Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
Nandrolone known as 19-nortestosterone, is an androgen and anabolic steroid, used in the form of esters such as nandrolone decanoate and nandrolone phenylpropionate. Nandrolone esters are used in the treatment of anemias, osteoporosis, breast cancer, for other indications, they must be given by injection into muscle. Side effects of nandrolone esters include symptoms of masculinization like acne, increased hair growth, voice changes, increased sexual desire, they are synthetic androgens and anabolic steroids and hence are agonists of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. Nandrolone esters have strong anabolic effects and weak androgenic effects, which give them a mild side effect profile and make them suitable for use in women and children, they are long-lasting prodrugs of nandrolone in the body. Nandrolone esters were first introduced for medical use in the late 1950s, they are among the most used AAS worldwide. In addition to their medical use, nandrolone esters are used to improve physique and performance, are said to be the most used AAS for such purposes.
The drugs are controlled substances in many countries and so non-medical use is illicit. Nandrolone esters are used clinically, although rarely, for people in catabolic states with major burns, AIDS, an ophthalmological formulation was available to support cornea healing; the positive effects of nandrolone esters include muscle growth, appetite stimulation and increased red blood cell production, bone density. Clinical studies have shown them to be effective in treating anemia and breast cancer. Nandrolone sulfate has been used in an eye drop formulation as an ophthalmic medication. Nandrolone esters are used for physique- and performance-enhancing purposes by competitive athletes and powerlifters. Side effects of nandrolone esters include masculinization among others. Other side effects of high doses of nandrolone can include erectile dysfunction and cardiovascular damage, as well as several ailments resulting from the drug's effect of lowering levels of luteinizing hormone through negative feedback.
Nandrolone is an agonist of the AR, the biological target of androgens like testosterone and DHT. Unlike testosterone and certain other AAS, nandrolone is not potentiated in androgenic tissues like the scalp and prostate, hence deleterious effects in these tissues are lessened; this is because nandrolone is metabolized by 5α-reductase to the much weaker AR ligand 5α-dihydronandrolone, which has both reduced affinity for the androgen receptor relative to nandrolone in vitro and weaker AR agonistic potency in vivo. The lack of alkylation on the 17α-carbon drastically reduces the hepatotoxic potential of nandrolone. Estrogen effects resulting from reaction with aromatase are reduced due to lessened enzyme interaction, but effects such as gynecomastia and reduced libido may still occur at sufficiently high doses. In addition to its AR agonistic activity, unlike many other AAS, nandrolone is a potent progestogen, it binds to the progesterone receptor with 22% of the affinity of progesterone. The progestogenic activity of nandrolone serves to augment its antigonadotropic effects, as antigonadotropic action is a known property of progestogens.
Nandrolone has a high ratio of anabolic to androgenic activity. In fact, nandrolone-like AAS like nandrolone itself and trenbolone are said to have among the highest ratio of anabolic to androgenic effect of all AAS; this is attributed to the fact that whereas testosterone is potentiated via conversion into dihydrotestosterone in androgenic tissues, the opposite is true with nandrolone and similar AAS. As such, nandrolone-like AAS, namely nandrolone esters, are the most used AAS in clinical settings in which anabolic effects are desired. However, AAS with a high ratio of anabolic to androgenic action like nandrolone still have significant androgenic effects and can produce symptoms of masculinization like hirsutism and voice deepening in women and children with extended use. Nandrolone has low affinity for human serum sex hormone-binding globulin, about 5% of that of testosterone and 1% of that of DHT, it is metabolized among others. Nandrolone is less susceptible to metabolism by 5α-reductase and 17β-hydroxysteroid dehydrogenase than testosterone.
