<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Human chorionic gonadotropin and can you explain it in depth? [/INST] Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation. The presence of hCG is detected in some pregnancy tests (HCG pregnancy strip tests). Some cancerous tumors produce this hormone; therefore, elevated levels measured when the patient is not pregnant may lead to a cancer diagnosis and, if high enough, paraneoplastic syndromes, however, it is not known whether this production is a contributing cause, or an effect of carcinogenesis. The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary gland of males and females of all ages.Various endogenous forms of hCG exist. The measurement of these diverse forms is used in the diagnosis of pregnancy and a variety of disease states. Preparations of hCG from various sources have also been used therapeutically, by both medicine and quackery. As of December 6, 2011, the United States Food and Drug Administration has prohibited the sale of "homeopathic" and over-the-counter hCG diet products and declared them fraudulent and illegal.Beta-hCG is initially secreted by the syncytiotrophoblast.

Structure
Human chorionic gonadotropin is a glycoprotein composed of 237 amino acids with a molecular mass of 36.7 kDa, approximately 14.5kDa αhCG and 22.2kDa βhCG.It is heterodimeric, with an α (alpha) subunit identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and β (beta) subunit that is unique to hCG.

The α (alpha) subunit is 92 amino acids long.
The β-subunit of hCG gonadotropin (beta-hCG) contains 145 amino acids, encoded by six highly homologous genes that are arranged in tandem and inverted pairs on chromosome 19q13.3 - CGB (1, 2, 3, 5, 7, 8). It is known that CGB7 has a sequence slightly different from that of the others.The two subunits create a small hydrophobic core surrounded by a high surface area-to-volume ratio: 2.8 times that of a sphere.  The vast majority of the outer amino acids are hydrophilic.beta-hCG is mostly similar to beta-LH, with the exception of a Carboxy Terminus Peptide (beta-CTP) containing four glycosylated serine residues that is responsible for hCGs longer half-life.

Function
Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum for the maternal recognition of pregnancy at the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus.It has been hypothesized that hCG may be a placental link for the development of local maternal immunotolerance. For example, hCG-treated endometrial cells induce an increase in T cell apoptosis (dissolution of T cells).  These results suggest that hCG may be a link in the development of peritrophoblastic immune tolerance, and may facilitate the trophoblast invasion, which is known to expedite fetal development in the endometrium. It has also been suggested that hCG levels are linked to the severity of morning sickness or Hyperemesis gravidarum in pregnant women.Because of its similarity to LH, hCG can also be used clinically to induce ovulation in the ovaries as well as testosterone production in the testes. As the most abundant biological source is in women who are presently pregnant, some organizations collect urine from pregnant women to extract hCG for use in fertility treatment.
Human chorionic gonadotropin also plays a role in cellular differentiation/proliferation and may activate apoptosis.

Production
Naturally, it is produced in the human placenta by the syncytiotrophoblast.
Like any other gonadotropins, it can be extracted from the urine of pregnant women or produced from cultures of genetically modified cells using recombinant DNA technology.
In Pubergen, Pregnyl, Follutein, Profasi, Choragon and Novarel, it is extracted from the urine of pregnant women. In Ovidrel, it is produced with recombinant DNA technology.

hCG forms
Three major forms of hCG are produced by humans, with each having distinct physiological roles. These include regular hCG, hyperglycosylated hCG, and the free beta-subunit of hCG. Degradation products of hCG have also been detected, including nicked hCG, hCG missing the C-terminal peptide from the beta-subunit, and free alpha-subunit, which has no known biological function. Some hCG is also made by the pituitary gland with a pattern of glycosylation that differs from placental forms of hCG.Regular hCG is the main form of hCG associated with the majority of pregnancy and in non-invasive molar pregnancies.  This is produced in the trophoblast cells of the placental tissue. Hyperglycosylated hCG is the main form of hCG during the implantation phase of pregnancy, with invasive molar pregnancies, and with choriocarcinoma.Gonadotropin preparations of hCG can be produced for pharmaceutical use from animal or synthetic sources. Some of these are medically justified, whereas others are of a quack nature.

Testing
Blood or urine tests measure hCG. These can be pregnancy tests. hCG-positive can indicate an implanted blastocyst and mammalian embryogenesis or can be detected for a short time following  childbirth or pregnancy loss. Tests can be done to diagnose and monitor germ cell tumors and gestational trophoblastic diseases.
Concentrations are commonly reported in thousandth international units per milliliter (mIU/mL). The international unit of hCG was originally established in 1938 and has been redefined in 1964 and in 1980. At the present time, 1 international unit is equal to approximately 2.35×10−12 moles, or about 6×10−8 grams.It is also possible to test for hCG to have an approximation of the gestational age.

Methodology
Most tests employ a monoclonal antibody, which is specific to the β-subunit of hCG (β-hCG). This procedure is employed to ensure that tests do not make false positives by confusing hCG with LH and FSH. (The latter two are always present at varying levels in the body, whereas the presence of hCG almost always indicates pregnancy.)
Many hCG immunoassays are based on the sandwich principle, which uses antibodies to hCG labeled with an enzyme or a conventional or luminescent dye.
Pregnancy urine dipstick tests are based on the lateral flow technique.

The urine test may be a chromatographic immunoassay or any of several other test formats, home-, physicians office-, or laboratory-based.  Published detection thresholds range from 20 to 100 mIU/mL, depending on the brand of test. Early in pregnancy, more accurate results may be obtained by using the first urine of the morning (when urine is most concentrated). When the urine is dilute (specific gravity less than 1.015), the hCG concentration may not be representative of the blood concentration, and the test may be falsely negative.
The serum test, using 2-4 mL of venous blood, is typically a chemiluminescent or fluorimetric immunoassay that can detect βhCG levels as low as 5 mIU/mL and allows quantification of the βhCG concentration.

Reference levels in normal pregnancy
The following is a list of serum hCG levels. (LMP is the last menstrual period dated from the first day of the last menstrual period.) The levels grow exponentially after conception and implantation.

Interpretation
The ability to quantitate the βhCG level is useful in monitoring germ cell and trophoblastic tumors, follow-up care after miscarriage, and diagnosis of and follow-up care after treatment of ectopic pregnancy. The lack of a visible fetus on vaginal ultrasound after βhCG levels reach 1500 mIU/mL is strongly indicative of an ectopic pregnancy. Still, even an hCG over 2000 IU/L does not necessarily exclude the presence of a viable intrauterine pregnancy in such cases.As pregnancy tests, quantitative blood tests and the most sensitive urine tests usually detect hCG between 6 and 12 days after ovulation. It must be taken into account, however, that total hCG levels may vary in a very wide range within the first 4 weeks of gestation, leading to false results during this period. A rise of 35% over 48 hours is proposed as the minimal rise consistent with a viable intrauterine pregnancy.Gestational trophoblastic disease like hydatidiform moles ("molar pregnancy") or choriocarcinoma may produce high levels of βhCG (due to the presence of syncytiotrophoblasts - part of the villi that make up the placenta) despite the absence of an embryo. This, as well as several other conditions, can lead to elevated hCG readings in the absence of pregnancy.
hCG levels are also a component of the triple test, a screening test for certain fetal chromosomal abnormalities/birth defects.
A study of 32 normal pregnancies came to the result that a gestational sac of 1–3 mm was detected at a mean hCG level of 1150 IU/L (range 800–1500), a yolk sac was detected at a mean level of 6000 IU/L (range 4500–7500) and fetal heartbeat was visible at a mean hCG level of 10,000 IU/L (range 8650–12,200).

Uses
Tumor marker
Human chorionic gonadotropin can be used as a tumor marker, as its β subunit is secreted by some cancers including seminoma, choriocarcinoma, germ cell tumors, hydatidiform mole, teratoma with elements of choriocarcinoma, and islet cell tumor. For this reason, a positive result in males can be a test for testicular cancer. The normal range for men is between 0-5 mIU/mL. Combined with alpha-fetoprotein, β-HCG is an excellent tumor marker for the monitoring of germ cell tumors.

Fertility
Human chorionic gonadotropin injection is extensively used for final maturation induction in lieu of luteinizing hormone. In the presence of one or more mature ovarian follicles, ovulation can be triggered by the administration of HCG. As ovulation will happen between 38 and 40 hours after a single HCG injection, procedures can be scheduled to take advantage of this time sequence, such as intrauterine insemination or sexual intercourse. Also, patients that undergo IVF, in general, receive HCG to trigger the ovulation process, but have an oocyte retrieval performed at about 34 to 36 hours after injection, a few hours before the eggs actually would be released from the ovary.
As HCG supports the corpus luteum, administration of HCG is used in certain circumstances to enhance the production of progesterone.
In the male, HCG injections are used to stimulate the Leydig cells to synthesize testosterone. The intratesticular testosterone is necessary for spermatogenesis from the sertoli cells. Typical uses for HCG in men include hypogonadism and fertility treatment, including during testosterone replacement therapy to restore or maintain fertility and prevent testicular atrophy.
Several vaccines against human chorionic gonadotropin (hCG) for the prevention of pregnancy are currently in clinical trials.

