726:) 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 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.
895:. 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 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
968:. 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 the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA
734:
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, 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.
2006:
1163:(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 the drug, to avoid harm. Medications with narrow therapeutic windows include
730:
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.
1238:
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
105:
For many drugs, severe toxicities in humans occur at sublethal doses, which limit their maximum dose. A higher safety-based therapeutic index 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
1150:
increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone. Therapeutic index also does not take into account 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
999:
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
729:
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 a calculated TI into something useful, the nature and limitations of pharmacological
1234:
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 the prescription and dispensing of
733:
In general, it 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,
947:
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
106:
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 the therapeutic effect of the drug.
116:
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
516:
For many substances, toxicity can occur at levels far below lethal effects (that cause death), and thus, if toxicity is properly specified, the protective index is often more informative about a substance's relative safety. Nevertheless, the safety-based therapeutic index
887:
or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment 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
934:
in M phase, suggesting it 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.
512:
948:
arrest has been a focus for therapeutic treatment. Irradiation of 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
1071:
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.
1132:
2010:
608:
382:
1012:
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.
292:
964:
mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of
1391:
Ratanajamit C, Soorapan S, Doang-ngern T, Waenwaisart W, Suwanchavalit L, Suwansiri S, Jantasaro S, Yanate I (November 2006). "Appropriateness of therapeutic drug monitoring for lithium".
201:
a quantitative measurement of the relative safety of a drug by comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect
694:
641:
547:
724:
42:) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the
433:
54:
refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.
919:
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.
1187:
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.
939:, 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
828:
Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include
1078:
1223:(and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing
926:. 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
743:
critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.
65:
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,
2056:
570:
1963:
1585:
1314:
1001:
87:
In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population (
2148:
2113:
1847:
Yokoya A, Shikazono N, Fujii K, Urushibara A, Akamatsu K, Watanabe R (2008-10-01). "DNA damage induced by the direct effect of radiation".
2842:
320:
1501:
230:
2832:
981:
2877:
2772:
2265:
392:
is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED
2300:
1235:
quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population.
2827:
2523:
2434:
2025:
298:
to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TI
2752:
2377:
1348:
Muller PY, Milton MN (October 2012). "The determination and interpretation of the therapeutic index in drug development".
1266:
1053:
980:(ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as
739:
95:
2305:
1420:"Estimating the minimum therapeutically effective dose of a compound via regression modelling and percentile estimation"
1207:. The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable
952:
of enhanced genetic instability such as micronucleation. This suggests an effect on cell-to-cell communication such as
2495:
1882:
118:
2230:
2049:
973:
2872:
2742:
2490:
2484:
900:
310:
increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vise-versa.
2807:
2509:
1812:
Thoms J, Bristow RG (October 2010). "DNA repair targeting and radiotherapy: a focus on the therapeutic ratio".
892:
1777:
1669:
2558:
2320:
2315:
2225:
2143:
1220:
779:, has a less forgiving therapeutic index of 100:1. Morphine is even less so with a therapeutic index of 70.
213:
72:) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED
1491:
2694:
2455:
2430:
2365:
2254:
2138:
992:
669:
644:
616:
520:
553:
of the protective index, and the former also has the advantages of objectivity and easier comprehension.
2802:
2594:
2396:
2073:
2042:
1208:
1200:
1005:
985:
944:
699:
58:
507:{\displaystyle {\text{Protective index}}={\frac {TD_{50}}{ED_{50}}}={\frac {1}{TI_{\text{efficacy}}}}}
2837:
2699:
2609:
2450:
2330:
2098:
1906:
Soriani RR, Satomi LC, Pinto Td (2005-07-01). "Effects of ionizing radiation in ginkgo and guarana".
1856:
1172:
957:
122:
2747:
2635:
2604:
2250:
2210:
2133:
996:
969:
875:
Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from
806:
consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively.
149:
62:
995:, in which the therapeutic agent is concentrated in its desirable area of effect. For example, in
2717:
2667:
2568:
2381:
2360:
2260:
2181:
2093:
1851:. The International Symposium on Charged Particle and Photon Interaction with Matter – ASR 2007.
1373:
1065:
1026:
799:
651:
43:
388:
is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD
1466:
2712:
2573:
2563:
2385:
2220:
1959:
1829:
1791:
1762:"Drug therapy in dental practice: general principles. Part 2 – pharmacodynamic considerations"
1741:
1692:
1647:
1581:
1497:
1447:
1439:
1400:
1365:
1310:
1009:
943:
cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with
841:
822:
791:
772:
66:
1000:
agents can be made more efficacious by attaching the agent to an oncophilic substance, as in
2757:
2645:
2640:
2440:
2410:
2196:
2176:
2158:
1915:
1864:
1821:
1781:
1773:
1731:
1723:
1684:
1637:
1629:
1525:
1490:
Goodman, Louis S. (2011). Brunton, Laurence L.; Chabner, Bruce; Knollmann, Björn C. (eds.).
