Method for inhibition of tumor growth

FIELD: experimental medicine, oncology, biology.

SUBSTANCE: invention relates to a method for inhibition of tumor growth using radiation therapy as ionizing radiation with additional administration of mixture of octa-4,5-carboxyphthalocyanine sodium cobalt salt or oxocobalamine with sodium ascorbate in the ratio = (1:10)-(1:30). Method of combined using irradiation and indicated mixture of substances provides enhancing the effectiveness of anti-tumor treatment resulting to 70-100% recovery of experimental animals and reducing radiation loading and toxicity.

EFFECT: improved method for inhibition.

2 tbl, 3 dwg, 3 ex

 

The present invention relates to biology and medicine, in particular relates to a method of suppressing tumor growth with the use of radiation therapy.

Radiation therapy is one of the leading methods in treatment of malignant neoplasms [Radiation therapy of malignant tumors. A guide for physicians /Esselamu, Gwholesale, Swine and other edited Essesential. - M.: Medicine, 1996]. Radiation therapy as an independent method of treatment used in different patients depending on the localization of the tumor and the radiosensitivity of the tumor.

The advantage of this method is conservative anticancer therapy is highly penetrating ionizing radiation, which allows to treat tumors deep in the tissues.

However, for the complete destruction of malignant tumors, a relatively high dose of radiation. At the same time, the use of high doses of ionizing radiation leads to the exposure of normal tissues, resulting in the loss of their ability to resorption damaged tumor and repair the defect formed on predshestvovavshaya tumors. In addition, the use of high doses causes severe local and systemic toxic reactions. Reduction to the s irradiation leads to a decrease in the effectiveness of the treatment and nedoobsudili peripheral parts of the tumor, which do not have clear boundaries with normal tissues, which subsequently leads to recurrence of the tumor.

The task of the invention was to provide such a method of suppressing tumor growth with the use of radiation therapy, which would have allowed at a relatively low dose of radiation to provide effective suppression of tumor growth.

To solve this problem, a method for suppression of tumor growth with the use of radiation therapy in which in addition to irradiation using a mixture of sodium salts of OCTA-4,5-carboxyfullerene cobalt (terephthal®, the drug Terephthal-lio”, TF) or oksikobalamina therapy (drug Oxidability-lio”, OK) with sodium ascorbate (officinal drug “Ascorbic acid”, AK) in a molar ratio of 1:10÷1:30 (hereinafter binary catalytic systems [BCS] "TF+AK" and "OK+AK"). The use of these drugs in a molar ratio beyond the lower limit, leads to a reduction in antitumor effectiveness of BCS, but values beyond the upper limit of the specified interval, to toxic effect.

Binary catalytic systems and their application in Oncology described:

- The patent of the Russian Federation 2106146, a 61 K 31/40, 10.03.98;

Connection of a number of B12 in combination with ascorbic acid as potential antitumor agents / M Is Wolpin, Riemurasia, Art, Vichissov etc. // Russian chemical journal, 1998, .XLII, No. 5, p.116.

The test of the proposed method was implemented on find below the method.

Method.

The test method was carried out on mice with ascitic Ehrlich tumor (UAE) and epidermoid Lewis lung carcinoma (LLC).

UAE instilled weinbrenner mice-females intraperitoneally in 0.1 ml of ascitic fluid obtained from a mouse donor on day 7 of tumor growth and diluted 1:1 with 0.9% sodium chloride solution.

LLC was inoculated subcutaneously in the thigh at 1 million cells per mouse from mouse donor 10-12 day of tumor growth.

Treatment of animals with the AEO was started 48 hours after inoculation of tumor material, LLC - 7 days.

Control animals were injected with placebo (0.9% sodium chloride solution).

Doses and modes of introduction binary catalytic systems and modes of exposure set forth in the examples below.

The radiation dose for the treatment of mice with UAE LLC and picked up eksperimetalne based on the radiosensitivity of these tumors.

The antitumor effect was evaluated by:

- survival (the kinetics of death from progression of the neoplastic process);

the increase in life expectancy (UPI), calculated by the formula:

UPI= [(ALEexperience-ALEcontrol)/ALEcontrol]×100%;

- inhibition of the growth of the tumor, calculated by the formula:

TRO(%)=[(Vcontrol-Vexperience)/Vcontrol]×100,

where V is the volume of the tumor in mm3.