HCG Pubergen, Pregnyl warnings
In the case of female patients who want to be treated with HCG Pubergen, Pregnyl:
a) Since infertile female patients who undergo medically assisted reproduction (especially those who need in vitro fertilization), are known to often be suffering from tubal abnormalities, after a treatment with this drug they might experience many more ectopic pregnancies. This is why early ultrasound confirmation at the beginning of a pregnancy (to see whether the pregnancy is intrauterine or not) is crucial. Pregnancies that have occurred after a treatment with this drug have a higher risk of multiple pregnancy. Female patients who have thrombosis, severe obesity, or thrombophilia should not be prescribed this medicine as they have a higher risk of arterial or venous thromboembolic events after or during a treatment with HCG Pubergen, Pregnyl. b)Female patients who have been treated with this medicine are usually more prone to pregnancy losses.
In the case of male patients: A prolonged treatment with HCG Pubergen, Pregnyl is known to regularly lead to increased production of androgen. Therefore: Patients who have overt or latent cardiac failure, hypertension, renal dysfunction, migraines, or epilepsy might not be allowed to start using this medicine or may require a lower dose of HCG Pubergen, Pregnyl. This drug should be used with extreme caution in the treatment of prepubescent teenagers in order to reduce the risk of precocious sexual development or premature epiphyseal closure. This type of patients skeletal maturation should be closely and regularly monitored.
Both male and female patients who have the following medical conditions must not start a treatment with HCG Pubergen, Pregnyl: (1) Hypersensitivity to this drug or to any of its main ingredients. (2) Known or possible androgen-dependent tumors for example male breast carcinoma or prostatic carcinoma.

Anabolic steroid adjunct
In the world of performance-enhancing drugs, HCG is increasingly used in combination with various anabolic-androgenic steroid (AAS) cycles. As a result, HCG is included in some sports illegal drug lists.
When exogenous AAS are put into the male body, natural negative-feedback loops cause the body to shut down its own production of testosterone via shutdown of the hypothalamic-pituitary-gonadal axis (HPGA). This causes testicular atrophy, among other things. HCG is commonly used during and after steroid cycles to maintain and restore testicular size as well as normal testosterone production.High levels of AASs, that mimic the bodys natural testosterone, trigger the hypothalamus to shut down its production of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Without GnRH, the pituitary gland stops releasing luteinizing hormone (LH). LH normally travels from the pituitary via the blood stream to the testes, where it triggers the production and release of testosterone. Without LH, the testes shut down their production of testosterone. In males, HCG helps restore and maintain testosterone production in the testes by mimicking LH and triggering the production and release of testosterone.
If HCG is used for too long and in too high a dose, the resulting rise in natural testosterone and estrogen would eventually inhibit endogenous production of luteinizing hormone via negative feedback on the hypothalamus and pituitary gland.Professional athletes who have tested positive for HCG have been temporarily banned from their sport, including a 50-game ban from MLB for Manny Ramirez in 2009 and a 4-game ban from the NFL for Brian Cushing for a positive urine test for HCG. Mixed Martial Arts fighter Dennis Siver was fined $19,800 and suspended 9 months for being tested positive after his bout at UFC 168.

HCG diet
British endocrinologist Albert T. W. Simeons proposed HCG as an adjunct to an ultra-low-calorie weight-loss diet (fewer than 500 calories). Simeons, while studying pregnant women in India on a calorie-deficient diet, and "fat boys" with pituitary problems (Frölichs syndrome) treated with low-dose HCG, observed that both lost fat rather than lean (muscle) tissue. He reasoned that HCG must be programming the hypothalamus to do this in the former cases in order to protect the developing fetus by promoting mobilization and consumption of abnormal, excessive adipose deposits.  Simeons in 1954 published a book entitled Pounds and Inches, designed to combat obesity. Simeons, practicing at Salvator Mundi International Hospital in Rome, Italy, recommended low-dose daily HCG injections (125 IU) in combination with a customized ultra-low-calorie (500 cal/day, high-protein, low-carbohydrate/fat) diet, which was supposed to result in a loss of adipose tissue without loss of lean tissue.Other researchers did not find the same results when attempting experiments to confirm Simeons conclusions, and in 1976 in response to complaints the FDA required Simeons and others to include the following disclaimer on all advertisements:
These weight reduction treatments include the injection of HCG, a drug which has not been approved by the Food and Drug Administration as safe and effective in the treatment of obesity or weight control. There is no substantial evidence that HCG increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or "normal" distribution of fat, or that it decreases the hunger and discomfort associated with calorie-restrictive diets.
There was a resurgence of interest in the "HCG diet" following promotion by Kevin Trudeau, who was banned  from making HCG diet weight-loss claims by the U.S. Federal Trade Commission in 2008, and eventually jailed over such claims.A 1976 study in the American Journal of Clinical Nutrition concluded that HCG is not more effective as a weight-loss aid than dietary restriction alone.A 1995 meta analysis found that studies supporting HCG for weight loss were of poor methodological quality and concluded that "there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight-loss or fat-redistribution, nor does it reduce hunger or induce a feeling of well-being".On November 15, 2016, the American Medical Association (AMA) passed policy that "The use of human chorionic gonadotropin (HCG) for weight loss is inappropriate."
There is no scientific evidence that HCG is effective in the treatment of obesity. The meta-analysis found insufficient evidence supporting the claims that HCG is effective in altering fat-distribution, hunger reduction, or in inducing a feeling of well-being. The authors stated "…the use of HCG should be regarded as an inappropriate therapy for weight reduction…" In the authors opinion, "Pharmacists and physicians should be alert on the use of HCG for Simeons therapy. The results of this meta-analysis support a firm standpoint against this improper indication. Restraints on physicians practicing this therapy can be based on our findings."
According to the American Society of Bariatric Physicians, no new clinical trials have been published since the definitive 1995 meta-analysis.The scientific consensus is that any weight loss reported by individuals on an "HCG diet" may be attributed entirely to the fact that such diets prescribe calorie intake of between 500 and 1,000 calories per day, substantially below recommended levels for an adult, to the point that this may risk health effects associated with malnutrition.

Homeopathic HCG for weight control
Controversy about, and shortages of, injected HCG for weight loss have led to substantial Internet promotion of "homeopathic HCG" for weight control. The ingredients in these products are often obscure, but if prepared from true HCG via homeopathic dilution, they contain either no HCG at all or only trace amounts </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Dipyridamole and can you explain it in depth? [/INST] Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation when given chronically and causes blood vessel dilation when given at high doses over a short time.

Medical uses
Dipyridamole is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease
Dipyridamole has been shown to lower pulmonary hypertension without significant drop of systemic blood pressure
It inhibits formation of pro-inflammatory cytokines (MCP-1, MMP-9) in vitro and results in reduction of hsCRP in patients.
It inhibits proliferation of smooth muscle cells in vivo and modestly increases unassisted patency of synthetic arteriovenous hemodialysis grafts.
It increases the release of tissue plasminogen activator from brain microvascular endothelial cells.
It results in an increase of 13-hydroxyoctadecadienoic acid and decrease of 12-hydroxyeicosatetraenoic acid in the subendothelial matrix and reduced thrombogenicity of the subendothelial matrix.
Pretreatment it reduced reperfusion injury in volunteers.
It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy.
It results in a reduction of the number of thrombin and PECAM-1 receptors on platelets in stroke patients.
Cyclic adenosine monophosphate impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Chronic therapy did not show significant drop of systemic blood pressure.
It inhibits the replication of mengovirus RNA.
It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills.

Stroke
A combination of dipyridamole and aspirin (acetylsalicylic acid/dipyridamole) is FDA-approved for the secondary prevention of stroke and has a bleeding risk equal to that of aspirin use alone. Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid and plain tablets. Modified release preparations are buffered and absorption is not affected.However, it is not licensed as monotherapy for stroke prophylaxis, although a Cochrane review suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischemia.A triple therapy of aspirin, clopidogrel, and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events.
Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Antara and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Intermezzo and can you explain it in depth? [/INST] In music, an intermezzo (, Italian pronunciation: [interˈmɛddzo], plural form: intermezzi), in the most general sense, is a composition which fits between other musical or dramatic entities, such as acts of a play or movements of a larger musical work. In music history, the term has had several different usages, which fit into two general categories: the opera intermezzo and the instrumental intermezzo.

