Misplaced Pages

#876123

55-560: MTD may refer to: Medicine [ edit ] Maximum tolerated dose , in drug development Muscle tension dysphonia , hyperfunctional musculature causing a hoarse voice Organizations [ edit ] Makkal Tamil Desam Katchi (People's Tamil Land Party), a political party in Tamil Nadu, India Metal Trades Department of the AFL-CIO Michael Tobias Design ,

110-436: 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

165-488: 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

220-442: A dose that without treatment will be lethal to 50% of the population within (respectively) 30 or 60 days. These measures are used more commonly within radiation health physics , for ionizing radiation , as survival beyond 60 days usually results in recovery. A comparable measurement is LCt 50 , which relates to lethal dosage from exposure, where C is concentration and t is time. It is often expressed in terms of mg-min/m . ICt 50

275-467: 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

330-405: 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

385-466: A manufacturer of electric bass guitars Movimiento de Trabajadores Desempleados , a type of unemployed worker's organization in Argentina MTD Products , an American manufacturer of outdoor power equipment for the mass market MTD, a German developer and manufacturer of line, bar and hyperspectral LED luminaires for industry Technology [ edit ] Memory technology device ,

440-649: 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

495-426: 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,

550-450: A substance's acute toxicity . A lower LD 50 is indicative of higher toxicity. The term LD 50 is generally attributed to John William Trevan. The test was created by J. W. Trevan in 1927. The term semilethal dose is occasionally used in the same sense, in particular with translations of foreign language text, but can also refer to a sublethal dose. LD 50 is usually determined by tests on animals such as laboratory mice . In 2011,

605-547: A time period used in business and accounting Moralistic therapeutic deism MTD(f) , a minimax search algorithm Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title MTD . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=MTD&oldid=1194173813 " Category : Disambiguation pages Hidden categories: Short description

SECTION 10

#1732852200877

660-459: 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,

715-634: A type of device file in Linux for interacting with flash memory Metadynamics , a computer simulation method in computational physics, chemistry and biology MTD (mobile network) , a former manual mobile network in Sweden, Norway and Denmark Other uses [ edit ] Making Tax Digital a UK Government initiative of HMRC A mass transit district, such as the Champaign-Urbana Mass Transit District Month-To-Date ,

770-416: A very wide range. The botulinum toxin as the most toxic substance known has an LD 50 value of 1 ng/kg, while the most non-toxic substance water has an LD 50 value of more than 90 g/kg; a difference of about 1 in 100 billion, or 11 orders of magnitude. As with all measured values that differ by many orders of magnitude, a logarithmic view is advisable. Well-known examples are the indication of

825-458: 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

880-442: 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

935-538: 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

990-497: 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

1045-415: Is different from Wikidata All article disambiguation pages All disambiguation pages Maximum tolerated dose Classically, for clinical indications of an approved drug, TI refers to 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

1100-419: Is equivalent to 10 minutes of 10 mg/m (1 × 100 = 100, as does 10 × 10 = 100). Some chemicals, such as hydrogen cyanide , are rapidly detoxified by the human body, and do not follow Haber's law. In these cases, the lethal concentration may be given simply as LC 50 and qualified by a duration of exposure (e.g., 10 minutes). The material safety data sheets for toxic substances frequently use this form of

1155-455: 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

SECTION 20

#1732852200877

1210-497: Is more useful to compare such substances by therapeutic index , which is simply the ratio of LD 50 to ED 50 . The following examples are listed in reference to LD 50 values, in descending order, and accompanied by LC 50 values, {bracketed}, when appropriate. human, smoking human, inhalation human, oral 3.3 μg/kg 10–1000 μg/kg 0.0000033 0.00001–0.001 human, oral 5.7 μg/kg 0.0000057 2.3–31.5 μg/kg 0.0000023 The LD 50 values have

1265-400: 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

1320-419: 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

1375-469: Is the dose that will cause incapacitation rather than death. These measures are commonly used to indicate the comparative efficacy of chemical warfare agents, and dosages are typically qualified by rates of breathing (e.g., resting = 10 L/min) for inhalation, or degree of clothing for skin penetration. The concept of Ct was first proposed by Fritz Haber and is sometimes referred to as Haber's law , which assumes that exposure to 1 minute of 100 mg/m

1430-493: 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,

1485-584: 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

1540-512: 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

1595-411: The median lethal dose , LD 50 (abbreviation for " lethal dose , 50%"), LC 50 (lethal concentration, 50%) or LCt 50 is a toxic unit that measures the lethal dose of a given substance . The value of LD 50 for a substance is the dose required to kill half the members of a tested population after a specified test duration. LD 50 figures are frequently used as a general indicator of

