The agent for topical application and a method for the treatment and prevention of neoplastic lesions of the liver and peritoneum with its use

 

(57) Abstract:

The invention relates to medicine, specifically to Oncology, and can be used in clinical practice Oncology hospitals. The agent for topical application contains the anticancer drug in a quantity of 0.5 to 25.0 wt.%, included in resorbable biopolymer basis. The base may be selected from collagen, gelatin and alginate calcium. Method for the treatment and prevention of neoplastic lesions of the liver and peritoneum is carried out by application of the specified medicines during surgery on diaphragmatic surface of the liver or the local area removal of metastases. New means and method of treatment provide a prolonged controlled release of anticancer drug and the excess of the index of inhibition of metastases. 2 S. and 4 C.p. f-crystals.

The invention relates to medicine, specifically to Oncology, and relates to tools for local use and method of treatment and prevention of malignant neoplasms of liver and peritoneal metastases using it.

The proposed remedy and treatment method intended for use in clinical practice Oncology hospitals (euodius, stomach cancer, breast cancer, ovarian cancer, testicular cancer, cancer of the Vater papilla, gallbladder cancer, lung cancer, kidney cancer, adrenal cancer, carcinoid and intraoperative secondary prevention (adjuvant regional chemotherapy) as the final stage of radical surgery in the treatment of uncommon cancer of the abdominal cavity). The tool and method are used for the treatment of tumors and their metastases that are potentially sensitive to chemotherapeutic effect.

There are many ways local drug treatment and prevention of cancer of the liver and peritoneal metastases: different modes infusion of chemotherapy into the hepatic artery [4], the use of intraoperative hyperthermic intraperitoneally chemotherapy [1, 2, 3], the method of applying solutions of chemical mixed with fibrin glue [5], which are used both in isolation and in various combinations with each other. All of these methods have proven clinical efficacy, but each of them have serious flaws.

When infusion of chemotherapy into the hepatic artery arises a large number of serious complications (spetsializirovannyh Hepatology centers [4].

The application of solutions of chemical mixed with fibrin glue there is a risk of transmission with glue, prepared from plasma donor, viral and prion infections, intake of chemical from the depot (fibrin clot) is uneven and cannot be controlled, exposure of chemical short (the time of the dissolution of the clot 7 days), you experience technical difficulties when applying the adhesive to hard-to-reach areas of the parietal peritoneum, the lower lobe of the liver, the method cannot be used for the prevention of neoplastic lesions of the liver, the method of the roads due to the use of large amounts of fibrin glue [5].

The closest analogue (prototype) to the claimed method of treatment is the way hyperthermic intraoperative intraperitoneally chemotherapy [1]. The way is long (over 1 hour) perfusion of the abdominal cavity heated to 39-40C solution anticancer drug. In 50% of cases when using this method there is a complication, as abdominal pain, during perfusion of anticancer drug massive protein loss with transudate from the abdominal cavity, the method is expensive because of the cost of additional eppard lengthens the period of anaesthesia for 1 hour.

In the described methods for drug treatment and prevention of cancer of the liver and peritoneal metastases are a high concentration of anticancer drugs, which have a General toxic effect on the body; when using the presented methods, it is impossible to achieve a long exposure of anticancer drugs.

Currently, a large number of drugs for local application on the basis of a resorbable biopolymer materials such as collagen, cellulose, gelatin and others [6].

Known means for collagen-based, which is the closest analogue (prototype) to the claimed tool for local use [7].

Known means includes as pharmacologically active additives sodium salt of DNA. Known means for collagen-based can be used in dentistry, as well as, mainly, for the treatment of burn wounds and traumatic defects of the skin.

In Oncology during surgical operations in neoplastic lesions of the liver and peritoneum resorbable biopolymer materials are not used.

Task, renania in Oncology and development of treatment and prevention of neoplastic lesions of the liver and peritoneum with its use.

The technical result that can be obtained by carrying out the present invention is to provide a prolonged, metered release of anticancer drugs from dosage forms, creating and maintaining, within a reasonable period of time effective, safe concentrations of drugs in metastases in the body, especially in areas distant metastases, reducing systemic toxicity of anticancer drugs, and in the lengthening of the survival period.

This technical result is a new tool for local use and method of treatment and prevention of neoplastic lesions of the liver and peritoneum.

