Abstract 1147: Drug Eluting Stents Do Not Delay Early Endothelialization But Show Distinct Differences In Endothelial Function

Late stent thrombosis and impaired endothelium dependent vasodilation in Cypher and Taxus are often attributed to delayed re-endothelialization. Data to support this hypothesis is scarce and the functional status of endothelium within these drug eluting stents is unknown. We compared 3 DES (Paclitaxel; Sirolimus (-limus via mTOR) and Tacrolimus (-limus via calcineurin)) to BMS in swine coronary arteries with respect to early endothelialization (%EC) at 5 days and function as assessed by immunocytochemistry for eNOS and vWF expression at 28 days (semiquantitative score) and in vitro vasoreactivity at 5 and 28 days. Results. There were no significant differences in %EC between DES and BMS at 5 days (Anova, p=0.7). While vWF expression was similar for all DES, PES showed diminished eNOS expression at 28 days. Microvascular function showed no overt impairment distal to both DES in EC-dependent dilation to bradykinin at 5 and 28 days. However, eNOS blockade by L-NAME uncovered a strongly depressed NO production in both DES at 5 days which recovered at 28 days. Conclusion. DES show no differences in re-endothelialization as compared to BMS. In vitro data showed that both DES induced a temporary reduction in NO production. However, only Paclitaxel showed a prolonged reduction in eNOS expression at 28 days. planimetry of endothelial presence and function

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Drug–Drug Interactions Involving Intestinal and Hepatic CYP1A Enzymes

Pharmaceutics ◽

10.3390/pharmaceutics12121201 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1201

Author(s):

Florian Klomp ◽

Christoph Wenzel ◽

Marek Drozdzik ◽

Stefan Oswald

Keyword(s):

Drug Interactions ◽

Therapeutic Index ◽

Human Intestine ◽

Drug Reactions ◽

Narrow Therapeutic Index ◽

Regulation Function ◽

And Function ◽

Vitro Data ◽

In Vitro Data

Cytochrome P450 (CYP) 1A enzymes are considerably expressed in the human intestine and liver and involved in the biotransformation of about 10% of marketed drugs. Despite this doubtless clinical relevance, CYP1A1 and CYP1A2 are still somewhat underestimated in terms of unwanted side effects and drug–drug interactions of their respective substrates. In contrast to this, many frequently prescribed drugs that are subjected to extensive CYP1A-mediated metabolism show a narrow therapeutic index and serious adverse drug reactions. Consequently, those drugs are vulnerable to any kind of inhibition or induction in the expression and function of CYP1A. However, available in vitro data are not necessarily predictive for the occurrence of clinically relevant drug–drug interactions. Thus, this review aims to provide an up-to-date summary on the expression, regulation, function, and drug–drug interactions of CYP1A enzymes in humans.

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Human BDCA-1 Positive Blood Dendritic Cells in Immunosuppressed Patients: Phenotype, Function and Maturation.

Blood ◽

10.1182/blood.v106.11.2231.2231 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2231-2231

Author(s):

Kathrin Sebelin ◽

Antje Meier ◽

Carola Beier ◽

Bernd Dörken ◽

Antonio Pezzutto ◽

...

Keyword(s):

T Cells ◽

Ex Vivo ◽

Immunosuppressive Drugs ◽

Tnf Alpha ◽

Hla Dr ◽

And Function ◽

Cellular Immune ◽

Vitro Data ◽

In Vitro Data

Abstract Immunosuppressive drugs used in patients (pts) after stem cell / organ transplantation (Tx) as well as in pts with autoimmune disease are known to impair the cellular immune response. This results in an increased incidence of viral infections and viral associated malignancies which has been ascribed to the effect of immunosuppressive drugs on lymphocytes. However, in vitro data indicate that immunosuppressive drugs also target Dendritic Cells (DCs), the most potent antigen-presenting cells and initiators of lymphocyte responses. So far, most studies are based on in vitro data obtained with DC culture in the presence of different concentrations of single immunosuppressive drugs. To investigate the effect of immunosuppression on DC phenotype and function in vivo, we quantitatively and qualitatively analyzed freshly isolated human BDCA-1(CD1c) positive DCs from 15 solid organ transplant (SOT) recipients under immunosuppressive treatment. The percentage of BDCA-1 positive cells among total PBMCs was not statistically different in pts vs ctrls (0,52 vs 0,65, p<0,18). BDCA-1 positive DCs were analyzed for expression of HLA class I and II, CD14, costimmulatory molecules and chemokine expression. Interestingly, CD14 was found to be significantly higher expressed on pt-DCs vs ctrl-DCs suggesting a more immature DC-phenotype. We observed a trend toward a reduced expression of HLA-DR and CD86 on pts-DCs as compared to ctrls-DCs (p=0,059). Surface profile of BDCA-1 positive DCs was also analyzed after 48h of LPS and CD40L stimulation. Here we found a marked upregulation of HLA-DR and CD86 in pts- DCs as well as ctrl-DCs. Supernatant of stimulated DCs was analyzed with cytokine capture beads for secretion of inflammatory cytokines. High secretion of IL-6, IL-1 beta and partially of TNF-alpha by stimulated DCs was observed in both groups. Other Th2 type cytokines (IL-10, IL-4, IL-5) and Th1 type cytokines like IFN-gamma and Il-2 were not significantly secreted. We additionally addressed the question if mature and functionally competent DCs could be generated ex vivo from this pts cohort. After 9 days of culture with GM-CSF, IL-4, IL-1, IL-6, TNF-alpha and PGE2 fully mature DCs could be generated. Co-culture of EBV-peptide-pulsed DCs with autologous T-cells resulted in significant expansion of EBV-specific T cells in pts and ctrls. These T cells were fully functional as shown by IFN-γ secretion detected by ELISPOT. In summary, this is the first analysis of freshly isolated BDCA-1 positive DCs from immunosuppressed pts. Our data support the notion that immunosuppressive drugs target DCs and contribute to a maturation defect of circulating blood DCs which may help to understand the mechanism of impaired cellular immune responses in immunosuppressed pts. However, ex vivo generated DCs from immunosuppressed pts do not show an impairment in phenotype and function, suggesting that they could be efficiently be used in immunotherapeutic strategies.

