<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acute radiation syndrome and can you explain it in depth? [/INST] Acute radiation syndrome (ARS), also known as radiation sickness or radiation poisoning, is a collection of health effects that are caused by being exposed to high amounts of ionizing radiation in a short period of time. Symptoms can start within an hour of exposure, and can last for several months. Early symptoms are usually nausea, vomiting and loss of appetite. In the following hours or weeks, initial symptoms may appear to improve, before the development of additional symptoms, after which either recovery or death follow.ARS involves a total dose of greater than 0.7 Gy (70 rad), that generally occurs from a source outside the body, delivered within a few minutes. Sources of such radiation can occur accidentally or intentionally. They may involve nuclear reactors, cyclotrons, certain devices used in cancer therapy, nuclear weapons, or radiological weapons. It is generally divided into three types: bone marrow, gastrointestinal, and neurovascular syndrome, with bone marrow syndrome occurring at 0.7 to 10 Gy, and neurovascular syndrome occurring at doses that exceed 50 Gy. The cells that are most affected are generally those that are rapidly dividing. At high doses, this causes DNA damage that may be irreparable. Diagnosis is based on a history of exposure and symptoms. Repeated complete blood counts (CBCs) can indicate the severity of exposure.Treatment of ARS is generally supportive care. This may include blood transfusions, antibiotics, colony-stimulating factors, or stem cell transplant. Radioactive material remaining on the skin or in the stomach should be removed. If radioiodine was inhaled or ingested, potassium iodide is recommended. Complications like leukemia and other cancers among those who survive are managed as usual. Short term outcomes depend on the dose exposure.ARS is generally rare. A single event can affect a large number of people, as happened in the atomic bombing of Hiroshima and Nagasaki and the Chernobyl nuclear power plant disaster. ARS differs from chronic radiation syndrome, which occurs following prolonged exposures to relatively low doses of radiation.

Signs and symptoms
Classically, ARS is divided into three main presentations: hematopoietic, gastrointestinal, and neuro vascular. These syndromes may be preceded by a prodrome. The speed of symptom onset is related to radiation exposure, with greater doses resulting in a shorter delay in symptom onset. These presentations presume whole-body exposure, and many of them are markers that are invalid if the entire body has not been exposed. Each syndrome requires that the tissue showing the syndrome itself be exposed (e.g., gastrointestinal syndrome is not seen if the stomach and intestines are not exposed to radiation). Some areas affected are:

Hematopoietic. This syndrome is marked by a drop in the number of blood cells, called aplastic anemia. This may result in infections, due to a low number of white blood cells, bleeding, due to a lack of platelets, and anemia, due to too few red blood cells in circulation. These changes can be detected by blood tests after receiving a whole-body acute dose as low as 0.25 grays (25 rad), though they might never be felt by the patient if the dose is below 1 gray (100 rad). Conventional trauma and burns resulting from a bomb blast are complicated by the poor wound healing caused by hematopoietic syndrome, increasing mortality.
Gastrointestinal. This syndrome often follows absorbed doses of 6–30 grays (600–3,000 rad). The signs and symptoms of this form of radiation injury include nausea, vomiting, loss of appetite, and abdominal pain. Vomiting in this time-frame is a marker for whole body exposures that are in the fatal range above 4 grays (400 rad). Without exotic treatment such as bone marrow transplant, death with this dose is common, due generally more to infection than gastrointestinal dysfunction.
Neurovascular. This syndrome typically occurs at absorbed doses greater than 30 grays (3,000 rad), though it may occur at doses as low as 10 grays (1,000 rad). It presents with neurological symptoms like dizziness, headache, or decreased level of consciousness, occurring within minutes to a few hours, with an absence of vomiting, and is almost always fatal, even with aggressive intensive care.Early symptoms of ARS typically include nausea, vomiting, headaches, fatigue, fever, and a short period of skin reddening. These symptoms may occur at radiation doses as low as 0.35 grays (35 rad). These symptoms are common to many illnesses, and may not, by themselves, indicate acute radiation sickness.

Dose effects
A similar table and description of symptoms (given in rems, where 100 rem = 1 Sv), derived from data from the effects on humans subjected to the atomic bombings of Hiroshima and Nagasaki, the indigenous peoples of the Marshall Islands subjected to the Castle Bravo thermonuclear bomb, animal studies and lab experiment accidents, have been compiled by the U.S. Department of Defense.A person who was less than 1 mile (1.6 km) from the atomic bomb Little Boys hypocenter at Hiroshima, Japan, was found to absorb about 9.46 grays (Gy) of ionizing radiation.The doses at the hypocenters of the Hiroshima and Nagasaki atomic bombings were 240 and 290 Gy, respectively.

Skin changes
Cutaneous radiation syndrome (CRS) refers to the skin symptoms of radiation exposure. Within a few hours after irradiation, a transient and inconsistent redness (associated with itching) can occur. Then, a latent phase may occur and last from a few days up to several weeks, when intense reddening, blistering, and ulceration of the irradiated site is visible. In most cases, healing occurs by regenerative means; however, very large skin doses can cause permanent hair loss, damaged sebaceous and sweat glands, atrophy, fibrosis (mostly keloids), decreased or increased skin pigmentation, and ulceration or necrosis of the exposed tissue. As seen at Chernobyl, when skin is irradiated with high energy beta particles, moist desquamation (peeling of skin) and similar early effects can heal, only to be followed by the collapse of the dermal vascular system after two months, resulting in the loss of the full thickness of the exposed skin. Another example of skin loss caused by high-level exposure of radiation is during the 1999 Tokaimura nuclear accident, where technician Hisashi Ouchi had lost a majority of his skin due to the high amounts of radiation he absorbed during the irradiation. This effect had been demonstrated previously with pig skin using high energy beta sources at the Churchill Hospital Research Institute, in Oxford.

Cause
ARS is caused by exposure to a large dose of ionizing radiation (> ~0.1 Gy) over a short period of time (> ~0.1 Gy/h). Alpha and beta radiation have low penetrating power and are unlikely to affect vital internal organs from outside the body. Any type of ionizing radiation can cause burns, but alpha and beta radiation can only do so if radioactive contamination or nuclear fallout is deposited on the individuals skin or clothing. Gamma and neutron radiation can travel much greater distances and penetrate the body easily, so whole-body irradiation generally causes ARS before skin effects are evident. Local gamma irradiation can cause skin effects without any sickness. In the early twentieth century, radiographers would commonly calibrate their machines by irradiating their own hands and measuring the time to onset of erythema.

Accidental
Accidental exposure may be the result of a criticality or radiotherapy accident. There have been numerous criticality accidents dating back to atomic testing during World War II, while computer-controlled radiation therapy machines such as Therac-25 played a major part in radiotherapy accidents. The latter of the two is caused by the failure of equipment software used to monitor the radiational dose given. Human error has played a large part in accidental exposure incidents, including some of the criticality accidents, and larger scale events such as the Chernobyl disaster. Other events have to do with orphan sources, in which radioactive material is unknowingly kept, sold, or stolen. The Goiânia accident is an example, where a forgotten radioactive source was taken from a hospital, resulting in the deaths of 4 people from ARS. Theft and attempted theft of radioactive material by clueless thieves has also led to lethal exposure in at least one incident.Exposure may also come from routine spaceflight and solar flares that result in radiation effects on earth in the form of solar storms. During spaceflight, astronauts are exposed to both galactic cosmic radiation (GCR) and solar particle event (SPE) radiation. The exposure particularly occurs during flights beyond low Earth orbit (LEO). Evidence indicates past SPE radiation levels that would have been lethal for unprotected astronauts. GCR levels that might lead to acute radiation poisoning are less well understood. The latter cause is rarer, with an event possibly occurring during the solar storm of 1859.

Intentional
Intentional exposure is controversial as it involves the use of nuclear weapons, human experiments, or is given to a victim in an act of murder. The intentional atomic bombings of Hiroshima and Nagasaki resulted in tens of thousands of casualties; the survivors of these bombings are known today as Hibakusha. Nuclear weapons emit large amounts of thermal radiation as visible, infrared, and ultraviolet light, to which the atmosphere is largely transparent. This event is also known as "Flash", where radiant heat and light are bombarded into any given victims exposed skin, causing radiation burns. Death is highly likely, and radiation poisoning is almost certain if one is caught in the open with no terrain or building masking-effects within a radius of 0–3 km from a 1 megaton airburst. The 50% chance of death from the blast extends out to ~8 km from a 1 megaton atmospheric explosion.Scientific testing on humans done without consent has been prohibited since 1997 in the United States. There is now a requirement for patients to give informed consent, and to be notified if experiments were classified. Across the world, the Soviet nuclear program involved human experiments on a large scale, which is still kept secret by the Russian government and the Rosatom agency. The human experiments that fall under intentional ARS exclude those that involved long term exposure. Criminal activity has involved murder and attempted murder carried out through abrupt victim contact with a radioactive substance such as polonium or plutonium.

