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Does Remdesivir cause bone marrow suppression?

Does Remdesivir cause bone marrow suppression?



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According to Wikipedia, Remdesivir is a prodrug of GS-441524 which is a nucleoside analog.

I know that nucleotides are the building blocks of both DNA and RNA, meaning nucleotide analogues that prevent the creation of viral RNA can also prevent the creation of normal cell DNA, meaning they can cause problems in dividing cells. This is also reflected in the nucleotide analogue article of Wikipedia:

They are not specific to viral DNA and also affect mitochondrial DNA. Because of this, they have side effects such as bone marrow suppression.

So does Remdesivir cause bone marrow suppression?

If not please explain why.


From Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent:

Overall, the cellular and biochemical assays demonstrated a low potential for RDV to elicit off-target toxicity, including mitochondria-specific toxicity, consistent with the reported clinical safety profile.

This isn't a very complete answer, but the wikipedia article doesn't go into detail or link references explaining the mechanism by which nucleoside analogues suppress bone marrow function. So I can't say if the assay results in my link rule out a suppression effect by remdesivir


Viruses and bone marrow failure

Some generalizations can be drawn from a review of virus-associated bone marrow failure. The story of B19 parvovirus illustrates that viral infection may be an occult cause of marrow failure. Although the epidemiology of transient aplastic crisis suggested a viral aetiology, the implication of a single virus was surprising the sporadic appearance of chronic bone marrow failure in immunosuppressed persons has had none of the features of a viral illness. The incrimination of parvovirus in these cases required development of specific immunological and molecular assays. Human and animal retrovirus studies have shown that small changes in the virus genome can have dramatic effects on the biology of the infectious agent and its pathogenicity in infected hosts. In Epstein-Barr virus infection, the host's immune response may play a more important role in mediating disease than virus cytotoxicity. Finally, the association of aplastic anaemia with hepatitis may be underestimated because of the inability to diagnose virus infection without obvious liver disease. The true spectrum of bone marrow disease due to virus infection is not known.


Hematologic toxicity of immunosuppressive treatment

The administration of immunosuppressive agents may be associated with the occurrence of hematologic toxicity, such as anemia, due to bone marrow suppression or hemolysis, leukopenia, and thrombocytopenia. The administration of azathioprine and mycophenolate mofetil is more frequently associated with bone marrow suppression, while hemolytic-uremic syndrome may occur after administration of cyclosporine, tacrolimus, or muromonab (OKT3) and may be associated with the loss of the allograft. Moreover, microangiopathic hemolytic anemia and thrombocytopenia are rare, but potentially severe, complications of immunosuppressive treatment with tacrolimus and cyclosporine they are characterized by intravascular hemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. Viral infections (cytomegalovirus), administration of antiviral agents (gancyclovir), inhibitors of angiotensin-converting enzyme and angiotensin II receptor antagonists, antibacterial agents (sulfamethoxazole and trimethoprim), and allopurinol may aggravate bone marrow suppression, particularly when administered with agents that interfere with purine biosynthesis, including azathioprine and mycophenolate mofetil.


Neutropenia

DIFFERENTIAL DIAGNOSIS

Bone marrow failure syndromes, including aplastic anemia and Fanconi anemia, and diseases involving bone marrow infiltration, such as malignancy or Gaucher disease, can initially present with neutropenia. Therefore, isolated neutropenia does not rule out global bone marrow dysfunction. Neutropenia is a complication of several metabolic diseases, particularly glycogen storage disease type IB. Pearson syndrome, a rare disorder in which there is bone marrow failure (typically anemia) and exocrine pancreatic insufficiency, should be considered whenever Shwachman-Diamond syndrome is diagnosed. In some cases, it is not possible to identify the underlying cause of a patient's neutropenia. The term chronic benign neutropenia has been used to describe neutropenia with an unclear cause in children with no history of severe or unusual infections.


Essay on the Treatment of Cancer | Diseases | Medical Science

In this essay we will discuss about the drugs that are used for the treatment of cancer.

Essay # 1. Cytotoxic Drugs:

The aim of chemotherapy of malignant disease is to kill the malignant cells without any harm to normal cells. Unfortunately, the metabolic process of the malignant cells and normal cells is so very similar or even the same, that cytotoxic drug also kill/damage the normal cells.

The cytotoxic drugs mainly act on rapidly dividing cells by interfering the functions of DNA and RNA. DNA is the vital component of the cell nucleus and is concerned with the cell division (mitotic phase). DNA contains the code, which determines the type of protein to be manufactured by RNA in the cytoplasm and thus ultimately the cell functions. The cells, which do not divide, are very resistant to chemotherapy.

Although the individual cytotoxic drug has its own toxicity, the commonly encountered side effects with cytotoxic drugs, in general, are on the cells of bone marrow, the lymphatic system and lining of the intestinal tract, which have a high rate of turnover. These result in nausea and vomiting, bone marrow suppression (vincristine and bleomycin exceptions) and alopecia.

Most cytotoxic drugs are teratogenic and should not be given during pregnancy, especially during the first trimester. Cytotoxic drugs fall into a number of classes, each with characteristic antitumour activity, sites of action, and toxicity.

iv. Platinum-containing drugs

vi. Miscellaneous cytotoxic drugs.

I. Alkylating Drugs:

These are chemically very active drugs, which are among the most widely used in cancer chemotherapy. They act by damaging DNA in the cell nucleus (cause DNA cross-linking and strand breaks), thus interfering with cell replication. Most alkylating drugs are cytotoxic to resting and dividing cells.

In addition to the side-effects common to many cytotoxic drugs, there are two problems associated with their prolonged usage. Firstly, they may cause irreversible sterility. Secondly, prolonged use of these drugs, particularly when combined with extensive radiation, is associated with a marked increase in the incidence of acute non-lymphocytic leukemia.

Chlormethine (mustine) is a very toxic drug and is now much less used in Hodgkin’s disease. Nausea and vomiting and bone marrow depression usually affecting the white cells and platelets are common side effects.

Cyclophosphamide is inactive until metabolized by the liver into cytotoxic metabolites. It is widely used in the treatment of chronic lymphocytic leukemia, the lymphomas, and solid tumors in combination with other cytotoxic drugs.

Depression of bone marrow and loss of hair are common side effects. A urinary metabolite, acrolein, can cause hemorrhagic cystitis, which is a very serious complication and can be avoided by giving a high fluid intake or combining it with mesna. Mesna reacts specifically with the urinary metabolite, preventing toxicity.

Ifosfamide is related to cyclophosphamide and is given intravenously. It is less damaging to the bone marrow, but more likely to damage the kidneys, bladder and CNS. Mesna is routinely given with it to reduce hemorrhagic cystitis. It is contraindicated in hepatic impairment.

Chlorambucil is commonly used to treat chronic lymphocytic leukemia (drug of choice), the indolent non-Hodgkin’s lymphomas, Hodgkin’s disease and ovarian cancer. Side effects, apart from bone marrow depression, are uncommon.

Chlorambucil is one of few cytotoxic drugs which are used continuously orally on an outpatient basis. The only contraindication to its use is rare widespread rashes which can even lead to toxic epidermal necrosis.

Melphalan is particularly used to treat myeloma and occasionally solid tumours and lymphomas. It is a powerful depressant of white cells and platelets and is usually given orally for a week, with further courses at intervals of 4-6 weeks monitored by blood count.

Busulfan is used almost exclusively to treat chronic myeloid leukaemia where it has a selective depressant action on abnormal white cells.

Busulfan causes myelosuppression which may result in irreversible bone marrow aplasia, hence treatment requires frequent blood counts. Hyperpigmentation of the skin and fibrosis of lungs are other side effects.

Lomustine is used mainly to treat Hodgkin’s disease and certain solid tumours. Bone marrow depression may occur which is delayed and the drug is given orally at intervals of 4-6 weeks. Apart from bone marrow depression, nausea and vomiting are common.

Carmustine has similar activity and toxicity to lomustine and is mainly used intravenously to treat myeloma, lymphoma and brain tumours. Renal damage and delayed pulmonary fibrosis may occur.

Estramustine is a combination of an estrogen and chlomethine (mustine). The drug concentrates in tissues that have estrogen receptors and both the estrogen and the cytotoxic chlormethine attack the cancer cell.

It is given by mouth in some cases of prostate cancer where it has both an antimitotic effect and (by reducing testosterone concentration) a hormonal effect. Unlike many other cytotoxic drugs estramustine does not destroy the DNA.

Estramustine causes gynecomastia because of the estrogenic effect, and heart and liver toxicity. It is contraindicated in heart and liver disease, and in patients with peptic ulcer.

Thiotepa is usually used as an intra-cavity drug for the treatment of malignant effusions or bladder cancer. Occasionally, it can be used to treat breast cancer, but requires IV administration.

Ii. Antimetabolites:

These are drugs which chemically have a similarity to the naturally occurring substances used by the cells for their metabolic processes. They, thus, become incorporated into nuclear material or combine with vital cellular enzymes and because they cannot be metabolized, the normal cellular division does not take place.

