Japan is an island country in East Asia. Located in the Pacific Ocean, it lies off the eastern coast of the Asian continent and stretches from the Sea of Okhotsk in the north to the East China Sea and the Philippine Sea in the south; the kanji that make up Japan's name mean "sun origin", it is called the "Land of the Rising Sun". Japan is a stratovolcanic archipelago consisting of about 6,852 islands; the four largest are Honshu, Hokkaido and Shikoku, which make up about ninety-seven percent of Japan's land area and are referred to as home islands. The country is divided into 47 prefectures in eight regions, with Hokkaido being the northernmost prefecture and Okinawa being the southernmost one; the population of 127 million is the world's tenth largest. 90.7 % of people live in cities. About 13.8 million people live in the capital of Japan. The Greater Tokyo Area is the most populous metropolitan area in the world with over 38 million people. Archaeological research indicates; the first written mention of Japan is in Chinese history texts from the 1st century AD.
Influence from other regions China, followed by periods of isolation from Western Europe, has characterized Japan's history. From the 12th century until 1868, Japan was ruled by successive feudal military shōguns who ruled in the name of the Emperor. Japan entered into a long period of isolation in the early 17th century, ended in 1853 when a United States fleet pressured Japan to open to the West. After nearly two decades of internal conflict and insurrection, the Imperial Court regained its political power in 1868 through the help of several clans from Chōshū and Satsuma – and the Empire of Japan was established. In the late 19th and early 20th centuries, victories in the First Sino-Japanese War, the Russo-Japanese War and World War I allowed Japan to expand its empire during a period of increasing militarism; the Second Sino-Japanese War of 1937 expanded into part of World War II in 1941, which came to an end in 1945 following the Japanese surrender. Since adopting its revised constitution on May 3, 1947, during the occupation led by SCAP, the sovereign state of Japan has maintained a unitary parliamentary constitutional monarchy with an Emperor and an elected legislature called the National Diet.
Japan is a member of the ASEAN Plus mechanism, UN, the OECD, the G7, the G8, the G20, is considered a great power. Its economy is the world's third-largest by nominal GDP and the fourth-largest by purchasing power parity, it is the world's fourth-largest exporter and fourth-largest importer. Japan benefits from a skilled and educated workforce. Although it has renounced its right to declare war, Japan maintains a modern military with the world's eighth-largest military budget, used for self-defense and peacekeeping roles. Japan is a developed country with a high standard of living and Human Development Index, its population enjoys the highest life expectancy and third lowest infant mortality rate in the world, but is experiencing issues due to an aging population and low birthrate. Japan is renowned for its historical and extensive cinema, influential music industry, video gaming, rich cuisine and its major contributions to science and modern technology; the Japanese word for Japan is 日本, pronounced Nihon or Nippon and means "the origin of the sun".
The character nichi means "sun" or "day". The compound therefore means "origin of the sun" and is the source of the popular Western epithet "Land of the Rising Sun"; the earliest record of the name Nihon appears in the Chinese historical records of the Tang dynasty, the Old Book of Tang. At the end of the seventh century, a delegation from Japan requested that Nihon be used as the name of their country; this name may have its origin in a letter sent in 607 and recorded in the official history of the Sui dynasty. Prince Shōtoku, the Regent of Japan, sent a mission to China with a letter in which he called himself "the Emperor of the Land where the Sun rises"; the message said: "Here, I, the emperor of the country where the sun rises, send a letter to the emperor of the country where the sun sets. How are you". Prior to the adoption of Nihon, other terms such as Yamato and Wakoku were used; the term Wa is a homophone of Wo 倭, used by the Chinese as a designation for the Japanese as early as the third century Three Kingdoms period.
Another form of Wa, Wei in Chinese) was used for an early state in Japan called Nakoku during the Han dynasty. However, the Japanese disliked some connotation of Wa 倭, it was therefore replaced with the substitute character Wa, meaning "togetherness, harmony"; the English word Japan derives from the historical Chinese pronunciation of 日本. The Old Mandarin or early Wu Chinese pronunciation of Japan was recorded by Marco Polo as Cipangu. In modern Shanghainese, a Wu dialect, the pronunciation of characters 日本; the old Malay word for Japan, Japun or Japang, was borrowed from a southern coastal Chinese dialect Fukienese or Ningpo – and this Malay word was encountered by Portuguese traders in Southeast Asia in the 16th century. These Early Portuguese traders brought the word
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
The Jmol applet, among other abilities, offers an alternative to the Chime plug-in, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1
Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
Panic is a sudden sensation of fear, so strong as to dominate or prevent reason and logical thinking, replacing it with overwhelming feelings of anxiety and frantic agitation consistent with an animalistic fight-or-flight reaction. Panic may occur singularly in individuals or manifest in large groups as mass panic; the word is a tribute to the ancient god, Pan. One of the many gods in the mythology of ancient Greece: Pan was the god of shepherds and of woods and pastures; the Greeks believed that he wandered peacefully through the woods, playing a pipe, but when accidentally awakened from his noontime nap he could give a great shout that would cause flocks to stampede. From this aspect of Pan's nature Greek authors derived the word panikos, “sudden fear,” the ultimate source of the English word: "panic"; the Greek term indicates the feeling of total fear, sudden and attributed to the presence of a god. In psychology, panic is identified as a disorder and is related to biological and psychological factors and their interactions.
