National Archives and Records Administration

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https://en.wikipedia.org/wiki/National_Archives_and_Records_Administration 

National Archives and Records Administration

NARA
Seal
National Archives logo, a stone eagle inspired by the architecture of the National Archives Building in Washington, D.C.
Agency overview
Formed	June 19, 1934 (Independent Agency April 1, 1985)
Preceding agency	National Archives and Records Service (GSA)
Type	Independent
Jurisdiction	U.S. Federal Government
Headquarters	National Archives Building 700 Pennsylvania Avenue NW, Washington, D.C., U.S.
Employees	3,112 (2014)
Annual budget	$391 million (FY 2012)
Agency executives	David Ferriero, Archivist Debra Steidel Wall, Deputy Archivist
Child agency	Office of the Federal Register
Website	www.archives.gov

The National Archives and Records Administration (NARA) is an independent agency of the United States government charged with the preservation and documentation of government and historical records. It is also tasked with increasing public access to those documents which make up the National Archive. NARA is officially responsible for maintaining and publishing the legally authentic and authoritative copies of acts of Congress, presidential directives, and federal regulations. NARA also transmits votes of the Electoral College to Congress.

The National Archives, and its publicly exhibited Charters of Freedom, which include the original United States Declaration of Independence, United States Constitution, United States Bill of Rights, and many other historical documents, is headquartered in the National Archives Building in Washington, D.C.

Organization

The Archivist of the United States is the chief official overseeing the operation of the National Archives and Records Administration. The Archivist not only maintains the official documentation of the passage of amendments to the U.S. Constitution by state legislatures, but has the authority to declare when the constitutional threshold for passage has been reached, and therefore when an act has become an amendment.

The Office of the Federal Register publishes the Federal Register, Code of Federal Regulations, and United States Statutes at Large, among others. It also administers the Electoral College.

The National Historical Publications and Records Commission (NHPRC)—the agency's grant-making arm—awards funds to state and local governments, public and private archives, colleges and universities, and other nonprofit organizations to preserve and publish historical records. Since 1964, the NHPRC has awarded some 4,500 grants.

The Office of Government Information Services (OGIS) is a Freedom of Information Act (FOIA) resource for the public and the government. Congress has charged NARA with reviewing FOIA policies, procedures and compliance of Federal agencies and to recommend changes to FOIA. NARA's mission also includes resolving FOIA disputes between Federal agencies and requesters.

History

The Rotunda of the National Archives Building, where the Charters of Freedom documents are publicly exhibited

Originally, each branch and agency of the U.S. government was responsible for maintaining its own documents, which often resulted in the loss and destruction of records. Congress created the National Archives Establishment in 1934 to centralize federal record keeping, with the Archivist of the United States serving as chief administrator. R.D.W. Connor was chosen to be the first leader of the organization.

After a recommendation by the first Hoover Commission in 1949, the National Archives was placed within the newly formed General Services Administration (GSA). NARA was officially given its independence from the GSA with the passing of the Records Administration Act of 1984, thus giving birth to the institution we have today.

In December 1978, millions of feet of news reels were destroyed in a fire at an offsite location in Suitland, Maryland. The reels, made of exceptionally flammable nitrate material, had been donated previously by Universal Pictures and were stored in special vaults to protect against fires. In total over 12.6 million feet of film was destroyed.

In March 2006, it was revealed by the Archivist of the United States in a public hearing that a memorandum of understanding between NARA and various government agencies existed to "reclassify", i.e., withdraw from public access, certain documents in the name of national security, and to do so in a manner such that researchers would not be likely to discover the process (the U.S. reclassification program). An audit indicated that more than one third withdrawn since 1999 did not contain sensitive information. The program was originally scheduled to end in 2007.

In 2010, Executive Order 13526 created the National Declassification Center to coordinate declassification practices across agencies, provide secure document services to other agencies, and review records in NARA custody for declassification.

The National Archives found itself under public scrutiny when it initially agreed, in 2017, to requests from the U.S. Immigration and Customs Enforcement agency (ICE) to allow certain documents be scheduled for destruction.

Records

NARA's holdings are classed into "record groups" reflecting the governmental department or agency from which they originated. Records include paper documents, microfilm, still pictures, motion pictures, and electronic media.