The method is performed by the application during surgery biopolymer absorbable plates containing the anticancer drug in a quantity of 0.5 to 25.0 wt.%, on (depending on the specific clinical situation): diaphragmatic surface of the liver (with the preventive purpose as a local adjuvant chemotherapy after surgical removal of primary tumor in a patient with uncommon cancer), the removal of malignant tumors, metastases in the liver and the/P>1 - combined operation consisting in the simultaneous removal of primary tumor malignancies and metastases in the liver and/or peritoneal metastases,

2 - operations, requiring only the removal of metastases in the liver and/or peritoneal metastases, as a second, planned delayed phase of surgical treatment of advanced cancers,

3 - operation, requiring only the removal of liver metastases in newly diagnosed metastases in the liver or peritoneal metastases after radical operations.

As the porous biopolymer resorbable plates for the release of anticancer drugs can be used:

- collagen plate: "Cutinol", "Tramacol", "Colortek surgical explants, collagen hemostatic sponge,

gelatin sponge "Steripen", "Spongostan" (gelatin plate - Denmark), "Gelfoam" (gelatin plate - USA), "Spongioblast", "Spaniel",

- lyophilized collagen sponge and collagen felt "Collastypt" (firm "V. Braun-Dexon", Germany), "Collastat-Kendall Co", "Tachotop" (firm "Hormonhemie Pentapharm Collagenvlies"), "Lyostipt" (company "B. Braun-Melsungen"), "Superstat" (firm "Interface Biomedical Laboratories Corparation"), "Instat" (firm "Jonson end Jonson"), "" (combined tool: collagen plate coated with fibrin glue - Norway),

plates of calcium alginate: "Kaltostat", "Sorbalgon", "Hartmann", "Amalgan", "Algifor", "Algamar", "Taralgon".

As anticancer drugs, you can use the following drugs and their combinations: robaxin, idarubicin, doxorubicin, cyclophosphamide, thiotepa, methotrexate, tomudex, Gemzar, hycamptin, irinotecan, bleomycin, Vepesid, lobaplatin, cisplatin, carboplatin, Taxol, Taxotere, mitomycin C, topotecan, 5-fluorouracil.

Preferably as an anticancer drug to use irinotecan.

Preferably, the anticancer drug to use in the amount of 1.0 to 15.0 wt.%.

Porous resorbable biopolymer plate currently manufactured mainly from recycled collagen and have a period of resorption in the abdominal cavity is 30-40 days. Biological biopolymer plates have a pronounced adsorption (binding) capacity, which is used when the composition of anticancer drugs (for example, when the soaking plates with a solution of anticancer drug). Molecule anticancer drug adsorbed on collagen (castnet is realized gradually, as resorption plate (30-40 days).

You can use biopolymer plates containing anticancer drugs, which are included in a wafer in the manufacture of industrial conditions.

This method is successfully used by us in three experiments: the first experiment on 50 rats with experimental colorectal cancer metastases to the liver, the second experiment on 20 rats who underwent induction of liver metastases, the third experiment on 50 rats with experimental metastases to the peritoneum.

Description of experiments (examples).

Experiment 1 (example 1).

The experiment consisted of three stages. stage 1 - operation with induction of liver metastases. stage 2 - cytoreductive surgery. stage 3 - sectional study material, assessment of results.

The induction of liver metastases in rats-males line BDJX weight 34025 g, 10 weeks of age (50 rats) was performed under General anesthesia (used 5% solution of ketamine). Performed a limited incision in the midline (verhnesadovoe laparotomy) and produced vnutricletocny injection of tumor cells (151.000.000) in a volume of 0.1 ml, after which the abdominal cavity is sutured.

All rats core group conducted cytoreductive surgery, which consists in removing all possible (resectable) liver metastasis within visually unchanged tissues by the method of husking. Resectable considered superficial metastases and intraparenchymatous metastases that are far from large vascular bundles of the liver. Then randomly rats were divided into 2 groups (15 rats) and In (15 rats). In rats subgroups And reorganize the abdomen with an antiseptic solution and subsequent suturing of the abdominal is Tannoy solution of irinotecan, on the diaphragmatic surface of the liver. Additionally used hemostatic and antibacterial effect of collagen plates. After you have carried out sanitation of the abdominal cavity with an antiseptic solution and suturing of the abdominal cavity.

Collagen plate used in operations in rats subgroups Within the main group, was prepared as follows: intraoperative sterile collagen plate size 3,01,50,2 cm was impregnated with 0.35 ml of a 2.0% solution of irinotecan (on the basis of a total dose of 700 mg/m2and considering the average period of complete resorption of the plate 42 days and the average surface area of rats, 100 cm2). Average time soaking plate was 5 minutes, the Concentration of irinotecan in collagen plate is of 11.0 wt. %.

For the evaluation of antimetastatic effect 21 days after the second operation on 8 rats from each group were killed by ether. Removed the liver and determined the degree of metastatic lesions (number and size of surface metastases). The remaining rats were left to clinical death in order to determine the life expectancy of rats in different groups. During the experiment at each stage were weighed alive is to THEM), considering 2 parameters: the frequency and intensity of metastasis.

