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72-468: From the Greek αγωνιστής (agōnistēs), contestant; champion; rival < αγων (agōn), contest, combat; exertion, struggle < αγω (agō), I lead, lead towards, conduct; drive Receptors can be activated by either endogenous agonists (such as hormones and neurotransmitters ) or exogenous agonists (such as drugs ), resulting in a biological response. A physiological agonist is a substance that creates

144-414: A magnesium ion unless the cell is also experiencing depolarization . These differences show that agonists have unique mechanisms of action depending on the receptor activated and the response needed. The goal and process remains generally consistent however, with the primary mechanism of action requiring the binding of the agonist and the subsequent changes in conformation to cause the desired response at

216-537: A pitch accent . In Modern Greek, all vowels and consonants are short. Many vowels and diphthongs once pronounced distinctly are pronounced as /i/ ( iotacism ). Some of the stops and glides in diphthongs have become fricatives , and the pitch accent has changed to a stress accent . Many of the changes took place in the Koine Greek period. The writing system of Modern Greek, however, does not reflect all pronunciation changes. The examples below represent Attic Greek in

288-436: A calculated TI into something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate in order to create a well balanced indication-specific efficacy vs safety profile. In general, it

360-488: A decrease in the level of DNA synthesis. Patients with Ataxia telangiectasia delays have hypersensitivity to radiation due to the delay of accumulation of p53. In this case, cells are able to replicate without repair of their DNA, becoming prone to incidence of cancer. Most cells are in G1 and S phase. Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment. Irradiation of

432-451: A drug is used therapeutically, it is important to understand the margin of safety that exists between the dose needed for the desired effect and the dose that produces unwanted and possibly dangerous side-effects (measured by the TD 50 , the dose that produces toxicity in 50% of individuals). This relationship, termed the therapeutic index , is defined as the ratio TD 50 : ED 50 . In general,

504-473: A drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect . The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity. Classically, for clinical indications of an approved drug, TI refers to

576-467: A free hydroxyl radical , hydronium and electron. The hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage the base region of DNA. Cancer cells cause an imbalance of signals in the cell cycle . G1 and G2/M arrest were found to be major checkpoints by irradiating human cells. G1 arrest delays the repair mechanism before synthesis of DNA in S phase and mitosis in M phase, suggesting it

648-405: A high safety-based therapeutic index ( T I safety {\displaystyle TI_{\text{safety}}} ) are preferable for a drug to have a favorable efficacy vs safety profile. At the early discovery/development stage, the clinical TI of a drug candidate is unknown. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI

720-472: A lack of contemporaneous evidence. Several theories exist about what Hellenic dialect groups may have existed between the divergence of early Greek-like speech from the common Proto-Indo-European language and the Classical period. They have the same general outline but differ in some of the detail. The only attested dialect from this period is Mycenaean Greek , but its relationship to the historical dialects and

792-419: A lesser degree. Pamphylian Greek , spoken in a small area on the southwestern coast of Anatolia and little preserved in inscriptions, may be either a fifth major dialect group, or it is Mycenaean Greek overlaid by Doric, with a non-Greek native influence. Regarding the speech of the ancient Macedonians diverse theories have been put forward, but the epigraphic activity and the archaeological discoveries in

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864-649: A narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include dimercaprol , theophylline , warfarin and lithium carbonate . Some antibiotics and antifungals require monitoring to balance efficacy with minimizing adverse effects , including: gentamicin , vancomycin , amphotericin B (nicknamed 'amphoterrible' for this very reason), and polymyxin B . Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from x-rays , gamma rays , or charged or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment

936-543: A prefix /e-/, called the augment . This was probably originally a separate word, meaning something like "then", added because tenses in PIE had primarily aspectual meaning. The augment is added to the indicative of the aorist, imperfect, and pluperfect, but not to any of the other forms of the aorist (no other forms of the imperfect and pluperfect exist). The two kinds of augment in Greek are syllabic and quantitative. The syllabic augment