Many antimetabolites resemble the purines or pyrimidine’s, which are the building blocks of DNA. They become incorporated in growing strand of DNA, interrupting replication. Their greatest toxicity occurs in tissues that are actively replicating, e.g. GI mucosa, hematopoietic cells.

Methotrexate is similar in structure to folic acid and inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines. It is given orally, intravenously or intrathecally. It is excreted by the kidneys and should be used with caution in renal impairment.

Methotrexate is used as maintenance therapy for childhood acute lymphoblastic leukaemia. It is also used in choriocarcinoma, non- Hodgkin’s lymphoma and a number of solid tumours. Intrathecal methotrexate is used in meningeal cancer or lymphoma.

In certain types of malignant disease, a large and potentially lethal dose of methotrexate is given, which is followed 24 hours after by folinic acid to reverse the action of methotrexate. This method is known as folinic acid rescue.

Methotrexate in low doses is used as immunosuppressant in rheumatoid arthritis and psoriasis. Bone marrow depression, liver damage, mouth ulceration (mucositis) and rarely pneumonitis may occur. Methotrexate is contraindicated in significant renal and severe hepatic impairment.

Mercaptopurine structurally resembles adenine and hypoxanthine and prevents cell division by competing with them. It is almost exclusively used for the maintenance therapy of acute leukaemia. Azathioprine, a derivative of mercaptopurine is used as an immunosuppressant in a number of autoimmune diseases, when corticosteroid therapy is ineffective. Side effects include depression of normal white cells. Hepatic cholestasis has also been observed.

Tioguanine is given orally to induce remissions in acute myeloid leukaemia. It is excreted by kidneys and should be used cautiously in renal impairment. Fluorouracil is pyrimidine antagonist which is given orally or intravenously to treat a number of solid tumours, including GIT cancers and breast cancer. It is commonly used with folinic acid in advanced colorectal cancer. It can also be applied locally in certain malignant and premalignant skin lesions. Toxicity is unusual, but may include myelosuppression, mucositis and rarely a cerebellar syndrome.

Cytarabine is pyrimidine antagonist and is mainly used to induce remissions in acute myeloblasts leukaemia. It is a potent myelosuppressant and treatment is guided by periodic blood counts. Raltitrexed blocks one of the enzymes involved in DNA synthesis, namely thymidylate synthetase. It is given intravenously for palliation of metastatic colorectal cancer, when drugs such as fluorouracil cannot be used. It is generally well tolerated but can cause gastrointestinal side effects and myelosuppression. It should be used cautiously in hepatic and renal impairment.

Fludarabine is an adenosine monophosphate analog that is used for B-cell chronic lymphocytic leukaemia, when treatment with an alkylating drug has failed. Though well tolerated, fludarabine may cause myelosuppression and immunosuppression. Gemcitabine is a nucleoside analog that is used for palliative treatment of locally advanced or metastatic non-small cell lung and pancreatic cancer. Though, generally well tolerated but may cause fever, edema, flu-like syndrome and rash. It should not be used concurrently with radical radiotherapy.

Iii. Plant Alkaloids:

These are naturally occurring nitrogenous bases. Most inhibit cell division through inhibition of mitotic spindle formation.

Vinca Alkaloids:

Vinblastine, vincristine, and vindesine are the alkaloids derived from periwinkle plant. Vinca alkaloids act by interfering with the assembly of DNA proteins during mitotic phase and thus the cell division does not occur. Vinca alkaloids are used to induce remissions in acute leukaemia and to treat lymphomas and some solid tumours, e.g. breast and lung cancer. Vinorelbine, a semisynthetic vinca alkaloid, is used in advanced breast cancer when anthracycline antibiotics are ineffective and in advanced non-small cell lung cancer.

Vinca alkaloids are highly toxic and are associated with neurological manifestations such as peripheral or autonomic neuropathy which may result in peripheral paraesthesia and loss of deep tendon reflexes, abdominal pain and constipation. Leucopenia (vincristine causes negligible myelosuppression) and irreversible alopecia is common. Extravasation causes severe local irritation and local tissue necrosis.

Etoposide is related to podophyllin, an extract of mandrake. It prevents cell division and is particularly useful in small cell carcinoma of the bronchus, the lymphomas and testicular cancer. Myelosuppression is the major dose-limiting toxicity.

Taxanes- Paclitaxel (Taxol) and Docetaxel (Taxotere) are obtained from yew. They inhibit cell division in the mitotic phase. They are highly toxic and given by IV infusion in advanced ovarian cancer and for secondary treatment of breast cancer, when other regimes have failed.

Premedication with dexamethasone and H1 and H2 blockers is required to prevent hypersensitivity reactions. Myelosuppression, peripheral neuropathy, arthralgias and arrhythmias are important side effects.

Irinotecan and topotescan are derivatives of an extract from tree bark and are chemically related to taxanes. They inhibit cell division by inhibiting topoisomerase I, an enzyme involved in DNA replication. They are given by IV infusion.

Irinotecan is indicated in metastatic colorectal cancer when treatment containing fluorouracil has failed. Topotescan is indicated in metastatic ovarian cancer when other therapies have failed. Side effects include dose-limiting myelosuppression, delayed diarrhea and asthenia.

Iv. Platinum-Containing Drugs:

These drugs prevent cell division by a direct action on the DNA itself, causing single and double-strand breaks in DNA. Cisplatin has an alkylating action. It is effective in a number of solid tumours, particularly in ovarian cancer and testicular teratoma. It is a highly toxic drug.

Side effects include severe nausea and vomiting, nephrotoxicity, myelotoxicity, ototoxicity, peripheral neuropathy, and hypo- magnescemia. Carboplatin, a derivative of cisplatin, is equally effective in ovarian cancer. It is also active in small cell lung cancer. It is better tolerated than cisplatin, but is more myelsuppressive. Oxaliplatin is effective in colorectal cancer and its use is associated with a sensory neuropathy.

V. Cytotoxic Antibiotics:

Cytotoxic antibiotics inhibit cell division in several ways by binding to the DNA, by inhibiting the adjacent DNA nucleotides interrupting DNA replication and transcription to cause strand breaks. They act as radiomimetics and simultaneous use of radiotherapy should be avoided. Cytotoxic antibiotics, in addition to the usual toxicity of cytotoxic drugs (e.g. nausea and vomiting, myelosuppression, mucositis and alopecia), are associated with cardiomyopathy consisting of intractable congestive heart failure and arrhythmias.

Doxorubicin (adriamycin) is the most successful and probably the most widely used cytotoxic antibiotics in acute leukaemias, lymphomas and a variety of solid tumours. It is also given by bladder instillation. A liposomal formulation is indicated for Kaposi’s sarcoma in AIDS patients. Doxorubicin is rapidly taken up by all tissues except brain, highest concentrations being found in thyroid, liver and heart. The drug is largely excreted by the biliary tract.

Mitoxantrone and epirubicin are structurally related to doxorubicin and are useful in the treatment of a variety of cancers. The incidence of adverse effects is relatively low and can be used on an outdoor basis.

Idarubucin is more rapidly taken up in cells than doxorubicin and may replace it in the treatment of acute leukaemias and advanced breast cancer. It can also be given by mouth.

Daunorubicin has also similar properties to those of doxorubicin and is used to treat acute leukaemias and Kaposi’s sarcoma in AIDS patients. Mucositis is dose-limiting toxicity.

Bleomycin has a relatively weaker anticancer activity and is used in combination to treat lymphomas and testicular cancers.

Unlike other anticancer drugs, bleomycin does not depress the bone marrow. Common side effects include dermatological toxicity, hypersensitivity reactions and progressive pulmonary fibrosis which may be fatal. Since, the drug is mainly excreted unchanged by the kidneys it should be used with caution in renal impairment.

Mitomycin alkylates DNA and has actions like alkylating drugs. It is given intravenously to treat upper GIT and breast cancers and superficial bladder tumours (bladder instillation).

Mitomycin causes delayed bone marrow toxicity and therefore, it is usually administered at weekly intervals. Prolonged use may cause permanent bone marrow damage, lung fibrosis and renal damage.

Vi. Miscellaneous Cytotoxic Drugs:

There are more than one dozen drugs of diverse chemical structure, which are used as a second line of treatment and/or as combination therapy in most forms of malignant disease.

Crisantaspase is the enzyme asparaginase which causes cessation of protein synthesis and cellular death. It is exclusively used for acute lymphocytic leukaemia. Adverse effects are common and include anaphylaxis, nausea, vomiting, CNS depression and liver function and blood lipid changes.

Dacarbazine is mainly used in treating melanomas and in combination therapy in Hodgkin’s disease. It is highly irritant and is given very slowly intravenously. Adverse effects are severe bone marrow depression and intense nausea and vomiting.

Hydroxycarbamide (Hydroxyurea) is an orally active drug and is used mainly for chronic myeloid leukemia. It can also be used in polycythemia (the usual treatment is venesection). Reversible myelosuppression is the major side effect. GIT and cutaneous disturbances occasionally occur.

Procarbazine is an oral agent that inhibits DNA, RNA, and protein synthesis. It is most often used as a combination therapy (MOPP — mustne, vincristine, procarbazine and prednisolone) in Hodgkin’s disease. Toxic effects include nausea, myelosuppression and a hypersensitivity rash preventing further use of the drug. It is a mild monoamine oxidase inhibitor and causes disulfiram-like reaction with simultaneous ingestion of alcohol.