Archival descriptions of the permanent holdings of the federal government in the custody of NARA are stored in the National Archives Catalog. The archival descriptions include information on traditional paper holdings, electronic records, and artifacts. As of December 2012, the catalog consisted of about 10 billion logical data records describing 527,000 artifacts and encompassing 81% of NARA's records. There are also 922,000 digital copies of already digitized materials.

Most records at NARA are in the public domain, as works of the federal government are excluded from copyright protection. However, records from other sources may still be protected by copyright or donor agreements. Executive Order 13526 directs originating agencies to declassify documents if possible before shipment to NARA for long-term storage, but NARA also stores some classified documents until they can be declassified. Its Information Security Oversight Office monitors and sets policy for the U.S. government's security classification system. 

Many of NARA's most requested records are frequently used for genealogy research. This includes census records from 1790 to 1940, ships' passenger lists, and naturalization records.

Archival Recovery Teams

Archival Recovery Teams investigate the theft of records.

Facilities and exhibition spaces

The National Archives Building from Constitution Avenue

The most well known facility of the National Archives and Records Administration is the National Archives Building (informally known as "Archives I"), located north of the National Mall on Constitution Avenue in Washington, D.C.. A sister facility, known as the National Archives at College Park ("Archives II") was opened 1994 near the University of Maryland, College Park. The Washington National Records Center (WNRC), also located in the Washington, D.C., metropolitan area, is a large warehouse facility where federal records that are still under the control of the creating agency are stored. Federal government agencies pay a yearly fee for storage at the facility. In accordance with federal records schedules, documents at WNRC are transferred to the legal custody of the National Archives after a certain time; this usually involves a relocation of the records to College Park. Temporary records at WNRC are either retained for a fee or destroyed after retention times have elapsed. WNRC also offers research services and maintains a small research room. 

Across the United States, the National Archives maintains both research facilities and additional federal records centers (FRCs). In many cases, the research rooms of regional archives are located at the same site as the federal records center, which are inaccessible to the public.

In April 2019 an unknown person set fire to an exterior wall of the archives building using a homemade incendiary device before firefighters were able to extinguish the flames.

Public–private partnerships

In an effort to make its holdings more widely available and more easily accessible, the National Archives began entering into public–private partnerships in 2006. A joint venture with Google will digitize and offer NARA video online. When announcing the agreement, Archivist Allen Weinstein said that this pilot program is

... an important step for the National Archives to achieve its goal of becoming an archive without walls. Our new strategic plan emphasizes the importance of providing access to records anytime, anywhere. This is one of many initiatives that we are launching to make our goal a reality. For the first time, the public will be able to view this collection of rare and unusual films on the Internet.

On January 10, 2007, the National Archives and Fold3.com (formerly Footnote) launched a pilot project to digitize historic documents from the National Archives holdings. Allen Weinstein explained that this partnership would "allow much greater access to approximately 4.5 million pages of important documents that are currently available only in their original format or on microfilm" and "would also enhance NARA's efforts to preserve its original records."

In July 2007, the National Archives announced it would make copies of its collection of Universal Newsreels from 1929 to 1967 available for purchase through CreateSpace, an Amazon.com subsidiary. During the announcement, Weinstein noted that the agreement would "... reap major benefits for the public-at-large and for the National Archives." Adding, "While the public can come to our College Park, Maryland, research room to view films and even copy them at no charge, this new program will make our holdings much more accessible to millions of people who cannot travel to the Washington, D.C. area." The agreement also calls for CreateSpace partnership to provide the National Archives with digital reference and preservation copies of the films as part of NARA's preservation program.

In May 2008, the National Archives announced a five-year agreement to digitize selected records including the complete U.S. Federal Census Collection, 1790–1930, passenger lists from 1820 to 1960 and World War I and World War II draft registration cards. The partnership agreement allows for exclusive use of the digitized records by Ancestry.com for a 5-year embargo period whereupon the digital records will be turned over to the National Archives.

Social media

The National Archives currently utilizes social media and Web 2.0 technologies in an attempt to communicate better with the public.

