Carcinogen

From Wikipedia, the free encyclopedia

 

Cigarettes have been known carcinogens for at least 60 years.

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise in both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

Cancer is any disease in which normal cells are damaged and do not undergo programmed cell death as fast as they divide via mitosis. Carcinogens may increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors. Usually, severe DNA damage leads to programmed cell death, but if the programmed cell death pathway is damaged, then the cell cannot prevent itself from becoming a cancer cell.

There are many natural carcinogens. Aflatoxin B₁, which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally occurring microbial carcinogen. Certain viruses such as hepatitis B and human papilloma virus have been found to cause cancer in humans. The first one shown to cause cancer in animals is Rous sarcoma virus, discovered in 1910 by Peyton Rous. Other infectious organisms which cause cancer in humans include some bacteria (e.g. Helicobacter pylori) and helminths (e.g. Opisthorchis viverrini and Clonorchis sinensis).

Dioxins and dioxin-like compounds, benzene, kepone, EDB, and asbestos have all been classified as carcinogenic. As far back as the 1930s, Industrial smoke and tobacco smoke were identified as sources of dozens of carcinogens, including benzo[a]pyrene, tobacco-specific nitrosamines such as nitrosonornicotine, and reactive aldehydes such as formaldehyde, which is also a hazard in embalming and making plastics. Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.

Co-carcinogens are chemicals that do not necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer.

After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation. The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. However, in some cases, these reactions can also convert a less toxic carcinogen into a more toxic carcinogen.

DNA is nucleophilic; therefore, soluble carbon electrophiles are carcinogenic, because DNA attacks them. For example, some alkenes are toxicated by human enzymes to produce an electrophilic epoxide. DNA attacks the epoxide, and is bound permanently to it. This is the mechanism behind the carcinogenicity of benzo[a]pyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.

IUPAC definition

Carcinogenicity: Ability or tendency to produce cancer. Note: In general, polymers are not known as carcinogens or mutagens,
however, residual monomers or additives can cause genetic mutations.

Radiation

CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation (alpha, beta, gamma, or neutron and the radioactive strength), its consequent capacity to cause ionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. Carcinogenicity of radiation depends on the type of radiation, type of exposure, and penetration. For example, alpha radiation has low penetration and is not a hazard outside the body, but emitters are carcinogenic when inhaled or ingested. For example, Thorotrast, a (incidentally radioactive) suspension previously used as a contrast medium in x-ray diagnostics, is a potent human carcinogen known because of its retention within various organs and persistent emission of alpha particles. Low-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.

Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum including radio waves, microwaves, infrared radiation and visible light are thought not to be, because they have insufficient energy to break chemical bonds. Evidence for carcinogenic effects of non-ionizing radiation is generally inconclusive, though there are some documented cases of radar technicians with prolonged high exposure experiencing significantly higher cancer incidence.

Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses. For most people, ultraviolet radiations from sunlight is the most common cause of skin cancer. In Australia, where people with pale skin are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.

Substances or foods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic. In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can produce secondary radiation through nuclear transmutation.

In prepared food

Chemicals used in processed and cured meat such as some brands of bacon, sausages and ham may produce carcinogens. For example, nitrites used as food preservatives in cured meat such as bacon have also been noted as being carcinogenic with demographic links, but not causation, to colon cancer. Cooking food at high temperatures, for example grilling or barbecuing meats, may also lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzo[a]pyrene). Charring of food looks like coking and tobacco pyrolysis, and produces carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by human enzymes into epoxides, which attach permanently to DNA. Pre-cooking meats in a microwave oven for 2–3 minutes before grilling shortens the time on the hot pan, and removes heterocyclic amine (HCA) precursors, which can help minimize the formation of these carcinogens.

Reports from the Food Standards Agency have found that the known animal carcinogen acrylamide is generated in fried or overheated carbohydrate foods (such as french fries and potato chips). Studies are underway at the FDA and Europe regulatory agencies to assess its potential risk to humans.

In cigarettes

There is a strong association of smoking with lung cancer; the risk of developing lung cancer increases significantly in smokers. A large number of known carcinogens are found in cigarette smoke. Potent carcinogens found in cigarette smoke include polycyclic aromatic hydrocarbons (PAH, such as benzo(a)pyrene), benzene, and nitrosamine.

Mechanisms of carcinogenicity

Carcinogens can be classified as genotoxic or nongenotoxic. Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-nitroso-N-methylurea (NMU) or non-chemical agents such as ultraviolet light and ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.

Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic compounds.

Classification

Approximate equivalences
between classification schemes

IARC	GHS	NTP	ACGIH	EU
Group 1	Cat. 1A	Known	A1	Cat. 1A
Group 2A	Cat. 1B	Reasonably suspected	A2	Cat. 1B
Group 2B
	Cat. 2		A3	Cat. 2
Group 3
			A4
Group 4			A5

International Agency for Research on Cancer

The International Agency for Research on Cancer (IARC) is an intergovernmental agency established in 1965, which forms part of the World Health Organization of the United Nations. It is based in Lyon, France. Since 1971 it has published a series of Monographs on the Evaluation of Carcinogenic Risks to Humans that have been highly influential in the classification of possible carcinogens.

• Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
• Group 2A: the agent (mixture) is probably (product more likely to be) carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
• Group 2B: the agent (mixture) is possibly (chance of product being) carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
• Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
• Group 4: the agent (mixture) is probably not carcinogenic to humans.

Globally Harmonized System

The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) is a United Nations initiative to attempt to harmonize the different systems of assessing chemical risk which currently exist (as of March 2009) around the world. It classifies carcinogens into two categories, of which the first may be divided again into subcategories if so desired by the competent regulatory authority:

• Category 1: known or presumed to have carcinogenic potential for humans
  • Category 1A: the assessment is based primarily on human evidence
  • Category 1B: the assessment is based primarily on animal evidence
• Category 2: suspected human carcinogens

U.S. National Toxicology Program

The National Toxicology Program of the U.S. Department of Health and Human Services is mandated to produce a biennial Report on Carcinogens. As of June 2011, the latest edition was the 12th report (2011). It classifies carcinogens into two groups:

• Known to be a human carcinogen
• Reasonably anticipated being a human carcinogen

American Conference of Governmental Industrial Hygienists

The American Conference of Governmental Industrial Hygienists (ACGIH) is a private organization best known for its publication of threshold limit values (TLVs) for occupational exposure and monographs on workplace chemical hazards. It assesses carcinogenicity as part of a wider assessment of the occupational hazards of chemicals.

• Group A1: Confirmed human carcinogen
• Group A2: Suspected human carcinogen
• Group A3: Confirmed animal carcinogen with unknown relevance to humans
• Group A4: Not classifiable as a human carcinogen
• Group A5: Not suspected as a human carcinogen

European Union

The European Union classification of carcinogens is contained in the Regulation (EC) No 1272/2008. It consists of three categories:

• Category 1A: Carcinogenic
• Category 1B: May cause cancer
• Category 2: Suspected of causing cancer

The former European Union classification of carcinogens was contained in the Dangerous Substances Directive and the Dangerous Preparations Directive. It also consisted of three categories:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances which should be regarded as if they are carcinogenic to humans.
• Category 3: Substances which cause concern for humans, owing to possible carcinogenic effects but in respect of which the available information is not adequate for making a satisfactory assessment.

This assessment scheme is being phased out in favor of the GHS scheme (see above), to which it is very close in category definitions.

Safe Work Australia

Under a previous name, the NOHSC, in 1999 Safe Work Australia published the Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(1999)]. Section 4.76 of this document outlines the criteria for classifying carcinogens as approved by the Australian government. This classification consists of three categories:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances that should be regarded as if they were carcinogenic to humans.
• Category 3: Substances that have possible carcinogenic effects in humans but about which there is insufficient information to make an assessment.

Common carcinogens

Occupational carcinogens

Occupational carcinogens are agents that pose a risk of cancer in several specific work-locations:

Carcinogen	Associated cancer sites or types	Occupational uses or sources
Arsenic and its compounds	Lung Skin Hemangiosarcoma	Smelting byproduct Component of: Alloys Electrical and semiconductor devices Medications (e.g. melarsoprol) Herbicides Fungicides Animal dips Drinking water from contaminated aquifers.
Asbestos	Lungs Asbestosis Gastrointestinal tract Pleural Mesothelioma Peritoneal Mesothelioma	Not in widespread use, but found in: Constructions Roofing papers Floor tiles Fire-resistant textiles Friction linings (brake pads) (only outside Europe) Replacement friction linings for automobiles still may contain asbestos
Benzene	Leukemia Hodgkin's lymphoma	Light fuel oil Former use as solvent commodity chemical
Beryllium and its compounds	Lung	Lightweight alloys Aerospace applications Nuclear reactors
Cadmium and its compounds	Prostate	Yellow pigments Phosphors Solders Batteries Metal paintings and coatings
Hexavalent chromium(VI) compounds	Lung	Paints Pigments Preservatives
Nitrosamines	Lung Esophagus Liver	cigarette smoke nitrite-treated foods (cured meats)
Ethylene oxide	Leukemia	commodity chemical Sterilant for hospital equipment
Nickel	Nose Lung	Nickel plating Ferrous alloys Ceramics Batteries Stainless-steel welding byproduct
Radon and its decay products	Lung	Uranium decay Quarries and mines Cellars and poorly ventilated places
Vinyl chloride	Hemangiosarcoma Liver	Production of polyvinyl chloride
Shift work that involves circadian disruption	Breast
Involuntary smoking (Passive smoking)	Lung
Radium-226, Radium-224, Plutonium-238, Plutonium-239 and other alpha particle emitters with high atomic weight	Bone (they are bone seekers) Liver	Nuclear fuel processing Radium dial manufacturing

Others

• Gasoline (contains aromatics)
• Lead and its compounds
• Alkylating antineoplastic agents (e.g. mechlorethamine)
• Styrene
• Other alkylating agents (e.g. dimethyl sulfate)
• Ultraviolet radiation from the sun and UV lamps
• Alcohol (causing head and neck cancers)
• Other ionizing radiation (X-rays, gamma rays, etc.)

Major carcinogens implicated in the four most common cancers worldwide

In this section, the carcinogens implicated as the main causative agents of the four most common cancers worldwide are briefly described. These four cancers are lung, breast, colon, and stomach cancers. Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths (for more detailed information on the carcinogens implicated in these and other cancers, see references).