This results in it being transformed less in so-called "androgenic" tissues like the skin, hair follicles, prostate gland and in the kidneys, respectively. Metabolites of nandrolone include 5α-dihydronandrolone, 19-norandrosterone, 19-noretiocholanolone, these metabolites may be detected in urine. Nandrolone known as 19-nortestosterone or as estrenolone, as well as estra-4-en-17β-ol-3-one or 19-norandrost-4-en-17β-ol-3-one, is a occurring estrane steroid and a derivative of testosterone, it is the C19 demethylated analogue of testosterone. Nandrolone is an endogenous intermediate in the production of estradiol from testosterone via aromatase in mammals including humans and is present in the body in trace amounts, it can be detected during pregnancy in women. Nandrolone esters have an ester such as phenylpropionate attached at the C17β position. A variety of esters of nandrolone have been used medically; the most used esters are nand
In medicine, a side effect is an effect, whether therapeutic or adverse, secondary to the one intended. Developing drugs is a complicated process, because no two people are the same, so drugs that have no side effects, might be difficult for some people, it is difficult to make a drug that targets one part of the body but that doesn’t affect other parts, the fact that increases the risk of side effects in the untargeted parts. Drugs are prescribed or procedures performed for their side effects. For instance, X-rays were used as an imaging technique; the probability or chance of experiencing side effects are characterised as: Very common, ≥ 1⁄10 Common, 1⁄10 to 1⁄100 Uncommon, 1⁄100 to 1⁄1000 Rare, 1⁄1000 to 1⁄10000 Very rare, < 1⁄10000 Bevacizumab, used to slow the growth of blood vessels, has been used against dry age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion. Buprenorphine has been shown experimentally to be effective against refractory depression.
Bupropion, an anti-depressant, is used as a smoking cessation aid. In Ontario, smoking cessation drugs are not covered by provincial drug plans. Therefore, some physicians prescribe Wellbutrin for both indications. Carbamazepine is an approved treatment for bipolar disorder and epileptic seizures, but it has side effects useful in treating attention-deficit hyperactivity disorder, phantom limb syndrome, paroxysmal extreme pain disorder and post-traumatic stress disorder. Dexamethasone and betamethasone in premature labor, to enhance pulmonary maturation of the fetus. Doxepin has been used to treat angiodema and severe allergic reactions due to its strong antihistamine properties. Gabapentin, approved for treatment of seizures and postherpetic neuralgia in adults, has side-effects which are useful in treating bipolar disorder1, essential tremor, hot flashes, migraine prophylaxis, neuropathic pain syndromes, phantom limb syndrome, restless leg syndrome. Hydroxyzine, an antihistamine, is used as an anxiolytic.
Magnesium sulfate in obstetrics for premature preeclampsia. Methotrexate, approved for the treatment of choriocarcinoma, is used for the medical treatment of an unruptured ectopic pregnancy; the SSRI medication sertraline is approved as an antidepressant but delays conjugal climax in men, thus may be supplied to those in which climax is premature. Sildenafil was intended for pulmonary hypertension. Terazosin, an α1-adrenergic antagonist approved to treat benign prostatic hyperplasia and hypertension, is used off-label to treat drug induced diaphoresis and hyperhidrosis. Echinacea – more than 20 different types of reactions have been reported, including asthma attacks, loss of pregnancy, swelling, aching muscles and gastrointestinal upsets. Feverfew – pregnant women should avoid using this herb, as it can trigger uterine contractions which could lead to premature labour or miscarriage. Asteraceae plants – which include feverfew, echinacea and chamomile. Side effects include hay fever. Pharmacogenetics: the use of genetic information to determine which type of drugs will work best for a patient MedEffect Canada definitions.pdf
Anabolic steroids known more properly as anabolic–androgenic steroids, are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects to testosterone. They are anabolic and increase protein within cells in skeletal muscles, have varying degrees of androgenic and virilizing effects, including induction of the development and maintenance of masculine secondary sexual characteristics such as the growth of facial and body hair; the word anabolic, referring to anabolism, comes from the Greek ἀναβολή anabole, "that, thrown up, mound". Androgens or AAS are one of three types of sex hormone agonists, the others being estrogens like estradiol and progestogens like progesterone. AAS were synthesized in the 1930s, are now used therapeutically in medicine to stimulate muscle growth and appetite, induce male puberty and treat chronic wasting conditions, such as cancer and AIDS; the American College of Sports Medicine acknowledges that AAS, in the presence of adequate diet, can contribute to increases in body weight as lean mass increases and that the gains in muscular strength achieved through high-intensity exercise and proper diet can be additionally increased by the use of AAS in some individuals.