The formula for calculating the MRI:

THEM(%)=((AtoXBto)-(Ucpa))/(AtoXBto)100,

where atothe frequency of metastasis in the control group;

The frequency of metastasis in experimental group;

INto- the average number of metastases in the control group;

- The average number of metastases in the experimental group.

Statistical analysis was performed by student's criterion.

The results of experiment No. 1.

In both subgroups of the main group marked decrease in the number of metastases and their sizes compared with the control group. The index of inhibition of metastases in the group And amounted to 60% in the subgroup of 96 percent. The average number of surface metastases on day 21 was 201,8 thousand cub., 51,7 and 1,00,9 in the control and subgroups a and b of the main group, respectively. All rats left to determine life expectancy, died within 92 days. The average life expectancy of animals was 434 days, 566 and 845 days respectively in the control group, the subgroups a and b of the main group.

During the experiment the animals subgroups Within the main group not nd group was 11% and was not statistically significant compared with animals of the subgroup And the main group (7%). Mortality during treatment was not observed. Section no animal subgroups Within the main group is not found, the development of ascites, whereas 1 of 15 individuals, subgroups And main group and 5 rats from 14 of the control group was noted ascites varying degrees of severity. Biological plate in rats subgroups Within the main group on the 21st day was half resorbed, any local no complications (abscess, hematoma under the plate).

The results obtained confirm the effectiveness of the presented method for the treatment of malignant tumors of the liver.

Experiment 2 (example 2).

The experiment consisted of two stages. stage 1 - operation with induction of liver metastases. stage 2 - sectional study material, assessment of results.

20 rats-males line BDJX weight 34025 g, 10 weeks of age randomly divided into 2 groups of 10 animals. Rats of the control group in phase 1 was conducted only by the induction of liver metastases. Under General anesthesia (used 5% solution of ketamine) did a limited incision in the midline and performed vnutricletocny injection of tumor cells (151.000.000) in a volume of 0.1 ml, then ora group at the first stage after similarly conducted induction of liver metastases and 20 minutes of exposure was performed intraoperatively applique collagen plate 3,01,50,2 cm, impregnated with 0.35 ml of 0.2% solution of irinotecan, on the diaphragmatic surface of the liver. The concentration of irinotecan in collagen plate is 1.1 wt.%. We then conducted sanation of abdominal cavity with an antiseptic solution and suturing of the abdominal cavity.

The second phase. At 21 days after surgery, all rats in both groups (20 animals) were killed by ether. Removed the liver and determined the degree of metastatic lesions (number and size of metastases). During the experiment at each stage was carried out weighing of animals. On the basis of the obtained data was calculated for all rats, the index of inhibition of metastasis, taking into account the 2 parameters: the frequency and intensity of metastasis.

Statistical analysis was performed by student's criterion.

The results of experiment 2.

In the study group showed a significant, significant decrease in the number of metastases and their sizes compared with the control group. The index of inhibition of metastasis was 98%. The average number of metastases on day 21 the animals of the control group was 283. Only 2 animals of the core group noted the development of metastases in the liver (y 1 - 3 of metastasis, 2nd - 2 metastasis).

During the experimental who ate amounted to 7%. Mortality during treatment was not observed. Section none of the animal's primary group is not found, the development of ascites, whereas 4 out of 10 animals in the control group was noted ascites varying degrees of severity. Biological plate 21 day were half resorbed, any local no complications (abscess, hematoma under the plate).

The results obtained confirm the effectiveness of the presented method for the prevention of liver malignant tumors.

Experiment 3 (example 3).

The experiment consisted of three stages. stage 1 - operation with induction of peritoneal metastases. stage 2 - operation with the subsequent introduction of chemotherapy drugs. stage 3 - sectional study material, assessment of results.

Induction of peritoneal metastases in rats-males line BDJX weight 34025 g, 10 weeks of age (50 rats) was performed under General anesthesia (used 5% solution of ketamine). Performed intraperitoneal injection of a suspension of tumor cells (151.000.000) in saline in a volume of 2 ml.

After 14 days was carried out the second operation (second stage). Under General anesthesia (used 5% solution of ketamine) vypolnennoi cavity to control inoculation of tumor was assessed by the number and size of metastases in the peritoneum, the presence of metastases in other organs of the abdominal cavity), then taken out from a study of rats with widespread peritoneal process (13 rats).

Next, remaining in the animal experiment (37 rats randomly divided into 2 groups: 1-control (13 rats), 2nd primary (24 rats). Rats of the control group carried out the reorganization of the abdomen with an antiseptic solution with further closure of the abdominal cavity.

