2. Drug Treatment of Special Infections (eg.pptx

Drug Treatment of Special Infections (eg: Lassa fever, Avian Influenza, SARS, Ebola, corona virus disease).  Lassa fever Lassa fever is an animal-borne, or zoonotic, acute viral illness. It is endemic in parts of West Africa including Sierra Leone, Liberia, Guinea and Ni...

Drug Treatment of Special Infections (eg: Lassa fever, Avian Influenza, SARS, Ebola, corona virus disease).  Lassa fever Lassa fever is an animal-borne, or zoonotic, acute viral illness. It is endemic in parts of West Africa including Sierra Leone, Liberia, Guinea and Nigeria. Neighboring countries are also at risk, as the animal vector for Lassa virus, the “multimammate rat” (Mastomys natalensis) is distributed throughout the region.  The illness was discovered in 1969 and is named after the town in Nigeria where the first cases occurred. An estimated 100,000 to 300,000 infections of Lassa fever occur annually, with approximately 5,000 deaths. Surveillance for Lassa fever is not standardized; therefore, these estimates are crude. In some areas of Sierra Leone and Liberia, it is known that 10-16% of people admitted to hospitals annually have Lassa fever, demonstrating the serious impact the disease has on the region.  Transmission The reservoir, or host, of Lassa virus is a rodent known as the “multimammate rat” (Mastomys natalensis). Once infected, this rodent is able to excrete virus in urine for an extended time period, maybe for the rest of its life. Mastomys rodents breed frequently, produce large numbers of offspring, and are numerous in the savannas and forests of west, central, and east Africa. In addition, Mastomys readily colonize human homes and areas where food is stored. All of these factors contribute to the relatively efficient spread of Lassa virus from infected rodents to humans.  Transmission of Lassa virus to humans occurs most commonly through ingestion or inhalation. Mastomys rodents shed the virus in urine and droppings and direct contact with these materials, through touching soiled objects, eating contaminated food, or exposure to open cuts or sores, can lead to infection.  Direct contact with infected rodents is not the only way in which people are infected; person-to-person transmission may occur after exposure to virus in the blood, tissue, secretions, or excretions of a Lassa virus-infected individual. Casual contact (including skin-to-skin contact without exchange of body fluids) does not spread Lassa virus.  Signs and symptoms Because the symptoms of Lassa fever are so varied and nonspecific, clinical diagnosis is often difficult. occur 1-3 weeks after the patient comes into contact with the virus. For the majority of Lassa fever virus infections (approximately 80%), symptoms are mild and are undiagnosed. Mild symptoms include slight fever, general malaise and weakness, and headache.  In 20% of infected individuals, however, disease may progress to more serious symptoms including hemorrhaging (in gums, eyes, or nose, as examples), respiratory distress, repeated vomiting, facial swelling, pain in the chest, back, and abdomen, and shock.  Neurological problems have also been described, including hearing loss, tremors, and encephalitis. Death may occur within two weeks after symptom onset due to multi- organ failure.  The most common complication of Lassa fever is deafness. Approximately 15%-20% of patients hospitalized for Lassa fever die from the illness. However, only 1% of all Lassa virus infections result in death. The death rates for women in the third trimester of pregnancy are particularly high. Spontaneous abortion is a serious complication of infection with an estimated 95% mortality in fetuses of infected pregnant mothers.  Lassa fever is also associated with occasional epidemics, during which the case-fatality rate can reach 50% in hospitalized patients.  Diagnosis Lassa fever is most often diagnosed by using enzyme-linked immunosorbent serologic assays (ELISA), which detect IgM and IgG antibodies as well as Lassa antigen.  Treatment Ribavirin, an antiviral drug, has been used with success in Lassa fever patients. It has been shown to be most effective when given early in the course of the illness. Patients should also receive supportive care consisting of maintenance of appropriate fluid and electrolyte balance, oxygenation and blood pressure, as well as treatment of any other complicating infections.  Ribavirin Chemistry and Antiviral Activity Ribavirin (1-β-D-ribofur- anosyl-1H- 1,2,4-triazole-3-carboxamide) is a purine nucleoside analog with a modified base and D-ribose sugar.  