Therapy of sporadic transudation of anthracyclines

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

 

The present invention relates to a method and a drug for pharmacological treatment of accidental extravasation of poisons for topoisomerase II, such as anthracyclines.

In particular, the present invention relates to systemic and local injection of an inhibitor of topo II, such as videocapturing ICRF-187 in the treatment of accidental extravasation of poison topoisomerase II, such as the anthracyclines daunorubicin, doxorubicin, epirubicin or idarubitsin.

Background of invention

Topoisomerase II poisons for topoisomerase II catalytic inhibitors of topoisomerase II

Topoisomerase II (topo II) belongs to the nuclear enzymes involved in the processing of DNA during the cell cycle. In General terms they are able to carry out a temporary splitting of the two chains of the DNA double helix, thus permitting the other of intact double-stranded DNA through cleavage site. Time saving splitting is very short. Medicines acting on the topo II are divided into two major categories, poisons for topo II catalytic inhibitors of topo II.

Poisons for topo II shift the balance of the catalytic cycle in the direction of cleavage, thereby increasing the concentration time-related protein breaks in the genome [1] (see figure 1). Thus, they capture the split com is lexi, making the necessary enzyme topo II in lethal [2].

Catalytic inhibitors of topo II are completely different group of medicines. They operate by creating obstacles in the implementation of catalytic functions that can occur in at least two ways. One of them is an initial inhibition of binding of topo II and DNA, as in the case of chloroquine [3] and aclarubicin [4, 5]. The other way works through blocking topo II being closed clamp after re-ligation, which is, apparently, in the case of ICRF-187 and its analogues [6-9].

The anthracyclines

The anthracyclines are a group of widely used cyto toxic compounds with activity expressed in various malignant diseases.

Daunorubicin, first anthracycline antibiotic, opened in the early 1960s, was isolated from cultures of streptomycin. Shortly after it was extracted doxorubicin and investigated clinically. Both drugs have a wide range of activity against malignant diseases: daunorubicin operates mainly in the case of hematologic malignancies, and doxorubicin in the case of solid tumors. Epirubicin is a stereoisomer of doxorubicin, with the same evidence is, however, somewhat less powerful and less cardiotoxicity, than the original drug. Idarubitsin (4-demethoxygeldanamycin) similar to daunorubicin, however, has no metaxylene group in position C-4. It is more lipophilic tool than other anthracycline compounds, which are more easily crosses the blood-brain barrier.

The mechanism of action of these drugs is not quite fully understood. The antitumor effect is due to the ability to inhibit the nuclear enzyme DNA topo II. Thus, the anthracyclines are classified as poisons for topo II. However, these drugs also interact with other enzymes, such as topo I - DNA-and RNA-polymerase and helicase. In addition, they are capable of intercalated DNA carrying out the process, which can initiate free-radical damage. During intracellular metabolism anthracycline his antrahinonovye nucleus turns into a free radical intermediate semifinal, which may cause local degradation of DNA. Moreover, anthracyclines can helatirovat iron and to form ternary complexes with DNA. However, the concentration of drug required for the induction of free radical damage to DNA is higher than that achieved when used in clinical concentrations. Thus, the mechanism by everything visibility, less important in relation to anti-tumor effect.

The most pronounced side effects observed during treatment with anthracyclines is cardiotoxicity [10-11], hematologic toxicity, gastrointestinal toxicity, and very severe local toxicity that may occur after accidental extravasation (see below).

ICRF-187

Videocapturing ICRF-187 (dexrazoxane) is a water-soluble (+) enantiomer razoxane (ICRF-159). He is highly specific catalytic inhibitor of topo II. There is a hypothesis that ICRF-187, as similar stationsmassive connection EDTA, protects from free-radical damage by binding and thus hides the iron from the oxygen [12]. However, the authors have recently shown that cells with acquired registertest to ICRF-187 carry mutations in topo IIα (subtype topo II), which are found in other sihah than mutations induced by poisons for topo II, such as daunorubicin and etoposide. When using gumanitarnogo topo IV from yeast, the authors confirmed that these mutations are functional [13, 14]. In this regard, the assumptions of the authors that ICRF-187 is a specific agent for topo II were correct. Was shown the possibility to resolve the death of cells caused by etoposide, daunorubicin and idarubitsina on 2 different studies is x (see also figure 2) in the cycle of enzymatic catalysis. Thus, intercalating drugs, such as chloroquine, inhibit the enzyme due to the fact that not allow to reach the desired target [3, 15, 16] and videocapturing ICRF-187 blocks the enzyme at the stage of the closed clamp[4, 17, 18].

ICRF-187 is a registered cardioprotective agent (Zinecard®, Cardioxane®)applied in the case of the development of cardiotoxicity caused by anthracyclines.

Transudate anthracyclines

Random transudate is determined from 0.6 to 6% of patients undergoing chemotherapy. Chemotherapeutic agents such as anthracyclines, which are associated with DNA, especially can cause severe damage to tissues transsoudata. Tissue damage may not appear for several days or even weeks and may continue to deteriorate for months, possibly due to the fact that the drug circulates in the surrounding tissue. Local toxicity characterized by the appearance of acute pain, erythema and swelling at the site of extravasation and often progresses with the formation of ulcerations. In fact, it was shown that the anthracyclines, such as doxorubicin, can persist in tissues for at least a month [20]. While a small ulceration can be cured,large ulceration require surgical excision to relief the pain and healing of the corresponding tissue. With acceptable treatment is early surgical intervention with an extensive reorganization of the captured region with subsequent skin graft [21].

In the last two decades has been investigated many possible treatment options.

Local ice cooling over time from 1 hour to 3 days or longer is a widely used method of treatment (22), which should begin immediately. The use of local injection or topical corticosteroids as anti-inflammatory treatment gives conflicting results in studies on animals and humans [23]. Most likely, the inflammation does not contribute to the pathophysiology, and corticosteroids may even worsen the situation. In experiments, we studied the effect of local injection of sodium bicarbonate [24], which gave different results than, for example, in the case of local injection of sodium thiosulfate, hyaluronidase [25] and beta-adrenergenic (agonists and antagonists) [26]. The treatment in the experiment and clinical use of local injection of dimethyl sulfoxide (DMSO) in a period of time from 2 to 7 days in the presence or in the absence of α-tocopherol (vitamin E) [27-29] have shown beneficial effects in animal studies, and in the case of uncontrolled clinical trials, at least in the case of DMSO. Od is ako the results are not homogeneous. In one trial of intraperitoneal (/b), as well as local, treatment α-tocopherol, Ginkgo biloba (Ginkgo biloba) or pentoxifylline in the case of intradermal () injection of doxorubicin in rats reduced the level of cellular malondialdehyde, which involves the incorporation of the process of binding of free radicals [29]. Bi(3,5-dimethyl-5-hydroxymethyl-2-exmortis-3-yl) (DGM) can interact with doxorubicin in vitro with the formation of active metabolite aglycone deoxy-doxorubicin, and thus treatment of extravasation by introducing into the lesion DCMF after the/to the introduction of doxorubicin from the pig gave some positive effect [30]. Since 1988, no published studies confirming these data.

Almost all studies on animals anthracyclin injected intradermally. It was believed that injections under the muscle layer of the skin of rodents, in the subcutaneous muscle of the neck (panniculus carnosus), can cause uneven ulcerative lesions, whereas intradermal injections lead to homogeneous skin necrosis and ulceration [32]. Specified/to injection anthracyclines also provided a method, studied in models of pigs.

Fluorescence frozen sections sections extravasation of doxorubicin and epirubicin has been reported as an effective method of detection of residual drug in the tissue,which could serve as an indication for surgical treatment infiltration [31, 33].

Histological changes were investigated on model rabbits, and it was shown that the earliest changes include the obliteration of vessels and necrobiosis of collagen. Nowhere it has been shown that inflammatory cells play a major role [34]. Small vesicles of unknown etiology were visible on the dead skin of rats [32]. No studies to determine whether apoptosis.

Brief disclosure of the invention

There are no publications for studies that would indicate ICRF-187, other videocamera.ini, and catalytic inhibitors of topo II as treatment option. Moreover, none of the published studies or reviews do not discuss the role of enzymes topo II as potential targets for antidotes in case of extravasation anthracyclines or other poisons for topo II. And finally, there have been many experiments with animals with local treatment intradermally allocated anthracyclines. According to the authors, subcutaneous administration best reflects the reality in the clinic. Moreover, as shown in the examples, the value expressed as the product of the area of the wound at the time (area under the curve, AUC)is well reproduced by the parameter.