On June 18, 2009, the National Archives announced the launching of a YouTube channel "to showcase popular archived films, inform the public about upcoming events around the country, and bring National Archives exhibits to the people." Also in 2009, the National Archives launched a Flickr photostream to share portions of its photographic holdings with the general public. A new teaching-with-documents Web site premiered in 2010 and was developed by the education team. The site features 3,000 documents, images, and recordings from the holdings of the Archives. It also features lesson plans and tools for creating new classroom activities and lessons.

In 2011, the National Archives initiated a WikiProject on the English Wikipedia to expand collaboration in making its holdings widely available through Wikimedia.

Controversy

In January 2020, a Washington Post reporter noticed blurred protest signs in a 2017 Women's March image at the Archives' public exhibit. Some of the signs contained potentially offensive language, some mentioned the president. Besides censoring language, the edits changed the meaning of some protest signs. The agency defended the edits were made "so as not to engage in current political controversy" but admitted it "made a mistake… we were wrong to alter the image."

Notable crimes

• In 1963, Robert Bradford Murphy and his wife, Elizabeth Irene Murphy were arrested and sentenced to ten years in prison for stealing documents from several federal depositories, including the National Archives.
• In 1987, Charles Merrill Mount was arrested and sentenced to five years in prison for stealing 400 documents from the National Archives.
• In 2002, Shawn Aubitz pleaded guilty to stealing dozens of documents and photographs from the National Archives during the 1990s.
• In 2005, Sandy Berger was charged with an unauthorized removal of documents from the National Archives; sentenced to 100 hours of community service and fined $50,000.
• In 2005, Howard Harner was sentenced to two years in prison and fined $10,000 after stealing 100 documents from the National Archives.
• In 2006, Denning McTague was sentenced to 15 months in prison and fined $3,000 after stealing 164 documents from the National Archives.
• In 2011, Leslie Waffen was sentenced to 18 months in prison after stealing 955 recordings from the National Archives.
• In 2011, Thomas Lowry was permanently banned from the National Archives after he confessed to altering the date on a presidential pardon signed by Abraham Lincoln.
• In 2011, Barry Landau and Jason Savedoff were arrested and sentenced to seven-and-a-half years in prison for stealing ten thousand documents from the National Archives.
• In 2018, Antonin DeHays was arrested for multiple thefts of military artifacts and records from the National Archive during the mid to late 2010s.

Sons of the American Revolution

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Sons_of_the_American_Revolution 

National Society
of the
Sons of the American Revolution

Emblem of the Sons of the American Revolution
Logo used by the SAR
Abbreviation	SAR, NSSAR
Motto	"Libertas et patria" (Latin) "Liberty and Country"
Established	April 30, 1889
Type	Patriotic-Hereditary society
Legal status	Federally chartered corporation
Purpose	Fraternal, patriotic, historical, charitable, educational
Headquarters	809 West Main Street, Louisville, Kentucky
Region served	Nationwide
Membership	35,111 (2019)
Official language	English
Affiliations	Daughters of the American Revolution Children of the American Revolution
Website	sar.org

Philadelphia Continental Chapter of the SAR at a ceremony commemorating the birth of General and President George Washington at the Tomb of the Unknown Revolutionary War Soldier in Washington Square, Philadelphia

The National Society of the Sons of the American Revolution (SAR or NSSAR) is an American congressionally chartered organization, founded in 1889 and headquartered in Louisville, Kentucky. A non-profit corporation, it has described its purpose as maintaining and extending "the institutions of American freedom, an appreciation for true patriotism, a respect for our national symbols, the value of American citizenship, [and] the unifying force of 'e pluribus unum' that has created, from the people of many nations, one nation and one people."

The members of the society are male descendants of people who served in the American Revolutionary War or who contributed to establishing the independence of the United States. It is dedicated to perpetuating American ideals and traditions, and to protecting the Constitution of the United States; the official recognition of Constitution Day, Flag Day, and Bill of Rights Day were established through its efforts. It has members in the United States, Canada, France, Germany, Mexico, Spain, Switzerland, and the United Kingdom.

The organization is distinct from the Sons of the Revolution, a separate descendants heritage organization founded on February 22, 1876 by businessman John Austin Stevens and members of The Society of the Cincinnati. SAR Founder William Osborn McDowell disagreed with the Sons of the Revolution requirement at that time that all state societies were to be subordinate to the New York society.