1008-426: A related group. For instance, the opioid painkiller remifentanil is very forgiving, offering a therapeutic index of 33,000:1, while Diazepam , a benzodiazepine sedative-hypnotic and skeletal muscle relaxant , has a less forgiving therapeutic index of 100:1. Morphine is even less so with a therapeutic index of 70. Less safe are cocaine (a stimulant and local anaesthetic ) and ethanol (colloquially,

1080-671: A separate historical stage, though its earliest form closely resembles Attic Greek , and its latest form approaches Medieval Greek , and Koine may be classified as Ancient Greek in a wider sense. There were several regional dialects of Ancient Greek; Attic Greek developed into Koine. Ancient Greek was a pluricentric language , divided into many dialects. The main dialect groups are Attic and Ionic , Aeolic , Arcadocypriot , and Doric , many of them with several subdivisions. Some dialects are found in standardized literary forms in literature , while others are attested only in inscriptions. There are also several historical forms. Homeric Greek

1152-609: A standard subject of study in educational institutions of the Western world since the Renaissance . This article primarily contains information about the Epic and Classical periods of the language, which are the best-attested periods and considered most typical of Ancient Greek. From the Hellenistic period ( c.  300 BC ), Ancient Greek was followed by Koine Greek , which is regarded as

1224-459: A tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameters distant from irradiated cells exhibit a phenotype of enhanced genetic instability such as micronucleation. This suggests an effect on cell-to-cell communication such as paracrine and juxtacrine signaling . Normal cells do not lose their DNA repair mechanism whereas cancer cells often lose it during radiotherapy. However,

1296-510: A vowel or /n s r/ ; final stops were lost, as in γάλα "milk", compared with γάλακτος "of milk" (genitive). Ancient Greek of the classical period also differed in both the inventory and distribution of original PIE phonemes due to numerous sound changes, notably the following: The pronunciation of Ancient Greek was very different from that of Modern Greek . Ancient Greek had long and short vowels ; many diphthongs ; double and single consonants; voiced, voiceless, and aspirated stops ; and

1368-458: Is a key checkpoint for survival of cells. G2/M arrest occurs when cells need to repair after S phase but before mitotic entry. It is known that S phase is the most resistant to radiation and M phase is the most sensitive to radiation. p53 , a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation. For example, irradiation of myeloid leukemia cells leads to an increase in p53 and

1440-556: Is a literary form of Archaic Greek (derived primarily from Ionic and Aeolic) used in the epic poems , the Iliad and the Odyssey , and in later poems by other authors. Homeric Greek had significant differences in grammar and pronunciation from Classical Attic and other Classical-era dialects. The origins, early form and development of the Hellenic language family are not well understood because of

1512-418: Is added to stems beginning with consonants, and simply prefixes e (stems beginning with r , however, add er ). The quantitative augment is added to stems beginning with vowels, and involves lengthening the vowel: Some verbs augment irregularly; the most common variation is e → ei . The irregularity can be explained diachronically by the loss of s between vowels, or that of the letter w , which affected

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1584-442: Is an important indicator of the probability of successful development. Recognizing drug candidates with potentially suboptimal TI at the earliest possible stage helps to initiate mitigation or potentially re-deploy resources. TI is the quantitative relationship between pharmacological efficacy and toxicological safety of a drug, without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert

1656-644: Is called 'East Greek'. Arcadocypriot apparently descended more closely from the Mycenaean Greek of the Bronze Age. Boeotian Greek had come under a strong Northwest Greek influence, and can in some respects be considered a transitional dialect, as exemplified in the poems of the Boeotian poet Pindar who wrote in Doric with a small Aeolic admixture. Thessalian likewise had come under Northwest Greek influence, though to

