What is the therapeutic index (TI) of a drug?
The larger the therapeutic index (TI), the safer the drug is. If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity.
When is a high therapeutic index (TI) preferable?
A high therapeutic index (TI) is preferable for a drug to have a favorable safety and efficacy profile. At early discovery/development stage, the clinical TI of a drug candidate is not known.
What is an example of a drug with a narrow therapeutic range?
Even less-safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1. Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include: paracetamol (acetaminophen), dimercaprol,...
What is Mic (minimal inhibitory concentration)?
Minimal inhibitory concentration (MIC) defines in vitro levels of susceptibility or resistance of specific bacterial strains to applied antibiotic. Reliable assessment of MIC has a significant impact on the choice of a therapeutic strategy, which affects efficiency of an infection therapy.
Is high therapeutic index preferable?
A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective. The larger the therapeutic index (TI), the safer the drug is.
Why is the difference between therapeutic index and therapeutic window important?
The therapeutic index is an important ratio to determine how close a toxic dose is to an effective one. Note that the term therapeutic index is often used more loosely, not just in these formulatic terms, and is often conflated with the therapeutic window, which we'll define soon.
Do you want a high or low therapeutic index?
A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect.
What does the therapeutic index of a drug indicate?
The therapeutic index (TI; also known as therapeutic ratio) is a ratio that compares the blood concentration at which a drug causes a therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies) [1].
What is a major disadvantage of the therapeutic ratio?
01) What is a major disadvantage of the therapeutic ratio? Feedback: The therapeutic ratio is an indication of the relative dose levels of a drug which will be effective, versus those which will be lethal. It gives no indication of chronic or non-lethal toxicity.
Why does the nurse monitor the patient closely when administering a drug of low therapeutic index?
It is vital that the nurse frequently monitors INR levels for a patient receiving warfarin to ensure the dosage appropriately reaches the therapeutic window and does not place the patient at risk for bleeding or clotting.
What is the significance of a drug's therapeutic index to a veterinary technician?
The larger value of TI indicates that there is a wide margin between the toxic and effective dose, whereas a smaller value indicates that there is a narrow margin between the effective and toxic dose. In case of drugs that have a low TI, even a small increase in the dosage can produce toxic effects.
What drugs have a high therapeutic index?
examples include:warfarin.lithium.digoxin.phenytoin.gentamicin.amphotericin.5-fluoro-urocil.zidovudine.
What are the limitations of therapeutic index?
The therapeutic index has many limitations, notably the fact that LD50 cannot be measured in humans and, when measured in animals, is a poor guide to the likelihood of unwanted effects in humans.
Why is a high therapeutic index important?
A high therapeutic index (TI) is preferable for a drug to have a favorable safety and efficacy profile. At early discovery/development stage, the clinical TI of a drug candidate is not known. 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 the successful development of a drug. Recognizing drug candidates with potentially suboptimal TI at earliest possible stage helps to initiate mitigation or potentially re-deploy resources.
What is therapeutic index?
Jump to navigation Jump to search. The therapeutic index ( TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.
How does therapeutic index affect radiation?
The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its 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 the agent to an oncophilic substance, as is done 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.
How does radiation therapy work?
Radiotherapy aims to minimize the size of tumors and kill cancer cells with high energy. The source of high energy arises from x-rays, gamma rays, charged particles and heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is related to the maximum radiation dose by which death of cancer cells is locally controlled and the minimum radiation dose by which cells in normal tissues have low acute and late morbidity. Both of parameters have sigmoidal dose-response curves. Thus, a favorable outcome in dose-response curve is the response of tumor tissue is greater than that of normal tissue to the same dose, meaning that the treatment is effective to tumors and does not cause serious morbidity to normal tissue. Reversely, overlapping response of two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment to tumors. The mechanism of radiation therapy is categorized into direct and indirect radiation. Both direct and indirect radiations induce DNA to have a mutation or chromosomal rearrangement during its repair process. Direct radiation creates a free DNA radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron. Then, hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage base region of DNA.
What are some examples of drugs with a narrow therapeutic range?
Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include: paracetamol (acetaminophen), dimercaprol, theophylline, warfarin and lithium carbonate.
What is TDM in medicine?
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.
What is protective index?
The protective index is a similar concept, except that it uses TD 50 (median toxic dose) in place of LD 50. For many substances, toxic effects can occur at levels far below those needed to cause death, and thus the protective index (if toxicity is properly specified) is often more informative about a substance's relative safety. Nevertheless, the therapeutic index is still useful as it can be considered an upper bound for the protective index, and the former also has the advantages of objectivity and easier comprehension.
How to calculate therapeutic index?