Renaissance intermezzo
The Renaissance intermezzo was also called the intermedio. It was a masque-like dramatic piece with music, which was performed between the acts of a play at Italian court festivities on special occasions, especially weddings. By the late 16th century, the intermezzo had become the most spectacular form of dramatic performance, and an important precursor to opera. The most famous examples were created for Medici weddings in 1539, 1565, and 1589. In Baroque Spain the equivalent entremés or paso was a one-act comic scene, often ending in music and dance, between jornadas (acts) of a play.

Opera intermezzo
The intermezzo, in the 18th century, was a comic operatic interlude inserted between acts or scenes of an opera seria. These intermezzi could be substantial and complete works themselves, though they were shorter than the opera seria which enclosed them; typically they provided comic relief and dramatic contrast to the tone of the bigger opera around them, and often they used one or more of the stock characters from the opera or from the commedia dellarte. In this they were the reverse of the Renaissance intermezzo, which usually had a mythological or pastoral subject as a contrast to a main comic play. Often they were of a burlesque nature, and characterized by slapstick comedy, disguises, dialect, and ribaldry. The most famous of all intermezzi from the period is Pergolesis La serva padrona, which was an opera buffa that after the death of Pergolesi kicked off the Querelle des Bouffons.
In some cases the intermezzo repertory spread more quickly than did the opera seria itself; the singers were often renowned, the comic effects were popular, and intermezzi were relatively easy to produce and stage. In the 1730s the style spread around Europe, and some cities—for example Moscow—recorded visits and performances by troupes performing intermezzi years before any actual opera seria were done.
The intermède (the French equivalent of the intermezzo) was the single most important outside operatic influence in Paris in the mid-18th century, and helped create an entire new repertory of opera in France (see opéra comique).
The word was used (with a hint of irony) as the title of Richard Strausss two-act opera, Intermezzo (1924), the scale of which far exceeds the intermezzo of tradition.
Many of the most celebrated intermezzi are from operas of the verismo period: Mascagnis Cavalleria rusticana and Lamico Fritz, Leoncavallos Pagliacci, Puccinis Manon Lescaut and Suor Angelica, Giordanos Fedora, Cileas Adriana Lecouvreur, and especially that from Massenets Thais, which became known as the Méditation.

Instrumental intermezzo
In the 19th century, the intermezzo acquired another meaning: an instrumental piece which was either a movement between two others in a larger work or a character piece that could stand on its own. These intermezzi show a wide variation in the style and function: in Mendelssohns incidental music to A Midsummer Nights Dream the intermezzo serves as musical connecting material for action in Shakespeares play; in chamber music by Mendelssohn and Brahms, the intermezzi are names for interior movements which would otherwise be called scherzi; and the piano intermezzi by Brahms, some of his last compositions, are sets of independent character pieces not intended to connect anything else together. Stylistically, intermezzi of the 19th century are usually lyrical and melodic, especially compared to the movements on either side, when they occur in larger works. The Brahms piano intermezzi in particular have an extremely wide emotional range, and are often considered some of the finest character pieces written in the 19th century.
Opera composers sometimes wrote instrumental intermezzi as connecting pieces between acts of operas. In this sense, an intermezzo is similar to the entracte. The most famous of this type of intermezzo is probably the intermezzo from Mascagnis Cavalleria rusticana. Puccini also wrote intermezzi for Manon Lescaut and Madama Butterfly, and examples exist by Wolf-Ferrari, Delius and others.
Also, incidental music for plays usually contained several intermezzi </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Balsalazide and can you explain it in depth? [/INST] Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. It is sold under the brand names Giazo, Colazal in the US and Colazide in the UK </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Penicillin and can you explain it in depth? [/INST] Penicillins (P, PCN or PEN) are a group of antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G (intramuscular or intravenous use) and penicillin V (given by mouth). Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are members of the β-lactam antibiotics. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.
About 10% of people report that they are allergic to penicillin; however, up to 90% of this group may not actually be allergic. Serious allergies only occur in about 0.03%. Research highlights the importance of both doctors and patients discussing recorded penicillin allergies. Those who are allergic to penicillin are most often given cephalosporin C (another β-lactam antibiotic) because there is only 10% crossover in allergy between the penicillins and cephalosporins.Penicillin was discovered in 1928 by Scottish scientist Alexander Fleming as a crude extract of P. rubens. Flemings student Cecil George Paine was the first to successfully use penicillin to treat eye infection (ophthalmia neonatorum) in 1930. The purified compound (penicillin F) was isolated in 1940 by a research team led by Howard Florey and Ernst Boris Chain at the University of Oxford. Fleming first used the purified penicillin to treat streptococcal meningitis in 1942. For the discovery, Fleming shared the 1945 Nobel Prize in Physiology or Medicine with Florey and Chain.
Several semisynthetic penicillins are effective against a broader spectrum of bacteria: these include the antistaphylococcal penicillins, aminopenicillins and the antipseudomonal penicillins.

Nomenclature
The term "penicillin" is defined as the natural product of Penicillium mould with antimicrobial activity. It was coined by Alexander Fleming on 7 March 1929 when he discovered the antibacterial property of Penicillium rubens. Fleming explained in his 1929 paper in the British Journal of Experimental Pathology that "to avoid the repetition of the rather cumbersome phrase Mould broth filtrate, the name penicillin will be used." The name thus refers to the scientific name of the mould, as described by Fleming in his Nobel lecture in 1945:I have been frequently asked why I invented the name "Penicillin". I simply followed perfectly orthodox lines and coined a word which explained that the substance penicillin was derived from a plant of the genus Penicillium just as many years ago the word "Digitalin" was invented for a substance derived from the plant Digitalis.In modern usage, the term penicillin is used more broadly to refer to any β-lactam antimicrobial that contains a thiazolidine ring fused to the β-lactam core, and may or may not be a natural product. Like most natural products, penicillin is present in Penicillium moulds as a mixture of active constituents (gentamicin is another example of a natural product that is an ill-defined mixture of active components). The principal active components of Penicillium are listed in the following table:
Other minor active components of Penicillium include penicillin O, penicillin U1 and penicillin U6. Other named constituents of natural Penicillium, such as penicillin A, were subsequently found not to have antibiotic activity and are not chemically related to antibiotic penicillins.The precise constitution of the penicillin extracted depends on the species of Penicillium mould used and on the nutrient media used to culture the mould. Flemings original strain of Penicillium rubens produces principally penicillin F, named after Fleming. But penicillin F is unstable, difficult to isolate, and produced by the mould in small quantities.The principal commercial strain of Penicillium chrysogenum (the Peoria strain) produces penicillin G as the principal component when corn steep liquor is used as the culture medium. When phenoxyethanol or phenoxyacetic acid are added to the culture medium, the mould produces penicillin V as the main penicillin instead.6-Aminopenicillanic acid (6-APA) is a compound derived from penicillin G. 6-APA contains the beta-lactam core of penicillin G, but with the side chains stripped off; 6-APA is a useful precursor for manufacturing other penicillins. There are many semi-synthetic penicillins derived from 6-APA and these are in three groups: antistaphylococcal penicillins, broad-spectrum penicillins, and antipseudomonal penicillins. The semi-synthetic penicillins are all referred to as penicillins because they are all derived ultimately from penicillin G.

Penicillin units
One unit of penicillin G sodium is defined as 0.600 micrograms. Therefore, 2 million units (2 megaunits) of penicillin G is 1.2 g.
One unit of penicillin V potassium is defined as 0.625 micrograms. Therefore 400,000 units of penicillin V is 250 mg.The use of units to prescribe penicillin is a historical accident and is largely obsolete outside of the US. Since the original penicillin was an ill-defined mixture of active compounds (an amorphous yellow powder), the potency of each batch of penicillin varied from batch to batch. It was therefore impossible to prescribe 1 g of penicillin because the activity of 1 g of penicillin from one batch would be different from the activity from another batch. After manufacture, each batch of penicillin had to be standardised against a known unit of penicillin: each glass vial was then filled with the number of units required. In the 1940s, a vial of 5,000 Oxford units was standard, but the depending on the batch, could contain anything from 15 mg to 20 mg of penicillin. Later, a vial of 1,000,000 international units became standard, and this could contain 2.5 g to 3 g of natural penicillin (a mixture of penicillin I, II, III, and IV and natural impurities). With the advent of pure penicillin G preparations (a white crystalline powder), there is little reason to prescribe penicillin in units.
The "unit" of penicillin has had three previous definitions, and each definition was chosen as being roughly equivalent to the previous one.

