Naloxone, sold under the brandname Narcan among others, is a medication used to block the effects of opioids in overdose. Naloxone may be combined with an opioid to decrease the risk of opioid misuse; when given intravenously, naloxone works within two minutes, when injected into a muscle, it works within five minutes. The effects of naloxone last about half an hour to an hour. Multiple doses may be required, as the duration of action of most opioids is greater than that of naloxone. Administration to opioid-dependent individuals may cause symptoms of opioid withdrawal, including restlessness, nausea, vomiting, a fast heart rate, sweating. To prevent this, small doses every few minutes can be given until the desired effect is reached. In those with previous heart disease or taking medications that negatively affect the heart, further heart problems have occurred, it appears to be safe after having been given to a limited number of women. Naloxone is a competitive opioid receptor antagonist, it works by reversing the depression of the central nervous system and respiratory system caused by opioids.
Naloxone was patented in 1961 and approved for opioid overdose in the United States in 1971. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Naloxone is available as a generic medication, its wholesale price in the developing world is between $0.50 and $5.30 per dose. Vials of naloxone are not expensive in the United States; the price for a package of two auto-injectors in the US, has increased from $690 in 2014 to $4,500 in 2016. The 2018 price for the NHS in the United Kingdom is about £5 per dose. Naloxone is useful both in acute opioid overdose and in reducing respiratory or mental depression due to opioids. Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear, it is included as a part of emergency overdose response kits distributed to heroin and other opioid drug users and emergency responders. This has been shown to reduce rates of deaths due to overdose. A prescription for naloxone is recommended if a person is on a high dose of opioid, is prescribed any dose of opioid accompanied by a benzodiazepine, or is suspected or known to use opioids nonmedically.
Prescribing naloxone should be accompanied by standard education that includes preventing and responding to an overdose. Naloxone is poorly absorbed when taken by mouth, so it is combined with a number of oral opioid preparations, including buprenorphine and pentazocine, so that when taken orally, just the opioid has an effect, but if misused by injecting, the naloxone blocks the effect of the opioid; this combination is used in an effort to prevent abuse. In Germany, tilidine is sold in a fixed combination with naloxone. Naloxone can be used on infants who were exposed to intrauterine opiates administered to mothers during delivery. However, there is insufficient evidence for the use of naloxone to lower cardiorespiratory and neurological depression in these infants. Infants exposed to high concentrations of opiates during pregnancy may have CNS damage in the setting of perinatal asphyxia. Naloxone has been studied to improve outcomes in this population, however the evidence is weak. In people with shock, including septic, hemorrhagic, or spinal shock, those who received naloxone had improved blood flow.
The importance of this is unclear. Naloxone is experimentally used in the treatment for congenital insensitivity to pain with anhidrosis, an rare disorder that renders one unable to feel pain or differentiate temperatures. Naloxone can be used as an antidote in overdose of clonidine, a medication that lowers blood pressure. Naloxone can be used to treat itchiness brought on by opioid use. Naloxone is most injected intravenously for fastest action, which causes the drug to act within a minute, lasts up to 45 minutes, it can be administered via intramuscular, subcutaneous injection, or nasal spray. There is a prepackaged nasal spray that delivers a consistent dose, it can be repeated. A non-FDA approved wedge device attached to a syringe may be used to create a mist that delivers the drug to the nasal mucosa; this is useful near facilities where many overdoses occur that stock injectors. If minimal or no response is observed within 2–3 minutes, dosing may be repeated every 2 minutes until the maximum dose of 10 mg has been reached.
If no response occurs at this time, alternative diagnosis and treatment should be pursued. The effects of naloxone may wear off before those of the opioids, they may require repeat dosing at a time. Patients experiencing effects should be monitored for respiratory rate, heart rate, blood pressure, temperature, ABGs and level of consciousness; those with a greater risk for respiratory depression should be identified prior to administration and watched closely. In April 2014, the US Food and Drug Administration approved a hand-held automatic injector naloxone product, pocket-sized and can be used in nonmedical settings such as in the home, it is designed for use by laypersons, including family members and caregivers of opioid users at-risk for an opioid emergency, such as an overdose. A nasal spray was developed in a partnership between LightLake Therapeutics and the National Institute on Drug Abuse; the approval process was fast-tracked as one initiative to reduce the death toll caused by opiate overdoses.
