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116-506: The average non-smoker maintains a systemic carboxyhemoglobin level under 3% COHb whereas smokers approach 10% COHb. The biological threshold for carboxyhemoglobin tolerance is 15% COHb, meaning toxicity is consistently observed at levels in excess of this concentration. The FDA has previously set a threshold of 14% COHb in certain clinical trials evaluating the therapeutic potential of carbon monoxide. The average red blood cell contains 250 million hemoglobin molecules. Hemoglobin contains

232-537: A CO-oximeter , and a variety of other analytical techniques. Most methods require laboratory equipment, skilled technicians, or expensive electronics therefore rapid and economical detection technologies remain in development. Breath carbon monoxide is another detection method that may correlate with carboxyhemoglobin levels. Carbon monoxide poisoning, also known as carboxyhemoglobinemia, has plagued humankind since primitive ancestors first harnessed fire. In modern times, carboxyhemoglobin data assist physicians in making

348-423: A coup d'état on the last Bonacolsi ruler, Rinaldo. Ludovico Gonzaga, who had been Podestà of Mantua since 1318, was duly elected Capitano del popolo . The Gonzagas built new walls with five gates and renovated the city in the 14th century; however, the political situation did not settle until the third ruler of Gonzaga, Ludovico III Gonzaga , who eliminated his relatives and centralised power to himself. During

464-509: A globin protein unit with four prosthetic heme groups (hence the name heme -o- globin ); each heme is capable of reversibly binding with one gaseous molecule (oxygen, carbon monoxide, cyanide, etc.), therefore a typical red blood cell may carry up to one billion gas molecules. As the binding of carbon monoxide with hemoglobin is reversible, certain models have estimated that 20% of the carbon monoxide carried as carboxyhemoglobin may dissociate in remote tissues. In biology, carbon monoxide

580-720: A medical practitioner 's supervision like ibuprofen . In 2014, the FDA added an Ebola treatment being developed by Canadian pharmaceutical company Tekmira to the Fast Track program , but halted the phase 1 trials in July pending the receipt of more information about how the drug works. This was widely viewed as increasingly important in the face of a major outbreak of the disease in West Africa that began in late March 2014 and ended in June 2016. During

696-460: A "FDA Compliant" or "FDA Acceptable". Medical countermeasures (MCMs) are products such as biologics and pharmaceutical drugs that can protect from or treat the health effects of a chemical, biological, radiological, or nuclear (CBRN) attack. MCMs can also be used for prevention and diagnosis of symptoms associated with CBRN attacks or threats. The FDA runs a program called the "FDA Medical Countermeasures Initiative" (MCMi), with programs funded by

812-613: A COHb half-life of 20 minutes compared to 300 minutes for a typical human (see § Toxicokinetics ). As a result, the metabolic kinetics, blood saturation point, and tolerance for carbon monoxide exposure vary across species, potentially leading to data inconsistencies pertaining to the toxicology of carbon monoxide poisoning and pharmacology of low-dose therapeutic protocols. Some deep-diving marine mammal species are known to contain concentrations of carbon monoxide in their blood that resembles levels seen in chronic cigarette smokers, which may provide benefits against hypoxia. Similarly,

928-425: A REMS program called iPLEDGE . Generic drugs are chemical and therapeutic equivalents of name-brand drugs, normally whose patents have expired. Approved generic drugs should have the same dosage, safety, effectiveness, strength, stability, and quality, as well as route of administration. In general, they are less expensive than their name brand counterparts, are manufactured and marketed by rival companies and, in

1044-745: A case. The FDA has a number of field offices across the United States, in addition to international locations in China, India, Europe, the Middle East, and Latin America. As of 2021, the FDA had responsibility for overseeing $ 2.7 trillion in food, medical, and tobacco products. Some 54% of its budget derives from the federal government, and 46% is covered by industry user fees for FDA services. For example, pharmaceutical firms pay fees to expedite drug reviews. According to Forbes, pharmaceutical firms provide 75% of

1160-513: A company may advertise or promote a drug only for the specific indication or medical use for which it was approved by FDA. Also, an advertisement must contain a "fair balance" between the benefits and the risks (side effects) of a drug. The regulation of drug advertising in the U.S. is divided between the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), based on whether

1276-426: A complaint brought against the FDA by Mylan Laboratories Inc. of Pittsburgh . When its application to manufacture generics were subjected to repeated delays by the FDA, Mylan, convinced that it was being discriminated against, soon began its own private investigation of the agency in 1987. Mylan eventually filed suit against two former FDA employees and four drug-manufacturing companies, charging that corruption within

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1392-441: A defensive water ring around the city, dried up at the end of the 18th century. The area and its environs are important not only in naturalistic terms, but also anthropologically and historically; research has highlighted a number of human settlements scattered between Barche di Solferino and Bande di Cavriana , Castellaro and Isolone del Mincio. These dated, without interruption, from Neolithic times (5th–4th millennium BC) to

1508-432: A long period of time. The studies are progressively longer, gradually adding more individuals as they progress from stage I to stage III, normally over a period of years, and normally involve drug companies, the government and its laboratories, and often medical schools and hospitals and clinics. However, any exceptions to the aforementioned process are subject to strict review and scrutiny and conditions, and are only given if

1624-555: A new master plan for this expansion in December 2018, and construction is expected to be completed by 2035, dependent on GSA appropriations. The Office of Regulatory Affairs is considered the agency's "eyes and ears", conducting the vast majority of the FDA's work in the field. Its employees, known as Consumer Safety Officers, or more commonly known simply as investigators, inspect production, warehousing facilities, investigate complaints, illnesses, or outbreaks, and review documentation in

1740-473: A nonmetallic element capable of oxidation, although the original degrees of oxides were based on diamond, graphite, coal and carbonic acid (CO 2 ) as the most oxidized form; Lavoisier's system was superseded by other obsolete oxide nomenclature systems. Upon discovering carbon monoxide through a series of experiments originating from coke (short for coal-cake), Cruickshank named the new molecule "gaseous oxide of carbon" which evolved to "carbonic oxide" and