History

Theodore Roosevelt, a member of the organization, signed its Congressional Charter in 1906

The first organization of descendants of Revolutionary War patriots was established in San Francisco, California, in 1876. A group of men who were descendants of Revolutionary War veterans gathered to celebrate the centennial of the Declaration of Independence and the founding of the United States. They also wanted to honor the men and women who pledged their lives, fortunes, and livelihood to the striving for independence from Great Britain. This group formed an organization called the Sons of Revolutionary War Sires (SRWS). There is, however, no direct link between the SRWS and the SAR except that members of the SRWS were permitted to join the SAR after its founding in 1889.

The history of the SAR can be traced to the founding of the Sons of the Revolution, the New York Society which was organized in 1876. The SR was founded by John Austin Stevens who envisioned an aristocratic social and hereditary organization along the lines of the Society of the Cincinnati. In 1889 William Osborn McDowell, a New Jersey financier and businessman, organized the New Jersey Society of the Sons of the Revolution but was unwilling to accept the SR's requirement that other state societies be subordinate to the New York society. Furthermore, McDowell wanted the society to become more of a mass movement of descendants of Revolutionary patriots rather than an exclusive social club. As a result, McDowell organized the Sons of the American Revolution (SAR) at Fraunces Tavern in New York on April 30, 1889. This was the centennial for the inauguration of George Washington as the First President of the United States of America in 1789. SAR membership number 1 was assigned to McDowell. In addition to organizing the SAR, McDowell worked with six women to organize the National Society Daughters of the American Revolution on July 29, 1890.

The SAR was formally granted a congressional charter by an act of Congress under Title 36 of the United States Code on June 9, 1906. The act was signed by President Theodore Roosevelt, who was a member.

Sons of the American Revolution grave marker, Old Ship Burying Ground, Hingham, Massachusetts

Membership

Membership in the society is open to any male of "good repute" who can prove lineal bloodline descent from an ancestor who actively supported the American Revolution. Acceptable ancestors include:

• military veterans of the American Revolutionary War, including those who served in the Continental Army, Continental Navy, and state militias and navies
• signers of the Declaration of Independence
• members of the Continental Congress
• civilians who provided arms or supplies to the American cause
• people who served on political bodies supporting the Revolution, signed oaths of allegiance, or those who gave similar support to the Patriot cause.
• Soldiers and sailors from allied nations such as France and Spain who fought in support of American independence.

No state society or chapter may discriminate against an applicant on the basis of race or creed. The SAR claims a membership of over 37,000 members in over 550 chapters representing all 50 states in the United States, as well as societies in Canada, France, Spain, Germany, Switzerland, and the United Kingdom. Overall, about 200,000 descendants have been admitted since the founding of the S.A.R. in 1890.

Governance

Horace Porter, U.S. Ambassador to France, served as President-General of the Sons of the American Revolution from 1892 to 1897.

The governance of the Sons of the American Revolution is made up of 10 National (General) Officers, 15 Vice-Presidents that preside over separate geographical regions and a Trustee elected from each state and international society. These officers meet several times over the year to discuss business pertaining to the society. The National Officers meet at least four times during their term of office, unless special meetings are called. The Trustees meet twice each year at the Society's Headquarters in Louisville, Kentucky. These meetings, known as the Fall and Spring Leadership Meetings, are normally held in late September and early March. During the Leadership Meetings committee recommendations and the society's budget are approved. While only the National Officers, Vice-Presidents and Trustees have the right to vote on the floor, all SAR members are welcome to attend and may request appointment to committees. The National Officers and Trustees also meet during the National Congress held in late June or early July of each year. Unlike the Leadership Meetings which always take place at the Society's National Headquarters, the National Congress is held in different locations throughout the United States. Locations are often selected in order to honor a historical event in United States history or in the history of the SAR, and there is an effort to alternate the meetings between the Eastern and Western United States. The National Congress is responsible for electing the National Officers and approving changes to the Society's constitution, along with any other motions brought before it. In addition to the National Officers, Vice-Presidents and Trustees, State and International Society Presidents and specially elected delegates from each society also attend with voting privileges. The number of delegates are determined by each State or International Society's membership size.

