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George Westinghouse

George Westinghouse Jr. (October 6, 1846 – March 12, 1914) was an American entrepreneur and engineer based in Pittsburgh, Pennsylvania who created the railway air brake and was a pioneer of the electrical industry, receiving his first patent at the age of 19. Westinghouse saw the potential of using alternating current for electric power distribution in the early 1880s and put all his resources into developing and marketing it. This put Westinghouse's business in direct competition with Thomas Edison, who marketed direct current for electric power distribution. In 1911 Westinghouse received the American Institute of Electrical Engineers's (AIEE) Edison Medal "For meritorious achievement in connection with the development of the alternating current system". He founded the Westinghouse Electric Corporation in 1886.

Early years
George Westinghouse was born in 1846 in Central Bridge, New York (see George Westinghouse Jr. Birthplace and Boyhood Home), the son of Emeline (Vedder) and George Westinghouse Sr., a machine shop owner. His ancestors came from Westphalia in Germany, who first moved to England and then emigrated to the US. The name had been Anglicized from Westinghausen.

From his youth, Westinghouse was talented with machinery and business. At the breakout of the Civil War in 1862, the 15-year-old Westinghouse enlisted in the New York National Guard and served until his parents urged him to return home. The following year, he persuaded his parents to allow him to re-enlist, whereupon he joined Company M of the 16th New York Cavalry and earned promotion to the rank of corporal. In December 1864 he resigned from the Army to join the Navy, serving as Acting Third Assistant Engineer on the gunboat USS Muscoota through the end of the war. After his military discharge in August 1865, he returned to his family in Schenectady and enrolled at Union College. He lost interest in the curriculum and dropped out in his first term.

Westinghouse was 19 years old when he created his first invention, a rotary steam engine. He also devised the Westinghouse Farm Engine. At age 21 he invented a "car replacer", a device to guide derailed railroad cars back onto the tracks, and a reversible frog, a device used with a railroad switch to guide trains onto one of two tracks. In 1868 he established residence with his wife in Pittsburgh, Pennsylvania, to gain access to less expensive steel for his railroad frogs, and where he developed his recently-invented railroad air brake concept.

Air brakes

He had witnessed a train wreck where two engineers saw one another, but were unable to stop their trains in time using the existing brakes. Brakemen had to run from car to car, on catwalks atop the cars, applying the brakes manually on each car.

In 1869, at age 22, Westinghouse first publicly demonstrated his new railroad braking system using compressed air. The Westinghouse system used a compressor on the locomotive, a reservoir and a special valve on each car, and a single pipe running the length of the train (with flexible connections) which both refilled the reservoirs and controlled the brakes, allowing the engineer to apply and release the brakes simultaneously on all cars. It was a failsafe system, in that any rupture or disconnection in the train pipe applied the brakes throughout the train. It was patented by Westinghouse on October 28, 1873.

Westinghouse pursued many improvements in railway signals (which then used oil lamps). In 1881 he founded the Union Switch and Signal Company to manufacture his signaling and switching inventions.

Electric power distribution

Westinghouse's interests in gas distribution and telephone switching led him to become interested in the then-new field of electrical power distribution in the early 1880s. Electric lighting was a growing business with many companies building outdoor direct current (DC) and alternating current (AC) arc lighting based street lighting systems. At the same time, Thomas Edison was launching the first DC electric utility designed to light homes and businesses with his patented incandescent bulb. In 1884, Westinghouse started developing his own DC domestic lighting system and hired physicist William Stanley to work on it. Westinghouse became aware of the new European alternating current systems in 1885 when he read about them in the UK technical journal Engineering. AC had the ability to be "stepped up" in voltage by a transformer for distribution and then "stepped down" by a transformer for consumer use, allowing large centralized power plants to supply electricity long distance in cities with more dispersed populations. This was an advantage over the low voltage DC systems being marketed by Thomas Edison's electric utility which had a limited range due to the low voltages used. Westinghouse saw AC's potential to achieve greater economies of scale as way to build a truly competitive system instead of simply building another barely competitive DC lighting system using patents just different enough to get around the Edison patents.

In 1885 Westinghouse imported several Gaulard–Gibbs transformers and a Siemens AC generator, to begin experimenting with AC networks in Pittsburgh. Stanley, assisted by engineers Albert Schmid and Oliver B. Shallenberger, developed the Gaulard–Gibbs transformer design into the first practical transformer. In 1886, with Westinghouse's backing, Stanley installed the first multiple-voltage AC power system in Great Barrington, Massachusetts, a demonstration lighting system driven by a hydroelectric generator that produced 500 volts AC stepped down to 100 volts to light incandescent bulbs in homes and businesses. That same year, Westinghouse formed the "Westinghouse Electric & Manufacturing Company"; in 1889 he renamed it as "Westinghouse Electric Corporation".