Drugs for Cytotoxic Induced Side Effects:

One of the common disadvantages of chemotherapy is nausea and vomiting. Nausea and vomiting depends on individual patient susceptibility and on the drug being administered. Many patients will respond to pretreatment with oral phenothiazines, metoclopramide and dexamethasone.

ii. 5-Hydroxytriptamine (Serotonin, 5-HT) Antagonists:

A specific 5-HT3 antagonist is a drug of choice for patients at a high risk of emesis with most severely cytotoxic emetic drugs, e.g. cisplatin, or when other antiemetic therapies are ineffective. It is believed that potent cytotoxic emetic drugs stimulate the 5-HT3 receptors in GIT and brain stem. Granisetron or ondansetron or tropisetron (5-HT3 antagonists) combined with dexamethasone are most effective in controlling early emesis of cytotoxic drugs. The 5-HT3 antagonists may be less effective for the control of delayed emesis.

iii. Mucositis (Mouth Ulceration):

Mucositis is due to the direct effect of cytotoxic drugs on the mucous membrane of the mouth and also due to general suppression of immunity (myelosuppression) which encourages the infection.

Fall in white blood cell count may result in candidal (fungus) infection of the mouth which can be treated by nystatin oral suspension or fluconazole and chlorhexidine (corsodyl) mouth wash.

Methotrexate induced mucositis can be counteracted by folinic acid or levofolinic acid. If ulceration develops, the pain can be relieved by a local anaesthetic benzydamine oral rinse.

iv. Bone Marrow Suppression (Myelosuppression):

Cytotoxic drugs except vincristine and bleomycin cause bone marrow suppression. This usually occurs after 7-10 days but may be delayed. Giving bone marrow growth factors can minimise the myelosuppression. These are recombinant human granulocyte- colony stimulating factor (rhG-CSF). Filgrastim or lenograstim increases the production of neutrophils.

Molgramostim (recombinant human granulocyte macrophase-colony stimulating factor) stimulates the production of all granulocytes and monocytes.

Reversible hair loss is a common complication particularly with doxorubicin, etoposide and ifosfamide. No pharmacological methods are available to prevent this complication.

vi. Reproductive Functions:

Most cytotoxics may cause permanent sterility in man and reversible amenorrhoea in women. They are teratogenic and should not be administered during the first trimester.

Essay # 2. Hormones and Hormone Antagonists:

Hormonal therapy has an important role in the treatment of cancer because it causes tumour regression in some cancers. Unlike cytotoxic drugs, it lacks direct cytotoxicity. Hormonal treatments are not curative, but may provide excellent palliation of symptoms, sometimes for a period of years.

Corticosteroids:

Prednisolone, a synthetic glucocorticoid, is widely used in malignant disease. It has a marked antitumour action in acute lymphoblastic leukaemia, Hodgkin’s disease and the non-Hodgkin lymphomas. It is also useful in causing tumour regression in hormone-responsive breast cancer. It is a part of palliative care in end-stage malignant disease as it lifts the patient’s mood and produces a sense of well-being.

Sex Hormones:

Sex hormones are useful in providing remissions in selected patients with the metastatic breast, prostate, and endometrial cancer and renal cell carcinoma.

Estrogens:

Estrogens are now rarely used, although diethylstilbestrol (synthetic estrogen) and its prodrug (fosfestrol) are occasionally used in prostate cancer and ethinylestradiol for breast cancer.

Progestogens:

Medroxyprogesterone and megestrol acetate are the most popular progestogens, which are used orally for endometrial cancer, renal cell carcinoma and as second or third- line treatment for breast cancer. They have also been used for the treatment of cachexia (a profound and marked state of constitutional disorder general ill health and malnutrition) associated with AIDS. Side effects are minor and include occasional nausea, weight gain and fluid retention.

Androgens:

Androgens are occasionally still used as second-or third-line treatments for breast cancer. However, their use is associated with many problems and contraindications.

Sex hormones, now more or less, are seldom indicated in the treatment of breast and prostate cancer, because the safer approach is to block the actions of sex hormones (estrogens and testosterone) at their receptors, which has been made possible with the availability of hormone antagonists.

Hormone Antagonists:

Hormone antagonists are oestrogen receptor antagonists and androgen receptor antagonists as well as the drugs which prevent the production of estrogens and testosterone and have virtually replaced the sex hormones in the treatment of hormone-responsive breast cancer and prostate cancer. In general, hormone antagonists have few serious adverse effects.

Breast Cancer:

Tamoxifen is a non-steroidal estrogen receptor antagonist. It is the adjuvant hormonal treatment of choice, particularly in estrogen dependant breast cancer.

Tamoxifen has also been reported to reduce the incidence of breast cancer in normal women at high risk.

Tamoxifen is also prescribed for anovulatory sterility, when the drug is taken on days 2, 3, 4 and 5 of the menstrual cycle.

Side effects are mild and include occasional nausea, hot flushes, fluid retention and a hormone flare (bone pain and hyercalcemia) which subsides within 7-10 days. Tamoxifen is contraindicated in breast-feeding and before planned pregnancy.

Long-term use of tamoxifen carries the risk of endometrial cancer. Toremifene, also an estrogen receptor antagonist, is used to treat hormone-dependent metastatic breast cancer in postmenopausal women. Aromatase inhibitors inhibit the conversion of androgens to estrogens in the peripheral tissues.

The first- and second-generation aromatose inhibitors inhibit the steroid synthesis in adrenals and require corticosteroid replacement therapy. Third generation aromatose inhibitors are better tolerated and are more specific since they do not suppress adrenal Cortisol production and are used in the treatment of advanced hormone-responsive breast cancer in postmenopausal women.

Two non-steroidal agents, anastrazole and letrozole and one steroidal agent, exemestane are the third generation aromatase inhibitors that have been found to be active in hormone-sensitive breast cancer. They may be slightly more effective than tamoxifen. Side effects are usually minimal and include hot flashes and night sweats, but thrombotic episodes may occur.

Prostate Cancer:

Prostatic carcinoma with metastases, usually, responds to hormonal treatment which deprives the cancer of androgen. With the availability of androgen receptor antagonists and better understanding of gonadotrophin-releasing hormone (GnRH), the treatment is generally carried out by drugs instead of bilateral sub-capsular orchidectomy. GnRH fgonadorelin) causes the release of LH and FSH from the anterior lobe of the pituitary gland. If, however, GnRH is given as a continuous treatment, it shuts down the production of luteinising hormone (LH) and therefore of testosterone.

Leuprolide and gosereljn are the commonly used GnRH synthetic analogues as monthly SC depot injection for the treatment of metastatic prostate cancer. They cause initial stimulation of LH release by the pituitary, which in turn causes testerone secretion from the testes this is followed by inhibition of LH release release, thus effectively shutting down testerone production.

During the first 1 to 2 weeks of therapy a number of patients develop a tumour “flare” which may cause spinal cord compression or increased bone pain. To avoid initial flare in tumour symptoms, anti-androgen treatment is started 3 days before GnRH agonists and continued for 3 weeks. Other side effects of GnRH analogues are similar to those of orchiectomy.

Androgen Receptor Antagonists:

Flutamide and bicalutamide block the actions of androgens at their receptor sites. They are used alone or with other treatment for prostate cancer. They should be prescribed before treating patients with GnRH agonists to cover the tumour “flare” which may occur with GnRH analogues, due to an initial release of testosterone from the testes before shutting them down.

Essay # 3. Immunotherapy:

Like hormonal therapy, immunotherapy provides an improvement in survival compared to chemotherapy alone in metastatic disease. They are, in fact, immunosuppressant which affects the immune response involved in cellular growth, cell proliferation and survival. Immunotherapeutic agents may be selective or nonspecific. Selective immunotherapy include biologies consisting of monoclonal antibodies, most of which are partially humanized.

Trastuzumab is a monoclonal antibody protein that binds to and inactivates a receptor called human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in many cancers, especially breast, lung, ovarian and prostate, and overexpression of HER2 is associated with a poor prognosis.

Trastuzumab is used in patients with metastatic breast cancer with paclitaxel in whom other approaches have failed. Side effects include IV infusion-related symptoms, hypersensitivity reactions and delayed GI upsets, and cardiotoxicity.

Rituximab and alemtuzumab are both monoclonal antibodies that block the lysis of B lymphocytes. Rituximab is used to treat diffuse large B cell non-Hodgkin’s lymphoma in conjunction with other chemotherapeutic drugs an advanced follicular lymphoma that is resistant to other chemotherapies.

Alemtuzumab is used for patients with chronic lymphocytic leukemia who have failed to respond to other treatments. Both the drugs can give rise to IV infusion related adverse effects, which requires prior administration of antihistamines and corticosteroid, especially with rituximab.

Nonspecific Immunotherapy:

Interferon-alpha is used for rare hairy-celled leukemia, chronic myelogenous leukemia and melanoma. Side effects include nausea and vomiting, flu-like symptoms and headaches. Aldesleukin (interleukin-2 prepared using recombinant DNA technology) produces remissions in melanoma and metastatic renal cell carcinoma. It is extremely toxic to several organs, including the thyroid, bone marrow, liver, kidney and brain.