At the time of approval, an estimated 16,000 annual deaths w
Buttock cells are cells having a notched appearance that are found in certain malignancies, such as non-Hodgkin's lymphoma, mycosis fungoides, Sézary syndrome. Clue cell Koilocyte Large cell
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding; the majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, villain, rival", derived from anti- and agonizesthai.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly; the activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses; this may be accomplished by binding to the allosteric site. In addition, antagonists may interact at unique binding sites not involved in the biological regulation of the receptor's activity to exert their effects.
The term antagonist was coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s; the current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by'blocking' the receptor from the agonist; this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states; the discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, antagonists inhibit the function of agonists, inverse agonists, partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.
The potency of an antagonist is defined by its half maximal inhibitory concentration. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar; the lower the IC50 the greater the potency of the antagonist, the lower the concentration of drug, required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects; the affinity of an antagonist for its binding site, i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used.
However, it is important. The effects of receptor desensitization on reaching equilibrium must als
Perelman School of Medicine at the University of Pennsylvania
The Perelman School of Medicine known as Penn Med, is the medical school of the University of Pennsylvania. It is located in the University City section of Philadelphia. Founded in 1765, the Perelman School of Medicine is the oldest medical school in the United States and is one of the seven Ivy League medical schools. Penn Med ranks among the highest recipients of NIH research awards, it is tied for 3rd place on U. S. News & World Report's "Best; the school of medicine was founded by Dr. John Morgan, a graduate of the College of Philadelphia and the University of Edinburgh Medical School. After training in Edinburgh and other European cities, Dr. Morgan returned to Philadelphia in 1765. With fellow University of Edinburgh Medical School graduate Dr. William Shippen Jr. Morgan persuaded the college's trustees to found the first medical school in the Original Thirteen Colonies. Only months before the medical school was created, Morgan delivered an address to the trustees and the citizens of Philadelphia, "Upon the Institution of Medical Schools in America" during which he expressed his desire for the new medical school to become a model institution: Perhaps this medical institution, the first of its kind in America, though small in its beginning, may receive a constant increase of strength, annually exert new vigor.
It may collect a number of young persons of more ordinary abilities, so improve their knowledge as to spread its reputation to different parts. By sending these abroad duly qualified, or by exciting an emulation amongst men of parts and literature, it may give birth to other useful institutions of a similar nature, or occasional rise, by its example to numerous societies of different kinds, calculated to spread the light of knowledge through the whole American continent, wherever inhabited; that autumn, students enrolled for "anatomical lectures" and a course on "the theory and practice of physick." Modeling the school after the University of Edinburgh Medical School, medical lectures were supplemented with bedside teaching at the Pennsylvania Hospital. The School of Medicine's early faculty included nationally renowned physicians and scientists such as Benjamin Rush, Philip Syng Physick, Robert Hare. In the mid-1800s, prominent faculty members included William Pepper, Joseph Leidy, Nathaniel Chapman..
William Osler and Howard Atwood Kelly, two of the "founding four" physicians of The Johns Hopkins Hospital were drawn from Penn's medical faculty. In 1910, the landmark Flexner Report on medical education reviewed Penn as one of the few medical schools of the era with high standards in medical instruction and research. In 2011, the University of Pennsylvania School of Medicine was renamed in recognition of a $225 million gift by Raymond and Ruth Perelman. Raymond Perelman and his son, Ronald Perelman, are both alumni of Penn's Wharton School, it was the single largest gift made in the University's history, it remains the largest donation made for naming rights to a medical school. Between 1765 and 1801, medical school lectures were held in Surgeon's Hall on 5th Street in Center City, Philadelphia. In 1801, medical instruction moved with the rest of the university to 9th Street. In the 1870s, the university moved across the Schuylkill River to a location in West Philadelphia; as part of this move, the medical faculty persuaded the university trustees to construct a teaching hospital adjacent to the new academic facilities.