Oxford or Florey unit (1941). This was originally defined as the minimum amount of penicillin dissolved in 50 ml of meat extract that would inhibit the growth of a standard strain of Staphylococcus aureus (the Oxford Staphylococcus). The reference standard was a large batch of impure penicillin kept in Oxford. The assay was later modified by Floreys group to a more reproducible "cup assay": in this assay, a penicillin solution was defined to contain one unit/ml of penicillin when 339 microlitres of the solution placed in a "cup" on a plate of solid agar produced a 24 millimetre zone of inhibition of growth of Oxford Staphylococcus.: 107
First International Standard (1944). A single 8 gram batch of pure crystalline penicillin G sodium was stored at The National Institute for Medical Research at Mill Hill in London (the International Standard). One penicillin unit was defined at 0.6 micrograms of the International Standard. An impure "working standard" was also defined and was available in much larger quantities distributed around the world: one unit of the working standard was 2.7 micrograms (the amount per unit was much larger because of the impurities). At the same time, the cup assay was refined, where instead of specifying a zone diameter of 24 mm, the zone size were instead plotted against a reference curve to provide a readout on potency.
Second International Standard (1953). A single 30 gram batch of pure crystalline penicillin G sodium was obtained: this was also stored at Mill Hill. One penicillin unit was defined as 0.5988 micrograms of the Second International Standard.There is an older unit for penicillin V that is not equivalent to the current penicillin V unit. The reason is that the US FDA incorrectly assumed that the potency of penicillin V is the same mole-for-mole as penicillin G. In fact, penicillin V is less potent than penicillin G, and the current penicillin V unit reflects that fact.

First international unit of penicillin V (1959). One unit of penicillin V was defined as 0.590 micrograms of a reference standard held at Mill Hill in London. This unit is now obsolete.A similar standard was also established for penicillin K.

Types
Natural penicillins
Penicillin G (benzylpenicillin) was first produced from a penicillium fungus that occurs in nature. The strain of fungus used today for the manufacture of penicillin G was created by genetic engineering to improve the yield in the manufacturing process. None of the other natural penicillins (F, K, N, X, O, U1 or U6) are currently in clinical use.

Semi-synthetic penicillin
Penicillin V (phenoxymethylpenicillin) is produced by adding the precursor phenoxyacetic acid to the medium in which a genetically modified strain of the penicillium fungus is being cultured.

Antibiotics created from 6-APA
There are three major groups of other semi-synthetic antibiotics related to the penicillins.  They are synthesised by adding various side-chains to the precursor 6-APA, which is isolated from penicillin G. These are the antistaphylococcal antibiotics, broad-spectrum antibiotics, and antipseudomonal antibiotics.

Antistaphylococcal antibiotics
Cloxacillin (by mouth or by injection)
Dicloxacillin (by mouth or by injection)
Flucloxacillin (by mouth or by injection)
Methicillin (injection only)
Nafcillin (injection only)
Oxacillin (by mouth or by injection)Antistaphylococcal antibiotics are so-called because they are resistant to being broken down by staphylococcal penicillinase. They are also, therefore, referred to as being penicillinase-resistant.

Broad-spectrum antibiotics
This group of antibiotics is called "broad-spectrum" because they are active against a wide range of Gram-negative bacteria such as Escherichia coli and Salmonella typhi, for which penicillin is not suitable. However, resistance in these organisms is now common.

Ampicillin
AmoxicillinThere are many ampicillin precursors in existence. These are inactive compounds that are broken down in the gut to release ampicillin. None of these pro-drugs of ampicillin are in current use:

Pivampicillin (pivaloyloxymethyl ester of ampicillin)
Bacampicillin
Metampicillin (formaldehyde ester of ampicillin)
Talampicillin
Hetacillin (ampicillin conjugated to acetone)Epicillin is an aminopenicillin that has never seen widespread clinical use.

Antipseudomonal antibiotics
The Gram-negative species, Pseudomonas aeruginosa, is naturally resistant to many antibiotic classes. There were many efforts in the 1960s and 1970s to develop antibiotics that are active against Pseudomonas species. There are two chemical classes within the group: carboxypenicillins and ureidopenicillins. All are given by injection: none can be given by mouth.

Carboxypenicillins
Carbenicillin
Ticarcillin
Temocillin

Ureidopenicillins
Mezlocillin
Piperacillin
Azlocillin

β-lactamase inhibitors
Clavulanic acid
Sulbactam
Tazobactam

Medical usage
The term "penicillin", when used by itself, may refer to either of two chemical compounds, penicillin G or penicillin V.

Penicillin G
Penicillin G is destroyed by stomach acid, so it cannot be taken by mouth, but doses as high as 2.4 g can be given (much higher than penicillin V). It is given by intravenous or intramuscular injection. It can be formulated as an insoluble salt, and there are two such formulations in current use: procaine penicillin and benzathine benzylpenicillin, which are used only in the treatment of syphilis. When a high concentration in the blood must be maintained, penicillin G must be administered at relatively frequent intervals, because it is eliminated quite rapidly from the bloodstream by the kidney.
Penicillin G is licensed for use to treat septicaemia, empyema, pneumonia, pericarditis, endocarditis and meningitis caused by susceptible strains of staphylococci and streptococci. It is also licensed for the treatment of anthrax, actinomycosis, cervicofacial disease, thoracic and abdominal disease, clostridial infections, botulism, gas gangrene (with accompanying debridement and/or surgery as indicated), tetanus (as an adjunctive therapy to human tetanus immune globulin), diphtheria (as an adjunctive therapy to antitoxin and for the prevention of the carrier state), erysipelothrix endocarditis, fusospirochetosis (severe infections of the oropharynx, lower respiratory tract and genital area), Listeria infections, meningitis, endocarditis, Pasteurella infections including bacteraemia and meningitis, Haverhill fever; rat-bite fever and disseminated gonococcal infections, meningococcal meningitis and/or septicaemia caused by penicillin-susceptible organisms and syphilis.

Penicillin V
Penicillin V can be taken by mouth because it is relatively resistant to stomach acid. Doses higher than 500 mg are not fully effective because of poor absorption. It is used for the same bacterial infections as those of penicillin G and is the most widely used form of penicillin. However, it is not used for diseases, such as endocarditis, where high blood levels of penicillin are required.

Bacterial susceptibility
Because penicillin resistance is now so common, other antibiotics are now the preferred choice for treatments. For example, penicillin used to be the first-line treatment for infections with Neisseria gonorrhoeae and Neisseria meningitidis, but it is no longer recommended for treatment of these infections.

Side effects
Common (≥ 1% of people) adverse drug reactions associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of people) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in people with epilepsy), and pseudomembranous colitis. Penicillin can also induce serum sickness or a serum sickness-like reaction in some individuals. Serum sickness is a type III hypersensitivity reaction that occurs one to three weeks after exposure to drugs including penicillin. It is not a true drug allergy, because allergies are type I hypersensitivity reactions, but repeated exposure to the offending agent can result in an anaphylactic reaction. Allergy will occur in 1-10% of people, presenting as a skin rash after exposure. IgE-mediated anaphylaxis will occur in approximately 0.01% of patients.Pain and inflammation at the injection site are also common for parenterally administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin. The condition is known as livedoid dermatitis or Nicolau syndrome.

Structure
The term "penam" is used to describe the common core skeleton of a member of the penicillins. This core has the molecular formula R-C9H11N2O4S, where R is the variable side chain that differentiates the penicillins from one another. The penam core has a molar mass of 243 g/mol, with larger penicillins having molar mass near 450—for example, cloxacillin has a molar mass of 436 g/mol. 6-APA (C8H12N2O3S) forms the basic structure of penicillins. It is made up of an enclosed dipeptide formed by the condensation of L-cystein and D-valine. This results in the formations of β-lactam and thiazolidinic rings.The key structural feature of the penicillins is the four-membered β-lactam ring; this structural moiety is essential for penicillins antibacterial activity. The β-lactam ring is itself fused to a five-membered thiazolidine ring. The fusion of these two rings causes the β-lactam ring to be more reactive than monocyclic β-lactams because the two fused rings distort the β-lactam amide bond and therefore remove the resonance stabilisation normally found in these chemical bonds. An acyl side side chain attached to the β-lactam ring.A variety of β-lactam antibiotics have been produced following chemical modification from the 6-APA structure during synthesis, specifically by making chemical substitutions in the acyl side chain. For example, the first chemically altered penicillin, methicillin, had substitutions by methoxy groups at positions 2’ and 6’ of the 6-APA benzene ring from penicillin G. This difference makes methicillin resistant to the activity of β-lactamase, an enzyme by which many bacteria are naturally unsusceptible to penicillins.