War of the currents
The Westinghouse company installed 30 more AC-lighting systems within a year and by the end of 1887 it had 68 alternating current power stations to Edison's 121 DC-based stations. This competition with Edison led in the late 1880s to what has been called the "war of currents" with Thomas Edison and his company joining in with a spreading public perception that the high voltages used in AC distribution were unsafe. Edison even suggested a Westinghouse AC generator be used in the State of New York's new electric chair. Westinghouse also had to deal with an AC rival, the Thomson-Houston Electric Company, which had built 22 power stations by the end of 1887 and by 1889 had bought out another competitor, the Brush Electric Company. Thomson-Houston was expanding its business while trying to avoid patent conflicts with Westinghouse, arranging deals such as coming to agreements over lighting company territory, paying a royalty to use the Stanley transformer patent, and allowing Westinghouse to use their Sawyer–Man incandescent bulb patent. The Edison company, in collusion with Thomson-Houston, managed to arrange in 1890 that the first electric chair was powered with a Westinghouse AC generator, forcing Westinghouse to try to block this move by hiring the best lawyer of the day to (unsuccessfully) defend William Kemmler, the first man scheduled to die in the chair. The War of Currents ended with financiers, such as J. P. Morgan, pushing Edison Electric towards AC and pushing out Thomas Edison. In 1892 the Edison company was merged with the Thomson-Houston Electric Company to form General Electric, a conglomerate with the board of Thomson-Houston in control.

Development and competition
During this period, Westinghouse continued to pour funds and engineering resources into the goal of building a completely integrated AC system — obtaining the Sawyer–Man lamp by buying Consolidated Electric Light, developing components such as an induction meter, and obtaining the rights to inventor Nikola Tesla's brushless AC induction motor along with patents for a new type of electric power distribution, polyphase alternating current. The acquisition of a feasible AC motor gave Westinghouse a key patent for his system, but the financial strain of buying up patents and hiring the engineers needed to build it meant development of Tesla's motor had to be put on hold for a while.

In 1890 Westinghouse's company was in trouble. The near collapse of Barings Bank in London triggered the financial panic of 1890, causing investors to call in their loans. The sudden cash shortage forced the company to refinance its debts. The new lenders demanded that Westinghouse cut back on what looked like excessive spending on acquisition of other companies, research, and patents.

In 1891 Westinghouse built a hydroelectric AC power plant, the Ames Hydroelectric Generating Plant near Ophir, Colorado. The plant supplied power to the Gold King Mine 3.5 miles away. This was the first successful demonstration of long-distance transmission of industrial-grade alternating current power and used two 100 hp Westinghouse alternators, one working as a generator producing 3000-volt, 133-Hertz, single-phase AC, and the other used as an AC motor. At the beginning of 1893 Westinghouse engineer Benjamin Lamme had made great progress developing an efficient version of Tesla's induction motor and Westinghouse Electric started branding their complete polyphase AC system as the "Tesla Polyphase System", announcing Tesla's patents gave them patent priority over other AC systems and their intentions to sue patent infringers.

In 1893, George Westinghouse won the bid to light the 1893 World's Columbian Exposition in Chicago with alternating current, slightly underbidding General Electric to get the contract. This World's Fair devoted a building to electrical exhibits. It was a key event in the history of AC power, as Westinghouse demonstrated the safety, reliability, and efficiency of a fully integrated alternating current system to the American public.

Westinghouse's demonstration that they could build a complete AC system at the Columbian Exposition was instrumental in them getting the contract for building a two-phase AC generating system, the Adams Power Plant, at Niagara Falls in 1895. At the same time, a contract to build the three-phase AC distribution system the project needed was awarded to General Electric. The early to mid-1890s saw General Electric, backed by financier J. P. Morgan, involved in costly takeover attempts and patent battles with Westinghouse Electric. The competition was so costly a patent-sharing agreement was signed between the two companies in 1896.

Other projects: natural gas, steam engines, shock absorbers
By 1883, Westinghouse had become interested in drilling for and distributing natural gas. Gas had been found a few years earlier in nearby Murrysville, Pennsylvania. He decided to drill for gas on his estate "Solitude" (today's Westinghouse Park) in Pittsburgh. When the drilling struck gas on the night of May 21, 1884, it caused a local sensation and encouraged him to further develop a natural gas distribution system to deliver gas to homes and businesses for heating and lighting. He obtained over 30 patents for this technology and founded the Philadelphia Company to market and promote the use of natural gas. In 1886 the company had 58 wells and 184 miles of distribution piping in Pittsburgh, and by 1887 it served over 12,000 private homes and 582 industrial customers. Growth of the business was limited in the 1890s by natural gas supply problems and ongoing concerns about the safety of gas distribution systems in homes and businesses. Westinghouse resigned as president of the Philadelphia Company in 1889 as his involvement with the generation and distribution of electricity were increasing.