Local treatment in comparison with the system l is rising very important, because of increased use of access devices to the Central veins. In the case when expected over a long period of time multiple infusions, you should consider the possibility of subcutaneous reservoirs in a long chain. This approach is also an option during anthracycline therapy. Accommodation for short term or for a long period of time permanent Central venous catheters has now become conventional surgical procedure performed in cancer patients.

However, such devices are not free from leakage problems associated with the placement or education of infectious blood clots. Observed frequency of extravasation 6.4% [35]. Obviously, it is difficult to treat local transudate from Central installed devices. In this situation, systemic treatment more acceptable, but up to the present time was unacceptable.

Description of the drawings

Figure 1 shows the capture of poisons for topo II split complexes, which makes the necessary enzyme topo II lethal.

Figure 2 shows the proposed structure and catalytic cycle of splitting topo II one segment of DNA (G) and passing in the other segment (Tons). The enzyme is a glycosilated, consisting of three segments. Poisons for topo II act on the stud is s 3-4, when the segment is split. Catalytic inhibitors are either in stage 1 (chloroquine and aclarubicin)or stage 5 (ICRF-187).

Figure 3 shows the results of example 2.

Figure 4 shows the results of example 4.

Figure 5 shows the results of example 6.

Figure 6 shows the results of example 9.

7 shows the results of example 11. The average area under the curve (AUC) of 7 independent experiments with daunorubicin, enter p in a dose of 3 mg/kg (p/C) +/- ICRF-187 in a dose of 250 mg/kg (b/W) at time t=0.= without ICRF-187;= plus ICRF-187; ---- = mean value; delimiters = standard error of the mean.

On figa shows the results of example 11. The average AUC values for different options for the introduction of ICRF-187 after s/C injection of daunorubicin dose of 3 mg/kg

On FIGU shows the results of example 11. The average AUC values for different options for the introduction of ICRF-187 after s/C injection idarubitsina dose of 0.75 mg/kg

On figs shows the results of example 11. The average AUC values for different options for the introduction of ICRF-187 after s/C injection of doxorubicin at a dose of 2 to 3 mg/kg

Figure 9 shows the results of example 11.

Left graph: trace circles indicate the distribution of AUC values for individual mice after s/C injection of daunorubicin dose of 3 mg/kg and then salt Rast is ora (O; n=56) or ICRF-187 in the/b introduction in a dose of 250 mg/kg at time t=0 (; n=55). Horizontal lines indicate the mean AUC values.

Right graph: the Average value of the square of the lesion with respect to time with the same data as in the left column:

DEX: dexrazoxane = ICRF-187; AUC: area under the curve.

Figure 10 shows the results of example 11.

Left graph: trace circles show the distribution of AUC values for individual mice after s/C injection of doxorubicin at a dose of 2 or 3 mg/kg followed in b/W the introduction of saline (n=56) or in b/W the introduction of ICRF-187 in a dose of 250 mg/kg at time t=0 (•; n=55). Horizontal lines indicate the mean AUC values.

Right graph: the Average value of the square of the wound in relation to the time when the same data as in the left column:

DEX: dexrazoxane = ICRF-187; AUC: area under the curve.

Detailed disclosure of the invention

The present invention relates to a system and/or local effective treatment of accidental extravasation of poisons for topoisomerase, such as the anthracyclines of daunorubicin, doxorubicin, epirubicin, idarubitsin, using a catalytic inhibitor of topo II, such as videocapturing ICRF-187.

In one embodiment implementing the present invention relates to a method for prevention or treatment of tissue damage associated with transsoudata the funds to topo II, including the anthracyclines, the patient undergoing treatment, usually systemic treatment poison topoisomerase II. This method includes the introduction of catalytic inhibitor of topo II to the patient, if necessary. Signs of possible extravasation of poisons topoisomerase II typically include an acute pain in the area of extravasation, so the treatment of tissue damage should be started without delay. However, the damage creates can be carried out over a long period of time after the occurrence of extravasation, so treatment catalytic inhibitor of topo II can be repeated as often as necessary to maintain optimal suppression of tissue damage.

Inhibitor of topo II in accordance with the present invention are preferably chosen from the group comprising videocamera.ini, quinoline, aclarubicin and acridine. The preferred videocapturing is ICRF-187 (dexrazoxane). This videocapturedevice connections, which include the present invention include bis (3,5-dioxopiperazinyl-1-yl)alkanes having the structure represented by the General formula I:

where R1and R2independently selected from hydrogen and optionally substituted C1-6-alkyl, or R1and R2together with the atoms to which they attaches a compass is carried out, form3-8-carbocyclic ring, where R3and R4chosen from hydrogen and optionally substituted C1-6-alkyl.

In the context of the present description, the term “C1-6-alkyl” denotes a linear or branched saturated hydrocarbon group containing from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclohexyl.

In the context of the present description, the term “C3-8-carbocyclic ring” refers to cyclopropyl, cyclobutyl, cyclopentyl, chicagocrime, cycloheptyl or cyclooctyl group. It should be understood that when R1and R2together with the atoms which they are attached, denote With3-8-carbocyclic ring”, dioxopiperazinyl rings can be attached to the specified carbocyclic ring or TRANS (E)or CIS (Z) position relative to the ring. It should be understood also that the very carbocyclic ring may be substituted by 1-3 groups selected from C1-6of alkyl, C1-6-alkoxy(=C1-6-alkyloxy) and other

In the context of the present description, the term “optionally substituted” means that the alkyl group may have from 1 to 3 substitutions of one or more the Islom groups, selected from C1-6-alkoxyl, oxo (which may be represented in the tautomeric enol form), carboxyl, amino, hydroxyl, mono - and di(C1-6alkyl) amino, carbamoyl, mono - and di(C1-6alkyl) aminocarbonyl, halogen (e.g. fluorine, chlorine, bromine and iodine), phenyl or heterocyclyl (for example, piperidine, piperazine, research, pyrroline, pyrrolidine, pyrazoline and imidazoline).

In a preferred implementation of the present invention, the values of the substituents R1, R2, R3and R4include combinations in which R1and R2selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxymethyl and ethoxymethyl and where R3and R4defined above, but preferably is selected from hydrogen and methyl.

In another preferred embodiment of the invention the values of the substituents R1, R2, R3and R4include combinations in which R1and R2together with the atoms to which they are attached, denote ecoprofile, cyclobutyl or cyclopentene ring and in which R3and R4basically defined above, but preferably they are selected from hydrogen and methyl.

In yet another preferred embodiment of the invention the values of the substituents R1, R2, R3and R4include combinations in which R3 and R4selected from hydrogen, methyl and methyl, substituted heterocyclyl, such as piperidine, piperazine, research, pyrroline, pyrrolidine, pyrazoline and imidazoline in which R1and R2mainly stated above, but preferably is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxymethyl and ethoxymethyl, particularly methyl.

In yet another preferred embodiment of the invention the values of the substituents R1, R2, R3and R4include combinations in which R1and R2selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxymethyl and ethoxymethyl and where R3and R4mean hydrogen.

It should be borne in mind that the substituents R1and R2can lead to optical form (that is, (S) and (R) forms or racemic mixtures of such forms.

Particularly preferred combinations in which R3and R4denote hydrogen, are those combinations in which R1=R2= hydrogen, methyl (meso), ethyl (meso), in which R1= hydrogen and R2= methyl (racemic mixture of (S)-(+) (dexrazoxane) or (R-(-) (laurazocca), preferably (S) - (+)), and ethyl, and also those in which R1= methyl, R2= ethyl, propyl, isopropyl and methoxymethyl, while the latter is in the Erythro or threo form, preferably in Erythro fo the IU.

The introduction of catalytic inhibitor of topo II can be carried out by local introduction in tissue affected by transsoudata of poison topoisomerase II. Specified the introduction includes an injection in such affected area, a direct application of the inhibitor or by using any form of the implant, through the bandages, spraying or in any other way. Local injection can be used as the sole treatment or as an additional treatment to systemic therapy. Local treatment is particularly advantageous in the case when transudate is located in the body cavity, such as the pleura.

In a preferred embodiment of the invention the introduction of catalytic inhibitor of topo II is effected by systemic injections into the tissue affected by transsoudata of poison topoisomerase II. A very important aspect of the invention is that the tissue damage can be prevented or cured with the systemic administration because the system introduction ensures that the inhibitor reaches the lesion tissue.

It is obvious that the introduction of the inhibitor will be carried out usually in the case when transudate is already a reality, or when it is considered that this has happened. However, in some cases it may be preferable to start preventive treatment. This requirement may, at the best in a situation, when the patient suffers from extravasation with early treatment poison topo II or in the case when there is a clear risk of extravasation, for example, when the patient is very sensitive veins, which often occurs during chemotherapy.