1431:
1357:
1248:
1224:
1037:
effect, which can vary, and can be greater or less than the therapeutically effective dose.
940:
912:
889:
884:
413:
77:
121:(TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with
2797:
2672:
2500:
2460:
2445:
2153:
2103:
1228:
811:
776:
1576:
Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics".
1305:
Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics".
404:. Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window.
2016:
1860:
847:
Some antibiotics and antifungals require monitoring to balance efficacy with minimizing
2787:
2767:
2686:
2528:
2270:
2215:
2018:
Report for
Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition
1786:
1761:
1736:
1711:
1642:
1617:
1260:
1212:
1147:
965:
860:
848:
769:
655:
1933:
1919:
1868:
1551:
2866:
2792:
2279:
2186:
1727:
1688:
153:
1825:
1377:
751:
The therapeutic index varies widely among substances, even within a related group.
2762:
2722:
2623:
2547:
2425:
2108:
2065:
1633:
1216:
1164:
904:
896:
833:
761:
1979:
907:
from radiation energy deposition that damages DNA. Indirect radiation occurs from
1239:
with treatment. Such examples include emotional "blunting" with antidepressants,
1211:
in a population, when the level of exposure is not sufficient to cause premature
1127:{\displaystyle {\text{Certain safety factor}}=\mathrm {\frac {LD_{1}}{ED_{99}}} }
2847:
2334:
2310:
1670:"Comparison of acute lethal toxicity of commonly abused psychoactive substances"
1049:
864:
829:
807:
550:
217:
17:
1517:
2727:
2659:
2551:
2326:
1219:. The maximum dose is used, rather than a lower dose, to reduce the number of
961:
923:
908:
856:
852:
758:
157:
1443:
1029:
used for non-therapeutic purposes, e.g. recreational use. In such cases, the
2505:
1530:
953:
949:
916:
880:
787:
81:
1833:
1795:
1745:
1696:
1651:
1435:
1419:
1404:
1369:
1451:
2627:
2599:
2586:
2355:
2275:
1286:
1240:
1204:
1176:
837:
803:
765:
603:{\displaystyle TI_{\text{efficacy}}={\frac {1}{\text{Protective index}}}}
172:
2088:
1244:
1168:
1143:
977:
931:
927:
818:
795:
783:
102:). In modern settings, more sophisticated toxicity endpoints are used.
1393:
Journal of the
Medical Association of Thailand = Chotmaihet Thangphaet
1227:
tolerances in foods. Maximum tolerated dose studies are also done in
755:
1361:
1203:
treatment that will produce the desired effect without unacceptable
764:
is very forgiving, offering a therapeutic index of 33,000:1, while
876:
187:
1524:. The International Union of Pure and Applied Chemistry (IUPAC).
2480:
2373:
2369:
2171:
1558:. Canadian Centre for Occupational Health and Safety. 2024-05-10
1281:
1276:
1271:
88:
2038:
2034:
377:{\displaystyle TI_{\text{efficacy}}={\frac {ED_{50}}{TD_{50}}}}
1493:
936:
650:
All the above types of therapeutic index can be used in both
287:{\displaystyle TI_{\text{safety}}={\frac {LD_{50}}{ED_{50}}}}
1580:(10th ed.). New York: McGraw-Hill Medical. p. 17.
1309:(10th ed.). New York: McGraw-Hill Medical. p. 17.
1142:
A therapeutic index does not consider drug interactions or
903:
during its repair process. Direct radiation creates a DNA
27:
Quantitative measurement of the relative safety of a drug
1778:
10.2344/0003-3006(2007)54[19:DTIDPG]2.0.CO;2
109:
For more details about types of therapeutic index, see
1199:(MTD) refers to the highest dose of a radiological or
863:(nicknamed 'amphoterrible' for this very reason), and
1081:
702:
672:
619:
573:
523:
436:
323:
233:
1958:(8th ed.). Churchill Livingstone. p. 125.
220:
of drugs, there are two types of therapeutic index:
2820:
2780:
2736:
2685:
2658:
2622:
2585:
2546:
2537:
2473:
2418:
2409:
2348:
2293:
2242:
2204:
2195:
2126:
2081:
2072:
1343:
1341:
1033:dose is the amount and frequency that produces the
991:The effective therapeutic index can be affected by
556:
Since the protective index (PI) is calculated as TD
61:of an approved drug, TI refers to the ratio of the
1663:
1661:
1126:
922:Cancer cells cause an imbalance of signals in the
718:
688:
635:
602:
541:
506:
376:
286:
1954:Rang H, et al. (2015). "Pharmacokinetics".
1807:
1805:
1604:, determined from quantal dose–response curves.
1333:, determined from quantal dose–response curves.
1263:– process of finding the correct dose of a drug
1146:effects. For example, the risk associated with
825:; its therapeutic index is approximately 2:1.