In addition to the larger meetings previously listed, there are over 60 standing and special committees that SAR members are appointed to in order to oversee the Society's welfare. Some of these committees include: facilities, insurance, genealogy, library, merchandise, medals and awards. All SAR members are welcome to participate on committees and are appointed by the Society's President General for a one-year term. There are no term-limits and all committee members have the right to vote on the committee's decisions.

The President-General for 2019-2020 is John T. Manning He was sworn in as President-General at the 129th National Congress in Orange County, CA. The Executive Director is Don Shaw of the Kentucky Society.

Genealogical library

The National Society of the Sons of the American Revolution has held a collection of genealogical reference dating back to 1889. Materials were originally kept by the Secretary General or Registrar General up until 1926, when the materials were moved to the Registrar General's office in Washington, D.C., in 1927, this collection was moved to the recently purchased Sixteenth Street Headquarters Building, and the collection had grown to 914 books by 1933. From this point until the move of Headquarters from Washington, D.C., to Louisville, Kentucky, the book collection grew at a rapid pace, growing to approximately 25,000 items by 1988. At this point, the Library was on the Second floor of the Headquarters building on South Fourth Street, and possessed a 544-square-foot vault for books not out in the library due to space.

Because of continuing growth, the SAR Library was moved in 2010 to a renovated building on West Main Street in the heart of the Historic Museum District of downtown Louisville. By this point, the Library collection had grown to over 58,000 items, mostly covering the Revolutionary War period, but also containing other genealogical materials. The library collection includes family histories, state genealogy materials, federal censuses, Revolutionary War pension applications, and CD collections, and the library separates materials based on State. The library also provides access to online research databases, including Ancestry.com, Footnote.com, and Heritage Quest Online.

Merchandise

The society operates a Merchandise Department that sells items intended for both SAR members and the general public. Among the products available to the general public are: clothing apparel for men and women, Revolutionary War replicas such as Liberty Bells and Field Cannons, jewelry for men and women such as lapel pins and cuff links, along with cups, mugs, key-chains, books, CDs, videos and knickknacks. Items intended for SAR members only include: clothing, decals, license plate holders and frames, certificates and medals corresponding to SAR activities, medals designed to reward active and retired military personnel, firefighters, EMS, JROTC and ROTC, individuals involved in education, Eagle Scouts and many others.

The Merchandise Department is located on the lower level of the SAR Genealogical Library, located at 809 West Main Street, just across the street from the Louisville Slugger Museum & Factory.

Activities

Indiana Society SAR Color Guard appearing with the recreated 19th US Infantry at an outdoor Fourth of July concert with the Indianapolis Symphony Orchestra.

The society is involved in historical research, raising funds for local scholarships and educational awards, and preservation of sites and documents related to the American Revolution. The SAR petitioned Congress to store Revolutionary era documents in a fire-proof area and make them available to the public, leading to the creation of the National Archives. It is also active in cataloging and marking Revolutionary War patriot graves and conducts an annual Eagle Scout scholarship program. The society is active in promoting "patriotism," and was instrumental in the establishment of Constitution Day. Several SAR societies and chapters have active color guard groups that appear in various public and private venues as a means of community outreach.

The Sons of the American Revolution hosts two Leadership Meetings and one National Congress every year. The two leadership meetings are held in the Spring and Fall in Louisville, KY at the Brown Hotel. The National Congress is held at a different location every year during the Summer. The 2017 National Congress took place in Knoxville, Tennessee, while the 2018 Congress will take place in Houston, Texas.

SAR national headquarters

The SAR's national headquarters, located along Museum Row in downtown Louisville, Kentucky, contains the organization's administrative staff offices, SAR Genealogical Research Library, and the future site of an American Revolutionary War Education Center. The SAR is currently raising funds to finish the Center's development. The building houses original and copied art that commemorates important people and events of the Revolutionary War, as well as historical uniforms, flags, documents, and other colonial era pieces.

Symbolism of the SAR insignia

The SAR insignia consists of a Maltese cross surrounded by a garland, with a relief of George Washington in a center circle.

