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Growth Factor Receptor Inhibitors

Growth Factor Receptor Inhibitors

Tyrosine kinase and growth factor receptor inhibitors are the main components of chemotherapy. Their effectiveness against cancer is based on the influence of the pathogenetic mechanism of the disease. They block the growth of cancer cells by interfering with the specific molecules necessary for carcinogenesis and tumor growth. Epidermal growth factor receptor (EGFR) inhibitors are quite common in the course of chemotherapy. This drug group includes tyrosine kinase inhibitors (TKI) and monoclonal antibodies (MA) (Drugs n.d.). The mechanism of TKI and EGFR relies not on the cytostatic effect and destruction of tumor cells but on the suppression of their activity and ability to replicate. The selectiveness of each drug increases the impact on the pathological tissue and minimizes side effects (Bhullar et al. 2018).

Epidermal growth factor (EGF) is a globular protein. It has a tyrosine kinase activity and high mitogenic activity. EGFR is expressed on the surface of both normal and transformed epithelial cells. Specific ligand triggers the process of dimerization and autophosphorylation of receptors on tyrosine residues. The whole mechanism leads to apoptosis reduction, cell proliferation, angiogenesis, invasion, and spreading (Bhullaret al.2018).

Tyrosine kinases are a special class of protein kinases. They phosphorylate proteins on tyrosine residues. There are two types of tyrosine kinases. Intracellular is involved in the process of signal transmission to the nucleus. Membrane kinases have a ligand-binding domain, which is involved in transmembrane signal transmission. Tyrosine kinase plays an important role in the formation and conduction of growth factor signals into the cell (Bhullaret al. 2018). Activation of these enzymes leads to the same effects as EGFR.

There is a wide range of TKI; a number of studied receptors determine it. Lapatinib has proved its effectiveness against breast cancer. Erlotinib is usually used to treat malignant tumors of the lungs and pancreas. These patients have good post-therapy results and longer lifetime expectancies. Dasatinib, nilotinib, and imatinib are the main chemotherapy drugs for myelogenous leukemia. Sunitinib is a new-generation medicine. It blocks a few types of receptors simultaneously (Bhullaret al. 2018).

Hormones in Cancer

Hormone therapy in oncology is rarely used as the primary treatment for cancer. It is effective only in hormone-dependent cancer tumors. Those are reproductive system tumors. Hormone therapy is normally applied in combination with other treatment options, such as radiation therapy, surgery, and chemotherapy (Cancer Research 2017). The goal of hormone therapy for cancer is to minimize the amount of hormone in the blood that stimulates tumor growth or to block the binding of the hormone to receptors in tumor cells (Cancer Research 2017).

Sex hormones are constantly circulating in the blood: estrogen and progesterone for women, and testosterone for men. They have a general effect on the cells of the body, acting on receptors on the cell surface. The number of receptors for different types of sex hormones differs depending on the tissue. Their highest number is in the breast, ovaries, and uterus in women, and the prostate in men. Most of all malignant reproductive system tumors are hormone-dependent (Cancer Research 2017).

Breast cancer is usually treated with hormone therapy. Tamoxifen is used widely against it. The inhibition of estrogen signal on the cells determines the effectiveness. In addition, tamoxifen is successful in prostate cancer treatment. To manage the level of estrogen, such aromatase inhibitors as anastrozole, exemestane are recommended. They decrease the production of sex hormones in women after menopause (Cancer Research 2017).

Prostate cancer treatment starts with stopping the production of luteinizing hormone since it stimulates the generation of testosterone. The most popular drugs in this group are goserelin and triptorelin. Gonadotrophin-releasing hormone blockers act indirectly on the pituitary gland’s work. They inhibit the signals from the hypothalamus to the gland. Degarelix refers to this group. Cyproterone acetate is a representative of anti-androgens. They competitively bind to testosterone receptors (Cancer Research 2017). Hormone therapy makes the malignant tumor smaller and reduces the amount of prostate-specific antigen (Health Encyclopedia n.d.).

Specific Cytotoxic and Biologic Agents for Different Types of Cancer

Biologic therapy uses the body’s defense mechanisms to treat cancer or to reduce the therapy’s side effects. Such treatment options can strengthen natural immunity. It includes monoclonal antibodies, receptor inhibitors, cytokines, chimeric antigen receptors, and vaccines. There are also methods to deliver active elements directly into the cell: virus therapy and radioimmunotherapy (OncoLink Team 2018). Cytotoxic agents are not differentiated by the type of cells affected. They block the replication of nucleic acids in all living cells. This makes cytotoxic agents dangerous for non-tumor cells (Dana-Farber Cancer Institute 2017).