Pathophysiology
The most commonly used predictor of ARS is the whole-body absorbed dose. Several related quantities, such as the equivalent dose, effective dose, and committed dose, are used to gauge long-term stochastic biological effects such as cancer incidence, but they are not designed to evaluate ARS. To help avoid confusion between these quantities, absorbed dose is measured in units of grays (in SI, unit symbol Gy) or rads (in CGS), while the others are measured in sieverts (in SI, unit symbol Sv) or rems (in CGS). 1 rad = 0.01 Gy and 1 rem = 0.01 Sv.In most of the acute exposure scenarios that lead to radiation sickness, the bulk of the radiation is external whole-body gamma, in which case the absorbed, equivalent, and effective doses are all equal. There are exceptions, such as the Therac-25 accidents and the 1958 Cecil Kelley criticality accident, where the absorbed doses in Gy or rad are the only useful quantities, because of the targeted nature of the exposure to the body.
Radiotherapy treatments are typically prescribed in terms of the local absorbed dose, which might be 60 Gy or higher. The dose is fractionated to about 2 Gy per day for "curative" treatment, which allows normal tissues to undergo repair, allowing them to tolerate a higher dose than would otherwise be expected. The dose to the targeted tissue mass must be averaged over the entire body mass, most of which receives negligible radiation, to arrive at a whole-body absorbed dose that can be compared to the table above.

DNA damage
Exposure to high doses of radiation cause DNA damage, later creating serious and even lethal chromosomal aberrations if left unrepaired. Ionizing radiation can produce reactive oxygen species, and does directly damage cells by causing localized ionization events. The former is very damaging to DNA, while the latter events create clusters of DNA damage. This damage includes loss of nucleobases and breakage of the sugar-phosphate backbone that binds to the nucleobases. The DNA organization at the level of histones, nucleosomes, and chromatin also affects its susceptibility to radiation damage. Clustered damage, defined as at least two lesions within a helical turn, is especially harmful. While DNA damage happens frequently and naturally in the cell from endogenous sources, clustered damage is a unique effect of radiation exposure. Clustered damage takes longer to repair than isolated breakages, and is less likely to be repaired at all. Larger radiation doses are more prone to cause tighter clustering of damage, and closely localized damage is increasingly less likely to be repaired.Somatic mutations cannot be passed down from parent to offspring, but these mutations can propagate in cell lines within an organism. Radiation damage can also cause chromosome and chromatid aberrations, and their effects depend on in which stage of the mitotic cycle the cell is when the irradiation occurs. If the cell is in interphase, while it is still a single strand of chromatin, the damage will be replicated during the S1 phase of cell cycle, and there will be a break on both chromosome arms; the damage then will be apparent in both daughter cells. If the irradiation occurs after replication, only one arm will bear the damage; this damage will be apparent in only one daughter cell. A damaged chromosome may cyclize, binding to another chromosome, or to itself.

Diagnosis
Diagnosis is typically made based on a history of significant radiation exposure and suitable clinical findings. An absolute lymphocyte count can give a rough estimate of radiation exposure. Time from exposure to vomiting can also give estimates of exposure levels if they are less than 10 Gray (1000 rad).

Prevention
A guiding principle of radiation safety is as low as reasonably achievable (ALARA). This means try to avoid exposure as much as possible and includes the three components of time, distance, and shielding.

Time
The longer that humans are subjected to radiation the larger the dose will be. The advice in the nuclear war manual entitled Nuclear War Survival Skills published by Cresson Kearny in the U.S. was that if one needed to leave the shelter then this should be done as rapidly as possible to minimize exposure.In chapter 12, he states that "[q]uickly putting or dumping wastes outside is not hazardous once fallout is no longer being deposited. For example, assume the shelter is in an area of heavy fallout and the dose rate outside is 400 roentgen (R) per hour, enough to give a potentially fatal dose in about an hour to a person exposed in the open. If a person needs to be exposed for only 10 seconds to dump a bucket, in this 1/360 of an hour he will receive a dose of only about 1 R. Under war conditions, an additional 1-R dose is of little concern." In peacetime, radiation workers are taught to work as quickly as possible when performing a task that exposes them to radiation. For instance, the recovery of a radioactive source should be done as quickly as possible.

Shielding
Matter attenuates radiation in most cases, so placing any mass (e.g., lead, dirt, sandbags, vehicles, water, even air) between humans and the source will reduce the radiation dose. This is not always the case, however; care should be taken when constructing shielding for a specific purpose. For example, although high atomic number materials are very effective in shielding photons, using them to shield beta particles may cause higher radiation exposure due to the production of bremsstrahlung x-rays, and hence low atomic number materials are recommended. Also, using material with a high neutron activation cross section to shield neutrons will result in the shielding material itself becoming radioactive and hence more dangerous than if it were not present.There are many types of shielding strategies that can be used to reduce the effects of radiation exposure. Internal contamination protective equipment such as respirators are used to prevent internal deposition as a result of inhalation and ingestion of radioactive material. Dermal protective equipment, which protects against external contamination, provides shielding to prevent radioactive material from being deposited on external structures. While these protective measures do provide a barrier from radioactive material deposition, they do not shield from externally penetrating gamma radiation. This leaves anyone exposed to penetrating gamma rays at high risk of ARS.
Naturally, shielding the entire body from high energy gamma radiation is optimal, but the required mass to provide adequate attenuation makes functional movement nearly impossible. In the event of a radiation catastrophe, medical and security personnel need mobile protection equipment in order to safely assist in containment, evacuation, and many other necessary public safety objectives.
Research has been done exploring the feasibility of partial body shielding, a radiation protection strategy that provides adequate attenuation to only the most radio-sensitive organs and tissues inside the body. Irreversible stem cell damage in the bone marrow is the first life-threatening effect of intense radiation exposure and therefore one of the most important bodily elements to protect. Due to the regenerative property of hematopoietic stem cells, it is only necessary to protect enough bone marrow to repopulate the exposed areas of the body with the shielded supply. This concept allows for the development of lightweight mobile radiation protection equipment, which provides adequate protection, deferring the onset of ARS to much higher exposure doses. One example of such equipment is the 360 gamma, a radiation protection belt that applies selective shielding to protect the bone marrow stored in the pelvic area as well as other radio sensitive organs in the abdominal region without hindering functional mobility.
More information on bone marrow shielding can be found in the "Health Physics Radiation Safety Journal". article Waterman, Gideon; Kase, Kenneth; Orion, Itzhak; Broisman, Andrey; Milstein, Oren (September 2017). "Selective Shielding of Bone Marrow: An Approach to Protecting Humans from External Gamma Radiation". Health Physics. 113 (3): 195–208. doi:10.1097/HP.0000000000000688. PMID 28749810. S2CID 3300412., or in the Organisation for Economic Co-operation and Development (OECD) and the Nuclear Energy Agency (NEA)s 2015 report: "Occupational Radiation Protection in Severe Accident Management" (PDF).

Reduction of incorporation
Where radioactive contamination is present, an elastomeric respirator, dust mask, or good hygiene practices may offer protection, depending on the nature of the contaminant. Potassium iodide (KI) tablets can reduce the risk of cancer in some situations due to slower uptake of ambient radioiodine. Although this does not protect any organ other than the thyroid gland, their effectiveness is still highly dependent on the time of ingestion, which would protect the gland for the duration of a twenty-four-hour period. They do not prevent ARS as they provide no shielding from other environmental radionuclides.

Fractionation of dose
If an intentional dose is broken up into a number of smaller doses, with time allowed for recovery between irradiations, the same total dose causes less cell death. Even without interruptions, a reduction in dose rate below 0.1 Gy/h also tends to reduce cell death. This technique is routinely used in radiotherapy.The human body contains many types of cells and a human can be killed by the loss of a single type of cells in a vital organ. For many short term radiation deaths (3–30 days), the loss of two important types of cells that are constantly being regenerated causes death. The loss of cells forming blood cells (bone marrow) and the cells in the digestive system (microvilli, which form part of the wall of the intestines) is fatal.

Management
Treatment usually involves supportive care with possible symptomatic measures employed. The former involves the possible use of antibiotics, blood products, colony stimulating factors, and stem cell transplant.

Antimicrobials
There is a direct relationship between the degree of the neutropenia that emerges after exposure to radiation and the increased risk of developing infection. Since there are no controlled studies of therapeutic intervention in humans, most of the current recommendations are based on animal research.The treatment of established or suspected infection following exposure to radiation (characterized by neutropenia and fever) is similar to the one used for other febrile neutropenic patients. However, important differences between the two conditions exist. Individuals that develop neutropenia after exposure to radiation are also susceptible to irradiation damage in other tissues, such as the gastrointestinal tract, lungs and central nervous system. These patients may require therapeutic interventions not needed in other types of neutropenic patients. The response of irradiated animals to antimicrobial therapy can be unpredictable, as was evident in experimental studies where metronidazole and pefloxacin therapies were detrimental.
Antimicrobials that reduce the number of the strict anaerobic component of the gut flora (i.e., metronidazole) generally should not be given because they may enhance systemic infection by aerobic or facultative bacteria, thus facilitating mortality after irradiation.An empirical regimen of antimicrobials should be chosen based on the pattern of bacterial susceptibility and nosocomial infections in the affected area and medical center and the degree of neutropenia. Broad-spectrum empirical therapy (see below for choices) with high doses of one or more antibiotics should be initiated at the onset of fever. These antimicrobials should be directed at the eradication of Gram-negative aerobic bacilli (i.e., Enterobacteriace, Pseudomonas) that account for more than three quarters of the isolates causing sepsis. Because aerobic and facultative Gram-positive bacteria (mostly alpha-hemolytic streptococci) cause sepsis in about a quarter of the victims, coverage for these organisms may also be needed.A standardized management plan for people with neutropenia and fever should be devised. Empirical regimens contain antibiotics broadly active against Gram-negative aerobic bacteria (quinolones: i.e., ciprofloxacin, levofloxacin, a third- or fourth-generation cephalosporin with pseudomonal coverage: e.g., cefepime, ceftazidime, or an aminoglycoside: i.e. gentamicin, amikacin).