The cross's vertical bar represents the commandment "You Shall Love Your God"; the horizontal bar represents the commandment "You Shall Love Your Neighbor as Yourself." The four limbs are a reminder of the four cardinal virtues; its eight points represent eight spiritual injunctions:

1. To have spiritual contentment
2. To live without malice
3. To weep over your sins
4. To humble yourself at insults
5. To love justice
6. To be merciful
7. To be sincere and open-hearted
8. To suffer persecution

Surrounding the relief of Washington in the center are the words "LIBERTAS ET PATRIA," a reminder of the United States Declaration of Independence and the United States Constitution.

The insignia is normally worn suspended by a ribbon of blue, white and gold (buff) on the wearer's left breast. National officers and former state and chapter presidents wear the insignia suspended from a neck ribbon of the Society's colors.

On other occasions a rosette in the Society's colors is worn on the wearers left lapel.

Simvastatin

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Simvastatin 

 

Simvastatin

Clinical data
Pronunciation	/ˈsɪmvəstætɪn/
Trade names	Zocor, other
AHFS/Drugs.com	Monograph
MedlinePlus	a692030
License data	EU EMA: by INN US FDA: Simvastatin
Pregnancy category	AU: D US: X (Contraindicated)
Routes of administration	by mouth
ATC code	C10AA01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: P (Pharmacy medicines) when ≤10 mg/day, POM (Prescription only) when >10 mg/day. US: ℞-only
Pharmacokinetic data
Bioavailability	5%
Protein binding	95%
Metabolism	Hepatic (CYP3A4)
Elimination half-life	2 hours for simvastatin and 1.9 hours for simvastatin acid
Excretion	Renal 13%, faecal 60%
Identifiers
IUPAC name[show]
CAS Number	79902-63-9
PubChem CID	54454
IUPHAR/BPS	2955
DrugBank	DB00641
ChemSpider	49179
UNII	AGG2FN16EV
KEGG	D00434
ChEBI	CHEBI:9150
ChEMBL	ChEMBL1064
CompTox Dashboard (EPA)	DTXSID0023581
ECHA InfoCard	100.115.749
Chemical and physical data
Formula	C25H38O5
Molar mass	418.574 g·mol−1
3D model (JSmol)	Interactive image

Simvastatin, marketed under the trade name Zocor among others, is a lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

Common side effects include constipation, headaches, and nausea. Serious side effects may include muscle breakdown, liver problems, and increased blood sugar levels. A lower dose may be needed in people with kidney problems. There is evidence of harm to the developing baby when taken during pregnancy and it should not be used by those who are breastfeeding. It is in the statin class of medications and works by decreasing the manufacture of cholesterol by the liver.

Simvastatin was patented by Merck in 1980, and came into medical use in 1992. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication and at a relatively low cost. Simvastatin is made from the fungus Aspergillus terreus. In 2017, it was the eighth most commonly prescribed medication in the United States, with more than 56 million prescriptions.

Medical uses

The primary uses of simvastatin are to treat dyslipidemia and to prevent atherosclerosis-related complications such as stroke and heart attacks in those who are at high risk. It is recommended to be used as an addition to a low-cholesterol diet.

In the Scandinavian Simvastatin Survival Study (a placebo-controlled, randomized clinical trial of five years' duration), simvastatin reduced overall mortality in people with existing cardiovascular disease and high LDL cholesterol by 30% and reduced cardiovascular mortality by 42%. The risks of heart attack, stroke, or needing a coronary revascularization procedure were reduced by 37%, 28%, and 37%, respectively.

The Heart Protection Study evaluated the effects of simvastatin in people with risk factors including existing cardiovascular disease, diabetes, or stroke, but having relatively low LDL cholesterol. In this trial, which lasted 5.4 years, overall mortality was reduced by 13% and cardiovascular mortality was reduced by 18%. People receiving simvastatin experienced 38% fewer nonfatal heart attacks and 25% fewer strokes.

Simvastatin has been used to explore whether statins have an effect on delaying on the onset and progression of age-related macular degeneration (AMD). Results from one trial showed participants assigned to simvastatin had lower odds (0.51 OR) of having AMD progression at three years compared to those assigned to placebo, though the results were not significant. Overall, evidence is insufficient to conclude that simvastatin has an effect in delaying the onset and progression of AMD.