Lung cancer

Lung cancer (pulmonary carcinoma) is the most common cancer in the world, both in terms of cases (1.6 million cases; 12.7% of total cancer cases) and deaths (1.4 million deaths; 18.2% of total cancer deaths). Lung cancer is largely caused by tobacco smoke. Risk estimates for lung cancer in the United States indicate that tobacco smoke is responsible for 90% of lung cancers. Other factors are implicated in lung cancer, and these factors can interact synergistically with smoking so that total attributable risk adds up to more than 100%. These factors include occupational exposure to carcinogens (about 9-15%), radon (10%) and outdoor air pollution (1-2%). Tobacco smoke is a complex mixture of more than 5,300 identified chemicals. The most important carcinogens in tobacco smoke have been determined by a “Margin of Exposure” approach. Using this approach, the most important tumorigenic compounds in tobacco smoke were, in order of importance, acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, cadmium, acetaldehyde, ethylene oxide, and isoprene. Most of these compounds cause DNA damage by forming DNA adducts or by inducing other alterations in DNA. DNA damages are subject to error-prone DNA repair or can cause replication errors. Such errors in repair or replication can result in mutations in tumor suppressor genes or oncogenes leading to cancer.

Breast cancer

Breast cancer is the second most common cancer [(1.4 million cases, 10.9%), but ranks 5th as cause of death (458,000, 6.1%)]. Increased risk of breast cancer is associated with persistently elevated blood levels of estrogen. Estrogen appears to contribute to breast carcinogenesis by three processes; (1) the metabolism of estrogen to genotoxic, mutagenic carcinogens, (2) the stimulation of tissue growth, and (3) the repression of phase II detoxification enzymes that metabolize ROS leading to increased oxidative DNA damage. The major estrogen in humans, estradiol, can be metabolized to quinone derivatives that form adducts with DNA. These derivatives can cause dupurination, the removal of bases from the phosphodiester backbone of DNA, followed by inaccurate repair or replication of the apurinic site leading to mutation and eventually cancer. This genotoxic mechanism may interact in synergy with estrogen receptor-mediated, persistent cell proliferation to ultimately cause breast cancer. Genetic background, dietary practices and environmental factors also likely contribute to the incidence of DNA damage and breast cancer risk.

Colon cancer

Colorectal cancer is the third most common cancer [1.2 million cases (9.4%), 608,000 deaths (8.0%)]. Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States. In addition, substantial evidence implicates bile acids as an important factor in colon cancer. Twelve studies (summarized in Bernstein et al.) indicate that the bile acids deoxycholic acid (DCA) or lithocholic acid (LCA) induce production of DNA-damaging reactive oxygen species or reactive nitrogen species in human or animal colon cells. Furthermore, 14 studies showed that DCA and LCA induce DNA damage in colon cells. Also 27 studies reported that bile acids cause programmed cell death (apoptosis). Increased apoptosis can result in selective survival of cells that are resistant to induction of apoptosis. Colon cells with reduced ability to undergo apoptosis in response to DNA damage would tend to accumulate mutations, and such cells may give rise to colon cancer. Epidemiologic studies have found that fecal bile acid concentrations are increased in populations with a high incidence of colon cancer. Dietary increases in total fat or saturated fat result in elevated DCA and LCA in feces and elevated exposure of the colon epithelium to these bile acids. When the bile acid DCA was added to the standard diet of wild-type mice invasive colon cancer was induced in 56% of the mice after 8 to 10 months. Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging carcinogens in colon cancer.

Stomach cancer

Stomach cancer is the fourth most common cancer [990,000 cases (7.8%), 738,000 deaths (9.7%)]. Helicobacter pylori infection is the main causative factor in stomach cancer. Chronic gastritis (inflammation) caused by H. pylori is often long-standing if not treated. Infection of gastric epithelial cells with H. pylori results in increased production of reactive oxygen species (ROS). ROS cause oxidative DNA damage including the major base alteration 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG resulting from ROS is increased in chronic gastritis. The altered DNA base can cause errors during DNA replication that have mutagenic and carcinogenic potential. Thus H. pylori-induced ROS appear to be the major carcinogens in stomach cancer because they cause oxidative DNA damage leading to carcinogenic mutations. Diet is thought to be a contributing factor in stomach cancer - in Japan where very salty pickled foods are popular, the incidence of stomach cancer is high. Preserved meat such as bacon, sausages, and ham increases the risk while a diet high in fresh fruit and vegetables may reduce the risk. The risk also increases with age.

Corticosteroid

From Wikipedia, the free encyclopedia

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

 

Corticosteroid
Cortisol (hydrocortisone), a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.
Class identifiers
Synonyms	Corticoid
Use	Various
ATC code	H02
Biological target	Glucocorticoid receptor, Mineralocorticoid receptor
Chemical class	Steroids

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

Some common naturally occurring steroid hormones are cortisol (C
₂₁H
₃₀O
₅), corticosterone (C
₂₁H
₃₀O
₄), cortisone (C
₂₁H
₂₈O
₅) and aldosterone (C
₂₁H
₂₈O
₅). (Note that cortisone and aldosterone are isomers.) The main corticosteroids produced by the adrenal cortex are cortisol and aldosterone.