Prognosis
The prognosis for ARS is dependent on the exposure dose, with anything above 8 Gy being almost always lethal, even with medical care. Radiation burns from lower-level exposures usually manifest after 2 months, while reactions from the burns occur months to years after radiation treatment. Complications from ARS include an increased risk of developing radiation-induced cancer later in life. According to the controversial but commonly applied linear no-threshold model, any exposure to ionizing radiation, even at doses too low to produce any symptoms of radiation sickness, can induce cancer due to cellular and genetic damage. The probability of developing cancer is a linear function with respect to the effective radiation dose. Radiation cancer may occur after ionizing radiation exposure following a latent period averaging 20 to 40 years.

History
Acute effects of ionizing radiation were first observed when Wilhelm Röntgen intentionally subjected his fingers to X-rays in 1895. He published his observations concerning the burns that developed that eventually healed, and misattributed them to ozone. Röntgen believed the free radical produced in air by X-rays from the ozone was the cause, but other free radicals produced within the body are now understood to be more important. David Walsh first established the symptoms of radiation sickness in 1897.Ingestion of radioactive materials caused many radiation-induced cancers in the 1930s, but no one was exposed to high enough doses at high enough rates to bring on ARS.
The atomic bombings of Hiroshima and Nagasaki resulted in high acute doses of radiation to a large number of Japanese people, allowing for greater insight into its symptoms and dangers. Red Cross Hospital Surgeon Terufumi Sasaki led intensive research into the syndrome in the weeks and months following the Hiroshima and Nagasaki bombings. Dr Sasaki and his team were able to monitor the effects of radiation in patients of varying proximities to the blast itself, leading to the establishment of three recorded stages of the syndrome. Within 25–30 days of the explosion, Sasaki noticed a sharp drop in white blood cell count and established this drop, along with symptoms of fever, as prognostic standards for ARS.  Actress Midori Naka, who was present during the atomic bombing of Hiroshima, was the first incident of radiation poisoning to be extensively studied. Her death on 24 August 1945 was the first death ever to be officially certified as a result of ARS (or "Atomic bomb disease").
There are two major databases that track radiation accidents: The American ORISE REAC/TS and the European IRSN ACCIRAD. REAC/TS shows 417 accidents occurring between 1944 and 2000, causing about 3000 cases of ARS, of which 127 were fatal. ACCIRAD lists 580 accidents with 180 ARS fatalities for an almost identical period. The two deliberate bombings are not included in either database, nor are any possible radiation-induced cancers from low doses. The detailed accounting is difficult because of confounding factors. ARS may be accompanied by conventional injuries such as steam burns, or may occur in someone with a pre-existing condition undergoing radiotherapy. There may be multiple causes for death, and the contribution from radiation may be unclear. Some documents may incorrectly refer to radiation-induced cancers as radiation poisoning, or may count all overexposed individuals as survivors without mentioning if they had any symptoms of ARS.

Notable cases
The following table includes only those known for their attempted survival with ARS. These cases exclude chronic radiation syndrome such as Albert Stevens, in which radiation is exposed to a given subject over a long duration. The "result" column represents the time of exposure to the time of death attributed to the short and long term effects attributed to initial exposure. As ARS is measured by a whole-body absorbed dose, the "exposure" column only includes units of Gray (Gy).

Other animals
Thousands of scientific experiments have been performed to study ARS in animals. There is a simple guide for predicting survival and death in mammals, including humans, following the acute effects of inhaling radioactive particles.

See also
References
This article incorporates public domain material from websites or documents of the U.S. Armed Forces Radiobiology Research Institute and the U.S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Photokeratitis and can you explain it in depth? [/INST] Photokeratitis or ultraviolet keratitis is a painful eye condition caused by exposure of insufficiently protected eyes to the ultraviolet (UV) rays from either natural (e.g. intense sunlight) or artificial (e.g. the electric arc during welding) sources. Photokeratitis is akin to a sunburn of the cornea and conjunctiva.
The injury may be prevented by wearing eye protection that blocks most of the ultraviolet radiation, such as welding goggles with the proper filters, a welders helmet, sunglasses rated for sufficient UV protection, or appropriate snow goggles. The condition is usually managed by removal from the source of ultraviolet radiation, covering the corneas, and administration of pain relief. Photokeratitis is known by a number of different terms including: snow blindness, arc eye, welders flash, bake eyes, corneal flash burns, flash burns, niphablepsia, or keratoconjunctivitis photoelectrica.

Signs and symptoms
Common symptoms include pain, intense tears, eyelid twitching, discomfort from bright light, and constricted pupils.

Cause
Any intense exposure to UV light can lead to photokeratitis. In 2010, the Department of Optometry at the Dublin Institute of Technology published that the threshold for photokeratitis is 0.12 J/m2. (Prior to this, in 1975, the Division of Biological Effects at the US Bureau of Radiological Health had published that the human threshold for photokeratitis is 50 J/m2.) Common causes include welding with failure to use adequate eye protection such as an appropriate welding helmet or welding goggles. This is termed arc eye, while photokeratitis caused by exposure to sunlight reflected from ice and snow, particularly at elevation, is commonly called snow blindness. It can also occur due to using tanning beds without proper eyewear. Natural sources include bright sunlight reflected from snow or ice or, less commonly, from sea or sand. Fresh snow reflects about 80% of the UV radiation compared to a dry, sandy beach (15%) or sea foam (25%). This is especially a problem in polar regions and at high altitudes, as with about every 300 m (1,000 ft) of elevation (above sea level), the intensity of UV rays increases by four percent.

Diagnosis
Fluorescein dye staining will reveal damage to the cornea under ultraviolet light.

Prevention
Photokeratitis can be prevented by using sunglasses or eye protection that transmits 5–10% of visible light and absorbs almost all UV rays </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ghost cell glaucoma and can you explain it in depth? [/INST] Ghost cell glaucoma (GCG) is a type of secondary glaucoma occurs due to long standing vitreous hemorrhage. The  rigid and less pliable degenerated red blood cells (ghost cells) block the trabecular meshwork and increase the pressure inside eyes.

Pathophysiology
The ghost cells develop within the vitreous cavity, 1–3 weeks after vitreous hemorrhage. They obstruct the trabecular meshwork and eventually the pressure inside eye (intraocular pressure) increases and leads to glaucoma. A variety of ocular conditions may cause GCG. Main causes include ocular trauma, diabetes, sickle cell disease, uveitis, UGH syndrome, many eye surgeries etc.

Signs and symptoms
Myriad small cells may be seen in the aqueous humor during slit lamp examination. Intraocular pressure rises up to 30 to 70 mm Hg </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Supernumerary nipple and can you explain it in depth? [/INST] A supernumerary nipple  is an additional instance of nipple occurring in mammals, including humans </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Subareolar abscess and can you explain it in depth? [/INST] Also called Zuskas disease (only nonpuerperal case), subareolar abscess is a subcutaneous abscess of the breast tissue beneath the areola of the nipple. It is a frequently aseptic inflammation and has been associated with squamous metaplasia of lactiferous ducts.
The term is usually understood to include breast abscesses located in the retroareolar region or the periareolar region but not those located in the periphery of the breast.
Subareolar abscess can develop both during lactation or extrapuerperal, the abscess is often flaring up and down with repeated fistulation.

Pathophysiology
90% of cases are smokers, however only a very small fraction of smokers appear to develop this lesion. It has been speculated that either the direct toxic effect or hormonal changes related to smoking could cause squamous metaplasia of lactiferous ducts. It is not well established whether the lesion regresses after smoking cessation.
Extrapuerperal cases are often associated with hyperprolactinemia or with thyroid problems. Also diabetes mellitus may be a contributing factor in nonpuerperal breast abscess.

Treatment
Treatment is problematic unless an underlying endocrine disorder can be successfully diagnosed and treated.
A study by Goepel and Panhke provided indications that the inflammation should be controlled by bromocriptine even in absence of hyperprolactinemia.Antibiotic treatment is given in case of acute inflammation. However, this alone is rarely effective, and the treatment of a subareaolar abscess is primarily surgical. In case of an acute abscess, incision and drainage are performed, followed by antibiotics treatment. However, in contrast to peripheral breast abscess which often resolves after antibiotics and incision and drainage, subareaolar breast abscess has a tendency to recur, often accompanied by the formation of fistulas leading from inflammation area to the skin surface. In many cases, in particular in patients with recurrent subareolar abscess, the excision of the affected lactiferous ducts is indicated, together with the excision of any chronic abscess or fistula. This can be performed using radial or circumareolar incision.There is no universal agreement on what should be the standard way of treating the condition. In a recent review article, antibiotics treatment, ultrasound evaluation and, if fluid is present, ultrasound-guided fine needle aspiration of the abscess with an 18 gauge needle, under saline lavage until clear, has been suggested as initial line of treatment for breast abscess in puerperal and non-puerperal cases including central (subareolar) abscess (see breast abscess for details). Elsewhere, it has been stated that treatment of subareolar abscess is unlikely to work if it does not address the ducts as such.Duct resection has been traditionally used to treat the condition; the original Hadfield procedure has been improved many times but long-term success rate remains poor even for radical surgery. Petersen even suggests that damage caused by previous surgery is a frequent cause of subareolar abscesses. Goepel and Pahnke and other authors recommend performing surgeries only with concomitant bromocriptine treatment.

