Results. Mean age was 68 years (SD 15) with 69% male, 80% dysvascular and 68% transtibial. The overall median inpatient rehabilitation length of stay was 39 days . Individuals with amputation entering rehabilitation each year had a higher number of comorbidities (β: 0.08; 95% CI: 0.05-0.11). Introduction of the IPP was associated with a significant reduction in time to initial prosthetic casting, independent walk and inpatient RLOS. Introduction of RRD's was associated with a significant reduction in time to wound healing, initial prosthetic casting and independent walk.Conclusions. Individuals with amputation were typically elderly, dysvascular, males with transtibial amputations. Independent walk is an outcome rarely reported and is
1. Gemigliptin (formerly known as LC15-0444) is a newly developed dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes. Following oral administration of 50 mg (5.4 MBq) [(14)C]gemigliptin to healthy male subjects, absorption, metabolism and excretion were investigated. 2. A total of 90.5% of administered dose was recovered over 192 hr postdose, with 63.4% from urine and 27.1% from feces. Based on urinary recovery of radioactivity, a minimum 63.4% absorption from gastrointestinal tract could be confirmed. 3. Twenty-three metabolites were identified in plasma, urine and feces. In plasma, gemigliptin was the most abundant component accounting for 67.2% ∼ 100% of plasma radioactivity. LC15-0636, a hydroxylated metabolite of gemigliptin, was the only human metabolite with systemic exposure more than 10% of total drug-related exposure. Unchanged gemigliptin accounted for 44.8% ∼ 67.2% of urinary radioactivity and 27.7% ∼ 51.8% of fecal radioactivity. The elimination of gemigliptin was balanced between metabolism and excretion through urine and feces. CYP3A4 was identified as the dominant CYP isozyme converting gemigliptin to LC15-0636 in recombinant CYP/FMO enzymes.
Dimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P‐glycoprotein (P‐gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experiments using CYP‐selective substrates with human liver microsomes showed 50% inhibitory concentrations (IC50) of >666 µmol/L for DMF and >750 µmol/L for MMF. MMF (≤250 μmol/L; 72 hours) was not cytotoxic in cultured human hepatocyte experiments and mRNA expression data indicated no CYP induction by MMF (1‐250 µmol/L). DMF (≤6.66 mmol/L) showed moderate‐to‐high absorption (apparent permeability [Papp] ≥2.3‐29.7 x 10−6 cm/s) across a Caucasian colon adenocarcinoma (Caco‐2) cell monolayer, while MMF (≤7.38 mmol/L) demonstrated low‐to‐moderate permeability (Papp 1.2‐8.9 × 10−6 cm/s). DMF was not a substrate for P‐gp (net efflux ratios ≤1.22) but was a weak inhibitor of P‐gp at supratherapeutic concentrations (estimated IC50 relative to solvent control of 1.5 mmol/L; [3H]digoxin efflux in Caco‐2 cells). This inhibition is unlikely to be clinically relevant. MMF was not a substrate or inhibitor of P‐gp. Thus, DMF and MMF should not affect the absorption, distribution, metabolism or excretion of coadministered drugs that are CYP and P‐gp substrates.
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