Mechanisms of Action and Resistance. The antiviral mechanism of ribavirin is incompletely understood It relates to alteration of cellular nucleotide pools and inhibition of viral messenger RNA synthesis Intracellular phosphorylation to the mono-, di-, and triphosphate derivatives is mediated by host cell enzymes. In both uninfected and RSV-infected cells, the predominant derivative (>80%) is the triphosphate, which has an intracellular 1/2t of less than 2 hours  Ribavirin monophosphate competitively inhibits cellular inosine-5′-phosphate dehydrogenase and interferes with the synthesis of GTP and thus nucleic acid synthesis in general. Ribavirin triphosphate also competitively inhibits the GTP-dependent 5′ capping of viral messenger RNA and specifically influenza virus transcriptase activity.  Ribavirin appears to have multiple sites of action, and some of these (e.g., inhibition of GTP synthesis) may potentiate others (e.g., inhibition of GTP dependent enzymes). Ribavirin also may enhance viral mutagenesis to an extent that some viruses may be inhibited in effective replication, so-called lethal mutagenesis.  Absorption, Distribution, and Elimination Ribavirin is actively taken up by nucleoside transporters in the proximal small bowel; oral bioavailability averages approximately 50% The apparent volume of distribution for ribavirin is large (~10 L/kg) owing to its cellular uptake. Plasma protein binding is negligible. The elimination of ribavirin is complex  Hepatic metabolism and renal excretion of ribavirin and its metabolites are the principal routes of elimination Ribavirin clearance decreases threefold in those with advanced renal insufficiency (Clcr = 10 to 30 ml/min);  Therapeutic Uses Intravenous ribavirin decreases mortality in Lassa fever and has been used in treating other arenavirus-related hemorrhagic fevers. Intravenous ribavirin is beneficial in hemorrhagic fever with renal syndrome owing to hantavirus infection but appears ineffective in hantavirus- associated cardiopulmonary syndrome or SARS. Oral ribavirin has been used for the treatment and prevention of Crimean–Congo hemorrhagic fever and treatment of Nipah virus infections  Oral ribavirin in combination with injected pegIFN alfa-2a or -2b has become standard treatment for chronic HCV infection Ribavirin aerosol is approved in the United States for treatment of RSV bronchiolitis and pneumonia in hospitalized children.  Side effect Systemic ribavirin causes dose-related reversible anemia owing to extravascular hemolysis and suppression of bone marrow. Associated increases occur in reticulocyte counts and in serum bilirubin, iron, and uric acid concentrations. High ribavirin triphosphate levels may cause oxidative damage to membranes, leading to erythrophagocytosis by the reticuloendothelial system. Bolus intravenous infusion may cause rigors. oral ribavirin increases the risk of fatigue, cough, rash, pruritus, nausea, insomnia, dyspnea, depression, and particularly, anemia.  Ebola virus disease Many common illnesses can have the same symptoms as EVD, including influenza (flu), malaria, or typhoid fever. EVD is a rare but severe and often deadly disease. Recovery from EVD depends on good supportive clinical care and the patient’s immune response. Studies show that survivors of Ebola virus infection have antibodies (proteins made by the immune system that identify and neutralize invading viruses) that can be detected in the blood up to 10 years after recovery. Survivors are thought to have some protective immunity to the type of Ebola that sickened them.  Transmission Scientists think people are initially infected with Ebola virus through contact with an infected animal, such as a fruit bat or nonhuman primate. This is called a spillover event. After that, the virus spreads from person to person, potentially affecting a large number of people.  The virus spreads through direct contact (such as through broken skin or mucous membranes in the eyes, nose, or mouth) with: Blood or body fluids of a person who is sick with or has died from EVD. Objects contaminated with body fluids from a person who is sick with or has died from EVD. Infected fruit bats or nonhuman primates (such as apes and monkeys). Semen from a man who recovered from EVD (through oral, vaginal, or anal sex). The virus can remain in certain body fluids (including semen) of a patient who has recovered from EVD, even if they no longer have symptoms of severe illness. There is no evidence that Ebola can be spread through sex or other contact with vaginal fluids from a woman who has had Ebola.  The period between exposure to an illness and having symptoms is known as the incubation period A person can only spread Ebola to other people after they develop signs and symptoms of Ebola There is no evidence that mosquitoes or other insects can transmit Ebola virus  Signs and Symptoms When people become infected with Ebola, they do not start developing signs or symptoms right away. Symptoms may appear anywhere from 2 to 21 days after contact with the virus, with an average of 8 to 10 days. The course of the illness typically progresses from “dry” symptoms initially (such as fever, aches and pains, and fatigue), and then progresses to “wet” symptoms (such as diarrhea and vomiting) as the person becomes sicker.  