Therapeutic index is an indicator or a drug's safety. It is calculated by determining the ratio of TD50 or LD50 to the ED50. TI= TD50/ED50. TI= LD50/ED50. Drugs with a high therapeutic index are considered safe whereas those with a low therapeutic index are considered unsafe.
Why do clinicians adjust the dose of drugs by body surface area?
Clinicians often adjust the dose of drugs by body surface area (BSA) because this partially accounts for body composition as well. Normal BSA for an adult is 1.73m2 so some drugs are dosed as mg/1.73m2. Pharmacogenetics is the study of the effect of DNA sequence variation to the clinical response of drugs.
What is ED50 in medicine?
What is the ED50. The average effective dose (ED50) is at the peak of the frequency distribution curve. The ED50 is the dose required to produce a thereapuetic response in 50% of the population. The ED50 is often used as the initial dose for therapy. Dosing Implications.
Why is the dose adjusted for the body weight of the patient?
For many drugs, the dose is adjusted for the body weight of the patient (i.e. mg drug/kg body weight) in order to compensate for differences in size.
Why do you need to adjust the dose of a drug?
The initial dose of a drug is a starting point, however many patients will require dose adjustments to optimize efficacy and minimize adverse events.
What is the study of the effect of DNA sequence variation to the clinical response of drugs?
Pharmacogenetics is the study of the effect of DNA sequence variation to the clinical response of drugs. Single Nucleotide Polymorphism (SNP, pronounced "SNIP") is a change in DNA sequence that involves a single nucleotide (A,T,C or G). SNPs can exist in genes that regulate drug metabolism, drug transport or drug receptors.
How are doses of drugs adjusted?
Doses of some drugs are adjusted based on a patient's genotype (genetic makeup). Guy with 2 polymorphisms gets smaller dose then 1 polymorphism, then no genetic issues gets largest dose of the three. Gender. A drug may be more effective in males or females.
What is the MIC of a test?
Minimum Inhibitory Concentration (MIC) is defined as the lowest concentration (expressed as mg/L or μg/μL) of an antimicrobial agent that inhibits the visible in-vitro growth of microorganisms. The MIC test determines the antimicrobial activity of a test agent against a specific bacteria. E-test, tube dilution method and agar dilution methods are employed to determine MIC value.
How is MIC and zone of inhibition related?
Relationship between MIC and Zone of Inhibition. The MIC and the zone diameter of inhibition are inversely correlated. The more susceptible the microorganism is to the antimicrobial agent, the lower the MIC and the larger the zone of inhibition. Conversely, the more resistant the microorganism, the higher the MIC and the smaller the zone ...
What is the lowest concentration of antimicrobial preventing appearance of turbidity (growth)?
While performing the dilution method, the lowest concentration (highest dilution) of the antimicrobial preventing appearance of turbidity (growth) is considered as MIC. At this dilution the antimicrobial agent is bacteriostatic, i.e some bacteria may still be alive.
What is the MBC of an antibiotic?
Minimum bactericidal concentration (MBC) is defined as the lowest concentration of antibiotic that kills 99.9% of the inoculum. Also termed as minimum lethal concentration (MLC), MBC of an antibacterial agent is determined by subculturing last clear MIC tube onto growth medium and examining for bacterial growth.
What is MIC compared to?
Once the MIC is calculated, it can be compared to known values for a given bacterium and antimicrobial agent and is interpreted as susceptible, susceptible-dose dependent (SSD), intermediate and resistant. The interpretive criteria for these categories are based on;
What is a broth/tube dilution test?
The broth/tube dilution test is the standard method for determining levels of microbial resistance to an antimicrobial agent. Serial dilutions of the test agent are made in a liquid microbial growth medium which is inoculated with a standardized number of organisms and incubated for a prescribed time. At the end of the incubation period (generally 18-24 hours), the tubes are visually examined for turbidity.
How long does it take for an antibiotic to be applied to an agar plate?
A plastic strip with a predefined gradient of one antibiotic is applied onto an inoculated agar plate. After 18-24 hours incubation, a drop-shaped inhibition zone intersects the graded test strip at the inhibitory concentration of the antibiotic.
What is NTI in medicine?
A narrow therapeutic index (NTI) of a drug implies that a tiny variation in the dosage of the drug might lead to treatment failure or severe adverse drug reactions [1] [2] [3] [4] [5]. It also hampers drug development since researchers have to conduct additional studies [6] to modify the compound structure, and some failures in drug research [7] are caused by the NTI of drug candidates. ...
Why is NTI important?