Health risks can be produced by long-term use or excessive doses of AAS. These effects include harmful changes in cholesterol levels, high blood pressure, liver damage, dangerous changes in the structure of the left ventricle of the heart; these risks are only increased when, as they do, athletes take steroids alongside other drugs, causing more damage to their bodies. The effect of anabolic steroids on the heart can cause Myocardial infarction, strokes as well. Conditions pertaining to hormonal imbalances such as gynecomastia and testicular size reduction may be caused by AAS. In women and children, AAS can cause irreversible masculinization. Ergogenic uses for AAS in sports and bodybuilding as performance-enhancing drugs are controversial because of their adverse effects and the potential to gain unfair advantage in physical competitions, their use is referred to as doping and banned by most major sporting bodies. Athletes have been looking for drugs to enhance their athletic abilities since the Olympics started in Ancient Greece.
For many years, AAS have been by far the most detected doping substances in IOC-accredited laboratories. In countries where AAS are controlled substances, there is a black market in which smuggled, clandestinely manufactured or counterfeit drugs are sold to users. Since the discovery and synthesis of testosterone in the 1930s, AAS have been used by physicians for many purposes, with varying degrees of success; these can broadly be grouped into anabolic and other uses. Bone marrow stimulation: For decades, AAS were the mainstay of therapy for hypoplastic anemias due to leukemia, kidney failure or aplastic anemia. Growth stimulation: AAS can be used by pediatric endocrinologists to treat children with growth failure. However, the availability of synthetic growth hormone, which has fewer side effects, makes this a secondary treatment. Stimulation of appetite and preservation and increase of muscle mass: AAS have been given to people with chronic wasting conditions such as cancer and AIDS. Stimulation of lean body mass and prevention of bone loss in elderly men, as some studies indicate.
However, a 2006 placebo-controlled trial of low-dose testosterone supplementation in elderly men with low levels of testosterone found no benefit on body composition, physical performance, insulin sensitivity, or quality of life. Prevention or treatment of osteoporosis in postmenopausal women. Nandrolone decanoate is approved for this use. Although they have been indicated for this indication, AAS saw little use for this purpose due to their virilizing side effects. Aiding weight gain following surgery or physical trauma, during chronic infection, or in the context of unexplained weight loss. Counteracting the catabolic effect of long-term corticosteroid therapy. Oxandrolone improves both short-term and long-term outcomes in people recovering from severe burns and is well-established as a safe treatment for this indication. Treatment of idiopathic short stature, hereditary angioedema, alcoholic hepatitis, hypogonadism. Methyltestosterone is used in the treatment of delayed puberty, hypogonadism and erectile dysfunction in males, in low doses to treat menopausal symptoms, postpartum breast pain and engorgement, breast cancer in women.
Androgen replacement therapy for men with low levels of testosterone. Induction of male puberty: Androgens are given to many boys distressed about extreme delay of puberty. Testosterone is now nearly the only androgen used for this purpose and has been shown to increase height and fat-free mass in boys with delayed puberty. Masculinizing hormone therapy for transgender men, other transmasculine people, intersex people, by producing masculine secondary sexual characteristics such as a voice deepening, increased bone and muscle mass, masculine fat distribution and body hair, clitoral enlargement, as well as mental changes such as alleviation of gender dysphoria and increased sex drive. Treatment of breast cancer in women, although they are now rarely used for this purpose due to their marked virilizing side effects. In low doses as a component of hormone therapy for postmenopausal and transgender women, for instance to increase energy, well-being, and
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, poison, or other substance is taken into the body. Routes of administration are classified by the location at which the substance is applied. Common examples include intravenous administration. Routes can be classified based on where the target of action is. Action may be enteral, or parenteral. Route of administration and dosage form are aspects of drug delivery. Routes of administration are classified by application location; the route or course the active substance takes from application location to the location where it has its target effect is rather a matter of pharmacokinetics. Exceptions include the transdermal or transmucosal routes, which are still referred to as routes of administration; the location of the target effect of active substances are rather a matter of pharmacodynamics. An exception is topical administration, which means that both the application location and the effect thereof is local. Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, sometimes as a local application location regardless of location of the effects.
Administration through the gastrointestinal tract is sometimes termed enteral or enteric administration. Enteral/enteric administration includes oral and rectal administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may occur in the stomach, as such gastrointestinal may be a more fitting term for this route of administration. Furthermore, some application locations classified as enteral, such as sublingual and sublabial or buccal, are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Enteral administration can be used for systemic administration, as well as local, such as in a contrast enema, whereby contrast media is infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects. Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy.
