Drug. I INTRODUCTION Drug, substance that affects the function of living cells, used

Drug. I INTRODUCTION Drug, substance that affects the function of living cells, used in medicine to diagnose, cure, prevent the occurrence of diseases and disorders, and prolong the life of patients with incurable conditions. The availability of new and more effective drugs, such as antibiotics, which fight bacterial infections, and vaccines, which prevent diseases caused by bacteria and viruses, helped increase the average American's life span from about 60 years in 1900 to about 78 years in 2005. Drugs have vastly improved the quality of life. During the 20th century, drugs enabled the eradication of smallpox, once a widespread and often fatal disease. By the early 21st century, vaccines had led to the near eradication of poliomyelitis, once feared as a cause of paralysis. II CLASSIFICATION OF DRUGS Drugs can be classified in many ways: by the way they are dispensed----over the counter or by prescription; by the substance from which they are derived--plant, mineral, or animal; by the form they take--capsule, liquid, or gas; and by the way they are administered--by mouth, injection, inhalation, or direct application to the skin (absorption). Drugs are also classified by their names. All drugs have three names: (1) a chemical name, which describes the exact structure of the drug; (2) a generic or proprietary name, which is the official medical name, assigned in the United States by the U.S. Adopted Name Council (a group composed of pharmacists and other scientists); and (3) a brand, or trade, name, given by the particular manufacturer that sells the drug. If a company holds the patent on a drug--that is, if the company has the exclusive right to make and sell a drug--then the drug is available under one brand name only. After the patent expires, typically after 17 years in the United States, other companies can also manufacture the drug and market it under the generic name, or give it a new brand name. Another way to categorize drugs is by the way they act against diseases or disorders: chemotherapeutic drugs attack specific organisms that cause a disease without harming the host, while pharmocodynamic drugs alter the function of bodily systems by stimulating or depressing normal cell activity in a given system. The most common way to categorize a drug is by its effect on a particular area of the body or a particular condition. A Endocrine Drugs Endocrine drugs correct the overproduction or underproduction of the body's natural hormones. For example, insulin is a hormone used as a drug to treat diabetes. Another example of endocrine drugs are birth control pills, which contain the female sex hormones estrogen and progesterone. B Drugs that Fight Infections Anti-infective drugs are classified as antibacterials, antivirals, or antifungals depending on the type of microorganism they combat. Anti-infective drugs interfere selectively with the functioning of a microorganism while leaving the human host unharmed. Antibacterial drugs, or antibiotics--sulfa drugs, penicillins, cephalosporins, and many others--either kill bacteria directly or prevent them from multiplying so that the body's immune system can destroy invading bacteria. Antibacterial drugs act by interfering with some specific characteristics of bacteria. For example, they may destroy bacterial cell walls or interfere with the synthesis of bacterial proteins or deoxyribonucleic acid (DNA)--the chemical that carries the genetic material of an organism. Antibiotics often cure an infection completely. However, bacteria can spontaneously mutate, producing strains that are resistant to existing antibiotics. Antiviral drugs interfere with the life cycle of a virus by preventing its penetration into a host cell or by blocking the synthesis of new viruses. Antiviral drugs may cure, but often only suppress, viral infections; and flare-ups of an infection can occur after symptom-free periods. With some viruses, such as human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), antiviral drugs can only prolong life, not cure the disease. Vaccines are used as antiviral drugs against diseases such like mumps, measles, smallpox, poliomyelitis, and influenza. Vaccines are made from either live, weakened viruses or killed viruses, both of which are designed to stimulate the immune system to produce antibodies, proteins that attack foreign substances. These antibodies protect the body from future infections by viruses of the same type (see Immunization). Antifungal drugs selectively destroy fungal cells by altering cell walls. The cells' contents leak out and the cells die. Antifungal drugs can cure, or may only suppress, a fungal infection. C Cardiovascular Drugs Cardiovascular drugs affect the heart and blood vessels and are divided into categories according to function. Antihypertensive drugs reduce blood pressure by dilating blood vessels and reducing the amount of blood pumped by the heart into the vascular system. Antiarrhythmic drugs normalize irregular heartbeats and prevent cardiac malfunction and arrest. D Drugs that Affect the Blood Antianemic drugs, such as certain vitamins or iron, enhance the formation of red blood cells. Anticoagulants like heparin reduce blood-clot formation and ensure