As a result, Penn's medical school and flagship teaching hospital form part of the university's main campus and are located in close proximity to the university's other schools and departments. Although they are independent institutions, the Children's Hospital of Philadelphia and the Wistar Institute are located on or adjacent to Penn's campus; the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Pennsylvania Hospital, the Children's Hospital of Philadelphia serve as the medical school's main teaching hospitals. Additional teaching takes place at Chester County Hospital, Lancaster General Hospital, the Philadelphia VA Medical Center. During the late nineteenth and early twentieth centuries, the School of Medicine was one of the earliest to encourage the development of the emerging medical specialties: neurosurgery, ophthalmology and radiology. Between 1910 and 1939, the chairman of the Department of Pharmacology, Alfred Newton Richards, played a significant role in developing the University as an authority of medical science, helping the United States to catch up with European medicine and begin to make significant advances in biomedical science.
In the 1950s and early 1960s, Dr. Jonathon E. Rhoads of the Department of Surgery, mentored Dr. Stanley Dudrick who pioneered the successful use of total parenteral nutrition for patients unable to tolerate nutrition through their GI tract. In the 1980s and 1990s, Dr. C. William Schwab, a trauma surgeon, led numerous advances in the concept of damage control surgery for injured trauma patients. In the 1990s and 2000s, Dr. Paul Offit, a professor of Pediatrics at the School of Medicine and Children's Hospital of Philadelphia, lead the scientific advances behind the modern RotaTeq vaccine for infectious childhood diarrhea. In 2006, Drs. Kaplan and Shore of the Department of Orthopedics discovered the causative mutation in fibrodysplasia ossificans progressiva, an rare disease of bone. Benchmark changes in the understanding of medical science and the practice of medicine have necessitated that the school change its methods of teaching, as well as its curriculu
Jean-Louis-Marc Alibert was a French dermatologist born in Villefranche-de-Rouergue, Aveyron. He was a pioneer of French dermatology. Planning to enter the priesthood, Alibert did not begin studying medicine until he was 26 years old; as a medical student in Paris, he studied with renowned physicians that included Pierre-Joseph Desault, Jean-Nicolas Corvisart, Marie Francois Xavier Bichat and Philippe Pinel. In 1801 he was appointed médecin adjoint to the Hôpital Saint-Louis, where he administered to patients with skin disorders and leprosy. Following the Restoration of the French monarchy, Alibert became a personal physician to Louis XVIII, he was a personal physician to Charles X, was awarded with the title of "baron". Being that there was no chair of dermatology in Paris, Alibert was appointed professor of materia medica and therapeutics in 1823. Alibert believed that when diagnosing skin disorders several criteria needed to be used, attempted to introduce a classification system for diseases, similar to the method Bernard and Antoine Laurent de Jussieu used in botany.
Alibert first classified dermatological disorders according to outer appearance he divided them into what he called families and species. This system of classification was represented pictorially by Alibert as the "Tree of Dermatoses". From his "tree", Alibert wished to introduce a method rather than a classification system. Alibert was a prodigious writer, his best known work being the beautifully illustrated Descriptions des maladies de la peau, his literary work included biographies of famed scientists such as Lazzaro Spallanzani and Luigi Galvani. In 1806, he was the first to describe a patient with mycosis fungoides; the disease was referred to as "Alibert-Bazin syndrome", named in conjunction with dermatologist Pierre-Antoine-Ernest Bazin. In 1818, he was the first to describe a patient with psoriatic arthritis. List of dermatologists Dissertation sur les fièvres pernicieuses ou ataxiques intermittentes, Doctoral thesis. Alibert JLM. Descriptions des maladies de la peau observées a l’Hôpital Saint-Louis, et exposition des meilleures méthodes suivies pour leur traitement.