All rats of the main group randomly divided into 2 subgroups a and b (12 individuals). All rats subgroups And after the suturing of the abdominal cavity was performed intraperitoneal injection of 10 ml of 0.2% solution of 5-fluorouracil. All rats subgroups conducted In the application of the collagen plate impregnated with a solution of 5-fluorouracil, areas of peritoneal metastases. It was further held suturing the abdominal cavity.

Collagen plates used in operations in the rat main group, was prepared as follows: intraoperative sterile collagen plate 12,01,50,2 cm was impregnated with 3.7 ml of 2% solution of fluorouracil. The concentration of 5-fluorouracil in collagen plate is to 23.8 wt.%. Then, the plate was into fragments with scissors into pieces so that poluester was 5 minutes

For the evaluation of antimetastatic effect 21 days after the second surgery all rats in both groups were killed with ether. After the section half resorbed collagen plates were removed, and all rats participating in the 3rd stage of the experiment, we determined the area of metastatic lesions.

On the basis of the obtained data was calculated for all rats, the index of inhibition of metastasis (MRI). Statistical analysis was performed by student's criterion.

The results of experiment 3.

In rats, the main group marked reduction in the size of metastases, the most significant in the subgroup Century In the subgroup of the main group, in contrast to the subgroups And the main group and the control group, new foci of tumor growth on the peritoneum was not. The index of inhibition of metastases in the group And amounted to 45%, in the subset of 84%. During the experiment the animals subgroups Within the main group showed no serious (severe) side effects. Maximum body weight loss in animals sub-groups In the main group was 13% and was not statistically significant compared with animals of the subgroup And the main group. Mortality during treatment was not observed. Section no animal subgroups basically In the control group were observed ascites varying degrees of severity. Biological plate in rats subgroups Within the main group on the 21st day was half resorbed, any local no complications (abscess, hematoma under the plate).

The results obtained confirm the effectiveness of the presented method for the treatment of malignant tumors of the peritoneum.

Sources of information

1. Davydov, M. I., Ter-Ovanesov M. D. et al. Hyperthermic intraoperative intraperitoneally chemotherapy in the combined treatment of locally advanced and disseminated gastric cancer.// Practical Oncology. - 2001. No. 3. - S. 59-66.

2. Mansvet Century, Bertrand C., Nackermann P. Study of the toxicity and results of Intraperitoneal hyperthermic chemotherapy in 28 patients with peritoneal carcinomatosis.// Ann. Chir. - 1997. - V51. - p.60-67.

3. Koga, S., Hamazoe R, Maeta M. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C.// Cancer. - 1998. - V. 61. - p.232-237.

4. Savier E., Azoulay D., Huguet, E., Lokiec F., Gil-Delgado m, Bismuth H. Percutaneous iaolated hepatic perfusion for chemotherapy: a phase 1 study.//Arch. Surg. - 2003. - V. 138. -13. - R. 325-332.

5. Kobayashi H., Nakagawa T., Kubota T. et al. Experimental study of intraoperative local chemotherapy with fibrin glue containing nitrosourea for malignant gliomas. // Surgical neurology. -1995. - V. 44. -12. - p.151-157.

6. L. A. Ivanova. Collagen in technology Lakers is="ptx2">

1. A means for local use, made of resorbable biopolymer framework including drug, wherein the polymer base is selected from collagen, gelatin and alginate calcium, and as a medicinal product means includes anticancer drug in the following ratio, wt.%:

The anticancer drug from 0.5 to 25.0

The specified polymer-based To 100

2. Means under item 1, characterized in that it contains the anticancer drug in an amount of 0.1 to 15.0 wt.%.

3. Means under item 1 or 2, characterized in that as an anticancer drug it contains a drug selected from the group of drugs, including irinotecan, robaxin, idarubicin, doxorubicin, cyclophosphamide, thiotepa, methotrexate, tomudex, Gemzar, hycamptin, bleomycin, Vepesid, lobaplatin, cisplatin, carboplatin, Taxol, Taxotere, mitomycin C, topotecan, 5-fluorouracil, and combinations thereof.

4. A tool according to any one of paragraphs.1-3, characterized in that as an anticancer drug it contains irinotecan or cisplatin.

5. A tool according to any one of paragraphs.1-4, characterized in that the specified components of the means and the within, at least 20 days.

6. Method for the treatment and prevention of neoplastic lesions of the liver and peritoneum, including the introduction of anticancer drug, wherein the anticancer drug is administered during surgery by application to the diaphragmatic surface of the liver or the local area removal of metastases medicines described in any of paragraphs.1-5.

 

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