Squamous metaplasia of lactiferous ducts
Squamous metaplasia of lactiferous ducts - abbreviated SMOLD is a change where the normal double layer cuboid epithelium of the lactiferous ducts is replaced by squamous keratinizing cell layers. The resulting epithelium is very similar to normal skin, hence some authors speak of epidermalization. SMOLD is rare in premenopausal women (possibly 0.1-3%) but more frequent (possibly up to 25%) in postmenopausal women where it does not cause any problems at all.
SMOLD appears to be a completely benign lesion and may exist without causing any symptoms. In principle it ought to be completely reversible as the classification as metaplasia would suggest. Because of difficulties in observing the actual changes and rare incidence of the lesion this does not appear to be documented.
The last section of the lactiferous ducts is always lined with squamous keratinizing epithelium which appears to have important physiological functions. For example, the keratin forms plugs sealing the duct entry and has bacteriostatic properties. In SMOLD the keratinizing lining which is supposed to form only the ends of the lactiferous ducts extends deep into the ducts.
SMOLD is distinct from squamous metaplasia that may occur in papilomatous hyperplasia. It is believed to be unrelated to squamous cell carcinoma of the breast which probably arises from different cell types.
The keratin plugs (debris) produced by SMOLD have been proposed as the cause for recurrent subareolar abscesses by causing secretory stasis. The epidermalized lining has also different permeability than the normal lining, hindering resorption of glandular secretions. The resorption is necessary to dispose of stalled secretions inside the duct - and at least equally important it affects osmotic balance which in turn is an important mechanism in the control of lactogenesis (this is relevant both in puerperal and nonpuerperal mastitis).
While in lactating women this would appear to be a very plausible pathogenesis, there is some uncertainty about the pathogenesis in non-lactating women where breast secretions should be apriori minimal. It appears pathologic stimulation of lactogenesis must be present as well to cause subareolar abscess and treatment success with bromocriptin appears to confirm this as compared to poor success rate of the usual antibiotic and surgical treatments documented by Hanavadi et al.Further uncertainty in the relation of SMOLD and the subareolar abscess is that squamous metaplasia is very often caused by inflammatory processes. SMOLD could be the cause of the inflammation – or the result of a previous or longstanding inflammation.
SMOLD usually affects multiple ducts and frequently (relative to extremely low absolute prevalence) both breasts hence it is very likely that systemic changes such as hormonal interactions are involved.
At least the following factors have been considered in the aetiology of SMOLD: reactive change to chronic inflammation, systemic hormonal changes, smoking, dysregulation in beta-catenin expression, changes in retinoic acid and vitamin D metabolism or expression.
Vitamin A deficiency may cause epidermilization of the ducts and squamous metaplasia and likely also contributes to infection. Vitamin A deficiency has been observed to cause squamous metaplasia in many types of epithelia </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sexual sadism disorder and can you explain it in depth? [/INST] Sexual sadism disorder is the condition of experiencing sexual arousal in response to the extreme pain, suffering or humiliation of others. Several other terms have been used to describe the condition, and the condition may overlap with other conditions that involve inflicting pain. It is distinct from situations in which consenting individuals use mild or simulated pain or humiliation for sexual excitement. The words sadism and sadist are derived from the French writer and libertine Marquis de Sade, who wrote several novels depicting sexualized torture and violence.

Related terms and conditions
Current terminology
Sexual sadism disorder is the term employed by the current version of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association.  It refers to the "recurrent and intense sexual arousal from the physical or psychological suffering of another person, as manifested by fantasies, urges, or behaviors" (p. 696).  It is classified as one of the paraphilias, called an "algolagnic disorder" (p. 685), which is one of the "anomalous activity preferences" (p. 685).  The formal diagnosis of Sexual Sadism Disorder would apply if the individual has acted on these urges with a non-consenting person or if the urges cause significant distress to the individual.
Sadomasochism appears in the current version of the International Classification of Diseases (ICD-10) of the World Health Organization. It refers to the "preference for sexual activity that involves bondage or the infliction of pain or humiliation" (p. 172), and divides sadomasochism into sadism and masochism according to whether the individual prefers to be the provider or recipient of it.  The ICD-10 specifies that mild forms of sadomasochism "are commonly used to enhance otherwise normal sexual activity" (p. 172), and that the diagnosis would apply only if the behavior is preferred or required for sexual gratification.  The condition is classified as one of the disorders of sexual preference, which includes the paraphilias (p. 170).
Paraphilic coercive disorder refers to the preference for non-consenting over consenting sexual partners. It differs from sexual sadism disorder in that although the individual with this disorder may inflict pain or threats of pain in order to gain the compliance of the victim, the infliction of pain is not the individuals actual goal. The condition is typically described as a paraphilia and continues to undergo research, but does not appear in the current DSM or ICD.  Alternate terms for the condition have included Biastophilia, Coercive Paraphilic Disorder, and Preferential Rape.BDSM or "bondage/discipline dominance/submission sadomasochism" is a colloquial term referring to the subculture of individuals who willingly engage in consenting forms of mild or simulated pain or humiliation. It is not currently a diagnosable condition in either the DSM or ICD system.  Alternative terms have included Bondage and Discipline (B&D), Domination and Submission (D&S), and Sadism and Masochism (S&M). In scientific research, this sexual preference has also been called the hyperdominance pattern of sexual behavior.  Unlike individuals with sexual sadism disorder or paraphilic coercive disorder, individuals with hyperdominance seek to provoke pleasure in their partner(s) with the pain/humiliation.

Previous terminology
Sexual sadism is the term previously employed by the DSM-III-R, DSM-IV, and DSM-IV-TR, where it was classified as a paraphilia.  In these versions of the DSM, sexual sadism pertained only to the infliction of real (not simulated) suffering (p. 530).  The condition was renamed sexual sadism disorder in DSM-5.
Sexual sadism was the term employed in the DSM-III, classifying the condition as a paraphilia.  The DSM-III noted that "the imagery in a Paraphilia, such as simulated bondage, may be playful and harmless and acted out with a mutually consenting partner….In more extreme form, paraphilic imagery is acted out with a nonconsenting partner, and is noxious and injurious to the partner" (p. 267). In DSM-III, sexual sadism could be diagnosed if:

the person repeatedly and intentionally inflicted suffering on a nonconsenting person, to experience sexual excitement
repeatedly or exclusively preferred simulated or mild suffering with a consenting sexual partner
employs extensive, permanent, or potentially fatal suffering to achieve sexual excitement, regardless of the consent of the other person.Sadism was the term employed by the DSM-II.  In that manual, the condition was classified as a sexual deviation, which was used to describe "individuals whose sexual interests are directed primarily toward…coitus performed under bizarre circumstances" (p. 44).  The term "paraphilia" did not exist in the DSM-II, and diagnoses did not have specific criteria until DSM-III.
Sexual sadism was the phrase mentioned in DSM-I as one of the sexual deviations (p. 39), but neither it (nor any of the other sexual deviations) received a specific label or diagnostic criteria </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Congenital stenosis of vena cava and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Stiff-person syndrome and can you explain it in depth? [/INST] Stiff-person syndrome (SPS), also known as stiff-man syndrome (SMS), is a rare neurologic disorder of unclear cause characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muscles and is superimposed by spasms, resulting in postural deformities. Chronic pain, impaired mobility, and lumbar hyperlordosis are common symptoms.
SPS occurs in about one in a million people and is most commonly found in middle-aged people. A small minority of patients have the paraneoplastic variety of the condition.  Variants of the condition, such as stiff-limb syndrome which primarily affects a specific limb, are often seen.
SPS was first described in 1956. Diagnostic criteria were proposed in the 1960s and refined two decades later. In the 1990s and 2000s the roles of antibodies in the condition became more clear. SPS patients generally have GAD antibodies, which seldom occur in the general population. In addition to blood tests for GAD, electromyography tests can help confirm the conditions presence.
Benzodiazepine-class drugs are the most common treatment; they are used for symptom relief from stiffness. Other common treatments include baclofen, intravenous immunoglobin and rituximab. There is a limited but encouraging therapeutic experience of hematopoietic stem cell transplantation for SPS.

