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15MEDICAL SCIENCES
CARDIOVASCULAR SIDE EFFECTS OF COLON CANCER THERAPY
Georgiyeva K.
Ryazan State Medical University, Florida, USA
Blake P.
NWSMUI.I. Mechnikov, Saint-Petersburg, Russia DOI: 10.5281/zenodo.7014308
ABSTRACT
Colon cancer and cardiovascular diseases present the major two causes of death worldwide, with colon cancer being the second most prevalent cancer in the United States. Furthermore, the treatment therapy used in different types of cancer often leads to cardiovascular side effects which affect the quality of life of patients receiving colon cancer treatment therapy. The field of cardio-oncology has emerged to study the cardiovascular side effects of cancer treatment therapy. The cardiovascular side effects of most used treatment therapies in colon cancer are discussed. This review studies the side effects of radiotherapy, monoclonal antibodies, Vascular endothelial growth factor (VEGF) targeted therapy, immunotherapy and chemotherapy involving anthracyclines, Histone deacetylase (HDAC) inhibitors, cyclooxygenas-2 (COX-2) inhibitors and antimetabolites. Major cardiovascular side effects reported from these treatment therapies include congestive heart failure, hypertension, ischemia, myocardial infarction, angina pectoris, atherosclerosis, thromboembolic events, and other vascular and pericardial diseases. The safety profile of several anticancer drugs is also discussed and compared for their relative safety in high-risk groups with underlying cardiovascular complications. Alternate methods are mentioned to reduce cardiotoxicity induced by anticancer treatment therapies, these methods suggest either using a combination therapy or replacing a therapy to enhance the safety profile of a drug.
Category: Oncology, Cardiology, Toxicology.
Keywords: cancer, colon cancer, chemotherapy, cardiotoxicity, radiotherapy, cardiovascular diseases, cancer drugs, side effects, adverse effects.
Introduction & Background
Colon cancer is referred to as colorectal cancer. It involves uncontrolled division of cells in parts of the large intestine, majorly the colon, it has three main forms: colitis associated, sporadic and hereditary colo-rectal cancer. It is prevalent worldwide with more than 41,000 annual cases emerging in the United Kingdom every year, making it the fourth most commonly occurring type of cancer. Whereas in the United States, 151,400 cases of colon cancer have been reported as of January 2022. Colon cancer has underlying genetic causes; however, obesity, smoking, exposure to radiation, alcohol consumption, inflammatory bowel disease, ulcerative colitis and low fibre diet prove to be the major risk factors and they may often elevate the symptoms of existing colon cancer [1]. Different traditional and innovative therapies are available for treatment of colon cancer. Most common therapeutic methods for colon cancer treatment include combination therapy involving chemotherapy, immunotherapy, radiotherapy, use of monoclonal antibodies, and targeted cancer therapy. Colon cancer diagnosed in its early stages can easily be treated by removing the tumour through surgery. Colon cancer is diagnosed by various tests including digital rectal exam, faecal occult blood test, colonos-copy, sigmoidoscopy, biopsy, DNA stool test.
With emerging technological advancements, cancer has been rendered treatable and survival rate of patients has enhanced. However, surviving patients treated with traditional cancer treatment methods have reported to suffer from cardiovascular side effects after the cancer treatment including angina pectoris, cardiac heart failure, hypertension, myocarditis, radiation in-
duced cardiovascular diseases, thromboembolism, car-diomyopathy, arrythmias and coronary artery disease [2]. In the United States, geriatrics are often diagnosed with both cancer and cardiac complications, the conventional and targeted cancer treatment methods tend to increase the risk of cardiovascular diseases and makes them a high-risk group for cardiac diseases [3]. Cancer treatment therapies not only elevate the symptoms of cardiovascular diseases but also create the underlying conditions for the emergence of these diseases. Studies report that the existence risk factors for cardiovascular diseases increase the incidence of cancer treatment led cardiotoxicity [4].