412:Similar to safety-based therapeutic index, the
1467:"The Minimum Effective Dose: Why Less is More"
2050:
696:) and a high safety-based therapeutic index (
549:) is still useful as it can be considered an
8:
1710:Bertolini A, Ferrari A, et al. (2006).
1592:The therapeutic index is the ratio of the TD
1321:The therapeutic index is the ratio of the TD
1578:Pharmacology Examination & Board Review
1307:Pharmacology Examination & Board Review
737:A review published by Muller and Milton in
564:, it can be mathematically expressed that:
2817:
2777:
2682:
2655:
2619:
2582:
2543:
2470:
2415:
2345:
2290:
2239:
2201:
2123:
2078:
2057:
2043:
2035:
1064:). This is a better safety index than the
1785:
1735:
1641:
1529:
1115:
1100:
1090:
1082:
1080:
710:
701:
680:
671:
627:
618:
590:
581:
572:
532:
524:
522:
495:
482:
470:
455:
445:
437:
435:
365:
350:
340:
331:
322:
275:
260:
250:
241:
232:
80:setting TI is calculated based on plasma
1025:is used, particularly when referring to
666:A low efficacy-based therapeutic index (
127:
1712:"Paracetamol New Vistas of an Old Drug"
1297:
1496:(12 ed.). New York: McGraw-Hill.
814:, also has a therapeutic index of 10.
302:increases as the difference between LD
1518:"IUPAC - median lethal dose (M03810)"
1002:peptide receptor radionuclide therapy
972:. Direct inhibitors target proteins (
160:that produces a biological response.
125:due to its narrow therapeutic range.
7:
689:{\displaystyle TI_{\text{efficacy}}}
636:{\displaystyle TI_{\text{efficacy}}}
542:{\displaystyle {TI_{\text{safety}}}}
2843:Minimum bactericidal concentration
1112:
1108:
1097:
1093:
719:{\displaystyle TI_{\text{safety}}}
294:It is desirous for the value of LD
25:
1920:10.1016/j.radphyschem.2005.01.003
1869:10.1016/j.radphyschem.2008.05.021
1618:"Anesthesia for the 21st century"
1552:"CCOHS: What is a LDâ‚…â‚€ and LCâ‚…â‚€?"
1430:(9–10): 925–932, discussion 933.
960:. Normal cells do not lose their
817:Even less safe are drugs such as
2833:Minimum inhibitory concentration
2009: This article incorporates
2004:
1728:10.1111/j.1527-3458.2006.00250.x
1689:10.1111/j.1360-0443.2004.00744.x
798:(colloquially, the "alcohol" in
314:Efficacy-based therapeutic index
2773:WHO list of essential medicines
2266:Non-specific effect of vaccines
1908:Radiation Physics and Chemistry
1849:Radiation Physics and Chemistry
1826:10.1016/j.semradonc.2010.06.003
810:, also known by its trade name
2828:Antimicrobial pharmacodynamics
2026:Congressional Research Service
1956:Rang & Dale's Pharmacology
1814:Seminars in Radiation Oncology
1634:10.1080/08998280.2000.11927635
1350:Nature Reviews. Drug Discovery
224:Safety-based therapeutic index
1:
2753:Functional analog (chemistry)
1750:Vol. 12, No. 3–4, pp. 250–275
1465:Street, Farnam (2014-02-13).
740:Nature Reviews Drug Discovery
400:, the greater the value of TI
98:for 50% of the population (ED
2306:Hill equation (biochemistry)
1056:to 99% of the population (LD
747:Range of therapeutic indices
1986:. National Cancer Institute
1616:Stanley TH (January 2000).
1418:Filloon, T. G. (May 1995).
1052:to 1% of population to the
119:therapeutic drug monitoring
2894:
2821:Antimicrobial pharmacology
2301:Dose–response relationship
2231:Desensitization (medicine)
1984:Dictionary of Cancer Terms
1247:, and blurred vision with
1044:, also referred to as the
911:of water, creating a free
110:
108:
57:Classically, for clinical
2743:Coinduction (anesthetics)
1887:National Cancer Institute
1760:Becker DE (Spring 2007).
901:chromosomal rearrangement
94:) divided by the minimum
2808:Multiple drug resistance
2781:Tolerance and resistance
2149:Physiological antagonist
1980:"maximum tolerated dose"
1772:(1): 19–23, quiz 24–25.
190:occurs in 50% of cases.
175:occurs in 50% of cases.
2559:Neuropsychopharmacology
2321:Cheng-Prussoff Equation
2316:Del Castillo Katz model
2243:Other effects of ligand
2226:Receptor (biochemistry)
2144:Irreversible antagonist
1883:"Ataxia Telangiectasia"
1531:10.1351/goldbook.M03810
1183:Optimal biological dose
2878:Life sciences industry
2695:Classical pharmacology
2456:Plasma protein binding
2431:Volume of distribution
2139:Competitive antagonist
2011:public domain material
1668:Gable RS (June 2004).