Westinghouse was interested in electrical power production. At the outset, the available generating sources were hydroturbines where falling water was available, and reciprocating steam engines where it was not. Westinghouse felt that reciprocating steam engines were clumsy and inefficient, and wanted to develop some class of "rotating" engine that would be more elegant and efficient. One of his first inventions had been a rotary steam engine, but it had proven impractical. The British engineer Charles Algernon Parsons began experimenting with steam turbines in 1884, beginning with a 10-horsepower (7.5 kW) turbine. Westinghouse bought rights to the Parsons turbine in 1885, improved the Parsons technology, and increased its scale. In 1898 Westinghouse demonstrated a 300-kilowatt unit, replacing reciprocating engines in his air-brake factory. The next year he installed a 1.5-megawatt, 1,200 rpm unit for the Hartford Electric Light Company.

Westinghouse then developed steam turbines for maritime propulsion. Large turbines were most efficient at about 3,000 rpm, while an efficient propeller operated at about 100 rpm. That required reduction gearing, but building reduction gearing that could operate at high rpm and at high power was difficult, since a slight misalignment would shake the power train to pieces. Westinghouse and his engineers devised an automatic alignment system that made turbine power practical for large vessels.

In 1889, Westinghouse purchased several mining claims in the Patagonia Mountains of southeastern Arizona and formed the Duquesne Mining & Reduction Company. A year later he founded Duquesne to use as his company headquarters; it is now a ghost town. He lived in a large Victorian frame house, which still stands, but in disrepair. Duquesne grew to over 1,000 residents and the mine reached its peak production in the mid-1910s.

With the introduction of the automobile after the turn of the century, Westinghouse went back to earlier inventions and devised a compressed air shock absorber for automobile suspensions.

At one time, Westinghouse began to work on heat pumps that could provide heating and cooling. Westinghouse was after a perpetual motion machine, and the British physicist Lord Kelvin, one of Westinghouse's correspondents, told him that he would be violating the laws of thermodynamics. Westinghouse replied that might be the case, but it made no difference. If he couldn't build a perpetual-motion machine, he would still have a heat pump system that he could patent and sell.

Personal life, later life, and death
In 1867, Westinghouse met and soon married Marguerite Erskine Walker. They were married for 47 years, and had one son, George Westinghouse III, who had six children.

Westinghouse remained a captain of American industry until 1907, when the financial panic of 1907 led to his resignation from control of the Westinghouse company. By 1911, he was no longer active in business, and his health was in decline.

George Westinghouse died on March 12, 1914, in New York City at age 67. He was initially interred in Woodlawn Cemetery, Bronx, NY then removed on December 14, 1915. As a Civil War veteran, he was buried in Arlington National Cemetery, along with his wife Marguerite, who survived him by three months. She had also been initially interred in Woodlawn and removed and reinterred at the same time as George.

Honors and awards
In 1918 his former home, Solitude, was razed and the land given to the City of Pittsburgh to establish Westinghouse Park. In 1930, the Westinghouse Memorial, funded by his employees, was placed in Schenley Park in Pittsburgh. Also named in his honor, George Westinghouse Bridge is near the site of his Turtle Creek plant. Its plaque reads:

The George Westinghouse Jr. Birthplace and Boyhood Home in Central Bridge, New York, was listed on the National Register of Historic Places in 1986.

In 1989, Westinghouse was inducted into the National Inventors Hall of Fame.

Patents

 * , grain and seed winnowers
 * , improvements in steam engine and pump
 * , improvement in atmospheric car-brake pipes
 * , improvement in steam-power-brake couplings
 * , improvement in valves for fluid brake-pipes
 * , pneumatic pump
 * , improvement in fluid-pressure brake apparatus
 * , fluid-pressure regulator
 * , electrical converter
 * , system of electrical distribution
 * , system for the protection of railroad-tracks and gas-pipe lines
 * , fluid-meter
 * , fluid-pressure automatic brake mechanism
 * , alternating current electric meter
 * , fluid-pressure automatic brake
 * , switch and signal apparatus
 * , pipe-coupling
 * , conduit electric railway
 * , draw-gear apparatus for cars
 * , incandescent electric lamp
 * , electric railway
 * , current-collecting device for railway-vehicles
 * , elevator
 * , electric railway
 * , fluid pressure automatic brake
 * , draft appliance for railway cars
 * , draw-gear and buffing apparatus
 * , electric railway system
 * , draw-gear and buffing apparatus
 * , automatic fluid pressure brake apparatus
 * , gearing
 * , elastic-fluid turbine
 * , electric railway

title: George Westinghouse


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Antiviral drug

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.

Medical uses
Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses, the hepatitis B and C viruses, and influenza A and B viruses.

Viruses use the host's cells to replicate and this makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and antiviral drugs is due to viral variation.

The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS).

The first experimental antivirals were developed in the 1960s, mostly to deal with herpes viruses, and were found using traditional trial-and-error drug discovery methods. Researchers grew cultures of cells and infected them with the target virus. They then introduced into the cultures chemicals which they thought might inhibit viral activity and observed whether the level of virus in the cultures rose or fell. Chemicals that seemed to have an effect were selected for closer study.

This was a very time-consuming, hit-or-miss procedure, and in the absence of a good knowledge of how the target virus worked, it was not efficient in discovering effective antivirals which had few side effects. Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did researchers begin to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their reproductive cycle.