For instance, studies report that the use of Fluoro-pyrimidine is linked to the emergence of angina pec-toris in patients during following their cancer treatment [5]. Patients are reported to have manifestations of arterial stiffness during the post-adjuvant chemotherapy for colorectal cancer, this indication is much lower in patients with non-metastatic colon cancer [6]. Doxorubicin is an effective anticancer drug; however, it is ineffective at low doses, and causes severe cardiotoxicity at high doses by initiating myocytes destruction. Radiation therapy has been linked to the emergence of pericardial diseases, myocardial fibrosis, and coronary artery disease [7]. A side effect of monoclonal antibodies such as Bevacizumab interferes in the process of angi-ogenesis by binding to VEGF and causes increased an-giogenesis which is crucial for tumour growth and metastasis. This often leads to arterial hypertension, thromboembolism, and congestive heart failure [8].
As cardiovascular diseases account for second most fatal diseases worldwide, it is crucial to study the mechanisms that link the use of cancer treatment with
cardiotoxicity to modify cancer treatment therapies and increase their safety. This objective will also help to reduce the chances of recurrence of cancer in patients. For this purpose, the field of cardio-oncology has emerged and has produced significant evidence regarding the link between emergence of cardiotoxicity and cancer treatments: systemic anti-cancer treatment and radiotherapy [2]. The discipline of cardio-oncology allows monitoring symptoms of patients alongside their cancer treatment and prevent the incidence of cardiovascular diseases or cardiotoxicity The field of cardio-oncology has allowed haematologists and oncologists to work together to identify the issue at hand.
Review
Several chemotherapeutic drugs used in colorectal cancer have reported to have cardiovascular side effects. The use of anthracyclines, 5-Fluorouracil, and administration of COX-2 inhibitors alongside anticancer drugs is directly associated with cardiotoxicity. For instance, cyclophosphamide is an alkylating agent with high efficacy in colorectal cancer; however, it is reported to cause heart failure within a week of its administration [2].
Cardiovascular side effects of Anthracyclines
Doxorubicin is an anthracycline anti-cancer drug that involves blocking topo-isomerase II with a resultant cardiovascular toxicity dependent on the dose administered. Doxorubicin is only prescribed in colorec-tal cancer during the advanced stages, high doses of doxorubicin in this phase often lead to severe cardiovascular toxicity [9]. At doses greater than 450 mg/m2, it commonly causes left ventricular dysfunction [7]. The main cardiovascular side effect of using Anthracy-clines (e.g., Doxorubicin) in colon cancer treatment is the emergence of late and irreversible heart failure [2]. Cancer patients aging less than five or greater than 65 are high risk groups for doxorubicin induced hypertension [7]. Recent research shows that the use of aldose reductase inhibitors alongside doxorubicin in cancer treatment not only increases its efficacy, but it also reduces its cardiovascular adverse effects in cancer patients [2]. The administration of beta-blockers, most commonly Carvedilol, alongside Doxorubicin has also proved to be cardioprotective.
Cardiovascular side effects of 5-Fluorouracil
Among the chemotherapeutic agents, 5-Flourouracil is an antimetabolite used commonly to treat colorectal cancer. Fluorouracil injection is approved by the Food and Drug Administration for use of colon cancer [10]. However, recent reports have revealed its severe cardiotoxic effects including vaso-spastic angina and angina pectoris. Sometimes the symptoms appear as early as 72 hours after administration of 5-Flourouracil [5]. Patients administering 5Fluorouracil suffering from cardiovascular side effects complain the occurrence of chest pain and shortness of breath after exercise or during rest.
Capecitabine and 5-Flourouracil produce the same extent of cardiotoxicity when used alone in colon cancer treatment; however, the use of capecitabine in combination therapy is much safe. Use of 5-Flourouracil in combination therapy for cancer treatment alongside ox-aliplatin and folinic acid (FOLFOX) has proved to have
significantly greater cardiovascular side effects and narrow safety profile in comparison to the combination therapy (CAPOX) including oxaliplatin and capecita-bine [11].