1436:10.1002/sim.4780140911
1424:Statistics in Medicine
1209:adverse health effects
1197:maximum tolerated dose
1191:Maximum tolerated dose
1128:
1048:, is the ratio of the
1046:Margin of Safety (MOS)
720:
690:
637:
604:
543:
508:
378:
288:
38:; also referred to as
2803:Antibiotic resistance
2595:Clinical pharmacology
2114:Physiological agonist
2074:Ligand (biochemistry)
1129:
1084:Certain safety factor
1042:Certain Safety Factor
1006:neuroendocrine tumors
986:insulin growth factor
945:Ataxia telangiectasia
802:, a widely available
721:
691:
647:of protective index.
638:
605:
544:
509:
379:
289:
76:). In contrast, in a
2700:Reverse pharmacology
2610:Pharmacoepidemiology
2451:Biological half-life
2331:Ligand binding assay
2205:Activity at receptor
2099:Irreversible agonist
1079:
970:double-strand breaks
958:juxtacrine signaling
893:dose–response curves
700:
670:
617:
571:
521:
434:
424:dose) in place of LD
321:
231:
46:. The related terms
2748:Combination therapy
2636:Pharmacoinformatics
2605:Medicinal chemistry
2211:Mechanism of action
1861:2008RaPC...77.1280Y
1766:Anesthesia Progress
1021:Sometimes the term
871:Cancer radiotherapy
800:alcoholic beverages
652:pre-clinical trials
2718:Immunopharmacology
2668:Pharmacotoxicology
2569:Psychopharmacology
2361:Intrinsic activity
2261:Pleiotropy (drugs)
2182:Agonist-antagonist
2094:Endogenous agonist
1855:(10–12): 1280–85.
1522:goldbook.iupac.org
1215:due to short-term
1161:therapeutic window
1155:Therapeutic window
1138:Synergistic effect
1124:
1027:psychoactive drugs
754:For instance, the
716:
686:
633:
600:
539:
504:
374:
284:
198:Therapeutic Index
186:the dose at which
171:the dose at which
48:therapeutic window
44:therapeutic effect
2860:
2859:
2856:
2855:
2816:
2815:
2713:Photopharmacology
2708:
2707:
2681:
2680:
2654:
2653:
2618:
2617:
2581:
2580:
2574:Electrophysiology
2564:Neuropharmacology
2519:
2518:
2469:
2468:
2405:
2404:
2392:Therapeutic index
2344:
2343:
2289:
2288:
2238:
2237:
2167:
2166:
2122:
2121:
1965:978-0-7020-5362-7
1934:"FAQs: Dr. Damaj"
1587:978-0-07-178924-0
1316:978-0-07-178924-0
1151:highly variable.
1122:
1085:
1010:chemoembolization
997:radiation therapy
842:lithium carbonate
823:cardiac glycoside
792:local anaesthetic
773:sedative-hypnotic
713:
683:
630:
613:which means that
598:
597:
584:
535:
502:
498:
477:
440:
372:
334:
282:
244:
205:
204:
40:therapeutic ratio
32:therapeutic index
16:(Redirected from
2885:
2873:Pharmacokinetics
2818:
2778:
2758:Polypharmacology
2683:
2656:
2646:Pharmacogenomics
2641:Pharmacogenetics
2620:
2583:
2544:
2471:
2441:Rate of infusion
2416:
2411:Pharmacokinetics
2346:
2291:
2240:
2202:
2197:Pharmacodynamics
2177:Neurotransmitter
2159:Enzyme inhibitor
2124:
2079:
2059:
2052:
2045:
2036:
2030:
2029:
2023:
2008:
2007:
2002:
1996:
1995:
1993:
1991:
1976:
1970:
1969:
1951:
1945:
1944:
1942:
1940:
1930:
1924:
1923:
1903:
1897:
1896:
1894:
1893:
1879:
1873:
1872:
1844:
1838:
1837:
1809:
1800:
1799:
1789:
1757:
1751:
1749:
1739:
1722:(3–4): 250–275.