1728-448: Is considered by some linguists to have been closely related to Greek . Among Indo-European branches with living descendants, Greek is often argued to have the closest genetic ties with Armenian (see also Graeco-Armenian ) and Indo-Iranian languages (see Graeco-Aryan ). Ancient Greek differs from Proto-Indo-European (PIE) and other Indo-European languages in certain ways. In phonotactics , ancient Greek words could end only in

1800-538: Is desirous for the value of LD 50 to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TI safety increases as the difference between LD 50 and ED 50 increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vise-versa. T I efficacy = E D 50 T D 50 {\displaystyle TI_{\text{efficacy}}={\frac {ED_{50}}{TD_{50}}}} Ideally

1872-497: Is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues. Both of these parameters have sigmoidal dose–response curves . Thus, a favorable outcome in dose–response for tumor tissue is greater than that of normal tissue for the same dose, meaning that the treatment is effective on tumors and does not cause serious morbidity to normal tissue. Conversely, overlapping response for two tissues

1944-455: Is highly likely to cause serious morbidity to normal tissue and ineffective treatment of tumors. The mechanism of radiation therapy is categorized as direct or indirect radiation. Both direct and indirect radiation induce DNA mutation or chromosomal rearrangement during its repair process. Direct radiation creates a DNA free radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating

2016-400: Is preferable instead of a lower one; an individual would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to induce the therapeutic effect of the drug. However, a lower efficacy-based therapeutic index is preferable instead of a higher one; an individual would have to take a higher dose of a drug to reach the toxic threshold than the dose taken to induce

2088-419: Is properly specified, the protective index is often more informative about a substance's relative safety. Nevertheless, the safety-based therapeutic index ( T I safety {\displaystyle {TI_{\text{safety}}}} ) is still useful as it can be considered an upper bound of the protective index, and the former also has the advantages of objectivity and easier comprehension. Since

2160-493: Is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure instead of dose to calculate TI. To account for delays between exposure and toxicity,

2232-698: The Greek region of Macedonia during the last decades has brought to light documents, among which the first texts written in Macedonian , such as the Pella curse tablet , as Hatzopoulos and other scholars note. Based on the conclusions drawn by several studies and findings such as Pella curse tablet , Emilio Crespo and other scholars suggest that ancient Macedonian was a Northwest Doric dialect , which shares isoglosses with its neighboring Thessalian dialects spoken in northeastern Thessaly . Some have also suggested an Aeolic Greek classification. The Lesbian dialect

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2304-584: The LD 50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another. A therapeutic index does not consider drug interactions or synergistic effects. For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone. Therapeutic index also does not take into account

2376-600: The ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: Mycenaean Greek ( c.  1400–1200 BC ), Dark Ages ( c.  1200–800 BC ), the Archaic or Epic period ( c.  800–500 BC ), and the Classical period ( c.  500–300 BC ). Ancient Greek was the language of Homer and of fifth-century Athenian historians, playwrights, and philosophers . It has contributed many words to English vocabulary and has been

2448-512: The effective dose is the amount and frequency that produces the desired effect, which can vary, and can be greater or less than the therapeutically effective dose. The Certain Safety Factor , also referred to as the Margin of Safety (MOS) , is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD 1 /ED 99 ). This is a better safety index than

2520-426: The muscarinic acetylcholine receptor and NMDA receptor and their respective agonists. For the muscarinic acetylcholine receptor , which is a G protein-coupled receptor (GPCR), the endogenous agonist is acetylcholine . The binding of this neurotransmitter causes the conformational changes that propagate a signal into the cell. The conformational changes are the primary effect of the agonist, and are related to

2592-501: The present , future , and imperfect are imperfective in aspect; the aorist , present perfect , pluperfect and future perfect are perfective in aspect. Most tenses display all four moods and three voices, although there is no future subjunctive or imperative. Also, there is no imperfect subjunctive, optative or imperative. The infinitives and participles correspond to the finite combinations of tense, aspect, and voice. The indicative of past tenses adds (conceptually, at least)

