A pilot study to assess the ability of an orally available selective thromboxane synthase inhibitor to improve renal function in cyclosporine-treated renal transplant recipients

Matthew R. Weir, David K. Klassen, James F. Burdick

Research output: Contribution to journalArticle

Abstract

Six cyclosporine (cyclosporine A (CsA))-treated renal transplant patients (4.3 ± 0.6 months posttransplantation) were studied to see if selective urinary thromboxane (TX) inhibition with CGS 12970 (TX synthase inhibitor) would improve renal function and lessen CsA-induced decrements in RPF and GFR as measured by (99Tc)DTPA and (131I)hippuran clearances. The baseline trough CsA levels of the patients were 208 ± 92 ng/mL Before treatment with CGS 12970 (100 mg twice a day for 7 days), all drugs known to affect renal function or CsA pharmacokinetics were stopped. CGS 12970 therapy did not alter RPF (203 ± 17 pre versus 200 ± 15 mL/min post), GFR (38.5 ± 3.2 pre versus 38.2 ± 3.9 mL/min post), or serum creatinine (creat) (1.9 ± .06 pre versus 1.8 ± 0.18 mg/dL post), despite an average of 81% suppression of urine TX (65 ± 14 pg/mg of creat pre versus 12 ± 4 pg/mg of creat post); P <0.01), as measured by gas chromatography/mass spectrometry. CGS 12970 had no significant effect on urinary 6-keto-prostaglandin F1a levels (63 ± 4 pg/mg of creat pre versus 85 ± 25 pg/mg of creat post). CGS 12970 did not alter CsA pharmacokinetics or drug levels, blood pressure, weight, or serum electrolytes of the patients. These results suggest that: (1) if TX is a mediator in CsA nephrotoxicity, 81% suppression by a selective TX synthase inhibitor may not be sufficient to improve renal function; (2) urinary TxB2 may not necessarily reflect adequate inhibition of TxA2 synthesis in the kidney; or (J) TX is not an important mediator of CsA-mediated reduction in renal function in recently transplanted patients with stable creatinine in the 1.5- to 2.0-mg/dL range.

Original languageEnglish (US)
Pages (from-to)1285-1290
Number of pages6
JournalJournal of the American Society of Nephrology
Volume2
Issue number8
StatePublished - Feb 1992

Fingerprint

Thromboxanes
Cyclosporine
Kidney
Creatinine
Pharmacokinetics
Pentetic Acid
Transplant Recipients
Serum
Pharmaceutical Preparations
Gas Chromatography-Mass Spectrometry
Electrolytes
Prostaglandins
3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid
Urine
Blood Pressure
Transplants
Weights and Measures
Therapeutics

Keywords

  • Cyclosporine
  • Renal function
  • Thromboxane

ASJC Scopus subject areas

  • Nephrology

Cite this

@article{a70f150c4303459bb33ea521ee1a02ee,
title = "A pilot study to assess the ability of an orally available selective thromboxane synthase inhibitor to improve renal function in cyclosporine-treated renal transplant recipients",
abstract = "Six cyclosporine (cyclosporine A (CsA))-treated renal transplant patients (4.3 ± 0.6 months posttransplantation) were studied to see if selective urinary thromboxane (TX) inhibition with CGS 12970 (TX synthase inhibitor) would improve renal function and lessen CsA-induced decrements in RPF and GFR as measured by (99Tc)DTPA and (131I)hippuran clearances. The baseline trough CsA levels of the patients were 208 ± 92 ng/mL Before treatment with CGS 12970 (100 mg twice a day for 7 days), all drugs known to affect renal function or CsA pharmacokinetics were stopped. CGS 12970 therapy did not alter RPF (203 ± 17 pre versus 200 ± 15 mL/min post), GFR (38.5 ± 3.2 pre versus 38.2 ± 3.9 mL/min post), or serum creatinine (creat) (1.9 ± .06 pre versus 1.8 ± 0.18 mg/dL post), despite an average of 81{\%} suppression of urine TX (65 ± 14 pg/mg of creat pre versus 12 ± 4 pg/mg of creat post); P <0.01), as measured by gas chromatography/mass spectrometry. CGS 12970 had no significant effect on urinary 6-keto-prostaglandin F1a levels (63 ± 4 pg/mg of creat pre versus 85 ± 25 pg/mg of creat post). CGS 12970 did not alter CsA pharmacokinetics or drug levels, blood pressure, weight, or serum electrolytes of the patients. These results suggest that: (1) if TX is a mediator in CsA nephrotoxicity, 81{\%} suppression by a selective TX synthase inhibitor may not be sufficient to improve renal function; (2) urinary TxB2 may not necessarily reflect adequate inhibition of TxA2 synthesis in the kidney; or (J) TX is not an important mediator of CsA-mediated reduction in renal function in recently transplanted patients with stable creatinine in the 1.5- to 2.0-mg/dL range.",
keywords = "Cyclosporine, Renal function, Thromboxane",
author = "Weir, {Matthew R.} and Klassen, {David K.} and Burdick, {James F.}",
year = "1992",
month = "2",
language = "English (US)",
volume = "2",
pages = "1285--1290",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "8",

}

TY - JOUR

T1 - A pilot study to assess the ability of an orally available selective thromboxane synthase inhibitor to improve renal function in cyclosporine-treated renal transplant recipients

AU - Weir, Matthew R.