Antiviral targeting
The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled. These "targets" should generally be as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects and toxicity. The targets should also be common across many strains of a virus, or even among different species of virus in the same family, so a single drug will have broad effectiveness. For example, a researcher might target a critical enzyme synthesized by the virus, but not by the patient, that is common across strains, and see what can be done to interfere with its operation.

Once targets are identified, candidate drugs can be selected, either from drugs already known to have appropriate effects or by actually designing the candidate at the molecular level with a computer-aided design program.

The target proteins can be manufactured in the lab for testing with candidate treatments by inserting the gene that synthesizes the target protein into bacteria or other kinds of cells. The cells are then cultured for mass production of the protein, which can then be exposed to various treatment candidates and evaluated with "rapid screening" technologies.

Approaches by virus life cycle stage
Viruses consist of a genome and sometimes a few enzymes stored in a capsule made of protein (called a capsid), and sometimes covered with a lipid layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own and instead propagate by subjugating a host cell to produce copies of themselves, thus producing the next generation.

Researchers working on such "rational drug design" strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects. Compounds isolated from fruiting bodies and filtrates of various mushrooms have broad-spectrum antiviral activities, but successful production and availability of such compounds as frontline antiviral is a long way away.

Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern:
 * 1) Attachment to a host cell.
 * 2) Release of viral genes and possibly enzymes into the host cell.
 * 3) Replication of viral components using host-cell machinery.
 * 4) Assembly of viral components into complete viral particles.
 * 5) Release of viral particles to infect new host cells.

Before cell entry
One antiviral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a sequence of steps to do this, beginning with binding to a specific "receptor" molecule on the surface of the host cell and ending with the virus "uncoating" inside the cell and releasing its contents. Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell before they can uncoat.

This stage of viral replication can be inhibited in two ways:
 * 1) Using agents which mimic the virus-associated protein (VAP) and bind to the cellular receptors. This may include VAP anti-idiotypic antibodies, natural ligands of the receptor and anti-receptor antibodies.
 * 2) Using agents which mimic the cellular receptor and bind to the VAP. This includes anti-VAP antibodies, receptor anti-idiotypic antibodies, extraneous receptor and synthetic receptor mimics.

This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies is partly trial and error, it can be a relatively slow process until an adequate molecule is produced.

Entry inhibitor
A very early stage of viral infection is viral entry, when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets a specific type of lymphocyte known as "helper T cells", and identifies these target cells through T-cell surface receptors designated "CD4" and "CCR5". Attempts to interfere with the binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.

HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor (differing depending on the cell type). Approaches to blocking this virus/cell fusion have shown some promise in preventing entry of the virus into a cell. At least one of these entry inhibitors—a biomimetic peptide called Enfuvirtide, or the brand name Fuzeon—has received FDA approval and has been in use for some time. Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual.

One possible advantage of the therapeutic approach of blocking viral entry (as opposed to the currently dominant approach of viral enzyme inhibition) is that it may prove more difficult for the virus to develop resistance to this therapy than for the virus to mutate or evolve its enzymatic protocols.

Uncoating inhibitors
Inhibitors of uncoating have also been investigated.

Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating.

Pleconaril works against rhinoviruses, which cause the common cold, by blocking a pocket on the surface of the virus that controls the uncoating process. This pocket is similar in most strains of rhinoviruses and enteroviruses, which can cause diarrhea, meningitis, conjunctivitis, and encephalitis.

Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable. Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers reported in Nature Communications in 2016.

Rhinoviruses are the most common cause of the common cold; other viruses such as respiratory syncytial virus, parainfluenza virus and adenoviruses can cause them too. Rhinoviruses also exacerbate asthma attacks. Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree.

During viral synthesis
A second approach is to target the processes that synthesize virus components after a virus invades a cell.

Reverse transcription
One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA, but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of reverse transcriptase (RNA to DNA) than with "normal" transcriptase (DNA to RNA).

The first successful antiviral, aciclovir, is a nucleoside analogue, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analogue.

An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections. One of these drugs, lamivudine, has been approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase.

Another target being considered for HIV antivirals include RNase H—which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA.

Integrase
Another target is integrase, which integrate the synthesized DNA into the host cell genome. Examples of integrase inhibitors include raltegravir, elvitegravir, and dolutegravir.

Transcription
Once a virus genome becomes operational in a host cell, it then generates messenger RNA (mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factors. Several antivirals are now being designed to block attachment of transcription factors to viral DNA.

Translation/antisense
Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug, based on "antisense" molecules. These are segments of DNA or RNA that are designed as complementary molecule to critical sections of viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes. A phosphorothioate antisense drug named fomivirsen has been introduced, used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus, and other antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is morpholino antisense.

Morpholino oligos have been used to experimentally suppress many viral types:
 * caliciviruses
 * flaviviruses (including West Nile virus)
 * dengue
 * HCV
 * coronaviruses

Translation/ribozymes
Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymes, which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable them.

