Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) ...parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.
We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.
A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.
The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.
Lipophilic (logP > 1) and amphiphilic drugs (also known as cationic amphiphilic drugs) with ionizable amines (pKa > 6) can accumulate in lysosomes, a process known as lysosomal trapping. This process ...contributes to presystemic extraction by lysosome-rich organs (such as liver and lung), which, together with the binding of lipophilic amines to phospholipids, contributes to the large volume of distribution characteristic of numerous cardiovascular and central nervous system drugs. Accumulation of lipophilic amines in lysosomes has been implicated as a cause of phospholipidosis. Furthermore, elevated levels of lipophilic amines in lysosomes can lead to high organ-to-blood ratios of drugs that can be mistaken for active drug transport. In the present study, we describe an in vitro fluorescence-based method (using the lysosome-specific probe LysoTracker Red) to identify lysosomotropic agents in immortalized hepatocytes (Fa2N-4 cells). A diverse set of compounds with various physicochemical properties were tested, such as acids, bases, and zwitterions. In addition, the partitioning of the nonlysosomotropic atorvastatin (an anion) and the lysosomotropics propranolol and imipramine (cations) were quantified in Fa2N-4 cells in the presence or absence of various lysosomotropic or nonlysosomotropic agents and inhibitors of lysosomal sequestration (NH4Cl, nigericin, and monensin). Cellular partitioning of propranolol and imipramine was markedly reduced (by at least 40%) by NH4Cl, nigericin, or monensin. Lysosomotropic drugs also inhibited the partitioning of propranolol by at least 50%, with imipramine partitioning affected to a lesser degree. This study demonstrates the usefulness of immortalized hepatocytes (Fa2N-4 cells) for determining the lysosomal sequestration of lipophilic amines.
Biological fate of low-calorie sweeteners Magnuson, Bernadene A; Carakostas, Michael C; Moore, Nadia H ...
Nutrition reviews,
11/2016, Letnik:
74, Številka:
11
Journal Article
Recenzirano
Odprti dostop
With continued efforts to find solutions to rising rates of obesity and diabetes, there is increased interest in the potential health benefits of the use of low- and no-calorie sweeteners (LNCSs). ...Concerns about safety often deter the use of LNCSs as a tool in helping control caloric intake, even though the safety of LNCS use has been affirmed by regulatory agencies worldwide. In many cases, an understanding of the biological fate of the different LNSCs can help health professionals to address safety concerns. The objectives of this review are to compare the similarities and differences in the chemistry, regulatory status, and biological fate (including absorption, distribution, metabolism, and excretion) of the commonly used LNCSs: acesulfame potassium, aspartame, saccharin, stevia leaf extract (steviol glycoside), and sucralose. Understanding the biological fate of the different LNCSs is helpful in evaluating whether reports of biological effects in animal studies or in humans are indicative of possible safety concerns. Illustrations of the usefulness of this information to address questions about LNCSs include discussion of systemic exposure to LNCSs, the use of sweetener combinations, and the potential for effects of LNCSs on the gut microflora.
Background
We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa ...inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed.
Methods
In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses.
Results
Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration–time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined.
Conclusion
This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation.
Clinical Trial Registration
EudraCT number: 2021-006643-39.
Metastasis impedes the successful chemotherapy for breast cancer. In this study, an Akt inhibitor (quercetin, Qu) was co-delivered with a chemotherapeutic agent (docetaxel, DTX) by using hyaluronic ...acid (HA)-modified nanoparticles (NPs) as vectors to block metastasis. Dual DTX/Qu-loaded HA/polylactic-co-glycolic acid-polyethyleneimine NPs (PP-HA/NPs) were prepared through a modified emulsion solvent evaporation technique. The particle size of PP-HA/NPs with narrow polydispersity was 209.8±10.8nm. Wound healing assay revealed that Qu co-delivery and HA modification elicited synergistic inhibitory effects on cell motility. The downregulation of p-Akt and matrix metalloproteinase-9 (MMP-9) expression contributed to the significant inhibition of cell migration and invasion with inhibition rates of 95.6% and 99.3%, respectively. Further studies indicated that PP-HA/NPs could be efficiently uptaken by 4T1 breast cancer cells and could further induce cytotoxicity, decrease colony formation and promote cell apoptosis. Biodistribution assay demonstrated PP-HA/NPs also enhanced drug accumulation in the tumor and lungs and predicted that PP-HA/NPs could be employed as an effective therapy for primary tumor and pulmonary metastasis. Therefore, PP-HA/NPs could be a promising delivery system to treat metastatic breast cancer effectively.