1856-647: A number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA also includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are usually food-related, some laboratories are equipped to analyze drugs, cosmetics, and radiation-emitting devices. The Office of Criminal Investigations was established in 1991 to investigate criminal cases. To do so, OCI employs approximately 200 Special Agents nationwide who, unlike ORA Investigators, are armed, have badges, and do not focus on technical aspects of

1972-517: A patient suffering from carbon monoxide poisoning may experience severe hypoxia and acidosis in addition to the toxicities of excess carbon monoxide binding to numerous hemoproteins, metallic and non-metallic targets which affect cellular machinery (such as inhibition of cytochrome c oxidase ). In common air under normal atmospheric conditions, a typical patient's carboxyhemoglobin has a half-life around 300 minutes. This time can be reduced to 90 minutes upon administration of high-flow pure oxygen, and

2088-435: A poisoning diagnosis. However, carboxyhemoglobin levels do not necessarily correlate with the symptoms of carbon monoxide poisoning. In general, 30% COHb is considered severe carbon monoxide poisoning. The highest reported non-fatal carboxyhemoglobin level was 73% COHb. Gas exchange is an essential process for many organisms to maintain homeostasis. Oxygen accounts for about 20% of Earth's atmospheric air . While inhaling air

2204-494: A role in monitoring safety through influence on ingredients, but they lack legal authority. According to the ACSH, it has reviewed about 1,200 ingredients and has suggested that several hundred be restricted—but there is no standard or systemic method for reviewing chemicals for safety, or a clear definition of what 'safety' even means so that all chemicals get tested on the same basis. However, on December 29, 2022, President Biden signed

2320-523: A satisfied requirement. The FDA does not approve applied coatings used in the food processing industry . There is no review process to approve the composition of nonstick coatings; nor does the FDA inspect or test these materials. Through their governing of processes, however, the FDA does have a set of regulations that cover the formulation, manufacturing, and use of nonstick coatings. Hence, materials like Polytetrafluoroethylene (Teflon) are not and cannot be considered as FDA Approved, but rather, they are

2436-483: A simplified synopsis of the molecular mechanism of systemic gas exchange, upon inhalation of air it was widely thought oxygen binding to any of the heme sites triggers a conformational change in the protein unit of hemoglobin which then enables the binding of additional oxygen to each of the other heme sites. Upon arrival to the cellular region, oxygen is released at the tissue due to a conformational change in hemoglobin as caused by ionization of hemoglobin's surface due to

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2552-440: A substantial amount of research and at least some preliminary human testing has shown that they are believed to be somewhat safe and possibly effective. (See FDA Special Protocol Assessment about Phase III trials.) The FDA's Office of Prescription Drug Promotion (OPDP) has responsibilities that revolve around the review and regulation of prescription drug advertising and promotion. This is achieved through surveillance activities and

2668-474: A sustained level of 16% COHb. Other human mutations have been described (see also: hemoglobin variants ). Structural variations and mutations across other hemoproteins likewise affect carbon monoxide's interaction with the heme prosthetic group as exemplified by Cytochrome P450 where certain forms of the CYP3A family is relatively less affected by the inhibitory effects of carbon monoxide. Murinae species have

2784-553: A warning to that effect. According to the industry advocacy group, the American Council on Science and Health , though the cosmetic industry is primarily responsible for its own product safety, the FDA can intervene when necessary to protect the public. In general, though, cosmetics do not require pre-market approval or testing. The ACSH says that companies must place a warning note on their products if they have not been tested, and that experts in cosmetic ingredient review also play

2900-530: Is a comune (municipality) in the Italian region of Lombardy , and capital of the province of the same name . In 2016, Mantua was designated as the "Italian Capital of Culture". In 2017, it was named as the "European Capital of Gastronomy", included in the Eastern Lombardy District (together with the cities of Bergamo , Brescia , and Cremona ). In 2008, Mantua's centro storico (old town) and

3016-401: Is a center of the FDA that regulates food additives and drugs that are given to animals. CVM regulates animal drugs, animal food including pet animal, and animal medical devices. The FDA's requirements to prevent the spread of bovine spongiform encephalopathy are also administered by CVM through inspections of feed manufacturers. CVM does not regulate vaccines for animals; these are handled by

3132-651: Is a separate process, and the drug must be approved through an NDA first. A drug that is approved is said to be "safe and effective when used as directed". Very rare, limited exceptions to this multi-step process involving animal testing and controlled clinical trials can be granted out of compassionate use protocols. This was the case during the 2015 Ebola epidemic with the use, by prescription and authorization, of ZMapp and other experimental treatments, and for new drugs that can be used to treat debilitating and/or very rare conditions for which no existing remedies or drugs are satisfactory, or where there has not been an advance in

3248-846: Is critical to supply cells with oxygen for aerobic respiration via the Bohr effect and Haldane effect (and perhaps local low oxygen partial pressure e.g. active muscles), exhaling the cellular waste product carbon dioxide is arguably the more critical aspect of respiration. Whereas the body can tolerate brief periods of hypoxia (as commonly occurs in anaerobic exercise , although the brain, heart, liver and kidney are significantly less tolerant than skeletal muscle), failure to expel carbon dioxide may cause respiratory acidosis (meaning bodily fluids and blood become too acidic thereby affecting homeostasis). In absence of oxygen, cells switch to anaerobic respiration which if prolonged may significantly increase lactic acid leading to metabolic acidosis . To provide

3364-455: Is currently in late clinical development. Similarly, maleimide PEG conjugated human carboxyhemoglobin had previously been the subject of pharmaceutical development. FDA The United States Food and Drug Administration ( FDA or US FDA ) is a federal agency of the Department of Health and Human Services . The FDA is responsible for protecting and promoting public health through