A ribozyme antiviral to deal with hepatitis C has been suggested, and ribozyme antivirals are being developed to deal with HIV. An interesting variation of this idea is the use of genetically modified cells that can produce custom-tailored ribozymes. This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by generating specialized proteins that block viral replication at various phases of the viral life cycle.

Protein processing and targeting
Interference with post translational modifications or with targeting of viral proteins in the cell is also possible.

Protease inhibitors
Some viruses include an enzyme known as a protease that cuts viral protein chains apart so they can be assembled into their final configuration. HIV includes a protease, and so considerable research has been performed to find "protease inhibitors" to attack HIV at that phase of its life cycle. Protease inhibitors became available in the 1990s and have proven effective, though they can have unusual side effects, for example causing fat to build up in unusual places. Improved protease inhibitors are now in development.

Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the shiitake mushroom (Lentinus edodes). The presence of this may explain the Shiitake mushrooms' noted antiviral activity in vitro.

Long dsRNA helix targeting
Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription. DRACO (double-stranded RNA activated caspase oligomerizer) is a group of experimental antiviral drugs initially developed at the Massachusetts Institute of Technology. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus, and was additionally found effective against influenza in vivo in weanling mice. It was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. DRACO effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases. The procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell.

Assembly
Rifampicin acts at the assembly phase.

Release phase
The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named zanamivir (Relenza) and oseltamivir (Tamiflu) that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.

Immune system stimulation
Rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. Some antivirals of this sort do not focus on a specific pathogen, instead stimulating the immune system to attack a range of pathogens.

One of the best-known of this class of drugs are interferons, which inhibit viral synthesis in infected cells. One form of human interferon named "interferon alpha" is well-established as part of the standard treatment for hepatitis B and C, and other interferons are also being investigated as treatments for various diseases.

A more specific approach is to synthesize antibodies, protein molecules that can bind to a pathogen and mark it for attack by other elements of the immune system. Once researchers identify a particular target on the pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. A monoclonal drug is now being sold to help fight respiratory syncytial virus in babies, and antibodies purified from infected individuals are also used as a treatment for hepatitis B.

Antiviral drug resistance
Antiviral resistance can be defined by a decreased susceptibility to a drug caused by changes in viral genotypes. In cases of antiviral resistance, drugs have either diminished or no effectiveness against their target virus. The issue inevitably remains a major obstacle to antiviral therapy as it has developed to almost all specific and effective antimicrobials, including antiviral agents.

The Centers for Disease Control and Prevention (CDC) inclusively recommends anyone six months and older to get a yearly vaccination to protect them from influenza A viruses (H1N1) and (H3N2) and up to two influenza B viruses (depending on the vaccination). Comprehensive protection starts by ensuring vaccinations are current and complete. However, vaccines are preventative and are not generally used once a patient has been infected with a virus. Additionally, the availability of these vaccines can be limited based on financial or locational reasons which can prevent the effectiveness of herd immunity, making effective antivirals a necessity.

The three FDA-approved neuraminidase antiviral flu drugs available in the United States, recommended by the CDC, include: oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab). Influenza antiviral resistance often results from changes occurring in neuraminidase and hemagglutinin proteins on the viral surface. Currently, neuraminidase inhibitors (NAIs) are the most frequently prescribed antivirals because they are effective against both influenza A and B. However, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent NAI binding. This was seen in the H257Y mutation, which was responsible for oseltamivir resistance to H1N1 strains in 2009. The inability of NA inhibitors to bind to the virus allowed this strain of virus with the resistance mutation to spread due to natural selection. Furthermore, a study published in 2009 in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir stockpiles with additional antiviral drugs including zanamivir. This finding was based on a performance evaluation of these drugs supposing the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the oseltamivir-resistance (His274Tyr) mutation, which is currently widespread in seasonal H1N1 strains.

Origin of antiviral resistance
The genetic makeup of viruses is constantly changing, which can cause a virus to become resistant to currently available treatments. Viruses can become resistant through spontaneous or intermittent mechanisms throughout the course of an antiviral treatment. Immunocompromised patients, more often than immunocompetent patients, hospitalized with pneumonia are at the highest risk of developing oseltamivir resistance during treatment. Subsequent to exposure to someone else with the flu, those who received oseltamivir for "post-exposure prophylaxis" are also at higher risk of resistance.

The mechanisms for antiviral resistance development depend on the type of virus in question. RNA viruses such as hepatitis C and influenza A have high error rates during genome replication because RNA polymerases lack proofreading activity. RNA viruses also have small genome sizes that are typically less than 30 kb, which allow them to sustain a high frequency of mutations. DNA viruses, such as HPV and herpesvirus, hijack host cell replication machinery, which gives them proofreading capabilities during replication. DNA viruses are therefore less error prone, are generally less diverse, and are more slowly evolving than RNA viruses. In both cases, the likelihood of mutations is exacerbated by the speed with which viruses reproduce, which provides more opportunities for mutations to occur in successive replications. Billions of viruses are produced every day during the course of an infection, with each replication giving another chance for mutations that encode for resistance to occur.

