Biosynthetic Human Proinsulin: Review of Chemistry, in Vitro and in Vivo Receptor Binding, Animal and Human Pharmacology Studies, and Clinical Trial Experience

Diabetes Care ◽  
1992 ◽  
Vol 15 (5) ◽  
pp. 666-692 ◽  
Author(s):  
J. A. Galloway ◽  
S. A. Hooper ◽  
C. T. Spradlin ◽  
D. C. Howey ◽  
B. H. Frank ◽  
...  
1990 ◽  
Vol 183 (5) ◽  
pp. 1623
Author(s):  
J.A.D.M. Tonnaer ◽  
P. Room ◽  
W.M.J.B. Van Gemert ◽  
L.P.C. Delbressine ◽  
T. de Boer ◽  
...  

1999 ◽  
Vol 79 ◽  
pp. 236
Author(s):  
Takeo Funakoshi ◽  
Shigeyuki Chaki ◽  
Ryoko Yoshikakwa ◽  
Shigeru Okuyama ◽  
Atsuro Nakazato ◽  
...  

1996 ◽  
Vol 124 (1-2) ◽  
pp. 57-73 ◽  
Author(s):  
A. Schotte ◽  
P. F. M. Janssen ◽  
W. Gommeren ◽  
W. H. M. L. Luyten ◽  
P. Van Gompel ◽  
...  

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S568-S568
Author(s):  
Jason Moore ◽  
Sonia Pahwa ◽  
Zhixia Yan Danielsen ◽  
Philip Colangelo

Abstract Background Nonclinical (animal and in vitro) models are commonly used during the development of antibacterial drugs. Pharmacokinetic (PK) and pharmacodynamic (PD) data obtained from these nonclinical models are used to generate a PK-PD target, which can then be bridged to humans in a probability of PK-PD target attainment (PTA) analysis to support selection of the dose regimen for phase 3 trials and in vitro susceptibility testing criteria (breakpoints) to guide clinical usage. Methods Two recently approved tetracycline antibacterial drugs, eravacycline (ERV) and omadacycline (OMD), were evaluated. PK-PD data from nonclinical models and clinical microbiological response were collected from each of the respective clinical pharmacology reviews and assessments published by FDA and EMA, respectively. The highest MICs (minimum inhibitory concentrations) reflecting 80% success in the ability of the drug to inhibit growth in the target bacteria were identified from clinical and nonclinical data and termed the MIC cutoff. The nonclinical MIC cutoff was obtained from the PTA analysis using the PK-PD targets from animal studies. The clinical MIC cutoff was obtained from microbiological response (microbiological intent-to-treat population) data from clinical trial experience. The ratios of the clinical and nonclinical MIC cutoffs were calculated and used to evaluate potential discrepancies between the animal model prediction and clinical trial experience. Results The drug development programs for ERV and OMD included murine infection models and in vitro models to characterize PK-PD. The clinical to nonclinical MIC cutoff ratios ranged from 4 to 32. Higher values of the MIC cutoff signify that the drug can treat larger proportions of the bacterial population; therefore, high clinical to nonclinical MIC cutoff ratios signify that the drugs had more activity in reducing the bacterial population in clinical than in nonclinical studies. Conclusion Thus, the nonclinical models for ERV and OMD under-predicted microbiological response and breakpoints. While nonclinical models are generally useful, more characterization of translational factors may be needed to allow nonclinical models to be more predictive of clinical trial outcomes. Disclosures All authors: No reported disclosures.


1986 ◽  
Vol 19 (4) ◽  
pp. 384-385 ◽  
Author(s):  
Joel S. Perlmutter ◽  
Marcus E. Raichle

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1429
Author(s):  
Theo Wallimann ◽  
Caroline H. T. Hall ◽  
Sean P. Colgan ◽  
Louise E. Glover

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that “oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn’s disease”. A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3–5 g of Cr per day for a time of 3–6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn’s disease.


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