3480-547: Is enforcement of the Federal Food, Drug, and Cosmetic Act (FD&C). However, the agency also enforces other laws, notably Section 361 of the Public Health Service Act as well as associated regulations. Much of this regulatory-enforcement work is not directly related to food or drugs but involves other factors like regulating lasers , cellular phones , and condoms . In addition, the FDA takes control of diseases in

3596-713: Is located in the White Oak area of Silver Spring, Maryland . The agency has 223 field offices and 13 laboratories located across the 50 states, the United States Virgin Islands , and Puerto Rico . In 2008, the FDA began to post employees to foreign countries, including China, India, Costa Rica, Chile, Belgium, and the United Kingdom. FDA headquarters facilities are currently located in Montgomery County and Prince George's County , Maryland. Since 1990,

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3712-459: Is naturally produced through many enzymatic and non-enzymatic pathways. The most extensively studied pathway is the metabolism of heme by heme oxygenase which occurs throughout the body with significant activity in the spleen to facilitate hemoglobin breakdown during erythrocyte recycling. Therefore heme can both carry carbon monoxide in the case of carboxyhemoglobin, or, undergo enzymatic catabolism to generate carbon monoxide. Carbon monoxide

3828-581: Is nonetheless outstanding, with many of Mantua's patrician and ecclesiastical buildings being uniquely important examples of Italian architecture. By car, Mantova can be reached on the A4 (Milan-Venice) Highway up to Verona, then the A22 ( Brennero - Modena ) Highway. Alternatively, the city can be reached from Milan on the State Road 415 (Milan-Cremona) to Cremona and from there State Road 10 (Cremona-Mantova), or from Verona on

3944-459: Is noted for its significant role in the history of opera ; the city is also known for its architectural treasures and artifacts, elegant palaces, and the medieval and Renaissance cityscape. It is the city where the composer Monteverdi premiered his 1607 opera L'Orfeo and to where Romeo was banished in Shakespeare 's 1597 play Romeo and Juliet . It is the nearest town to the birthplace of

4060-503: Is slightly more acidic at pH 7.371). The "T-state" of hemoglobin is deoxygenated in venous blood partially due to protonation/ionization as caused by the acidic environment hence causing a conformation unsuited for oxygen-binding (i.e. oxygen is 'ejected' upon arrival at the cell due to H ions bombarding the hemoglobin surface residues to convert Hb from "R-state" to "T-state"). Furthermore, the mechanism for formation of carbaminohemoglobin generates additional H ions that may further stabilize

4176-539: Is south of Verona , east of Cremona , north-east of Parma , northwest of Ferrara , and west-southwest of Padua . Mantua was an island settlement which was first established about the year 2000 BC on the banks of River Mincio , which flows from Lake Garda to the Adriatic Sea . In the 6th century BC, Mantua was an Etruscan village which, in the Etruscan tradition, was re-founded by Ocnus . The name may derive from

4292-449: Is the branch of the FDA responsible for ensuring the safety and efficacy of biological therapeutic agents. These include blood and blood products, vaccines, allergenics, cell and tissue-based products, and gene therapy products. New biologics are required to go through a premarket approval process called a Biologics License Application (BLA), similar to that for drugs. The original authority for government regulation of biological products

4408-737: Is the branch of the FDA responsible for the premarket approval of all medical devices , as well as overseeing the manufacturing, performance and safety of these devices. The definition of a medical device is given in the FD&;C Act, and it includes products from the simple toothbrush to complex devices such as implantable neurostimulators . CDRH also oversees the safety performance of non-medical devices that emit certain types of electromagnetic radiation . Examples of CDRH-regulated devices include cellular phones , airport baggage screening equipment , television receivers , microwave ovens , tanning booths , and laser products . CDRH regulatory powers include

4524-416: Is the term adopted by English literature. Hoppe-Seyler likewise coined the name Kohlenoxydhämoglobin which may have similarly been directly translated back into English as "carbonic oxide hæmoglobin". The term carboxyhæmoglobin appeared as early as 1895 in works by John Haldane while the name for CO was still widely regarded as carbonic oxide. The term "carbon monoxide" was formally introduced in 1879, but

4640-696: Is used for a different purpose, or undergoes any substantial change. The most rigorous requirements apply to new molecular entities : drugs that are not based on existing medications. New drugs receive extensive scrutiny before FDA approval in a process called a new drug application (NDA). Under the Presidency of Donald Trump , the agency has worked to make the drug-approval process go faster. Critics, however, argue that FDA standards are not sufficiently rigorous to prevent unsafe or ineffective drugs from getting approval. New drugs are available only by prescription by default. A change to over-the-counter (OTC) status

4756-451: Is voluntary. While this remains the primary tool of post-market safety surveillance , FDA requirements for post-marketing risk management are increasing. As a condition of approval, a sponsor may be required to conduct additional clinical trials , called Phase IV trials. In some cases, the FDA requires risk management plans called Risk Evaluation and Mitigation Strategies (REMS) for some drugs that require actions to be taken to ensure that

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4872-561: The Bronze Age (2nd–1st millennium BC) and the Gallic phases (2nd–1st centuries BC), and ended with Roman residential settlements, which can be traced to the 3rd century AD. In 2017, Legambiente ranked Mantua as the best Italian city for quality of life and environment. Mantua lies in the east of the region of Lombardy , halfway between Milan and Venice , on the River Mincio . It

4988-671: The Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER) and offices for the Center for Veterinary Medicine (CVM). With the passing of the FDA Reauthorization Act of 2017, the FDA projects a 64% increase in employees to 18,000 over the next 15 years and wants to add approximately 1,600,000 square feet (150,000 square metres) of office and special use space to their existing facilities. The National Capital Planning Commission approved

5104-687: The Frankish Empire . Partitions of the empire (due to the Franks' use of partible inheritance ) in the Treaties of Verdun and Prüm led to Mantua passing to Middle Francia in 843, then the Kingdom of Italy in 855. In 962 Italy was invaded by King Otto I of Germany , and Mantua thus became a vassal of the newly formed Holy Roman Empire . In the 11th century, Mantua became a possession of Boniface of Canossa , marquis of Tuscany . The last ruler of that family