Signs and symptoms
Patients with stiff-person syndrome (SPS) experience progressive stiffness in their truncal muscles (torso muscles), which become rigid and stiff because the lumbar and abdominal muscles engage in constant contractions. Initially, stiffness occurs in the thoracolumbar paraspinal and
abdominal muscles. It later affects the proximal leg and abdominal wall muscles. The stiffness leads to a change in posture, and patients develop a rigid gait. Persistent lumbar hyperlordosis often occurs as it progresses. The muscle stiffness initially fluctuates, sometimes for days or weeks, but eventually begins to consistently impair mobility. As the disease progresses, patients sometimes become unable to walk or bend. Chronic pain is common and worsens over time but sometimes acute pain occurs as well. Stress, cold weather, and infections lead to an increase in symptoms, and sleep decreases them.SPS patients experience superimposed spasms and extreme sensitivity to touch and sound. These spasms primarily occur in the proximal limb and axial muscles. There are co-contractions of agonist and antagonist muscles. Spasms usually last for minutes and can recur over hours. Attacks of spasms are unpredictable and are often caused by fast movements, emotional distress, or sudden sounds or touches. In rare cases, facial muscles, hands, feet, and the chest can be affected and unusual eye movements and vertigo occur. There are brisk stretch reflexes and clonus occurs in patients. Late in the diseases progression, hypnagogic myoclonus can occur. Tachycardia and hypertension are sometimes also present.Because of the spasms, patients may become increasingly fearful, require assistance, and lose the ability to work, leading to depression, anxiety, and phobias, including agoraphobia and dromophobia. Most patients are psychologically normal and respond reasonably to their situations.Paraneoplastic SPS tends to affect the neck and arms more than other variations. It progresses very quickly, is more painful, and is more likely to include distal pain than classic SPS. Patients with paraneoplastic SPS generally lack other autoimmune issues but may have other paraneoplastic conditions.Stiff-limb syndrome is a variant of SPS. This syndrome develops into full SPS about 25% of the time. Stiffness and spasms are usually limited to the legs and hyperlordoisis generally does not occur. The stiffness begins in one limb and remains most prominent there. Sphincter and brainstem issues often occur with stiff-limb syndrome. Progressive encephalomyelitis with rigidity, another variant of the condition, includes symptoms of SPS with brainstem issues and autonomic disturbances. It involves polio-encephalomyelitis in the spine and brainstem. There is cerebellar and brainstem involvement. In some cases, the limbic system is affected, as well. Most patients have upper motoneuron issues and autonomic disturbances. Jerking SPS is another subtype of the condition. It begins like classical SPS and progresses for several years; up to 14 in some cases. It is then distinguished by the development of myoclonus as well as seizures and ataxia in some cases.

Causes
Patients with SPS generally have high amounts of high glutamic acid decarboxylase antibody titers. About 80 percent of SPS patients have GAD antibodies, compared with about one percent of the general population. The overwhelming majority of people who have GAD antibodies do not contract SPS, indicating that systematic synthesis of the antibody is not the sole cause of SPS. GAD, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way that autoantibodies affect SPS patients are not known. Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein (GABARAP). Autoantibodies against amphiphysin and gephyrin are also sometimes found in SPS patients. The antibodies appear to interact with antigens in the brain neurons and the spinal cord synapses, causing a functional blockade with gamma-aminobutyric acid. This leads to GABA impairment, which probably causes the stiffness and spasms that characterizes SPS. There are low GABA levels in the motor cortexes of SPS patients.It is not known why GAD autoimmunity occurs in SPS patients, and whether SPS qualifies as a neuro-autoimmune disorder has been questioned. It is also unknown whether these antibodies are pathogenic. The amount of GAD antibody titers found in SPS patients does not correlate with disease severity, indicating that titre levels do not need to be monitored. It has not been proven that GAD antibodies are sole cause of SPS, and the possibility exists that they are a marker or an epiphenomenon of the conditions cause.In SPS patients, motor unit neurons fire involuntarily in a way that resembles a normal contraction. Motor unit potentials fire while the patient is at rest, particularly in the stiff muscles. The excessive firing of motor neurons may be caused by malfunctions in spinal and supra-segmental inhibitory networks that utilize GABA. Involuntary actions show up as voluntary on EMG scans; even when the patient tries to relax, there are agonist and antagonist contractions.In a minority of patients with SPS, breast, ovarian, or lung cancer manifests paraneoplasticly as proximal muscle stiffness. These cancers are associated with the synaptic proteins amphiphysin and gephyrin. Paraneoplastic SPS with amphiphysin antibodies and breast adenocarcinoma tend to occur together. These patients tend not to have GAD antibodies. Passive transfer of the disease by plasma injection has been shown in paraneoplastic SPS but not classical SPS.There is evidence of genetic risk of SPS. The HLA class II locus makes patients susceptible to the condition. Most SPS patients have the DQB1* 0201 allele. This allele is also associated with type 1 diabetes.

Diagnosis
SPS is diagnosed by evaluating clinical findings and excluding other conditions. There is no specific laboratory test that confirms its presence. Underdiagnosis and misdiagnosis are common.The presence of antibodies against GAD is the best indication of the condition that can be detected by blood and cerebrospinal fluid (CSF) testing. Anti-GAD65 is found in about 80 percent of SPS patients. Anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, and anti-gliadin are also often present in blood tests. Electromyography (EMG) demonstrates involuntary motor unit firing in SPS patients. EMG can confirm the diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves. Responsiveness to diazepam helps confirm that the patient has SPS, as this decreases stiffness and motor unit potential firing.The same general criteria are used to diagnose paraneoplastic SPS as the normal form of the condition. Once SPS is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic. CT scans are indicated for SPS patients who respond poorly to therapy to determine if this is the case.A variety of conditions have similar symptoms to SPS, including myelopathies, dystonias, spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia, and some psychogenic disorders. Tetanus, neuroleptic malignant syndrome, malignant hyperpyrexia, chronic spinal interneuronitis, serotonin syndrome, Multiple sclerosis, Parkinsons disease, and Isaacs syndrome should also be excluded.Patients fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic, and they are sometimes suspected of malingering. It takes an average of six years after the onset of symptoms before the disease is diagnosed.

Treatment
There is no evidence-based criterion for treating SPS, and there have been no large controlled trials of treatments for the condition. The rarity of the disease complicates efforts to establish guidelines.GABAA agonists, usually diazepam but sometimes other benzodiazepines, are the primary treatment for SPS. Drugs that increase GABA activity alleviate muscle stiffness caused by a lack of GABAergic tone. They increase pathways that are dependent upon GABA and have muscle relaxant and anticonvulsant effects, often providing symptom relief. Because the condition worsens over time, patients generally require increased dosages, leading to more side effects. For this reason, gradual increase in dosage of benzodiazepines is indicated. Baclofen, a GABAB agonist, is generally used when individuals taking high doses of benzodiazepines have high side effects. In some cases it has shown improvements in electrophysiological and muscle stiffness when administered intravenously. Intrathecal baclofen administration may not have long-term benefits though, and there are potential serious side effects.Treatments that target the autoimmune response are also used. Intravenous immunoglobin is the best second-line treatment for SPS. It often decreases stiffness and improves quality of life and startle reflex. It is generally safe, but there are possible serious side effects and it is expensive. The European Federation of Neurological Societies suggests it be used when disabled patients do not respond well to diazepam and baclofen. Steroids, rituximab, and plasma exchange have been used to suppress the immune system in SPS patients, but the efficacy of these treatments is unclear. Botulinum toxin has been used to treat SPS, but it does not appear to have long-term benefits and has potential serious side effects. In paraneoplastic cases, tumors must be managed for the condition to be contained. Opiates are sometimes used to treat severe pain, but in some cases they exacerbate symptoms.Hematopoietic stem cell transplantation (HSCT) with high intensity conditioning protocol has been performed in a few cases with severe anti-GAD positive SPS, resulting in clinical remission. In carefully selected cases of severe, treatment refractory SPS, HSCT may be an effective therapeutic option.

Prognosis
The progression of SPS depends on whether it is a typical or abnormal form of the condition and the presence of comorbidities. Early recognition and neurological treatment can limit its progression. SPS is generally responsive to treatment, but the condition usually progresses and stabilizes periodically. Even with treatment, quality of life generally declines as stiffness precludes many activities. Some patients require mobility aids due to the risk of falls. About 65 percent of SPS patients are unable to function independently. About ten percent of SPS patients require intensive care at some point; sudden death occurs in about the same number of patients. These deaths are usually caused by metabolic acidosis or an autonomic crisis.

Epidemiology
SPS is estimated to have a prevalence of about one per million. Underdiagnosis and misdiagnosis hinder epidemiological information about the condition and may have led to its prevalence being underestimated. In the United Kingdom, 119 cases were identified between 2000 and 2005. It does not predominantly occur in any racial or ethnic group. The age of onset varies from about 30 to 60, and it most frequently occurs in people in their 40s. Five to ten percent of patients with SPS have the paraneoplastic variant of the condition. In one group of 127 patients, only 11 of them had paraneoplastic symptoms. About 35 percent of SPS patients have type I diabetes.