Classes

Cortisol

Cortisone

Corticosterone

Aldosterone

• Glucocorticoids such as cortisol affect carbohydrate, fat, and protein metabolism, and have anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive effects. Anti-inflammatory effects are mediated by blocking the action of inflammatory mediators (transrepression) and inducing anti-inflammatory mediators (transactivation). Immunosuppressive effects are mediated by suppressing delayed hypersensitivity reactions by direct action on T-lymphocytes. Anti-proliferative effects are mediated by inhibition of DNA synthesis and epidermal cell turnover. Vasoconstrictive effects are mediated by inhibiting the action of inflammatory mediators such as histamine.
• Mineralocorticoids such as aldosterone are primarily involved in the regulation of electrolyte and water balance by modulating ion transport in the epithelial cells of the renal tubules of the kidney.

Medical uses

Synthetic pharmaceutical drugs with corticosteroid-like effects are used in a variety of conditions, ranging from brain tumors to skin diseases. Dexamethasone and its derivatives are almost pure glucocorticoids, while prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. Fludrocortisone (Florinef) is a synthetic mineralocorticoid. Hydrocortisone (cortisol) is typically used for replacement therapy, e.g. for adrenal insufficiency and congenital adrenal hyperplasia.

Medical conditions treated with systemic corticosteroids:

• Allergy and respirology medicine
  • Asthma (severe exacerbations)
  • Chronic obstructive pulmonary disease (COPD)
  • Allergic rhinitis
  • Atopic dermatitis
  • Hives
  • Angioedema
  • Anaphylaxis
  • Food allergies
  • Drug allergies
  • Nasal polyps
  • Hypersensitivity pneumonitis
  • Sarcoidosis
  • Eosinophilic pneumonia
  • Some other types of pneumonia (in addition to the traditional antibiotic treatment protocols)
  • Interstitial lung disease
• Dermatology
  • Pemphigus vulgaris
  • Contact dermatitis
• Endocrinology (usually at physiologic doses)
  • Addison's disease
  • Adrenal insufficiency
  • Congenital adrenal hyperplasia
• Gastroenterology
  • Ulcerative colitis
  • Crohn's disease
  • Autoimmune hepatitis
• Hematology
  • Lymphoma
  • Leukemia
  • Hemolytic anemia
  • Idiopathic thrombocytopenic purpura
  • Multiple Myeloma
• Rheumatology/Immunology
  • Rheumatoid arthritiseas
  • Systemic lupus erythematosus
  • Polymyalgia rheumatica
  • Polymyositis
  • Dermatomyositis
  • Polyarteritis
  • Vasculitis
• Ophthalmology
  • Uveitis
  • Optic neuritis
  • Keratoconjunctivitis
• Other conditions
  • Multiple sclerosis relapses
  • Organ transplantation
  • Nephrotic syndrome
  • Chronic hepatitis (flare ups)
  • Cerebral edema
  • IgG4-related disease
  • Prostate cancer
  • Tendinosis
  • Lichen planus

Topical formulations are also available for the skin, eyes (uveitis), lungs (asthma), nose (rhinitis), and bowels. Corticosteroids are also used supportively to prevent nausea, often in combination with 5-HT3 antagonists (e.g. ondansetron).

Typical undesired effects of glucocorticoids present quite uniformly as drug-induced Cushing's syndrome. Typical mineralocorticoid side-effects are hypertension (abnormally high blood pressure), steroid induced diabetes mellitus, psychosis, poor sleep, hypokalemia (low potassium levels in the blood), hypernatremia (high sodium levels in the blood) without causing peripheral edema, metabolic alkalosis and connective tissue weakness. Wound healing or ulcer formation may be inhibited by the immunosuppressive effects.

Clinical and experimental evidence indicates that corticosteroids can cause permanent eye damage by inducing central serous retinopathy (CSR, also known as central serous chorioretinopathy, CSC). This should be borne in mind when treating patients with optic neuritis. There is experimental and clinical evidence that, at least in optic neuritis speed of treatment initiation is important.

A variety of steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical skin creams, to eye drops (Tobradex), to prednisone have been implicated in the development of CSR.

Corticosteroids have been widely used in treating people with traumatic brain injury. A systematic review identified 20 randomised controlled trials and included 12,303 participants, then compared patients who received corticosteroids with patients who received no treatment. The authors recommended people with traumatic head injury should not be routinely treated with corticosteroids.

Pharmacology

Corticosteroids act as agonists of the glucocorticoid receptor and/or the mineralocorticoid receptor.

In addition to their corticosteroid activity, some corticosteroids may have some progestogenic activity and may produce sex-related side effects.

Pharmacogenetics

Asthma

Patients' response to inhaled corticosteroids has some basis in genetic variations. Two genes of interest are CHRH1 (corticotropin-releasing hormone receptor 1) and TBX21 (transcription factor T-bet). Both genes display some degree of polymorphic variation in humans, which may explain how some patients respond better to inhaled corticosteroid therapy than others. However, not all asthma patients respond to corticosteroids and large sub groups of asthma patients are corticosteroid resistant.

Adverse effects

Lower arm of a 47-year-old female showing skin damage caused by topical corticosteroid use.