5220-685: The Ghibellines , Pinamonte Bonacolsi took advantage of the chaotic situation to seize power of the podesteria in 1273. He was declared the Captain General of the People . The Bonacolsi family ruled Mantua for the next two generations and made it more prosperous and artistically beautiful. On 16 August 1328 Luigi Gonzaga, an official in Bonacolsi's podesteria, and his family staged a public revolt in Mantua and forced

5336-567: The Gonzaga-Nevers , a cadet French branch of the family. The War of the Mantuan Succession broke out, and in 1630 an Imperial army of 36,000 mercenaries under Matthias Gallas and Johann von Aldringen besieged and sacked Mantua, bringing the plague with them. Ferdinand Carlo IV , an inept ruler, whose only interest was in holding parties and theatrical shows, allied with France in the War of

5452-544: The Turks . Under Ludovico and his heirs, the famous Renaissance painter Andrea Mantegna worked in Mantua as court painter, producing some of his most outstanding works. The first Duke of Mantua was Federico II Gonzaga , who acquired the title from the Holy Roman Emperor Charles V in 1530. Federico commissioned Giulio Romano to build the famous Palazzo Te , on the periphery of the city, and profoundly improved

5568-545: The United States Department of Agriculture . The FDA regulates tobacco products with authority established by the 2009 Family Smoking Prevention and Tobacco Control Act . This Act requires color warnings on cigarette packages and printed advertising, and text warnings from the U.S. Surgeon General . Mantua Mantua ( / ˈ m æ n tj u ə / MAN -tew-ə ; Italian : Mantova [ˈmantova] ; Lombard and Latin : Mantua )

5684-639: The coronavirus pandemic , FDA granted emergency use authorization for personal protective equipment (PPE), in vitro diagnostic equipment, ventilators and other medical devices. On March 18, 2020, FDA inspectors postponed most foreign facility inspections and all domestic routine surveillance facility inspections. In contrast, the USDA's Food Safety and Inspection Service (FSIS) continued inspections of meatpacking plants, which resulted in 145 FSIS field employees who tested positive for COVID-19, and three who died. The Center for Biologics Evaluation and Research

5800-399: The "acidification" of the tissue's local pH (meaning a relatively higher concentration of 'acidic' protons / hydrogen ions annotated as H; an acidic pH is commonly referenced to as either low pH based on the acidity of pH 1-7 having a low number, or, referred to as a high pH due to the high concentration of H ions as the scale approaches pH 1); the local acidity is caused by an increase in

5916-606: The '2023 Consolidated Budget Act', which includes the 'Cosmetics Regulatory Modernization Act of 2022 (MoCRA)', which is a stricter regulation that is different from the previous regulations. MoCRA requires compliance with matters such as serious adverse event reporting, safety substantiation, additional labeling, record keeping, and Good Manufacturing Practices (GMP). MoCRA also calls on the FDA to grant Mandatory Recall Authority and establish regulations for GMP rules, flavor allergen labeling rules, and testing methods for cosmetics containing talc. The Center for Veterinary Medicine (CVM)

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6032-448: The 1600s, and M. Antoine Portal in the late 1700s. Phlogiston theory is a trace origin for the first chemical explanations of endogenous carboxyhemoglobin exemplified by the work of Joseph Priestley in the eighteenth century who suspected phlogiston to be a cellular waste product carried by the blood of animals which was subsequently exhaled. Thomas Beddoes , James Watt , Humphry Davy , James Lind , and many others investigated

6148-406: The 1990s, accounted for about a third of all prescriptions written in the United States. For a pharmaceutical company to gain approval to produce a generic drug, the FDA requires scientific evidence that the generic drug is interchangeable with or therapeutically equivalent to the originally approved drug. This is called an Abbreviated New Drug Application (ANDA). 80% of prescription drugs sold in

6264-625: The Austrian Duchy of Mantua briefly united with the Duchy of Milan until 1791. On 4 June 1796 during the War of the First Coalition , Mantua was besieged by Napoleon Bonaparte 's French army. The first Austrian attempt to break the siege was successful and the siege was abandoned on 1 August. The Austrian army was defeated at the Battle of Castiglione on 5 August and left the area. The French resumed

6380-521: The Etruscan god Mantus . After being conquered by the Cenomani , a Gallic tribe, Mantua was subsequently fought between the first and second Punic wars against the Romans , who attributed its name to Manto , a daughter of Tiresias . This territory was later populated by veteran soldiers of Augustus . Mantua's most famous ancient citizen is the poet Virgil , or Publius Vergilius Maro ( Mantua me genuit ), who

6496-501: The FD&C Act. OCI Special Agents often come from other criminal investigations backgrounds, and frequently work closely with the Federal Bureau of Investigation , Assistant Attorney General , and even Interpol . OCI receives cases from a variety of sources—including ORA, local agencies, and the FBI, and works with ORA Investigators to help develop the technical and science-based aspects of

6612-622: The FDA exercises differ from one category to the next. Furthermore, legislation had granted the FDA a variety of means to address violations of standards for a given substance category. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the FDA is responsible for ensuring that manufacturers and distributors of dietary supplements and dietary ingredients meet the current requirements. These manufacturers and distributors are not allowed to advertise their products in an adulterated way, and they are responsible for evaluating

6728-687: The FDA has had employees and facilities on 130 acres (53 hectares) of the White Oak Federal Research Center in the White Oak area of Silver Spring, Maryland . In 2001, the General Services Administration (GSA) began new construction on the campus to consolidate the FDA's 25 existing operations in the Washington metropolitan area , its headquarters in Rockville , and several fragmented office buildings. The first building,