free blood flow through major organs in the body. Thrombolytic drugs dissolve blood clots, which can block blood vessels and deprive the heart or brain of blood and oxygen, possibly leading to heart attack or stroke. E Central Nervous System Drugs Central nervous system drugs--that is, drugs that affect the spinal cord and the brain--are used to treat several neurological (nervous system) and psychiatric problems. For instance, antiepileptic drugs reduce the activity of overexcited brain areas and reduce or eliminate seizures. Antipsychotic drugs are used to regulate certain brain chemicals called neurotransmitters, which do not function properly in people with psychoses, major mental disorders often characterized by extreme behaviors and hallucinations, such as in schizophrenia. Antipsychotic drugs can often significantly alleviate hallucinations and other abnormal behaviors. Antidepressant drugs reduce mental depression. Antimanic drugs reduce excessive mood swings in people with bipolar disorder (also called manic-depressive illness), which is characterized by behavioral fluctuations between highs of extreme excitement and activity and lows of lethargy and depression. Both types of drugs act by normalizing chemical activity in the emotional centers of the brain. Antianxiety drugs, also referred to as tranquilizers, treat anxiety by decreasing the activity in the anxiety centers of the brain. Sedative-hypnotic drugs are used both as sedatives to reduce anxiety and as hypnotics to induce sleep. Sedative-hypnotic drugs act by reducing brain-cell activity. Stimulant drugs, on the other hand, increase neuronal (nerve cell) activity and reduce fatigue and appetite. Analgesic drugs reduce pain and are generally categorized as narcotics and non-narcotics. Narcotic analgesics, also known as opioids, include opium and the natural opium derivatives codeine and morphine; synthetic derivatives of morphine, such as heroin (the use of which is illegal in the United States); and synthetic drugs such as meperidine and propoxyphene hydrochloride. Narcotics relieve pain by acting on specific structures, called receptors, located on the nerve cells of the spinal cord or brain. Non-narcotic analgesics such as aspirin, acetaminophen, and ibuprofen reduce pain by inhibiting the formation of nerve impulses at the site of pain. Some of these drugs can also reduce fever and inflammation. General anesthetics, used for surgery or painful procedures, depress brain activity, causing a loss of sensation throughout the body and unconsciousness. Local anesthetics are directly applied to or injected in a specific area of the body, causing a loss of sensation without unconsciousness; they prevent nerves from transmitting impulses signaling pain (see Anesthesia). F Anticancer Drugs Anticancer drugs eliminate some cancers or reduce rapid growth and spread. These drugs do not affect all cancers but are specific for cancers in certain tissues or organs such as the bladder, brain, liver, or bones. Anticancer drugs interfere with specific cancer-cell components. For example, alkylating agents are cytotoxic (cellpoisoning) drugs that alter the DNA of cancer cells. Vinca alkaloids, chemicals produced by the periwinkle plant, prevent cancer cell division. G Other Drugs Many other categories of drugs also exist, such as anti-inflammatory, antiallergic, antiParkinson (see Parkinson Disease), antiworm (see Anthelmintic Drugs), diuretic, gastrointestinal, pulmonary, and muscle-relaxant drugs. Often a drug in one category can also be used for problems in other categories. For example, lidocaine can be used as a local anesthetic or as a cardiac drug. III HOW DRUGS MOVE THROUGH THE BODY The effect of a drug on the body depends on a number of processes that the drug undergoes as it moves through the body. All these processes together are known as pharmacokinetics (literally, "motion of the drug"). First in these processes is the administration of the drug after which it must be absorbed into the bloodstream. From the bloodstream, the drug is distributed throughout the body to various tissues and organs. As the drug is metabolized, or broken down and used by the body, it goes through chemical changes that produce metabolites, or altered forms of the drug, most of which have no effect on the body. Finally, the drug and its metabolites are eliminated from the body. A Administration Depending on the drug and its desired effect, there are a variety of administration methods. Most drugs are administered orally--that is, through the mouth. Only drugs that will not be destroyed by the digestive processes of the stomach or intestines can be given orally. Drugs can also be administered by injection into a vein (intravenously), which assures quick distribution through the bloodstream and a rapid effect; under the skin (subcutaneously) into the tissues, which results in localized action at a particular site as with local anesthetics; or into a muscle (intramuscularly), which enables rapid absorption through the many blood vessels found in muscles. An intramuscular injection may also be given as a depot preparation, in which the drug is combined with other substances so that it is slowly released into the blood. Inhaled drugs are designed to act in the nose or lungs. General anesthetics