2664-472: The protective index uses TD 50 (median toxic dose) in place of LD 50 . Protective index = T D 50 E D 50 = 1 T I efficacy {\displaystyle {\text{Protective index}}={\frac {TD_{50}}{ED_{50}}}={\frac {1}{TI_{\text{efficacy}}}}} For many substances, toxicity can occur at levels far below lethal effects (that cause death), and thus, if toxicity

2736-428: The "alcohol" in alcoholic beverages , a widely available sedative consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively. Paracetamol , alternatively known by its trade names Tylenol or Panadol, also has a therapeutic index of 10. Even less safe are drugs such as digoxin , a cardiac glycoside ; its therapeutic index is approximately 2:1. Other examples of drugs with

2808-1031: The 5th century BC. Ancient pronunciation cannot be reconstructed with certainty, but Greek from the period is well documented, and there is little disagreement among linguists as to the general nature of the sounds that the letters represent. /oː/ raised to [uː] , probably by the 4th century BC. Greek, like all of the older Indo-European languages , is highly inflected. It is highly archaic in its preservation of Proto-Indo-European forms. In ancient Greek, nouns (including proper nouns) have five cases ( nominative , genitive , dative , accusative , and vocative ), three genders ( masculine , feminine , and neuter ), and three numbers (singular, dual , and plural ). Verbs have four moods ( indicative , imperative , subjunctive , and optative ) and three voices (active, middle, and passive ), as well as three persons (first, second, and third) and various other forms. Verbs are conjugated through seven combinations of tenses and aspect (generally simply called "tenses"):

2880-490: The Archaic period of ancient Greek (see Homeric Greek for more details): Μῆνιν ἄειδε, θεά, Πηληϊάδεω Ἀχιλῆος οὐλομένην, ἣ μυρί' Ἀχαιοῖς ἄλγε' ἔθηκε, πολλὰς δ' ἰφθίμους ψυχὰς Ἄϊδι προΐαψεν ἡρώων, αὐτοὺς δὲ ἑλώρια τεῦχε κύνεσσιν οἰωνοῖσί τε πᾶσι· Διὸς δ' ἐτελείετο βουλή· ἐξ οὗ δὴ τὰ πρῶτα διαστήτην ἐρίσαντε Ἀτρεΐδης τε ἄναξ ἀνδρῶν καὶ δῖος Ἀχιλλεύς. The beginning of Apology by Plato exemplifies Attic Greek from

2952-558: The Classical period of ancient Greek. (The second line is the IPA , the third is transliterated into the Latin alphabet using a modern version of the Erasmian scheme .) Ὅτι [hóti Hóti μὲν men mèn ὑμεῖς, hyːmêːs hūmeîs,   Therapeutic index The therapeutic index ( TI ; also referred to as therapeutic ratio ) is a quantitative measurement of the relative safety of

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3024-492: The DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks . Direct inhibitors target proteins ( PARP family ) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as EGFR and insulin growth factor . The effective therapeutic index can be affected by targeting , in which

3096-481: The ED 50 is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD 50 is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED 50 and TD 50 , the greater the value of TI efficacy . Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window. Similar to safety-based therapeutic index,

3168-511: The NMDA receptor requires both the endogenous agonists , N-methyl-D-aspartate (NMDA) and glycine . These co-agonists are both required to induce the conformational change needed for the NMDA receptor to allow flow through the ion channel , in this case calcium. An aspect demonstrated by the NMDA receptor is that the mechanism or response of agonists can be blocked by a variety of chemical and biological factors. NMDA receptors specifically are blocked by

3240-593: The TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose. A review published by Muller and Milton in Nature Reviews Drug Discovery critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics. The therapeutic index varies widely among substances, even within

3312-513: The agent to an oncophilic substance, as in peptide receptor radionuclide therapy for neuroendocrine tumors and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity. Sometimes the term safety ratio is used, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use. In such cases,