Use of corticosteroids has numerous side-effects, some of which may be severe:

• Severe amebic colitis: Fulminant amebic colitis is associated with high case fatality and can occur in patients infected with the parasite Entamoeba histolytica after exposure to corticosteroid medications.
• Neuropsychiatric: steroid psychosis, and anxiety, depression. Therapeutic doses may cause a feeling of artificial well-being ("steroid euphoria"). The neuropsychiatric effects are partly mediated by sensitization of the body to the actions of adrenaline. Therapeutically, the bulk of corticosteroid dose is given in the morning to mimic the body's diurnal rhythm; if given at night, the feeling of being energized will interfere with sleep. An extensive review is provided by Flores and Gumina.
• Cardiovascular: Corticosteroids can cause sodium retention through a direct action on the kidney, in a manner analogous to the mineralocorticoid aldosterone. This can result in fluid retention and hypertension.
• Metabolic: Corticosteroids cause a movement of body fat to the face and torso, resulting in "moon face", "buffalo hump", and "pot belly" or "beer belly", and cause movement of body fat away from the limbs. This has been termed corticosteroid-induced lipodystrophy. Due to the diversion of amino-acids to glucose, they are considered anti-anabolic, and long term therapy can cause muscle wasting.
• Endocrine: By increasing the production of glucose from amino-acid breakdown and opposing the action of insulin, corticosteroids can cause hyperglycemia, insulin resistance and diabetes mellitus.
• Skeletal: Steroid-induced osteoporosis may be a side-effect of long-term corticosteroid use. Use of inhaled corticosteroids among children with asthma may result in decreased height.
• Gastro-intestinal: While cases of colitis have been reported, corticosteroids are often prescribed when the colitis, although due to suppression of the immune response to pathogens, should be considered only after ruling out infection or microbe/fungal overgrowth in the gastrointestinal tract. While the evidence for corticosteroids causing peptic ulceration is relatively poor except for high doses taken for over a month, the majority of doctors as of 2010 still believe this is the case, and would consider protective prophylactic measures.
• Eyes: chronic use may predispose to cataract and glaucoma.
• Vulnerability to infection: By suppressing immune reactions (which is one of the main reasons for their use in allergies), steroids may cause infections to flare up, notably candidiasis.
• Pregnancy: Corticosteroids have a low but significant teratogenic effect, causing a few birth defects per 1,000 pregnant women treated. Corticosteroids are therefore contraindicated in pregnancy.
• Habituation: Topical steroid addiction (TSA) or red burning skin has been reported in long-term users of topical steroids (users who applied topical steroids to their skin over a period of weeks, months, or years). TSA is characterised by uncontrollable, spreading dermatitis and worsening skin inflammation which requires a stronger topical steroid to get the same result as the first prescription. When topical steroid medication is lost, the skin experiences redness, burning, itching, hot skin, swelling, and/or oozing for a length of time. This is also called 'red skin syndrome' or 'topical steroid withdrawal' (TSW). After the withdrawal period is over the atopic dermatitis can cease or is less severe than it was before.
• In children the short term use of steroids by mouth increases the risk of vomiting, behavioral changes, and sleeping problems.

Biosynthesis

Steroidogenesis, including corticosteroid biosynthesis.

The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).

Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is mediated either by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and zona glomerulosa.

Classification of corticosteroids

By chemical structure

In general, corticosteroids are grouped into four classes, based on chemical structure. Allergic reactions to one member of a class typically indicate an intolerance of all members of the class. This is known as the "Coopman classification".

The highlighted steroids are often used in the screening of allergies to topical steroids.

Group A – Hydrocortisone type

Hydrocortisone, Hydrocortisone acetate, Cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone

Group B – Acetonides (and related substances)

Amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide.

Group C – Betamethasone type

Beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

Group D – Esters

Group D₁ – Halogenated (less labile)

Alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate.

Group D₂ – Labile prodrug esters

Ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate.

By route of administration

Topical steroids

For use topically on the skin, eye, and mucous membranes.

Topical corticosteroids are divided in potency classes I to IV in most countries (A to D in Japan). Seven categories are used in the United States to determine the level of potency of any given topical corticosteroid.

Inhaled steroids

For nasal mucosa, sinuses, bronchi, and lungs. This group includes:

• Flunisolide
• Fluticasone furoate
• Fluticasone propionate
• Triamcinolone acetonide
• Beclomethasone dipropionate
• Budesonide
• Mometasone furoate
• Ciclesonide

There also exist certain combination preparations such as Advair Diskus in the United States, containing fluticasone propionate and salmeterol (a long-acting bronchodilator), and Symbicort, containing budesonide and formoterol fumarate dihydrate (another long-acting bronchodilator). They are both approved for use in children over 12 years old.

Oral forms

Such as prednisone, prednisolone, methylprednisolone, or dexamethasone.

Systemic forms

Available in injectables for intravenous and parenteral routes.

History

Introduction of early corticosteroids

Corticosteroid	Introduced
Cortisone	1948
Hydrocortisone	1951
Fludrocortisone acetate	1954
Prednisolone	1955
Prednisone	1955
Methylprednisolone	1956
Triamcinolone	1956
Dexamethasone	1958
Betamethasone	1958
Triamcinolone acetonide	1958
Fluorometholone	1959

Tadeusz Reichstein, Edward Calvin Kendall. and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine in 1950 for their work on hormones of the adrenal cortex, which culminated in the isolation of cortisone.