6844-703: The FDA released a statement regarding new guidelines to help food and drug manufacturers "implement protections against potential attacks on the U.S. food supply". One of the guidelines includes the Intentional Adulteration (IA) rule, which requires strategies and procedures by the food industry to reduce the risk of compromise in facilities and processes that are significantly vulnerable. The FDA also uses tactics of regulatory shaming, mainly through online publication of non-compliance, warning letters, and "shaming lists." Regulation by shaming harnesses firms' sensitivity to reputational damage. For example, in 2018,

6960-581: The FDA's drug review budget Emergency Use Authorization (EUA) is a mechanism that was created to facilitate the availability and use of medical countermeasures, including vaccines and personal protective equipment, during public health emergencies such as the Zika virus epidemic, the Ebola virus epidemic and the COVID-19 pandemic. The programs for safety regulation vary widely by the type of product, its potential risks, and

7076-871: The Food and Drug Administration is governed by various statutes enacted by the United States Congress and interpreted by the FDA. Pursuant to the Federal Food, Drug, and Cosmetic Act and accompanying legislation, the FDA has authority to oversee the quality of substances sold as food in the United States, and to monitor claims made in the labeling of both the composition and the health benefits of foods. The FDA subdivides substances that it regulates as food into various categories—including foods, food additives , added substances (human-made substances that are not intentionally introduced into food, but nevertheless end up in it), and dietary supplements . Dietary supplements or dietary ingredients include vitamins, minerals, herbs, amino acids , and enzymes . Specific standards

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7192-487: The IUPAC guidance, carboxyhemoglobin remains the most widely used term (akin to the survival of bicarbonate nomenclature). Historically, carboxyhemoglobin detection has been achieved by colorimetric analysis , chemical reactivity, spectrophotometry , gasometric and thermoelectric detection methods. Gas chromatography analysis emerged in 1961 and remains a commonly used method. Modern methods include pulse oximetry with

7308-661: The Italian Renaissance, the Gonzaga family softened their despotic rule and further raised the level of culture and refinement in Mantua. Mantua became a significant center of Renaissance art and humanism. Marquis Gianfrancesco Gonzaga had brought Vittorino da Feltre to Mantua in 1423 to open his famous humanist school, the Casa Giocosa. Isabella d'Este , Marchioness of Mantua, married Francesco II Gonzaga, Marquess of Mantua in 1490. When she moved to Mantua from Ferrara (she

7424-829: The Kingdom of Venetia (including the capital city, Venice ). Mantua reconnected with the region of Lombardy and was incorporated into the Kingdom of Italy . During World War II , in November 1943, Nazi Germany relocated the Stalag 337 prisoner-of-war camp from Leśna in German-occupied Poland to Mantua. The camp was dissolved in February 1944, and in April 1944 the Dulag 339 transit camp for British, Italian, American, French, Greek and Yugoslav POWs

7540-623: The Life Sciences Laboratory, was dedicated and opened with 104 employees in December 2003. As of December 2018, the FDA campus has a population of 10,987 employees housed in approximately 3,800,000 square feet (350,000 square metres) of space, divided into ten offices and four laboratory buildings. The campus houses the Office of the Commissioner (OC), the Office of Regulatory Affairs (ORA), 

7656-685: The Roman classical poet Virgil , who is commemorated by a statue at the lakeside park "Piazza Virgiliana". Mantua is surrounded on three sides by artificial lakes , created during the 12th century as the city's defence system. These lakes receive water from the River Mincio , a tributary of the River Po , which descends from Lake Garda . The three lakes are called Lago Superiore , Lago di Mezzo , and Lago Inferiore ("Upper", "Middle", and "Lower" Lakes, respectively). A fourth lake, Lake Pajolo, which once served as

7772-888: The Spanish Succession . After the French defeat, he took refuge in Venice and carried with him a thousand pictures. At his death in 1708, the Duke of Mantua was declared deposed and his family of Gonzaga lost Mantua forever in favour of the Habsburgs of Austria. Under Austrian rule, Mantua enjoyed a revival and during this period the Royal Academy of Sciences, Letters and Arts, the Scientific Theatre, and numerous palaces were built. In 1786, ten years before Napoleon Bonaparte 's campaign of Europe,

7888-487: The State Road 62. Mantova railway station , opened in 1873, lies on the train routes of Milan - Codogno - Cremona -Mantua and Verona -Mantua- Modena . The station is a terminus for three regional lines, to Cremona and Milan , to Monselice , and to Verona Porta Nuova and Modena . Trenitalia operates a daily high-speed connection with Rome . The closest airport is Verona-Villafranca Airport. The direct shuttle bus service running to and from Mantova railway station

8004-477: The United States are generic brands. In 1989, a major scandal erupted involving the procedures used by the FDA to approve generic drugs for sale to the public. Charges of corruption in generic drug approval first emerged in 1988 during the course of an extensive congressional investigation into the FDA. The oversight subcommittee of the United States House Energy and Commerce Committee resulted from

8120-497: The affinity of carbon monoxide for hemoglobin varies both across species and within a species. In the 1950s, Esther Killick was among the first to recognize a difference in carbon monoxide affinity between adult and foetal blood, and a difference between humans and sheep. In humans, the Hb-Kirklareli mutation has a relative 80,000 times greater affinity for carbon monoxide than oxygen resulting in systemic carboxyhemoglobin reaching

8236-608: The agency published an online "black list", in which it named dozens of branded drug companies that are supposedly using unlawful or unethical means to attempt to impede competition from generic drug companies. The FDA frequently works with other federal agencies, including the Department of Agriculture , the Drug Enforcement Administration , Customs and Border Protection , and the Consumer Product Safety Commission . They also often work with local and state government agencies in performing regulatory inspections and enforcement actions. The regulation of food and dietary supplements by

8352-468: The authority to require certain technical reports from the manufacturers or importers of regulated products, to require that radiation-emitting products meet mandatory safety performance standards, to declare regulated products defective, and to order the recall of defective or noncompliant products. CDRH also conducts limited amounts of direct product testing. Clearance requests are required for medical devices that prove they are "substantially equivalent" to

