by ram chowdary

Narcotic

From Wikipedia, the free encyclopedia

ads not by this site

This article is about the drug classification. For the scuba diving reference, see Nitrogen narcosis. For the sedative agent, see Sedative. For pain control medications of both narcotic and non-narcotic varieties, see Analgesic. For the album by Muslimgauze, see Narcotic (album).

Heroin, a powerful opioid and narcotic.

The term narcotic , from ancient Greek ναρκῶ narkō, “Ι benumb”) originally referred medically to any psychoactive compound with any sleep-inducing properties. In the United States of America it has since become associated with opioids, commonly morphine and heroin and their derivatives, such as hydrocodone. The term is, today, imprecisely defined and typically has negative connotations. When used in a legal context in the US, a narcoticdrug is simply one that is totally prohibited, or one that is used in violation of strict governmental regulation, such as heroin or morphine.

From a pharmacological standpoint it is not a useful term, as is evidenced by the historically varied usage of the word.

“	Alcohol is the principle that gives to ardent spirit and wine their intoxicating power; while the narcotic principle to opium and tobacco imparts similar properties. In popular language, alcohol is classed among the stimulants; and opium and tobacco among the narcotics; which are substances whose ultimate effect upon the animal system is to produce torpor and insensibility; but taken in small quantities they at first exhilarate. And since alcohol does the same, most medical writers, at the present day, class it among the narcotics.	”
—Edward Hitchcock, American Temperance Society (1830)[4]

Statutory classification of a drug as a narcotic often increases the penalties for violation of drug control statutes. For example, although federal law classifies bothcocaine and amphetamines as "Schedule II" drugs, the penalty for possession of cocaine is greater than the penalty for possession of amphetamines because cocaine, unlike amphetamines, is classified as a narcotic.

[edit]
Single Convention on Narcotic Drugs, 1961United Nations

[edit]

The adoption of this Convention is regarded as a milestone in the history of international drug control. The Single Convention codified all existing multilateral treaties on drug control and extended the existing control systems to include the cultivation of plants that were grown as the raw material of narcotic drugs. The principal objectives of the Convention are to limit the possession, use, trade in, distribution, import, export, manufacture and production of drugs exclusively to medical and scientific purposes and to address drug trafficking through international cooperation to deter and discourage drug traffickers. The Convention also established the International Narcotics Control Board, merging the Permanent Central Board and the Drug Supervisory Board.^[6]

The 1961 Convention exercises control over more than 116 narcotic drugs. They include mainly plant-based products such as opium and its derivatives morphine, codeine and heroin, but also synthetic narcotics such as methadone and pethidine, as well as cannabis, coca and cocaine. The Convention divides drugs into four groups, or schedules, in order to enforce a greater or lesser degree of control for the various substances and compounds. Opium smoking and eating, coca leaf chewing, cannabis resin smoking and the non-medical use of cannabis are prohibited. The 1972 Protocol to this Convention calls for increased efforts to prevent illicit production of, traffic in and use of narcotics. It also highlights the need to provide treatment and rehabilitation services to drug abusers.^[7]

[edit]INCB Yellow List

This document contains the current list of narcotic drugs under international control and additional information to assist governments in filling in the International Narcotics Control Board questionnaires related to narcotic drugs, namely, form A, form B and form C.

[edit]UNODC terminology and information on drugs

narcotic drug

In medicine, a chemical agent that induces stupor, coma, or insensibility to pain (also called narcotic analgesic).

In the context of international drug control, “narcotic drug” means any drug defined as such under the 1961 Convention.^[9]

[edit]World Health Organization

[edit]Studies on the definition of counterfeit medicines in WHO member states

4. Assessment of the definitions of counterfeit medicines (or equivalent) in Member States

4.2 The nature of legal definitions: the unambiguity requirement

In order to avoid room for difference in interpretation, law-makers (codificators) sometimes deviate from etymological (definiendum plus definientia) definitions. In doing so, they approach the term from the law enforcement point of view. The best example is the definition of narcotics in the United Nations Conventions. Narcotics are substances and preparations that induce drowsiness, sleep, stupor, insensibility, etc., and that these effects (and their rate) are complicated to prove, e.g. during litigation. Thus, the legal definition of a narcotic is whether or not it is listed on the Schedules of the Convention. If it is on some of the Schedules, it is narcotic.