Initially hailed as a miracle cure and liberally prescribed during the 1950s, steroid treatment brought about adverse events of such a magnitude that the next major category of anti-inflammatory drugs, the nonsteroidal anti-inflammatory drugs (NSAIDs), was so named in order to demarcate from the opprobrium. Corticosteroids were voted Allergen of the Year in 2005 by the American Contact Dermatitis Society.

Lewis Sarett of Merck & Co. was the first to synthesize cortisone, using a 36-step process that started with deoxycholic acid, which was extracted from ox bile. The low efficiency of converting deoxycholic acid into cortisone led to a cost of US$200 per gram. Russell Marker, at Syntex, discovered a much cheaper and more convenient starting material, diosgenin from wild Mexican yams. His conversion of diosgenin into progesterone by a four-step process now known as Marker degradation was an important step in mass production of all steroidal hormones, including cortisone and chemicals used in hormonal contraception.

In 1952, D.H. Peterson and H.C. Murray of Upjohn developed a process that used Rhizopus mold to oxidize progesterone into a compound that was readily converted to cortisone. The ability to cheaply synthesize large quantities of cortisone from the diosgenin in yams resulted in a rapid drop in price to US$6 per gram, falling to $0.46 per gram by 1980. Percy Julian's research also aided progress in the field. The exact nature of cortisone's anti-inflammatory action remained a mystery for years after, however, until the leukocyte adhesion cascade and the role of phospholipase A2 in the production of prostaglandins and leukotrienes was fully understood in the early 1980s.

Etymology

The cortico- part of the name refers to the adrenal cortex, which makes these steroid hormones. Thus a corticosteroid is a "cortex steroid".

Health care

From Wikipedia, the free encyclopedia

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

Global concentrations of healthcare resources, as depicted by the number of physicians per 10,000 individuals, by country.

Graphic of hospital beds per 1000 people globally in 2013, at top; New York–Presbyterian Hospital in New York City is one of the world's busiest hospitals, below. Pictured is the Weill-Cornell facility (white complex at the center)

Health care (also health-care or healthcare) is the maintenance or improvement of health via the prevention, diagnosis, treatment, recovery, or cure of disease, illness, injury, and other physical and mental impairments in people. Health care is delivered by health professionals and allied health fields. Medicine, dentistry, pharmacy, midwifery, nursing, optometry, audiology, psychology, occupational therapy, physical therapy, athletic training and other health professions are all part of health care. It includes work done in providing primary care, secondary care, and tertiary care, as well as in public health.

Access to health care may vary across countries, communities, and individuals, influenced by social and economic conditions as well as health policies. Providing health care services means "the timely use of personal health services to achieve the best possible health outcomes". Factors to consider in terms of healthcare access include financial limitations (such as insurance coverage), geographic barriers (such as additional transportation costs, the possibility to take paid time off of work to use such services), and personal limitations (lack of ability to communicate with healthcare providers, poor health literacy, low income). Limitations to health care services affects negatively the use of medical services, the efficacy of treatments, and overall outcome (well-being, mortality rates).

Health care systems are organizations established to meet the health needs of targeted populations. According to the World Health Organization (WHO), a well-functioning health care system requires a financing mechanism, a well-trained and adequately paid workforce, reliable information on which to base decisions and policies, and well maintained health facilities to deliver quality medicines and technologies.

An efficient health care system can contribute to a significant part of a country's economy, development, and industrialization. Health care is conventionally regarded as an important determinant in promoting the general physical and mental health and well-being of people around the world. An example of this was the worldwide eradication of smallpox in 1980, declared by the WHO as the first disease in human history to be eliminated by deliberate health care interventions.

Delivery

Primary care may be provided in community health centers.

The delivery of modern health care depends on groups of trained professionals and paraprofessionals coming together as interdisciplinary teams. This includes professionals in medicine, psychology, physiotherapy, nursing, dentistry, midwifery and allied health, along with many others such as public health practitioners, community health workers and assistive personnel, who systematically provide personal and population-based preventive, curative and rehabilitative care services.

While the definitions of the various types of health care vary depending on the different cultural, political, organizational and disciplinary perspectives, there appears to be some consensus that primary care constitutes the first element of a continuing health care process and may also include the provision of secondary and tertiary levels of care. Health care can be defined as either public or private.

The emergency room is often a frontline venue for the delivery of primary medical care.

Primary care

Hospital train "Therapist Matvei Mudrov" in Khabarovsk, Russia

Primary care refers to the work of health professionals who act as a first point of consultation for all patients within the health care system. Such a professional would usually be a primary care physician, such as a general practitioner or family physician. Another professional would be a licensed independent practitioner such as a physiotherapist, or a non-physician primary care provider such as a physician assistant or nurse practitioner. Depending on the locality, health system organization the patient may see another health care professional first, such as a pharmacist or nurse. Depending on the nature of the health condition, patients may be referred for secondary or tertiary care.

Primary care is often used as the term for the health care services that play a role in the local community. It can be provided in different settings, such as Urgent care centers that provide same-day appointments or services on a walk-in basis.