Most Common Bone Marrow Diseases

Leukemia

Leukemia is a type of cancer that occurs in the white blood cells of the blood, so it is also known as white blood cell cancer. As in all cancers, the disease occurs because too many cells are created uncontrollably.

White blood cells, which can be Granulocytes or Lymphocytes , Develop in the bone marrow from stem cells. The problem that occurs in leukemia is that the stem cells are not able to mature into white blood cells, they stay in an intermediate step called leukemia cells.

The leukemic cells do not degenerate, so they continue to grow and multiply uncontrollably, occupying the space of red blood cells and platelets. Therefore, these cells do not perform the function of white blood cells and, in addition, prevent the correct functioning of the rest of blood cells.

The main symptoms of patients with leukemia are bruising and / or bleeding with any blow and the continuous feeling of being tired or weak.

In addition, they may suffer from the following symptoms:

  • Difficulty breathing.
  • Pallor.
  • Petechiae (flat spots under the skin caused by bleeding).
  • Pain or feeling of satiety under the ribs on the left side.

The prognosis of this disease is better as fewer mother cells Have become leukemic cells, therefore, it is very important to see your doctor if you feel some of the symptoms to make an early diagnosis.

Treatment depends on the type of leukemia, age and patient characteristics. Possible treatments include the following:

  • Chemotherapy.
  • Directed therapy (molecularly).
  • Radiotherapy.
  • Stem cell or bone marrow transplantation.

Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) include a number of diseases that affect the bone marrow and blood. The main problem of these syndromes is that the bone marrow each time produces less blood cells, even stopping production altogether.

Patients suffering from MDS may have:

  • Anemia due to low levels of red blood cells.
  • Infections as they increase the odds due to low levels of white blood cells.
  • Bleeding due to low platelet levels.

There are several types of MDS, some are mild and can be easily treated, while others are serious and may even evolve into a leukemia called acute myelogenous leukemia.

Most people with this disease are over 60 years old, although it can appear at any age. Some factors can increase the likelihood of suffering from this disease, such as exposure to industrial chemicals or radiation. In some cases, the MDS is produced by the chemotherapy treatment that the person was following to treat another disease.

The symptoms depend on the severity of the disease. It is usual that at the onset of the disease no symptoms are felt and yet the disease is diagnosed because problems are found in a routine analytic. It is therefore very important to have periodic check-ups.

The general symptoms are similar to those of leukemia and include tiredness, shortness of breath, pallor, ease of infection and bleeding.

Treatment usually begins with medications and chemotherapy , Although in many cases a blood transfusion or a bone marrow transplant is necessary.

Myeloproliferative disorders

Myeloproliferative disorders are a heterogeneous group of diseases characterized by the excessive production of one or more types of blood cells (red blood cells, white blood cells or platelets).

Patients suffering from this type of disorder are more likely to have thrombi and bleeding. In addition, they may end up developing acute leukemia due to both underlying disease and treatment.

The symptoms and signs that can be experienced by patients who have these disorders are as follows:

  • Tiredness and weakness.
  • Weight loss, early satiety or even anorexia, especially if they suffer from chronic myelogenous leukemia or agnogenous myeloid metaplasia.
  • Bruising, bleeding or thrombus easily.
  • Inflammation and joint pain. , Tinnitus The stupidity of leucostasis. And / or ecchymosis (purple coloration).
  • Spleen and / or palpable liver.
  • Acute febrile neutrophilic dermatosis o Sweet's syndrome (Fever and painful injuries to the trunk, arms, legs and face).

4 - aplastic anemia

Aplastic anemia is a rare blood disease that can become very dangerous. This disease is characterized by the bone marrow of people suffering from aplastic anemia, is unable to produce enough blood cells.

This disease occurs because bone marrow stem cells are damaged. There are several factors that can affect the stem cells, in addition these conditions can be both hereditary and acquired, although in many cases it is not known what the cause is.

Among the acquired causes we can find the following:

  • Intoxication with substances such as pesticides, arsenic or benzene.
  • To receive radiotherapy Or chemo.
  • Take certain medications.
  • Suffer some infections such as hepatitis, Epstein-Barr virus or HIV.
  • Suffer an autoimmune disease.
  • Be pregnant.

This disorder is progressive, therefore, the symptoms are getting worse as time passes. At the onset of the disease, people diagnosed with aplastic anemia suffer from symptoms such as tiredness, weakness, dizziness, and difficulty breathing. In more severe cases they may have heart problems such as arrhythmia or heart failure. In addition, they can suffer frequent infections and bleeding.

The diagnosis of this disease is based on the personal and family history of the person, a medical examination and some medical tests such as blood tests.

The treatment should be individualized for the person, but in general, it usually includes blood transfusions, bone marrow transplants and / or medicines.

Iron deficiency anemia

Iron deficiency anemia occurs when red blood cell levels are very low or they do not work well. This type of anemia is the most common and is characterized because the cells of our body do not get enough iron through the blood.

The body uses iron to make hemoglobin , A protein that is responsible for transporting oxygen through the bloodstream. Without this protein the organs and muscles do not get enough oxygen, that prevents them from burning the nutrients to get energy and, therefore, can not function efficiently. In short, the lack of iron in the blood causes the muscles and organs to malfunction.

Many people who suffer from anemia do not even realize they have any problems. Women are at increased risk for this type of anemia due to blood loss during menstruation or pregnancy.

This disease can also occur because the person does not take enough iron in his diet or some intestinal diseases that cause problems absorbing iron.

Treatment depends on why the anemia has been caused, but usually involves a change of Diet and iron supplements .

6- Plasma cell neoplasia

Plasma cell neoplasms are diseases that are characterized because the bone marrow makes too many cells of this type. Plasma cells are developed from B lymphocytes , Which in turn have matured from stem cells.

When some external agent (such as viruses or bacteria) enter our body, lymphocytes usually become plasma cells, because they create antibodies to fight infection.

The problem for people suffering from these disorders is that their plasma cells are damaged and divide uncontrollably, these damaged plasma cells are called myeloma cells.

In addition, myeloma cells give rise to a protein that is useless for the body, since it does not act against infections, protein M. The high density of these proteins causes the blood to thicken. Also, because they are useless, our body is continually discarding them, so they can cause kidney problems.

Continuous reproduction of plasma cells causes tumors to appear, which may be benign or may develop in cancer.

Neoplasms include the following conditions:

  • Monoclonal gammopathy of uncertain significance (MSG). This pathology is mild, as abnormal cells represent less than 10% of blood cells and do not usually develop cancer. In most cases, patients do not notice any type of sign or symptom. Although there are more serious cases in which they can suffer nervous, cardiac or renal affections.
  • Plasmocytoma. In this disease, anomar cells (myelomas) are stored in the same site, so they create a single tumor called plasmacytoma. There are two types of plasmacytomas:
    • Plasmacytoma of bone. In this type of plasmocytoma, as its name implies, the tumor is created around a bone. Patients usually do not notice other symptoms apart from those due to the tumor itself, such as fragility in the bones and localized pain, although in some cases it may be aggravated over time and may lead to the development of multiple myeloma.
    • Extramedullary plasmacytoma. In this case, the tumor is not located in a bone, but in some soft tissue such as the throat, amygdala or paranasal sinuses. The symptoms suffered by patients with this type of plasmacytoma, depend on the exact location where the tumor is located. For example, a plasmacytoma in the throat may cause difficulties in swallowing.
    • Pain located in the bones.
    • Bone fragility.
    • Fever without a known cause or frequent infections.
    • Presence of bruising and bleeding with ease.
    • Difficulty breathing.
    • Weakness in extremities.
    • Extreme and continuous tiredness.

    If tumors occur in the bones they can cause Hypercalcemia , Ie too much calcium in the blood. This condition can cause serious problems such as loss of appetite, nausea and vomiting, thirst, frequent urination, constipation, tiredness, muscle weakness and confusion or difficulty concentrating.


    AskScience AMA Series: COVID Variants and Vaccines - We are a physician scientist and emergency physician, ask us anything!

    We will be answering your questions related to the latest information about COVID variants and vaccines starting 11a ET (15 UT). We want to bring clarity to the available science and data based on what is currently known.