Multiple strains of one virus can be present in the body at one time, and some of these strains may contain mutations that cause antiviral resistance. This effect, called the quasispecies model, results in immense variation in any given sample of virus, and gives the opportunity for natural selection to favor viral strains with the highest fitness every time the virus is spread to a new host. Recombination, the joining of two different viral variants, and reassortment, the swapping of viral gene segments among viruses in the same cell, also play a role in resistance, especially in influenza.

Antiviral resistance has been reported in antivirals for herpes, HIV, hepatitis B and C, and influenza, but antiviral resistance is a possibility for all viruses. Mechanisms of antiviral resistance vary between virus types.

Detection of antiviral resistance
National and international surveillance is performed by the CDC to determine effectiveness of the current FDA-approved antiviral flu drugs. Public health officials use this information to make current recommendations about the use of flu antiviral medications. WHO further recommends in-depth epidemiological investigations to control potential transmission of the resistant virus and prevent future progression. As novel treatments and detection techniques to antiviral resistance are enhanced so can the establishment of strategies to combat the inevitable emergence of antiviral resistance.

Treatment options for antiviral resistant pathogens
If a virus is not fully wiped out during a regimen of antivirals, treatment creates a bottleneck in the viral population that selects for resistance, and there is a chance that a resistant strain may repopulate the host. Viral treatment mechanisms must therefore account for the selection of resistant viruses.

The most commonly used method for treating resistant viruses is combination therapy, which uses multiple antivirals in one treatment regimen. This is thought to decrease the likelihood that one mutation could cause antiviral resistance, as the antivirals in the cocktail target different stages of the viral life cycle. This is frequently used in retroviruses like HIV, but a number of studies have demonstrated its effectiveness against influenza A, as well. Viruses can also be screened for resistance to drugs before treatment is started. This minimizes exposure to unnecessary antivirals and ensures that an effective medication is being used. This may improve patient outcomes and could help detect new resistance mutations during routine scanning for known mutants. However, this has not been consistently implemented in treatment facilities at this time.

Direct-acting antivirals
The term Direct-acting antivirals (DAA) has long been associated with the combination of antiviral drugs used to treat hepatitis C infections. These are the more effective than older treatments such as ribavirin (partially indirectly acting) and interferon (indirect acting). The DAA drugs against hepatitis C are taken orally, as tablets, for 8 to 12 weeks. The treatment depends on the type or types (genotypes) of hepatitis C virus that are causing the infection. Both during and at the end of treatment, blood tests are used to monitor the effectiveness of the treatment and subsequent cure.

The DAA combination drugs used include:
 * Harvoni (sofosbuvir and ledipasvir)
 * Epclusa (sofosbuvir and velpatasvir)
 * Vosevi (sofosbuvir, velpatasvir, and voxilaprevir)
 * Zepatier (elbasvir and grazoprevir)
 * Mavyret (glecaprevir and pibrentasvir)

The United States Food and Drug Administration approved DAAs on the basis of a surrogate endpoint called sustained virological response (SVR). SVR is achieved in a patient when hepatitis C virus RNA remains undetectable 12–24 weeks after treatment ends. Whether through DAAs or older interferon-based regimens, SVR is associated with improved health outcomes and significantly decreased mortality. For those who already have advanced liver disease (including hepatocellular carcinoma), however, the benefits of achieving SVR may be less pronounced, though still substantial.

Despite its historical roots in hepatitis C research, the term "direct-acting antivirals" is becoming more broadly used to also include other anti-viral drugs with a direct viral target such as aciclovir (against herpes simplex virus), letermovir (against cytomegalovirus), or AZT (against human immunodeficiency virus). In this context it serves to distinguish these drugs from those with an indirect mechanism of action such as immune modulators like interferon alfa. This difference is of particular relevance for potential drug resistance mutation development.

Use and distribution
Guidelines regarding viral diagnoses and treatments change frequently and limit quality care. Even when physicians diagnose older patients with influenza, use of antiviral treatment can be low. Provider knowledge of antiviral therapies can improve patient care, especially in geriatric medicine. Furthermore, in local health departments (LHDs) with access to antivirals, guidelines may be unclear, causing delays in treatment. With time-sensitive therapies, delays could lead to lack of treatment. Overall, national guidelines, regarding infection control and management, standardize care and improve healthcare worker and patient safety. Guidelines, such as those provided by the Centers for Disease Control and Prevention (CDC) during the 2009 flu pandemic caused by the H1N1 virus, recommend, among other things, antiviral treatment regimens, clinical assessment algorithms for coordination of care, and antiviral chemoprophylaxis guidelines for exposed persons. Roles of pharmacists and pharmacies have also expanded to meet the needs of public during public health emergencies.