A view described one of its incidences as a specific psychological vulnerability of people to interpret normal physical sensations in a catastrophic way. Leonard J. Schmidt and Brooke Warner describe panic as “that terrible, profound emotion that stretches us beyond our ability to imagine any experience more horrible” adding that “physicians like to compare painful clinical conditions on some imagined ‘Richter scale’ of vicious, mean hurt … to the psychiatrist there is no more vicious, mean hurt than an exploding and disintegrating panic attack.”Panic in social psychology is considered infectious since it can spread to a multitude of people and those affected are expected to act irrationally as a consequence. Psychologists identify different types of this panic event with varying descriptions and these include mass hysteria, mass psychosis, mass panic, social contagion. An influential theoretical treatment of panic is found in Neil J. Smelser's Theory of Collective Behavior; the science of panic management has found important practical applications in the armed forces and emergency services of the world.
Prehistoric humans used mass panic as a technique when hunting animals ruminants. Herds reacting to unusually strong sounds or unfamiliar visual effects were directed towards cliffs, where they jumped to their deaths when cornered. Humans are vulnerable to panic and it is considered infectious, in the sense one person's panic may spread to other people nearby and soon the entire group acts irrationally, but people have the ability to prevent and/or control their own and others' panic by disciplined thinking or training. Architects and city planners try to accommodate the symptoms of panic, such as herd behavior, during design and planning using simulations to determine the best way to lead people to a safe exit and prevent congestion; the most effective methods are non-intuitive. A tall column or columns, placed in front of the door exit at a calculated distance, may speed up the evacuation of a large room, as the obstacle divides the congestion well ahead of the choke point. Many publicized cases of deadly panic occurred during massive public events.
The layout of Mecca was extensively redesigned by Saudi authorities in an attempt to eliminate frequent stampedes, which kill an average of 250 pilgrims every year. Football stadiums have seen deadly crowd rushes and stampedes, such as at Heysel stadium in Belgium in 1985 with more than 600 casualties, including 39 deaths, at Hillsborough stadium in Sheffield, England, in 1989 when 96 people were killed in a crush. Panic! How it works and What To Do About It — by Bruce Tognazzini. "Panic: Myth or Reality?" — Professor Lee Clarke, Contexts Magazine, 2002
Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on efficacy, they are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial – their approval does not mean that the therapy is'safe' or effective, only that the trial may be conducted. Depending on product type and development stage, investigators enroll volunteers or patients into small pilot studies, subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, they can involve a single research center or multiple centers, in one country or in multiple countries.
Clinical study design aims to ensure the scientific reproducibility of the results. Costs for clinical trials can range into the billions of dollars per approved drug; the sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become an approved drug; some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to patients with specific health conditions who are willing to try an experimental treatment; when participants are healthy volunteers who receive financial incentives, the goals are different than when the participants are sick. During dosing periods, study subjects remain under supervision for one to 40 nights. Pilot experiments are conducted to gain insights for design of the clinical trial to follow.
There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy" or "effectiveness". Neither is an absolute criterion; the benefits must outweigh the risks. For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care, are used for a life-threatening condition. In the US, the elderly constitute 14 % of the population. People over 55 are excluded from trials because their greater health issues and drug use complicate data interpretation, because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are frequently excluded. Pregnant women are excluded due to potential risks to the fetus; the sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type of patients might benefit.
If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, whether improvement or worsening of the condition targeted by the study drug occurs; the researchers send the data to the trial sponsor, who analyzes the pooled data using statistical tests. Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: On a specific kind of patient, for example, a patient, diagnosed with Alzheimer's disease At varying dosages, for example, a 10 milligram dose instead of a 5 milligram dose For a new indication Evaluation for improved efficacy in treating a patient's condition as compared to the standard therapy for that condition Evaluation of the study drug or device relative to two or more approved/common interventions for that condition, for example, device A versus device B, or therapy A versus therapy B)While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo.
Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures that all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects; as a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method the experimental step. The most common clinical trials evaluate new pharmaceutical products, medical devices, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation. To drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket appr
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, poison, or other substance is taken into the body. Routes of administration are classified by the location at which the substance is applied. Common examples include intravenous administration. Routes can be classified based on where the target of action is. Action may be enteral, or parenteral. Route of administration and dosage form are aspects of drug delivery. Routes of administration are classified by application location; the route or course the active substance takes from application location to the location where it has its target effect is rather a matter of pharmacokinetics. Exceptions include the transdermal or transmucosal routes, which are still referred to as routes of administration; the location of the target effect of active substances are rather a matter of pharmacodynamics. An exception is topical administration, which means that both the application location and the effect thereof is local. Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, sometimes as a local application location regardless of location of the effects.
Administration through the gastrointestinal tract is sometimes termed enteral or enteric administration. Enteral/enteric administration includes oral and rectal administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may occur in the stomach, as such gastrointestinal may be a more fitting term for this route of administration. Furthermore, some application locations classified as enteral, such as sublingual and sublabial or buccal, are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Enteral administration can be used for systemic administration, as well as local, such as in a contrast enema, whereby contrast media is infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects. Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy.
Substances may be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach; the rectal route is an effective route of administration for many medications those used at the end of life. The walls of the rectum absorb many medications and effectively. Medications delivered to the distal one-third of the rectum at least avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration.
The parenteral route is any route, not enteral. Parenteral administration can be performed by injection, that is, using a needle and a syringe, or by the insertion of an indwelling catheter. Locations of application of parenteral administration include: central nervous systemepidural, e.g. epidural anesthesia intracerebral direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain; the intracerebral route can interrupt the blood brain barrier from holding up against subsequent routes. Intracerebroventricular administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain. Epicutaneous, it can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route. Sublingual and buccal medication administration is a way of giving someone medicine orally.
Sublingual administration is. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the cheek. These medications can come in the form of films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, barbiturates, opioid analgesics with poor gastrointestinal bioavailability and vitamins and minerals. Extra-amniotic administration, between the endometrium and fetal membranes nasal administration (th