8468-498: The biotransformation of carbon dioxide waste into carbonic acid via carbonic anhydrase . In other words, oxygenated arterial blood arrives to cells in the " hemoglobin R-state " which has deprotonated/unionized amino acid residues (regarding hemoglobin's amines transitioning between the deprotonated/unionized Hb-NH2 to the protonated/ionized Hb-NH3 state) based on the less-acidic pH (arterial blood averages pH 7.407 whereas venous blood

8584-473: The case of medical devices, drugs, biological products, and other items where it may be difficult to conduct a physical examination or take a physical sample of the product. The Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. The districts are based roughly on the geographic divisions of the Federal court system . Each district comprises a main district office and

8700-406: The city. In the late 16th century, Claudio Monteverdi came to Mantua from his native Cremona. He worked for the court of Vincenzo I Gonzaga , first as a singer and violist, then as music director, marrying the court singer Claudia Cattaneo in 1599. In 1627, the direct line of the Gonzaga family came to an end with the vicious and weak Vincenzo II , and Mantua slowly declined under the new rulers,

8816-502: The contexts varying from household pets to human sperm donated for use in assisted reproduction . The FDA is led by the commissioner of Food and Drugs , appointed by the President with the advice and consent of the Senate . The commissioner reports to the secretary of health and human services . Robert Califf is the current commissioner as of February 17, 2022. The FDA's headquarters

8932-404: The control and supervision of food safety , tobacco products, caffeine products, dietary supplements , prescription and over-the-counter pharmaceutical drugs (medications), vaccines , biopharmaceuticals , blood transfusions , medical devices , electromagnetic radiation emitting devices (ERED), cosmetics, animal foods & feed and veterinary products . The FDA's primary focus

9048-563: The course of River Mincio, creating what the Mantuans call "the four lakes" to reinforce the city's natural protection. Three of these lakes still remain today and the fourth one, which ran through the centre of town, was reclaimed during the 18th century. From 1215, the city was ruled under the podesteria of the Guelph poet-statesman Rambertino Buvalelli . During the struggle between the Guelphs and

9164-416: The decomposition of carboxyhemoglobin back to hemoglobin: As carbon monoxide is now understood to have a therapeutic potential, pharmaceutical efforts have focused on development of carbon monoxide-releasing molecules and selective heme oxygenase inducers. An alternative method for drug delivery consists of carbon monoxide immobilized on polyethylene glycol (PEG)-lyated bovine carboxyhemoglobin which

9280-466: The drug in question is a prescription drug or an over-the-counter (OTC) drug. The FDA oversees the advertising of prescription drugs, while the FTC regulates the advertising of OTC drugs. The term off-label refers to the practice of prescribing a drug for a different purpose than what the FDA approved. Due to this approval requirement, manufacturers were prohibited from advertising COVID-19 vaccines during

9396-416: The drug is used safely. For example, thalidomide can cause birth defects, but has uses that outweigh the risks if men and women taking the drugs do not conceive a child; a REMS program for thalidomide mandates an auditable process to ensure that people taking the drug take action to avoid pregnancy; many opioid drugs have REMS programs to avoid addiction and diversion of drugs. The drug isotretinoin has

9512-678: The early 1990s, the U.S. Securities and Exchange Commission filed securities fraud charges against the Bolar Pharmaceutical Company, a major generic manufacturer based in Long Island, New York. Over-the-counter (OTC) are drugs like aspirin that do not require a doctor's prescription. The FDA has a list of approximately 800 such approved ingredients that are combined in various ways to create more than 100,000 OTC drug products. Many OTC drug ingredients had been previously approved prescription drugs now deemed safe enough for use without

9628-792: The elevated levels in smokers has been suggested to be a basis for the smoker's paradox . Prolonged exposure to carbon monoxide and elevated carboxyhemoglobin, such as in smoking, results in erythremia . Furthermore, humans can acclimate to toxic levels of carbon monoxide based on findings reported by Esther Killick . A bright red skin complexion is commonly associated with elevated carboxyhemoglobin levels. Trace evidence for an endogenous presence of carbon monoxide dates back to Marcellus Donato circa 1570 who noted an unusually red complexion upon conducting an autopsy of victims who died from charcoal fumes in Mantua . Similar findings pertaining to red complexion later emerged as documented by Johann Jakob Wepfer in

9744-648: The federal agency resulted in racketeering and in violations of antitrust law . "The order in which new generic drugs were approved was set by the FDA employees even before drug manufacturers submitted applications" and, according to Mylan, this illegal procedure was followed to give preferential treatment to certain companies. During the summer of 1989, three FDA officials (Charles Y. Chang, David J. Brancato, Walter Kletch) pleaded guilty to criminal charges of accepting bribes from generic drugs makers, and two companies ( Par Pharmaceutical and its subsidiary Quad Pharmaceuticals) pleaded guilty to giving bribes. Furthermore, it

9860-436: The federal government. It helps support "partner" agencies and organisations prepare for public health emergencies that could require MCMs. The Center for Drug Evaluation and Research uses different requirements for the three main drug product types: new drugs, generic drugs, and over-the-counter drugs. A drug is considered "new" if it is made by a different manufacturer, uses different excipients or inactive ingredients,

9976-541: The following year. The first analytical method to detect carboxyhemoglobin emerged in 1858 with a colorimetric method developed by Felix Hoppe-Seyler , and the first quantitative analysis method emerged in 1880 with Josef von Fodor . Carbon is derived from the Latin term carbo , meaning coal, via the French charbone , which first appeared in print in 1786. The etymology of oxygen is generally accepted mean 'acid' based on Lavoisier's system, which also recognized carbon as

10092-634: The insurrection in the County of Tyrol against Napoleon. After the brief period of French rule, Mantua returned to Austria in 1814, becoming one of the Quadrilatero fortress cities in northern Italy. Under the Congress of Vienna (1815) , Mantua became a province in the Austrian Empire's Kingdom of Lombardy–Venetia . Agitation against Austria, however, culminated in a revolt which lasted from 1851 to 1855, but it