Stockpiling
Public Health Emergency Preparedness initiatives are managed by the CDC via the Office of Public Health Preparedness and Response. Funds aim to support communities in preparing for public health emergencies, including pandemic influenza. Also managed by the CDC, the Strategic National Stockpile (SNS) consists of bulk quantities of medicines and supplies for use during such emergencies. Antiviral stockpiles prepare for shortages of antiviral medications in cases of public health emergencies. During the H1N1 pandemic in 2009–2010, guidelines for SNS use by local health departments was unclear, revealing gaps in antiviral planning. For example, local health departments that received antivirals from the SNS did not have transparent guidance on the use of the treatments. The gap made it difficult to create plans and policies for their use and future availabilities, causing delays in treatment.

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title: Antiviral drug


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Reductionism

Reductionism is any of several related philosophical ideas regarding the associations between phenomena which can be described in terms of other simpler or more fundamental phenomena. It is also described as an intellectual and philosophical position that interprets a complex system as the sum of its parts.

Definitions
The Oxford Companion to Philosophy suggests that reductionism is "one of the most used and abused terms in the philosophical lexicon" and suggests a three-part division:
 * 1) Ontological reductionism: a belief that the whole of reality consists of a minimal number of parts.
 * 2) Methodological reductionism: the scientific attempt to provide an explanation in terms of ever-smaller entities.
 * 3) Theory reductionism: the suggestion that a newer theory does not replace or absorb an older one, but reduces it to more basic terms. Theory reduction itself is divisible into three parts: translation, derivation, and explanation.

Reductionism can be applied to any phenomenon, including objects, problems, explanations, theories, and meanings.

For the sciences, application of methodological reductionism attempts explanation of entire systems in terms of their individual, constituent parts and their interactions. For example, the temperature of a gas is reduced to nothing beyond the average kinetic energy of its molecules in motion. Thomas Nagel and others speak of 'psychophysical reductionism' (the attempted reduction of psychological phenomena to physics and chemistry), and 'physico-chemical reductionism' (the attempted reduction of biology to physics and chemistry). In a very simplified and sometimes contested form, reductionism is said to imply that a system is nothing but the sum of its parts.

However, a more nuanced opinion is that a system is composed entirely of its parts, but the system will have features that none of the parts have (which, in essence is the basis of emergentism). "The point of mechanistic explanations is usually showing how the higher level features arise from the parts."

Other definitions are used by other authors. For example, what John Polkinghorne terms 'conceptual' or 'epistemological' reductionism is the definition provided by Simon Blackburn and by Jaegwon Kim: that form of reductionism which concerns a program of replacing the facts or entities involved in one type of discourse with other facts or entities from another type, thereby providing a relationship between them. Richard Jones distinguishes ontological and epistemological reductionism, arguing that many ontological and epistemological reductionists affirm the need for different concepts for different degrees of complexity while affirming a reduction of theories.

The idea of reductionism can be expressed by "levels" of explanation, with higher levels reducible if need be to lower levels. This use of levels of understanding in part expresses our human limitations in remembering detail. However, "most philosophers would insist that our role in conceptualizing reality [our need for a hierarchy of "levels" of understanding] does not change the fact that different levels of organization in reality do have different 'properties'."

Reductionism does not preclude the existence of what might be termed emergent phenomena, but it does imply the ability to understand those phenomena completely in terms of the processes from which they are composed. This reductionist understanding is very different from ontological or strong emergentism, which intends that what emerges in "emergence" is more than the sum of the processes from which it emerges, respectively either in the ontological sense or in the epistemological sense.

Ontological reductionism
Richard Jones divides ontological reductionism into two: the reductionism of substances (e.g., the reduction of mind to matter) and the reduction of the number of structures operating in nature (e.g., the reduction of one physical force to another). This permits scientists and philosophers to affirm the former while being anti-reductionists regarding the latter.

Nancey Murphy has claimed that there are two species of ontological reductionism: one that claims that wholes are nothing more than their parts; and atomist reductionism, claiming that wholes are not "really real". She admits that the phrase "really real" is apparently senseless but she has tried to explicate the supposed difference between the two.

Ontological reductionism denies the idea of ontological emergence, and claims that emergence is an epistemological phenomenon that only exists through analysis or description of a system, and does not exist fundamentally.

In some scientific disciplines, ontological reductionism takes two forms: token-identity theory and type-identity theory. In this case, "token" refers to a biological process.

Token ontological reductionism is the idea that every item that exists is a sum item. For perceivable items, it affirms that every perceivable item is a sum of items with a lesser degree of complexity. Token ontological reduction of biological things to chemical things is generally accepted.

Type ontological reductionism is the idea that every type of item is a sum type of item, and that every perceivable type of item is a sum of types of items with a lesser degree of complexity. Type ontological reduction of biological things to chemical things is often rejected.

Michael Ruse has criticized ontological reductionism as an improper argument against vitalism.

Methodological reductionism
In a biological context, methodological reductionism means attempting to explain all biological phenomena in terms of their underlying biochemical and molecular processes.

In religion
Anthropologists Edward Burnett Tylor and James George Frazer employed some religious reductionist arguments.