    • Gregory A. Poland, M.D., FIDSA, MACP, FRCP (London) is a physician-scientist and the founding and current director of Mayo Clinic's Vaccine Research Group - a state-of-the-art research group and laboratory that seeks to understand genetic drivers of viral vaccine response and application of systems biology approaches to the generation of immunity, as well as the development of novel vaccines against emerging pathogens important to public health. The Poland lab developed the field of viral vaccine immunogenetics, the immune response network theory, and the field of vaccinomics and adversomics. Dr. Poland holds the academic rank of professor of medicine and infectious diseases and molecular pharmacology and experimental therapeutics. He is the Distinguished Investigator of the Mayo Clinic, and is the Editor-in-Chief for the journal Vaccine.
    • Elizabeth P. Clayborne, MD, MA Bioethics is an Adjunct Assistant Professor at the University of Maryland School of Medicine Department of Emergency Medicine with an academic focus on ethics, health policy, end of life care, health disparities, and innovation/entrepreneurship. She developed a novel epistaxis device, bleedfreeze.com, as a resident and in 2015 was awarded the NSF I-Corps grant which helped to launch her company Emergency Medical Innovation, LLC. She is the former Chair of the MedChi Committee on Ethics and Judicial Affairs, serves on the Ethics Committee of the American College of Emergency Physicians and is an active member of the Society of Academic Emergency Medicine, the American Medical Association and the National Medical Association. Please follow her on Twitter and [email protected]
    • Medscape is the leading online global destination for physicians and healthcare professionals worldwide, offering the latest medical news, expert perspectives, and relevant professional education and CME. Twitter @[email protected]

    Poland and Clayborne sit on the steering committee for Medscape Education's Neutralizing the Pandemic Clinical Advances center, a clinician resource offering expert commentaries, CME opportunities, and new insights that aim to improve health outcomes for all patients. https://www.medscape.org/sites/advances/neutralizing-antibodies

    Posted: 12 May 2021 10:13 AM PDT

    Wind aside, and assuming the satellite's altitude adjusts to counteract the weight of the extremely long rope to maintain geo-stationary orbit, could this actually happen?

    Posted: 12 May 2021 10:09 PM PDT

    Not sure if linking an article is allowed or if this is the right subreddit for this but this is the article in question- https://phys.org/news/2020-01-rna-effect-dna.html?_escaped_fragment_=&deviceType=desktop#:

    I'm just really confused by this article. It makes almost no sense to me and I thought I understood the science of protein creation relatively okay. If RNA is modified then it wouldn't enter the nucleus right? I thought RNA was a one-direction thing, once it's made it leaves the nucleus never to return.

    Posted: 12 May 2021 11:31 AM PDT

    I have been recently told (by high-school teachers, for what it's worth) that apparently geologists don't think the asthenosphere is a thing anymore. Having been through uni over 10 years ago, I could very well be out of date, but honestly, it came as a shock to me.

    Posted: 12 May 2021 01:30 PM PDT

    Almost two months ago there was a research that says that ultrasound waves could actually damages Covid-19, but OC this was a computed simulation, Is there any further research? Does anyone know if this treatment has been aplied on any Covid-19 patient?

    Posted: 12 May 2021 11:21 AM PDT

    According to Wikipedia, Remdesivir is a prodrug of GS-441524 which is a nucleoside analog.

    I know that nucleotides are the building blocks of both DNA and RNA, meaning nucleotide analogues that prevent the creating of viral RNA can also prevent the creation of normal cell DNA, meaning they can cause problems in dividing cells. This is also reflected in the nucleotide analogue article of Wikipedia:

    They are not specific to viral DNA and also affect mitochondrial DNA. Because of this, they have side effects such as bone marrow suppression.

    So does Remdesivir cause bone marrow suppression?

    If not please explain why.

    Posted: 11 May 2021 02:21 PM PDT

    For example, if someone ejaculates very rarely, will their body ramp down sperm production? Or conversely, if they ejaculate very frequently, will it increase?

    I'm interested specifically in the rate of production, not the sperm count in the ejaculate.

    Sorry this is probably an odd question.

    Posted: 11 May 2021 01:30 PM PDT

    Are the fossilized cow or horse bones being found in America yet? Are there half-fossilized bones that are found?

    Posted: 11 May 2021 01:21 PM PDT

    Is it some kind of birthright? Genetic? Do they just choose the biggest bee? Is there a raffle?


    Hemolysis

    Hemolysis indicates reduced RBC lifespan due to destruction of RBC. Red blood cells are destroyed when they are prematurely removed from the circulation by macrophages, which phagocytize the cells before their normal lifespan is up. This is called extravascular hemolysis and the phagocytosis by macrophages is occurring within the spleen, in particular, but also other organs such as the liver and bone marrow. Extravascular hemolysis (phagocytosis of RBC by macrophages) is always occurring in a hemolytic anemia. In a few animals with hemolytic />anemia, their RBC may also rupture (“pop”) within blood vessels. This is called intravascular hemolysis but it does not occur in all cases of hemolytic anemia, only in some unfortunate patients with some causes of hemolytic anemia (e.g. oxidant injury, immune-mediated hemolytic anemia). So, all patients with hemolytic anemia have extravascular hemolysis (usually the major reason why they are anemic), whereas some patients will have concurrent intravascular hemolysis.

    Hemolytic anemia (whether there is an intravascular component or not) can result in icterus, i.e. increased total bilirubin, which is mostly indirect (unconjugated) bilirubin (the porphyrin ring of hemoglobin is converted into unconjugated bilirubin within macrophages). Because iron is also high in RBCs and iron increases in serum with increased RBC turnover (as occurs in a hemolytic anemia), we can also see high iron and iron saturation (total iron binding capacity is normal) in a hemolytic anemia. Total protein is usually not decreased like it can be in hemorrhage. Also, a hemolytic anemia can induce a stronger regenerative response than a hemorrhagic anemia (particularly that due to external hemorrhage) and if a blood smear is examined, a cause for the hemolytic anemia may be identified (e.g. RBC shape change, presence of an erythroparasite).

    Extravascular hemolysis

    Extravascular hemolysis occurs when RBCs are phagocytized by macrophages in the spleen, liver and bone marrow (see image of an erythrophage to the right). Extravascular hemolysis is always present in an animal with a hemolytic anemia in animals. In some patients with some diseases, it may be accompanied by intravascular hemolysis (luckily this does not happen too often as intravascular hemolysis is bad for a patient because it can cause acute renal injury). Note that during the normal aging of red blood cells in the circulation, effete RBCs are destroyed by macrophages, i.e. extravascular hemolysis is always occurring to some degree in our body when RBCs have finished living. This is mediated by phosphatidylserine expression on red blood cells as a consequence of natural cell death (apoptosis or eryptosis) or due to binding of natural antibodies against the red blood cell band 3 protein, which clusters with age (probably due to accumulating oxidative injury). However, this is a physiologic process and does not result in anemia or excessive unconjugated bilirubin production.

    With extravascular hemolysis, the erythrocytes are degraded within macrophages (see image above), so hemoglobin is not released free into the cytoplasm. Thus, we do not see hemoglobinemia or hemoglobinuria with extravascular hemolysis alone, unless it is accompanied by intravascular hemolysis.

    Causes of extravascular hemolysis

    Oxidant-induced hemolytic anemia in a cat

    • Immune-mediated hemolytic anemia: This is a common cause of extravascular hemolysis in the dog. Attachment of IgG or IgM causes fixation of complement (to C3b) on red cell membranes. Macrophages possess receptors for the Fc portion of IgG and IgM as well as for C3b, thus causing red blood cells with attached immunoglobulin or C3b to be phagocytized. Partial phagocytosis of erythrocytes forms spherocytes which, in large numbers, are pathognomonic for IMHA. Note, that spherocytes are most readily seen in the dog, because central pallor is usually present in canine erythrocytes. They are difficult to observe in other species. The immunoglobulin- and complement that are attached to or coating the red blood cells can be detected in a direct Coombs test using a Coombs reagent, which consists of species-specific anti-Ig and/or anti-C3. Thus, a positive Coombs test is further supportive evidence of IMHA, but false positives and negatives do occur. IMHA can be primary or secondary to drugs (e.g. penicillin in horses) or erythroparasites.
    • Erythroparasites: Many erythroparasites cause a hemolytic anemia due to extravascular hemolysis, e.g. Mycoplasma haemofelis (feline infectious anemia), Anaplasma bovis,Babesia species. With many of these organisms, there is a concurrent immune-mediated component to the anemia (the organisms make the RBC antigenic). Babesia species also induces a concurrent intravascular hemolysis. Note, that not all erythroparasites are associated with an anemia. CandidatumMycoplasma haemolamae and Mycoplasma haemominutum and turicensis are not always associated with a hemolytic anemia, although the lifespan of RBC with attached organisms is likely reduced.
    • Other infectious agents: Bacteria, such as Leptospira, can cause an extravascular hemolytic anemia, as can rickettsial and viral (e.g. equine infectious anemia) agents. Infections caused by gram negative or positive bacteria (e.g. Staphylococcus aureus, Escherischia coli) do not usually result in extravascular hemolysis unless there is concurrent DIC.
    • Oxidant injury: Oxidant injury (e.g. acetaminophen toxicity in cats) can result in extravascular hemolysis. Heinz bodies, eccentrocytes and pyknocytes are seen with oxidant injury (although this is species dependent). The Heinz body-containing red blood cells are removed prematurely from the circulation by macrophages (principally in the spleen). Inherited defects in red cell enzymes that help the red blood cell combat oxidant injury (e.g. glucose-6-phosphate dehydrogenase deficiency in horses) can result in an oxidant-induced hemolytic anemia. As noted above, some forms of oxidant injury (e.g. copper poisoning in sheep, red maple leaf toxicity in horses) can induce concurrent intravascular hemolysis. With intravascular hemolysis, ghost RBCs may be seen in smears (but must be distinguished from ghosts formed during smear preparation or a consequence of in vitro hemolysis – see more below).
    • Fragmentation injury: This usually occurs secondary to vascular disease (e.g. hemangiosarcoma), liver disease or disseminated intravascular coagulation (DIC). Keratocytes, schistocytes, and acanthocytes are observed in peripheral blood in fragmentation anemias. A few spherocytes may be observed in fragmentation anemias and do not indicate immune-mediated disease in this setting. Fragmentation anemias may be non-regenerative as cytokines associated with the primary disease often suppress the bone marrow. Note that some degree of intravascular hemolysis does also occur with fragmentation injury (particularly when fibrin strands shear RBC in DIC), however the amount of hemoglobin released into the circulation is insufficient to cause visible hemoglobinemia or hemoglobinuria. The term “microangiopathic” hemolytic anemia can be used to describe an anemia associated with RBC fragmentation, which is due to small vessel disease, including fibrin thrombi formation (DIC and other causes of microvascular thrombosis), vasculitis and hemangiosarcoma.
    • Histiocytic disorders: In these disorders, instead of RBC destruction occuring due to the RBC being abnormal, they are destroyed because the macrophages are stimulated by cytokines (usually liberated from T cells, i.e. the macrophages are reactive) or are neoplastic (e.g. histiocytic sarcoma). Erythrophagocytic macrophage variants of histiocytic sarcoma (Moore et al 2006) have been identified in dogs (particularly large breeds, like Golden Retrievers and Labradors) and can produce an extravascular hemolytic anemia, that can mimic IMHA.
    • Inherited red blood cell defects: Inherited defects of RBC enzymes (e.g. pyruvate kinase deficiency in Beagles and Basenjis) and membranes (e.g. hereditary stomatocytosis) can result in extravascular hemolytic anemias. These have primarily been identified in dogs, but can also occur in other species, including cats (pyruvate kinase deficiency in Abyssinian, Somali and domestic shorthair cats) and cattle (hereditary spherocytosis).