3384-413: The agonist's binding affinity and agonist efficacy . Other agonists that bind to this receptor will fall under one of the different categories of agonist mentioned above based on their specific binding affinity and efficacy. The NMDA receptor is an example of an alternate mechanism of action, as the NMDA receptor requires co-agonists for activation. Rather than simply requiring a single specific agonist,

3456-550: The aorist. Following Homer 's practice, the augment is sometimes not made in poetry , especially epic poetry. The augment sometimes substitutes for reduplication; see below. Almost all forms of the perfect, pluperfect, and future perfect reduplicate the initial syllable of the verb stem. (A few irregular forms of perfect do not reduplicate, whereas a handful of irregular aorists reduplicate.) The three types of reduplication are: Irregular duplication can be understood diachronically. For example, lambanō (root lab ) has

3528-419: The augment when it was word-initial. In verbs with a preposition as a prefix, the augment is placed not at the start of the word, but between the preposition and the original verb. For example, προσ(-)βάλλω (I attack) goes to προσ έ βαλoν in the aorist. However compound verbs consisting of a prefix that is not a preposition retain the augment at the start of the word: αὐτο(-)μολῶ goes to ηὐ τομόλησα in

3600-438: The center of Greek scholarship, this division of people and language is quite similar to the results of modern archaeological-linguistic investigation. One standard formulation for the dialects is: West vs. non-West Greek is the strongest-marked and earliest division, with non-West in subsets of Ionic-Attic (or Attic-Ionic) and Aeolic vs. Arcadocypriot, or Aeolic and Arcado-Cypriot vs. Ionic-Attic. Often non-West

3672-455: The concentration of agonist needed to elicit half of the maximum biological response of the agonist. The EC 50 value is useful for comparing the potency of drugs with similar efficacies producing physiologically similar effects. The smaller the EC 50 value, the greater the potency of the agonist, the lower the concentration of drug that is required to elicit the maximum biological response. When

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3744-494: The cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing chemical residue tolerances in foods. Maximum tolerated dose studies are also done in clinical trials . MTD is an essential aspect of a drug's profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent

3816-441: The desired effect without unacceptable toxicity . The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects . The maximum dose is used, rather than a lower dose, to reduce the number of test subjects (and, among other things,

3888-611: The dialect of Sparta ), and Northern Peloponnesus Doric (including Corinthian ). All the groups were represented by colonies beyond Greece proper as well, and these colonies generally developed local characteristics, often under the influence of settlers or neighbors speaking different Greek dialects. After the conquests of Alexander the Great in the late 4th century BC, a new international dialect known as Koine or Common Greek developed, largely based on Attic Greek , but with influence from other dialects. This dialect slowly replaced most of

3960-426: The drug, to avoid harm. Medications with narrow therapeutic windows include theophylline , digoxin , lithium , and warfarin . Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity. The maximum tolerated dose (MTD) refers to the highest dose of a radiological or pharmacological treatment that will produce

4032-438: The early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population ( LD 50 ) divided by the minimum effective dose for 50% of the population (ED 50 ). In modern settings, more sophisticated toxicity endpoints are used. For many drugs, severe toxicities in humans occur at sublethal doses, which limit their maximum dose. A higher safety-based therapeutic index

4104-448: The ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable. The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of

4176-418: The high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of carcinogenesis . This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of

4248-556: The historical Dorians . The invasion is known to have displaced population to the later Attic-Ionic regions, who regarded themselves as descendants of the population displaced by or contending with the Dorians. The Greeks of this period believed there were three major divisions of all Greek people – Dorians, Aeolians, and Ionians (including Athenians), each with their own defining and distinctive dialects. Allowing for their oversight of Arcadian, an obscure mountain dialect, and Cypriot, far from

4320-472: The historical circumstances of the times imply that the overall groups already existed in some form. Scholars assume that major Ancient Greek period dialect groups developed not later than 1120 BC, at the time of the Dorian invasions —and that their first appearances as precise alphabetic writing began in the 8th century BC. The invasion would not be "Dorian" unless the invaders had some cultural relationship to

