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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
The therapeutic range is the optimal concentration range for a drug for which the drug is efficacious yet not toxic. It is usually defined as between the minimum effective concentration and the minimum toxic concentration. As can be seen from Figure 4a, concentrations above the range will result in toxicity while low concentrations mean loss of efficacy. This can be especially important in drugs with narrow therapeutic ranges, such as phenytoin and theophylline. Drugs with narrow therapeutic ranges may benefit from serum drug concentration monitoring [5].
Immunohistochemistry of the Pulmonary Extracellular Matrix
Published in Joan Gil, Models of Lung Disease, 2020
Antonio Martinez-Hernandez, Peter S. Amenta
Many cells, such as neutrophils and macrophages, contain peroxidatic enzymes and all heme-containing proteins are potential peroxidases. Incubation with diaminobenzidine hydrochloride (DAB) and H202 in the presence of these peroxidases will yield reaction product unrelated to antibody localization. Oxidation with hydrogen peroxide in methanol or treatment with acids has been used to inactivate the intrinsic peroxidatic activity (Martinez-Hernandez, 1987a,b; Amenta and Martinez-Hernandez, 1987). The lowest effective concentration should be used to minimize any deleterious effects to the tissues (Amenta et al., 1986). If colloidal gold rather than peroxidase is used as the marker, this step is unnecessary (Karkavelas et al., 1988).
Inhaled therapeutics in chronic obstructive pulmonary disease
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Tejas Sinha, Paul Dejulio, Philip Diaz
β-agonists, including short-acting and long-acting agents, enhance airflow by relaxing airway smooth muscle (16). The onset and duration of LABA therapy depends on the time it takes for the drug to achieve and maintain effective concentration at the β-2 receptor. Time to effective concentration is affected directly by the concentration of the drug in the airway as well as the receptor selectivity of the agent (17). Activation of the β-2 receptor stimulates the activity of intracellular adenyl cyclase. This enzyme subsequently facilitates synthesis of cyclic 3′5′ adenosine monophosphate (cAMP), which mediates the relaxation of smooth muscle cells (18). The unique pharmacologic properties of each LABA agent dictate its duration and onset of action. For example, formoterol has higher water solubility and lower lipophilicity relative to salmeterol, explaining why it has a more rapid onset of action but slightly shorter duration of action (19). Newer, very long-acting beta agonists such as vilanterol are highly lipophilic (20). There is evidence that LABAs may have anti-inflammatory effects in the lung (21). However, the clinical significance of such effects is not clear (22).
A translational strategy employing physiologically based modelling to predict the pharmacological active dose of RO7119929, an oral prodrug of a targeted cancer immunotherapy TLR7 agonist
Published in Xenobiotica, 2022
Caroline Rynn, Kenichi Umehara, Tianyi Jiang, Malika Ait-Goughoulte, Neil Parrott
PBMCs were seeded at 5 × 106 cells/mL in RPMI1640 containing 10% FBS and 1× penicillin/streptomycin in a 24 well plate (0.5 mL of the cell suspension per well). For the cytotoxicity measurement, 50 µL were seeded in a 96 well plate and cultured at 37 °C for 24 h. PBMCs were subsequently treated 24 h after seeding with active drug at concentrations of 1, 0.2, 0.04, 0.008, and 0.0016 µM and a final DMSO concentration of 0.2%. The treated cells were incubated for an additional 24 h at 37 °C, before harvest. After incubation, cell culture supernatants were collected to measure the levels of secreted cytokines including IFN-α, IP10, TNF-α, and IL6 with respective AlphaLisa kits (PerkinElmer, USA) according to manufacturer’s instructions. Minimum effective concentration values were defined as the concentration of the active drug that produce a cytokine concentration at least three-fold above the DMSO control and that the next highest concentration of the active drug also produces a cytokine concentration at least three-fold over background (i.e. the beginning of a dose-response curve). Viability was analysed using Cell-titre GLO (Promega, Germany) cell viability reagent according to the manufacturer’s instruction. Luminescence was measured on a EnVision Alpha reader (Perkin Elmer) at 615 nm for both Alphalisa and Cell-titre GLO assays.
Development, characterization, comparative pharmacokinetic and pharmacodynamic studies of iloperidone solid SMEDDS and liquisolid compact
Published in Drug Development and Industrial Pharmacy, 2020
Dinesh Suram, Arjun Narala, Kishan Veerabrahma
Administration of drugs through oral route is favorable and conventional to treat many diseases in which the patient compliance is achieved [1]. The drug should maintain its concentration above the minimum effective concentration level to show therapeutic activity [2]. Water insolubility is the major drawback for lipophilic drugs which leads to poor dissolution and poor bioavailability [3]. To increase the absorption and bioavailability many formulation approaches were reported like lipid based delivery systems [4], complexation [5], micronization [6], solid dispersions [7], liquisolid technique [8] and salt formation [9]. Oral bioavailability of the lipophilic drugs was improved when taken with rich fat meal [10]. This observation resulted in the development of various lipid based delivery systems to improve the drug solubility and permeation across the gastro intestinal barrier [11].
Oligochitosan-pluronic 127 conjugate for delivery of honokiol
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Zhimei Song, Jingjie Sun, Peizong Deng, Feilong Zhou, Hongmei Xu, Yi Wen, Fangfang Teng, Di Ge, Runliang Feng
The premise for drug action is that drug’s effective concentration must reach around its acting site. The effective concentration depends on distribution of honokiol-loaded micelles around the fungi and honokiol release rate from the drug-loaded micelles. The results this section indicated that honokiol’s release from the drug-loaded micelles was slow in comparison with pure honokiol. It was reasonable that the slow release would reduce drug concentration around the fungi to below effective dosage and decrease contact between drug and fungi in honokiol-loaded micelles group, resulting in low antifungal activity. However, both of them showed same in vitro activities (Figure 5(A)). The former study confirmed that the drug-loaded micelles showed positive zeta potential originated from oligochitosan fragments. The positive charge made the honokiol-loaded micelles bind more efficiently with negative fungi. In addition, F127 is an amphiphilic copolymer having good surface activity. It can interact with various membrane components of the fungi cells to promote the accumulation of the honokiol-loaded micelles around the fungi cells. It also should change microviscosity of the membrane, leading to drug permeation into fungi. Hence, the similar activity of honokiol-loaded micelles to pure honokiol might be related to its higher cellular uptake.