Cardiovascular side effects of Histone deacety-lates (HDAC) inhibitors
Histone deacetylases (HDAC) are post-transcrip-tional modifiers that regulate the process of transcription and protein synthesis, they are characterized into four classes: HDAC-I, HDACII, HDAC-III, HDAC-IV. Four histone deacetylase (HDAC) inhibitors are approved by Food and Drug Administration including Be-linostat, Panobinostat, Vorinostat, and Romidepsen for use in colorectal cancer, as they upregulate the p21 gene in the cell cycle, balance the proapoptotic and anti-apoptotic proteins to induce controlled cell division and inhibit uncontrolled cell proliferation and metastasis. Studies in mice report that three to four months post-Histone deacetylase (HDAC) inhibitors treatment, the signs and symptoms of cardiac hypertrophy and cardiac fibrosis emerge [12]. Studies reported severe cardiovascular adverse effects including severe anaemia and thrombocytopenia in patients administered with the intravenous doses of Vorinostat [13]. However, combination therapy in colon cancer can be used to reduce the cardiovascular adverse effects of Histone deacetylase (HDAC) inhibitors.
Side effects of selective cyclooxygenase-2 (COX-2) inhibitors
Selective clooxygenase-2 inhibitors are used in cancer treatment along with anticancer drugs to reduce metastasis as COX-2 inhibitors block prostaglandins by binding with cyclooxygenase and inhibiting prosta-glandin-endoperoxide synthase, these prostaglandins are inflammatory substances that signal metastasis and angiogenesis in the presence of cancer cells. The use of selective cyclooxygenase-2 (COX-2) inhibitor, predominantly Celecoxib, is effective in suppressing colo-rectal cancer. However, its added adverse effect of car-diotoxicity presents a narrow safety profile for the cancer patient by increasing the incidence of atherothrombotic implications and hypertension [14].
Celecoxib has proved to be highly efficacious in prevention of adenomas according to a study conducted in the United States: Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) study. In this study it reduced the cases of adenoma recurrence in colorectal cancer patients by one third. However, the study also reported severe cardiovascular adverse effects [15]. The clinical signs of cardiotoxicity appeared 12-18 months after the administration of cyclooxygenase-2 (COX-2) inhibitors. Hence, it presents a possibility that the cardiotoxicity induced in this therapy can be prevented by stopping the administration of COX-2 inhibitors before one year as cardiotoxicity only appears after 12-18 months of continuous administration of cy-clooxygenase-2 (COX-2) inhibitors [15].
Other relevant research involving Celecoxib reports similar cardiovascular side effects. At a daily dose of 400 mg twice a day, Celecoxib increases the risk of emergence of thromboembolism in the cancer patient by two and a half fold. Lowering the dose to >200 mg twice a day reported less severe cardiotoxicity [16].
Hence, Celecoxib induced cardiotoxicity and cardiovascular side effects are dose dependent. The patho-physiology of Celecoxib induced cardiovascular adverse effects can be understood by analysing its role in inhibiting endothelial cyclooxygenase-2 (COX-2) that resultantly inhibits prostacyclin along with Prostaglan-din E2 (PGE-2). These events majorly have an effect to cause the cardiovascular toxicity. This creates a possibility of introducing the use of selective PGE-2 inhibitors in place of COX-2 inhibitors to reduce Celecoxib induced cardiovascular side effects [16]. When Celecoxib is combined with low dose Aspirin and administered in patients that are high risk groups for car-diotoxicity, this therapy also shows less severe cardiovascular adverse effects [15].
Side effects of radiotherapy in colon cancer treatment
Most colon cancer patients are treated with radiotherapy as an adjuvant treatment with efficacious anticancer properties. However, radiotherapy leads to severe cardiovascular adverse effects including ischemic heart disease, vascular diseases including carotid artery stenosis, vascular venous insufficiency, and pericardial diseases: acute pericarditis and constrictive pericarditis, and non-ischemic cardiomyopathy [17]. The pre-existence of risk factors for cardiovascular diseases in colon cancer patients make them high risk groups for cardio-toxicity when treated with radiotherapy, these risk factors commonly include smoking, hyperlipidaemia, and diabetes. The pathophysiology of radiotherapy induced cardiovascular adverse effects can be explained by studying the effect of radiotherapy on release of signalling factors. Radiotherapy has an effect of triggering the release of interleukin-1 (IL-1), interleukin6 (IL-6), in-terleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-a) which increase the incidence of atherosclerosis and increased fibrin deposition in the heart, hence resulting in radiation induced heart disease [17].
