KR100883999B1 - Use of sulglicotide for the treatment of mucositis - Google Patents

Abstract

Use of sulfoglycide in the treatment or prevention of mucositis.

Description

USE OF SULGLICOTIDE FOR THE TREATMENT OF MUCOSITIS}

Mucositis is a common inflammatory condition that affects the mucosa, especially after chemotherapy or radiation therapy in patients with tumors.

In addition to acting on neoplastic cells, these types of therapies actually work on cells of healthy tissues, particularly rapidly replicating.

As a result, the oral cavity is one of the areas greatly affected by the complications arising from this treatment; In fact, about 40% of virtually all patients treated for head and neck tumors and those receiving radiation-chemotherapy for tumors elsewhere (leukemia or lymphoma) develop complications that affect the oral cavity ( Minerva Stomatol. 2002: 51: 173-86).

In general, the term “mucositis” is understood to mean a clinical condition characterized by a painful symptomatic complex and the presence of reduced epithelial thickness, intense erythema and ulceration associated with possible occurrence of infection and bleeding (Oncologist 1998: 3: 446-52; Oncologist 1999: 11: 261-6).

The biological mechanisms inherent in the development of mucositis, particularly oral mucositis, are subdivided into four stages: the first inflammatory / vascular stage, during which epithelial tissue causes the first local tissue damage following radiation- or chemotherapy, for example interleukin 1 Or excretion of large amounts of cytokines such as TNF-α; Secondary epithelial stage, which affects the division of epithelial basal cells resulting in reduced regeneration of the cells, atrophy of tissue and ulcer formation; Tertiary ulceration / bacterial stage, which is the most intense time with bacterial colonization of the affected area. This tertiary phase is also consistent with severe neutrophil reduction in the patient; The fourth and final characteristic stage of mucositis is considered to be a therapeutic stage with the restoration of proliferation and differentiation of epithelial cells, a gradual increase in white blood cells and normalization of local bacterial flora.

At present, both prophylactic and curative treatments are provided for mucositis. In the first case, substances that can reduce mucosal absorption of chemotherapy drugs (such as cryotherapy, allopurinol or pilocarpine), substances that reduce changes in epithelial proliferation (such as beta carotene, glutamine or silver nitrate, etc.) Or anti-inflammatory and antimicrobial substances (such as mesalazine and / or chlorhexidine).

In particular, cryotherapy is the most widely accepted prophylactic treatment today with respect to oral mucositis; This method is based on administering an ice cube to remain in the mouth for 30 minutes for the purpose of inducing vasoconstriction of the oral mucosa to reduce the temperature dependent toxicity of any chemotherapeutic agent. Unfortunately, cryotherapy has proved to be of substantial preventive efficacy only in patients treated with chemotherapeutic agents (fluorouracil) that can be administered as a bolus, and in the case of continuous perfused chemotherapy It has been proven ineffective because the drug is permanently present in the circulating blood and local vasoconstriction has no advantage (Oral Oncology 1999; 35: 453-70).

In the second case, substances that protect the mucous membranes (e.g. sodium bicarbonate), anesthetics or analgesics (e.g. lidocaine, morphine and derivatives thereof), substances that accelerate the treatment process (e.g. vitamin E, tretinoin, laser therapy, etc.) or Special diets and / or special oral hygiene therapies are used.

Other methods of treating mucositis are described in US patent applications US2003 / 0064913 and US2003 / 0236217, which are incorporated herein by reference.

However, none of these prophylactic strategies or therapies approaches due to chemotherapy and / or radiation therapy, in particular, which remains the cause of pain in patients with tumors, such as mucositis in the oral cavity of patients with head and / or neck tumors. It has not been proven to be completely effective in the prevention or treatment of mucositis.

Sullycotide is a sulfur polyester of glycopeptides obtained by extraction from porcine duodenum. Sullycotide is obtained by enzymatic proteolysis, repeated purification and subsequent sulfated steps; The final product is confirmed by electrophoresis on cellulose acetate.

Sullycotide is a gastric protective and antiulcer drug; It is not absorbed intestinal and produces effects only within the lumen of the stomach.

In fact, sulfoglycide is usually administered as a gastroprotective agent to individuals whose stomach wall has been attacked by drugs such as, for example, aspirin and taurocholic acid, or by generic nonsteroidal anti-inflammatory drugs. Clinical studies have demonstrated efficacy in preventing the development of gastric or duodenal ulcers associated with the use of such nonsteroidal anti-inflammatory drugs by administering sullycotides to patients suffering from rheumatoid arthritis and receiving indomethacin and diclofenac (Scand) J. Gastroenterol. 1993 Oct .; 28 (10): 875-8).

The mechanism of action is due to stimulation of the secretion of mucus and bicarbonate by gastric mucosal cells, in addition to those associated with pepsin inactivation.

In particular, sulfoglycotide is known as a drug of choice for the treatment of gastric conditions associated with Helicobacter pylori inflammation.

Helicobacter pylori is a spiral gram-negative bacterium that, due to its various properties, survives in the acidic environment of the gastric mucosa, proliferates under the mucus coating the inner wall of the stomach and adheres to the mucosa cell itself. It is one of the main causes of chronic gastritis and of course duodenal ulcer. Current treatment is based on antibiotics, and on certain frequent cases of antibiotic resistance variants and recurrences, based on specific anti-ulcer drugs.