Pharmacology
Entry into bacteria
Penicillin can easily enter bacterial cell in case of Gram-positive species. This is because Gram-positive bacteria do not have an outer cell membrane and are simply enclosed in a thick cell wall. Penicillin molecules are small enough to pass through the spaces of glycoproteins in the cell wall. For this reason Gram-positive bacteria are very susceptible to penicillin (as first evidenced by the discovery of penicillin in 1928).Penicillin, or any other molecule, enters Gram-negative bacteria in a different manner. The bacteria have thinner cell walls but the external surface is coated with an additional cell membrane, called the outer membrane. The outer membrane is a lipid layer (lipopolysaccharide chain) that blocks passage of water-soluble (hydrophilic) molecules like penicillin. It thus acts as the first line of defence against any toxic substance, which is the reason for relative resistance to antibiotics compared to Gram-positive species But penicillin can still enter Gram-negative species by diffusing through aqueous channels called porins (outer membrane proteins), which are dispersed among the fatty molecules and can transport nutrients and antibiotics into the bacteria. Porins are large enough to allow diffusion of most penicillins, but the rate of diffusion through them is determined by the specific size of the drug molecules. For instance, penicillin G is large and enters through porins slowly; while smaller ampicillin and amoxicillin diffuse much faster. In contrast, large vancomycin can not pass through porins and is thus ineffective for Gram-negative bacteria. The size and number of porins are different in different bacteria. As a result of the two factors—size of penicillin and porin—Gram-negative bacteria can be unsusceptible or have varying degree of susceptibility to specific penicillin.

Mechanism of action
The chemical structure of penicillin is triggered with a very precise, pH-dependent directed mechanism, affected by a unique spatial assembly of molecular components, which can activate by protonation. It can travel through bodily fluids, targeting and inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria, meanwhile avoiding the surrounding non-targets. Penicillin can protect itself from spontaneous hydrolysis in the body in its anionic form while storing its potential as a strong acylating agent, activated only upon approach to the target transpeptidase enzyme and protonated in the active centre. This targeted protonation neutralizes the carboxylic acid moiety, which is weakening of the β-lactam ring N–C(=O) bond, resulting in a self-activation. Specific structural requirements are equated to constructing the perfect mousetrap for catching targeted prey.Penicillin kills bacteria by inhibiting the completion of the synthesis of peptidoglycans, the structural component of bacterial cell wall. It specifically inhibits the activity of enzymes that are needed for the cross-linking of peptidoglycans during the final step in cell wall biosynthesis. It does this by binding to penicillin binding proteins with the β-lactam ring, a structure found on penicillin molecules. This causes the cell wall to weaken due to fewer cross-links and means water uncontrollably flows into the cell because it cannot maintain the correct osmotic gradient. This results in cell lysis and death.
Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. During the last stages of peptidoglycan biosynthesis, uridine diphosphate-N-acetylmuramic acid pentapeptide (UDP-MurNAc) is formed in which the fourth and fifth amino acids are both D-alanyl-D-alanine. The transfer of D-alanine is done (catalysed) by the enzyme DD-transpeptidase (penicillin-binding proteins are such type). The structural integrity of bacterial cell wall depends on the cross linking of UDP-MurNAc and N-acetyl glucosamine. Penicillin and other β-lactam antibiotics act as an analogue of D-alanine-D-alanine (the dipeptide) in UDP-MurNAc owing to conformational similarities. The DD-transpeptidase then binds the four-membered β-lactam ring of penicillin instead of UDP-MurNAc. As a consequence, DD-transpeptidase is inactivated, the formation of cross-links between UDP-MurNAc and N-acetyl glucosamine is blocked so that an imbalance between cell wall production and degradation develops, causing the cell to rapidly die.The enzymes that hydrolyze the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death (cytolysis). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell walls peptidoglycans. The small size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the glycopeptide antibiotics vancomycin and teicoplanin, which are both much larger than the penicillins.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 spheroplasts after treatment with penicillin.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 photosynthetic organelles 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.Some bacteria produce enzymes that break down the β-lactam ring, called β-lactamases, which make the bacteria resistant to penicillin. Therefore, some penicillins are modified or given with other drugs for use against antibiotic-resistant bacteria or in immunocompromised patients. The use of clavulanic acid or tazobactam, β-lactamase inhibitors, alongside penicillin gives penicillin activity against β-lactamase-producing bacteria. β-Lactamase inhibitors irreversibly bind to β-lactamase preventing it from breaking down the beta-lactam rings on the antibiotic molecule. Alternatively, flucloxacillin is a modified penicillin that has activity against β-lactamase-producing bacteria due to an acyl side chain that protects the beta-lactam ring from β-lactamase.

Pharmacokinetics
Penicillin has low protein binding in plasma. The bioavailability of penicillin depends on the type: penicillin G has low bioavailability, below 30%, whereas penicillin V has higher bioavailability, between 60 and 70%.Penicillin has a short half-life and is excreted via the kidneys. This means it must be dosed at least four times a day to maintain adequate levels of penicillin in the blood. Early manuals on the use of penicillin, therefore, recommended injections of penicillin as frequently as every three hours, and dosing penicillin has been described as being similar to trying to fill a bath with the plug out. This is no longer required since much larger doses of penicillin are cheaply and easily available; however, some authorities recommend the use of continuous penicillin infusions for this reason.

Resistance
When Alexander Fleming discovered the crude penicillin in 1928, one important observation he made was that many bacteria were not affected by penicillin. This phenomenon was realised by Ernst Chain and Edward Abraham while trying to identify the exact of penicillin. In 1940, they discovered that unsusceptible bacteria like Escherichia coli produced specific enzymes that can break down penicillin molecules, thus making them resistant to the antibiotic. They named the enzyme penicillinase. Penicillinase is now classified as member of enzymes called β-lactamases. These β-lactamases are naturally present in many other bacteria, and many bacteria produce them upon constant exposure to antibiotics. In most bacteria, resistance can be through three different mechanisms: reduced permeability in bacteria, reduced binding affinity of the penicillin-binding proteins (PBPs) or destruction of the antibiotic through the expression of β-lactamase. Using any of these, bacteria commonly develop resistance to different antibiotics, a phenomenon called multi-drug resistance.
The actual process of resistance mechanism can be very complex. In case of reduced permeability in bacteria, the mechanisms are different between Gram-positive and Gram-negative bacteria. In Gram-positive bacteria, blockage of penicillin is due to changes in the cell wall. For example, resistance to vancomycin in S. aureus is due to additional peptidoglycan synthesis that makes the cell wall much thicker preventing effective penicillin entry. Resistance in Gram-negative bacteria is due to mutational variations in the structure and number of porins. In bacteria like Pseudomonas aeruginosa, there is reduced number of porins; whereas in bacteria like Enterobacter species, Escherichia coli and Klebsiella pneumoniae, there are modified porins such as non-specific porins (such as OmpC and OmpF groups) that cannot transport penicillin.Resistance due to PBP alterations is highly varied. A common case is found in Streptococcus pneumoniae where there is mutation in the gene for PBP, and the mutant PBPs have decreased binding affinity for penicillins. There are six mutant PBPs in S. pneumoniae, of which PBP1a, PBP2b, PBP2x and sometimes PBP2a are responsible for reduced binding affinity. S. aureus can activate a hidden gene that produces a different PBP, PBD2, which has low binding affinity for penicillins. There is a different strain of S. aureus named methicillin-resistant S. aureus (MRSA) which is resistant not only to penicllin and other β-lactams, but also to most antibiotics. The bacterial strain developed after introduction of methicillin in 1959. In MRSA, mutations in the genes (mec system) for PBP produce a variant protein called PBP2a (also termed PBP2), while making four normal PBPs. PBP2a has poor binding affinity for penicillin and also lacks glycosyltransferase activity required for complete peptidoglycan synthesis (which is carried out by the four normal PBPs). In Helicobacter cinaedi, there are multiple mutations in different genes that make PBP variants.Enzymatic destruction by β-lactamases is the most important mechanism of penicillin resistance, and is described as "the greatest threat to the usage [of penicillins]". It was the first discovered mechanism of penicillin resistance. During the experiments when purification and biological activity tests of penicillin were performed in 1940, it was found that E. coli was unsusceptible. The reason was discovered as production of an enzyme penicillinase (hence, the first β-lactamase known) in E. coli that easily degraded penicillin. There are over 2,000 types of β-lactamases each of which has unique amino acid sequence, and thus, enzymatic activity. All of them are able to hydrolyse β-lactam rings but their exact target sites are different. They are secreted on the bacterial surface in large quantities in Gram-positive bacteria but less so in Gram-negative species. Therefore, in a mixed bacterial infection, the Gram-positive bacteria can protect the otherwise penicillin-susceptible Gram-negative cells.There are unusual mechanisms in P. aeruginosa, in which there can be biofilm-mediated resistance and formation of multidrug-tolerant persister cells.