[edit]Lexicon of alcohol and drug terms published by the World Health Organization

narcotic

A chemical agent that induces stupor, coma, or insensibility to pain. The term usually refers to opiates or opioids, which are called narcotic analgesics. In common parlance and legal usage, it is often used imprecisely to mean illicit drugs, irrespective of their pharmacology. For example, narcotics control legislation in Canada, USA, and certain other countries includes cocaine and cannabis as well as opioids (see also conventions, international drug). Because of this variation in usage, the term is best replaced by one with a more specific meaning (e.g. opioid).^[11]

[edit]United States Code of Federal Regulations

Section 1300.01 Definitions relating to controlled substances.

(b) As used in parts 1301 through 1308 and part 1312 of this chapter, the following terms shall have the meanings specified:

(30) The term narcotic drug means any of the following whether produced directly or indirectly by extraction from substances of vegetable origin or independently by means of chemical synthesis or by a combination of extraction and chemical synthesis:

(i) Opium, opiates, derivatives of opium and opiates, including their isomers, esters, ethers, salts, and salts of isomers, esters, and ethers whenever the existence of such isomers, esters, ethers and salts is possible within the specific chemical designation. Such term does not include the isoquinoline alkaloids of opium.

(ii) Poppy straw and concentrate of poppy straw.

(iii) Coca leaves, except coca leaves and extracts of coca leaves from which cocaine, ecgonine and derivatives of ecgonine or their salts have been removed.

(iv) Cocaine, its salts, optical and geometric isomers, and salts of isomers.

(v) Ecgonine, its derivatives, their salts, isomers and salts of isomers.

(vi) Any compound, mixture, or preparation which contains any quantity of any of the substances referred to in paragraphs (b)(31)(i) through (v) of this section.^[12]

A 1984 amendment to 21 USC (Controlled Substances Act), Section 802 expanded and revised definition of "narcotic drug", including within term poppy straw, cocaine, and ecgonine.^[13]

[edit]US v Stieren

608 F.2d 1135

United States Court of Appeals, Eighth Circuit. Decided Oct. 31, 1979. LAY, Circuit Judge.

John Arthur Stieren appeals from the judgment of conviction for possession of cocaine with intent to distribute and dispense under 21 U.S.C. § 841(a)(1). Stieren contends that the statute is unconstitutional because "cocaine is classified as a narcotic under Schedule II of 21 U.S.C. § 812(c), when as a matter of scientific and medical fact cocaine is not a narcotic but is a non-narcotic stimulant."

The sufficiency of the evidence is not disputed. Stieren was convicted after special agents testified that he was in possession of and attempted to sell them a large quantity of cocaine. Defendant urges that the testimony and reports by physicians and scientists demonstrate that cocaine is not a narcotic. He also cites cases which hold that cocaine is not a narcotic under the pharmacological definition of the term. State v. Erickson, 574 P.2d 1 (Alaska 1978).

It is within the legislative prerogative to classify cocaine, which is a non-narcotic central nervous system stimulant, as a narcotic for penalty and regulatory purposes. 21 U.S.C. § 802(16)(A). The use of cocaine poses serious problems for the community and has a high potential for abuse. Congress' choice of penalty reflects a societal policy which must be adhered to by the courts.2 Congress has the power to reclassify cocaine. This power has been delegated to the Attorney General. 21 U.S.C. § 811(a)(1). If cocaine is to be reclassified, defendant's arguments should be made to the legislative branch, not the courts.

We hold that Congress had a rational legislative purpose when it classified cocaine as a Schedule II narcotic drug for the purpose of imposing penalties.

JUDGMENT AFFIRMED.