may be given through inhalation. Some drugs are administered through drug-filled patches that stick to the skin. The drug is slowly released from the patch and enters the body through the skin. Drugs may be administered topically--that is, applied directly to the skin; or rectally--absorbed through an enema (an injection of liquid into the rectum) or a rectal suppository (a pellet of medication that melts when inserted in the rectum). B Absorption Absorption is the transfer of a drug from its site of administration to the bloodstream. Drugs that are inhaled or injected enter the bloodstream more quickly than drugs taken orally. Oral drugs are absorbed by the stomach or small intestine and then passed through the liver before entering the bloodstream. C Distribution Distribution is the transport of a drug from the bloodstream to tissue sites where it will be effective, as well as to sites where the drug may be stored, metabolized, or eliminated from the body. Once a drug reaches its intended destination, the drug molecules move from blood through cellular barriers to various tissues. These barriers include the walls of blood vessels, the walls of the intestines, the walls of the kidneys, and the special barrier between the brain and the bloodstream that acts as a filtration system to protect the brain from exposure to potentially harmful substances. The drug molecules move from an area of high drug concentration--the bloodstream--to an area of low drug concentration--the tissues--until a balance between the two areas is reached. This process is known as diffusion. When a drug reaches its highest concentration in the tissues, the body begins to eliminate the drug and its effect on the body begins to diminish. The time it takes for the level of a drug to fall by 50 percent is known as the drug's half-life. Depending on the drug, this measurement can vary from a few minutes to hours or even days. For example, if a drug's highest concentration level in the blood is 1 mg/ml and this level falls to 0.5 mg/ml after five hours, the half-life of the drug is five hours. A drug's half-life is used to determine frequency of dosage and the amount of drug administered. Distribution of a drug may be delayed by the binding of the drug to proteins in the blood. Because the proteins are too large to pass through blood vessel walls, the drug remains in the blood for a longer period until it is eventually released from the proteins. While this process may increase the amount of time the drug is active in the body, it may decrease the amount of the drug available to the tissues. D Metabolism and Elimination While circulating through the body, a drug undergoes chemical changes as it is broken down in a process called metabolism, or biotransformation. Most of these changes occur in the liver, but they can take place in other tissues as well. Various enzymes oxidize (add oxygen to), reduce (remove oxygen from), or hydrolyze (add water to) the drug. These changes produce new chemicals or metabolites that may continue to be medically active in the body or may have no activity at all. A drug may be broken down into many different metabolites. Eventually, most drugs or their metabolites circulate through the kidney, where they are discharged, or eliminated, into the urine. Drugs can also be excreted in the body's solid waste products, or evaporated through perspiration or the breath. E Dose-Response Relationship The extent of the body's response to a drug depends on the amount administered, called the dose. At a low dose, no response may be apparent. A higher dose, however, may produce the desired effect. An even higher dose may produce an undesirable or harmful response. For example, to relieve a headache most adults require two tablets of aspirin. A half tablet may provide no relief from pain while ten tablets may cause burning pain in the stomach or nausea. The doses prescribed by physicians are those recommended by each drug's manufacturer to produce the best therapeutic, or medically beneficial, responses in the majority of patients. However, doses may need to be adjusted in certain individuals. For example, a person may be born without the enzyme required to metabolize a particular drug while other individuals may suffer from lung disorders that prevent them from absorbing inhaled drugs. Factors such as alcohol consumption, age, the method of drug administration, and whether or not the individual has taken the drug previously can affect an individual's response to a drug. F Receptors Drugs interact with cell receptors, small parts of proteins that control a multitude of chemical reactions and functions in the body. Receptors have a specific, chemical structure compatible only with certain drugs or endogenous compounds--substances that originate within the body such as hormones and neurotransmitters. This relationship can be compared to that of a lock and key: A drug molecule--the "key"--attaches briefly to its specific receptor--the "lock" that only this molecule can open. The lock-and-key combination of the drug and receptor results in a cascade of chemical events. The extent of the response is determined by the number of receptors activated. Stimulation of only a few receptors may not produce a response while stimulation of a certain number of