An appropriate therapeutic index is crucial for drug discovery and development since narrow therapeutic index (NTI) drugs with slight dosage variation may induce severe adverse drug reactions or potential treatment failure. To date, the shared characteristics underlying the targets of NTI drugs have been explored by several studies, which have been applied to identify potential drug targets. However, the association between the drug therapeutic index and the related disease has not been dissected, which is important for revealing the NTI drug mechanism and optimizing drug design. Therefore, in this study, two classes of disease (cancers and cardiovascular disorders) with the largest number of NTI drugs were selected, and the target property of the corresponding NTI drugs was analyzed. By calculating the biological system profiles and human protein-protein interaction network properties of drug targets and adopting an AI-based algorithm, differentiated features between two diseases were discovered to reveal the distinct underlying mechanisms of NTI drugs in different diseases. Consequently, ten shared features and four unique features were identified for both diseases to distinguish NTI from NNTI drug targets. These computational discoveries, as well as the newly found features, suggest that in the clinical study of avoiding narrow therapeutic index in those diseases, the ability of target to be a hub and the efficiency of target signaling in the human PPI network should be considered, and it could thus provide novel guidance in the drug discovery and clinical research process and help to estimate the drug safety of cancer and cardiovascular disease.
What are the limitations of antifungal drugs?
The limited set of antifungal drugs has critical constraints such as resistance development and/or adverse side effects. One approach to overcome these limitations is to mimic naturally occurring antifungal peptides called defensins. Inspired by their advantageous amphiphilic properties, a library of 35 synthetic, linear, ternary polyacrylamides was prepared by controlled/living radical polymerization. The effect of the degree of polymerization (20, 40, and 100) and varying hydrophobic functionalities (branched, linear, cyclic, or aromatic differing in their number of carbons) on their antifungal activity was investigated. Short copolymers with a calculated log P of ∼1.5 revealed optimal activity against the major human fungal pathogen Candida albicans and other pathogenic fungal species with limited toxicity to mammalian host cells (red blood cells and fibroblasts). Remarkably, selected copolymers outperformed the commercial antifungal drug amphotericin B, with respect to the therapeutic index, highlighting their potential as novel antifungal compounds.
What is bioprospecting in medicine?
Bioprospecting is the exploration, extraction and screening of biological material and sometimes indigenous knowledge to discover and develop new drugs and other products. Most antibiotics in current clinical use (eg. β-lactams, aminoglycosides, tetracyclines, macrolides) were discovered using this approach, and there are strong arguments to reprioritize bioprospecting over other strategies in the search for new antibacterial drugs. Academic institutions should be well positioned to lead the early stages of these efforts given their many thousands of locations globally and because they are not constrained by the same commercial considerations as industry. University groups can lack the full complement of knowledge and skills needed though (eg. how to tailor screening strategy to biological source material). In this article, we review three key aspects of the bioprospecting literature (source material and in vitro antibacterial and toxicity testing) and present an integrated multidisciplinary perspective on (a) source material selection, (b) legal, taxonomic and other issues related to source material, (c) cultivation methods, (d) bioassay selection, (e) technical standards available, (f) extract/compound dissolution, (g) use of minimum inhibitory concentration and selectivity index values to identify progressible extracts and compounds, and (h) avoidable pitfalls. The review closes with recommendations for future study design and information on subsequent steps in the bioprospecting process.
What is the SI in toxicology?
It is important to highlight that the selectivity index (SI) is an indicator of potential antiproliferative effects on normal tissues; however, as an on-target toxicology approach (the expected drug effect), SI does not predict other systemic effects [24].
What is the role of NLRP3 in inflammation?
We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. In that study, we used a well-known Hsp90 inhibitor geldanamycin, but it cannot be used as a therapy due to its adverse effects, including ocular toxicity. Here, we have tested the effects of a novel Hsp90 inhibitor, TAS-116, on NLRP3 activation using geldanamycin as a reference compound. Using our existing protocol, inflammasome activation was induced in IL-1α-primed ARPE-19 cells with the proteasome and autophagy inhibitors MG-132 and bafilomycin A1, respectively. Intracellular caspase-1 activity was determined using a commercial caspase-1 activity kit and the FLICA assay. The levels of IL-1β were measured from cell culture medium samples by ELISA. Cell viability was monitored by the 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and lactate dehydrogenase (LDH) measurements. Our findings show that TAS-116 could prevent the activation of caspase-1, subsequently reducing the release of mature IL-1β. TAS-116 has a better in vitro therapeutic index than geldanamycin. In summary, TAS-116 appears to be a well-tolerated Hsp90 inhibitor, with the capability to prevent the activation of the NLRP3 inflammasome in human RPE cells.
What is a T>MIC?
T>MIC (the expression tc>MIC would be more accurate) is mainly used to predict the efficacy of time-dependent antibiotics (e.g. β-lactams, glycopeptides, macrolides, clindamycin and oxazolidinones). Drugs that belong to these classes show no or little enhancement of the effect with an increase in antibiotic concentration. The optimal concentration is mostly the two- to four-fold MIC of the pathogen. 28
What are the pharmacological indices used for antibiotics?