[edit]History

The term "narcotic" is believed to have been coined by the Greek physician Galen to refer to agents that numb 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 numbing or the numbed state. Galen listed mandrake root, altercus (eclata).^[15] seeds, and poppy juice (opium) as the chief examples.It originally referred to any substance that relieved pain, dulled the senses, or induced sleep. Now, the term is used in a number of ways. Some people define narcotics as substances that bind atopioid receptors (cellular membrane proteins activated by substances like heroin or morphine) while others refer to any illicit substance as a narcotic. From a legal perspective, narcotic refers to opium, opium derivatives, and their semi-synthetic substitutes. Though in U.S. law, due to its numbing properties, cocaine is also considered a narcotic.

Sense of "any illegal drug" first recorded 1926, Amer.Eng. The adj. is first attested c.1600.

[edit]Non-narcotic

Main article: non-narcotic

Analgesics: Drugs that relieve pain. There are two main types: non-narcotic analgesics for mild pain, and narcotic analgesics for severe pain.

by ranco group of pharmacyyyyyyyyyyy

Pencillin

Penicillin core structure, where "R" is the variable group.

Penicillin (sometimes abbreviated PCN or pen) is a group of antibiotics derived from Penicillium fungi.^[1] They include penicillin G, procaine penicillin,benzathine penicillin, and penicillin V. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis, and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are β-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.

[edit]
The term "penicillin" is often used generically to refer to benzylpenicillin (penicillin G), procaine benzylpenicillin (procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), andphenoxymethylpenicillin (penicillin V).Medical uses

Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period. Phenoxymethylpenicillin is less active against Gram-negative bacteria than benzylpenicillin.^[2][3] Benzylpenicillin, procaine penicillin and benzathine penicillin are given by injection (parenterally), but phenoxymethylpenicillin is given orally.

[edit]Adverse effects

Main article: Penicillin drug reaction

Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (includingcandidiasis). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and pseudomembranous colitis.^[4]

[edit]Mechanism of action

Main article: Beta-lactam antibiotic

Penicillin and other β-lactam antibiotics act by inhibitingpenicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.

Bacteria that attempt to divide in the presence of penicillin fail to do so and end up shedding their cell walls in the process.

Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, but have no direct effect on cell wall degradation. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due to osmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the bacteria's existing peptidoglycan. This imbalance between cell wall production and degradation is responsible for the rapid cell-killing action of this class of drugs, even in the absence of cell division. In addition, the relatively small size of the penicillin molecule allows it to penetrate deeply into the cell wall, affecting its entire depth. This is in contrast to the other major class of anitbiotics that inhibit cell wall synthesis, the glycopeptide antibiotics (which includes vancomycin and teicoplanin).

Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplastsafter treatment with penicillin.^{[citation needed]}

Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.

Penicillins, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosyntheticorganelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants.^[5]

[edit]Structure

Chemical structure of Penicillin G

Penicillin core structure, in 3D. Purple areas are variable groups.

The term "penam" is used to describe the core skeleton of a member of the penicillin antibiotics. This skeleton has the molecular formula R-C₉H₁₁N₂O₄S, where R is a variable side chain.

Normal penicillin has a molecular weight of 313^[6] to 334^[7][8] g/mol (latter for penicillin G). Penicillin types with additional molecular groups attached may have a molar mass around 500 g/mol. For example, cloxacillin has a molar mass of 476 g/mol and dicloxacillin has a molar mass of 492 g/mol.^[9]

[edit]Biosynthesis

Penicillin biosynthesis

Overall, there are three main and important steps to the biosynthesis of penicillin G (benzylpenicillin).

• The first step is the condensation of three amino acids — L-α-aminoadipic acid, L-cysteine, L-valine into a tripeptide.^[10][11][12] Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine.^[13][14] The condensed tripeptide is named δ-(L-α-aminoadipyl)-L-cysteine-D-valine (ACV). The condensation reaction and epimerization are both catalyzed by the enzyme δ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase (ACVS), anonribosomal peptide synthetase or NRPS.
• The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which is encoded by the gene pcbC.^[10][11] Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.^[13]
• The final step is an transamidation by isopenicillin N N-acyltransferase, in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for aphenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.^[10]

[edit]Production

Penicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin.

