RESUMEN
This is a phase 1, open-label, single-sequence, multiple-dose, single-center trial conducted in the US (NCT03790839), to evaluate the clinical pharmacokinetics, safety and pharmacodynamics of dorzagliatin co-administered with sitagliptin in patients with T2D and obesity. The trial has completed. 15 patients with T2D and obesity were recruited and treated with sitagliptin 100 mg QD on Day 1-5, followed by a combination of sitagliptin 100 mg QD with dorzagliatin 75 mg BID at second stage on Day 6-10 and the third stage of dorzagliatin 75 mg BID alone on Day 11-15. Primary outcomes include pharmacokinetic geometric mean ratio (GMR), safety and tolerability. Secondary outcomes include the incremental area under the curve for 4 hours post oral glucose tolerance test (iAUC) of pharmacodynamic biomarkers and glucose sensitivity. GMR for AUC0-24h and Cmax were 92.63 (90% CI, 85.61, 100.22) and 98.14 (90% CI, 83.73, 115.03) in combination/sitagliptin, and 100.34 (90% CI, 96.08, 104.79) and 102.34 (90% CI, 86.92, 120.50) in combination/dorzagliatin, respectively. Combination treatment did not increase the adverse events and well-tolerated in T2D patients. Lack of clinically meaningful pharmacokinetic interactions between dorzagliatin and sitagliptin, and an improvement of glycemic control under combination potentially support their co-administration for diabetes management.
Asunto(s)
Diabetes Mellitus Tipo 2 , Fosfato de Sitagliptina , Humanos , Fosfato de Sitagliptina/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Hipoglucemiantes/efectos adversos , Interacciones Farmacológicas , Obesidad/tratamiento farmacológico , Obesidad/inducido químicamenteRESUMEN
AIMS: Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults. METHODS AND RESULTS: Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50-75 years. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing. CONCLUSIONS: Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.
Asunto(s)
Piridonas , Rivaroxabán , Administración Oral , Adulto , Anciano , Anticoagulantes , Arginina/análogos & derivados , Dabigatrán , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Piperazinas , Pirazoles , Piridonas/efectos adversos , Rivaroxabán/efectos adversosRESUMEN
Factors used in environmental remedial decision making concerning ecological risk are not well understood or necessarily consistent. Recent Records of Decision (RODs) for Army CERCLA sites were reviewed to select case studies where remedial management occurred in response to ecological risks. Thirty-four Army RODs were evaluated representing decisions promulgated between 1996 and 2004. Five were selected based on assessments that remedial actions were clearly linked to concern for ecological receptors. The Ecological Risk Assessment (ERA) approach and the subsequent risk management process were reviewed for each site. The case studies demonstrated that the ERA findings, as well as critical management decisions regarding interpretation of identified ecological risks, were determinants of remedial action objectives. Decisions regarding the selection of remedial alternatives were based on a set of criteria prescribed by Superfund requirements and guidance. Remedial alternative evaluations require protection of human health and the environment, but protective conditions were determined using different methods at each site. Examining the remedial management process for the 5 case study sites revealed that uncertainty in the risk assessment and decisions regarding appropriate spatial scales for both risk assessment and remediation were important factors influencing remedial action decisions. The case reviews also revealed that levels of documentation were variable from site to site. In the future, more detailed documentation of decision criteria and the development of criteria that consider the resilience of the site will result in more technically defensible ecological risk management.