Indeed, the administration of sulfiglitide in both animal models and various clinical studies has resulted in substantial improvement of inflammation by H. pylori with significant antiulcer activity in the stomach (J. Physiol. Pharmacol. 1999 Jun .; 50 ( 2): 197-210). Sullycotide acts primarily by preventing somatostatin-receptor binding, thereby inhibiting the effects of LPS (lipopolysaccharide) produced by bacteria that cause gastrin overproduction and acid secretion associated with subsequent ulcer formation.

It has now surprisingly been found that the use of sulfiglitide in the treatment of mucositis leads to significant improvements with regard to inflammatory signs complex and mucosal damage, and that the function of epithelial cells is significantly restored.

In particular, sulfoglycote shows its effectiveness in the treatment of oral mucositis. More specifically, sulfoglycotide is active in the treatment of mucositis by chemotherapy and / or radiation therapy.

Sullycotide leads to increased secretion of mucus and normalized regeneration of epithelial cells of the mucosa by increasing the levels of both PGE ₂ type and PGI ₂ type prostaglandins. Furthermore, sulfoglycotide can ensure both the onset of much less severe conditions of the mucosa and the acceleration of the course of treatment of such conditions by increasing the secretion of EGF (epidermal growth factor).

Increasing the amount of EGF or its receptors actually leads to increased proliferation of epithelial cells and the formation of superstratum of the cells and subsequent thickening of the mucous membranes, in particular the oral and / or gastrointestinal mucosa, which is thus cytotoxic. It acts as a barrier to attack from (eg radiation) and can significantly reduce any damage.

Growth factors, particularly EGF, are factors that essentially determine the sensitivity of epithelial cells to cytotoxic substances.

Thus, the use of sulfoglidide in mucositis, in particular oral mucositis, before and / or during chemotherapy and / or radiation therapy in patients with tumors such as head and neck tumors (such as larynx, pharynx or esophageal carcinoma). With the reduction of and low toxicity of the antitumor treatment, it leads to subsequent degradation of mucositis associated with it.

In the end, according to the present invention, sulfoglycotide is active in the prevention and treatment of mucositis, especially oral mucositis by anti-tumor treatment such as chemotherapy and / or radiation therapy.

Experimental part

Animal tests were conducted for the purpose of evaluating the efficacy of sulfoglycotide in protecting clonogenic cells of the intestinal mucosa from radiation-induced damage. The protection of clonal cells ensures the survival of the intestinal glands, which promotes normal epithelial repair.

Animals treated in this study do not have H. pylori , or their gastrointestinal mucosa does not show characteristic signs of inflammation caused by this bacterium.

In this test, inflammatory damage was caused by 13 Gy X-ray radiation dose. Sixty male BDF1 mice were treated in groups of six ten each. As a prophylactic measure, sulfoglycotide was administered in four doses (and one control / saline solution group) at various doses via gastric tubes daily for three days before irradiation, ie 12 mg / kg, 50 mg / kg, respectively, Administration was at 200 mg / kg and 800 mg / kg and the final dose was 30 minutes before irradiation.

The other four groups (and one control group / saline solution group) were also treated via gastric duct at various doses, 12.5 mg / kg, 50 mg / kg, 200 mg / kg and 800 mg / kg, respectively, immediately after irradiation and for three days thereafter. As a daily administration of sulfoglycote as a sacrifice, it was sacrificed on day 4.

All animals survived and no side effects were observed. All animals were collected and sacrificed 4 days after irradiation. Ten intestinal circumferences (60 per group) were measured for each animal and surviving glands and their widths were calculated and averaged for each group. Only glands containing intact circumference and at least 10 clonal cells were included.

The data obtained are summarized in Table 1 below. The accompanying figures show that the normal gland morphology (FIG. 1) or after irradiation with regeneration centers shows that the surviving glands have only one or more clonal cells and the other mesenchyme is completely absent (FIG. 2). Shows. These individuals develop diarrhea and die from mucositis. 3 shows intestinal morphology with islets or glands containing less than 10 cells.

result:

The data collected highlight the efficacy and ability of sulfiglitide to irradiate damage and the association between different doses. At the lowest dose (12.5 mg / kg and 50 mg / kg), sulglicotide shows no prophylactic effect on damage to clonal cells and intestinal glands; Evidence of increased gland survival and thus protection from irradiation injury is found at the dose of 200 mg / kg (35%). Dosages greater than 200 mg / kg also show no protective effect. However, the dosage of 200 mg / kg is effective from the point of view of prophylaxis, but is not active in the treatment group after irradiation.

In these cases, only a high dose of 800 mg / kg has a significant therapeutic effect on the damage caused by X-rays.

In conclusion, sulfoglycotide has been shown to be effective in the prevention or treatment of radiation damage when administered to mice without Helicobacter pylori through gavage at various doses.

Claims (8)

A pharmaceutical composition comprising sulglicotide as an active ingredient for the treatment or prevention of oral mucositis by antitumor treatment. delete The method of claim 1, The pharmaceutical composition is a pharmaceutical composition, characterized in that for the prevention of oral mucositis by the anti-tumor treatment. The method of claim 1, The anti-tumor treatment is a chemotherapy, radiation therapy or a combination therapy of chemotherapy and radiation therapy. The method according to any one of claims 1, 3 and 4, The sulglicotide is a pharmaceutical composition, characterized in that administered in an amount of 12.5mg / kg to 800mg / kg. The method according to any one of claims 1, 3 and 4, The pharmaceutical composition is characterized in that the topical dosage form. The method according to any one of claims 1, 3 and 4, The pharmaceutical composition is characterized in that the oral dosage form. The method according to any one of claims 1, 3 and 4, The pharmaceutical composition is characterized in that the parenteral dosage form.

Images