A preferred variant of the invention includes the situation when a catalytic inhibitor of topo II is entered after treatment poison topoisomerase II. In a more preferred embodiment of the invention the specified inhibitor is administered after treatment with poison topoisomerase II during the period until the tissue still contains the poison topoisomerase II or its active metabolites. In such cases, it may be treated with inhibitor with the inclusion of the interval, depending on the location and extent of tissue damage. Any person with an average level of knowledge in this field in the state on the basis of currently available information to offer specific treatment in specific situations, as the main problem lies in the fact that the inhibitor are present in the relevant field all the time, until the poison is active in the specified area of the fabric.

Poisons for topoisomerase II, which can cause tissue damage and which can be treated in accordance with the method of the present invention include etoposide phosphate etopozi is a, teniposide, daunorubicin, doxorubicin, idarubitsin, epirubicin, mitoxantrone, m-AMSA and anthracyclin. Moreover, any poison topoisomerase II, which inhibits the stage of re-ligating nuclear topoisomerase II, the stage at which the enzyme creates a split complex in DNA, is included in the scope of the present invention.

Basically there is no reason to enter the inhibitor long before the introduction of the poison and therefore it is most preferable to introduce the inhibitor essentially simultaneously with the introduction of the poison topoisomerase II in a situation where it is desirable preventive treatment.

In the case where a catalytic inhibitor of topo II is injected after the injection of the poison of topoisomerase II, this period should mainly cover 3 weeks after injection of poison topoisomerase II, such as within 2 weeks, preferably 1 week, more preferably within 5 days, more preferably within 3 days after and even more preferably within 1 day after the injection of the poison of topoisomerase II. A 3-week period may illustrate the situation where the poison or its metabolites are still active in the patient's body.

Basically catalytic inhibitor of topo II should be entered within the period of 18 hours after the injection of the poison of topoisomerase II, such as within 12 hours, prefer the LNA within 6 hours after, more preferably within 4 hours, even more preferably within 2 hours and most preferably within 1 hour after and most preferably immediately after the injection of the poison of topoisomerase II with the aim of preventing the development of tissue damage as a result of extravasation. However, other reasons may be more acceptable to watch will be any transudate, and then the patient is treated with the inhibitor as soon as possible. Accordingly in another aspect the method of the present invention refers to a situation in which a catalytic inhibitor of topo II impose upon discovery or suspicion of extravasation of poison topoisomerase II.

In a preferred embodiment of the invention a catalytic inhibitor of topo II is administered in at least two repeated doses, such as at least 3 repeated doses. These repeated dosing may be identical or to be a gradual dose reduction. Preferably, re-dosing was administered every 3 days from first dose, preferably at intervals of 2 days, more preferably with an interval of 1 day. However, small intervals, less than 24 hours, such as intervals of up to 18 hours, more preferably up to 6 hours, such as the intervals at which Erno 3 hours, after the first dose catalytic inhibitor of topo II showed amazing results. The intervals should not be identical in the sense that treatment with increasing intervals can be very successful. Any person with an average level of skill in the art can appreciate views of “saturation” relatively high doses or doses in small intervals, with the consequent increase of the intervals after the introduction of catalytic inhibitor of topo II.

Catalytic inhibitor of topo II should be introduced within 12 hours, preferably within 6 hours after detection or suspicion for the presence of extravasation of poison topoisomerase II. It should be noted that the introduction may be conducted by the conventional method, in order to prevent tissue damage from extravasation.

In a preferred embodiment of the invention a catalytic inhibitor of topo II is videocapturing and poison topoisomerase II is anthracyclin. It is now known that anthracyclin responsible for the most serious cases of tissue damage. In accordance with this method, in which anthracyclin selected from daunorubicin, doxorubicin, idarubitsina and epirubicin, is a very important aspect of the invention.

Inhibitor of topo II according to the present invention can be videocapturing with the above formula and preferred videocapturing represents ICRF-187 (dexrazoxane).

In view of the specific features of the present invention is very difficult to specify the exact dosage of the inhibitor. However, in regard to ICRF-187, concentration and dosage used tools known from other medical indications and the same dosage can be used in the methods according to the present invention. In other cases, a specialist with the average level of knowledge in this area able to offer the right dosage, including by introducing increasing doses in accordance with the volume of extravasation of poison. In General, the risk of tissue damage increases the risk of side effects caused by the inhibitor. The aim of the method according to the present invention is the introduction of the inhibitor of topo II in a quantity sufficient to ensure that he was present in the tissue and could prevent the development or healing of tissue damage. As follows from the examples of successful treatment, it may be repeated dosages in the range from 1000 to 500 mg/kg, injected patients-women. However, in accordance with the present invention can be used in repeated dosages of 100 to 5000 mg/kg the Exact dose depends on is the introduction of a single dose or 3 or more repeated doses, which is preferable in a particular situation. As was shown in the experimental nth mice and pigs, input re-dosing, less than 25 mg/kg, give a very good effect. These dosages are included in the scope of the present invention.

Another object of the present invention is the use of catalytic inhibitor of topo II to obtain a medicinal product intended for the treatment or prevention of tissue damage caused by transsoudata of poison topoisomerase II in a patient undergoing treatment, such as systemic treatment poison topoisomerase II. Accordingly, the present invention relates to the use of catalytic inhibitor of topo II in obtaining medicinal products intended for use under any of the following methods.

In the context of the present description, the term “treatment poison topoisomerase” means directly carried out treatment (for example, a patient undergoing a specific treatment or a situation in which the patient has already been treated.

The present invention also relates to a pharmaceutical kit used for the prevention or treatment of tissue damage caused by transsoudata poisons for topoisomerase II, including anthracyclines in patients undergoing systemic treatment with the drug, with a specified set includes:

a) the standard dose of poison to topoisomers the s II and optionally a pharmaceutically acceptable carrier and

b) the standard dose of catalytic inhibitor of topo II and optionally a pharmaceutically acceptable carrier, used either for local or intravenous, and optional

(c) a description of the procedure of the introduction of catalytic inhibitor of topo II to a patient in case of extravasation.

In a preferred embodiment implementing the present invention relates to a pharmaceutical kit, intended for the prevention or treatment of tissue damage caused by transsoudata anthracyclines, patients undergoing systemic treatment with anthracyclines, with a specified set includes:

a) the standard dose of anthracycline and optionally a pharmaceutically acceptable carrier for intravenous and

b) the standard dose videocapturing and optionally a pharmaceutically acceptable carrier suitable for either local or intravenous, as well as optional

(c) a description of procedures for conducting catalytic inhibition of topo II videocapturing the patient in case of introduction when extravasation videocapturing.

The specified set may include any suitable solvents for the active ingredients and procedures of local and/or systemic use of inhibitor.

In a preferred embodiment of the invention specified n the Bor only includes any of the above in the description of catalytic inhibitors of topo II, without poison topo II.

Set preferably are in the form of a kit for emergency, which must be available immediately when possible occurrence of extravasation.

The present invention is further illustrated by the following examples.

Examples

Materials and methods

General remarks

Experiments were performed in the laboratory of experimental medical Oncology (Laboratory of Experimental Medical Oncology) Finsen (Finsen) and in the laboratories of the national University hospital (Laboratory Centres at the National University Hospital) (Ringshospitalet), Copenhagen, Denmark). Inventors No. 1 and No. 2 licensed (Ministry of Justice) for experiments on living animals, and thus, they are subject to the conventions 86/609/EEC (60) AND CE (61).

Mouse

Female B6D2F1 hybrid mice derived from M&A/S, Denmark, and maintained under controlled conditions with free access of food and water. All the mice went through a period of preexperiments acclimatization at least one week. The weight of the animals ranged from 19 to 21 g in the beginning of the experiment.

Drugs

Below are commercially available medicines.

Hydrochloride ICRF-187 (Cardioxane®, Chiron)

Hydrochloride doxorubicin (Doxorubicin "Paranova"®, Pharmacia)

Hydrochloride, daunorubicin (Cerubidin®, Rhône-Poulenc Rorer)

Hydrochloride idarubitsina (Zavedos®, Pharmacia & decision Upjohn)

Hydra is the chloride of epirubicin (Farmorubicin®, Pharmacia & decision Upjohn)

Fentanyl-fluanisone (Hypnorm®, Janssen)

Midazolam (Dormicum®, Roche)

Anesthesia

In all experiments, the authors used standard solutions containing 1 part of fentanyl-fluanisone, 1 part of midazolam and 2 parts isotonic saline at a dose of 0.1 ml/10 g for intraperitoneal administration (62).

Injection technique

The coat was removed with electric razor.