History
SPS was first described by Moersch and Woltman in 1956. Their description of the disease was based on 14 cases that they had observed over 32 years. Using electromyography, they noted that motor-unit firing suggested that voluntary muscle contractions were occurring in their patients. Previously, cases of SPS had been dismissed as psychogenic problems. Moersch and Woltman initially called the condition "stiff-man syndrome", but the first female patient was confirmed in 1958 and a young boy was confirmed to have it in 1960. Clinical diagnostic criteria were developed by Gordon et al. in 1967. They observed "persistent tonic contraction reflected in constant firing, even at rest" after providing patients with muscle relaxants and examining them with electromyography. In 1989, criteria for an SPS diagnosis were adopted that included episodic axial stiffness, progression of stiffness, lordosis, and triggered spasms. The name of the disease was shifted from "stiff-man syndrome" to the gender-neutral "stiff-person syndrome" in 1991.In 1988, Solimena et al. discovered that autoantibodies against GAD played a key role in SPS. Two years later, Solimena found the antibodies in 20 out of 33 patients examined. In the late 1980s, it was also demonstrated that the serum of SPS patients would bind to GABAergic neurons. In 2006, the role of GABARAP in SPS was discovered. The first case of paraneoplastic SPS was found in 1975. In 1993, antiamphiphysin was shown to play a role in paraneoplastic SPS, and seven years later antigephyrin was also found to be involved in the condition.In 1963, it was determined that diazepam helped alleviate symptoms of SPS. Corticosteroids were first used to treat the condition in 1988, and plasma exchange was first applied the following year. The first use of intravenous immunoglobulin to treat the condition came in 1994.

See also
Satoyoshi syndrome
Hyperekplexia

References
Bibliography
Alexopoulos, Harry; Dalakas, Marinos (2010). "A Critical Update on the Immunopathogenesis of Stiff Person Syndrome". European Journal of Clinical Investigation. 40 (11): 1018–25. doi:10.1111/j.1365-2362.2010.02340.x. PMID 20636380. S2CID 30688501.
Ali, Fatima; Rowley, Merrill; Jayakrishnan, Bindu; Teuber, Suzanne; Gershwin, Eric; Mackay, Ian (2011). "Stiff-Person Syndrome (SPS) and Anti-GAD-Related CNS Degenerations: Protean Additions to the Autoimmune Central Neuropathies". Journal of Autoimmunity. 37 (2): 79–87. doi:10.1016/j.jaut.2011.05.005. PMID 21680149.
Ciccotto, Giuseppe; Blaya, Maike; Kelley, Roger (2013). "Stiff Person Syndrome". Neurologic Clinics. 31 (1): 319–28. doi:10.1016/j.ncl.2012.09.005. PMID 23186907.
Darnell, Robert; Posner, Jerome (2011). Paraneoplastic Syndromes. Oxford University Press. ISBN 978-0-19-977273-5.
Duddy, Martin; Baker, Mark (2009). The Immunological Basis for Treatment of Stiff Person Syndrome. Stiff Person Syndrome. Frontiers of Neurology and Neuroscience. Vol. 26. pp. 147–66. doi:10.1159/000212375. ISBN 978-3-8055-9141-6. PMID 19349711.
Hadavi, Shahrzad; Noyce, Alastair; Leslie, David; Giovannoni, Gavin (2011). "Stiff Person Syndrome". Practical Neurology. 11 (5): 272–82. doi:10.1136/practneurol-2011-000071. PMID 21921002. S2CID 31265775.
Holmøy, Trygve; Geis, Christian (2011). "The Immunological Basis for Treatment of Stiff Person Syndrome". Journal of Neuroimmunology </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Small plaque parapsoriasis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Menotropin and can you explain it in depth? [/INST] Menotropin (also called human menopausal gonadotropin or hMG) is a hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are extracted from the urine of postmenopausal women.

Description and usage
Urine of postmenopausal women reflects the hypergonadotropic state of menopause -levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) are high - and contain a mixture of these gonadotropins. Other protein substances may be present, including small amounts of human chorionic gonadotropin (hCG) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Asfotase alfa and can you explain it in depth? [/INST] Asfotase alfa, sold under the brand name Strensiq, is a medication used in the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia.The most common side effects include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.The enzyme tissue non-specific alkaline phosphatase (ALP) plays a key role in creating and maintaining healthy bones, and managing calcium and phosphate in the body. People with hypophosphatasia cannot make enough working ALP, which leads to weak bones. Asfotase alfa is a version of the human ALP enzyme and serves as a replacement, thereby increasing levels of working ALP.

Medical uses
In the United States, asfotase alfa is indicated for the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).In the European Union, asfotase alfa is indicated for long-term enzyme replacement therapy in people with paediatric-onset hypophosphatasia to treat the bone manifestations of the disease.

Adverse effects
The most common adverse effects in studies included injection site reactions (pain, itching, erythema, etc.), headache, limb pain, and haematoma. Possible rare side effects could not be assessed because of the low number of patients.

Interactions
Asfotase alfa interferes with alkaline phosphatase measurements. As asfotase alfa is a glycoprotein (as opposed to a small molecule), no relevant interactions via the cytochrome P450 liver enzymes are expected.

Pharmacology
Mechanism of action
Hypophosphatasia is caused by a genetic defect of tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme that plays a role in bone mineralization. Asfotase alfa is a recombinant glycoprotein that contains the catalytic domain (the active site) of TNSALP. It is thus a form of enzyme replacement therapy.

Pharmacokinetics
After subcutaneous injection, asfotase alfa has a bioavailability of 46–98% and reaches highest blood plasma concentrations after 24 to 48 hours. Elimination half life is five days.

Chemistry
The peptide part of the glycoprotein asfotase alfa consists of two identical chains of 726 amino acids each, containing (1) the catalytic domain of TNSALP, (2) the Fc region of human immunoglobulin G1, and (3) a sequence of ten L-aspartate residues at the carboxy terminus. The two chains are linked by two disulfide bridges. Each chain also contains four internal disulfide bridges.The complete peptide sequence of one chain is
LVPEKEKDPK YWRDQAQETL KYALELQKLN TNVAKNVIMF LGDGMGVSTV TAARILKGQL
HHNPGEETRL EMDKFPFVAL SKTYNTNAQV PDSAGTATAY LCGVKANEGT VGVSAATERS
RCNTTQGNEV TSILRWAKDA GKSVGIVTTT RVNHATPSAA YAHSADRDWY SDNEMPPEAL
SQGCKDIAYQ LMHNIRDIDV IMGGGRKYMY PKNKTDVEYE SDEKARGTRL DGLDLVDTWK
SFKPRYKHSH FIWNRTELLT LDPHNVDYLL GLFEPGDMQY ELNRNNVTDP SLSEMVVVAI
QILRKNPKGF FLLVEGGRID HGHHEGKAKQ ALHEAVEMDR AIGQAGSLTS SEDTLTVVTA
DHSHVFTFGG YTPRGNSIFG LAPMLSDTDK KPFTAILYGN GPGYKVVGGE RENVSMVDYA
HNNYQAQSAV PLRHETHGGE DVAVFSKGPM AHLLHGVHEQ NYVPHVMAYA ACIGANLGHC
APASSLKDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV
KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE
KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT
TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGKDIDDDD
DDDDDD

Asfotase alfa is produced in Chinese hamster ovary cells.

History
Asfotase alfa was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in September 2008.Asfotase alfa is manufactured by Alexion Pharmaceuticals and it was granted breakthrough therapy designation by the U.S. FDA in 2015 as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. It was approved in October 2015, in the U.S. and in August 2015, in the EU.The safety and efficacy of asfotase alfa were established in 99 participants with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Metoprolol and can you explain it in depth? [/INST] Metoprolol, sold under the brand name Lopressor, among others, is a selective β1 receptor blocker medication. It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an abnormally fast heart rate. By working on the beta-1 receptor of the cardiac muscle cells, it yields both a chronotropic and inotropic effect.  It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines.Metoprolol is sold in formulations that can be taken by mouth or given intravenously. The medication is often taken twice a day. The extended-release formulation is taken once per day. Metoprolol may be combined with hydrochlorothiazide (a diuretic) in a single tablet.Common side effects include trouble sleeping, feeling tired, feeling faint, and abdominal discomfort. Large doses may cause serious toxicity. Risk in pregnancy has not been ruled out. It appears to be safe in breastfeeding. The metabolism of metoprolol can vary widely between patients, often as a result of hepatic impairment or CYP2D6 polymorphism. Care should be taken in patients with asthma; metoprolol should only be used in these patients when the benefits outweigh the risks, for example in heart failure. Stopping this drug should be done slowly to decrease the risk of further health problems.Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1982. It is on the World Health Organizations List of Essential Medicines. It is available as a generic drug. In 2020, it was the sixth most commonly prescribed medication in the United States, with more than 66 million prescriptions.

Medical uses
Metoprolol is used for a number of conditions, including hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches.  It is an adjunct in the treatment of hyperthyroidism.The different salt versions of metoprolol – metoprolol tartrate and metoprolol succinate – are approved for different conditions and are not interchangeable.Off-label uses include supraventricular tachycardia and thyroid storm.

Available forms
Metoprolol is sold in formulations that can be taken by mouth or given intravenously. The medication is often taken twice a day. The extended-release formulation is taken once a day. Metoprolol may be combined with hydrochlorothiazide (a diuretic) in a single tablet.