Primary care involves the widest scope of health care, including all ages of patients, patients of all socioeconomic and geographic origins, patients seeking to maintain optimal health, and patients with all types of acute and chronic physical, mental and social health issues, including multiple chronic diseases. Consequently, a primary care practitioner must possess a wide breadth of knowledge in many areas. Continuity is a key characteristic of primary care, as patients usually prefer to consult the same practitioner for routine check-ups and preventive care, health education, and every time they require an initial consultation about a new health problem. The International Classification of Primary Care (ICPC) is a standardized tool for understanding and analyzing information on interventions in primary care based on the reason for the patient's visit.

Common chronic illnesses usually treated in primary care may include, for example: hypertension, diabetes, asthma, COPD, depression and anxiety, back pain, arthritis or thyroid dysfunction. Primary care also includes many basic maternal and child health care services, such as family planning services and vaccinations. In the United States, the 2013 National Health Interview Survey found that skin disorders (42.7%), osteoarthritis and joint disorders (33.6%), back problems (23.9%), disorders of lipid metabolism (22.4%), and upper respiratory tract disease (22.1%, excluding asthma) were the most common reasons for accessing a physician.

In the United States, primary care physicians have begun to deliver primary care outside of the managed care (insurance-billing) system through direct primary care which is a subset of the more familiar concierge medicine. Physicians in this model bill patients directly for services, either on a pre-paid monthly, quarterly, or annual basis, or bill for each service in the office. Examples of direct primary care practices include Foundation Health in Colorado and Qliance in Washington.

In context of global population aging, with increasing numbers of older adults at greater risk of chronic non-communicable diseases, rapidly increasing demand for primary care services is expected in both developed and developing countries. The World Health Organization attributes the provision of essential primary care as an integral component of an inclusive primary health care strategy.

Secondary care

Secondary care includes acute care: necessary treatment for a short period of time for a brief but serious illness, injury, or other health condition. This care is often found in a hospital emergency department. Secondary care also includes skilled attendance during childbirth, intensive care, and medical imaging services.

The term "secondary care" is sometimes used synonymously with "hospital care". However, many secondary care providers, such as psychiatrists, clinical psychologists, occupational therapists, most dental specialties or physiotherapists, do not necessarily work in hospitals. Some primary care services are delivered within hospitals. Depending on the organization and policies of the national health system, patients may be required to see a primary care provider for a referral before they can access secondary care.

In countries that operate under a mixed market health care system, some physicians limit their practice to secondary care by requiring patients to see a primary care provider first. This restriction may be imposed under the terms of the payment agreements in private or group health insurance plans. In other cases, medical specialists may see patients without a referral, and patients may decide whether self-referral is preferred.

In other countries patient self-referral to a medical specialist for secondary care is rare as prior referral from another physician (either a primary care physician or another specialist) is considered necessary, regardless of whether the funding is from private insurance schemes or national health insurance.

Allied health professionals, such as physical therapists, respiratory therapists, occupational therapists, speech therapists, and dietitians, also generally work in secondary care, accessed through either patient self-referral or through physician referral.

Tertiary care

The National Hospital for Neurology and Neurosurgery in London, United Kingdom is a specialist neurological hospital.

Tertiary care is specialized consultative health care, usually for inpatients and on referral from a primary or secondary health professional, in a facility that has personnel and facilities for advanced medical investigation and treatment, such as a tertiary referral hospital.

Examples of tertiary care services are cancer management, neurosurgery, cardiac surgery, plastic surgery, treatment for severe burns, advanced neonatology services, palliative, and other complex medical and surgical interventions.

Quaternary care

The term quaternary care is sometimes used as an extension of tertiary care in reference to advanced levels of medicine which are highly specialized and not widely accessed. Experimental medicine and some types of uncommon diagnostic or surgical procedures are considered quaternary care. These services are usually only offered in a limited number of regional or national health care centers.

Home and community care

Many types of health care interventions are delivered outside of health facilities. They include many interventions of public health interest, such as food safety surveillance, distribution of condoms and needle-exchange programs for the prevention of transmissible diseases.

They also include the services of professionals in residential and community settings in support of self-care, home care, long-term care, assisted living, treatment for substance use disorders among other types of health and social care services.

Community rehabilitation services can assist with mobility and independence after the loss of limbs or loss of function. This can include prostheses, orthotics, or wheelchairs.

Many countries, especially in the west, are dealing with aging populations, so one of the priorities of the health care system is to help seniors live full, independent lives in the comfort of their own homes. There is an entire section of health care geared to providing seniors with help in day-to-day activities at home such as transportation to and from doctor's appointments along with many other activities that are essential for their health and well-being. Although they provide home care for older adults in cooperation, family members and care workers may harbor diverging attitudes and values towards their joint efforts. This state of affairs presents a challenge for the design of ICT (information and communication technology) for home care.

Because statistics show that over 80 million Americans have taken time off of their primary employment to care for a loved one, many countries have begun offering programs such as the Consumer Directed Personal Assistant Program to allow family members to take care of their loved ones without giving up their entire income.

With obesity in children rapidly becoming a major concern, health services often set up programs in schools aimed at educating children about nutritional eating habits, making physical education a requirement and teaching young adolescents to have a positive self-image.

