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Drug Synergy refers to the interaction between two or more drugs that causes the total therapeutic effect of the drugs to be larger than the sum of the discrete effects of each drug. From: Bioorganic Chemistry, William W. Supra-additivity or synergism occurs when a mixture of two or more drugs produces a greater response than expected i. Drug synergism can be expected when drugs that Drug potentiation example by different mechanisms of action are mixed together.
Various drug combinations e.
Synergistic drug combinations are the basis for many multimodal drug combinations but must be administered carefully because unwanted and potentially toxic effects may also be potentiated e. Synergistic drug combinations have been viewed by many to be a promising approach to treat multiple chronic bacterial diseases Yin et al. Nonetheless, chronic combination treatment regimens can interact in unpredictable ways and show not only drug synergy but also drug antagonism. Drug development aimed at optimizing a synergistic increase in drug efficacy and reducing drug resistance is a highly pursued approach of combinational drug development Zheng et al.
Synergistic drug combinations have the potential to be extremely efficacious by attaining more specific drug targets and reducing the development of drug resistance Worthington and Melander, In recent years, many insights into the process of achieving drug synergy aimed at NTM have been gained, resulting in increasing awareness that this approach can successfully lead to a patient cure van Ingen et al.
Recent preclinical animal models Orme and Ordway, ; Bernut et al. This study highlights the importance Drug potentiation example synergistic compounds capable of enhanced efficacy against M. Additional studies using the zebrafish model demonstrated bedaquiline was highly efficacious against M.
However, clofazimine alone was bacteriostatic for both M. Clofazimine-amikacin was synergistic against M. Evaluation of time kill kinetic assays Ferro et al. The mechanism of clofazimine and bedaquiline combination treatment synergy has been evaluated in an animal model against drug-resistant strains of M. These studies demonstrated clofazimine appears to act as a prodrug, which is reduced by NADH dehydrogenase NDH-2leading to the release of reactive oxygen species upon reoxidation by O 2 Lechartier and Cole, Importantly, clofazimine likely competes with menaquinone MK-4a main cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2 Lechartier and Cole, Additional studies investigated the effect of MK-4 supplementation on the action of clofazimine against M.
Additional studies are required to elucidate the synergistic mechanisms of clofazimine and bedaquiline drug combination treatments against NTM. Preclinical murine models evaluating the efficacy of bedaquiline against M. Preclinical studies using bedaquiline for treatment failure of lung disease caused by M. Eighty percent of patients enrolled in the study had macrolide-resistant isolate eight out of ten Philley et al. Drug potentiation example the patients were treated with the same bedaquiline dosage mg daily and received the best available companion drugs mean, 5.
All patients completed six months of therapy and remain on bedaquiline. However, additional preclinical studies evaluating the efficacy of bedaquiline treatment in patients with Mycobacterium intracellulare pulmonary disease showed seven out of 13 patients with an initial culture conversion resulted in relapse Alexander et al.
Subsequent sequencing revealed nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates, Drug potentiation example the need for further optimization of treatment regimens to prevent the emergence of mmpT5 variants and relapse Alexander et al. In spite of this, bedaquiline and clofazimine combination treatments in the absence of rifamycin may increase drug exposure enhancing efficacy against NTM.
Frequently standard treatment for NTM pulmonary disease is not possible because of drug intolerance, antibiotic resistance, or progression of the disease. Second-line treatment such as inhaled amikacin, clofazimine, bedaquiline, and delamanid are considered, regardless of only a few studies to guide their use Lande et al. Kevin Baird, Ric N. Price, in Advances in Parasitology Two 8-aminoquinoline drugs, primaquine and tafenoquine, represent the only likely agents of anti-relapse therapy for the coming decade.
The threat that these drugs pose to unscreened patients with G6PDd severely limits their effectiveness in combating endemic malaria. Shorter duration, higher dose regimens of primaquine, like pamaquine before it, were not considered because of the threat such dosing posed to unscreened G6PDd patients. Tafenoquine progressed through 30 years of development almost solely Drug potentiation example the promise of shorter duration dosing and, presumably, assured exclusion of G6PDd patients from perhaps catastrophic exposure to drug.
Malaria drug developers may solve the problem of 8-aminoquinoline Drug potentiation example in G6PDd patients by simply mining the phenomenon of co-drug synergy to discover, perhaps, a co-drug whether it happens to be a blood schizontocide or not that provides complete efficacy against hypnozoites at doses below the threshold of harm to the most sensitive G6PDd variants. This phenomenon, recognized in as the hypnozoitocide development program was drawing to a close, was not further leveraged to improve the therapeutic index of primaquine. Schmidt began an exploration of co-drug synergy in the s for that expressed purpose, but the Army abandoned tafenoquine for radical cure in favour of a chemoprophylaxis development strategy.
A full exploration of co-drug synergy with primaquine and tafenoquine should at last be carried out. Rather than dose reduction, detoxifying the 8-aminoquinoline at standard dosing appears possible. Ironically, the logical starting point for that exploration is precisely that which launched modern antimalarial drugs — the aniline dye methylene blue.