Subcutaneous deposition of anthracycline was performed using a Hamilton syringe (Hamilton®) with a fixed volume dispensing 0.05 ml and the size of the needle 27G × 3/4". The injection site was chosen about 1 cm above the base of the tail when pulling back the skin on his back.

ICRF-187 was administered intraperitoneally in a volume of approximately 0.2 ml with needle 27G × 3/4".

Entering into defeat ICRF-187 were injected with through a separate puncture the skin immediately after the introduction of anthracycline in a volume of 0.05 ml using a syringe for applying a fixed dose (Hamilton®).

Identification

Each mouse had on the ear mark for individual identification.

Observation

Fluorescent measurements were carried out on the two longest perpendicular diameters of the lesion with a ruler. The wound was defined as a lesion of tissue about the size of at least 2 mm2. Healing was defined as complete return of hair growth in the affected area. Poliitikana all RAS mice were subjected to euthanasia.

Data handling and statistical processing

The size of the wound was calculated on the basis of the two longest perpendicular diameters in mm the size of the wound over time, i.e. the area under the curve (AUC)was calculated for each individual mouse. Presented in the next section, the data contain the average value of the AUC. AUC values, the time of appearance of wounds and duration of symptoms RAS were compared using the test Mann-Whitney (Mann-Whitney). To compare levels of ulceration used t-test Fisher.

Reduction

Used the following abbreviations:

AUC = area under the curve

TTWw= time of occurrence of the wound, the mouse without RAS excluded

DWw= duration of symptoms RAS, mouse without RAS excluded

Nw/NG= level ulceration

SEM = standard error of the mean

in a/b = intraperitoneal administration

p/C = subcutaneous injection

in/n = ingestion defeat

in/in = intravenous

Example 1

Experiments with doxorubicin

Example 1 examine the effect of different concentrations of ICRF-187 entered in a/b at time t=0, i.e. simultaneously with doxorubicin. The concentration of doxorubicin is 2 mg/kg, and the amount previously specified. The control group in/b injected saline. Using twenty-seven mice.

The results are shown in table p is the iMER 1. Processing using ICRF-187 in a dose of 125 mg/kg/W, leads to a 91% decrease in AUC from 543 to 48 mm2× days (p<0,05). Stepwise increasing concentrations of ICRF-187 to 250 and 375 mg/kg leads to a complete prevention of the formation of the Russian Academy of Sciences. Level ulceration reduced from 86%to 14%, 0 and 0%, respectively. Due to the small number of studies in the group of animals treated with ICRF-187, statistical comparison of changes in TTW and DW are insignificant. While there were no deaths related to treatment.

Example 2

Time of introduction of ICRF-187

36 mice examine the time of the introduction of ICRF-187. As in example 1, the concentration of doxorubicin is 2 mg/kg and saline to serve as control. ICRF-187 introducing/b at a concentration of 250 mg/kg in simultaneous mode, 3 hours after or 6 hours after injection of doxorubicin, respectively. The results obtained are shown in table No. 2.

Processing using ICRF-187 results 82-92% decrease in AUC with 458 45, 52 and 81 mm2× days, respectively. There was a statistically insignificant trend towards a smaller decrease in AUC in the case when the introduction was performed 6 hours after doxorubicin, compared with the case of simultaneous introduction. The time of appearance of the wound and duration of symptoms of the wound is tsichlis. This was not observed deaths related to treatment. The average AUC values are shown graphically in figure 3.

In General, treatment with ICRF-187 in the time period t=0 in examples 1 and 2 reduced the levels of ulceration from 14/16 to 6/29, that is, from 88% to 21% (p<0,05).

Example 3

Experiments with daunorubicin

The effect of different doses of ICRF-187 is investigated in example 3. Saline served as control, which gives the values of AUC 764 mm2× days. Co-administration with ICRF-187 in a dose of 250 and 375 mg/kg leads to a decrease in AUC 48 and 93%, respectively (p=<0,05). Level ulceration reduced from 87 to 83 and 25%. It was noted the contradictory results from the point of view of the duration of the manifestation of the wounds in group 2.

In any case, the statistical evaluation of the characteristics of several RAS is insignificant.

Observed no deaths related to treatment.

Example 4

Comparison of two concentrations of p/C input daunorubicin.

Comparison of two concentrations of subcutaneously injected daunorubicin conduct concurrent treatment ICRF-187 in a dose of 250 mg/kg and without it. In the table for example 4 shows the results.

The average AUC values shown in figure 4.

The introduction of ICRF-187 results in lower AUC values for 100 and 75% in the group with low and you the Oka dose, respectively (p< 0/05). Similar dose-dependent differences between the AUC in the two control groups (1 and 3) are statistically significant and effect of ICRF-187 on the average duration of symptoms of RAS in groups 1 versus 2 and 3 versus 4, respectively. Reducing ulceration in the groups receiving daunorubicin dose of 1 mg/kg, similar statistically significant, while the same trend was observed in the group with a dose of 3 mg/kg, Although the latter was not statistically significant.

Example 5

Repetition of the experiment with large groups

In example 5 the experiment is repeated with a larger group, using 36 mice. As shown in the table of example 5, there is a decrease in the level of ulceration between mice not receiving, and mice that receive treatment with ICRF-187. In addition, ICRF-187 was reduced (p<0.05) value of AUC by 73% and 83% in the groups receiving a dose of 1 and 3 mg/kg, respectively. In addition, differences in AUC, TTW and DW between the two controls was statistically significant. Tends to reduce the values of DW and increase the value of TTW between the two groups with a low dose, which, however, was not statistically significant. In the groups receiving a dose of 3 mg/kg, the differences were significant.

The comparison group with the group in the framework of examples 4 and 5 shows no statistically is nazimah differences between similar types of treatment, it is possible to obtain the same results in two examples. Thus, the generalized data of the two experiments have increased the statistical significance of differences in AUC, TTW and DW between groups receiving treatment for ICRF-187, and the groups not receiving ICRF-187, as well as between the groups receiving low and high doses.

Example 6

The effect of different time of the introduction of ICRF-187

ICRF-187 is injected at the same time as daunorubicin, after 3 and 6 hours after administration, respectively. Saline served as control. The dose of daunorubicin is 3 mg/kg, s/C and ICRF-187 introducing/b in solution in a dose of 250 mg/kg is Used twenty-eight mice. The results are shown in the data table No. 6, and the average AUC is shown graphically in figure 5.

Change the value of the AUC reflects the effect of the treatment with ICRF-187 in the case of the introduction of it at the same time, and daunorubicin, and after 3 hours. Thus, the AUC is reduced by 70% at time t=0 (p<0.05) and 70% at time t=+3 hours (p<0,05). However, 6-hour delay in the introduction of ICRF-187 leads to a statistically significant 34% decrease. Regardless of the time of introduction of the application of ICRF-187 reduces the duration of symptoms RAS (p<0,05).

Example 7

The impact of the introduction of ICRF-187 inside of defeat

ICRF-187 in a dose of 100 mg/kg injected in p is dainow the pimple, formed by the injection of daunorubicin. The specified treatment compared with the control, which is injected into the lesion saline, with a/b the introduction of saline as a control and with a/b by treatment with ICRF-187. In each group there were 9 of mice and observed no deaths related to treatment.

Intraperitoneal administration IRF-187 leads to lower AUC values by 51% (p<0,05). Local (inside the lesion) injection for the treatment of saline does not cause reduction of AUC values, and this effect is not associated with any effect of breeding. In addition, the introduction of ICRF-187 inside the lesion gives the same or slightly greater decline in the value of the AUC in comparison with the value obtained in b/W treatment. The time of manifestation of the Academy of Sciences was longer than in the group of animals with a/b introduction ICRF-187 (p<0.05), reduced duration of symptoms RAS in the/b or C/p the introduction of ICRF-187 was statistically significant.

Example 8

Experiments with epirubicin

In example 8 use of 28 mice, which impose epirubicin subcutaneously at a dose of 4 mg/kg Intraperitoneal injection of saline served as control, while treatment includes a/b introduction to ICRF-187 in doses of 125, 250 or 375 mg/kg, respectively. The results are presented in the table for the example 8.

Was not observed statistically significant differences in AUC values between the 4 groups. However, if you take into account the values of AUC and the level of ulceration, there is a tendency to a dependent dose-dependent beneficial effect of treatment with ICRF-187. Statistical analysis differences in the duration of the manifestations of RAS or time of occurrence of the RAS is not significant.

Most likely the dose of epirubicin in example 8 was too low. In this regard, the effect of higher doses of epirubicin is a subject for further research. Similarly, the influence of time of introduction of ICRF-187 on transudation of epirubicin was not investigated.