receptors is needed to produce the desired effect. IV THERAPEUTIC RESPONSES AND ADVERSE REACTIONS The same receptors can be found in different tissues and organs in the body, but receptors produce different responses depending on their location. As a result, a specific drug can affect the body in more than one way. Desirable effects are called therapeutic or beneficial responses. Undesirable or harmful effects are called adverse reactions. Some adverse reactions, or side effects, can be predicted. The most common side effects are drowsiness, headache, sleeplessness, nausea, and diarrhea. Other reactions, such as those that occur only in specific individuals for unexpected reasons, called idiosyncratic reactions, and those that occur with the triggering of the body's immune system, called allergic reactions, are less predictable. Drug toxicity, or poisoning, can occur when drugs are given in too large a dose or when individuals take a particular drug over a long period of time--the drug may build up to dangerous levels in the kidneys and liver and damage these organs. For some drugs, such as those used to treat epilepsy, the difference between therapeutic and toxic concentrations is small. Physicians constantly monitor the precise levels of such drugs in an individual's bloodstream to prevent drug poisoning. Other drugs, such as those used to treat cancer, are known to have toxic effects; however, the benefits outweigh the risks--that is, treatment without them may result in death. A Drug Interactions When taken together, drugs can interact with one another and produce desirable or undesirable results. Some drugs have an additive effect--that is, they increase the effect of other drugs. For example, alcoholic beverages intensify the drowsiness-producing effect of some sedatives. Other drugs have a reducing effect--that is, they interfere with the action of drugs already present in the body. For example, antacids prevent antibiotics from being absorbed by the stomach. Some drugs combine with other drugs to create a substance that has no medical benefit. In some cases, however, drug interactions can produce desirable results. Doctors have found that using three drugs to fight AIDS is more effective than using one drug alone. Drugs are most effective when properly prescribed by physicians and taken correctly by patients. Missing doses, taking drugs at the wrong time of the day or with instead of before meals, and stopping drug use too soon can markedly reduce the medical benefits of many drugs. V DRUG ABUSE Drug abuse is characterized by taking more than the recommended dose of prescription drugs such as barbiturates without medical supervision, or using governmentcontrolled substances such as marijuana, cocaine, heroin, or other illegal substances. Legal substances, such as alcohol and nicotine, are also abused by many people. Abuse of drugs and other substances can lead to physical and psychological dependence (see Drug Dependence). Drug abuse can cause a wide variety of adverse physical reactions. Long-term drug use may damage the heart, liver, and brain. Drug abusers may suffer from malnutrition if they habitually forget to eat, cannot afford to buy food, or eat foods lacking the proper vitamins and minerals. Individuals who abuse injectable drugs risk contracting infections such as hepatitis and HIV from dirty needles or needles shared with other infected abusers. One of the most dangerous effects of illegal drug use is the potential for overdosing--that is, taking too large or too strong a dose for the body's systems to handle. A drug overdose may cause an individual to lose consciousness and to breathe inadequately. Without treatment, an individual may die from a drug overdose. Drug addiction is marked by a compulsive craving for a substance. Successful treatment methods vary and include psychological counseling, or psychotherapy, and detoxification programs--medically supervised programs that gradually wean an individual from a drug over a period of days or weeks. Detoxification and psychotherapy are often used together. The illegal use of drugs was once considered a problem unique to residents of poor, urban neighborhoods. Today, however, people from all economic levels, in both cities and suburbs, abuse drugs. Some people use drugs to relieve stress and to forget about their problems. Genetic factors may predispose other individuals to drug addiction. Environmental factors such as peer pressure, especially in young people, and the availability of drugs, also influence people to abuse drugs. VI HISTORY Humans have always experimented with substances derived from minerals, plants, and animal parts to treat pain, illness, and restore health. In ancient Egypt, physicians prescribed figs, dates, and castor oil as laxatives and used tannic acid to treat burns. The early Chinese and Greek pharmacies included opium, known for its pain-relieving qualities, while Hindus used the cannabis and henbane plants as anesthetics and the root of the plant Rauwolfia serpentina, which contains reserpine, as a tranquilizer. A school of pharmacy established in Arabia from 750 to 1258 AD discovered many substances effective against illness, such as burned sponge (which contains iodine) for the treatment of goiters--a noncancerous enlargement