Ratings

Health care ratings are ratings or evaluations of health care used to evaluate the process of care and health care structures and/or outcomes of health care services. This information is translated into report cards that are generated by quality organizations, nonprofit, consumer groups and media. This evaluation of quality is based on measures of:

• hospital quality
• health plan quality
• physician quality
• MERHS healthcare treatment
• quality for other health professionals
• of patient experience

Related sectors

Health care extends beyond the delivery of services to patients, encompassing many related sectors, and is set within a bigger picture of financing and governance structures.

Health system

A health system, also sometimes referred to as health care system or healthcare system is the organization of people, institutions, and resources that deliver health care services to populations in need.

Healthcare industry

The healthcare industry incorporates several sectors that are dedicated to providing health care services and products. As a basic framework for defining the sector, the United Nations' International Standard Industrial Classification categorizes health care as generally consisting of hospital activities, medical and dental practice activities, and "other human health activities." The last class involves activities of, or under the supervision of, nurses, midwives, physiotherapists, scientific or diagnostic laboratories, pathology clinics, residential health facilities, patient advocates or other allied health professions.

In addition, according to industry and market classifications, such as the Global Industry Classification Standard and the Industry Classification Benchmark, health care includes many categories of medical equipment, instruments and services including biotechnology, diagnostic laboratories and substances, drug manufacturing and delivery.

For example, pharmaceuticals and other medical devices are the leading high technology exports of Europe and the United States. The United States dominates the biopharmaceutical field, accounting for three-quarters of the world's biotechnology revenues.

Health care research

The quantity and quality of many health care interventions are improved through the results of science, such as advanced through the medical model of health which focuses on the eradication of illness through diagnosis and effective treatment. Many important advances have been made through health research, biomedical research and pharmaceutical research, which form the basis for evidence-based medicine and evidence-based practice in health care delivery. Health care research frequently engages directly with patients, and as such issues for who to engage and how to engage with them become important to consider when seeking to actively include them in studies. While single best practice does not exist, the results of a systematic review on patient engagement suggest that research methods for patient selection need to account for both patient availability and willingness to engage.

Health services research can lead to greater efficiency and equitable delivery of health care interventions, as advanced through the social model of health and disability, which emphasizes the societal changes that can be made to make populations healthier. Results from health services research often form the basis of evidence-based policy in health care systems. Health services research is also aided by initiatives in the field of artificial intelligence for the development of systems of health assessment that are clinically useful, timely, sensitive to change, culturally sensitive, low-burden, low-cost, built into standard procedures, and involve the patient.

Health care financing

Total health spending as a fraction of GDP.

There are generally five primary methods of funding health care systems:

1. General taxation to the state, county or municipality
2. Social health insurance
3. Voluntary or private health insurance
4. Out-of-pocket payments
5. Donations to health charities

In most countries, there is a mix of all five models, but this varies across countries and over time within countries. Aside from financing mechanisms, an important question should always be how much to spend on healthcare. For the purposes of comparison, this is often expressed as the percentage of GDP spent on healthcare. In OECD countries for every extra $1000 spent on healthcare, life expectancy falls by 0.4 years. A similar correlation is seen from the analysis carried out each year by Bloomberg. Clearly this kind of analysis is flawed in that life expectancy is only one measure of a health system's performance, but equally, the notion that more funding is better is not supported.

In 2011, the health care industry consumed an average of 9.3 percent of the GDP or US$ 3,322 (PPP-adjusted) per capita across the 34 members of OECD countries. The US (17.7%, or US$ PPP 8,508), the Netherlands (11.9%, 5,099), France (11.6%, 4,118), Germany (11.3%, 4,495), Canada (11.2%, 5669), and Switzerland (11%, 5,634) were the top spenders, however life expectancy in total population at birth was highest in Switzerland (82.8 years), Japan and Italy (82.7), Spain and Iceland (82.4), France (82.2) and Australia (82.0), while OECD's average exceeds 80 years for the first time ever in 2011: 80.1 years, a gain of 10 years since 1970. The US (78.7 years) ranges only on place 26 among the 34 OECD member countries, but has the highest costs by far. All OECD countries have achieved universal (or almost universal) health coverage, except the US and Mexico.

In the United States, where around 18% of GDP is spent on health care, the Commonwealth Fund analysis of spend and quality shows a clear correlation between worse quality and higher spending.

Administration and regulation

The management and administration of health care is vital to the delivery of health care services. In particular, the practice of health professionals and the operation of health care institutions is typically regulated by national or state/provincial authorities through appropriate regulatory bodies for purposes of quality assurance. Most countries have credentialing staff in regulatory boards or health departments who document the certification or licensing of health workers and their work history.

Health information technology

Health information technology (HIT) is "the application of information processing involving both computer hardware and software that deals with the storage, retrieval, sharing, and use of health care information, data, and knowledge for communication and decision making."

Health information technology components:

• Electronic Health Record (EHR) - An EHR contains a patient's comprehensive medical history, and may include records from multiple providers.
• Electronic Medical Record (EMR) - An EMR contains the standard medical and clinical data gathered in one's provider's office.
• Personal Health Record (PHR) - A PHR is a patient's medical history that is maintained privately, for personal use.
• Medical Practice Management software (MPM) - is designed to streamline the day-to-day tasks of operating a medical facility. Also known as practice management software or practice management system (PMS).
• Health Information Exchange (HIE) - Health Information Exchange allows health care professionals and patients to appropriately access and securely share a patient's vital medical information electronically.