Example 9

Experiments with idarubitsina

In example 9 mice (54 mouse) were injected subcutaneously idarubitsin in increasing concentrations from 0.05 to 0.75 mg/kg half of the groups served as control received saline, while the other half of the group were injected W/ICRF-187 in a dose of 250 mg/kg at time t=0. The results are shown in table data for example 9. This was not observed deaths associated with treatment.

The introduction of ICRF-187 in a dose of 0.75 mg/kg leads to a 90% decrease in the AUC values compared to option saline, employee controls (p<0,05), see Fig.6. In addition, the level of ulceration is reduced from 100% to 22% (p<0,05). the modify in AUC values between groups, undergoing treatment with ICRF-187, and control with the introduction of low doses idarubitsina, were not statistically significant, the number of wounds was too small for further statistical analysis. It was noted a dose-dependent increase in the mean AUC values in the control groups (p<0,05).

Example 10

Extended experiments with daunorubicin

It was performed twenty-eight experiments. Seven experiments (n=6, 7, 7, 9, 9, 9 and 9) were conducted with daunorubicin, injected subcutaneously at a dose of 3 mg/kg) plus saline solution injected in b/W at time t=0, and the seven experiments (n=6, 7, 1, 9, 9, 8 and 9) with daunorubicin, injected subcutaneously at a dose of 3 mg/kg, plus ICRF-187 in a dose of 250 mg/kg b/W at time t=0 and two experiments (n=9 and 4), in which ICRF-187 entries in doses of 62.5, and 375 mg/kg, respectively, in two (n=7 and 9) dose was 125 mg/kg of ICRF-187 in a dose of 250 mg/kg was injected into/in one experiment (n=9). ICRF-187 was introduced in the form of three courses in three experiments: one (n=8) dose was 250 mg/kg, in/b/ at day 0, 1 and 2. In the other two ICRF-187 were injected with in the time t=0.3 and 6 hours after s/C injection of daunorubicin dose of 125 (n=9) and 62.5 mg/kg (n=9), respectively.

Example 11

Extended experiments with doxorubicin

It was performed twenty-eight experiments. Six experiments (n=9, 9, 18, 9, 9 and 7) were conducted with doxorubicin, BBO is Imam subcutaneously at a dose of 2 or 3 mg/kg, plus saline solution injected in b/W at time t = 0, and six experiments (n=9, 8, 16, 6, 9 and 9) were conducted with doxorubicin, s/to the dose of 2 or 3 mg/kg and with ICRF-187 entered in a/b at a dose of 250 mg/kg at time t=0. In two experiments (n=9 and 7) ICRF-187 was administered at a dose of 125 mg/kg, in one experiment (n=7) dose was 375 mg/kg/W, and in one (n=9) dose was 62.5 mg/kg/B. In one experiment (n=9) after s/C injection of doxorubicin at a dose of 3 mg/kg immediately enter/ICRF-187 in a dose of 250 mg/kg of ICRF-187 injected into the three-mode three experiments: one (n=9) dose of doxorubicin was 250 mg/K, V/b at day 0, 1 and 2. The other two ICRF-187 was introduced at time t=0, 3 h and 6 hours after s/C injection of doxorubicin at a dose of 125 mg/kg (n=9) and 62.5 mg/kg (n=9), respectively. In some experiments (n=9) doxorubicin injected s/C at a dose of 1 mg/kg with saline solution, b/W, and in one experiment (n=9) with 250 mg/kg ICRF-187, b/W. ICRF-187 in a dose of 250 mg/kg injected in b/W three (n=9, and 9) or six hours (n=9 and 9) after s/C injection of doxorubicin at a dose of 2 or 3 mg/kg in four other experiments. And finally, in two experiments using a pre-mixed doxorubicin at a dose of 3 mg/kg with ICRF-187 in a dose of 250 mg/kg (n=9) or 30 mg/kg (n=9) for s/C injection.

Results

Doxorubicin induced lesions, similar in size and duration as when s/to the introduction of 2 or 3 mg/kg Thus, DV is specified doses were combined (table a). Biexponentially variations in the average AUC in seven experiments with daunorubicin when s/to the dose of 3 mg/kg) plus saline solution, b/W, were very small (p>0,05). There were no differences in AUC values in seven experiments, where the introduction of daunorubicin dose of 3 mg/kg was accompanied by a/b the introduction of ICRF-187 in a dose of 250 mg/kg at time t=0 (Fig.7). The same apparent reproducibility was presented in experiments with doxorubicin, enter p in a dose of 2 or 3 mg/kg) plus saline solution, b/W plus or ICRF-187, b/b at a dose of 250 mg/kg in Addition, since the treatment with ICRF-187 leads to a statistically significant decrease in the values of AUC in all the above experiments (individual tests Mann-Whitney, all p<0.01), and specific data were combined into two “main” option with the number of mice (n=61 and 58 (doxorubicin) and n=56 and 55 (daunorubicin), respectively, as shown in Table A.

A single on/b injection ICRF-187 in a dose of 250 mg/kg, conducted immediately after s/C injection of daunorubicin in the amount of 3 mg/kg, reduced the average AUC by 70% (p<0,0001) (Fig and 9). The number of mice with wounds decreased from 96 to 78% (p=0,0041). Mice detected by the stripes of the average time of occurrence of RAS slowed down by 76%, from 5.5 to 9.7 days (p<0,0001). In addition, ICRF-187 reduced the average duration of symptoms of RAS by 35%, from 26.6 to 17.4 days (p<0,0001).

p> In the case of the introduction doxorubicin (Fig and 10) the average AUC value after s/C injection at a dose of 2 or 3 mg/kg decreased by 96% (p<0,0001) when in b/W the introduction of ICRF-187 in a dose of 250 mg/kg at time t=0. The number of mice with wounds decreased from 77% to 14% (p<0.0001)and duration of symptoms RAS decreased to 28% (p=0,0035). There was no delay in the time of occurrence of wounds.

In both cases, the lesions induced by daunorubicin and doxorubicin, there was no statistically significant difference in the levels of protection provided in b/W injection ICRF-187, compared to the/in the introduction.

Reduce the dose of daunorubicin from 3 to 1 mg/kg resulted in significantly lower AUC values (p<0.0001)and when that was not observed differences in the frequency of occurrence of RAS, time, or duration of symptoms RAS. In a/b introduction to ICRF-187 also leads to a statistically significant decrease in the values of AUC (p<0,0001) with a low dose of daunorubicin. Doxorubicin, injectable p/C in doses below 2 mg/kg did not cause any wounds.

When lesions induced by daunorubicin, AUC values decreased from 70% to 45% (p=0,0175) at lower doses of ICRF-187 to 250 mg/kg to 125 mg/kg In contrast, protection against damage by doxorubicin was equally effective if all doses of ICRF-187.

The delay in the introduction of ICRF-187 on three or even six hours do not worsen the degree of protection from damage by doxorubicin in which the alignment effect, obtained by processing at time t=0. Similarly, in the case when ICRF-187 was administered 3 hours after injection of daunorubicin, the protective effect did not differ from that level of protection was achieved by immediate introduction of ICRF-187. However, protection was not achieved, if the delay was 6 hours.

The treatment in b/W the introduction of ICRF-187 in a dose of 250 mg/kg for three consecutive days completely prevented development of defeat doxorubicin and daunorubicin. Moreover, the three-fold in b/W the introduction of ICRF-187 in a dose of 62.5 or 125 mg/kg at 0, 3 and 6 hours after injection of daunorubicin or doxorubicin led to at least the same level of protection as a single on/b injection ICRF-187 in a dose of 250 mg/kg

Dose ICRF-187 is in inverse relation to the protection against the occurrence of wound damage, as was shown in two experiments in which ICRF-187 and doxorubicin were mixed before s/C injection. So, s/C injection of a mixture of ICRF-187 in a dose of 30 mg/kg) and doxorubicin at a dose of 3 mg/kg resulted in complete protection against the occurrence of RAS. However, higher doses of ICRF-187 to 250 mg/kg at the same time led to the emergence of wounds in seven of the nine treated mice.

From Fig.7 shows that the induction of the formation of the Russian Academy of Sciences p/entered by daunorubicin and protection from injury due to/b introduction ICRF-187 is highly reproducible.

Sredneetazhnye area under the curve (AUC) of 7 independent experiments with daunorubicin, p/C in a dose of 3 mg/kg +/- ICRF-187, a/b, at a dose of 250 mg/kg at time t=0. Variations between experiments were statistically insignificant in the case of experimental animals (plus ICRF-187; R=>0.05; student's t test-Neumann-Cents) or controls (without ICRF-187; R=>0,05). The introduction of ICRF-187 leads to a statistically lower mean AUC (p<0,001) in all experiments.