Risk of VEGF-induced ca
Side effects of modern targeted therapy and im-munotherapy in colon cancer treatment
Immunotherapy stimulates body's immune system to fight cancer. It includes checkpoint inhibitors, T-cell transfer therapy, monoclonal antibodies, and immune system modulators. Pembrolizumab and nivolumab are highly efficacious immune checkpoint inhibitors used in colorectal cancer. However, checkpoint inhibitors report to cause cardiovascular side effects, while the use of tyrosine kinase inhibitors is reported to increase the risk of peripheral artery disease. The combination of nivolumab and ipilimumab trigger immune responses that cause autoimmune lymphocytic myocarditis [18]. Sunitinib (kinase inhibitor) and Aflibercept (vascular endothelial growth factor-A (VEGF-A) antagonist) prescribed in colorectal cancer have reported to cause cardiovascular side effects, most predominantly hypertension [19].
Side effects of VEGF-targeted anticancer tyro-sine kinase inhibitors
Vascular endothelial growth factor (VGEF) inhibitors are agents that primarily inhibit the process of an-giogenesis which makes them highly efficacious in the treatment of cancer. VEGF-targeted therapy in treatment of colorectal cancer has reported severe cardio-toxicity and a narrow pharmacokinetic safety profile in high-risk groups with underlying pathological conditions including risk factors for cardiovascular diseases due to the involvement of VEGF in vascular homeosta-sis. Studies report that the cardiovascular adverse effects majorly recorded after the use of VEGF-targeted therapy are arterial thrombotic events, congestive heart failure and pulmonary embolism [20]. The frequency of cardiovascular side effects is mentioned in the table 1, the crude cumulative incidence predicts the possibility of risk of emergence of side effects.
Table 1
adverse effects
VEGF-therapy induced cardiovascular adverse effect Crude Cumulative Incidence (%)
Major adverse cardiovascular events (Myocardial infarction, heart failure and pulmonary embolism) 9.79
Arterial thrombotic events 3.99
Rhythm disorders 2.66
Pulmonary embolism 1.57
Side effects of monoclonal antibodies
Another example of modern targeted anticancer therapy is the use of monoclonal antibodies that specifically target cancer cells. Monoclonal antibodies used in colorectal cancer include Bevacizumab, Cetuximab, Imatinib, Sunitinib and Panitumumab. Although targeted monoclonal antibodies have reduced the overall side effects of chemotherapy, but they still produce cardiovascular side effects after treatment that are detrimental to the patient's health. Studies show the emergence of congestive heart failure, hypertension, left ventricular dysfunction and thromboembolic events as a cardiovascular adverse effect after the administration of monoclonal antibodies [21]. Bevacizumab was the
first FDA approved humanised monoclonal antibody for use in colorectal cancer, both Bevacizumab and Sunitinib are known to cause grade three hypertension as a cardiovascular side effect [22]. This can be effectively controlled by using angiotensin-converting enzyme (ACE) inhibitor. It is also associated with venous thromboembolism in the age group >65. The patho-physiology of Bevacizumab induced cardiovascular effects can be understood by studying its inhibitory effect on VEGF. This in turn disrupts the collateral vessel formation by interfering with the repair process of myocardial damage. [22]
Alternate methods to reduce cardiovascular side effects induced by treatment therapy
In the treatment therapy of colorectal cancer, cardiovascular side effects can be managed by introducing alternate methods in place of the conventional anti-cancer therapy. Naturally extracted bioactive compounds can reduce treatment therapy induced cardiotoxicity and cardiovascular side effects [23]. Introduction of different combination therapies or substitution of a drug with one that has less severe side effect and a broader pharmacokinetic safety profile can reduce car-diotoxicity in colon cancer treatment [23]. For instance, Doxorubicin can be administered alongside aldose re-ductase inhibitors or Carvedilol to reduce its cardiovascular adverse effects [7], Celecoxib can be added with low dose Aspirin, and the combination of CAPOX can be used instead of FOLFOX to reduce cardiovascular side effects. These techniques can enhance the quality of life of cancer survivors and reduce the risk of cardiovascular diseases.