10208-545: The issuance of enforcement letters to pharmaceutical manufacturers. Advertising and promotion for over-the-counter drugs is regulated by the Federal Trade Commission . The FDA also implements regulatory oversight through engagement with third-party enforcer-firms. It expects pharmaceutical companies to ensure that third-party suppliers and labs comply with the agency's health and safety guidelines . The drug advertising regulation contains two broad requirements: (1)

10324-495: The lung prior to exhalation. Later in 1854, Adrien Chenot similarly suggested carbon monoxide could remove oxygen from blood and be oxidized within the body to carbon dioxide. The mechanism for carbon monoxide poisoning in the context of carboxyhemoglobin formation is widely credited to Claude Bernard whose memoirs beginning in 1846 and published in 1857 notably phrased, "prevents arterials blood from becoming venous". Felix Hoppe-Seyler independently published similar conclusions in

10440-463: The name would not become mainstream for several decades. Variations of COHb terminology, such as carbonmonoxyhemoglobin, followed and eventually evolved and simplified back into "carboxyhemoglobin". As carboxy is now firmly associated with the CO 2 carboxyl group, and carbon monoxide is generally regarded as a carbonyl , IUPAC has recommended "carbonylhemoglobin" as the preferred COHb nomenclature. Despite

10556-467: The nearby comune of Sabbioneta were declared by UNESCO to be a World Heritage Site . Mantua's historic power and influence under the Gonzaga family between 1328 and 1708 made it one of the main artistic, cultural , and especially musical hubs of Northern Italy and of Italy as a whole. It had one of the most splendid courts of Europe of the fifteenth, sixteenth, and early seventeenth centuries. Mantua

10672-399: The oxygen in blood, and Beddoes and Watt likewise speculated hydrocarbonate has a greater affinity for animal fiber than oxygen in 1796. After the discovery of carbon monoxide by William Cruickshank in 1800, Johann Dömling (1803) and John Bostock (1804) developed hypotheses suggesting blood returned to the heart loaded with carbon monoxide to subsequently be oxidized to carbon dioxide in

10788-533: The period in which they had only been approved under Emergency Use Authorization . After NDA approval, the sponsor must then review and report to the FDA every single patient adverse drug experience it learns of. They must report unexpected serious and fatal adverse drug events within 15 days, and other events on a quarterly basis. The FDA also receives directly adverse drug event reports through its MedWatch program. These reports are called "spontaneous reports" because reporting by consumers and health professionals

10904-422: The predicate devices already on the market. Approved requests are for items that are new or substantially different and need to demonstrate "safety and efficacy", for example they may be inspected for safety in case of new toxic hazards. Both aspects need to be proved or provided by the submitter to ensure proper procedures are followed. Cosmetics are regulated by the Center for Food Safety and Applied Nutrition ,

11020-506: The protonated/ionized deoxygenated hemoglobin. Upon return of venous blood into the lung and subsequent exhalation of carbon dioxide, the blood is "de-acidified" (see also: hyperventilation ) for the deprotonation/unionization of hemoglobin to re-enable oxygen binding as part of the transition to arterial blood (note this process is complex due to involvement of chemoreceptors , pH buffers and other physiochemical functionalities). Carbon monoxide poisoning disturbs this physiological process hence

11136-566: The regulated industries. Rather, OCI agents pursue and develop cases when individuals and companies commit criminal actions, such as fraudulent claims or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving violations of Title 18 of the United States Code (e.g., conspiracy, false statements, wire fraud, mail fraud), in addition to prohibited acts as defined in Chapter III of

11252-470: The regulatory powers granted to the agency. For example, the FDA regulates almost every facet of prescription drugs, including testing, manufacturing, labeling, advertising, marketing, efficacy, and safety—yet FDA regulation of cosmetics focuses primarily on labeling and safety. The FDA regulates most products with a set of published standards enforced by a modest number of facility inspections. Inspection observations are documented on Form 483 . In June 2018,

11368-448: The safety and labeling of their product. The FDA has a "Dietary Supplement Ingredient Advisory List" that includes ingredients that sometimes appear on dietary supplements but need further evaluation. An ingredient is added to this list when it is excluded from use in a dietary supplement, does not appear to be an approved food additive or recognized as safe, and/or is subjected to the requirement for pre-market notification without having

11484-458: The same branch of the FDA that regulates food. Cosmetic products are not, in general, subject to premarket approval by the FDA unless they make "structure or function claims" that make them into drugs (see Cosmeceutical ). However, all color additives must be specifically FDA approved before manufacturers can include them in cosmetic products sold in the U.S. The FDA regulates cosmetics labeling, and cosmetics that have not been safety tested must bear

11600-539: The siege on August 27 and accepted surrender of the city on 2 February 1797. The city was recaptured by the Austrians in the War of the Second Coalition after a siege lasting from 8 April to 28 July 1799. Later, the city again passed into Napoleon's control and became a part of Napoleon's Kingdom of Italy. In 1810 Andreas Hofer was shot by Porta Giulia, a gate of the town at Borgo di Porto (Cittadella) for leading

11716-547: The terms are conjoined with an -o- . Regarding haem, the use of "ae / æ" remains prevalent in British English in modern day whereas the American English spelling evolved to heme from hema. Felix Hoppe-Seyler coined the name "hämoglobin" in 1864. In German, an umlaut such as ä is synonymous with spelling as "ae", therefore hämoglobin is commonly spelled as haemoglobin throughout German literature, hence haemoglobin

11832-519: The therapeutic potential of inhaling factitious airs in the late eighteenth century (see also: Pneumatic Institution ). Among the gases experimented with, hydrocarbonate had received significant attention. Hydrocarbonate is water gas generated by passing steam over coke , the process of which generates carbon monoxide and hydrogen, and some considered it contain phlogiston . Beddoes and Watt recognized hydrocarbonate brightened venous blood in 1793. Watt suggested coal fumes could act as an antidote to