Primary signs and symptoms of Ebola often include some or several of the following: Fever Aches and pains, such as severe headache and muscle and joint pain Weakness and fatigue Sore throat Loss of appetite Gastrointestinal symptoms including abdominal pain, diarrhea, and vomiting Unexplained hemorrhaging, bleeding or bruising  Other symptoms may include red eyes skin rash and hiccups (late-stage)  Diagnosis To determine whether EVD is a possible diagnosis, there must be a combination of symptoms suggestive of EVD AND a possible exposure (earlier listed) to EVD within 21 days before the onset of symptoms. Ebola virus can be detected in blood after onset of symptoms. It may take up to three days after symptoms start for the virus to reach detectable levels. Polymerase chain reaction (PCR) is one of the most commonly used diagnostic methods because of its ability to detect low levels of Ebola virus.  Drug treatment currently two treatments The first drug approved in October 2020, Inmazeb™external icon, is a combination of three monoclonal antibodies. The second drug, Ebanga™external icon, is a single monoclonal antibody and was approved in December 2020.  Both of these treatments, along with two others, were evaluated in a randomized controlled trial during the 2018-2020 Ebola outbreak in the Democratic Republic of the Congo. Overall survival was much higher for patients receiving either of the two treatments that are now approved by the FDA. Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn) a mixture of three monoclonal antibodies, the first FDA-approved treatment for Zaire ebolavirus (Ebola virus) infection in adult and pediatric patients.  Mechanism of action Inmazeb targets the glycoprotein that is on the surface of Ebola virus. Glycoprotein attaches to the cell receptor and fuses the viral and host cell membranes allowing the virus to enter the cell. The three antibodies that make up Inmazeb can bind to this glycoprotein simultaneously and block attachment and entry of the virus into the cells.  Side effects The most common symptoms included: fever, chills, tachycardia (fast heart rate), tachypnea (fast breathing), and vomiting; however, these are also common symptoms of Ebola virus infection. Hypersensitivity, can occur in patients  Note Inmazeb received an Orphan Drug designation for the treatment of Ebola virus infection. The Orphan Drug designation provides incentives to assist and encourage drug development for rare diseases. Ebanga (Ansuvimab-zykl) a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease.  Mechanism of action Monoclonal antibodies (often abbreviated as mAbs) are proteins produced (in a lab or other manufacturing facility) that act like natural antibodies to stop a germ (such as a virus) from replicating after it has infected a person. These particular mAbs(Ebanga) bind to a portion of the Ebola virus’s surface called the glycoprotein, which prevents the virus from entering a person’s cells.  Side effects The most common symptoms experienced while receiving Ebanga include: fever, tachycardia, diarrhea, vomiting, hypotension, tachypnea and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.  Avian Influenza Influenza is an acute systemic viral infection that primarily affects the respiratory tract; it carries a significant mortality. It is caused by influenza A virus or, in milder form, influenza B virus. Infection is seasonal, and variation in the haemagglutinin (H) and neuraminidase (N) glycoproteins on the surface of the virus leads to disease of variable intensity each year.  Avian influenza is caused by transmission of avian influenza A viruses to humans. Avian viruses, such as H5N1, possess alternative haemagglutinin antigens to seasonal influenza strains. Most cases have had contact with sick poultry, predominantly in South-east Asia, and person to- person spread has been limited to date.  presentation After an incubation period of 1–3 days, uncomplicated disease leads to fever, malaise and cough. Viral pneumonia may occur, although pulmonary complications Infections with H5N1(Avian) viruses have been severe, with enteric features and respiratory failure. Treatment depends on the resistance pattern but often involves oseltamivir  Diagnosis The diagnosis of influenza A(H5N1) virus infection should be included in the differential diagnosis of all persons presenting with acute febrile respiratory illness in those countries or territories where influenza A(H5N1) viruses have been identified as a cause of infection in animal populations. The use of commercially available, rapid site- of-care influenza detection tests for individual patient diagnosis is generally not recommended.  