History
Discovery
Starting in the late 19th century there had been reports of the antibacterial properties of Penicillium mould, but scientists were unable to discern what process was causing the effect. Scottish physician Alexander Fleming at St Marys Hospital in London (now part of Imperial College) was the first to show that Penicillium rubens had antibacterial properties. On 3 September 1928 he observed that fungal contamination of a bacterial culture (Staphylococcus aureus) appeared to kill the bacteria. He confirmed this observation with a new experiment on 28 September 1928. He published his experiment in 1929, and called the antibacterial substance (the fungal extract) penicillin.C. J. La Touche identified the fungus as Penicillium rubrum (later reclassified by Charles Thom as P. notatum and P. chrysogenum, but later corrected as P. rubens). Fleming expressed initial optimism that penicillin would be a useful antiseptic, because of its high potency and minimal toxicity in comparison to other antiseptics of the day, and noted its laboratory value in the isolation of Bacillus influenzae (now called Haemophilus influenzae).Fleming did not convince anyone that his discovery was important. This was largely because penicillin was so difficult to isolate that its development as a drug seemed impossible. It is speculated that had Fleming been more successful at making other scientists interested in his work, penicillin would possibly have been developed years earlier.The importance of his work has been recognized by the placement of an International Historic Chemical Landmark at the Alexander Fleming Laboratory Museum in London on 19 November 1999.

Medical application
In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, successfully treated ophthalmia neonatorum, a gonococcal infection in infants, with penicillin (fungal extract) on November 25, 1930.In 1940, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Chain, Edward Abraham, Arthur Duncan Gardner, Norman Heatley, Margaret Jennings, Jean Orr-Ewing and Arthur Gordon Sanders) at the Sir William Dunn School of Pathology, University of Oxford made progress in making concentrated penicillin from fungal culture broth that showed both in vitro and in vivo bactericidal action. In 1941, they treated a policeman, Albert Alexander, with a severe face infection; his condition improved, but then supplies of penicillin ran out and he died. Subsequently, several other patients were treated successfully. In December 1942, survivors of the Cocoanut Grove fire in Boston were the first burn patients to be successfully treated with penicillin.The first successful use of pure penicillin was when Fleming treated Harry Lambert of fatal infection of the nervous system (streptococcal meningitis) in 1942. By that time the Oxford team could produce only a small amount. Florey willingly gave the only available sample to Fleming. Lambert showed improvement from the very next day of the treatment, and was completely cured within a week. Fleming published his clinical trial in The Lancet in 1943. Following the medical breakthrough the British War Cabinet set up the Penicillin Committee on 5 April 1943 that led to projects for mass production.

Mass production
As the medical application was established, the Oxford team found that it was impossible to produce usable amounts in their laboratory. Failing to persuade the British government,  Florey and Heatley travelled to the US in June 1941 with their mould samples in order to interest the US government for large-scale production. They approached the USDA Northern Regional Research Laboratory (NRRL, now the National Center for Agricultural Utilization Research) at Peoria, Illinois, where facilities for large-scale fermentations were established. Mass culture of the mould and search for better moulds immediately followed.On March 14, 1942, the first patient was treated for streptococcal sepsis with US-made penicillin produced by Merck & Co. Half of the total supply produced at the time was used on that one patient, Anne Miller. By June 1942, just enough US penicillin was available to treat ten patients. In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. The results of fermentation research on corn steep liquor at the NRRL allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. After a worldwide search in 1943, a mouldy cantaloupe in a Peoria, Illinois market was found to contain the best strain of mould for production using the corn steep liquor process. Pfizer scientist Jasper H. Kane suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin.: 109  Large-scale production resulted from the development of a deep-tank fermentation plant by chemical engineer Margaret Hutchinson Rousseau. As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin, wherein he combined his knowledge of mushroom spawn with the function of the Sharples Cream Separator.
By 1943, Rettews lab was producing most of the worlds penicillin.  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. 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. Methods for mass production of penicillin were patented by Andrew Jackson Moyer in 1945. Florey had not patented penicillin, having been advised by Sir Henry Dale that doing so would be unethical.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. 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 penicillins 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. Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.After World War II, Australia was the first country to make the drug available for civilian use. In the U.S., penicillin was made available to the general public on March 15, 1945.Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine for the development of penicillin.

Structure determination and total synthesis
The chemical structure of penicillin was first proposed by Edward Abraham in 1942 and was later confirmed in 1945 using X-ray crystallography by Dorothy Crowfoot Hodgkin, who was also working at Oxford. She later in 1964 received the Nobel Prize for Chemistry for this and other structure determinations.
Chemist John C. Sheehan at the Massachusetts Institute of Technology (MIT) completed the first chemical synthesis of penicillin in 1957. Sheehan had started his studies into penicillin synthesis in 1948, and during these investigations developed new methods for the synthesis of peptides, as well as new protecting groups—groups that mask the reactivity of certain functional groups. Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehans synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin.6-APA was discovered by researchers at the Beecham Research Laboratories (later the Beecham Group) in Surrey in 1957 (published in 1959). Attaching different groups to the 6-APA nucleus of penicillin allowed the creation of new forms of penicillins which are more versatile and better in activity.

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 in 1961. It offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, 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.

Production
Penicillin is produced by the fermentation of various types of sugar by the fungus penicillium rubens. The fermentation process produces penicillin as a secondary metabolite when the growth of the fungus is inhibited by stress </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Rolapitant and can you explain it in depth? [/INST] Rolapitant (INN, trade name Varubi  və-ROO-bee in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor). It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.

Medical uses
Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT3 antagonist.

Contraindications
Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant. Under the European approval, it is contraindicated in combination with St. Johns Wort, which is expected to accelerate inactivation of rolapitant.

Side effects
In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).

Overdose
Up to eightfold therapeutic doses have been given in studies without problems.

Interactions
Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphan have increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.

Pharmacology
Pharmacodynamics
Both rolapitant and its active metabolite M19 block the NK1 receptor with high affinity and selectivity: to block the closely related receptor NK2 or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.

Pharmacokinetics
Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Methazolamide and can you explain it in depth? [/INST] Methazolamide (trade name Neptazane) is a potent carbonic anhydrase inhibitor. It is indicated in the treatment of increased intraocular pressure (IOP) in chronic open-angle glaucoma and secondary glaucoma. Also it is used preoperatively in acute angle-closure (narrow-angle) glaucoma where lowering the IOP is desired before surgery.
This drug has displayed teratogenic effects in rats. Compared to another drug in the same class, Acetazolamide, Methazolamide requires a lower dose when administered to patients.

References
Iyer G, Bellantone R, Taft D (1999). "In vitro characterization of the erythrocyte distribution of methazolamide: a model of erythrocyte transport and binding kinetics". J Pharmacokinet Biopharm. 27 (1): 45–66. doi:10.1023/A:1020630712388. PMID 10533697. S2CID 24294348.
RxList. "Neptazane". Archived from the original on August 12, 2006. Retrieved August 20, 2006.
Shirato S, Kagaya F, Suzuki Y, Joukou S (1997) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Omeprazole and can you explain it in depth? [/INST] Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper gastrointestinal bleeding in people who are at high risk. Omeprazole is a proton-pump inhibitor (PPI) and its effectiveness is similar to other PPIs. It can be taken by mouth or by injection into a vein.Common side effects include nausea, vomiting, headaches, abdominal pain, and increased intestinal gas. Serious side effects may include Clostridium difficile colitis, an increased risk of pneumonia, an increased risk of bone fractures, and the potential of masking stomach cancer. It is unclear if it is safe for use in pregnancy. It works by blocking the release of stomach acid.Omeprazole was patented in 1978, and approved for medical use in 1988. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the eighth most commonly prescribed medication in the United States, with more than 56 million prescriptions. It is also available without a prescription in the United States.

Medical uses
Omeprazole can be used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcers, erosive esophagitis, Zollinger–Ellison syndrome, and eosinophilic esophagitis.

Peptic ulcers
Peptic ulcers may be treated with omeprazole. Treatment of a Helicobacter pylori infection can be completed by taking a triple therapy combination of omeprazole, amoxicillin, and clarithromycin for 7–14 days. Amoxicillin may be replaced with metronidazole in patients who are allergic to penicillin.

Adverse effects
Adverse effects occurring in at least 1% of people include:
Central nervous system: headache (7%), dizziness (2%)
Respiratory: upper respiratory tract infection (2%), cough (1%)
Gastrointestinal: abdominal pain (5%), diarrhea (4%), nausea (4%), vomiting (3%), flatulence (3%), acid regurgitation (2%), constipation (2%)
Neuromuscular and skeletal: back pain (1%), weakness (1%)
Dermatologic: rash (2%)Other concerns related to adverse effects are:

Recurrence of Clostridium difficile associated diarrhea
Osteoporosis-related fractures
HypomagnesemiaConcern has been expressed regarding vitamin B12 and iron malabsorption, but effects seem to be insignificant, especially when supplement therapy is provided.Since their introduction, proton-pump inhibitors (PPIs, especially omeprazole) have also been associated with several cases of acute interstitial nephritis, an inflammation of the kidneys that often occurs as an adverse drug reaction.