Paris: Barrois l’ainé. P. 286. Archived from the original on 2012-12-12. Alibert JLM. Physiologie des passions, ou, Nouvelle doctrine des sentimens moraux. Paris: Béchet jeune. Alibert JLM. Monographie des dermatoses. Paris: Germer Balliere. Jean-Louis-Marc Alibert @. French Society for the History of Dermatology "Paris choosing a dermatological hero for the millennium" by Daniel Wallach "Baron Jean-Louis ALIBERT 1768 - 1837 Médecin, dermatologue français" Portraites de Medecins
Food and Drug Administration
The Food and Drug Administration is a federal agency of the United States Department of Health and Human Services, one of the United States federal executive departments. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, dietary supplements and over-the-counter pharmaceutical drugs, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, animal foods & feed and veterinary products; as of 2017, 3/4th of the FDA budget is paid by people who consume pharmaceutical products, due to the Prescription Drug User Fee Act. The FDA was empowered by the United States Congress to enforce the Federal Food and Cosmetic Act, which serves as the primary focus for the Agency; these include regulating lasers, cellular phones and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction. The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate.
The Commissioner reports to the Secretary of Human Services. Scott Gottlieb, M. D. is the current commissioner, who took over in May 2017. The FDA has its headquarters in Maryland; the agency has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, Puerto Rico. In 2008, the FDA began to post employees to foreign countries, including China, Costa Rica, Chile and the United Kingdom. In recent years, the agency began undertaking a large-scale effort to consolidate its 25 operations in the Washington metropolitan area, moving from its main headquarters in Rockville and several fragmented office buildings to the former site of the Naval Ordnance Laboratory in the White Oak area of Silver Spring, Maryland; the site was renamed from the White Oak Naval Surface Warfare Center to the Federal Research Center at White Oak. The first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees on the campus in December 2003. Only one original building from the naval facility was kept.
All other buildings are new construction. The project is slated to be completed by 2021, assuming future Congressional funding While most of the Centers are located in the Washington, D. C. area as part of the Headquarters divisions, two offices – the Office of Regulatory Affairs and the Office of Criminal Investigations – are field offices with a workforce spread across the country. The Office of Regulatory Affairs is considered the "eyes and ears" of the agency, conducting the vast majority of the FDA's work in the field. Consumer Safety Officers, more called Investigators, are the individuals who inspect production and warehousing facilities, investigate complaints, illnesses, or outbreaks, review documentation in the case of medical devices, biological products, other items where it may be difficult to conduct a physical examination or take a physical sample of the product; the Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. Districts are based on the geographic divisions of the federal court system.
Each district comprises a main district office and a number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are food-related, some laboratories are equipped to analyze drugs and radiation-emitting devices; the Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, don't focus on technical aspects of the regulated industries. OCI agents pursue and develop cases where individuals and companies have committed criminal actions, such as fraudulent claims, or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving Title 18 violations, in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents come from other criminal investigations backgrounds, work with the Federal Bureau of Investigation, Assistant Attorney General, Interpol.
OCI receives cases from a variety of sources—including ORA, local agencies, the FBI—and works with ORA Investigators to help develop the technical and science-based aspects of a case. OCI is a smaller branch; the FDA works with other federal agencies, including the Department of Agriculture, Drug Enforcement Administration and Border Protection, Consumer Product Safety Commission. Local and state government agencies work with the FDA to provide regulatory inspections and enforcement action; the FDA regulates more than US$2.4 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements. Much of these expenditures are for goods imported into the United States; the FDA's federal budget request for fiscal year 2012 totaled $4.36 billion, while the proposed 2014 budget is $4.7 billion. About $2 billion of this budget is generated by user fees.
Pharmaceutical firms pay th
Human T-lymphotropic virus
The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and a demyelinating disease called HTLV-1 associated myelopathy/tropical spastic paraparesis. The HTLVs belong to a larger group of primate T-lymphotropic viruses. Members of this family that infect humans are called HTLVs, the ones that infect Old World monkeys are called Simian T-lymphotropic viruses. To date, four types of HTLVs and four types of STLVs have been identified. HTLV types HTLV-2 viruses are the first retroviruses which were discovered. Both belong to the oncovirus subfamily of retroviruses and can transform human lymphocytes so that they are self-sustaining in vitro; the HTLVs are believed to originate from intraspecies transmission of STLVs. The HTLV-1 genome is diploid, composed of two copies of a single-stranded RNA virus whose genome is copied into a double-stranded DNA form that integrates into the host cell genome, at which point the virus is referred to as a provirus.