1716:CNS Drug Reviews
1707:
1701:
1700:
1674:
1665:
1656:
1655:
1645:
1613:
1607:
1606:
1573:
1567:
1566:
1564:
1563:
1548:
1542:
1541:
1539:
1538:
1533:
1514:
1508:
1507:
1487:
1481:
1480:
1478:
1477:
1462:
1456:
1455:
1415:
1409:
1408:
1388:
1382:
1381:
1345:
1336:
1335:
1302:
1249:anticholinergics
1225:chemical residue
1133:
1131:
1130:
1125:
1123:
1121:
1120:
1119:
1106:
1105:
1104:
1091:
1086:
1083:
941:myeloid leukemia
913:hydroxyl radical
725:
723:
722:
717:
715:
714:
711:
695:
693:
692:
687:
685:
684:
681:
662:Drug development
642:
640:
639:
634:
632:
631:
628:
609:
607:
606:
601:
599:
596:Protective index
595:
591:
586:
585:
582:
548:
546:
545:
540:
538:
537:
536:
533:
513:
511:
510:
505:
503:
501:
500:
499:
496:
483:
478:
476:
475:
474:
461:
460:
459:
446:
441:
439:Protective index
438:
414:protective index
408:Protective index
383:
381:
380:
375:
373:
371:
370:
369:
356:
355:
354:
341:
336:
335:
332:
293:
291:
290:
285:
283:
281:
280:
279:
266:
265:
264:
251:
246:
245:
242:
128:
78:drug development
21:
18:Therapeutic dose
2893:
2892:
2888:
2887:
2886:
2884:
2883:
2882:
2863:
2862:
2861:
2852:
2812:
2798:Drug resistance
2776:
2732:
2704:
2677:
2673:Neurotoxicology
2650:
2614:
2577:
2539:
2533:
2515:
2465:
2461:Bioavailability
2446:Onset of action
2401:
2340:
2285:
2234:
2191:
2163:
2154:Inverse agonist
2118:
2104:Partial agonist
2068:
2063:
2033:
2021:
2015:Jasper Womach.
2014:
2005:
2003:
1999:
1989:
1987:
1978:
1977:
1973:
1966:
1953:
1952:
1948:
1938:
1936:
1932:
1931:
1927:
1905:
1904:
1900:
1891:
1889:
1881:
1880:
1876:
1846:
1845:
1841:
1811:
1810:
1803:
1759:
1758:
1754:
1709:
1708:
1704:
1672:
1667:
1666:
1659:
1615:
1614:
1610:
1603:
1599:
1595:
1588:
1575:
1574:
1570:
1561:
1559:
1550:
1549:
1545:
1536:
1534:
1516:
1515:
1511:
1504:
1489:
1488:
1484:
1475:
1473:
1464:
1463:
1459:
1417:
1416:
1412:
1399:(11): 1954–60.
1390:
1389:
1385:
1362:10.1038/nrd3801
1347:
1346:
1339:
1332:
1328:
1324:
1317:
1304:
1303:
1299:
1295:
1257:
1229:clinical trials
1201:pharmacological
1193:
1185:
1157:
1148:benzodiazepines
1140:
1111:
1107:
1096:
1092:
1077:
1076:
1069:
1063:
1059:
1019:
873:
849:adverse effects
777:muscle relaxant
749:
706:
698:
697:
676:
668:
667:
664:
656:clinical trials
623:
615:
614:
577:
569:
568:
563:
559:
528:
519:
518:
491:
487:
466:
462:
451:
447:
432:
431:
427:
419:
403:
399:
395:
391:
387:
361:
357:
346:
342:
327:
319:
318:
309:
305:
301:
297:
271:
267:
256:
252:
237:
229:
228:
210:
145:Effective Dose
114:
101:
92:
75:
70:
28:
23:
22:
15:
12:
11:
5:
2891:
2889:
2881:
2880:
2875:
2865:
2864:
2858:
2857:
2854:
2853:
2851:
2850:
2845:
2840:
2838:Bacteriostatic
2835:
2830:
2824:
2822:
2814:
2813:
2811:
2810:
2805:
2800:
2795:
2790:
2788:Drug tolerance
2784:
2782:
2775:
2770:
2768:Lists of drugs
2765:
2760:
2755:
2750:
2745:
2740:
2738:
2734:
2733:
2731:
2730:
2725:
2720:
2715:
2709:
2706:
2705:
2703:
2702:
2697:
2691:
2689:
2687:Drug discovery
2679:
2678:
2676:
2675:
2670:
2664:
2662:
2652:
2651:
2649:
2648:
2643:
2638:
2632:
2630:
2616:
2615:
2613:
2612:
2607:
2602:
2597:
2591:
2589:
2579:
2578:
2576:
2571:
2566:
2561:
2556:
2554:
2541:
2535:
2534:
2532:
2531:
2529:Bioequivalence
2526:
2520:
2517:
2516:
2514:
2513:
2503:
2498:
2493:
2488:
2477:
2475:
2467:
2466:
2464:
2463:
2458:
2453:
2448:
2443:
2438:
2428:
2422:
2420:
2413:
2407:
2406:
2403:
2402:
2400:
2399:
2394:
2389:
2363:
2358:
2352:
2350:
2342:
2341:
2339:
2338:
2323:
2318:
2313:
2308:
2303:
2297:
2295:
2287:
2286:
2284:
2283:
2273:
2271:Adverse effect
2268:
2263:
2258:
2246:
2244:
2236:
2235:
2233:
2228:
2223:
2218:
2216:Mode of action
2213:
2208:
2206:
2199:
2193:
2192:
2190:
2189:
2184:
2179:
2174:
2168:
2165:
2164:
2162:
2161:
2156:
2151:
2146:
2141:
2136:
2130:
2128:
2120:
2119:
2117:
2116:
2111:
2106:
2101:
2096:
2091:
2085:
2083:
2076:
2070:
2069:
2064:
2062:
2061:
2054:
2047:
2039:
2032:
2031:
1997:
1971:
1964:
1946:
1925:
1898:
1874:
1839:
1801:
1752:
1702:
1657:
1608:
1601:
1597:
1593:
1586:
1568:
1543:
1509:
1502:
1482:
1457:
1410:
1383:
1356:(10): 751–61.
