The U.S. Food and Drug Administration's Experience with Ivacaftor in Cystic Fibrosis. Establishing Efficacy Using In Vitro Data in Lieu of a Clinical Trial

2018 ◽  
Vol 15 (1) ◽  
pp. 1-2 ◽  
Author(s):  
Anthony G. Durmowicz ◽  
Robert Lim ◽  
Hobart Rogers ◽  
Curtis J. Rosebraugh ◽  
Badrul A. Chowdhury
Author(s):  
Thomas Bjarnsholt ◽  
Tim Tolker-Nielsen ◽  
Niels Høiby ◽  
Michael Givskov

Pseudomonas aeruginosais the best described bacterium with regards to quorum sensing (QS), in vitro biofilm formation and the development of antibiotic tolerance. Biofilms composed ofP. aeruginosaare thought to be the underlying cause of many chronic infections, including those in wounds and in the lungs of patients with cystic fibrosis. In this review, we provide an overview of the molecular mechanisms involved in QS, QS-enabled virulence, biofilm formation and biofilm-enabled antibiotic tolerance. We now have substantial knowledge of the multicellular behaviour ofP. aeruginosain vitro. A major task for the future is to investigate how such in vitro data correlate with the in vivo behaviour ofP. aeruginosa, and how to treat chronic infections of this bacterium in patients.


Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 4824-4825 ◽  
Author(s):  
Felicetto Ferrara

In this issue of Blood, Karp and colleagues describe preclinical and clinical effects of the combination of tipifarnib with etoposide. The study represents an admirable example of successful translation of in vitro data to a phase 1 clinical trial.


1993 ◽  
Vol 21 (2) ◽  
pp. 173-180
Author(s):  
Gunnar Johanson

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.


2021 ◽  
Vol 9 ◽  
pp. 2050313X2110349
Author(s):  
Brett D Edwards ◽  
Ranjani Somayaji ◽  
Dina Fisher ◽  
Justin C Chia

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.


2011 ◽  
Vol 40 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Brooke M. VandenBrink ◽  
Robert S. Foti ◽  
Dan A. Rock ◽  
Larry C. Wienkers ◽  
Jan L. Wahlstrom

1993 ◽  
Vol 13 (2_suppl) ◽  
pp. 367-371 ◽  
Author(s):  
Erich Keller

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.


1998 ◽  
Vol 42 (1) ◽  
pp. 164-169 ◽  
Author(s):  
A. Nzila-Mounda ◽  
E. K. Mberu ◽  
C. H. Sibley ◽  
C. V. Plowe ◽  
P. A. Winstanley ◽  
...  

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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