Conclusions: Recent advancements in medicine have provided modern treatment therapies for colorec-tal cancer with enhanced survival rates. However, treatment therapies used in colorectal cancer are often associated with the occurrence of cardiovascular side effects and cardiotoxicity that are reported in the lifetime of cancer patients after treatment. The field of cardio-oncology has emerged to study the cardiovascular and haematological side effects of anti-cancer therapies so that the incidence of side effects can be reduced. Cardiovascular side effects reported after colon cancer treatment therapy frequently include congestive heart failure, thromboembolic events, hypertension, vascular and pericardial diseases. The pathophysiology and molecular mechanism of cardiovascular side effects associated with each colorectal treatment therapy are studied to provide alternate methods including replacement of a therapy or using a combination therapy to reduce the incidence of cardiovascular side effects and enhance the safety profile of treatment therapies to provide a better quality of life to cancer survivors.
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ПОРУШЕННЯ МОТОРНО1 ФУНКЦП КИШЕЧНИКА У Д1ТЕЙ: Д1АГНОСТИКА,
КОРЕКЦ1Я
Боднар Г.Б.
Буковинський державний медичний унгверситет, м. Чертвцi
Боднар О.В.
Буковинський державний медичний yHiверситет, м. Чернiвцi
VIOLATIONS OF THE MOTOR FUNCTION OF THE INTESTINE IN CHILDREN: DIAGNOSIS,
CORRECTION
Bodnar G.
Bukovinian State Medical University Bodnar O.
Bukovinian State Medical University DOI: 10.5281/zenodo.7014314
АНОТАЦ1Я
В остант роки серед гастроентеролопчно1' патологи у Дтей вГдзначаеться зростання вроджених аномалш розвитку товсто1 кишки, яю е основою для розвитку оргатчних та функцюнальних захворювань Bciei' травно1 системи.
Метою дослГдження визначено встановити механiзми формування порушень евакуаторно! функцii кишечнику, встановити ix основнi ланки та розробити адекватну програму профiлакгики та лшування направлену на ix лшввдацш, що в свою чергу дозволить запобпти розвитку ускладнень та декомпенсаций патологiчного про-цесу в дней iз долixосигмою.
Нами дослiджено порушення циркадiанноi регулярностi евакуаторно! функцii кишечнику 252 дггей вiком вiд 4 до 15 рокГв за допомогою використання методом xроноентерографiя.
Встановлено, що у дггей iз декомпенсованим перебиом xронiчного запору на фонi вродженого подов-ження сигмоподабног ободово1' кишки спостерГгаеться сповiльнення евакуаторно1' функцп товсто! кишки у ви-гляд бращентерп III-IV ступенiв Гз песимальною актофазою та тенденцiею до розвитку аентери.
Регулярнiсть циркадГанного ритму евакуаторно1' функцп кишечнику е одним Гз атрибутивних власти-востей функцюнування травно1' системи. Нами запропоновано для корекцп дисинхронозу використання принципу «FPh» (Four Ph), який мГстить основш напрямки заходГв щодо профилактики виникнення та про-гресування хрошчного запору у дитей Гз долГхосигмою.
Отже, при дотхосигш спостерГгаеться збГльшення пащенпв Гз II ступенем бращентерп за рахунок зменшення шлькостГ пащенпв Гз ознаками III-IV ступешв. Використання хронометричного тдходу до корекцп порушень моторно-евакуаторно1' функцп товсто1 кишки в дитей Гз хрошчним запором, зумовленим вродженим подовженням сигмоподГбно1' ободово1' кишки, дозволяе досягнути позитивно! динашки клшь чно! симптоматики i може бути використане як складова програми лшувально-профшактичних заходГв при вродженому подовженш сигмоподГбно1' кишки.
ABSTRACT
In recent years, among gastroenterological pathologies in children, an increase has been noted in congenital malformations of the colon causing the development of organic and functional diseases of the entire digestive system.
Research objective. To identify onset mechanisms of the bowel evacuation function disorders, to establish their main links and develop an adequate medical and preventive treatment program aimed at their elimination, which in turn will allow preventing the development of pathologic complications and decompensation in children with dolichocolon.