Drug treatment Many influenza viruses have become resistant to the effects of a category of antiviral drugs that includes amantadine and rimantadine (Flumadine). Recommended is the use of oseltamivir (Tamiflu) or, if oseltamivir can't be used, zanamivir (Relenza). These drugs must be taken within two days after the appearance of symptoms.  Modified regimens of oseltamivir treatment, including two-fold higher dosage longer duration and possibly combination therapy with amantadine or rimantadine (in countries where A(H5N1) viruses are likely to be susceptible to adamantanes) may be considered on a case by case basis, especially in patients with pneumonia or progressive disease. oseltamivir  Is a sialic acid analogue with broad spectrum activity covering influenza A (amantadine sensitive as well as resistant), H5N1 (bird flu), nH1N1 (swine flu) strains and influenza B. Oseltamivir phosphate is an ethyl ester prodrug of oseltamivir carboxylate.  Mechanism of action Oseltamivir carboxylate is an analogue of sialic acid and is a competitive inhibitor of the influenza virus neuraminidase that cleaves the terminal sialic acid residues and destroys the receptors recognized by viral haemagglutinin present on the cell surface of progeny virions and in respiratory secretions.  Neuraminidase activity is needed for release of new virions from infected cells. When oseltamivir carboxylate binds to the neuraminidase it causes a conformational change at the active site, thereby inhibiting sialic acid cleavage. This leads to viral aggregation at the cell surface and reduced viral spread in the respiratory tract.  Kinetics Oral oseltamivir phosphate is absorbed orally and de-esterified by gastro-intestinal and hepatic esterases to the active carboxylate. The bioavailability of the carboxylate approaches 80% and its mean elimination t1/2 is between six and ten hours. Both parent and metabolite are eliminated by renal tubular secretion.  Adverse effects include headache, nausea, vomiting and abdominal discomfort (noted more frequently in patients with active influenza than if the agent is used for prophylaxis). Adverse effects are reduced by taking the drug with food. ZANAMIVIR This is another inhibitor of influenza virus neuraminidase enzymes. If given early during influenza A or B infection via intranasal route it is effective in reducing symptoms.  Adamantanes (amantadine and rimantadine). Early amantadine treatment of patients with adamantane-susceptible A(H5N1) virus infections in Hong Kong (SAR) in 1997 may have been associated with clinical benefit. monotherapy of seasonal influenza with this drug is associated with a high frequency of rapid resistance emergence, globally the majority of A(H3N2) and some A(H1N1) influenza viruses currently show resistance to adamantanes In addition, many A(H5N1) virus isolates now show primary resistance. When neuraminidase inhibitors are available, monotherapy with amantadine or rimantadine is not recommended. Severe acute respiratory syndrome (SARS) a viral respiratory illness caused by a coronavirus, called SARS-associated coronavirus (SARS-CoV). SARS was first reported in Asia in February 2003. The main way that SARS seems to spread is by close person-to-person contact  The virus that causes SARS is thought to be transmitted most readily by respiratory droplets (droplet spread) produced when an infected person coughs or sneezes. Droplet spread can happen when droplets from the cough or sneeze of an infected person are propelled a short distance (generally up to 3 feet) through the air and deposited on the mucous membranes of the mouth, nose, or eyes of persons who are nearby.  WHO received reports of >8,000 SARS cases and nearly 800 deaths. early clinical recognition of SARS-CoV disease still relies on a combination of clinical and epidemiologic features. The diagnosis of SARS-CoV disease and the implementation of control measures should be based on the risk of exposure.  early clinical symptoms (e.g., fever or lower respiratory symptoms in the absence of pneumonia), while still low, may be sufficiently high — when combined with an epidemiologic link to settings Diagnosis of SARS-CoV Disease In the absence of person-to-person transmission of SARS-CoV anywhere in the world, the diagnosis of SARS-CoV disease should be considered only in patients who require hospitalization for radiographically confirmed pneumonia and who have an epidemiologic history that raises the suspicion of SARS-CoV disease. The suspicion for SARS-CoV disease is raised if, within 10 days of symptom onset, the patient: Has a history of recent travel to mainland China, Hong Kong, or Taiwan (see Figure 1, footnote 3) or close contact with ill