Prodrug

A prodrug is a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into an active metabolite. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion (ADME) optimization. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor.
Additionally, the use of a prodrug strategy increases the selectivity of the drug for its intended target. An example of this can be seen in many chemotherapy treatments, in which the reduction of adverse effects is always of paramount importance. Drugs used to target hypoxic cancer cells, through the use of redox-activation, utilise the large quantities of reductase enzyme present in the hypoxic cell to convert the drug into its cytotoxic form, essentially activating it. As the prodrug has low cytotoxicity prior to this activation, there is a markedly lower chance of it "attacking" healthy, non-cancerous cells which reduces the side-effects associated with these chemotherapeutic agents.
In rational drug design, the knowledge of chemical properties likely to improve absorption and the major metabolic pathways in the body allows the modification of the structure of new chemical entities for improved bioavailability. Sometimes the use of a prodrug is unintentional, however, especially in the case of serendipitous drug discoveries, and the drug is only identified as a prodrug after extensive drug metabolism studies.

Generic drug

A generic drug (generic drugs, short: generics) is a drug which is produced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredient.
A generic must contain the same active ingredients as the original formulation. According to the U.S. Food and Drug Administration (FDA), generic drugs are identical or within an acceptable bioequivalent range to the brand name counterpart with respect to pharmacokinetic and pharmacodynamic properties. By extension, therefore, generics are considered (by the FDA) identical in dose, strength, route of administration, safety, efficacy, and intended use. The FDA's use of the word identical is very much a legal interpretation, and is not literal. In most cases, generic products are available once the patent protections afforded to the original developer have expired. When generic products become available, the market competition often leads to substantially lower prices for both the original brand name product and the generic forms. The time it takes a generic drug to appear on the market varies. In the US, drug patents give twenty years of protection, but they are applied for before clinical trials begin, so the effective life of a drug patent tends to be between seven and twelve years.

Narcotic

The term narcotic (ναρκωτικός) is believed to have been coined by the Greek physician Galen to refer to agents that benumb or deaden, causing loss of feeling or paralysis. It is based on the Greek word ναρκωσις (narcosis), the term used by Hippocrates for the process of benumbing or the benumbed state. Galen listed mandrake root, altercus (eclata) seeds, and poppy juice (opium) as the chief examples.
Use of the word "narcotic" to refer to any illegal or unlawfully possessed drug including marijuana and cocaine is common worldwide, although these substances are not considered narcotics in a medical context. The central drug policy making body within the United Nations, for instance, is the Commission on Narcotic Drugs, although the United Nations officially defines a narcotic drug to be "any of the substances, natural or synthetic, in Schedules I and II of the Single Convention on Narcotic Drugs, 1961, and that Convention as amended by the 1972 Protocol Amending the Single Convention on Narcotic Drugs, 1961"
In U.S. legal context, the term "narcotic" specifically refers to opium, opium derivatives, and their semi-synthetic or fully synthetic substitutes as well as cocaine and coca leaves.
Because the term is often used so broadly or pejoratively outside of medical contexts, most medical professionals advocate the use of more precise terms such as "opioid" and "opioid analgesic" to refer to the natural, semi-synthetic, and synthetic substances that behave pharmacologically like morphine and are used primarily for their pain-relieving qualities. The use of the term "narcotic" in various nonclinical contexts is not of educational or of informative value. The decision to term all illegal drugs as narcotics is often used as a shorthand way to politicize and demonize any illegal drug.

Bextra Alert – Bextra Has Been Recalled

Bextra, the drug chemically known as valdecoxib, is a COX-2 Inhibitor drug used primarily to alleviate the painful inflammation common to many forms of arthritis. Like similar medications Vioxx and Celebrex, it is designed to reduce pain, swelling, and fever without irritating the stomach and lower digestive tract like aspirin and other NSAIDs (Non-Steroidal Anti-Inflammatory Drugs).
NSAIDs work by effectively blocking a chemical in the body called cyclooxygenase, of which there are two main derivatives. Cyclooxygenase-1, or COX-1, shields the stomach from the harsh hydrochloric acid it contains, and Cyclooxygenase-2, or COX-2, is found in inflamed tissues and causes the pain of fever, infection, and arthritis. The drugs were effective for alleviating the pain and inflammation but the relief benefits were limited because the traditional NSAIDs caused stomach irritation. Taking an NSAID like aspirin caused discomfort because it blocked both chemicals, relieving pain but also disabling the stomach protection of COX-1.

FDA issues warnings about more pain relievers

The U.S. Food & Drug Administration said yesterday that warnings about heart or stomach risks must be placed on all pain relievers in a class called “non-steroidal anti-inflammatory drugs.” It excluded aspirin and acetaminophen, which is sold under the brand name Tylenol.
Chemical name / Brand name
Celecoxib / Celebrex
Valdecoxib / Bextra
Rofecoxib / Vioxx
Diclofenac / Cataflam, Voltaren, Arthrotec (combination with misoprostol)/Diflunisal / Dolobid
Etodolac / Lodine, Lodine XL
Fenoprofen / Nalfon Nalfon 200
Flurbiprofen / Ansaid
Ibuprofen / Motrin, Motrin IB, Motrin Migraine Pain, Advil, Advil Migraine
Liqui-gels, Ibu-Tab 200, Medipren, Cap-Profen, Tab-Profen, Profen, Ibuprohm, Children’s Elixsure, Vicoprofen (combination with hydrocodone), Combunox (combination with oxycodone)

Side-effects and withdrawal from market

On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA, citing an increased risk of heart attack and stroke and also the risk of a serious, sometimes fatal, skin reaction. This was a result of recent attention to prescription NSAIDs, such as Merck's Vioxx. Other reported side-effects were angina and Stevens-Johnson syndrome.
Pfizer first acknowledged cardiovascular risks associated with Bextra in October 2004. The American Heart Association soon after was presented with a report indicating patients using Bextra while recovering from heart surgery were 2.19 times more likely to suffer a stroke or heart attack than those taking placebos.
Recently in a large study published in JAMA 2006, valdecoxib appears less adverse for renal (kidney) disease and heart arrhythmia compared to Vioxx, however elevated renal risks were slightly suggested.

Cyclooxygenase 2 inhibitors: drug discovery and development

Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s). Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the procursor of a variety of prostanoids with diverse and potent biological actions. Cyclooxygenases have two main isoforms that are called COX-1 and COX-2 (as well as a COX-3). COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.

Off-label Settlement

On September 2, 2009, the United States Department of Justice fined Pfizer $2.3 billion after one of its subsidiaries, Pharmacia & UpJohn Company, pled guilty to marketing four drugs including Bextra "with the intent to defraud or mislead." Pharmacia & UpJohn admitted to criminal conduct in the promotion of Bextra, and agreed to pay the largest criminal fine every imposed in the United States for any matter, $1.195 billion. A former Pfizer district sales manager was indicted and sentenced to home confinement for destroying documents regarding the illegal promotion of Bextra. In addition, a Regional Manager pled guilty to distribution of a mis-branded product, and was fined $75,000 and twenty-four months on probation.
The remaining $1 billion dollars of the fine was paid to resolve allegations under the civil False Claims Act case and is the largest civil fraud settlement against a pharmaceutical company. Six whistle-blowers were awarded more than $102 million for their role in the investigation. Former Pfizer sales representative John Kopchinski acted as a qui tam relator and filed a complaint in 2004 outlining the illegal conduct in the marketing of Bextra. Kopchinski was awarded $51.5 million for his role in the case because the improper marketing of Bextra was the largest piece of the settlement at $1.8 billion.