= without ICRF-187;= plus ICRF-187; ---- = mean value; separator: = SEM.

From Fig shows that protection against lesions induced by daunorubicin, is largely dependent on dose and time than against lesions caused p/to the introduction of doxorubicin. Expressed the protection achieved at three times the introduction of ICRF-187 is quite unexpected. On the bar chart compares the average values of AUC in various embodiments, the introduction of ICRF-187 after s/C injection of 3 mg/kg daunorubicin (figa), 0.75 mg/kg idarubitsina (pigv) and 2 or 3 mg/kg doxorubicin (figs), respectively.

The average AUC values: the Average area under the curve (mm2× days); n - number of mice; the comma - SEM.

Description: with the exception of delimiters that identify the salt solution, the description refers to the dose, route of administration and time of administration ICRF-187.

From figure 9 it is seen that a single systemic injection of ICRF-187 significantly nijaat the number of Russian Academy of Sciences, induced p/to the introduction of daunorubicin.

Left graph: Scattered points, shows the distribution of AUC values for individual mice after s/C injection of 3 mg/kg daunorubicin followed in b/W the introduction of saline (; n=56) or ICRF-187, b/b at a dose of 250 mg/kg at time t=0; n=55). Horizontal lines indicate the mean AUC values.

Right graph: the Average value of the square of the wound against time on the same days as in the left graph. Differences in AUC values are highly significant. In addition, the curves reveal delaying the emergence and reduction in the duration of wound lesions.

DEX: dexrazoxane = ICRF-187; AUC: area under the curve.

From figure 10 it is seen that a single systemic injection of ICRF-187 significantly reduces the number of RAS induced p/to the introduction of doxorubicin.

Left graph: Scattered points, shows the distribution of AUC values for individual mice after s/C injection of 2 or 3 mg/kg doxorubicin followed in b/W the introduction of saline (; n=56) or ICRF-187, b/b at a dose of 250 mg/kg at time t=0 (; n=55). Horizontal lines indicate the mean AUC values.

Right graph: Average values of the area of the wound in relation to the time in those days, as in the left graph. Differences in the AUC values of Visokosniy.

DEX: dexrazoxane = ICRF-187; AUC: area under the curve.

Table And

The results of the treatment of wounds in mice caused p/to the introduction of daunorubicin, idarubitsina and doxorubicin. Unless explicitly noted, treatment (ICRF-187 or saline) hold at time t=0.

DEX: dexrazoxane = ICRF-187; AUC: Average area under the curve (mm2× days); FW: Some mice with wounds (%); TTW: the Average time of occurrence of RAS (days); DW: the Average duration of symptoms RAS (days); Brackets: Standard error of the mean, SEM; *: the combined data (see Detailed results); n: Number of mice.

Example 12

A pilot study on pigs

Used Danish pigs weighing about 30 kg of the Animal fully anaesthetize and do artificial ventilation during s/C injection of 1 ml of anthracycline. In one experiment (n=2) wounds appear after s/C injection of 3 mg of doxorubicin in pigs not treated with ICRF-187, while pigs fed/injection 25 mg/kg ICRF-187 at time t=0, did not show signs of developing ulcers. In the second experiment (n=3) after s/C injection of 1 ml of daunorubicin in pigs, which was introduced in/25 mg/kg ICRF-187 daily for three days, did not appear wounds; small wounds appeared in pigs, which input the or/50 mg/kg at time t=0, and major wounds appeared in animals, not held of treatment.

In short we can conclude that the experiments on pigs, confirmed the results obtained in previous experiments with mice, namely that ICRF-187 protects against the occurrence of lesions induced by p/introduction anthracyclines, dependent on the mode of administration.

Example 13

Clinical results patients

The patient is a woman, which was infusional 149 mg of doxorubicin subcutaneously instead of entering through the catheter was subjected to the treatment according to the present invention.

Treatment with ICRF-187 started 2 hours 30 minutes after extravasation, using ICRF-187 in doses of 1000 mg/m2on the first day, 1000 mg/m2on the second day and 500 mg/m2on the third day. In the weeks that followed, she had no marked adverse effects from treatment. A weekly examination of the Clinician-oncologist and surgeon, specialist in plastic surgery, and diagnosis using ultrasound revealed a subcutaneous mass of approximately 3×4 cm, which has not changed in size during the 30-day observation period after the incident. 't developed any sores or signs of skin necrosis despite the introduction of massive doses of doxorubicin. The patient continued chemotherapy with a delay of only one week without holding Hiro the policy intervention.

References

1. Company Froelich-Ammon SJ, Osheroff N. Topoisomerase poisons:

Harnessing the dark side of enzyme mechanism. J Biol Chem 1995; 270:21429-32.

2. Chen AY, Liu LF. DNA topoisomerases: Essential enzymes and lethal targets. Annu Rev Pharma Toxicol 1994; 34:191-218.

3. Jensen PB, Sorensen BS, Sehested M, Grue P, Demant EJF, Hansen HH. Targeting the cytotoxicity of topoisomerase II directed epipodophyllotoxins to tumor cells in acidic environments. Cancer Res. 1994; 54:2959-63.

4. Sehested m, Jensen PB. Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle. Biochem. Pharmacol. 1996; 51:879-86.

5. Sorensen BS, Sinding J, Andersen AH, Alsner J, Jensen PB, Westergaard 0. Mode of action of topoisomerase II targeting agents at a specific DNA sequence: Uncoupling the DNA binding, cleavage and religation events. J Mol Biol 1992; 228:778-86.

6. Tanabe K, Ikegami Y. Ishida R, Andoh T. Inhibition of topoisomerase II by antitumor agents bis(2,6-dioxopiperazine) derivatives. Cancer Res 1991; 51:4903-8.

7. Berger JM, Gamblin SJ, Harrison SC. Wang JC. Structure and mechanism of DNA topoisomerase II. Nature 1996; 379:225-32.

8. Roca J, Ishida R, Berger JM, Andoh T, Wang JC. Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc Natl Acad Sci USA 1994; 91:1781-5.

9. Roca J, Berger JM, Harrison SC, Wang JC. DNA transport by a type II topoisomerase: Direct evidence for a two-gate mechanism. Proc Natl Acad Sci USA 1996; 93:4057-62.

10. Von Hoff DD, Layard MV, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med. 1979; 91:710-7.

11. Von Hoff DD, Layard. Risk factors for development of daunorubicin-cardiotoxicity. Cancer Treat. Rep. 1981; 65 ((suppi 4)):19-23.

12. Hasinoff BB. The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-y1)propane). Agents and Actions 1990; 29:374-81.

13. Sehested M, Wessel I, Jensen LH, Holm B, Olivieri RS, Kenwrick S, Creighton AM, Nitiss JL, Jensen PB. Chinese hamster ovary cells rsistant to the topoisomerase II catalytic inhibitor ICRF-159; a Tyr49Phe mutation confers high level resistance to bisdioxopiperazines. Cancer Res. 1998; 58:1460-8.

14. Wessel I, Jensen LH, Jensen PB, Falck J. Roerth M, Nitiss JL, Sehested M. Human small cell lung cancer NYH cells selected for resistance to the bisdioxopiperazine topoisomerase II (topoll) catalytic inhilbitor ICRF-187 (NYH/187) demonstrate a functional Argl62Gln mutation in the Walker A consensus ATP binding site of the a isoform. [Abstract] Proc. AACR 1998; 39:375

15. Sorensen M, Sehested M, Jensen PB. pH-dependent regulation of camptothecin induced cytotoxicity and cleavable complex formation by the antimalarial agent chloroquin. Biochem. Pharmacol. 1997; 54:373-80.

16. Ishida R, Miki T, Narita T, Yui R, Sato M, Utsumi KR, Tanabe K, Andoh T. Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives: Mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors. Cancer Res 1991; 51:4909-16.

17. Roca J. Wang JC. DNA transport by a type II DNA topoisomerase: Evidence in favor of a two-gate mechanism. Cell 1994; 77:609-16.

18. Sehested M, Jensen PB, Sorensen BS, Holm B, Friche E, Demant EJF. Antagonistic effect of the cardioprotector (+)-1,2,-bis(3,5-dioxopiperazinyl-1-y1)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II-directed drugs daunorubicin and etoposide (VP-16). Biochem. Pharmacol. 1993; 46:389-93.

19. Loth TS, Eversmann WW. Jr. Treatment methods for extravasations of chemotherapeutic agents: a comparative study. J. Hand Surg. Am. 1986; 11(3):388-96.