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In Vitro Data Reveals Potential Novel Mechanism of Action of Teriflunomide on CNS Microglia and Astrocytes

10.26226/morressier.59a3eda8d462b8028d8951bb ◽

2017 ◽

Author(s):

Andrea Edling

Keyword(s):

Mechanism Of Action ◽

Vitro Data ◽

In Vitro Data

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Faculty Opinions recommendation of Simulation and prediction of in vivo drug metabolism in human populations from in vitro data.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1091007.544382 ◽

2007 ◽

Author(s):

Marival Bermejo

Keyword(s):

Drug Metabolism ◽

Human Populations ◽

In Vivo Drug Metabolism ◽

Vitro Data ◽

In Vitro Data

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Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

Alternatives to Laboratory Animals ◽

10.1177/026119299302100209 ◽

1993 ◽

Vol 21 (2) ◽

pp. 173-180

Author(s):

Gunnar Johanson

Keyword(s):

Risk Assessment ◽

Whole Body ◽

External Exposure ◽

Target Dose ◽

Toxic Response ◽

Route Of Exposure ◽

Vitro Data ◽

In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

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Lymphocutaneous spread of Mycobacterium elephantis in an immunocompetent individual: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x211034913 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110349

Author(s):

Brett D Edwards ◽

Ranjani Somayaji ◽

Dina Fisher ◽

Justin C Chia

Keyword(s):

Case Report ◽

Chronic Lung Disease ◽

Contaminated Soil ◽

Lung Abscess ◽

Immunocompetent Individual ◽

First Case ◽

Antimycobacterial Agents ◽

Vitro Data ◽

In Vitro Data

Mycobacterium elephantis was first described when isolated from an elephant that succumbed to lung abscess. However, despite this namesake, it is not associated with animals and has been described most often as a probable colonizer rather than pathogen in humans with chronic lung disease. In this report, we describe the first case of lymphocutaneous infection from M. elephantis, likely as a result of cutaneous inoculation with contaminated soil. This offers further evidence to its capabilities as a pathogen. We provide a review of the limited prior reports of M. elephantis and outline the available in vitro data on efficacy of various antimycobacterial agents.

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Prediction of CYP2D6 Drug Interactions from In Vitro Data: Evidence for Substrate-Dependent Inhibition

Drug Metabolism and Disposition ◽

10.1124/dmd.111.041210 ◽

2011 ◽

Vol 40 (1) ◽

pp. 47-53 ◽

Cited By ~ 43

Author(s):

Brooke M. VandenBrink ◽

Robert S. Foti ◽

Dan A. Rock ◽

Larry C. Wienkers ◽

Jan L. Wahlstrom

Keyword(s):

Drug Interactions ◽

Dependent Inhibition ◽

Vitro Data ◽

In Vitro Data

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Pharmacokinetics and Pharmacodynamics of Antistaphylococcal Antibiotics in Continuous Ambulatory Peritoneal Dialysis Patients

Peritoneal Dialysis International ◽

10.1177/089686089301302s92 ◽

1993 ◽

Vol 13 (2_suppl) ◽

pp. 367-371 ◽

Cited By ~ 3

Author(s):

Erich Keller

Keyword(s):

Peritoneal Dialysis ◽

Continuous Ambulatory Peritoneal Dialysis ◽

Inhibitory Concentration ◽

Pharmacokinetic Data ◽

Pharmacokinetics And Pharmacodynamics ◽

Antistaphylococcal Activity ◽

Cure Rates ◽

Vitro Data ◽

In Vitro Data

Staphylococci are the leading pathogens In continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Vancomycin appears to be an outstanding antistaphylococcal drug because resistance to It Is nearly absent. The pharmacokinetics of vancomycin and clinical cure rates of peritonitis with different dosing guidelines have been studied extensively. Different dosing guidelines with IP or IV loading doses followed or not followed by IP maintenance doses are used successfully, despite the fact that some of the dosing schemes produce apparently suboptimal drug levels referring to In vitro data like the MIC value (minimum Inhibitory concentration). Alternatively, amlnoglycosldes, cephalosporlns, Isoxazolyl penicillins, and broad-spectrum penicillins combined with betalactamase Inhibitors may be used for the treatment of gram-positive peritonitis. For the above panicillins pharmacokinetic data are scarce, and clinical experience is limited. Rifampin has excellent Intracellular antistaphylococcal activity and should be used In combination with other antibiotics. Although pharmacokinetic data are lacking, rifampin dosages do not require adaptation to renal function or replacement therapy.

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Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.1.164 ◽

1998 ◽

Vol 42 (1) ◽

pp. 164-169 ◽

Cited By ~ 65

Author(s):

A. Nzila-Mounda ◽

E. K. Mberu ◽

C. H. Sibley ◽

C. V. Plowe ◽

P. A. Winstanley ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Dihydrofolate Reductase ◽

Drug Response ◽

Point Mutations ◽

Distinct Group ◽

Wild Type ◽

Field Isolates ◽

Vitro Data ◽

In Vitro Data

ABSTRACT Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

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