Contraindications

Simvastatin is contraindicated with pregnancy, breastfeeding, and liver disease. Pregnancy must be avoided while on simvastatin due to potentially severe birth defects. Patients cannot breastfeed while on simvastatin due to potentially disrupting the infant's lipid metabolism. High doses of simvastatin are also contraindicated with the widely used antihypertensive amlodipine. A lower dose is also recommended in people taking the calcium channel blockers, verapamil and diltiazem, as well as those taking amiodarone.

Adverse effects

Common side effects (>1% incidence) may include indigestion and eczema. Rare side effects include joint pain, memory loss, and muscle cramps. Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis (destruction of muscles and blockade of renal system), and myositis have been reported in patients receiving the drug chronically. Serious allergic reactions to simvastatin are rare. If the following signs of a serious allergic reaction occur, seek medical attention immediately: rash, hoarseness itching/swelling, dizziness, or difficulty swallowing/breathing.

A type of DNA variant known as a single nucleotide polymorphism (SNP) may help predict individuals prone to developing myopathy when taking simvastatin; a study ultimately including 32,000 patients concluded the carriers of one or two risk alleles of a particular SNP, rs4149056, were at a five-fold or 16-fold increased risk, respectively. In 2012, the Clinical Pharmacogenetics Implementation Consortium has released guidelines regarding the use of rs4149056 genotype in guiding dosing of simvastatin and updated the guideline in 2014.

In March 2012, the U.S. Food and Drug Administration (FDA) updated its guidance for statin users to address reports of memory loss, liver damage, increased blood sugar, development of type 2 diabetes, and muscle injury. The new guidance indicates:

• FDA has found that liver injury associated with statin use is rare but can occur.
• The reports about memory loss, forgetfulness, and confusion span all statin products and all age groups. The FDA says these experiences are rare, but that those affected often report feeling "fuzzy" or unfocused in their thinking.
• A small increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported with the use of statins.
• Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain.

On 19 March 2010, the FDA issued another statement regarding simvastatin, saying it increases the risk of muscle injury (myopathy) when taken at high doses or at lower doses in combination with other drugs. The highest dose rate causes muscle damage in 610 of every 10,000 people in contrast to a lower dose, which causes muscle damage in eight of 10,000 people. The FDA warning, released again on 8 June 2011, suggested that high-dose "simvastatin should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury" and that it "should not be started in new patients, including patients already taking lower doses of the drug."

Interactions

Simvastatin has important interactions with grapefruit juice and other drugs, including some that are commonly used for the treatment of cardiovascular disease. These interactions are clinically important because increasing simvastatin serum levels above those normally provided by the maximum recommended dose increases the risk of muscle damage, including the otherwise rare and potentially fatal side effect of rhabdomyolysis.

Consuming large amounts of grapefruit juice increases serum levels of simvastatin by up to three-fold, increasing the risk of side effects. The FDA recommends that people taking statins should avoid consuming more than a quart (946 ml) of grapefruit juice per day.

Simvastatin also interacts with other drugs, including some used to treat cardiovascular problems. It should not be taken by people who are also taking the antifungal drugs fluconazole, itraconazole, or posaconazole; the antibiotics erythromycin, clarithromycin, or telithromycin; HIV protease inhibitors; the antidepressant nefazodone; the cardiovascular drug gemfibrozil; the immunosuppressant ciclosporin, or the endometriosis drug danazol. Reduced maximum doses of simvastatin apply for patients taking certain other drugs, including the cardiovascular drugs verapamil, diltiazem, amiodarone, amlodipine, and ranolazine.

Pharmacology

All statins act by inhibiting 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase. HMG-CoA reductase, the rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration, but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration. This is a major piece of evidence that statins work in another way than the lowering of cholesterol (called pleiotropic effects).

The drug is in the form of an inactive lactone that is hydrolyzed after ingestion to produce the active agent. It is a white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol, and ethanol.

Simvastatin is an effective serum lipid-lowering drug that can decrease low density lipoprotein (LDL) levels by up to 50%. Simvastatin had been shown to interact with lipid-lowering transcription factor PPAR-alpha  and that interaction might control the neurotrophic action of the drug.