Theory reductionism
Theory reduction is the process by which a more general theory absorbs a special theory. It can be further divided into translation, derivation, and explanation. For example, both Kepler's laws of the motion of the planets and Galileo's theories of motion formulated for terrestrial objects are reducible to Newtonian theories of mechanics because all the explanatory power of the former are contained within the latter. Furthermore, the reduction is considered beneficial because Newtonian mechanics is a more general theory—that is, it explains more events than Galileo's or Kepler's. Besides scientific theories, theory reduction more generally can be the process by which one explanation subsumes another.

In mathematics
In mathematics, reductionism can be interpreted as the philosophy that all mathematics can (or ought to) be based on a common foundation, which for modern mathematics is usually axiomatic set theory. Ernst Zermelo was one of the major advocates of such an opinion; he also developed much of axiomatic set theory. It has been argued that the generally accepted method of justifying mathematical axioms by their usefulness in common practice can potentially weaken Zermelo's reductionist claim.

Jouko Väänänen has argued for second-order logic as a foundation for mathematics instead of set theory, whereas others have argued for category theory as a foundation for certain aspects of mathematics.

The incompleteness theorems of Kurt Gödel, published in 1931, caused doubt about the attainability of an axiomatic foundation for all of mathematics. Any such foundation would have to include axioms powerful enough to describe the arithmetic of the natural numbers (a subset of all mathematics). Yet Gödel proved that, for any consistent recursively enumerable axiomatic system powerful enough to describe the arithmetic of the natural numbers, there are (model-theoretically) true propositions about the natural numbers that cannot be proved from the axioms. Such propositions are known as formally undecidable propositions. For example, the continuum hypothesis is undecidable in the Zermelo–Fraenkel set theory as shown by Cohen.

In science
Reductionist thinking and methods form the basis for many of the well-developed topics of modern science, including much of physics, chemistry and molecular biology. Classical mechanics in particular is seen as a reductionist framework. For instance, we understand the solar system in terms of its components (the sun and the planets) and their interactions. Statistical mechanics can be considered as a reconciliation of macroscopic thermodynamic laws with the reductionist method of explaining macroscopic properties in terms of microscopic components, although it has been argued that reduction in physics 'never goes all the way in practice'.

In computer science
The role of reduction in computer science can be thought as a precise and unambiguous mathematical formalization of the philosophical idea of "theory reductionism". In a general sense, a problem (or set) is said to be reducible to another problem (or set), if there is a computable/feasible method to translate the questions of the former into the latter, so that, if one knows how to computably/feasibly solve the latter problem, then one can computably/feasibly solve the former. Thus, the latter can only be at least as "hard" to solve as the former.

Reduction in theoretical computer science is pervasive in both: the mathematical abstract foundations of computation; and in real-world performance or capability analysis of algorithms. More specifically, reduction is a foundational and central concept, not only in the realm of mathematical logic and abstract computation in computability (or recursive) theory, where it assumes the form of e.g. Turing reduction, but also in the realm of real-world computation in time (or space) complexity analysis of algorithms, where it assumes the form of e.g. polynomial-time reduction.

Free will
Philosophers of the Enlightenment worked to insulate human free will from reductionism. Descartes separated the material world of mechanical necessity from the world of mental free will. German philosophers introduced the concept of the "noumenal" realm that is not governed by the deterministic laws of "phenomenal" nature, where every event is completely determined by chains of causality. The most influential formulation was by Immanuel Kant, who distinguished between the causal deterministic framework the mind imposes on the world—the phenomenal realm—and the world as it exists for itself, the noumenal realm, which, as he believed, included free will. To insulate theology from reductionism, 19th century post-Enlightenment German theologians, especially Friedrich Schleiermacher and Albrecht Ritschl, used the Romantic method of basing religion on the human spirit, so that it is a person's feeling or sensibility about spiritual matters that comprises religion.

Causation
Most common philosophical understandings of causation involve reducing it to some collection of non-causal facts. Opponents of these reductionist views have given arguments that the non-causal facts in question are insufficient to determine the causal facts.

Alfred North Whitehead's metaphysics opposed reductionism. He refers to this as the "fallacy of the misplaced concreteness". His scheme was to frame a rational, general understanding of phenomena, derived from our reality.

In science
An alternative term for ontological reductionism is fragmentalism, often used in a pejorative sense. In cognitive psychology, George Kelly developed "constructive alternativism" as a form of personal construct psychology and an alternative to what he considered "accumulative fragmentalism". For this theory, knowledge is seen as the construction of successful mental models of the exterior world, rather than the accumulation of independent "nuggets of truth". Others argue that inappropriate use of reductionism limits our understanding of complex systems. In particular, ecologist Robert Ulanowicz says that science must develop techniques to study ways in which larger scales of organization influence smaller ones, and also ways in which feedback loops create structure at a given level, independently of details at a lower level of organization. He advocates and uses information theory as a framework to study propensities in natural systems. The limits of the application of reductionism are claimed to be especially evident at levels of organization with greater complexity, including living cells, neural networks (biology), ecosystems, society, and other systems formed from assemblies of large numbers of diverse components linked by multiple feedback loops.

title: Reductionism