α-ketoglutarate + AcCoA → homocitrate → L-α-aminoadipic acid → L-lysine + β-lactam

The by-product, l-lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production.

The Penicillium cells are grown using a technique called fed-batch culture, in which the cells are constantly subject to stress, which is required for induction of penicillin production. The available carbon sources are also important: Glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled.

The biotechnological method of directed evolution has been applied to produce by mutation a large number of Penicillium strains. These techniques include error-prone PCR, DNA shuffling, ITCHY, and strand-overlap PCR.

Semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.

History

[edit]Discovery

Main article: History of penicillin

The discovery of penicillin is attributed to Scottish scientist and Nobel laureate Alexander Fleming in 1928.^[15] He showed that, if Penicillium notatum were grown in the appropriate substrate, it would exude a substance with antibiotic properties, which he dubbed penicillin. This serendipitous observation began the modern era of antibiotic discovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate Howard Walter Florey, together with the German Nobel laureate Ernst Chain and the English biochemist Norman Heatley.

However, several others reported the bacteriostatic effects of Penicillium earlier than Fleming. The use of bread with a blue mould (presumed to be Penicillium) as a means of treating suppurating wounds was a staple of folk medicine in Europe since the Middle Ages.^{[citation needed]}

The first published reference appears in the publication of the Royal Society in 1875, by John Tyndall.^[16] Joaquim Monteiro Caminhoá, Professor of Botany and Zoology of the Faculty of Medicine of Rio de Janeiro, Brazil, also recognised the antibiotic activity of Penicillium and other fungi in 1877. In his book, "Elements of General and Medical Botany" (under a section titled 'Useful fungi, harmful and curious'), he stated:

O bolor (Penicillium infestans, Penicillium glaucum, fig 1680, Ascophora e tantos outros) é util porque nutre-se decompondo e destruindo as materias organicas em putrefacção, e de modo que o cheiro infecto não se produz, em via de regra, ou produz-se em proporções infinitamente menores. [Translation: "The mould (Penicillium infestans, Penicillium glaucum, figure 1680, Ascophora and many others) is useful because it feeds on decaying organic matter and destroys putrifaction so that, as a rule, the odour of infection does not occur, or is produced in infinitely smaller amounts."]^[17]

In 1895, Vincenzo Tiberio, physician of the University of Naples published a research about a mold ( Penicillium ) in a water well that had a antibacterial action.^[18][19]

Ernest Duchesne documented it in an 1897 paper, which was not accepted by the Institut Pasteur because of his youth. In March 2000, doctors at the San Juan de Dios Hospital in San José, Costa Rica, published the manuscripts of the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight(1887–1944). They reported Picado's observations on the inhibitory actions of fungi of the genus Penicillium between 1915 and 1927. Picado reported his discovery to the Paris Academy of Sciences, yet did not patent it, even though his investigations started years before Fleming's. Joseph Lister was experimenting with Penicillum in 1871 for his aseptic surgery. He found that it weakened the microbes, but then he dismissed the fungi.

These early investigations did not lead to the use of antibiotics to treat infection because they took place in obscure circumstances, and the idea that infections were caused by transmissible agents was not widely accepted at the time. Sterilization measures had been shown to limit the outbreak and spread of disease; however, the mechanism of transmission of disease by parasites, bacteria, viruses and other agents was unknown. In the late 19th century, there was increasing knowledge of the mechanisms by which living organisms become infected, how they manage infection once it has begun and, most importantly in the case of penicillin, the effect that natural and man-made agents could have on the progress of infection.