History

The development of simvastatin was closely linked with lovastatin. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s.^[35] In 1956, mevalonic acid was isolated from a yeast extract by Karl Folkers, Carl Hoffman, and others at Merck, while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis. In 1959, the HMG-CoA reductase enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.

By 1976, Akira Endo had isolated the first inhibitor, mevastatin, from the fungus Penicillium citrinium while working at Daiichi Sankyo in Japan. In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus Aspergillus terreus. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product of A. terreus, which was designated MK-733 (later to be named simvastatin).

In 1994, publication of the results of the Scandinavian Simvastatin Survival Study (4S) provided the first unequivocal evidence that lowering LDL cholesterol via statin treatment reduces cardiovascular events and overall mortality. A total of 4,444 people with coronary heart disease 5.5 to 8.0 mmol/L were randomized to simvastatin treatment or placebo and followed for an average of 5 years. Compared to the placebo group, those treated with simvastatin experienced a 30% decrease in overall mortality, a 42% reduction in coronary death, a 34% reduction in major coronary events, and a 37% reduction in revascularization procedures.

Society and culture

Cost

Simvastatin is relatively inexpensive. The wholesale cost in some LMIC is around US$0.01 to 0.15 per 20 mg dose as of 2014. The defined daily dose is 30 mg per the World Health Organization. The price decreased from roughly US$1,200 to $40 per year of medication in LMIC following the patent expiring in 2006. In the United States, it costs about US$10 to 20 per month since patent protection ended. In the UK in 2008, the typical per-patient cost to the NHS of simvastatin was about £1.50 per month. (40 mg/day costs UK NHS £1.37/month in 2012) The price in Canada is about $CAD 130 to 160 per year as of 2016. Under provisions of the Patient Protection and Affordable Care Act (PPACA) in the United States, there is no cost for simvastatin 10 mg, 20 mg, and 40 mg for adults aged 40–75 years based on United States Preventive Services Task Force (USPSTF) recommendations.

Economics

Simvastatin was introduced in the late 1980s, and since 2006 in many countries, it is available as a generic preparation. This has led to a decrease of the price of most statin drugs, and a reappraisal of the health economics of preventive statin treatment.

Prior to losing U.S. patent protection, simvastatin was Merck & Co.'s largest-selling drug and second-largest selling cholesterol-lowering drug in the world. In 2005, recorded US$3.1 billion of sales in the United States and US$4.4 billion worldwide.

Zocor had an original patent expiry date of 24 December 2005 but was extended by the United States Patent and Trademark Office (USPTO) to expire on 23 June 2006. The USPTO granted the patent extension after Merck submitted data from studies of the drug's positive effect on children. In the UK, the patent for simvastatin had expired by 2004.

In the UK, simvastatin was the most prescribed medication in the community in 2013, with 39.9 million items dispensed. This compares to 30.9 million items for aspirin, and 27.7 million for levothyroxine sodium, the second- and third-most prescribed drugs in the UK in 2013.

Marketing

Simvastatin was initially marketed by Merck & Co under the trade name Zocor but is available generically in most countries following the patent expiry. A combination of simvastatin along with ezetimibe is sold under the brand name Vytorin and is jointly marketed by Merck and Schering-Plough.

Brand names include Zocor, Zocor Heart Pro, marketed by the pharmaceutical company Merck & Co., Simlup, Simvotin, Simcard [India], Denan (Germany), Liponorm, Sinvacor, Sivastin (Italy), Lipovas (Japan), Lodales (France), Zocord (Austria and Sweden), Zimstat, Simvahexal (Australia), Lipex (Australia and New Zealand), Simvastatin-Teva, Simvacor, Simvaxon, Simovil (Israel), available in Thailand under the brand Bestatin manufactured by Berlin Pharmaceutical Industry Co Ltd and others.

The U.S. patent for Zocor expired on 23 June 2006. Ranbaxy Laboratories (at the 80-mg strength) and Teva Pharmaceutical Industries through its Ivax Pharmaceuticals unit (at all other strengths) were given approval by the FDA to manufacture and sell simvastatin as a generic drug with 180-day exclusivity. Dr. Reddy's Laboratories also has a license from Merck & Co. to sell simvastatin as an authorized generic drug.