These indices facilitate comparison of the activity of different antibiotics and serve as a sound basis for antibiotic dosing. Pharmacokinetic parameters (e.g. AUC, Cmax) and pharmacodynamic parameters (mostly MIC) are used for this purpose. For the so-called concentration-dependent antibiotics, the pharmacological indices AUC/MIC and Cmax /MIC are used, whereas for time-dependent antibiotics, the pharmacological index T>MIC is used. Some authors believe that the index AUC/MIC can be used as a universal index, but, not all experts accept this generalization. As the various pharmacological indices have been defined inconsistently in the literature, the International Society for Anti-Infective Pharmacology (ISAP) has published a paper on the terminology of pharmacokinetic and pharmacodynamic parameters and the pharmacological indices. This paper will help to ensure uniform use of terminology. In addition, we point out that the use of pharmacological indices should consider the differences in pharmacokinetics (patient characteristics and localization of the infection) and the differences in pharmacodynamics of antibiotics (beyond MICs) with different pathogens (e.g. Gram-positive and Gram-negative).
What is ISAP in medicine?
The International Society for Anti-Infective Pharmacology (ISAP) is an interdisciplinary scientific society that promotes the study of the PK and the PD of antibiotics so as to improve dosing regimens. 26 Since the foundation of the ISAP in 1991, the study and use of pharmacokinetic and pharmacodynamic principles in antibiotic therapy has increased greatly. Based on their mode of action, antibacterial drugs are divided into time- and concentration-dependent antibiotics.
How does A.U.I.C work?
The program calculates antibiotic specific AUC/MIC values for a given dosage by using standard parameters for renal function and organism MIC. On the other hand, based on an AUC/MIC value of 125 h it calculates the dose of the antibiotic also using the same standard parameters for renal function, etc. Each parameter can be modified by the user to suit the patient or the clinical situation in question. Based on diagnosis, demographic data and so-called infection factors, the program selects possible infecting organisms on a ranked scale of probability of most likely, less likely and least likely pathogens. For each antibiotic, the user can customize antibiotic- or organism-specific susceptibilities, and can also obtain information about antibiotic cost. The authors state: ‘The program provides an objective analysis of underlying patient conditions, infection site specifics, nosocomial and community epidemiology and antibiotic susceptibility data, and the program will alert the user to the likely causative bacteria and indicate appropriate antibiotic regimens’.
What is Craig's research?
A major area of research for Craig and his colleagues is the examination of the efficacy of antibiotics in animal models. They have mainly utilized results of the murine lung and thigh infection models to correlate the pharmacological indices with the survival of the animals and the decreasing number of pathogens at the site of infection. 24
When should AUC/MIC be used?
According to ISAP, the expression AUC/MIC should be used for all practical purposes and the AUIC should be reserved for those cases where actual inhibitory titres have been measured and used in the calculations.
Is AUIC a universal index?
Some authors use AUIC as a universal index. 23, 30 Because of the diverse definitions of the AUC/MIC and AUIC in the literature, an objective comparison between the various publications and breakpoints is difficult. However, many authors use the definition of AUIC by Schentag.
Why is it important to monitor vancomycin levels?
Monitoring the level of vancomycin is important because its effectiveness relies on keeping blood levels above a minimum concentration for the entire duration of therapy (also referred to as total drug exposure).
What is the benefit of Bayesian AUC?
A benefit of using Bayesian AUC estimates is it can be applied to all patients (including obese, critically-ill patients, pediatrics, and patients with kidney dysfunction). Currently, it is preferred to estimate the Bayesian AUC on two vancomycin concentrations (peak and trough).
Why is it important to individualize the dose of vancomycin?
To maintain this steady-state, it’s important to individualize the dose because each person’s body will process and remove vancomycin at different rates based upon their age, underlying health status, weight, kidney function, and other medications they are taking.
Is vancomycin trough only monitored?
Dosing vancomycin using trough-only monitoring is no longer recommended.
When should troughs be collected?
The trough should be collected before the 4th dose is administered (prior to steady state). Unfortunately, the practice of waiting until the fourth dose to measure the trough level may expose a patient to several days of sub-optimal therapy. In 2019, a new set of draft guidelines were posted for public review.
Does vancomycin affect trough level?
In the past, vancomycin doses have been adjusted to target a specific trough level. It is now increasingly clear that the trough level does not accurately reflect total vancomycin exposure. New retrospective studies also show that AUC-guided vancomycin dosing may reduce the occurrence of vancomycin-associated AKI.