PMID- 28596840
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210109
IS  - 2052-1707 (Print)
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 5
IP  - 1
DP  - 2017 Feb
TI  - Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated 
      with unexpected renal effects.
PG  - e00292
LID - 10.1002/prp2.292 [doi]
LID - e00292
AB  - The antisense compound ISIS 388626 selectively inhibits renal glucose 
      reabsorption by inhibiting the sodium-glucose cotransporter-2 (SGLT2) mRNA 
      expression. It is developed as an insulin-independent treatment approach for type 
      2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and 
      pharmacodynamics after subcutaneous administration of the drug were planned to be 
      evaluated in healthy volunteers in a single-ascending-dose study (50-400 mg) and 
      a multiple-ascending-dose study (6 weeks; weekly doses of 50-400 mg with loading 
      dose regimen of three doses during the first week). The study was halted early 
      because increases in serum creatinine occurred in the subjects participating in 
      the 100 mg multiple-dose cohort. The pronounced changes in serum creatinine were 
      accompanied by increased urinary excretion of beta-2-microglobulin and KIM1. The 
      possible mechanisms for these findings remain elusive and are in contrast to 
      preclinical findings as comparable treatment with ISIS 388626 of animals did not 
      reveal similar changes. Although exposure was limited, there was an indication 
      that glucosuria increased upon active treatment. Before the concept of 
      antisense-mediated blocking of SGLT2 with ISIS 388626 can be explored further, 
      more preclinical data are needed to justify further investigations.
FAU - van Meer, Leonie
AU  - van Meer L
AUID- ORCID: 0000-0003-1424-0120
AD  - Centre for Human Drug Research Zernikedreef 82333 CL Leiden The Netherlands.
FAU - van Dongen, Marloes
AU  - van Dongen M
AD  - Centre for Human Drug Research Zernikedreef 82333 CL Leiden The Netherlands.
FAU - Moerland, Matthijs
AU  - Moerland M
AD  - Centre for Human Drug Research Zernikedreef 82333 CL Leiden The Netherlands.
FAU - de Kam, Marieke
AU  - de Kam M
AD  - Centre for Human Drug Research Zernikedreef 82333 CL Leiden The Netherlands.
FAU - Cohen, Adam
AU  - Cohen A
AD  - Centre for Human Drug Research Zernikedreef 82333 CL Leiden The Netherlands.
FAU - Burggraaf, Jacobus
AU  - Burggraaf J
AD  - Centre for Human Drug Research Zernikedreef 82333 CL Leiden The Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20170117
PL  - United States
TA  - Pharmacol Res Perspect
JT  - Pharmacology research & perspectives
JID - 101626369
PMC - PMC5461644
OTO - NOTNLM
OT  - Antisense
OT  - SGLT2 inhibitor
OT  - oligonucleotide
OT  - phase 1 study
OT  - renal toxicity
EDAT- 2017/06/10 06:00
MHDA- 2017/06/10 06:01
PMCR- 2017/01/17
CRDT- 2017/06/10 06:00
PHST- 2016/06/17 00:00 [received]
PHST- 2016/11/04 00:00 [revised]
PHST- 2016/11/09 00:00 [accepted]
PHST- 2017/06/10 06:00 [entrez]
PHST- 2017/06/10 06:00 [pubmed]
PHST- 2017/06/10 06:01 [medline]
PHST- 2017/01/17 00:00 [pmc-release]
AID - PRP2292 [pii]
AID - 10.1002/prp2.292 [doi]
PST - epublish
SO  - Pharmacol Res Perspect. 2017 Jan 17;5(1):e00292. doi: 10.1002/prp2.292. 
      eCollection 2017 Feb.