Minimum criteria activity:

- UPS>25%; TRO>50% [HOWTO for the study of antitumor activity of pharmacological substances / Tresalia E.M., Zhukov O.S, G. Gerasimov, etc // Guidance on experimental (preclinical) study of new pharmacological substances. M: JJA Remedium, 2000, s; Experimental evaluation of anticancer drugs in the USSR and the USA / edited by Spoofing, Aberkane, Agordina, Alaina. M: “Medicine”, 1980].

Statistical processing of the obtained results was carried out according to the methods of variation and alternative statistics and the method of student-Fisher relation using the statistical program "STATISTICA" at p≤0,05.

The invention is illustrated by the following reamers.

Example 1.

Studies conducted on mice with ascitic Ehrlich tumor.

BCS “OK+AK” was injected once intraperitoneally at a dose of 75 mg/kg (QA; the molar ratio OK:AK-1:30).

As the radiation source used60With (γ-radiation).

Dose of 0.5 Gy.

The mode of application of the BCS “OK+AK” and radiotherapy:

γradiation → BCS “OK+AK”.

Data characterizing the antitumor what Yu efficiency of complex treatment of mice with the AEO using methods of radiation and the binary catalytic therapy (BCS “OK+AK”), presented in figure 1 and in table 1.

As can be seen from table 1 and figure 1, radiation therapy at a dose of 0.5 Gy, and BCS “OK+AK” in a dose of 75 mg/kg (QA; the molar ratio OK:AK-1:30), monovariant lead to an increase in life expectancy of animals by 21% and 71%, respectively.

Table 1
 Exposure to 0.5 GyOK-lio+AK, 75 mg/kg (M:M-1:30)Irradiation→“OK+AK”
UPI,%2171 
Cure, %NoNo100
Note: M:M is the molar sootnoshenie OK-lio and AK

In the complex treatment of mice with the AEO using radiation therapy at a dose of 0.5 Gy, and BCS “OK+AK” in a dose of 75 mg/kg (QA; the molar ratio OK:AK-1:30), mode - γradiation → BCS “OK+AK” noted a 100% cure animals from the tumor (figure 1, table 1).

Example 2.

Studies conducted on mice with epidermoid lung carcinoma Lewis.

BCS “OK+AK” was administered once intravenously at a dose of 50 mg/kg (QA; the molar ratio OK:AK-1:10).

As the radiation source used60With (γ-radiation).

The radiation dose of 25 Gy.

Mode p is imeneniya BCS “OK+AK” and radiotherapy:

γradiation → BCS “OK+AK”.

Data characterizing the antitumor efficacy of combined treatment of mice with LLC using methods of radiation and the binary catalytic therapy (BCS “OK+AK”), presented in figure 2.

As can be seen from figure 2, radiation therapy at a dose of 25 Gy in monovariate has antitumor activity, leading to inhibition of tumor growth on 80-72% (saving effect within 15 days after treatment).

The effectiveness of BCS “OK+AK” after a single intravenous dose of 50 mg/kg (QA; the molar ratio OK:AK-1:10), estimated by measure TRO, did not exceed 11%.

Combined treatment of mice with LLC using the methods of radiation therapy and binary catalytic therapy had a greater therapeutic effect than radiation therapy is used as an independent method of treatment - TRO-level 80-75% remained within 23 days after treatment (figure 2).

Example 3.

Studies conducted on mice with ascitic Ehrlich tumor.

BCS “TF+AK” drove once intraperitoneally at a dose of 30 mg/kg (TF; the molar ratio of HF:AK-1:10).

As the radiation source used60With (γ-radiation).

Dose of 1.5 Gy.

The mode of application of the BCS “TF+AK” and radiotherapy:

BCS “TF+AK” → γ-radiation./p>

Data characterizing the antitumor efficacy of combined treatment of mice with the AEO using methods of radiation and the binary catalytic therapy (BCS “TF+AK”), presented in figure 3 and in table 2.

Table 2
 Exposure to 1.5 GyTF+AK, 30 mg/kg (M:M-1:10)“TF+AK”→irradiation
UPI,%2922-
Cure, %NoNo70
Note: M:M is the molar sootnoshenie TT and AK.