    Intravascular hemolysis

    Intravascular hemolysis results from the rupture or lysis of RBC within the circulation, i.e. the RBC are lysing in vivo. When the membrane of erythrocytes rupture, they release their hemoglobin into the plasma. Because hemoglobin concentrations >20 mg/dL will cause visible discoloration of plasma (light pink to dark red, depending on how much hemoglobin is present), hemoglobinemia is usually visible with intravascular hemolysis. When hemoglobin-binding proteins, such as haptoglobin, are saturated, the excess hemoglobin (“free”) spills into urine (one of its fates) so we see concurrent hemoglobinuria. We may also see ghost RBCs in blood smears – these are RBCs that consist only of membrane remnants (ghosts of their former cells) because they have ruptured and released their hemoglobin. However, these are only usually obvious when there is a decent amount of intravascular hemolysis occurring. We also see hemoglobinemia in all samples collected from the patient (EDTA, clot tube, heparin, citrate – depending on the tests requested). On our chemistry panels, the hemolytic index is often quite high in patients with intravascular hemolysis (i.e. > 200 units). The image above shows severe hemolysis (red discolored supernatant plasma of blood centrifuged in a microhematocrit tube from EDTA plasma as part of a hemogram, where we assess plasma appearance) in a dog with an immune-mediated hemolytic anemia (the dog has extravascular and intravascular hemolysis). The hemolytic index in such a patient would be > 500 units. The dog concurrently had marked hemoglobinuria as shown in the image to the right. Note that such hemolysis will interfere with clinical pathologic test results, including hemogram results. In an animal with intravascular hemolysis, the result that reflects oxygen-carrying capacity (or oxygen that can be delivered to tissues) on a hemogram is the RBC count because the hemoglobin measurement reflects both that within the RBCs (the machine lyses the intact RBCs to liberate hemoglobin) and that already in plasma (which cannot carry oxygen to tissues). The hematocrit (HCT) may also be accurate as long as the mean cell volume (MCV) is accurate (because the hematocrit is equal to the MCV x RBC count). A packed cell volume (PCV) is likely more accurate than the HCT because it is a directly measured value (as long as we can still manually detect the top of the RBC layer in the microhematocrit tube, which can be difficult in animals with severe hemolysis).

    Once hemoglobin is liberated into plasma, the free hemoglobin (which is a tetramer) breaks down into hemoglobin dimers in plasma and has two fates:

    1. It can bind haptoglobin (an α-2 globulin produced in the liver) and the hemoglobin-haptoglobin complexes are taken up by hepatocytes and macrophages (the complex binds to the haptoglobin receptor, CD163, initiating phagocytosis), to a lesser extent. Once within macrophages or hepatocytes, the hemoglobin is broken down into unconjugated bilirubin (see image to the right on the sequence of events of how hemoglobin is converted to unconjugated bilirubin). This process is similar to that which occurs when hemoglobin is released from red blood cells that are being destroyed within macrophages during extravascular hemolysis.
    2. When hemoglobin is in excess of haptoglobin (this occurs at around a hemoglobin concentration of 150 mg/dL), the excess hemoglobin dimers are filtered readily through the glomerulus (free hemoglobin is fairly small, since a hemoglobin monomer is around 17 kD, well below the glomerular filtration barrier limit). This will cause a hemoglobinuria (see image to the right and above) and a positive reaction for heme on the dipstick (with no erythrocytes evident in the urine sediment and no evidence of severe skeletal muscle injury producing myoglobinuria). Since renal tubules are capable of taking up hemoglobin, creating unconjugated bilirubin which they can then conjugate and release back into the urine, a positive reaction for bilirubin (indicating the presence of conjugated bilirubin) in the urine (i.e. bilirubinuria) may be seen in animals that have an intravascular component to their hemolytic anemia. However in most of these animals, there is concurrent cholestasis that is responsible for the bilirubinuria.

    Renal conjugation of bilirubin

    Thus we can detect the presence of a concurrent intravascular hemolysis if we see hemoglobinemia and hemoglobinuria in an anemic patient. However, we can only make this conclusion, if we rule out in vitro (false) hemolysis first. Intravascular hemolysis is not good for the patient. It results in acute kidney injury because free hemoglobin is nephrotoxic. The mechanisms of this nephrotoxicity is multifold. Free hemoglobin in plasma scavenges nitric oxide which is an important vasodilator of the renal medulla (the part of the kidney that works the hardest). This results in renal ischemia and acute tubular injury or necrosis. The hemoglobin that is filtered into urine also gets taken up by the renal tubules. Within the tubules, free iron can be liberated resulting in free radical injury. You can actually see the hemoglobin within the tubules in patients with severe intravascular hemolysis and it is called a hemoglobinuric nephropathy (heme is toxic to tubules, causing oxidant injury, and also scavenges nitric oxide, an important vasodilator in the renal medulla). Therefore, the presence of intravascular hemolysis in an animal with a hemolytic anemia usually indicates a poorer prognosis.

    In vivo versus in vitro hemolysis
    Note that RBCs can also lyse or rupture in vitro (either in the blood collection tube or during collection). When this occurs, the hemolysis is considered an artifact and does not indicate the animal has a hemolytic anemia. Artifactual hemolysis results from poor venipuncture technique, prolonged blood storage, exposure to temperature extremes (hot or cold enough to freeze the cells), and certain anticoagulants (fluoride-oxalate) will cause artifactual red blood cell lysis. Red blood cells are also more fragile in lipemic samples and tend to lyse more readily in these samples, even if the blood is stored or handled correctly. This artifactual red blood cell lysis can mimic intravascular hemolysis and it can be very difficult to tell them apart (particularly in the laboratory where all we see is the sample and not the patient). They both will result in hemoglobinemia and ghost cells. However, if the animal is anemic and has hemoglobinuria, true intravascular hemolysis, i.e. a pathological hemolytic anemia, is likely. In the laboratory, we can also sometimes tell if hemolysis in plasma is an artifact. If we see pink or red plasma when examining plasma appearance as a part of a hemogram (collected into EDTA) but the serum or plasma in the chemistry panel shows no evidence of hemolysis (hemolytic index <20 units), in vitro hemolysis is likely. We see this frequently in mailed in samples in the dead of winter, where samples may freeze during shipping. We frequently see more hemolysis in serum samples than plasma samples, because RBCs are ruptured manually during removal of serum from the clot. With in vitro hemolysis, the RBC result that most accurately reflects the oxygen-carrying capacity is the hemoglobin (because the analyzer lyses the RBCs to measure hemoglobin, it does not matter if they were “prelysed” in the tube). Conversely, as described above, the hemoglobin may over-estimate the oxygen carrying capacity in a “true” in vivo hemolytic anemia. With both in vivio or in vitro hemolysis, the MCH and MCHC may be falsely increased (because hemoglobin is the common numerator for these calculated indices and is higher than the denominators, which are RBC count and HCT, respectively).