Multifunctional injectable thermo-/pH-responsive hydrogels as release systems for the oral delivery of small molecule drugs and the local delivery of protein are presented. The injectable ...interpenetrating polymer network (IPN) hydrogels based on poly(ethylene glycol) methacrylate, N-isopropylacrylamide, and methacrylated alginate were prepared by using ammonium persulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TEMED) as a redox initiator system at body temperature, and the obtained hydrogels overcame the instability of calcium cross-linked alginate hydrogels under physiological conditions. The hydrogels showed good mechanical strength by rheometer and exhibited temperature and pH sensitivity by a swelling test. Diclofenac sodium (DCS) as a model for small molecule water-soluble anti-inflammatory drugs and bovine serum albumin (BSA) as a model for protein drugs were encapsulated in situ in the hydrogel. The DCS and BSA release results indicated that these hydrogels, as carriers, have great potential for use in the oral delivery of small molecule drugs and for long-term localized protein release. Furthermore, the cytotoxicity of these hydrogels was studied via live/dead viability and alamarBlue assays using adipose tissue-derived mesenchymal stem cells.
Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles ...leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol and the effects of various CYP2D6-inhibitors cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.
Background
Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium
N
-(8-2-hydroxybenzoyl amino) caprylate ...(SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin.
Methods
In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1.
Results
There were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration (
C
max
) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the
C
max
was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists.
Conclusions
Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.
Exenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent ...insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus.
Patients with type 2 diabetes participated in either a single-dose trial (n = 62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER.
Exenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6-7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (-42.7 ± 15.7 mg/dL with the 0.8 mg dose and -39.0 ± 9.3 mg/dL with the 2 mg dose; both p < 0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC(50)) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2 mg doses of exenatide ER). The 2 mg dose reduced bodyweight (-3.8 ± 1.4 kg; p < 0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbA(1c)) levels were reduced with the 0.8 mg dose (-1.4 ± 0.3%; baseline 8.6%) and with the 2 mg dose (-1.7 ± 0.3%; baseline 8.3%) both p < 0.001 vs placebo. Adverse events were generally transient and mild to moderate in intensity.
These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. Clinicaltrials.gov Identifier: NCT00103935.
Convection enhanced delivery is an effective alternative to routine delivery methods to overcome the blood brain barrier. However, its treatment efficacy remains disappointing in clinic owing to the ...rapid drug elimination in tumour tissue. In this study, multiphysics modelling is employed to investigate the combination delivery of anti-angiogenic and cytotoxic drugs from the perspective of intratumoural transport. Simulations are based on a 3-D realistic brain tumour model that is reconstructed from patient magnetic resonance images. The tumour microvasculature is targeted by bevacizumab, and six cytotoxic drugs are included, as doxorubicin, carmustine, cisplatin, fluorouracil, methotrexate and paclitaxel. The treatment efficacy is evaluated in terms of the distribution volume where the drug concentration is above the corresponding LD90. Results demonstrate that the infusion of bevacizumab can slightly improve interstitial fluid flow, but is significantly efficient in reducing the fluid loss from the blood circulatory system to inhibit the concentration dilution. As the transport of bevacizumab is dominated by convection, its spatial distribution and anti-angiogenic effectiveness present high sensitivity to the directional interstitial fluid flow. Infusing bevacizumab could enhance the delivery outcomes of all the six drugs, however, the degree of enhancement differs. The delivery of doxorubicin can be improved most, whereas, the impacts on methotrexate and paclitaxel are limited. Fluorouracil could cover the comparable distribution volume as paclitaxel in the combination therapy for effective cell killing. Results obtain in this study could be a guide for the design of this co-delivery treatment.
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