Adverse effects
Adverse effects, especially with higher doses, include dizziness, drowsiness, fatigue, diarrhea, unusual dreams, trouble sleeping, depression, and vision problems. β-blockers, including metoprolol, reduce salivary flow via inhibition of the direct sympathetic innervation of the salivary glands. Metoprolol may also cause the hands and feet to feel cold. Due to the high penetration across the blood-brain barrier, lipophilic beta blockers such as propranolol and metoprolol are more likely than other less lipophilic beta blockers to cause sleep disturbances such as insomnia, vivid dreams and nightmares.Serious side effects that are advised to be reported immediately include symptoms of bradycardia (resting heart rate slower than 60 beats per minute), persistent symptoms of dizziness, fainting and unusual fatigue, bluish discoloration of the fingers and toes and/or lips, numbness/tingling/swelling of the hands or feet, sexual dysfunction, erectile dysfunction, hair loss, mental/mood changes, depression, breathing difficulty, cough, dyslipidemia and increased thirst. Consuming alcohol while taking metoprolol may cause mild body rashes and is not advised.

Precautions
It’s well documented that metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure. A meta-analysis further supports reduced incidence of heart failure worsening in patients treated with beta-blockers compared to placebo. However, in some circumstances, particularly when initiating metoprolol in patients with more symptomatic disease, an increased prevalence of hospitalisation and mortality has been reported within the first two months of starting. Patients should monitor for swelling of extremities, fatigue, and shortness of breath.This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate. It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.Greater care is required with use in those with liver problems or asthma. Stopping this drug should be done slowly to decrease the risk of further health problems.

Pregnancy and breastfeeding
Risk for the fetus has not been ruled out, per being rated pregnancy category C in the United States. Metoprolol is category C in Australia, meaning that it may be suspected of causing harmful effects on the human fetus (but no malformations). It appears to be safe in breastfeeding.

Overdose
Excessive doses of metoprolol can cause severe hypotension, bradycardia, metabolic acidosis, seizures, and cardiorespiratory arrest. Blood or plasma concentrations may be measured to confirm a diagnosis of overdose or poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 200 μg/L during therapeutic administration, but can range from 1–20 mg/L in overdose victims.

Pharmacology
General pharmacological principles of metoprolol:
beta-1 selective
moderately lipophilic
without intrinsic sympathomimetic activity
with weak membrane stabilizing activity
decreases heart rate, contractility, and cardiac output, therefore decreasing blood pressure

Mechanism of action
Metoprolol blocks β1 adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential (reducing Na+ uptake) and prolonging repolarization of phase 3 (slowing down K+ release). It also suppresses the norepinephrine-induced increase in the sarcoplasmic reticulum (SR) Ca2+ leak and the spontaneous SR Ca2+ release, which are the major triggers for atrial fibrillation.

Pharmacokinetics
It undergoes α-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6.

Chemistry
The active substance metoprolol is employed either as metoprolol succinate or as metoprolol tartrate (where 100 mg metoprolol tartrate corresponds to 95 mg metoprolol succinate). The tartrate is an immediate-release formulation and the succinate is an extended-release formulation.

Stereochemistry
Metoprolol contains a stereocenter and consists of two enantiomers. This is a racemate, i.e. a 1:1 mixture of (R)- and the (S)-form:

Legal status
Metoprolol was discovered in 1969 by Bengt Ablad and Enar Carlsson. Within the UK it is classified as a prescription-only drug in the beta blocker class and is regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The MHRA is a government body set up in 2003 and is responsible for regulating medicines, medical devices, and equipment used in healthcare. The MHRA acknowledges that no product is completely risk free but takes into account research and evidence to ensure that any risks associated are minimal.The use of beta blockers such as metoprolol was approved in the U.S. by the Food and Drug Administration (FDA) in 1967. The FDA has approved beta blockers for the treatment of cardiac arrhythmias, hypertension, migraines, and others. Prescribers may choose to prescribe beta blockers for other treatments if there is just cause even though it is not approved by the FDA. Drug manufacturers, however, are unable to advertise beta blockers for other purposes that have not been approved by the FDA. Since the FDA does not regulate the practice of medicine after the drug has been approved, it is legal to prescribe beta blockers for other treatments such as performance anxiety.

Legislation
On 23 September 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) granted the Intas Pharmaceuticals Limited marketing authorization (licences) for metoprolol tartrate (50 mg and 100 mg tablets) for medicinal prescription only; this was after it was established that there were no new or unexpected safety concerns and that the benefits of metoprolol tartrate were greater than the risks. Metoprolol tartrate is a generic version of Lopressor, which was licensed and authorized on 6 June 1997 to Novartis Pharmaceuticals.

In sport
Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery, Metoprolol is banned by the world anti-doping agency in some sports. Some bans, as in all forms of billiards, darts, and golf, apply during competition only. In others, such as riflery competition, any form of beta blocker is banned by the National Collegiate Athletic Association.Urine tests are used to detect if beta blockers are present. Uncharged drugs and/or metabolites of beta blockers can be analysed by gas chromatography-mass spectrometry in selected ion monitoring (GC-MS-SIM). However, in modern times it is increasingly difficult to detect the presence of beta blockers used for sports doping purposes. A disadvantage to using GC-MS-SIM is that prior knowledge of the molecular structure of the target drugs/metabolites is required. Modern times have shown a variance in structures and hence novel beta blockers can go undetected.

Lawsuit
In the 2000s a lawsuit was brought against the manufacturers of Toprol XL (a time-release formula version of metoprolol) and its generic equivalent (metoprolol-succinate) claiming that to increase profits, lower cost generic versions of Toprol XL were intentionally kept off the market. It alleged such action by the pharmaceutical companies AstraZeneca AB, AstraZeneca LP, AstraZeneca Pharmaceuticals LP, and Aktiebolaget Hassle violated antitrust and consumer protection law.  A settlement was reached in 2012, with the above manufacturers paying out $11 million in damages.

Environmental presence
In 2021, metoprolol was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro.

References
Further reading
Dean L (2017) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sufentanil and can you explain it in depth? [/INST] Sufentanil, sold under the brand names Dsuvia and Sufenta, is a synthetic opioid analgesic drug approximately 5 to 10 times as potent as its parent drug, fentanyl, and 500 times as potent as morphine.  Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring (which increases potency but is believed to reduce duration of action), and the replacement of the phenyl ring by thiophene. Sufentanil first was synthesized at Janssen Pharmaceutica in 1974.Sufentanil is marketed for use by specialist centers under different trade names, such as Sufenta and Sufentil. Sufentanil with and without lidocaine or mepivacaine is available as a transdermal patch similar to Duragesic in Europe under trade names such as Chronogesic. It is available as a sublingual tablet under the trade name Dsuvia.

Medical uses
The main use of this medication is in operating suites and critical care where pain relief is required for a short period of time. It also offers properties of sedation and this makes it a good analgesic component of anesthetic regimen during an operation.Because of its extremely high potency, it is often used in surgery and post-operative pain management for patients that are heavily opioid dependent/opioid tolerant because of long term opiate use for chronic pain or illicit opiate use.  Currently sufentanil is the most potent opioid painkiller available for use in humans.  Although more potent narcotic pain medications do exist, all medications stronger than sufentanil are approved for veterinary use only.  It is also used in surgery and post operative pain control in patients that are taking high dose buprenorphine for chronic pain because it is the only opioid that has a potency and binding affinity strong enough to displace buprenorphine from the opioid receptors in the central nervous system and provide analgesia.In 2018, the Food and Drug Administration (FDA) approved Dsuvia, a sublingual tablet form of the drug, that was developed in a collaboration between AcelRx Pharmaceuticals and the United States Department of Defense for use in battlefield settings where intravenous (IV) treatments may not be readily available </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hydrocodone/ibuprofen and can you explain it in depth? [/INST] Hydrocodone/ibuprofen (INNs), sold under the brand name Vicoprofen, is a fixed-dose combination analgesic medication used in short-term therapy to relieve severe pain. Vicoprofen combines the analgesic and antitussive properties of hydrocodone with the analgesic, anti-inflammatory, and antipyretic properties of ibuprofen. In contrast to hydrocodone/acetaminophen combination analgesics such as Vicodin, this hydrocodone/ibuprofen avoids some of the liver toxicity which may occur from acetaminophen, but still presents significant dangers in hydrocodone overdose, namely respiratory depression. Vicoprofen is supplied in a fixed dose combination tablet which contains hydrocodone bitartrate, USP 7.5 mg with ibuprofen, USP 200 mg.  Additional strengths of generic Vicoprofen are now available, in combinations of 5 mg/200 mg and 10 mg/200 mg respectively.

Medical uses
Hydrocodone/ibuprofen has a labeled indication for "short-term (generally <10 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate".

Pregnancy
Opioids such as hydrocodone cross the placenta, and can therefore affect the fetus.  Studies have shown a possible association between opioids and adverse outcomes such as birth defects, poor fetal growth, stillbirth, and preterm delivery. Prolonged use of opioids by a pregnant mother can also lead to neonatal withdrawal syndrome.  NSAIDs such as ibuprofen should generally be avoided in pregnancy, as there are conflicting reports of birth defects after in utero exposure. However, it is accepted that NSAIDs prevent closure of the fetal ductus arteriosus, which happens during the later stages of pregnancy.  Because of this, ibuprofen should be avoided after 30 weeks gestation.

Breastfeeding
Hydrocodone and ibuprofen are excreted in breast milk, so appropriate caution should be taken when prescribing to breastfeeding mothers.

Special populations
There is no evidence to support altered pharmacokinetic properties due to differences in gender or age.  However, this drug combination has not been tested in children.