    Differentiating in vivo from in vitro hemolysis
    Finding In vivo (true) In vitro (artifactual)
    Hemoglobinemia in fresh sample Yes Unlikely – possible if poor sample collection
    Hemoglobinemia in stored sample Yes Yes
    Ghost cells Likely Likely
    Identifiable cause (e.g. oxidant) Maybe No
    Hemoglobinuria Yes No
    RBC result reflecting oxygen-carrying capacity RBC count, HCT, PCV Hgb

    Causes of intravascular hemolysis

    • Immune-mediated hemolytic anemia: Complement fixation by IgG or IgM causes assembly of the membrane attack complex (MAC, C6-C9) on red blood cell membranes in vivo which lyses the cells. A variant of an immune-mediated hemolytic anemia is an acute hemolytic transfusion reaction where transfusion of incompatible blood into an animal will cause acute intravascular hemolysis when antibodies bind to the transfused “foreign” red blood cells and activate the complement cascade.
    • Erythroparasites: Babesiaspecies replicate inside erythrocytes and rupture the cells when they exit to continue their life cycle. This results in an intravascular hemolysis. Indeed, Babesia bovis infections are often called “red-water” disease due to the accompanying hemoglobinuria.
    • Other organisms: Specific bacteria that produce toxins that lyse RBC, such as Clostridium species and Leptospira, can cause lysis of RBC in vivo, either directly through the action of toxins or indirectly via inducing an immune-mediated anemia (Reef 1983, Weiss and Moritz 2003, Andersen et al 2013). There have been reports of bee stings (Noble and Armstrong 1999, Lewis and Racklyeft 2014) spider bites and snake venoms causing intravascular hemolysis (due to phospholipases in the venom) (Masserdotti 2009, Arce-Bejanaro et al 2014, Pagano et al 2016). : Oxidant injury (e.g. copper toxicity in sheep [Solie and Froslie 1977] or dogs [Watson et al 1983], red maple or Pistacea toxicity in horses or camelids [Dewitt et al 2004, Alward et al 2006, Walter et al 2014], zinc toxicity in dogs from ingesting zinc pennies minted after 1982 [Latimer et al 1989, Meurs et al 1991]) can result in intravascular hemolysis.
    • Metabolic conditions: Acute liver disease in horses can result in intravascular hemolysis (the mechanism is unknown, however increased bile acids, which can emulsify membranes, have been postulated as a cause). Because phosphate is essential for ATP production and maintenance of the integrity of red blood cell membranes, intravascular hemolysis can occur with severe hypophosphatemia (e.g. phosphate depleted dogs and cats with diabetes mellitus that are treated with insulin, post-partum hypophosphatemia in dairy cows). Water intoxication can also result in intravascular hemolysis.
    • Inherited red blood cell defects: Dogs with phosphofructokinase deficiency (reported in English Springer Spaniel, American Cocker Spaniel and other breeds) can suffer from bouts of intravascular hemolysis with exercise, due to alkaline fragility of their red blood cells (Giger and Harvey 1987, Owen and Harvey 2012).

    Results

    Creation of CKD

    We created uremic mice as described previously [ 20, 21]. Six weeks after surgery, serum urea nitrogen (89.3 ± 3.5 versus 35.4 ± 1.2 mg/dL, P < 0.0001) and creatinine (0.5 ± 0.05 versus 0.3 ± 0.02 mg/dL, P < 0.0001) concentrations were significantly increased in uremic mice as compared with control animals. Hct levels were significantly lower in uremic mice (40.8 ± 2.4 versus 53.7 ± 1.3% P = 0.001). Body weight did not differ between the uremic (23.4 ± 0.3, 24.3 ± 0.2 and 24.3 ± 0.6 g at 0, 2 and 6 weeks after surgery, respectively) and control (22.7 ± 0.2, 24.7 ± 0.3 and 24.9 ± 0.5 g at 0, 2 and 6 weeks after surgery, respectively) mice throughout the study.

    Characterization of MSCs

    Both uremic and control MSCs were positive for the cell surface antigens Sca-1, CD44 and PDGFR-α and negative for CD45 and CD11b ( Supplemental Figure 1A and B ) as previously reported [ 27, 28]. MSC multipotency was confirmed by positive differentiation into adipocytes ( Supplemental Figure 1C ) and osteocytes ( Supplemental Figure 1D ).

    Expression of angiogenic factors in MSCs

    Since there is a growing body of evidence that supports the hypothesis that paracrine mechanisms mediated by factors released by MSCs play an important role in the reparative process [ 17–19], we measured angiogenic growth factors in both uremic and control MSCs. Uremia was associated with decreased mRNA expression of VEGF and its receptor VEGFR1 ( Figure 1A). As previously reported [ 22], murine MSCs did not express VEGFR2 (data not shown). Similarly, immunoblot analysis of VEGFR1 and ELISA for VEGF showed significant reductions as compared with control MSCs ( Figure 1B). The expression of SDF-1α was significantly decreased in uremic MSCs at both mRNA and protein levels ( Figure 1C). Additionally, mRNA expression of fibroblast-specific protein-1, which is a marker of myofibroblast differentiation, was significantly higher in uremic MSCs than nonuremic control MSCs ( Figure 1D), suggesting that uremia induces a myofibroblast-like phenotype in MSCs. In order to determine whether uremic toxin is directly involved in the reduced expression of VEGF, VEGFR1 and SDF-1α in the uremic MSCs, we examined the effects of uremic toxins on the expression of those factors. Since IS has been reported to be taken up into cells by organic anion transporters (OAT) [ 29], we first confirmed that OAT-3 was expressed in MSCs using real-time RT–PCR (data not shown). Both IS and p-cresol significantly decreased mRNA expression of VEGF, VEGFR1 and SDF-1α ( Supplemental Figure 2A and B ).

    Expression of multiple factors in uremic and nonuremic MSCs. (A) Real-time RT–PCR was performed to measure the level of gene expression from MSCs. (B) ELISA for VEGF and immunoblot analysis of VEGFR1 in uremic and control MSCs. (C) SDF-1α expression in uremic and nonuremic control MSCs. mRNA was detected using real-time RT–PCR, and protein was detected by ELISA. (D) mRNA expression of fibroblast-specific protein-1 in uremic and nonuremic MSCs. Data are mean ± SE n = 6 for control and n = 5 for uremic MSCs lines isolated independently * P < 0.05 versus sham.

    Expression of multiple factors in uremic and nonuremic MSCs. (A) Real-time RT–PCR was performed to measure the level of gene expression from MSCs. (B) ELISA for VEGF and immunoblot analysis of VEGFR1 in uremic and control MSCs. (C) SDF-1α expression in uremic and nonuremic control MSCs. mRNA was detected using real-time RT–PCR, and protein was detected by ELISA. (D) mRNA expression of fibroblast-specific protein-1 in uremic and nonuremic MSCs. Data are mean ± SE n = 6 for control and n = 5 for uremic MSCs lines isolated independently * P < 0.05 versus sham.

    MSC proliferation and senescence

    The effect of uremia on the proliferation of MSCs was passage dependent. At Passage 6, MSC proliferation was not different between the uremic and control groups. However, at Passage 11, uremia significantly reduced cell proliferation ( Figure 2A). Similarly, a concentration–response relationship between IS and MSC proliferation was observed between 0.25 and 5 mM IS ( Supplemental Figure 2C ). p-cresol at 0.1 mM also induced a decrease in MSC proliferation ( Supplemental Figure 2D ). We reasoned that the lack of proliferation in uremic MSCs was due to their high rate of intrinsic senescence. Using the senescence biomarker SA-β-gal, we measured the degree of senescence in uremic and control MSCs at matched passages. At Passages 6, 9 and 11, uremic MSCs contained 1.4, 2.6 and 17.9% SA-β-gal-positive cells, whereas control MSCs contained 0.4, 0.5 and 1.4% SA-β-gal-positive cells (P < 0.05, Figure 2B), suggesting premature senescence of MSCs in uremia.

    Cell proliferation and senescence in uremic and nonuremic MSCs. (A) Cell proliferation was measured by BrdU incorporation. Data are mean ± SE n = 3 experiments performed in triplicate using independently isolated MSC lines * P < 0.05 versus sham. (B) The degree of senescence was measured using the senescence biomarker SA-β-gal in uremic and nonuremic MSCs at different passages. Representative phase-contrast images of control and uremic MSCs are shown on the left (×40), and the quantitative assessment is on the right. Data are mean ± SE n = 6 for control and n = 5 for uremic MSC lines isolated independently. The experiments were performed in triplicate * P < 0.05 versus sham.

    Cell proliferation and senescence in uremic and nonuremic MSCs. (A) Cell proliferation was measured by BrdU incorporation. Data are mean ± SE n = 3 experiments performed in triplicate using independently isolated MSC lines * P < 0.05 versus sham. (B) The degree of senescence was measured using the senescence biomarker SA-β-gal in uremic and nonuremic MSCs at different passages. Representative phase-contrast images of control and uremic MSCs are shown on the left (×40), and the quantitative assessment is on the right. Data are mean ± SE n = 6 for control and n = 5 for uremic MSC lines isolated independently. The experiments were performed in triplicate * P < 0.05 versus sham.

    MSC migration and in vitro tube formation

    To further analyze the effect of uremia on the biological function of MSCs, its effect on MSC migration was studied. As shown in Figure 3A, migration toward VEGF or SDF-1α was significantly reduced in uremic MSCs as compared to control cells. We next tested whether uremia diminishes tube formation of MSCs using matrigel assays. A significant reduction in tube formation was observed in uremic MSCs when compared with control MSCs at both 4 and 6 h after incubation ( Figure 3B).