4392-421: The narrower this margin, the more likely it is that the drug will produce unwanted effects. The therapeutic index emphasizes the importance of the margin of safety, as distinct from the potency, in determining the usefulness of a drug. Ancient Greek language Ancient Greek ( Ἑλληνῐκή , Hellēnikḗ ; [hellɛːnikɛ́ː] ) includes the forms of the Greek language used in ancient Greece and

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4464-499: The older dialects, although the Doric dialect has survived in the Tsakonian language , which is spoken in the region of modern Sparta. Doric has also passed down its aorist terminations into most verbs of Demotic Greek . By about the 6th century AD, the Koine had slowly metamorphosed into Medieval Greek . Phrygian is an extinct Indo-European language of West and Central Anatolia , which

4536-487: The perfect stem eilēpha (not * lelēpha ) because it was originally slambanō , with perfect seslēpha , becoming eilēpha through compensatory lengthening. Reduplication is also visible in the present tense stems of certain verbs. These stems add a syllable consisting of the root's initial consonant followed by i . A nasal stop appears after the reduplication in some verbs. The earliest extant examples of ancient Greek writing ( c.  1450 BC ) are in

4608-450: The potential to bind in different locations and in different ways depending on the type of agonist and the type of receptor. The process of binding is unique to the receptor-agonist relationship, but binding induces a conformational change and activates the receptor. This conformational change is often the result of small changes in charge or changes in protein folding when the agonist is bound. Two examples that demonstrate this process are

4680-506: The protective index (PI) is calculated as TD 50 divided by ED 50 , it can be mathematically expressed that: which means that T I efficacy {\displaystyle TI_{\text{efficacy}}} is a reciprocal of protective index. All the above types of therapeutic index can be used in both pre-clinical trials and clinical trials . A low efficacy-based therapeutic index ( T I efficacy {\displaystyle TI_{\text{efficacy}}} ) and

4752-399: The ratio of the dose of the drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD 50 ) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED 50 ). In contrast, in a drug development setting TI is calculated based on plasma exposure levels. In

4824-399: The receptor. This response as discussed above can vary from allowing flow of ions to activating a GPCR and transmitting a signal into the cell . Potency is the amount of agonist needed to elicit a desired response. The potency of an agonist is inversely related to its half maximal effective concentration (EC 50 ) value. The EC 50 can be measured for a given agonist by determining

4896-445: The same bodily responses but does not bind to the same receptor. New findings that broaden the conventional definition of pharmacology demonstrate that ligands can concurrently behave as agonist and antagonists at the same receptor, depending on effector pathways or tissue type. Terms that describe this phenomenon are " functional selectivity ", "protean agonism", or selective receptor modulators . As mentioned above, agonists have

4968-517: The syllabic script Linear B . Beginning in the 8th century BC, however, the Greek alphabet became standard, albeit with some variation among dialects. Early texts are written in boustrophedon style, but left-to-right became standard during the classic period. Modern editions of ancient Greek texts are usually written with accents and breathing marks , interword spacing , modern punctuation , and sometimes mixed case , but these were all introduced later. The beginning of Homer 's Iliad exemplifies

5040-456: The therapeutic agent is concentrated in its desirable area of effect. For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching

5112-754: The therapeutic effect of the drug. Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of its blood levels in the person taking it. This may be achieved through therapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range. Based on efficacy and safety of drugs, there are two types of therapeutic index: T I safety = L D 50 E D 50 {\displaystyle TI_{\text{safety}}={\frac {LD_{50}}{ED_{50}}}} It

5184-475: Was Aeolic. For example, fragments of the works of the poet Sappho from the island of Lesbos are in Aeolian. Most of the dialect sub-groups listed above had further subdivisions, generally equivalent to a city-state and its surrounding territory, or to an island. Doric notably had several intermediate divisions as well, into Island Doric (including Cretan Doric ), Southern Peloponnesus Doric (including Laconian ,

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