1337:
1330:
1326:
1322:
1315:
1296:
1294:
1291:
1290:
1289:
1284:
1279:
1274:
1269:
1267:Effective dose
1264:
1261:Drug titration
1256:
1253:
1192:
1189:
1184:
1181:
1156:
1153:
1139:
1136:
1135:
1134:
1118:
1114:
1110:
1103:
1099:
1095:
1089:
1067:
1061:
1057:
1054:effective dose
1018:
1015:
966:carcinogenesis
872:
869:
861:amphotericin B
782:Less safe are
770:benzodiazepine
748:
745:
709:
705:
679:
675:
663:
660:
626:
622:
611:
610:
594:
589:
580:
576:
561:
557:
531:
527:
494:
490:
486:
481:
473:
469:
465:
458:
454:
450:
444:
425:
417:
410:
409:
401:
397:
393:
389:
385:
384:Ideally the ED
368:
364:
360:
353:
349:
345:
339:
330:
326:
316:
315:
307:
303:
299:
295:
278:
274:
270:
263:
259:
255:
249:
240:
236:
226:
225:
209:
206:
203:
202:
199:
196:
192:
191:
184:
181:
177:
176:
169:
166:
162:
161:
146:
143:
139:
138:
135:
132:
99:
96:effective dose
90:
73:
68:
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
2890:
2879:
2876:
2874:
2871:
2870:
2868:
2849:
2846:
2844:
2841:
2839:
2836:
2834:
2831:
2829:
2826:
2825:
2823:
2819:
2809:
2806:
2804:
2801:
2799:
2796:
2794:
2793:Tachyphylaxis
2791:
2789:
2786:
2785:
2783:
2779:
2774:
2771:
2769:
2766:
2764:
2761:
2759:
2756:
2754:
2751:
2749:
2746:
2744:
2741:
2739:
2735:
2729:
2726:
2724:
2721:
2719:
2716:
2714:
2711:
2710:
2701:
2698:
2696:
2693:
2692:
2690:
2688:
2684:
2674:
2671:
2669:
2666:
2665:
2663:
2661:
2657:
2647:
2644:
2642:
2639:
2637:
2634:
2633:
2631:
2629:
2625:
2621:
2611:
2608:
2606:
2603:
2601:
2598:
2596:
2593:
2592:
2590:
2588:
2584:
2575:
2572:
2570:
2567:
2565:
2562:
2560:
2557:
2555:
2553:
2549:
2545:
2542:
2536:
2530:
2527:
2525:
2522:
2521:
2511:
2507:
2504:
2502:
2499:
2497:
2494:
2492:
2489:
2486:
2482:
2479:
2478:
2476:
2472:
2462:
2459:
2457:
2454:
2452:
2449:
2447:
2444:
2442:
2439:
2436:
2432:
2429:
2427:
2424:
2423:
2421:
2417:
2414:
2412:
2408:
2398:
2395:
2393:
2390:
2387:
2383:
2379:
2375:
2371:
2367:
2364:
2362:
2359:
2357:
2354:
2353:
2351:
2347:
2336:
2332:
2328:
2324:
2322:
2319:
2317:
2314:
2312:
2309:
2307:
2304:
2302:
2299:
2298:
2296:
2292:
2281:
2280:Neurotoxicity
2277:
2274:
2272:
2269:
2267:
2264:
2262:
2259:
2256:
2252:
2249:Selectivity (
2248:
2247:
2245:
2241:
2232:
2229:
2227:
2224:
2222:
2219:
2217:
2214:
2212:
2209:
2207:
2203:
2200:
2198:
2194:
2188:
2187:Pharmacophore
2185:
2183:
2180:
2178:
2175:
2173:
2170:
2169:
2160:
2157:
2155:
2152:
2150:
2147:
2145:
2142:
2140:
2137:
2135:
2132:
2131:
2129:
2125:
2115:
2112:
2110:
2107:
2105:
2102:
2100:
2097:
2095:
2092:
2090:
2087:
2086:
2084:
2080:
2077:
2075:
2071:
2067:
2060:
2055:
2053:
2048:
2046:
2041:
2040:
2037:
2027:
2020:
2019:
2012:
2001:
1998:
1985:
1981:
1975:
1972:
1967:
1961:
1957:
1950:
1947:
1935:
1929:
1926:
1921:
1917:
1914:(4): 239–42.