This compound is a d therapy for a of indications, including Drug potentiation example of the profound methaemoglobinemia of nitrite poisoning. It is at least plausible that this therapeutic effect could uncouple the oxidative events that lead to 8-aminoquinoline-induced haemolysis. Confirming Drug potentiation example optimizing this effect at high doses of primaquine, along with co-formulation, would perhaps provide universally safe and effective therapy against relapse.
Another approach to minimizing harm is to effectively exclude those at risk. Among patients and subjects considered good candidates for the treatment, the 8-aminoquinolines are remarkably safe and well tolerated when administered with food, even in relatively massive doses e.
Such development is at last underway and shows promise Kim et al. Lader, Drug potentiation example Encyclopedia of Stress Second Edition The most common unwanted side effects are tiredness, drowsiness, and torpor, so-called oversedation. These effects are dose and time related, being most marked within the first 2 h after large doses. Furthermore, drowsiness is most common during the first week of treatment.
Both psychomotor skills, such as driving, and intellectual and cognitive skills are affected. As with most depressant drugs, potentiation of the effects of alcohol can occur. Paradoxical behavioral responses may occur in patients taking benzodiazepines. Such events include increased aggression and hostility, acute rage reactions, uncharacteristic criminal behavior such as shoplifting, and uncontrollable weeping.
Other unwanted effects include excessive weight gain, skin rash, Drug potentiation example of sexual function, menstrual irregularities, and, rarely, agranulocytosis. In pregnant women, benzodiazepines pass readily into the fetus and have been suspected of producing respiratory depression in the neonate. Finally, benzodiazepines Drug potentiation example present in the mother's milk and can oversedate the baby.
Although overdose with benzodiazepines is extremely common, deaths due to these drugs alone are uncommon. Phillip Lerche, William W. Many analgesic drugs are additive or synergistic supraadditive when administered together. Synergism or supraadditivity implies that the combination of two or more products produces more than additive effects.
In more qualitative terms, the combination of two drugs produces a better effect analgesia than expected. Drug synergism usually allows the dose of most drugs to be reduced, thereby reducing the potential for side effects. Drug combinations that are likely to be synergistic are produced when Drug potentiation example that act by different and distinct mechanisms of action are combined.
Synergism or supraadditivity has been demonstrated when local anesthetics are combined with opioids or dissociative anesthetics and when NSAIDs are combined with opioids. Cattle are exquisitely sensitive to the respiratory depressant effects of xylazine. The administration of adjunctive drugs tranquilizers in conjunction with major analgesic drugs may potentiate analgesic effects and produces additional calming effects. The simultaneous or sequential administration of acepromazine and meperidine neuroleptanalgesia or acepromazine and xylazine potentiates analgesia.
Several of the major analgesics e. Wang, J. Biological systems are not static, but are highly dynamic. Dynamic modeling is, therefore, an essential computational approach in systems chemical biology. It can simulate how a variety of perturbations of a biological system induced by a small molecule affect the behavior of the system. Such simulations are very helpful for deriving mechanistic insights about the system. Discrete logical modeling simplifies biological reality, ignores quantitative kinetic parameters, and, thus, can make qualitative or semiquantitative dynamic predictions of system behaviors.
Flobak et al. With the aid of the software GINsim, the model can cope with the vast state space, simulate the perturbations of the network caused by anticancer drug combinations, and predict the synergistic growth-inhibitory action of some combinations of drugs. In addition, molecular dynamics simulations play an increasingly important role in drug discovery.
For example, atomistic dynamic simulations of protein receptors and their small-molecule ligands are very useful in computer-aided drug discovery, 50 including virtual compound screening, identification of binding sites both orthosteric and allostericand prediction of binding energies. Okimoto et al. This screening method has a much higher enrichment performance than molecular docking alone.
Lastly, when specific kinetic and binding constants are known and extracellular species concentration can be calculated, forward dynamic modeling by ordinary differential equations, stochastic differential equations, or mixed models can be used to determine the combinations of drugs that maximize pathway effects and minimize ADEs.
Si, D. Best, in Diagnostic Molecular Pathology Over the past several years, new advances have been made in the development of novel therapeutic agents that target the pathophysiological process at the CFTR chloride channel. In the wake of these findings, CF may no longer be considered a disease with only supportive therapy. Three main of new drugs potentiators, read-through agents, and correctors have Drug potentiation example developed to target the different classes of CFTR gene mutations and are already in phase 2 and phase 3 clinical trials [67,68].
For example, the potentiator category of drug targets class III mutations and is intended to interact with mutant CFTR protein at the apical membrane and enhance the ability of the protein to transport chloride. Likewise, read-through agents target class I mutations by promoting polymerase read-through of nonsense mutations. Finally, correctors act like a pharmacological chaperone and promote trafficking rescue of the mutated CFTR protein. Inthe first mutation targeted drug, Ivacaftor, was approved by the FDA for the treatment of CF in patients 6 years of age or older .
Ivacaftor belongs to the potentiator category of CF drugs Drug potentiation example works to enhance the ability of the mutant CFTR channel to transport chloride in those patients with class III—V mutations . Specifically, this drug has been shown to be effective in the treatment of patients carrying at least one copy of the p.
GlyAsp a class III mutation . Ivacaftor has also been approved for the use in patients who may carry any one of eight additional mutations: p. GlyArg, p. SerAsn, p. SerArg, p. GlySer, p.Drug potentiation example
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