AU - Klassen, David K.

AU - Burdick, James F.

PY - 1992/2

Y1 - 1992/2

N2 - Six cyclosporine (cyclosporine A (CsA))-treated renal transplant patients (4.3 ± 0.6 months posttransplantation) were studied to see if selective urinary thromboxane (TX) inhibition with CGS 12970 (TX synthase inhibitor) would improve renal function and lessen CsA-induced decrements in RPF and GFR as measured by (99Tc)DTPA and (131I)hippuran clearances. The baseline trough CsA levels of the patients were 208 ± 92 ng/mL Before treatment with CGS 12970 (100 mg twice a day for 7 days), all drugs known to affect renal function or CsA pharmacokinetics were stopped. CGS 12970 therapy did not alter RPF (203 ± 17 pre versus 200 ± 15 mL/min post), GFR (38.5 ± 3.2 pre versus 38.2 ± 3.9 mL/min post), or serum creatinine (creat) (1.9 ± .06 pre versus 1.8 ± 0.18 mg/dL post), despite an average of 81% suppression of urine TX (65 ± 14 pg/mg of creat pre versus 12 ± 4 pg/mg of creat post); P <0.01), as measured by gas chromatography/mass spectrometry. CGS 12970 had no significant effect on urinary 6-keto-prostaglandin F1a levels (63 ± 4 pg/mg of creat pre versus 85 ± 25 pg/mg of creat post). CGS 12970 did not alter CsA pharmacokinetics or drug levels, blood pressure, weight, or serum electrolytes of the patients. These results suggest that: (1) if TX is a mediator in CsA nephrotoxicity, 81% suppression by a selective TX synthase inhibitor may not be sufficient to improve renal function; (2) urinary TxB2 may not necessarily reflect adequate inhibition of TxA2 synthesis in the kidney; or (J) TX is not an important mediator of CsA-mediated reduction in renal function in recently transplanted patients with stable creatinine in the 1.5- to 2.0-mg/dL range.

AB - Six cyclosporine (cyclosporine A (CsA))-treated renal transplant patients (4.3 ± 0.6 months posttransplantation) were studied to see if selective urinary thromboxane (TX) inhibition with CGS 12970 (TX synthase inhibitor) would improve renal function and lessen CsA-induced decrements in RPF and GFR as measured by (99Tc)DTPA and (131I)hippuran clearances. The baseline trough CsA levels of the patients were 208 ± 92 ng/mL Before treatment with CGS 12970 (100 mg twice a day for 7 days), all drugs known to affect renal function or CsA pharmacokinetics were stopped. CGS 12970 therapy did not alter RPF (203 ± 17 pre versus 200 ± 15 mL/min post), GFR (38.5 ± 3.2 pre versus 38.2 ± 3.9 mL/min post), or serum creatinine (creat) (1.9 ± .06 pre versus 1.8 ± 0.18 mg/dL post), despite an average of 81% suppression of urine TX (65 ± 14 pg/mg of creat pre versus 12 ± 4 pg/mg of creat post); P <0.01), as measured by gas chromatography/mass spectrometry. CGS 12970 had no significant effect on urinary 6-keto-prostaglandin F1a levels (63 ± 4 pg/mg of creat pre versus 85 ± 25 pg/mg of creat post). CGS 12970 did not alter CsA pharmacokinetics or drug levels, blood pressure, weight, or serum electrolytes of the patients. These results suggest that: (1) if TX is a mediator in CsA nephrotoxicity, 81% suppression by a selective TX synthase inhibitor may not be sufficient to improve renal function; (2) urinary TxB2 may not necessarily reflect adequate inhibition of TxA2 synthesis in the kidney; or (J) TX is not an important mediator of CsA-mediated reduction in renal function in recently transplanted patients with stable creatinine in the 1.5- to 2.0-mg/dL range.

KW - Cyclosporine

KW - Renal function

KW - Thromboxane

UR - http://www.scopus.com/inward/record.url?scp=0026812484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026812484&partnerID=8YFLogxK

M3 - Article

C2 - 1627753

AN - SCOPUS:0026812484

VL - 2

SP - 1285

EP - 1290

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 8

ER -