20. Sonneveld P, Wassenaar. Nooter K. Long persistence of doxorubicin in human skin after extravasation. Cancer Treat. Rep. 1984; 68(6):895-6.

21. Banerjee A. Cancer chemotherapy agent-induced perivenous extravasation injuries. Postgrad. Med. 1987; 635-9.

22. Dorr RT, Alberts DS, A. Stone Cold protection and heat enhancement of doxorubicin skin toxicity in the mouse. Cancer Treat. Rep. 1985; 69(4):431-7.

23. Dorr RT, Alberts DS, Chen HS. The limited role of corticosteroids in ameliorating experimental doxorubicin skin toxicity in the mouse. Cancer Chemother. Pharmacol. 1980; 5:17

24. Bartowski DL, Daniels JR. Use of sodium bicarbonate heat treatment as a means of ameliorating doxorubicin-induced dermal necrosis in the rat. Cncer Chemother. Pharmacol. 1981; 4:179

25. Disa JJ, Chang RR, Mucci SJ, Goldberg NH. Prevention of adriamycin-induced full-thickness skin loss using hyaluronidase infiltration. Plast. Reconstr. Surg. 1998; 101(2):370-4.

26. Dorr RT, Alberts DS. Modulation of experimental doxorubicin skin toxicity by beta-adrenergic compounds. Cancer Res. 1981; 41 (6):2428-32.

27. Dorr RT, Alberts DS. Failure of DMSO and vitamin E to prevent doxorubicin skin ulceration in the mouse. Cancer Treat. Rep. 1983; 67(5):499-501.

28. Soble M, Dorr RT, Plezia P, Breckenridge S. Dose-dependent skin ulcers in mice treated with DNA binding antitumor antibiotics. Cancer Chemother. Pharmacol. 1987; 20:33-6.

29. Bekerecioglu M, Kutluhan A, Demirtas I Karaayvaz M. Prevention of adriamycin-induced skin necrosis with various free radical scavengers. J. Surg. Res. 1998; 75(1):61-5.

30. Averbuch SD, Gaudiano G. Koch TH, Bachur NR. Doxorubicin-induced skin necrosis in the swine model: protection with a novel radical dimer. J. Clin. Oncol. 1986; 4(1):88-94.

31. Dahlström KK, Chenoufi HL, S. Daugaard Fluorescence microscopic demonstration and demarcation of doxorubicin extravasation. Experimental and clinical studies. Cancer 1990; 65(8):1722-6.

32. Rudolph R, Suzuki M, Luce JK. Experimental skin necrosis produced by adriamycin. Cancer Treat. Rep. 1979; 63(4):529-37.

33. Bleicher JN, Haynes W. Massop DW, Daneff RM. The delineation of adriamycin extravasation using fluorescence microscopy. Plast. Reconstr. Surg. 1984; 74(1):114-6.

34. Luedke DW, Kennedy PS, Rietschel RL. Histopathogenesis of skin and subcutaneous injury induced by adriamycin. Plast. Reconstr. Surg. 1979; 63(4); 463-5.

35. Brothers TE, Von Moll LK, Niederhuber JE, Roberts JA, Walker-Andrews S, Ensminger WD. Experience with subcutaneous infusion ports in three hundred patients. Surg Gynecol Obstet 1988; 166:295

36. European Communities Council In 86 A.D.; 86/609/EEC.

37. The Council of Europe Convention S 1986;

38. Svendsen P. Svendsen P and Hau J, editors. Handbook of Laboratory Animal Science. 1 ed. CRC Press Inc; 1994. R.

1. Drug to treat or prevent tissue damage caused by the accidental, transudative the cytotoxic poison topoisomerase II in the injection of the poison of topoisomerase II to a patient, were treated with the specified poison topoisomerase II, where the tool includes videocapturing.

2. The drug according to claim 1, where the tool is a means for local introduction videocapturing in the tissue which is damaged due to extravasation of poison topoisomerase II.

3. The drug according to claim 1, where the specified tool is a tool for system introduction videocapturing in the tissue which is damaged due to extravasation of poison topoisomerase II.

4. The drug according to any one of the preceding paragraphs, where the poison topoisomerase II are selected from the group consisting of etoposide, etoposide phosphate, teniposide, daunorubicin, doxorubicin, idarubitsina, epirubicin, mitoxantrone, m-AMSA and anthracycline.

5. The drug according to claim 4, where anthracycline selected from the group consisting of daunorubicin, doxorubicin, idarubitsina and epirubicin.

6. The drug according to any one of the preceding paragraphs, where the specified drug is presented in the form of single or multiple introductions.

7. The drug according to any one of the preceding paragraphs, where the specified drug is administered after treatment with poison topoisomerase II.

8. The drug according to any one of the preceding paragraphs, where the specified drug the lead after treatment poison topoisomerase II and until then, while the fabric contains poison topoisomerase II or its active metabolites.

9. The drug according to any one of claims 1 to 6, where the specified drug is administered after manifestation of accidental extravasation of the specified poison topoisomerase II.

10. The drug according to any one of claims 1 to 6, where the specified drug is administered after the first manifestations of pain, erythema, or swelling caused by random transsoudata specified poison topoisomerase II.

11. The drug according to any one of claims 1 to 6, where the specified drug is administered essentially simultaneously with the introduction of the poison topoisomerase II.

12. The drug according to any one of claims 1 to 6, where the specified drug is administered within a period of 3 weeks after the injection of the poison of topoisomerase II, for example, within 2 weeks, preferably within 1 week, more preferably, within 5 days, more preferably within 3 days, more preferably within 1 day after the injection of the poison of topoisomerase II.

13. The drug according to any one of claims 1 to 6, where the specified drug is administered within a period of 18 h after injection of poison topo II, for example, within 12 hours, preferably within 6 hours, more preferably within 4 hours, even more preferably within 2 hours, and even more predpochtitelno, within 1 h, for example 20 min after the injection of the poison of topoisomerase II.

14. The drug according to any one of the preceding paragraphs, where the specified drug is administered at least two repeated dosages.

15. The drug according to any one of the preceding paragraphs, where the specified drug is administered in at least three repeated doses.

16. The drug according to any one of the preceding paragraphs, where the specified drug is administered at least four repeated doses.

17. The drug according to any one of p-16, where these re-injected with a dosage range of 1 to 3 days after the first dose, preferably at intervals of 2 days, more preferably, with an interval of 1 day.

18. The drug according to any one of p-16, where these re-injected with a dosage interval of more than 24 h, preferably more than 18 hours, more preferably more than 6 hours, for example, at intervals of approximately 3 hours after the first dose of the specified medicines.

19. The drug according to any one of the preceding paragraphs, where the specified drug is administered within 12 hours, preferably within 6 hours after detection or suspicion on random transudation of poison topoisomerase II.

20. Medical environments, the creation according to any one of the preceding paragraphs, where the specified drug is administered within 12 hours, preferably within 6 h after injection of the poison of topoisomerase II.

21. The drug according to any one of the preceding paragraphs, where the specified drug is an ICRF-187 (dexrazoxane).

22. Application videocapturing to obtain drugs for the prevention or treatment of tissue damage caused by accidental transsoudata cytotoxic poison topoisomerase in the injection of the poison of topoisomerase II to a patient, which were treated with the specified poison topoisomerase II.

23. The application of article 22, where the poison topoisomerase II are selected from the group consisting of etoposide, etoposide phosphate, teniposide, daunorubicin, doxorubicin, idarubitsina, epirubicin, mitoxantrone, m-S and anthracycline.

24. The application of item 23, where anthracycline selected from the group consisting of daunorubicin, doxorubicin, idarubitsina and epirubicin.

25. The use according to any one of p-24, where videocapturing represents ICRF-187 (dexrazoxane).

26. A method of treating or preventing tissue damage caused by accidental transsoudata cytotoxic poison topoisomerase in the injection of the poison of topoisomerase II to a patient, which were treated with the specified poison topoisomerase II, characterized in that idiosepiidae enter in the quantity enough so that he was present in the tissue and prevented development of tissue damage caused by the poison of topoisomerase II, or cured tissue damage caused by the poison of topoisomerase II.

27. The method according to p, where the introduction videocapturing in tissue affected by transsoudata of poison topoisomerase II, is carried out locally.

28. The method according to p, where the introduction videocapturing in tissue affected by transsoudata of poison topoisomerase II, is carried out systematically.

29. The method according to any of PP-28, where the poison topoisomerase II are selected from the group consisting of etoposide, etoposide phosphate, teniposide, mitoxantrone and m-AMSA.