The treatment of leukemia requires a complex approach to cytotoxic and biological agents. Vosaroxin is a first-line therapy drug. It blocks the DNA topoisomerase II and, consequently, causes breaks of DNA chains (Kadia et al. 2016). It is effective in all stages of the disease. Biological therapy has also shown its effectiveness in patients with acute myeloid leukemia. Monoclonal antibodies give a great result combined with cytotoxic drugs. SGN-33a combines with CD33, which does not let nucleic acids form a chain (Kadia et al. 2016).

Specific cytotoxic therapy for breast cancer is absent. The biological therapy depends on the presence of the HER2 gene. Trastuzumab is used for HER2-positive cancer (Martin 2017). It can be applied alone or in combination with cytotoxic drugs. Everolimus and exemestane are used in the absence of HER2 (Martin 2017). Treatment strategies for lymphomas are quite diverse as they depend on the type of cells, and the stage of the disease. They are well-treated with chlorambucil, cyclophosphamide, and doxorubicin. These drugs affect DNA reproduction and many related processes (Vinjamaram 2018). Immunology therapy is represented in a wide range of medicines: radiolabeled antibodies, pembrolizumab, CART-cell therapy, bortezomib, rituximab, etc. (Vinjamaram 2018). Chemotherapy for myeloma does not much differ from lymphoma treatment. The drugs can be combined with each other and various treatment types. Daratumumab blocks the CD38 protein represented in cancer cells (American Cancer Society n.d.).Cisplatinis is effective against prostate, lung, and gastrointestinal cancer. It helps break the cancer cell cycle. The taxanes are applied in case of metastasis (Huang et al. 2017).

Monoclonal Antibodies in Oncology and Immunology

Monoclonal antibodies selectively bind to the tumor cell receptors and cause its death. Antibodies mark them for subsequent radiation therapy. The high specificity of antibodies provides predictability of therapeutic effect. The development of this drug group is one of the fastest-growing areas in modern pharmacology. Currently, monoclonal antibodies have proved their clinical effectiveness in cancer treatment (Dana-Farber Cancer Institute 2017).

They are presented in native and conjugated forms. In the first case, antibodies may indicate cancer cells in the own immune system of the organism. Binding to specific receptors on the cell surface, they cause the death of these cells. In the second case, monoclonal antibodies are cytotoxic recognition modules. They are very toxic quite often. Their adherence to the antibody is completely necessary to minimize exposure in the body due to the local accumulation of toxins in the tumor (Khan 2016).

In recent years, monoclonal antibodies are used to deliver cytotoxic substances directly to tumor cells. This avoids damage to healthy tissues, as some antibodies penetrate deep into the solid tumor tissue. Depending on the active substance attached to antibodies, they divide into the following groups: radioactive particles (radioimmunotherapy), cytostatic particles, and toxins (immune toxins) (Khan 2016).

Ibritumomab and tositumomab are radioimmunotherapy drugs. Yttrium-90 and radioactive isotope Iodine-131 are part of these drugs respectively (Khan 2016). Immunotoxins are obtained by attaching bacterial or plant toxins to antibodies. The results of the first clinical trials of immune toxins showed a high potential of the method. The only immune toxin currently registered for the treatment of malignant diseases is gemtuzumab ozogamicin used in the treatment of acute myeloblastic leukemia in the elderly (Khan 2016).

Monoclonal antibodies are also used in immunology. They help sort cells into the desired populations (for example, dividing stem hematopoietic cells for transplantation). It is possible to create monoclonal antibodies to antigens of viruses, bacteria, and other pathogens for the treatment of infectious diseases. They can help identify and treat autoimmune diseases (Khan 2016).

Updates to Treatment of Sepsis

Sepsis is a systemic inflammatory reaction to infectious or toxins in the blood (Levy, Evans, & Rhodes 2018). It is characterized by a severe progressive course and the absence of a tendency to spontaneous recovery. Despite the increased possibilities of antibacterial and antifungal therapy, the mortality rate for sepsis remains quite high. Most often, it develops in people with a weakened immune system due to serious diseases, extensive operations, excessive blood loss, malnutrition, or the use of immunosuppressive drugs (Levy, Evans, & Rhodes 2018).

This year, the Surviving Sepsis Campaign has updated the recommendations for sepsis management. They are based on a number of research and trials. The reanimation and emergency measures organization has to start immediately. Now, the medical staff has only one hour to begin the correction of a patient’s state. There are five main steps in managing sepsis. They include defining the lactate level and getting the blood sample to identify the infectious agent and its antibiotic sensitivity. Antibacterial therapy must start only after obtaining a blood sample. Broad-spectrum drugs must be administered. Infusion therapy should also begin during the first hour from 30ml/kg of crystalloids. In the case of arterial blood pressure reduction, vasopressors must be administered (Levy, Evans, & Rhodes 2018).