Long-term use
Long-term use of PPIs is strongly associated with the development of benign polyps from fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. No association is seen between PPI use and cancer, but use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.There is a possible association between long term use and dementia which requires further study to confirm.A review article in U.S. Pharmacist in 2013 states that long-term use of PPIs is associated with decreased calcium absorption (causing increased risk of osteoporosis and fractures), decreased magnesium absorption (causing electrolyte disturbances), and increased risk of certain infections such as C. difficile and community-acquired pneumonia. They hypothesize that this is due to decreased stomach acid production.

Pregnancy and breastfeeding
The safety of using omeprazole has not been established in pregnant or breastfeeding women. Epidemiological data do not show an increased risk of major birth defects after maternal use of omeprazole during pregnancy.No clinical trials have deeply evaluated the potential consequences of the use of omeprazole in breastfeeding. However, the pharmacokinetics of the omeprazole molecule strongly suggest the safety of omeprazole use during breastfeeding:

Omeprazole has a high plasma protein binding rate (95%), indicating that a little amount of drug is transferred to the milk duct during breast milk formation.
Omeprazole needs to be administered in an enteric-coated formulation due to its rapid degradation in the acidic conditions of the stomach. This suggests that most of the free molecules ingested by the infant are likely degraded before being absorbed.Omeprazole at normal doses is likely safe during breastfeeding.

Interactions
Important drug interactions are rare. However, the most significant major drug interaction concern is the decreased activation of clopidogrel when taken together with omeprazole. Although still controversial, this may increase the risk of stroke or heart attack in people taking clopidogrel to prevent these events.
This interaction is possible because omeprazole is an inhibitor of the enzymes CYP2C19 and CYP3A4. Clopidogrel is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form. Inhibition of CYP2C19 may block the activation of clopidogrel, which could reduce its effects.Almost all benzodiazepines are metabolised by the CYP3A4 and CYP2D6 pathways, and inhibition of these enzymes results in a higher area under the curve (i.e., the total effect over time of a given dose). Other examples of drugs dependent on CYP3A4 for their metabolism are escitalopram, warfarin, oxycodone, tramadol, and oxymorphone. The concentrations of these drugs may increase if they are used concomitantly with omeprazole.Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs.Drugs that depend on an acidic stomach environment (such as ketoconazole or atazanavir) may be poorly absorbed, whereas acid-labile antibiotics (such as erythromycin which is a very strong CYP3A4 inhibitor) may be absorbed to a greater extent than normal due to the more alkaline environment of the stomach.St. Johns wort (Hypericum perforatum) and Gingko biloba significantly reduce plasma concentrations of omeprazole through induction of CYP3A4 and CYP2C19.Proton-pump inhibitors like omeprazole have been found to increase the plasma concentrations of methotrexate.

Pharmacology
Omeprazole irreversibly blocks the enzyme system on parietal cells that is needed for the secretion of gastric acid. It is a specific H+/K+ATPase inhibitor. This is the enzyme needed for the final step in the secretion of gastric acid.

Mechanism of action
Omeprazole is a selective and irreversible proton pump inhibitor. It suppresses stomach acid secretion by specific inhibition of the H+/K+-ATPase system found at the secretory surface of gastric parietal cells. Because this enzyme system is regarded as the acid (proton, or H+) pump within the gastric mucosa, omeprazole inhibits the final step of acid production.Omeprazole also inhibits both basal and stimulated acid secretion irrespective of the stimulus as it blocks the last step in acid secretion. The drug binds non-competitively so it has a dose-dependent effect.The inhibitory effect of omeprazole occurs within 1 hour after oral administration. The maximum effect occurs within 2 hours. The duration of inhibition is up to 72 hours. When omeprazole is stopped, baseline stomach acid secretory activity returns after 3 to 5 days. The inhibitory effect of omeprazole on acid secretion will plateau after 4 days of repeated daily dosing.

Pharmacokinetics
The absorption of omeprazole takes place in the small intestine and is usually completed within 3 to 6 hours. The systemic bioavailability of omeprazole after repeated doses is about 60%. Omeprazole has a volume of distribution of 0.4 L/kg. It has high plasma protein binding of 95%.Omeprazole, as well as other PPIs, are only effective on active H+/K+-ATPase pumps. These pumps are stimulated in the presence of food to aid in digestion. For this reason, patients should be advised to take omeprazole with a glass of water on an empty stomach. Additionally, most sources recommend that after taking omeprazole, at least 30 minutes should be allowed to elapse before eating (at least 60 minutes for immediate-release omeprazole plus sodium bicarbonate products, such as Zegerid), though some sources say that with delayed-release forms of omeprazole, waiting before eating after taking the medication is not necessary.Omeprazole is completely metabolized by the cytochrome P450 system, mainly in the liver, by CYP2C19 and CYP3A4 isoenzymes. Identified metabolites are the sulfone, the sulfide, and hydroxy-omeprazole, which exert no significant effect on acid secretion. About 77% of an orally given dose is excreted as metabolites in the urine, and the remainder is found in the feces, primarily originating from bile secretion. Omeprazole has a half life of 0.5 to 1 hour. The pharmacological effects of omeprazole last longer as it is covalently bonded to proton pump on parietal cells to induce effects.

Chemistry
Omeprazole contains a tricoordinated sulfinyl sulfur in a pyramidal structure and therefore can exist as either the (S)- or (R)-enantiomers. Omeprazole is a racemate, an equal mixture of the two. In the acidic conditions of the canaliculi of parietal cells, both enantiomers are converted to achiral products (sulfenic acid and sulfenamide configurations) which react with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid.
AstraZeneca also developed esomeprazole (Nexium) which is a eutomer, purely the (S)-enantiomer, rather than a racemate like omeprazole.
Omeprazole undergoes a chiral shift in vivo which converts the inactive (R)-enantiomer to the active (S)-enantiomer, doubling the concentration of the active form. This chiral shift is accomplished by the CYP2C19 isozyme of cytochrome P450, which is not found equally in all human populations. Those who do not metabolize the drug effectively are called "poor metabolizers". The proportion of the poor metabolizer phenotype varies widely between populations, from 2.0 to 2.5% in African Americans and white Americans to >20% in Asians. Several pharmacogenomics studies have suggested that PPI treatment should be tailored according to CYP2C19 metabolism status.

Measurement in body fluids
Omeprazole may be quantified in plasma or serum to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients. Plasma omeprazole concentrations are usually in a range of 0.2–1.2 mg/L in persons receiving the drug therapeutically by the oral route and 1–6 mg/L in people with acute overdose. Enantiomeric chromatographic methods are available to distinguish esomeprazole from racemic omeprazole.

History
Omeprazole was first made in 1979 by Swedish AB Hässle, part of Astra AB. It was the first of the proton pump inhibitors (PPI). Astra AB, now AstraZeneca, launched it as an ulcer medicine under the name Losec in Sweden. It was first sold in the United States in 1989 under the brand name Losec. In 1990, at the request of the U.S. Food and Drug Administration, the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide). The new name led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.When Prilosecs U.S. patent expired in April 2001, AstraZeneca introduced esomeprazole (Nexium) as a patented replacement drug. Many companies introduced generics as AstraZenecas patents expired worldwide, which are available under many brand names.

Society and culture
Dosage forms
It can be taken by mouth, as a capsule, tablet, or suspension, or by injection into a vein.Omeprazole is available in strengths of 10, 20, 40, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating enteric-coated granules within capsules, enteric-coated tablets, and the multiple-unit pellet system (MUPS). An immediate release formulation was approved by the FDA in the United States, which does not require enteric coating.
It is also available for use in injectable form (IV) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Each 10 mL clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg, equivalent to 40 mg of omeprazole.
Omeprazole is also available as an oral suspension of enteric-coated beads in the UK as an unlicensed product. Oral suspensions are predominantly used for children, but can also be used by those with difficulty swallowing or those using a feeding tube.

Brand names
Brand names include Losec, Prilosec, Zegerid, Miracid, and Omez.

References
Further reading
Dean L (2012) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Loteprednol and can you explain it in depth? [/INST] Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used to treat inflammations of the eye </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Galantamine and can you explain it in depth? [/INST] Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimers disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of Galanthus nivalis (Common snowdrop), Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronovs snowdrop), and some other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily).  It can also be produced synthetically.
Studies of usage in modern medicine began in the Soviet Union in the 1950s. Galantamine was isolated for the first time from bulbs of Galanthus nivalis (common snowdrop) by the Bulgarian chemist D. Paskov and his team in 1956. The active ingredient was extracted, identified, and studied, in particular in relation to its acetylcholinesterase (AChE)-inhibiting properties. The first industrial process was developed in 1959. However, it was not until the 1990s when full-scale synthesis was upscaled and optimized.Since the alkaloid was isolated from a botanical source, it only had contents around 0.1%, which caused the yield to also be extremely low—in the single digits.