1913:
1909:
1902:
1899:
1888:
1884:
1878:
1875:
1870:
1866:
1862:
1858:
1854:
1850:
1843:
1840:
1835:
1831:
1827:
1823:
1820:(4): 217–22.
1819:
1815:
1808:
1806:
1802:
1797:
1793:
1788:
1783:
1779:
1775:
1771:
1767:
1763:
1756:
1753:
1747:
1743:
1738:
1733:
1729:
1725:
1721:
1717:
1713:
1706:
1703:
1698:
1694:
1690:
1686:
1683:(6): 686–96.
1682:
1678:
1671:
1664:
1662:
1658:
1653:
1649:
1644:
1639:
1635:
1631:
1627:
1623:
1619:
1612:
1609:
1605:
1589:
1583:
1579:
1572:
1569:
1557:
1553:
1547:
1544:
1532:
1527:
1523:
1519:
1513:
1510:
1505:
1503:9780071624428
1499:
1495:
1494:
1486:
1483:
1472:
1471:Farnam Street
1468:
1461:
1458:
1453:
1449:
1445:
1441:
1437:
1433:
1429:
1425:
1421:
1414:
1411:
1406:
1402:
1398:
1394:
1387:
1384:
1379:
1375:
1371:
1367:
1363:
1359:
1355:
1351:
1344:
1342:
1338:
1334:
1318:
1312:
1308:
1301:
1298:
1292:
1288:
1285:
1283:
1280:
1278:
1275:
1273:
1270:
1268:
1265:
1262:
1259:
1258:
1254:
1252:
1250:
1246:
1242:
1236:
1232:
1230:
1226:
1222:
1221:test subjects
1218:
1217:toxic effects
1214:
1210:
1206:
1202:
1198:
1190:
1188:
1182:
1180:
1178:
1174:
1170:
1166:
1162:
1154:
1152:
1149:
1145:
1137:
1116:
1101:
1087:
1075:
1074:
1073:
1070:
1055:
1051:
1047:
1043:
1038:
1036:
1032:
1028:
1024:
1016:
1014:
1011:
1007:
1003:
998:
994:
989:
987:
983:
979:
975:
971:
967:
963:
959:
955:
951:
946:
942:
938:
933:
929:
925:
920:
918:
914:
910:
906:
902:
898:
894:
891:
886:
882:
878:
870:
868:
866:
862:
858:
854:
851:, including:
850:
845:
843:
839:
835:
831:
826:
824:
820:
815:
813:
809:
805:
801:
797:
793:
789:
785:
780:
778:
775:and skeletal
774:
771:
767:
763:
760:
757:
752:
746:
744:
742:
741:
735:
731:
727:
707:
703:
677:
673:
661:
659:
657:
653:
648:
646:
624:
620:
592:
587:
578:
574:
567:
566:
565:
560:divided by ED
554:
552:
529:
525:
514:
492:
488:
484:
479:
471:
467:
463:
456:
452:
448:
442:
429:
423:
415:
407:
406:
405:
366:
362:
358:
351:
347:
343:
337:
328:
324:
313:
312:
311:
276:
272:
268:
261:
257:
253:
247:
238:
234:
223:
222:
221:
219:
215:
207:
200:
197:
194:
193:
189:
185:
182:
179:
178:
174:
170:
167:
164:
163:
159:
155:
154:concentration
151:
147:
144:
141:
140:
136:
133:
130:
129:
126:
124:
120:
112:
107:
103:
97:
93:
85:
83:
79:
71:
64:
60:
55:
53:
52:safety window
49:
45:
41:
37:
33:
19:
2763:Chemotherapy
2723:Cell biology
2624:Biochemistry
2548:Neuroscience
2496:Distribution
2426:Loading dose
2391:
2109:Superagonist
2066:Pharmacology
2017:
2000:
1988:. Retrieved
1983:
1974:
1955:
1949:
1937:. Retrieved
1928:
1911:
1907:
1901:
1890:. Retrieved
1886:
1877:
1852:
1848:
1842:
1817:
1813:
1769:
1765:
1755:
1719:
1715:
1705:
1680:
1676:
1625:
1621:
1611:
1591:
1577:
1571:
1560:. Retrieved
1556:www.ccohs.ca
1555:
1546:
1535:. Retrieved
1521:
1512:
1492:
1485:
1474:. Retrieved
1470:
1460:
1427:
1423:
1413:
1396:
1392:
1386:
1353:
1349:
1320:
1306:
1300:
1237:
1233:
1196:
1194:
1186:
1165:theophylline
1160:
1158:
1141:
1045:
1041:
1039:
1034:
1030:
1023:safety ratio
1022:
1020:
1017:Safety ratio
990:
921:
905:free radical
897:DNA mutation
874:
846:
834:theophylline
827:
816:
781:
762:remifentanil
753:
750:
738:
736:
732:
728:
665:
649:
612:
555:
515:
430:
421:
411:
317:
227:
211:
183:Lethal Dose
115:
111:§ Types
104:
86:
56:
51:
47:
39:
35:
31:
29:
2848:Bactericide
2524:Compartment
2335:Patch clamp
2311:Schild plot
1628:(1): 7–10.