A related virus is bovine leukemia virus BLV. The original name for HIV, the virus that causes AIDS, was HTLV-3. Confusingly, since reassignment, the virus now called HTLV-3 is not HIV. HTLV-1 is an abbreviation for human T-cell lymphotropic virus type 1 called human T-cell leukemia type 1, a virus, implicated in several kinds of diseases, including HTLV-1-associated myelopathy, as a virus cancer link for leukemia. HTLV-1 has six reported subtypes; the great majority of infections are caused by the cosmopolitan subtype A. HTLV was discovered by Robert Gallo and colleagues in 1980. Between 1 in 20 and 1 in 25 infected people are thought to develop cancer as a result of the virus. HTLV-1 infection is thought to spread only through dividing cells since reverse transcriptase generates proviral DNA from genomic viral RNA, the provirus is integrated into the host genome by viral integrase after transmission. Therefore, the quantification of provirus reflects the number of HTLV-1-infected cells. So, an increase in numbers of HTLV-1-infected cells using cell division, by actions of accessory viral genes Tax, may provide an enhancement of infectivity.
Tax expression induces proliferation, inhibits the apoptosis of HTLV-1-infected cells and, evokes the host immune response, including cytotoxic T cells, to kill virus-infected cells. Interesting, HTLV-1 Tax viral gene is known to dampen innate antiviral signaling pathways to avoid host detection and elimination, through SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein. A virus related to HTLV-1 discovered by Robert Gallo and colleagues; the family of Human T-lymphotropic virus can be further categorized into four sub types. The figure divides the retroviruses into exogenous and endogenous. Retroviruses can exist as two different forms: endogenous which consist of normal genetic components and exogenous which are horizontally transferred genetic components that are infectious agents that cause disease i.e. HIV. In open reading frames are shown which can if translated can predict which genes will be present and this can help to better understand human retroviruses. Of the four subtypes, HTLV-2 may be linked to Cutaneous T-cell lymphoma.
In one study involving cultured lymphocytes from patients with mycosis fungoides, PCR amplification showed gene sequences of HTLV-II. This finding may suggest a possible correlation with HTLV-2 and CTCL. Further research and studies must be conducted to show a positive relationship. HTLV-3 and HTLV-4 have been used to describe characterized viruses; these viruses were discovered in 2005 in rural Cameroon, were, it is presumed, transmitted from monkeys to hunters of monkeys through bites and scratches. HTLV-3 is similar to STLV-3. Multiple strains have been identified, it expresses gag and env, among other proteins. HTLV-4 is substantially identical to STLV-4 hosted in gorillas, it is not yet known how much further transmission has occurred among humans, or whether the viruses can cause disease. The use of these names can cause some confusion, because the name HTLV-3 was one of the names for HIV in early AIDS literature, but has since fallen out of use; the name HTLV-4 has been used to describe HIV-2.
A large Canadian study documented this confusion among healthcare workers, where >90% of HTLV tests ordered by physicians were intended to be HIV tests. HTLV-1 and HTLV-2 can be transmitted sexually, by blood via breast feeding. Two HTLVs are well established. HTLV-1 and HTLV-2 are both involved in spreading epidemics, affecting 15-20 million people worldwide. HTLV-1 is the most clinically significant of the two: at least 500,000 of the individuals infected with HTLV-1 develop an rapidly fatal leukemia, while others will develop a debilitative myelopathy, yet others will experience uveitis, infectious dermatitis, or another inflammatory disorder. HTLV-2 is associated with chronic pulmonary infections. In the United States, HTLV-1/2 seroprevalence rates among volunteer blood donors average 0.016 percent. No specific illnesses have yet been associated with HTLV-3 and HTLV-4. While there is no present licensed vaccine, there are many factors which make a vaccine against HTLV-1 feasible; the virus di