Uses in mythology
In Homers Odyssey the god Hermes gives Odysseus a herb with "a black root, but milklike flower" called "moly", which Hermes claims will make Odysseus immune to the sorceress Circes drugs. It is believed that moly is the snowdrop Galanthus nivalis, which is a source of galantamine. The descriptions of moly given by Greek physician and herbalist Dioscorides support molys identity as Galanthus nivalis. It has been proposed that the drugs Circe used were an extract from Datura stramonium (also known as jimsonweed), which causes memory loss and delirium. This would give a basis for the snowdrops use as an antidote, as Datura stramonium is anticholinergic, while galantamine is an acetylcholinesterase inhibitor.

Medical uses
Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimers. In the United States, it is approved by the Food and Drug Administration as safe and effective for the treatment of mild to moderate dementia. As with other cholinesterase inhibitors, galantamine may not be effective for treating mild cognitive impairment.The FDA considers galantamine to have dual status as a prescription drug and as a OTC dietary supplement.

Alzheimers disease
Alzheimers disease is characterized by the impairment of cholinergic function. One hypothesis is that this impairment contributes to the cognitive deficits caused by the disease. This hypothesis forms the basis for use of galantamine as a cholinergic enhancer in the treatment of Alzheimers. Galantamine inhibits acetylcholinesterase, an enzyme which hydrolyzes acetylcholine. As a result of acetylcholinesterase inhibition, galantamine increases the availability of acetylcholine for synaptic transmission. Additionally, galantamine binds to the allosteric sites of nicotinic receptors, which causes a conformational change. This allosteric modulation increases the nicotinic receptors response to acetylcholine. The activation of presynaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine. Galantamines competitive inhibition of acetylcholinesterase and allosteric nicotinic modulation serves as a dual mechanism of action.To reduce the prevalence of negative side effects associated with galantamine, such as nausea and vomiting, a dose-escalation scheme may be used. The use of a dose-escalation scheme has been well accepted in countries where galantamine is used. A dose-escalation scheme for Alzheimers treatment involves a recommended starting dosage of 4 mg galantamine tablets given twice a day (8 mg/day). After a minimum of 4 weeks, the dosage may then be increased to 8 mg given twice a day (16 mg/day). After a minimum of 4 weeks at 16 mg/day, the treatment may be increased to 12 mg given twice a day (24 mg/day). Dosage increases are based upon the assessment of clinical benefit as well as tolerability of the previous dosage. If treatment is interrupted for more than three days, the process is usually restarted, beginning at the starting dosage, and re-escalating to the current dose. It has been found that a dosage between 16–24 mg/day is the optimal dosage.

Available forms
The product is supplied in prescription form only in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution.

Side effects
Galantamines side effect profile was similar to that of other cholinesterase inhibitors, with gastrointestinal symptoms being the most notable and most commonly observed. One study reports higher proportions of patients treated with galantamine experiencing nausea and vomiting as opposed to the placebo group. Another study using a dose-escalation treatment has found that incidences of nausea would decrease to baseline levels soon after each increase in administered dosage. In practice, some other cholinesterase inhibitors might be better tolerated; however, a careful and gradual titration over more than three months may lead to equivalent long-term tolerability.The U.S. Food and Drug Administration (FDA) and international health authorities have published an alert of galantamine based on data from two studies during the treatment for  mild cognitive impairment (MCI); higher mortality rates were seen in drug-treated patients. However, it reduced mortality in Alzheimers patients. On April 27, 2006, FDA approved labeling changes concerning all form of galantamine preparations (liquid, regular tablets, and extended release tablets) warning of the risk of bradycardia (slow resting heart rate), and sometimes atrioventricular block, especially in predisposed persons. At the same time, the risk of syncope (fainting) seems to be increased relative to placebo. "In randomized controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but was rarely severe and rarely led to treatment discontinuation" These side effects have not been reported in Alzheimers Disease related studies.

Pharmacology
Galantamines chemical structure contains a tertiary amine. At a neutral pH, this tertiary amine will often bond to a hydrogen, and appear mostly as an ammonium ion.Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α4β2, α3β4, and α6β4, and chicken/mouse nAChRs α7/5-HT3 in certain areas of the brain. By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to acetylcholine. This modulation of the nicotinic cholinergic receptors on cholinergic neurons in turn causes an increase in the amount of acetylcholine released.
However, recent studies suggest that Galantamine does not functionally act at human nAChRs α4β2 or α7 as a positive allosteric modulator.Galantamine also works as a weak competitive and reversible cholinesterase inhibitor in all areas of the body. By inhibiting acetylcholinesterase, it increases the concentration and thereby action of acetylcholine in certain parts of the brain. Galantamines effects on nAChRs and complementary acetylcholinesterase inhibition make up a dual mechanism of action. It is hypothesized that this action might relieve some of the symptoms of Alzheimers.

Galantamine in its pure form is a white powder. The atomic resolution 3D structure of the complex of galantamine and its target, acetylcholinesterase, was determined by X-ray crystallography in 1999 (PDB code: 1DX6; see complex). There is no evidence that galantamine alters the course of the underlying dementing process.

Pharmacokinetics
Absorption of galantamine is rapid and complete and shows linear pharmacokinetics.  It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a terminal elimination half-life of seven hours. Peak effect of inhibiting acetylcholinesterase was achieved about one hour after a single oral dose of 8 mg in some healthy volunteers.
The coadministration of food delays the rate of galantamine absorption, but does not affect the extent of absorption.Plasma protein binding of galantamine is about 18%, which is relatively low.

Metabolism
Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that hepatic CYP2D6 and CYP3A4 are involved in galantamine metabolism. Within 24 hours of intravenous or oral administration approximately 20% of a dose of galantamine will be excreted unreacted in the urine.In humans, several metabolic pathways for galantamine exist. These pathways lead to the formation of a number of different metabolites. One of the metabolites that may result can be formed through the glucuronidation of galantamine. Additionally, galantamine may undergo oxidation or demethylation at its nitrogen atom, forming two other possible metabolites. Galantamine can undergo demethylation at its oxygen atom, forming an intermediate which can then undergo glucuronidation or sulfate conjugation. Lastly, galantamine may be oxidized and then reduced before finally undergoing demethylation or oxidation at its nitrogen atom, or demethylation and subsequent glucuronidation at its oxygen atom.

For Razadyne ER, the once-a-day formulation, CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. About 7% of the population has this genetic mutation; however, because the drug is individually titrated to tolerability, no specific dosage adjustment is necessary for this population.

Drug interactions
Since galantamine is metabolized by CYP2D6 and CYP3A4, inhibiting either of these isoenzymes will increase the cholinergic effects of galantamine. Inhibiting these enzymes may lead to adverse effects. It was found that paroxetine, an inhibitor of CYP2D6, increased the bioavailability of galantamine by 40%. The CYP3A4 inhibitors ketoconazole and erythromycin increased the bioavailability of galantamine by 30% and 12%, respectively.

Synthesis
Galantamine is produced from natural resources, but also has many industrial syntheses. Companies such as Janssen, Ortho-McNeil Pharmaceutical, Sanochemia Pharmazeutika, Shire, and Takeda Pharmaceutical Company have industrial processes for synthesizing Galantamine.

Research
Organophosphate poisoning
The toxicity of organophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase. Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown. In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors. This leads to severe skeletal muscle fasciculations (involuntary contractions). The effects on the central nervous system include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma. As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition. Additionally, galantamine has anticonvulsant properties which may make it even more desirable as an antidote.Research supported in part by the US Army has led to a US patent application for the use of galantamine and/or its derivatives for treatment of organophosphate poisoning. The indications for use of galantamine in the patent application include poisoning by nerve agents "including but not limited to soman, sarin, and VX, tabun, and Novichok agents".  Galantamine was studied in the research cited in the patent application for use along with the well-recognized nerve agent antidote atropine.  According to the investigators, an unexpected synergistic interaction occurred between galantamine and atropine in an amount of 6 mg/kg or higher. Increasing the dose of galantamine from 5 to 8 mg/kg decreased the dose of atropine needed to protect experimental animals from the toxicity of soman in dosages 1.5 times the dose generally required to kill half the experimental animals.

Autism
Galantamine given in addition to risperidone to autistic children has been shown to improve some of the symptoms of autism such as irritability, lethargy, and social withdrawal. Additionally, the cholinergic and nicotinic receptors are believed to play a role in attentional processes </s>


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