The rest of the treatment steps did not change since the previous 2016 Guidelines (Levy, Evans, & Rhodes 2018). The patient has to receive respiratory support. The staff has to look after renal and metabolic systems. In case of septic shock, the failure of these systems develops quickly. Blood components transfusion may be accomplished to regulate coagulation disorders, anemia, and massive blood loss. The prophylaxes of vein thrombosis and coagulation disorders have to be accomplished. There has to be constant control of sugar levels. Hypoglycemia elevates the risk of mortality. To prevent sepsis, patients who have burns, cancer, diabetes, and multiple traumas require special attention and care from medical staff (Kalil 2018).

Pharmacogenomics and Individualizing Therapy

Individualizing medicine studies the genetic characteristics of a person, his predisposition to various diseases and develops preventive measures to eliminate those (Buckles 2016). In the treatment of diseases with modern drugs, there is an acute question about the tolerance of drugs and prevention of the development of adverse reactions. They can also be determined by the genetic characteristics of a patient. Individualizing therapy is based on working with each patient separately. The most profitable drug is selected for each one depending on the individual clinical case. This approach to therapy is most pronounced in oncology. Cancer treatment relies on the selection of various methods and drugs.

Pharmacogenomics studies the complete genome of groups of people to identify genetic factors influencing human response to medication (Relling & Evans 2015). Pharmacogenomics combines traditional pharmaceutical sciences, such as biochemistry, and an understanding of the main variations of DNA in the human genome. Recently, scientists took different measures to limit the cost of medical treatment worldwide. At the same time, large pharmaceutical companies develop fewer new active compounds than is necessary to maintain a growth rate (Relling & Evans 2015).

Pharmacogenomics will help identify the optimal “targets” for pharmacological effects, screening unpromising compounds at the preclinical stages of their development and selecting groups of patients for clinical trials. Several companies are already actively developing the newest pharmacogenomic preparations. According to pharmacology experts’ estimate, new drugs will take into account the individual reactions of the patient (Relling & Evans 2015). The first samples may appear in the next several years. The pharmacogenomics data will be used to increase therapeutic efficacy and reduce the risk of adverse reactions to the drugs that are already applied in clinical practice (Relling & Evans 2015).

Drug Allergy

Allergy is an immunological reaction of the body, accompanied by damage to its own tissues. The cause of allergic diseases is an allergen. It appears in certain conditions of the external environment and reactivity of the organism. Any drug can lead to the development of drug allergies. Drugs or their metabolites are haptens (Mayo n.d.).

The repeated use of the same or similar chemical structure and antigenic properties of drugs facilitates the development of drug sensitization. The ingestion of an antigen causes it. Even in children who have not previously received them, allergic reactions are possible because of ingestion through the placenta or mother’s milk (latent sensitization). Sensitization to medical drugs can persist for a long time and, as a rule, is polyvalent. It is an immunologically mediated increase of the body’s sensitivity to antigens (allergens) of exogenous or endogenous origin (Mayo n.d.).

Reactions can be pseudo-allergic in nature or caused by drug intolerance. The British Society of Allergy and Clinical Immunology (BSACI) defines drug allergy as an adverse reaction to drugs with an established immunological mechanism (Gotter 2018). Without a special investigation, it is not always possible to find out whether an allergy is the cause of an adverse reaction to the use of a pharmaceutical preparation. Drug allergy can manifest with anaphylactic shock. It is the immune response of the sensitized organism to an acutely developing critical circulatory dysfunction, resulting in insufficient tissue perfusion, reduced oxygen delivery, and nutritional substrates to tissues. This does not meet their needs for maintaining aerobic metabolism and leads to multiple organ failure syndrome and death. Medical aid must be given immediately. Firstly, we have to stop the intake of the allergen that triggered the reaction. If anaphylaxis is caused by intravenous injection of medicine, then removing the needle from the vein is counter-indicative. Secondly, we immediately call for help and inject adrenaline intravenously (Gotter 2018).

Post Exposure and Pre-Exposure Prophylaxis for HIV Infection

The post-exposure method is used after the risk of HIV infection has been altered. The prophylaxis includes taking antiretroviral drugs for the first three days after the risky contact. Prevention means preventing the risk of HIV transmission. Post-exposure prophylaxis is used when there is a risk of HIV transmission; it involves taking antiretroviral drugs used in the treatment of HIV infection as early as possible after the risk of HIV transmission so that this risk situation does not lead to transmission of the virus (Centers for Disease Control and Prevention 2016).

These drugs are available only by prescription, which only a doctor can fill. Post-exposure prophylaxis must be taken within the first 24-36 hours after the risk, but no later than 72 hours (Centers for Disease Control and Prevention 2016). You should take antiretroviral drugs for 4 weeks if there is no difficulty. It applies to healthcare workers who have a risk of transmitting HIV. The post-exposure course requires taking three medicines. Those are tenofovir (300 mg) with emtricitabine (200 mg) and raltegravir (400 mg twice a day) (Centers for Disease Control and Prevention 2016). However, before initiating prophylaxis, it is necessary to reconfirm the HIV status of the patient, since there is no information about the safety of complete ART for the body (Centers for Disease Control and Prevention 2016).