Adverse effects
The side effects for hydrocodone/ibuprofen are a combination of the side effects of the component drugs.  Side effects experienced in more than 10% of the population taking the drug include: headache, drowsiness, dizziness, constipation, nausea, and dyspepsia.

Pharmacology
Pharmacokinetics
The two active components of the drug, ibuprofen and hydrocodone, do not affect each others absorption characteristics or other pharmacokinetic parameters. After an oral dose, the peak level of hydrocodone in the blood is reached 1.7 hours after administration.  The blood levels of ibuprofen peak 1.8 hours after oral administration.

History
Discovery and development
The patent for Vicoprofen was filed in December 1984, and U.S. patent number 4,587,252 was granted in May 1986. Although ibuprofen and hydrocodone were already available on the market at this time, the fact that they had never been supplied together in a single formulation required approval from the FDA as if it were a new drug. Knoll filed an investigational new drug application on 30 December 1986.  A new drug application was later filed by Knoll on 25 April 1996, and received final approval from the FDA on 23 September 1997. Vicoprofen tablets were initially formulated and packaged by Knoll, with ibuprofen supplied by Albemarle Corporation and hydrocodone supplied by Mallinckrodt Pharmaceuticals.The validity of Knolls patent on Vicoprofen has been challenged in federal court. In September 2002, the U.S. District Court for the Norther District of Illinois granted a motion of invalidity filed by Teva Pharmaceuticals against Knolls patent on Vicoprofen, ruling the patent was invalid as obvious. This ruling paved the way for Tevas abbreviated new drug application to be approved by the FDA which would allow them to manufacture and market their own generic.  Knoll appealed the decision.  In April 2003, Teva announced that its abbreviated new drug application had been approved by the FDA, and its generic would begin shipping immediately.  In May 2004, the United States Court of Appeals for the Federal Circuit vacated the previous judgment by the U.S. District Court for the Northern District of Illinois, and the case was remanded back for further court proceedings. Teva continued to sell its generic during this time. The patent for Vicoprofen expired on 18 December 2004, officially opening the drug to generic manufacture.  In July 2016, the FDA approved another generic equivalent, manufactured by Aurobindo Pharma Limited.

Ownership and promotion
Knoll pharmaceuticals, originally founded in Germany in 1886, became a subsidiary of BASF (a German chemical company) in 1975.  It was under their control when Vicoprofen was originally developed and approved. In March 2000, Knoll Pharmaceuticals and Abbott Laboratories, an American health care company, announced a co-promotion agreement for Vicoprofen, in which Abbott would promote Vicoprofen to its network of buyers, including physicians, hospitals, and surgical centers. In June 2002, Abbott Laboratories, paid $6.9 billion to acquire the entire Knoll pharmaceutical unit from BASF, including Vicoprofen.

DEA classification
Vicoprofen was originally approved as a schedule III drug, but was later reclassified to a schedule II drug based on the DEA reclassification of hydrocodone containing products effective 6 October 2014.

Research
The new drug application for Vicoprofen was approved based on data from both single and multiple dose analgesia trials.
The single dose analgesia studies occurred in multiple surgical settings, including dental, back, and abdominal/gynecologic surgery in the U.S. and Puerto Rico.  There were 1,537 patients enrolled over all trials, with 79% of the participants being female. There were 10 single dose analgesia trials included in the new drug application.  All studies were similarly designed: after completion of a procedure in which pain was rated as moderate or severe, patients would be randomized into various treatment groups.  The treatment groups included: ibuprofen only, hydrocodone only, Vicoprofen (hydrocodone/ibuprofen), and placebo. The participants pain would then be tracked over the next several hours by the self reporting of pain scores.There were four multiple dose trials included in the new drug application.  These studies were all completed in the U.S., in settings including burn unit, post-operatively, and chronic pain settings.  A total of 683 patients were enrolled in all of the multiple dose trials, with 57% of the participants being women </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Captopril and can you explain it in depth? [/INST] Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.
Captopril was patented in 1976 and approved for medical use in 1980.

Structure–activity relationship
Captopril has an L-proline group which allows for it to be more bioavailable within oral formulations. The thiol moiety within the molecule has been associated with two significance adverse effects: the hapten or immune response. This immune response, also known as agranulocytosis, can explain the adverse drug events which may be seen in captopril with the allergic response, which would be: hives, severe stomach pain, difficulty breathing, swelling of the face, lips, tongue or throat.In terms of interaction with the enzyme, the molecules thiol moiety will attach to the binding site of the ACE enzyme. This will inhibit the port at which the angiotensin-1 molecule would normally bind, therefore inhibiting the downstream effects within the renin-angiotensin system.

Medical uses
Captoprils main uses are based on its vasodilation and inhibition of some renal function activities.  These benefits are most clearly seen in:

Hypertension
Cardiac conditions such as congestive heart failure and after myocardial infarction
Preservation of kidney function in diabetic nephropathy.Additionally, it has shown mood-elevating properties in some patients. This is consistent with the observation that animal screening models indicate putative antidepressant activity for this compound, although one study has been negative. Formal clinical trials in depressed patients have not been reported.It has also been investigated for use in the treatment of cancer. Captopril stereoisomers were also reported to inhibit some metallo-β-lactamases.

Adverse effects
Adverse effects of captopril include cough due to increase in the plasma levels of bradykinin, angioedema, agranulocytosis, proteinuria, hyperkalemia, taste alteration, teratogenicity, postural hypotension, acute renal failure, and leukopenia.
Except for postural hypotension, which occurs due to the short and fast mode of action of captopril, most of the side effects mentioned are common for all ACE inhibitors. Among these, cough is the most common adverse effect. Hyperkalemia can occur, especially if used with other drugs which elevate potassium level in blood, such as potassium-sparing diuretics. Other side effects are:

Itching
Headache
Tachycardia
Chest pain
Palpitations
Dysgeusia
WeaknessThe adverse drug reaction (ADR) profile of captopril is similar to other ACE inhibitors, with cough being the most common ADR. However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique thiol moiety.

Overdose
ACE inhibitor overdose can be treated with naloxone.

History
In the late 1960s, John Vane of the Royal College of Surgeons of England was working on mechanisms by which the body regulates blood pressure. He was joined by Sérgio Henrique Ferreira of Brazil, who had been studying the venom of a Brazilian pit viper, the jararaca (Bothrops jararaca), and brought a sample of the vipers venom. Vanes team found that one of the venoms peptides selectively inhibited the action of angiotensin-converting enzyme (ACE), which was thought to function in blood pressure regulation; the snake venom functions by severely depressing blood pressure. During the 1970s, ACE was found to elevate blood pressure by controlling the release of water and salts from the kidneys.
Captopril, an analog of the snake venoms ACE-inhibiting peptide, was first synthesized in 1975 by three researchers at the U.S. drug company E.R. Squibb & Sons Pharmaceuticals (now Bristol-Myers Squibb): Miguel Ondetti, Bernard Rubin, and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976, which was granted in September 1977, and captopril was approved for medical use in 1980. It was the first ACE inhibitor developed and was considered a breakthrough both because of its mechanism of action and also because of the development process. In the 1980s, Vane received the Nobel prize and was knighted for his work and Ferreira received the National Order of Scientific Merit from Brazil.
The development of captopril was among the earliest successes of the revolutionary concept of ligand-based drug design. The renin–angiotensin–aldosterone system had been extensively studied in the mid-20th century, and this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE. Captopril was the culmination of efforts by Squibbs laboratories to develop an ACE inhibitor.
Ondetti, Cushman, and colleagues built on work that had been done in the 1960s by a team of researchers led by John Vane at the Royal College of Surgeons of England. The first breakthrough was made by Kevin K.F. Ng in 1967, when he found  the conversion of angiotensin  I to angiotensin II took place in the pulmonary circulation instead of in the plasma. In contrast, Sergio Ferreira found bradykinin disappeared in its passage through the pulmonary circulation. The conversion of angiotensin I to angiotensin II and the inactivation of bradykinin were thought to be mediated by the same enzyme.
In 1970, using bradykinin potentiating factor (BPF) provided by Sergio Ferreira, Ng and Vane found the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation. BPF was later found to be a peptide in the venom of a lancehead viper (Bothrops jararaca), which was a “collected-product inhibitor” of  the converting enzyme.  Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl moiety of the peptide provided a high potency of ACE inhibition.Captopril gained FDA approval on April 6, 1981. The drug became a generic medicine in the U.S. in February 1996, when the market exclusivity held by Bristol-Myers Squibb for captopril expired.

Chemical synthesis
A chemical synthesis of captopril by treatment of L-proline with (2S)-3-acetylthio-2-methylpropanoyl chloride under basic conditions (NaOH), followed by aminolysis of the protective acetyl group to unmask the drugs free thiol, is depicted in the figure at right.
Procedure 2 taken out of patent US4105776. See examples 28, 29a and 36.

Mechanism of action
Captopril blocks the conversion of angiotensin I to angiotensin II and prevents the degradation of vasodilatory prostaglandins, thereby inhibiting vasoconstriction and promoting systemic vasodilation.

Pharmacokinetics
Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other being lisinopril) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ethinylestradiol/drospirenone and can you explain it in depth? [/INST]  </s>