11948-412: The time is further reduced when oxygen is administered with 5% carbon dioxide as first identified by Esther Killick . Additionally, treatment in a hyperbaric chamber is a more effective manner of reducing the half-life of carboxyhemoglobin to 30 minutes and allows oxygen to dissolve in biological fluids for delivery to tissues. Supplemental oxygen takes advantage of Le Chatelier's principle to quicken

12064-532: The venous blood of poisoning patients is bright red akin to arterial blood since the carbonyl/carbon monoxide is retained, whereas deoxygenated hemoglobin is dark red and carbaminohemoglobin has a blue hue. At toxic concentrations, carbon monoxide as carboxyhemoglobin significantly interferes with respiration and gas exchange by simultaneously inhibiting acquisition and delivery of oxygen to cells, and preventing formation of carbaminohemoglobin which accounts for approximately 30% of carbon dioxide exportation. Therefore

12180-508: Was a vociferous collector and such was her reputation that Niccolò da Corregio called her 'la prima donna del mondo'. Through a payment of 120,000 golden florins in 1433, Gianfrancesco I was appointed Marquis of Mantua by the Emperor Sigismund , whose niece Barbara of Brandenburg married his son, Ludovico. In 1459, Pope Pius II held the Council of Mantua to proclaim a crusade against

12296-762: Was born in the year 70 BC at a village near the city which is now known as Virgilio. After the fall of the Western Roman Empire at the hands of Odoacer in 476 AD, Mantua was, along with the rest of Italy, conquered by the Ostrogoths . It was retaken by the Eastern Roman Empire in the middle of the 6th century following the Gothic war but was subsequently lost again to the Lombards . They were in turn conquered by Charlemagne in 774, thus incorporating Mantua into

12412-471: Was canceled on 1 January 2015. Public connection is now provided by the airport bus running to and from Verona Porta Nuova railway station, and the Verona-Mantova railway line. Local bus services, urbano (within the city area and suburbs) and interurbano (within the surrounding towns and villages) are provided by APAM. Since local government political reorganization in 1993, Mantua has been governed by

12528-514: Was ceded to France, who transferred Lombardy to Piedmont-Sardinia in return for Nice and Savoy . Mantua, although a constituent province of Lombardy, still remained under the Austrian Empire along with Venetia. In 1866, Prussia-led North German Confederation sided with the newly established, Piedmont-led Kingdom of Italy against the Austrian Empire in the Third Italian War of Independence . The quick defeat of Austria led to its withdrawal of

12644-492: Was characterized as a neurotransmitter in 1993 and has since been subcategorized as a gasotransmitter . Most endogenously produced carbon monoxide is stored as carboxyhemoglobin. The gas primarily undergoes pulmonary excretion, however trace amounts may be oxidized to carbon dioxide by certain cytochromes , metabolized by resident microbiota , or excreted by transdermal diffusion. Compared to oxygen, carbon monoxide binds with approximately 240 times greater affinity, however

12760-533: Was discovered that several manufacturers had falsified data submitted in seeking FDA authorization to market certain generic drugs. Vitarine Pharmaceuticals of New York, which sought approval of a generic version of the drug Dyazide , a medication for high blood pressure, submitted Dyazide, rather than its generic version, for the FDA tests. In April 1989, the FDA investigated 11 manufacturers for irregularities; and later brought that number up to 13. Dozens of drugs were eventually suspended or recalled by manufacturers. In

12876-534: Was established by the 1902 Biologics Control Act , with additional authority established by the 1944 Public Health Service Act . Along with these Acts, the Federal Food, Drug, and Cosmetic Act applies to all biologic products, as well. Originally, the entity responsible for regulation of biological products resided under the National Institutes of Health ; this authority was transferred to the FDA in 1972. The Center for Devices and Radiological Health (CDRH)

12992-419: Was established in its place, and remained operational until April 1945. The Gonzagas protected the arts and culture, and were hosts to several important artists such as Leone Battista Alberti , Andrea Mantegna , Giulio Romano , Donatello , Peter Paul Rubens , Pisanello , Domenico Fetti , Luca Fancelli and Nicolò Sebregondi. Though many of the masterworks have been dispersed, the cultural value of Mantua

13108-714: Was finally suppressed by the Austrian army. One of the most famous episodes of the Italian Risorgimento took place in the valley of the Belfiore, where a group of rebels was hanged by the Austrians. At the Battle of Solferino ( Second Italian War of Independence ) in 1859, the House of Savoy 's Piedmont-Sardinia sided with the French Emperor Napoleon III against the Austrian Empire. Following Austria's defeat, Lombardy

13224-520: Was the countess Matilda of Canossa (d. 1115), who, according to legend, ordered the construction of the precious Rotonda di San Lorenzo (or St. Lawrence's Roundchurch) in 1082. The Rotonda still exists today and was renovated in 2013. After the death of Matilda of Canossa, Mantua became a free commune and strenuously defended itself from the influence of the Holy Roman Empire during the 12th and 13th centuries. In 1198, Alberto Pitentino altered

13340-588: Was the daughter of Duke Ercole the ruler of Ferrara ) she created her famous studiolo firstly in Castello di San Giorgio for which she commissioned paintings from Mantegna , Perugino and Lorenzo Costa . She later moved her studiolo to the Corte Vecchia and commissioned two paintings from Correggio to join the five from Castello di San Giorgio. It was unusual for a woman to have a studiolo in 15th century Italy given they were regarded as masculine spaces. Isabella

13456-578: Was translated into German as "kohlenoxyd". Kohlen is the German word for coal. As carbonic acid (CO 2 ) was considered to be the most highly oxidized form in Lavoisier's system, the name carbonic oxide implied an intermediate oxidized species between coal and carbonic acid (i.e. use of the word acid indicated maximum oxidation). Haem is derived from Greek meaning blood, and globin is Latin derived from globus typically accepted to mean glob/spherical/round object;

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