1650-472: 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

1705-428: 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

MTD - Misplaced Pages Continue

1760-492: 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

1815-481: 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,

1870-593: 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

1925-475: The U.S. Food and Drug Administration approved alternative methods to LD 50 for testing the cosmetic drug Botox without animal tests. The LD 50 is usually expressed as the mass of substance administered per unit mass of test subject, typically as milligrams of substance per kilogram of body mass, sometimes also stated as nanograms (suitable for botulinum ), micrograms , or grams (suitable for paracetamol ) per kilogram. Stating it this way allows

1980-513: 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,

2035-731: The baseline substance is neatly 1 in the negative logarithmic toxin scale. Animal-rights and animal-welfare groups, such as Animal Rights International, have campaigned against LD 50 testing on animals. Several countries, including the UK , have taken steps to ban the oral LD 50 , and the Organisation for Economic Co-operation and Development (OECD) abolished the requirement for the oral test in 2001 (see Test Guideline 401, Trends in Pharmacological Sciences Vol 22, February 22, 2001). A number of procedures have been defined to derive

2090-494: 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

2145-441: 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,

2200-630: 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 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

2255-426: 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

MTD - Misplaced Pages Continue

2310-497: The earthquake strength using the Richter scale , the pH value , as a measure for the acidic or basic character of an aqueous solution or of loudness in decibels . In this case, the negative decimal logarithm of the LD 50 values, which is standardized in kg per kg body weight, is considered −log 10 (LD 50 ) . The dimensionless value found can be entered in a toxin scale. Water as

2365-448: 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

2420-471: The exposure time is important (see below). The choice of 50% lethality as a benchmark avoids the potential for ambiguity of making measurements in the extremes and reduces the amount of testing required. However, this also means that LD 50 is not the lethal dose for all subjects; some may be killed by much less, while others survive doses far higher than the LD 50 . Measures such as "LD 1 " and "LD 99 " (dosage required to kill 1% or 99%, respectively, of

2475-418: 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

2530-399: The number of LD 50 s to some test animal. In biological warfare infective dosage is the number of infective doses per cubic metre of air times the number of minutes of exposure (e.g., ICt 50 is 100 medium doses - min/m ). As a measure of toxicity, LD 50 is somewhat unreliable and results may vary greatly between testing facilities due to factors such as the genetic characteristics of

2585-566: The physiological differences between mice, rats, and humans. Many venomous snakes are specialized predators on mice, and their venom may be adapted specifically to incapacitate mice; and mongooses may be exceptionally resistant. While most mammals have a very similar physiology, LD 50 results may or may not have equal bearing upon every mammal species, such as humans, etc. Note: Comparing substances (especially drugs) to each other by LD 50 can be misleading in many cases due (in part) to differences in effective dose (ED 50 ). Therefore, it

2640-650: The prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population. Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patient's health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional "blunting" with antidepressants, pruritus with opiates , and blurred vision with anticholinergics . LD50 In toxicology ,

2695-506: 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

2750-423: The relative toxicity of different substances to be compared and normalizes for the variation in the size of the animals exposed (although toxicity does not always scale simply with body mass). For substances in the environment, such as poisonous vapors or substances in water that are toxic to fish, the concentration in the environment (per cubic metre or per litre) is used, giving a value of LC 50 . But in this case,

2805-489: The sample population, animal species tested, environmental factors and mode of administration. There can be wide variability between species as well; what is relatively safe for rats may very well be extremely toxic for humans ( cf. paracetamol toxicity ), and vice versa. For example, chocolate, comparatively harmless to humans, is known to be toxic to many animals . When used to test venom from venomous creatures, such as snakes , LD 50 results may be misleading due to

SECTION 50

#1732852200877

2860-471: The term even if the substance does follow Haber's law. For disease-causing organisms, there is also a measure known as the median infective dose and dosage. The median infective dose (ID 50 ) is the number of organisms received by a person or test animal qualified by the route of administration (e.g., 1,200 org/man per oral). Because of the difficulties in counting actual organisms in a dose, infective doses may be expressed in terms of biological assay, such as

2915-432: The test population) are occasionally used for specific purposes. Lethal dosage often varies depending on the method of administration ; for instance, many substances are less toxic when administered orally than when intravenously administered. For this reason, LD 50 figures are often qualified with the mode of administration, e.g., "LD 50 i.v." The related quantities LD 50 /30 or LD 50 /60 are used to refer to

2970-456: 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

3025-754: 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

#876123