixed until dissolved (binder solution). Cardioxan®, starch and hydroxypropyl methylcellulose residue are mixed in a granulator and mixed for 10 minutes. The granulation process is initiated by spraying the binder solution. After spraying and homogenizing, the product in this apparatus is dried and removed when its water content is less than 2.8 to 3.0%. The granulate passes through an oscillating granulator equipped with a 1.2 mm stainless steel screen. The granulate is mixed with starch, microcrystalline cellulose and colloidal silica during 20 minutes of rotation. Magnesium stearate is added and mixed with the granulate. The final product is compressed in 130 mg portions on a rotary tablet unit equipped with 10 mm lens punches.

Example 7:

An ointment of the following composition is prepared:

g / 100 g ointment

Cardioxan® 1.5 g liquid paraffin 10g polyoxyethylene-20-stearyl ether 15g propylene glycol 5g white petrolatum 40 g cleaned water 28,5 g

Cardioxan® is restored to its original state in cold water. The other components are melted at 60 ° C and mixed. Cardioxan® is added and the product is blended to cool.

• 9 9 φ φ φ φ

Example 8: A cream of the following composition is prepared g / 100 g cream Cardioxan® 1 g glycerin monostearate (Tegin M®) 4g PEG-20-glycerin monostearate (Tagat S2®) 7g cetylstearyl alcohol 6g viscous paraffin 7,5 g white petrolatum 25 g glycerol 85% 10 g magnesium sulfate heptahydrate 0.5 g cleaned water 39 g

Glycerin monostearate, PEG-20-glycerin monostearate, cetyl stearyl alcohol, paraffin and petrolatum are heated to 60 ° C and stirred. A minor portion of the water is rapidly heated to boiling and cooled to 60 ° C, magnesium sulfate and glycerol are added and mixed. Cardioxan® is restored in another part of the water and added to the solution. An emulsion is now prepared from the two phases in the emulsifier and, after cooling, a homogeneous cream is obtained.

Example 9:

A gel of the following composition is prepared:

g / 100 g of gel

Cardioxan® 1.2 g isopropyl alcohol 20 g glycerol 100% 2g hydroxyethylcellulose 1.8 g purified water 75 g

Half of the total amount of water and glycerol are heated to 50 ° C; hydroxyethylcellulose is added and the mixture is stirred until a homogeneous gel is obtained. Cardioxan® is restored to the rest of the water and added with constant stirring. The gel is cooled to 25 ° C, isopropyl alcohol is added thereto, and the mixture is stirred under vacuum until a homogeneous gel is obtained.

Claims (31)