As can be seen from figure 3 and table 2, radiation therapy at a dose equivalent to 1.5 G, and the BCS “TF+AK” in a dose of 30 mg/kg (TF; the molar ratio of HF:AK-1:10), monovariant lead to an increase in life expectancy of animals at 29% and 22%, respectively.

The combined use of radiation therapy at a dose equivalent to 1.5 G, and the BCS “TF+AK” in a dose of 30 mg/kg (TF; the molar ratio of HF:AK-1:10), in the BCS regime “TF+AK”→γ-radiation” had a stronger antitumor effect than exposure and BCS monovariant - when using this scheme anticancer therapy watched the cure tumors 70% of the animals (figure 3, table 2).

Thus, before agemy method of suppressing tumor growth, combining irradiation and application of BCS, improves the efficiency of treatment: cure reaches 70-100%.

The method of suppressing tumor growth with the use of radiation therapy in the form of ionizing radiation, characterized in that it further using a mixture of sodium salts of OCTA-4,5-carboxyfullerene cobalt or oksikobalamina therapy with sodium ascorbate at a ratio of 1:10-1:30.



 

Same patents:

FIELD: medicine, oncology.

SUBSTANCE: method involves surgery treatment and chemotherapy. In preoperative period 150 ml of blood is taken off in patients, blood is centrifuged for separating for plasma and formed elements. Standard dose of cytostatic agent is separated and placed into the first flask with 20-40 ml of autoplasma and remained plasma part and formed elements are placed into the second flask. Flasks are incubated separately for 40 min at 37°C followed by carrying out a procedure when blood incubated with the chemopreparation from the second flask is administrated by intravenous route by drops. After removing tumor its bed in infiltrated with autoplasma incubated with the chemopreparation from the first flask or autoplasma with the chemopreparation are added in blood vessels in zone of regional blood supply of tumor. Method provides reducing frequency of topical relapses and alienated metastasis after surgery treatment of solid tumors and shows low toxicity. Invention can be used in the complex cancer treatment, in particular, regionally distributed cancer in large intestine and mammary glands.

EFFECT: enhanced effectiveness of treatment.

3 ex

FIELD: medicine.

SUBSTANCE: the method deals with 2 courses of polychemotherapy at the first stage due to regional intra-arterial introduction of cisplatin at the dosage of 100 mg/m2 during the first day of every course and 6-h-long intra-arterial infusion of 5-fluorouracil at total dose of 750 mg/m2 in the morning since the 2nd to the 6th d of every course. Chemotherapy should be performed at the background of total magnetotherapy at frequency of magnetic field being 98-112 Hz, intensity of 25-30 oersted, duration of every seance being 30 min, the number of seances corresponds to the duration of chemotherapeutic courses. At the second stage in 2-3 wk after finishing chemotherapy it is necessary to conduct the course of distance radiation therapy (DRT) at multifractioning the dosage by SFD being 1.2 Gy twice daily 5 times weekly up to TFD being equivalent to TDF (time-dosage-fraction) of 62-70 Gy onto primary focus and 40-46 Gy onto areas of regional lymph outflow. As modifiers one should apply cisplatin during the first 2 wk of radiation therapy, hyperbaric oxygenation during the first 10 d of radiation therapy and total magnetotherapy since the 11th d of DRT course till its ending. At the third stage in case of residual metastases in lymph nodes of patient's neck in 2-3 wk after the end of radiation therapy one should conduct operative interference in lymph outflow pathways. The method enables to decrease toxicity of chemo-and radiation therapy due to decreased radiation reactions, stimulation of immune system and improved microcirculation.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5,7-diones of the general formula (1)

wherein: -R1 means residue of mono- or disaccharide in pyranose form taken among the group: D-Rib, L-Ara, D-Xyl, D-Gal, D-Glc, D-Lac; -R2 means hydrogen atom, methyl group or residue of mono- or disaccharide; -R3 means hydrogen atom, hydroxyl group, amino-group or formamido-group; each -X1 and -X2 means independently of one another hydrogen atom or bromine atom under condition that they can't mean hydrogen atom simultaneously and under condition also that if R1 means disaccharide residue then R2 differs from hydrogen atom. Prepared derivatives show, in particular, cytotoxic and antitumor activity against melanoma B16 and Ehrlich tumor.