Substances may be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach; the rectal route is an effective route of administration for many medications those used at the end of life. The walls of the rectum absorb many medications and effectively. Medications delivered to the distal one-third of the rectum at least avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration.
The parenteral route is any route, not enteral. Parenteral administration can be performed by injection, that is, using a needle and a syringe, or by the insertion of an indwelling catheter. Locations of application of parenteral administration include: central nervous systemepidural, e.g. epidural anesthesia intracerebral direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain; the intracerebral route can interrupt the blood brain barrier from holding up against subsequent routes. Intracerebroventricular administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain. Epicutaneous, it can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route. Sublingual and buccal medication administration is a way of giving someone medicine orally.
Sublingual administration is. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the cheek. These medications can come in the form of films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, barbiturates, opioid analgesics with poor gastrointestinal bioavailability and vitamins and minerals. Extra-amniotic administration, between the endometrium and fetal membranes nasal administration (th
The androgen receptor known as NR3C4, is a type of nuclear receptor, activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in the cytoplasm and translocating into the nucleus. The androgen receptor is most related to the progesterone receptor, progestins in higher dosages can block the androgen receptor; the main function of the androgen receptor is as a DNA-binding transcription factor that regulates gene expression. Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype. In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an more potent agonist for androgen receptor activation. Testosterone appears to be the primary androgen receptor-activating hormone in the Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the urogenital sinus, urogenital tubercle, hair follicles.
Testosterone is therefore responsible for the development of male primary sexual characteristics, whilst dihydrotestosterone is responsible for secondary male characteristics. Androgens cause slow epiphysis, or maturation of the bones, but more of the potent epiphysis effect comes from the estrogen produced by aromatization of androgens. Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in androgen insensitivity syndrome or estrogen insensitivity syndrome. AR knockout-mice studies have shown that AR is essential for normal female fertility, being required for development and full functionality of the ovarian follicles and ovulation, working through both intra-ovarian and neuroendocrine mechanisms. Via the androgen receptor, androgens play a key role in the maintenance of male skeletal integrity; the regulation of this integrity by androgen receptor signaling can be attributed to both osteoblasts and osteocytes.
The primary mechanism of action for androgen receptors is direct regulation of gene transcription. The binding of an androgen to the androgen receptor results in a conformational change in the receptor that, in turn, causes dissociation of heat shock proteins, transport from the cytosol into the cell nucleus, dimerization; the androgen receptor dimer binds to a specific sequence of DNA known as a hormone response element. Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific gene transcription. Up-regulation or activation of transcription results in increased synthesis of messenger RNA, which, in turn, is translated by ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the insulin-like growth factor I receptor. Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior. One function of androgen receptor, independent of direct binding to its target DNA sequence, is facilitated by recruitment via other DNA-binding proteins.
One example is serum response factor, a protein that activates several genes that cause muscle growth. Androgen receptor is modified by post translational modification through acetylation, which directly promotes AR mediated transactivation and contact independent growth of prostate cancer cells. AR acetylation determines recruitment into chromatin; the AR acetylation site is a key target of NAD-dependent and TSA-dependent histone deacetylases and long non coding RNA. More androgen receptors have been shown to have a second mode of action; as has been found for other steroid hormone receptors such as estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA. Androgen receptors interact with certain signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.
In humans, the androgen receptor is encoded by the AR gene located on the X chromosome at Xq11-12. The androgen insensitivity syndrome known as testicular feminization, is caused by a mutation of the androgen receptor gene located on the X chromosome; the androgen receptor is defective in Kennedy's disease. In addition, point mutations and trinucleotide repeat polymorphisms has been linked to a number of additional disorders; the AR gene contains CAG repeats which affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists, with African-Americans having fewer repeats than non-Hispanic white Americans; the racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these groups. Two isoforms of the androgen receptor have been identified: AR-A - 87 kDa - N-terminus truncated, which results from in vitro proteolysis.
AR-B - 110 kDa - full length Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional domains labeled A through F: A/B) - N-terminal regulatory domain contains:activa