    Cell migration and matrigel assay in uremic and nonuremic MSCs. (A) MSCs were seeded into the upper chamber of the ChemoTx cell migration system, and the lower chamber was filled with VEGF or SDF-1α then the chambers were incubated at 37°C for 4 h. The number of cells that had migrated to the lower chamber was quantified with a nucleic acid-binding fluorescent dye. Data are mean ± SE n = 3–4 experiments performed in triplicate using independently isolated MSC lines * P < 0.05 versus sham. (B) Representative photomicrographs of MSCs after plating on matrigel. Quantitative evaluation of tube formation is shown on the right. Data are mean ± SE n = 6 for control and n = 5 for uremic MSC lines isolated independently. The experiments were performed in triplicate * P < 0.05 versus sham. Scale bar represents 500 μm.

    Cell migration and matrigel assay in uremic and nonuremic MSCs. (A) MSCs were seeded into the upper chamber of the ChemoTx cell migration system, and the lower chamber was filled with VEGF or SDF-1α then the chambers were incubated at 37°C for 4 h. The number of cells that had migrated to the lower chamber was quantified with a nucleic acid-binding fluorescent dye. Data are mean ± SE n = 3–4 experiments performed in triplicate using independently isolated MSC lines * P < 0.05 versus sham. (B) Representative photomicrographs of MSCs after plating on matrigel. Quantitative evaluation of tube formation is shown on the right. Data are mean ± SE n = 6 for control and n = 5 for uremic MSC lines isolated independently. The experiments were performed in triplicate * P < 0.05 versus sham. Scale bar represents 500 μm.

    HIF-1α, VEGF and VEGFR1 expression under hypoxia and VEGF-induced Akt phosphorylation

    Since HIF-1 is the central mediator of angiogenesis by controlling the expression of multiple angiogenic growth factors, we investigated the effect of uremia on HIF-1α expression in MSCs. Immunoblot assays detected a high level of HIF-1α protein expression in control MSCs under hypoxic conditions but not in uremic MSCs ( Figure 4A). Enhancement of VEGF and VEGFR1 expression under hypoxic condition, which is regulated by HIF-1α [ 22], was also significantly decreased by uremia ( Figure 4B and C). Since Akt is not only a general mediator of survival gene [ 30] upregulating the expression of secreted factors [ 17] but also is a downstream signaling molecule of VEGF/VEGFR1 in MSCs [ 22], we assessed the phosphorylation of Akt in both basal and VEGF-stimulated states. As shown in Figure 4D, uremia significantly reduced Akt phosphorylation in the basal state without producing any enhancement in response to VEGF.

    (AC) Immunoblot analysis of HIF-1α, VEGF and VEGFR1 under normoxia (N) and 1% hypoxia (H) in control and uremic MSCs. Cells were cultured for 10 h under normoxic or hypoxic conditions. Data are mean ± SE n = 5 MSC lines isolated independently * P < 0.05 versus normoxia, † P < 0.05 versus control. (D) Akt phosphorylation in MSCs. Cells were stimulated with VEGF (100 ng/mL) for 10 min after overnight starvation in 0.1% bovine serum albumin. Immunoblot analysis was performed using antibodies specific for Akt phosphorylated at serine 473 or total Akt. Data are mean ± SE n = 4 MSC lines isolated independently * P < 0.05 versus without VEGF stimulation, † P < 0.05 versus nonuremic controls.

    (AC) Immunoblot analysis of HIF-1α, VEGF and VEGFR1 under normoxia (N) and 1% hypoxia (H) in control and uremic MSCs. Cells were cultured for 10 h under normoxic or hypoxic conditions. Data are mean ± SE n = 5 MSC lines isolated independently * P < 0.05 versus normoxia, † P < 0.05 versus control. (D) Akt phosphorylation in MSCs. Cells were stimulated with VEGF (100 ng/mL) for 10 min after overnight starvation in 0.1% bovine serum albumin. Immunoblot analysis was performed using antibodies specific for Akt phosphorylated at serine 473 or total Akt. Data are mean ± SE n = 4 MSC lines isolated independently * P < 0.05 versus without VEGF stimulation, † P < 0.05 versus nonuremic controls.

    Paracrine effect on endothelial proliferation

    Having demonstrated the effects of a uremic environment on MSCs, we next tested whether conditioned media from uremic MSCs would have reduced effect on endothelial cell proliferation. Conditioned media from both control and uremic MSCs significantly enhanced endothelial proliferation in a dose-dependent manner over DMEM with 10% FBS. However, the mitogenic effect of uremia-conditioned media was significantly lower than that of control-conditioned media ( Figure 5).

    Effect of conditioned media from uremic and nonuremic MSCs on the proliferation of HUVEC. HUVEC were cultured under varying dilutions of conditioned media from either control or uremic MSCs and DMEM with 10% FBS for 72 h then recovered and counted. Values were expressed as % of the cells cultured in EGM-2. Data are mean ± SE n = 4 using conditioned media from different MSC lines * P < 0.05 versus DMEM with 10% FBS, † P < 0.05 versus nonuremic conditioned media. EGM-2, endothelial growth media-2.

    Effect of conditioned media from uremic and nonuremic MSCs on the proliferation of HUVEC. HUVEC were cultured under varying dilutions of conditioned media from either control or uremic MSCs and DMEM with 10% FBS for 72 h then recovered and counted. Values were expressed as % of the cells cultured in EGM-2. Data are mean ± SE n = 4 using conditioned media from different MSC lines * P < 0.05 versus DMEM with 10% FBS, † P < 0.05 versus nonuremic conditioned media. EGM-2, endothelial growth media-2.

    In vivo angiogenesis

    To assess the effect of uremia on in vivo angiogenesis, cell spheroids of control or uremic MSCs were implanted on dorsal skinfold chambers of athymic nude mice. From Day 0 of implantation, the growth of the vascular network was evaluated every 1–2 days using intravital microscopy. Implantation of control MSCs could lead to the formation of a dense microvascular network by Day 9 ( Figure 6A). In contrast, when uremic MSCs were implanted, some vessels sprouted but did not form a dense vascular network ( Figure 6B).

    Cell spheroids of control or uremic MSCs were implanted on dorsal skinfold chambers of athymic nude mice. Implantation of control MSCs could lead to the formation of dense microvascular network by Day 9 (A). In contrast, when uremic MSCs were implanted, some vessels sprouted but did not form a dense vascular network (B). Arrow indicates implanted spheroids. Original magnification ×40. Data are representative of three independent experiments.

    Cell spheroids of control or uremic MSCs were implanted on dorsal skinfold chambers of athymic nude mice. Implantation of control MSCs could lead to the formation of dense microvascular network by Day 9 (A). In contrast, when uremic MSCs were implanted, some vessels sprouted but did not form a dense vascular network (B). Arrow indicates implanted spheroids. Original magnification ×40. Data are representative of three independent experiments.


    Contents

    These agents can be used against hepatitis B virus, hepatitis C virus, herpes simplex, and HIV. Once they are phosphorylated, they work as antimetabolites by being similar enough to nucleotides to be incorporated into growing DNA strands but they act as chain terminators and stop viral DNA polymerase. They are not specific to viral DNA and also affect mitochondrial DNA. Because of this they have side effects such as bone marrow suppression.

    There is a large family of nucleoside analogue reverse transcriptase inhibitors, because DNA production by reverse transcriptase is very different from normal human DNA replication, so it is possible to design nucleoside analogues that are preferentially incorporated by the former. Some nucleoside analogues, however, can function both as NRTIs and polymerase inhibitors for other viruses (e.g., hepatitis B).

    Less selective nucleoside analogues are used as chemotherapy agents to treat cancer, e.g. gemcitabine. They are also used as antiplatelet drugs to prevent the formation of blood clots, ticagrelor and cangrelor.

    Resistance can develop quickly with as little as one mutation. [1] Mutations occur in the enzymes that phosphorylate the drug and activate it: in the case of herpes simplex, resistance to acyclovir arises thanks to a mutation affecting the viral enzyme thymidine kinase. Since nucleoside analogues require two phosphorylations to be activated, one carried out by a viral enzyme and the other by enzymes in the host cell, mutations in viral thymidine kinase interfere with the first of these phosphorylations in such cases the drug remains ineffective. There are, however, several different nucleoside analogue drugs and resistance to one of them is usually overcome by switching to another drug of the same kind (e. g. famciclovir, penciclovir, valaciclovir).

    Nucleoside analogue drugs include:

      analogues:
        (ddI)(HIV) (antiviral)
        (Ebola) (Ebola)(Marburg)(Coronavirus)
        (chemotherapy) (Chemotherapy) (FTC)(HIV) (3TC)(HIV, hepatitis B) (ddC)(HIV)
        (HIV) (hepatitis B)
        (d4T) (hepatitis B) (azidothymidine, or AZT)(HIV)

      Related drugs are nucleobase analogs, which don't include a sugar or sugar analog, and nucleotide analogues, which also include phosphate groups.

      Nucleoside antibiotics are a class of antibiotics that inhibit the Mray enzyme in peptidoglycan biosynthesis pathway of mycobacteria, gram positive and gram negative strains. [2]