Pre-exposure prophylaxis is used for HIV-negative people with a high risk of HIV infection. They constantly take ART to protect themselves from the virus. Such people include HIV-negative partners in heterosexual and homosexual relationships. Clinical trial data has shown that pre-exposure prophylaxis is effective in protecting and preventing HIV. However, WHO (2012) recommends using it only associated with condoms and constant testing for HIV and sexually transmitted infections. They also insist on the importance of a strict schedule for taking medications. In the USA, pre-exposure prophylaxis is conducted with Truvada (tenofovir and emtricitabine) (Pebody 2018). There are several generics in other countries: Tenvir-EM (Cipla), Tavin EM (Emcure), and Tenof EM (Genx) (Pebody 2018).

Immunosuppressive Antibodies

Immunosuppressive therapy aims to inhibit unwanted immune reactions of the organism. It is used to treat autoimmune diseases, prevent rejection of the transplanted organ and in allogeneic transplantation. Immunosuppressive therapy entails an increased risk of infectious complications and should be combined with their reduction measures. The group of immunosuppressive drugs includes a broad range of medicines. Some of them are in the list of anticancer drugs (Pellegrino 2016).

Classification of immunosuppressive drugs (Pellegrino 2016):

Antimetabolites mercaptopurine, azathioprine, methotrexate, brequinar, mycophenolate mofetil, allopurinol
Alkylating compounds cyclophosphane, hlorbutin
Antibiotics cyclosporin A, tacrolimus chloramphenicol, antitumor (dactinomycin)
Alkaloids vincristine, vinblastine
GKS hydrocortisone, prednisone, dexamethasone
Antibodies anti-lymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal antibodies (OCT-3, Simulekt, Zenapax)
Derivatives of various groups of NSAIDs acetylsalicylic acid, paracetamol, diclofenac sodium, naproxen, mefenamic acid, etc.), Enzyme preparations (asparaginase), derivatives of 4-aminoquinoline (delagil), heparin, aminocaproic acid, gold preparations, penicillamine

The immunosuppression on cells of the immune system is nonspecific. Its influence is directed to the fundamental mechanisms of cell division and key stages of protein biosynthesis in various cells. Despite the universal cytostatic properties, immunosuppressants differ in the direction of action at certain stages of immunogenesis. It is important to consider while choosing a drug for each specific situation (Pellegrino 2016).

Immunosuppressive agents are recommended to appoint at the very beginning of the disease since the majority of true immunosuppressives have limited effect on the main mechanisms of the immune response. Some drugs that are used in chemotherapy are also applied for immunosuppression. The treatment of these patients’ categories is based on different principles. For autoimmune diseases and during transplantation, cytostatic is used daily in low doses. While the same drugs for chemotherapy are prescribed intermittently in large doses (Pellegrino 2016).

Drug Therapy to Prevent Mother-to-Child Transmission of HIV

HIV infection can transmit from mother to child intrauterine, intranasally, or through breastfeeding. The risk of infection of the newborn is closely related to the state of the mother, obstetric situations, and drug therapy. The prevention of vertical transmission of HIV infection aims to reduce the viral load in the mother’s blood to an undetectable level. The prevention of the newborn infection also focuses on protecting him from the mother’s biological fluids (AIDS Info 2017).

Centers for Disease Control and Prevention (2016) describe the reduction in the frequency of mother-to-child HIV transmission when initiating ART prior to pregnancy. They concluded that the later prevention began, the greater the chance of infection. Prevention of transmission of the virus should start as soon as a woman finds out about pregnancy. Ideally, she should plan a pregnancy and take an ART course before it. During pregnancy, the woman continues to take ART in the usual regimen (AIDS Info 2017).

WHO recommends taking tenofovir, lamivudine, and emtricitabine (Avert 2018). This allows controlling the number of copies of the virus in the blood and will not let it transmit to the child (Avert 2018). The changes are possible only if there is a threat to her health or the child’s condition. ART drugs do not have a pathological effect on the fetus. 2 weeks before giving birth, a pregnant woman must pass a viral load test. It is necessary to choose the tactics of childbirth. After the birth, the fetus receives zidovudine for 4-6 weeks for prophylaxis. If there is a need, then another drug can be added to treatment with zidovudine (AIDS Info 2017). In case if a child tests positive for HIV, ART must start immediately. Infants usually receive nevirapine. The infant receives it simultaneously with his mother. The therapy duration depends on the type of feeding (Avert 2018).