30. The method according to clause 29, where the poison topoisomerase II is anthracyclin.

31. The method according to item 30, where the poison topoisomerase II is chosen from the group consisting of daunorubicin, doxorubicin, idarubitsina and epirubicin.

32. The method according to any of PP-29, where the poison topoisomerase II is a daunorubicin.

33. The method according to any of PP-29, where the poison topoisomerase II is a doxorubicin.

34. The method according to any of PP-29, where the poison topoisomerase II is a idarubitsin.

35. The method according to any of PP-29, where the poison topoisomerase II is epirubicin.

36. The method according to any of PP-35, where videocapturing is administered after treatment with poison for toposa erase II.

37. The method according to any of PP-36, where videocapturing is administered after treatment with poison topoisomerase II and up until the fabric contains poison topoisomerase II or its active metabolites.

38. The method according to any of PP-35, where videocapturing administered after manifestation of accidental extravasation of the specified poison topoisomerase II.

39. The method according to § 38, where videocapturing injected after the first manifestations of pain, erythema, or swelling caused by random transsoudata specified poison topoisomerase II.

40. The method according to § 38, where videocapturing enter more than 24 h after injection of the poison of topoisomerase II.

41. The method according to § 38, where videocapturing enter the first time more than 24 h after injection of the poison of topoisomerase II.

42. The method according to any of PP-35, where videocapturing administered essentially simultaneously with the introduction of the poison topoisomerase II.

43. The method according to any of PP-35, where videocapturing injected within a period of 3 weeks after the injection of the poison of topoisomerase II.

44. The method according to any of PP-35, where videocapturing injected within a period of 18 h after injection of the poison of topoisomerase II.

45. The method according to any of PP-35, where videocapturing enter at least two repeated dosages.

46. The method according to item 45, where repeated dosing is performed with an interval of 1-3 days pic is E. the first dose.

47. The method according to item 45, where repeated dosing carried out at intervals of not more than 24 h after the first dose.

48. The method according to any of p-47, where the catalytic topoisomerase II inhibitor is administered at least three repeated doses.

49. The method according to p, where the catalytic topoisomerase II inhibitor is administered at least four repeated doses.

50. The method according to any of PP-35, where videocapturing administered for a period of 12 h after symptoms or suspected accidental transudate specified poison topoisomerase II.

51. The method according to any of PP-35, where videocapturing injected within a period of 12 hours after the injection of the poison of topoisomerase II.

52. The method according to any of p-51, where videocapturing enter in sufficient quantity to the presence in the tissue for the prevention or treatment of tissue damage.

53. The method according to any of PP-52 where videocapturing injected within a period of 6 h after injection of the poison of topoisomerase II.

54. The method according to any of PP-52 where videocapturing injected within a period of 4 h after injection of the poison of topoisomerase II.

55. The method according to any of PP-52 where videocapturing injected within a period of 2 h after injection of the poison of topoisomerase II.

56. The method according to any of p-55, where videocapturing represents ICRF-187 (dexrex is n).

57. Pharmaceutical kit for the treatment or prevention of tissue damage caused by accidental transsoudata cytotoxic poison topoisomerase II in the injection of the poison of topoisomerase II to a patient, which were treated with the specified poison topoisomerase II, where the specified set includes videocapturing in the form of a single dose (single dose) and a description of the procedures for imposing videocapturing patient.

58. The pharmaceutical kit according to § 57, where a single dose videocapturing contains a pharmaceutically acceptable carrier suitable for local or intravenous injection.

59. The pharmaceutical kit according to any one of § 57 or 58, where videocapturing represents ICRF-187 (dexrazoxane).



 

Same patents:

FIELD: genetic engineering, in particular genes for cell cycle controlling point.

SUBSTANCE: polynucleotide encoding rad3 polypeptide ATR homologue is cloned into expression vector, having functionality in eucariotic cells. Polypeptide of rad3 polypeptide ATR homologue is obtained by cultivation of eucariotic cell culture, transformed by vector. Monoclonal antibody to rad3 polypeptide ATR homologue is obtained by hybridoma technologies. Polyclonal antibodies are obtained by inoculation of rad3 polypeptide ATR homologue in host animal. Polynucleotide presence in animal tissue sample is detected by contacting of this sample containing DNA or RNA with polynucleotide encoding rad3 polypeptide ATR homologue under hybridization conditions. Polypeptide in biological sample is detected by sample contact with monoclonal or polyclonal antibodies. Substances having anticancer activity are screened on the base of reduced activity of ATR polypeptide on substrate or reduced chelating of ATR homologue in presence of candidate substance. Present invention makes it possible to produce human or S.pombe rad3 polypeptide ATR homologue and is useful in investigation ATR role as gene for cell cycle controlling point in cell culture in vivo or in vitro.

EFFECT: new anticancer substances.

24 cl, 1 dwg

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: medicine.

SUBSTANCE: after keeping during pharmaceutically acceptable period oxaliplatinum is placed in transparent, colorless and residue-free solution at concentration of, at least, 7 mg/ml, and a solvent contains sufficient quantity of, at least, one hydroxylated derivative chosen among of 1.2-propandiol, glycerol, maltite, saccharose and inositol. The innovation describes the way to obtain such a preparation. The preparation is stable during pharmaceutically acceptable period of time, that is it remains transparent, colorless and free of any residue within the range of 2-30 C that could be available during its transportation, storage and/or any handling.

EFFECT: higher efficiency of application.

14 cl, 6 ex, 4 tbl

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

FIELD: organic chemistry and medicine.

SUBSTANCE: invention relates to new imidazole derivatives of general formula I useful as adenosine A3-receptor modulators, as well as to method for cancer treatment and detection of tumor cells using claimed derivatives.

EFFECT: compounds for treatment and diagnosis of improved activity.

13 cl, 4 dwg, 19 ex

FIELD: medicine; veterinary medicine.

SUBSTANCE: method involves using biologically active substances obtainable by means of bacteriological synthesis. Individual avermectines or their complexes are applied in vitro in concentrations of 0.01-10 ng/ml and in vivo at a dose of 0.01-1 mg/kg.

EFFECT: enhanced effectiveness of treatment; reduced toxic effect.

4cl, 2 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: invention relates to application of NO-releasing non-steroid antiinflammation agent as wall as pharmaceutically acceptable salt or enantiomer thereof for production of drug useful in treating of disorders associates or mediated with Helicobacter pylory; pharmaceutical composition for treating of bacterial infections, including NO-releasing non-steroid antiinflammation agent as main ingredient; and similar composition including additionally inhibitor of acid-sensitive proton pump.

EFFECT: effective agents and pharmaceutical compositions for treating of bacterial infections.

19 cl, 4 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with enhancing circulation and trophicoregenerative processes. The suggested curative-prophylactic balsam includes fresh-water sulfide-free average-ash sapropel mud of Kirek Lake, turpentine oil (oleoresin turpentine), peroxide, anionic SAS, starch taken at a certain quantitative ratio. The suggested balsam enables to efficiently enhance circulation and trophicoregenerative processes.

EFFECT: higher efficiency of application.

3 ex, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition for oral administration in treatment or prophylaxis of obesity or hyperlipidemia. The composition comprises orlistat and at least one ester of fatty acids and polyols. Melting point of fatty acid ester exceeds the body temperature and polyol is taken among group including glycerol, sugars, derivatives of sugars and their mixtures. Also, invention relates to a method for preparing above described composition and to a method for treatment or prophylaxis of obesity. Invention enhances effectiveness and activity of orlistat by reducing variability of effectiveness and/or activity of orlistat between patients and frequency and severity of adverse effects.

EFFECT: improved and valuable pharmaceutical properties of compositions.

24 cl, 1 tbl, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compositions eliciting an antilipidemic effect and comprising inhibitor of bile acid transport in jejunum of the general formula (I): and inhibitor of HMG-CoA-reductase. Also, invention relates to a method for carrying out the combined therapy.

EFFECT: improved treatment method, valuable medicinal properties of compositions.

15 cl, 9 tbl, 1401 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

EFFECT: valuable medicinal properties of composition.

9 cl, 6 dwg, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

The invention relates to genetic engineering and can be used for therapeutic purposes, in particular in the treatment of neoplastic processes

The invention relates to pharmaceutical compositions comprising a stable water-insoluble complex, consisting of stable amorphous form of the therapeutically active compound dispersed on a molecular level in the water-insoluble ionic polymer

FIELD: chemical engineering; pharmaceutical engineering.

SUBSTANCE: method involves applying substances of macrolide group showing high inhibition degree with respect to protein of tyrosine kinase.

EFFECT: enhanced effectiveness in suppressing infection and proliferation of human immune deficiency virus in macrophages.

4 cl, 25 dwg

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