EFFECT: valuable medicinal properties of derivatives.

3 cl, 3 tbl, 2 dwg, 8 ex

FIELD: chemistry of peptides, medicine, oncology, pharmaceutical chemistry.

SUBSTANCE: invention relates to the development of medicinal agent of peptide nature eliciting an antitumor effect and can be used in treatment of endocrine and hormone-dependent tumors. Agent represents peptide of the general formula: . Invention provides enhancement of the therapeutic effect and reducing toxicity.

EFFECT: valuable medicinal properties of agent.

3 cl, 4 tbl, 2 ex

FIELD: biochemistry, medicine, pharmacy.

SUBSTANCE: leaves of Mikania micrantha, Mikania scandens and Mikania cordata are milled and dries and a solvent - toluene, ethyl acetate, their mixture, mixture of toluene with acetone, mixture of ethyl acetate with heptane or mixture of heptane with acetone is added in the ratio (7:3)-(3:7), mixture is filtered and concentrated up to 2.5-10% as measure for dry extract. Then extract is contacted with a mixture containing 10-50% of methanol or ethanol in water, an aqueous-alcoholic phase is washed out with n-hexane or heptane and alcohol is removed. An aqueous phase is extracted with ethyl acetate, prepared phase is dried, solvents are evaporated and dry extracted is purified. Dry extract prepared from leaves is dissolved in ethyl acetate and hydrogenated at 10-35°C in the presence of hydrogenation catalyst under pressure 1-2 atm. After hydrogenation dihydromikanolid is crystallized. Mikanolid and dihydromikanolid are used for treatment proliferative diseases and parasitic diseases. Also, invention relates to a medicinal agent containing above indicated vegetable extract. Invention provides realization of indicated designation.

EFFECT: valuable properties of agents.

12 cl, 3 tbl, 3 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical composition comprising the known antibiotic eliciting an antitumor activity and derivative of hydroxamic acid of the formula (1) wherein the weight ratio of two active agents is (1:50)-(50:1), respectively. The composition reduces adverse effects and elicits the enhanced antitumor effect.

EFFECT: improved valuable medicinal properties of composition.

4 cl, 1 tbl, 5 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation should be applied at adjuvant chemotherapy in case of tumors of central nervous system. Moreover, while carrying out lumbar puncture it is necessary to perform catheterization of subarachnoidal space. Moreover, one should daily sample liquor at the quantity of 10 ml to be incubated with chemopreparation in vitro for 30 min at 38 C. One should daily introduce chemopreparations upon autoliquor through catheter during the whole period of therapy course. The method enables to choose any mode and duration of endolumbar chemotherapy at its decreased toxicity.

EFFECT: higher efficiency of chemotherapy.

1 ex

Antitumor agent // 2253446

FIELD: drugs, medicine.

SUBSTANCE: invention relates to application of 2-METHYL-4-chlorophenoxyacetic acid tris-(2-hydroxyethyl)ammonia salt, which represents known microorganism living function stimulator, as antitumor agent and metastasis inhibitor. Present invention makes it possible to produce drugs for treatment cancers, in particular hepatoma, melanocytoma, lymphadenoma, etc.

EFFECT: new drug for cancer treatment.

2 tbl, 2 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: the method deals with 2 courses of polychemotherapy at the first stage due to regional intra-arterial introduction of cisplatin at the dosage of 100 mg/m2 during the first day of every course and 6-h-long intra-arterial infusion of 5-fluorouracil at total dose of 750 mg/m2 in the morning since the 2nd to the 6th d of every course. Chemotherapy should be performed at the background of total magnetotherapy at frequency of magnetic field being 98-112 Hz, intensity of 25-30 oersted, duration of every seance being 30 min, the number of seances corresponds to the duration of chemotherapeutic courses. At the second stage in 2-3 wk after finishing chemotherapy it is necessary to conduct the course of distance radiation therapy (DRT) at multifractioning the dosage by SFD being 1.2 Gy twice daily 5 times weekly up to TFD being equivalent to TDF (time-dosage-fraction) of 62-70 Gy onto primary focus and 40-46 Gy onto areas of regional lymph outflow. As modifiers one should apply cisplatin during the first 2 wk of radiation therapy, hyperbaric oxygenation during the first 10 d of radiation therapy and total magnetotherapy since the 11th d of DRT course till its ending. At the third stage in case of residual metastases in lymph nodes of patient's neck in 2-3 wk after the end of radiation therapy one should conduct operative interference in lymph outflow pathways. The method enables to decrease toxicity of chemo-and radiation therapy due to decreased radiation reactions, stimulation of immune system and improved microcirculation.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medical engineering.