persons with a history of recent travel to such areas, or Is employed in an occupation at particular risk for SARS- CoV exposure, including a healthcare worker with direct patient contact or a worker in a laboratory that contains live SARS-CoV, or Is part of a cluster of cases of atypical pneumonia without an alternative diagnosis  COVID 19 The Corona Virus Disease 2019 (COVID 19) pandemic caused by the Severe Acute Respiratory Syndrome Corona virus -2 (SARS-CoV-2) led to a World Health Organization declared global pandemic on March 11, 2020. The coronavirus disease 2019 (COVID-19) is a communicable respiratory disease caused by a new strain of coronavirus that causes illness in humans. It is thought that the virus began in animals; at some point, one or more humans acquired infection from an animal.  Transmission The disease spreads from person to person through infected air droplets that are projected during sneezing or coughing. It can also be transmitted when humans have contact with hands or surfaces that contain the virus and touch their eyes, nose, or mouth with the contaminated hands  There have been concerted attempts to seek preventive and interventional modalities to arrest the spread of the contagion by public health measures Such as masking, social distancing, self isolation and hygiene (frequent hand washing), or more recently by vaccines  Presentation Range from asymptomatic/mild symptoms to severe illness and mortality. Common symptoms have included fever, cough, and shortness of breath. Other symptoms, such as malaise and respiratory distress, have also been described. Symptoms may develop 2 days to 2 weeks after exposure to the virus.  The following symptoms may indicate COVID-19 Fever or chills Cough Shortness of breath or difficulty breathing Fatigue Muscle or body aches Headache New loss of taste or smell Sore throat Congestion or runny nose Nausea or vomiting Diarrhea  Other reported symptoms include the following: Sputum production Malaise Respiratory distress Neurologic (eg, headache, altered mentality)  Diagnosis The PCR test Suspected with symptoms earlier listed  Treatment All infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases As of October 22, 2020, remdesivir, an antiviral agent, was the only drug approved for treatment of COVID-19. It is indicated for treatment of COVID-19 disease in hospitalized adults and children 12 years and older who weigh at least 40 kg.  Continuation The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deployment of potential therapies for investigation and investigational therapies with emerging evidence So some other antiviral/drugs were permitted: bamlanivimab (Bamlanivimab may be used in combination with etesevimab); monoclonal antibodies casirivimab and imdevimab ; sotrovimab; baricitinib in combination with remdesivir  NSAIDS do not increase the risk of adverse events or affect acute healthcare utilization, long-term survival, or quality of life Other investigational antivirals continue to emerge. Clinical trials of existing drugs with antiviral properties Eg Nitazoxanide (); Niclosamide(is an anthelmintic agent used primarily for tapeworms); ivectmectin  Remdesivir (Veklury) The broad-spectrum antiviral is a nucleotide analog prodrug. indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. children younger than 12 years who weigh at least 3.5 kg were later added. cost is approximately $520/100-mg vial, totaling $3,120 for a 5-day treatment course  IVERMECTIN Ivermectin, an anti-parasitic medicine whose discovery won the Nobel Prize in 2015, has proven, highly potent, anti-viral and anti- inflammatory properties in laboratory studies. In the past 4 months, numerous, controlled clinical trials from multiple centers and countries worldwide are reporting consistent, large improvements in COVID-19 patient outcomes when treated with ivermectin.  exhibited broad spectrum antiparasitic, anti-bacterial and antiviral properties against many RNA viruses. Ivermectin is extensively used, with good safety profile in Nigeria and other African nations in treating ocular onchocerciasis. Of more current import, Ivermectin was shown to exhibit a 5000-fold reduction in SARS-C0V-2 viral RNA in vitro in Vero-h/SLAM cells in a study from Australia  Mechanism of action There are several mechanisms by which Ivermectin may inhibit SARS-CoV-2 in COVID 19 patients, including by inhibition of RNA -dependent RNA polymerase (RdRP) required for viral replication abolition of importin-α/β1 heterodimer nuclear transport of SARS-CoV-2 from the cytosol to the nucleus,and inhibition of viral mRNA and viral protein translation  References https://www.medicalnewstoday.com/a rticles/7543 https://emedicine.medscape.com/arti cle/2500114-treatment#d10 www.flccc.net © 2020 FLCCC Alliance · I-MASK+ Protocol v8 · Jan 12, 202