1622:Proceedings
1600:) to the ED
1329:) to the ED
1144:synergistic
1050:lethal dose
974:PARP family
865:polymyxin B
830:dimercaprol
808:Paracetamol
551:upper bound
168:Toxic Dose
137:Definition
59:indications
2867:Categories
2728:Physiology
2660:Toxicology
2552:psychology
2501:Metabolism
2491:Absorption
2485:Liberation
2327:Organ bath
2255:Functional
2134:Antagonist
2127:Inhibitory
2082:Excitatory
1892:2016-04-11
1562:2024-07-25
1537:2024-07-25
1476:2023-05-23
1293:References
962:DNA repair
924:cell cycle
909:radiolysis
881:gamma rays
857:vancomycin
853:gentamicin
759:painkiller
645:reciprocal
2510:Clearance
2506:Excretion
2325:Methods (
1939:4 October
1677:Addiction
1444:0277-6715
1213:mortality
1031:effective
993:targeting
954:paracrine
950:phenotype
917:hydronium
890:sigmoidal
788:stimulant
212:Based on
134:Full form
2628:genetics
2600:Pharmacy
2587:Medicine
2397:Affinity
2356:Efficacy
2294:Analysis
2276:Toxicity
1834:20832013
1796:17352523
1746:17227290
1697:15139867
1652:16389318
1405:17205880
1378:29777090
1370:22935759
1287:Hormesis
1255:See also
1241:pruritus
1205:toxicity
1177:warfarin
838:warfarin
804:sedative
766:Diazepam
682:efficacy
629:efficacy
583:efficacy
497:efficacy
420:(median
402:efficacy
333:efficacy
300:efficacy
214:efficacy
173:toxicity
84:levels.
82:exposure
2538:Related
2481:(L)ADME
2435:Initial
2419:Metrics
2366:Potency
2349:Metrics
2251:Binding
2221:Binding
2089:Agonist
1990:26 July
1857:Bibcode
1787:1821133
1737:6506194
1643:1312206
1452:7569511
1245:opiates
1173:lithium
1169:digoxin
1035:desired
1008:and in
978:kinases
932:mitosis
928:S phase
885:charged
819:digoxin
812:Tylenol
796:ethanol
784:cocaine
416:uses TD
123:lithium
2540:fields
1962:
1832:
1794:
1784:
1744:
1734:
1695:
1650:
1640:
1596:(or LD
1584:
1500:
1450:
1442:
1403:
1376:
1368:
1325:(or LD
1313:
1175:, and
976:) and
877:x-rays
794:) and
756:opioid
712:safety
534:safety
396:and TD
306:and ED
243:safety
218:safety
2737:Other
2474:LADME
2022:(PDF)
2013:from
1673:(PDF)
1374:S2CID
1243:with
883:, or
643:is a
422:toxic
208:Types
188:death
156:of a
2626:and
2550:and
2386:TD50
2382:LD50
2378:ED50
2374:IC50
2370:EC50
2172:Drug
1992:2010
1960:ISBN
1941:2015
1830:PMID
1792:PMID
1742:PMID
1693:PMID
1648:PMID
1582:ISBN
1498:ISBN
1448:PMID
1440:ISSN
1401:PMID
1366:PMID
1311:ISBN
1282:LD50
1277:IC50
1272:EC50
1195:The
1159:The
1040:The
1004:for
984:and
982:EGFR
956:and
930:and
840:and
821:, a
790:and
768:, a
654:and
216:and
158:drug
150:dose
148:the
131:Term
63:dose
30:The
2483:: (
1916:doi
1865:doi
1822:doi
1782:PMC
1774:doi
1732:PMC
1724:doi
1685:doi
1638:PMC
1630:doi
1526:doi
1432:doi
1358:doi
1060:/ED
937:p53
899:or
844:.
786:(a
195:TI
180:LD
165:TD
152:or
142:ED
50:or
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1179:.
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296:50
277:50
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89:LD
74:50
69:50
67:TD
36:TI
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1994:.
1968:.
1943:.
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1895:.
1871:.
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1836:.
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1407:.
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1113:D
1109:E
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708:I
704:T
678:I
674:T
625:I
621:T
593:1
588:=
579:I
575:T
530:I
526:T
517:(
493:I
489:T
485:1
480:=
468:D
464:E
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449:T
443:=
363:D
359:T
348:D
344:E
338:=
329:I
325:T
273:D
269:E
258:D
254:L
248:=
239:I
235:T
113:.
34:(
20:)
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