SUBSTANCE: device has active zone of water-to-water nuclear reactor, biological reactor protection concrete mass, slow neutron collimator, which internal surface is coated with material like polyethylene having large scattering cross-section and conically shaped, filter for cleaning slow neutron radiation beam from gamma-quanta and aperture for regulating slow neutron radiation beam diameter. Retarder manufactured from beryllium or graphite or heavy water is available in the space between whole-metal water pool tank casing and adjacent active zone surface. Retarder height and width is not less than corresponding dimensions of the adjacent active zone surface. A hole is available in the bulk of biological reactor protection concrete mass for discharging slow neutrons. The collimator is arranged in the hole so that spatial angle cut out with it contains the whole active zone surface. Its outlet opening is manufactured flush with the external wall of the bulk of biological reactor protection concrete mass and conjugated with the aperture.

EFFECT: high density of slow neutron flux; reduced share of fast neutrons.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: the innovation deals with irradiating lymphatic collector, that is: at the first stage it is necessary to perform irradiation for the whole volume of affected lymph collector at total focal dose being 26 Gy, at the second stage one should carry out irradiation at collector's areas depending upon the degree of their destruction at decreasing the size of fields: for the area of residual lymph nodes remained after polychemotherapy - up to the total focal dose being 44 Gy, for the area of massively affected lymph nodes in case of total effect after polychemotherapy - up to 36 Gy, for the area of moderately affected lymph nodes in case of total effect after polychemotherapy - up to 30 Gy. The method enables to decrease the number of complications and local relapses, shorten terms for therapy, improve values for patients' survival rate at decreasing total integral dose of irradiation.

EFFECT: higher efficiency of radiation therapy.

2 ex

FIELD: medical equipment; radiation therapy.

SUBSTANCE: radioactive source has radioisotope disposed inside air-tight biocompatible container. At least some part of container is made profiled and have rough, non-smooth surface. Radioactive source is made by loading it inside air-tight container. Composition has assemblage of radioactive sources mounted in line onto biologically decomposed material. Invention helps to improve ultrasonic visibility of source and/or reduce the trend of source to migrate in patient's body after implantation.

EFFECT: improved quality of treatment.

22 cl, 8 dwg

FIELD: medicine.

SUBSTANCE: method involves carrying out argon plasma of tracheal and/or bronchial lumen recanalization by applying power of 60-90 W with argond discharge rate being 2.0-2.4 l/min large. Brachitherapy is applied next to it moving the source with 5 mm large step. Trajectory length is 5 to 20 cm large. Reference isodose depth is 10 mm far from the source with applicator moving above and below the tumor from 1 to 3 cm. Dose from 14 to 28 Gr is to be administered once a week in 7 Gr large portions.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; prolonged remission period.

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of uterus body topically spread cancer involving applying chemotherapy and intrauterus irradiation. Method is carried out by the following manner: at the 1-st day of treatment cyclophosphan is administrated in the dose 1200-1600 mg by interstitial paratumoral route; at the 2-d day cream-like based fluorouracil in the dose 300-550 mg or adriablastin in the dose 20-30 mg is administrated into uterus cavity; on the next day sйance of intracavitary irradiation is carried out in the dose 10 Gr. All these procedures are repeated three times with interval for 6 days. Method provides high topical concentrations of chemopreparations in tumor zone in reducing their adverse toxic effect that results to the curative effect of patients of elderly age with accompanying therapeutic diseases.

EFFECT: improved method for treatment.

1 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

The invention relates to medicine, Oncology
The invention relates to medicine, in particular to cancer, and can be used in the treatment of locally common forms of lung cancer, including inoperable
The invention relates to medicine, in particular to Oncology

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

Up!