of the thyroid gland, visible as a swelling at the front of the neck. In Europe, the 15th century Swiss physician and chemist Philippus Aureolus Paracelsus identified the characteristics of numerous diseases such as syphilis, a chronic infectious disease usually transmitted in sexual intercourse, and used ingredients such as sulfur and mercury compounds to counter the diseases. During the 17th and 18th centuries, physicians treated malaria, a disease transmitted by the bite of an infected mosquito, with the bark of the cinchona tree (which contains quinine). Heart failure was treated with the leaves of the foxglove plant (which contains digitalis); scurvy, a disease caused by vitamin C deficiency, was treated with citrus fruit (which contains vitamin C); and smallpox was prevented using inoculations of cells infected with a similar viral disease known as cowpox. The therapy developed for smallpox stimulated the body's immune system, which defends against disease-causing agents, to produce cowpox- and smallpox-specific antibodies. In the 19th century scientists continued to discover new drugs including ether, morphine, and a vaccine for rabies, an infectious, often fatal, viral disease of mammals that attacks the central nervous system and is transmitted by the bite of infected animals. These substances, however, were limited to those occurring naturally in plants, minerals, and animals. A growing understanding of chemistry soon changed the way drugs were developed. Heroin and aspirin, two of the first synthetic drugs created from other elements or compounds using chemical reactions, were produced in the late 1800s. This development, combined with the establishment of a new discipline called pharmacology, the study of drugs and their actions on the body, signaled the birth of the modern drug industry. VII DRUG DEVELOPMENT Today most drugs are synthesized by chemists in the laboratory. Synthetic drugs are better controlled than those occurring naturally, which ensures that each dose imparts the same effect. Some new synthetic drugs are developed by modifying the structure of existing substances. These new drugs are called analogues. For example, prednisone is an analogue of the hormone cortisone (see Hydrocortisone). Because scientists can selectively alter the drug's structure, analogues may be more effective and cause fewer side effects than the drugs from which they were derived. One of the newer methods for developing drugs involves the use of gene splicing, or recombinant DNA (see Genetic Engineering). In drug research, this technique joins the DNA of a specific type of human cell to the DNA of a second organism, usually a harmless bacterium, to produce a recombinant (or "recombined") DNA. The altered organism then begins to produce the substance produced by the human cell. This substance is extracted from the bacteria and purified for use as a drug. The first drug produced in this manner was the hormone insulin in 1982, which was created in large quantities by inserting the human insulin gene in Escherichia coli (E. coli) bacteria. This recombinant insulin has largely replaced versions of the drug extracted from pig and cattle pancreases. Since 1982 other genetically engineered drugs for humans have been developed, including tissue plasminogen activator (tPA), an enzyme used to dissolve blood clots in people who have suffered heart attacks, and erythropoetin, a hormone used to stimulate the production of red blood cells in people with severe anemia. Because of the great expense and time involved, most new drugs are created by large, well-funded pharmaceutical companies. From idea to production, the development of a new drug can take up to ten years and cost about $200 million. The process usually starts with the idea that an existing chemical substance has therapeutic value or that the structure of an existing drug can be modified for new clinical uses. Out of 10,000 chemicals tested in a laboratory, only one may eventually become a drug. Once drug researchers have determined that a new substance may have medical value, an elaborate testing program begins. The drug is tested first on small animals such as rats and mice, and then on larger animals such as monkeys and dogs. If these tests indicate that the new drug is effective against its intended target--such as a particular disease--and shows an acceptably low level of toxicity, the drug company requests government permission to test the drug in humans. In the United States, the Food and Drug Administration (FDA), an agency of the U.S. Department of Health and Human Services, grants or denies these requests. If the agency approves the request, clinical trials on humans can begin. These experiments are usually divided into three phases, each of which can last from several months to several years. In the first phase, the drug is tested on a small number of healthy individuals to determine its effect on the body. The second phase tests the drug on a small number of people who have the disease or disorder the drug manufacturer hopes the drug will treat. These individuals are divided into two groups: those who receive the drug and those who receive a placebo, or inactive compound. Neither the investigating physicians nor the members of the test group know who is receiving the