Fleming recounted that the date of his discovery of penicillin was on the morning of Friday, September 28, 1928.^[20] It was a fortuitous accident: in his laboratory in the basement of St. Mary's Hospital in London (now part of Imperial College), Fleming noticed a Petri dish containing Staphylococcus plate culture he mistakenly left open, was contaminated by blue-green mould, which formed a visible growth. There was a halo of inhibited bacterial growth around the mould. Fleming concluded that the mould released a substance that repressed the growth and lysing the bacteria. He grew a pure culture and discovered it was a Penicillium mould, now known to be Penicillium notatum. Charles Thom, an American specialist working at the U.S. Department of Agriculture, was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mould. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, and noted its laboratory value in the isolation of Bacillus influenzae (now Haemophilus influenzae).^[21] After further experiments, Fleming was convinced penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying it after 1931. He restarted clinical trials in 1934, and continued to try to get someone to purify it until 1940.^[22]

[edit]Medical application

Florey (pictured), Fleming and Chain shared a Nobel Prize in 1945 for their work on penicillin.

In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to use penicillin to treat sycosis barbae, eruptions in beard follicles, but was unsuccessful, probably because the drug did not penetrate the skin deeply enough. Moving on to ophthalmia neonatorum, a gonococcal infection in infants, he achieved the first recorded cure with penicillin, on November 25, 1930. He then cured four additional patients (one adult and three infants) of eye infections, failing to cure a fifth.^[23]

In 1939, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Boris Chain, Arthur Duncan Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed because of insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved it harmless and effective on mice.^[24]

Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford, England. These trials continue to be cited by some sources as the first cures using penicillin, though the Paine trials took place earlier.^[23] On March 14, 1942, John Bumstead and Orvan Hess saved a dying patient's life using penicillin.^[25][26]

[edit]Mass production

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945^{[chronology citation needed]}. Penicillin has since become the most widely used antibiotic to date, and is still used for many Gram-positive bacterial infections. A team of Oxford research scientists led by Australian Howard Florey and including Ernst Boris Chain and Norman Heatley devised a method of mass-producing the drug. Florey and Chain shared the 1945 Nobel Prize in Medicine with Fleming for their work. After World War II, Australia was the first country to make the drug available for civilian use. Chemist John C. Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production.

The challenge of mass-producing this drug was daunting. On March 14, 1942, the first patient was treated for streptococcal septicemia with U.S.-made penicillin produced by Merck & Co.^[27] Half of the total supply produced at the time was used on that one patient. By June 1942, there was just enough U.S. penicillin available to treat ten patients.^[28] In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe.^[29] A mouldy cantaloupe in a Peoria, Illinois, market in 1943 was found to contain the best and highest-quality penicillin after a worldwide search.^[30] The discovery of the cantaloupe, and the results of fermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. Large-scale production resulted from the development of deep-tank fermentation by chemical engineer Margaret Hutchinson Rousseau.^[31] As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.^[29]

Penicillin was being mass-produced in 1944.

G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin.^[32] During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%–15% of lives.^{[citation needed]} Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug, necessitating frequent dosing. Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration. Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused.^[33] This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.^[33] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.^[4]

[edit]Unethical experimentation

In a 1946 to 1948 study in Guatemala, U.S. researchers used prostitutes to infect prison inmates, insane asylum patients, and Guatemalan soldiers with syphilis and other sexually transmitted diseases (STDs), to test the effectiveness of penicillin in treating such diseases. They later tried infecting people with "direct inoculations made from syphilis bacteria poured into the men's penises and on forearms and faces that were slightly abraded ... or in a few cases through spinal punctures".^[34] Approximately 1300 people were infected as part of the study (including orphaned children). The study was sponsored by the Public Health Service, the National Institutes of Health and the Pan American Health Sanitary Bureau (now the World Health Organization's Pan American Health Organization) and the Guatemalan government. The team was led by John Charles Cutler, who later participated in the Tuskegee syphilis experiments. Cutler chose to do the study in Guatemala because he would not have been permitted to do it in the United States.^{[35][36][37][38]} The Presidential Commission for the Study of Bioethical Issues determined that 83 people died; however, it was not possible to determine whether the experiments were the direct cause of death. ^[39]

[edit]Developments from penicillin

The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin(bioavailability, spectrum, stability, tolerance).

The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, includingflucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus (MRSA) strains that subsequently emerged.

Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most important, the cephalosporins, still retain it at the center of their structures.^[40]