PATENT CLAIMS Use of dexrazoxane, the 1,2-bis (3,5-dioxopiperazin-1-yl) propane d-isomer, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the treatment of psoriasis, the compound having the formula Use according to claim 1, wherein the physiologically acceptable salt is dexroxan.HCl. Use according to claim 1 or 2, wherein the medicament is useful for injection or infusion. Use according to claim 3, wherein the medicament comprises a powder for reconstitution prior to injection. Use according to claim 1 or 2, wherein the medicament is in a form that can be administered topically, transdermally or percutaneously. Use according to claim 5, wherein the medicament is in the form of an ointment, lotion or patch. Use according to claim 1 or 2, wherein the medicament is in the form administered orally. Use according to claim 1 or 2, wherein the medicament is in the form of a suppository. Use according to claims 3 or 4, wherein the medicament is in unit dosage form and contains between 250 and 750 mg (eg 500 mg) of dexrazoxane calculated as dexrazoxane hydrochloride. · · T t t t t t t t t t t t t t t t t t t t t t t tr t t tr ··· · Use according to claims 3 or 4, wherein the medicament is in unit dosage form and contains between 750 and 1250 mg (eg 1000 mg) of dexrazoxane calculated as dexrazoxane hydrochloride. Use according to claims 3 or 4, wherein the medicament is in unit dosage form and contains between 1250 and 1750 mg (eg 1500 mg) of dexrazoxane calculated as dexrazoxane hydrochloride. Use according to claim 11, wherein the medicament is in the form of a topically administrable preparation, and the dexrazoxane is in the medicament in a concentration of 0.1 to 5 weight percent. The use of claim 11, wherein the medicament is adapted for topical administration to avoid oral or parenteral administration or administration by injection or infusion. Use according to claim 1 or 2, wherein the medicament is in the form of administered by injection or infusion and is adapted for administration to an adult human according to a protocol comprising: (a) administration of the drug by infusion or injection at a dose between 250 and 750 mg calculated as dexrazoxane hydrochloride; b) the next day, the drug is administered by infusion or injection at a dose of between 750 and 1250 mg, calculated as dexrazoxane hydrochloride; c) the next day the drug is administered by infusion or injection at a dose of between 1250 and 1750 mg, calculated as dexrazoxane hydrochloride. 15. An article specially comprising a topical or parenterally administered composition comprising dexrazoxane or a physiologically acceptable salt thereof and an agent suitable for treating or alleviating psoriasis as a combined composition for simultaneous, separate or sequential use in the treatment of psoriasis. 16. A method of treating psoriasis in a patient comprising administering to the patient a therapeutically effective amount of dexrazoxane, the d-isomer of 1,2bis (3,5-dioxopiperazin-1-yl) propane, a compound of formula • or a physiologically acceptable salt thereof. salts. 17. The method of claim 16, wherein the dexrazoxane is co-administered with a physiologically acceptable diluent, carrier or excipient. The method of claims 16 or 17, wherein the physiologically acceptable salt is dexroxane.HCl. The method of any one of claims 16 to 18, wherein the dexrazoxane is administered by injection or infusion. The method of any one of claims 16 to 18, wherein the dexrazoxane is administered topically, transdermally, or percutaneously. The method of claim 20, wherein the dexrazoxane is in the form of an ointment, lotion or patch. The method of any one of claims 16 to 18, wherein the dexrazoxane is administered orally. The method of any one of claims 16 to 18, wherein the dexrazoxane is in the form of a suppository. The method of any one of claims 16 to 23, wherein the patient is an adult and the method comprises the step of administering dexrazoxane by infusion or injection at a dose of between 250 and 750 mg, calculated as dexrazoxane hydrochloride. . • 99 99 99 99 9 9 9 9 9 9 9 9 9 999 9999 9 9 9 999 · 9999 The method of any one of claims 16 to 24, wherein the patient is an adult and the method comprises the step of administering dexrazoxane by infusion or injection at a dose of between 750 and 1250 mg, calculated as dexrazoxane hydrochloride. The method of any one of claims 16 to 25, wherein the patient is an adult and the method comprises the step of administering dexrazoxane by infusion or injection at a dose of between 1250 and 1750 mg, calculated as dexrazoxane hydrochloride. The method of any one of claims 16 to 23, wherein the patient is an adult and the method comprises the steps of: (a) administration of dexrazoxane by infusion or injection at a dose of between 250 and 750 mg, calculated as dexrazoxane hydrochloride; (b) the following day, dexrazoxane is administered by infusion or injection at a dose of between 750 and 1250 mg, calculated as dexrazoxane hydrochloride; and c) the next day the drug is administered by infusion or injection at a dose of between 1250 and 1750 mg, calculated as dexrazoxane hydrochloride. 28. The method of claim 16, wherein the dexrazoxane is administered topically. The method of claim 28, wherein the dexrazoxane is administered as a topical preparation containing from 1 to 2 weight percent dexrazoxane calculated as dexrazoxane hydrochloride. 30. A method for the manufacture of a medicament for treating psoriasis comprising treating a dexrazone or a physiologically acceptable salt thereof to form such a medicament. The method of claim 30, further comprising the feature (s) of any one or more of claims 2 to 14.