drug or who is receiving the placebo. This technique, called a double-blind study, ensures that no one consciously or unconsciously influence the drug's effect. The third phase tests the drug on a much larger group of people and determines specific doses, possible interactions with other drugs, responses related to gender, and other information used for drug labeling. At the end of the third phase, a drug manufacturer compiles the results of the clinical trials and submits them to the FDA in a new product application. If the drug has been proven effective and safe, and its benefits outweigh any risks, the agency approves the drug for marketing. FDA approval of a new drug may take up to 18 months; however, the agency is working to reduce the time to 12 months for most drugs and 6 months for highly effective drugs that treat previously incurable conditions. VIII DRUG REGULATION Because drugs can produce harmful effects when manufactured or taken improperly, most governments control drug development as well as availability. In the United States, the FDA determines how drugs are produced and how they are sold. Drugs that can be sold over the counter (OTC)--that is, without a prescription from a physician--are called proprietary drugs. They are considered safe for unsupervised use by the general population. Drugs that must be prescribed by physicians and dispensed by pharmacists are known as ethical drugs. Their use is monitored closely by medical personnel. The FDA regulates the sale and manufacture of drugs in the United States as outlined in applicable laws enacted over the past century. Legal standards for composition and preparation of drugs in the United States are found in the publication known as the United States Pharmacopeia (USP). Drugs that can be abused, such as the powerful narcotic heroin, are regulated by the Drug Enforcement Administration (DEA) of the U.S. Department of Justice to ensure that they are not prescribed or sold illegally. Before 1900 any individual could sell a drug and claim it offered therapeutic benefits without medical proof. This changed after 1906 with the passage of the Pure Food and Drug Act, which required drug manufacturers to state the content, strength, and purity of each drug they produced. The Pure Food and Drug Act ended the practice of including morphine, cocaine, and heroin in drugs without the public's knowledge. In 1914 the U.S. legislature began to strictly regulate the trade of narcotics with the enactment of the Harrison Narcotic Act; in 1937 the government added marijuana to this list of controlled substances (the Marijuana Tax Act). The Federal Food, Drug, and Cosmetic Act was enacted in 1938 requiring that new drugs be safe for humans; however, it did not require that manufacturers prove their drugs' effectiveness. It would be 24 years before legislation was passed that would require proof of the efficacy of new drugs (the Kefaver-Harris Amendments, 1962). Enforcement of this law was entrusted to the FDA. Two laws enacted in the 1960s strengthened the FDA's efforts to reduce drug abuse. The Drug Abuse Control Amendments of 1965 provided penalties for the illegal sale or possession of stimulants, sedatives, and hallucinogens, and the Narcotic Addict Rehabilitation Act of 1966 set up a federal program for addicts that provided them with the option of receiving treatment for their drug problems in place of a prison sentence. In 1970 the Comprehensive Drug Abuse Prevention and Control Act established rules for manufacturing and prescribing habit-forming drugs. It stipulated that physicians can prescribe all drugs, but a special license is required to prescribe drugs with a high abuse potential. This license is issued by the Drug Enforcement Administration. The Anti-Drug Abuse Acts, signed into law in 1986 and 1988, set up funding for the treatment of drug abuse and for the creation of law-enforcement programs to fight the illegal sale of drugs. These acts also detailed severe punishments for individuals selling and possessing drugs illegally. Harsh penalties for using anabolic steroids (hormones that promote the storage of protein and the growth of tissue that are sometimes abused by competitive athletes) were included in the 1988 act, along with the requirement that all alcoholic beverages be labeled with warnings about alcohol's potentially dangerous effect on the body. The 1988 act also established the Office of National Drug Control Policy to develop an action plan that would involve the public, as well as private agencies, in eliminating the illegal sale of drugs; in helping individuals who use drugs to stop; and in preventing nonusers from ever starting to use drugs. The U.S. government and its regulatory agencies continually monitor the development and use of all drugs sold in the United States to ensure that the American public has access only to drugs that are safe and effective. Sometimes, adverse reactions to a drug come to light after it has been approved by the FDA and used by large numbers of patients. For example, the analgesic Vioxx was approved in 1999, but in 2004 the FDA asked the drug's maker to remove it from the market because it had been linked to heart attacks and strokes. Microsoft ® Encarta ® 2009. © 1993-2008 Microsoft Corporation. All rights reserved.