[Show abstract][Hide abstract] ABSTRACT: Background
Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats.Methods
Nine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5—D5), and when rats were severely cachectic (Day 10—D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters.ResultsAll three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (−80.5%, −79.8%, and −72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019).Conclusions
Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events.
Journal of Cachexia, Sarcopenia and Muscle 03/2015; 6(1):45-52. DOI:10.1002/jcsm.12012 · 7.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Polypharmacy is common in patients with chronic heart failure (HF) and/or chronic obstructive pulmonary disease (COPD), but little is known about the prevalence and significance of drug-drug interactions (DDIs). This study evaluates DDIs in hospitalized patients.
Material and methods
We retrospectively screened medical charts over a 6-month period for diagnosis of chronic HF and/or COPD. Potential DDIs were evaluated using Lexi-Interact software.
Seven hundred and seventy-eight patients were included in the study (median age 75 years, 61% men). The median number of drugs on admission and discharge was 6 (interquartile range (IQR) 4–9) and 7 (IQR 5–), respectively (p = 0.10). We recorded 6.5 ±5.7 potential DDIs per patient on admission and 7.2 ±5.6 on discharge (p = 0.2). From admission to discharge, type-C and type-X potential DDIs increased (p < 0.05 for both). Type X interactions were rare (< 1%), with the combination of a β-blocker and a β2 agonist being the most common (64%). There were significantly more type-C and type-D potential DDIs in patients with chronic HF as compared to patients with COPD (p < 0.001). Patients with concomitant chronic HF and COPD had more type-C and type-X potential DDIs when compared to those with individual disease (p < 0.005). An aldosterone antagonist and ACE inhibitor/ARB were prescribed to 3% of chronic HF patients with estimated glomerular filtration rate < 30 ml/(min × 1.73 m2).
The DDIs are common in patients with chronic HF and/or COPD, but only a few appear to be of clinical significance. The increase in potential DDIs from admission to discharge may reflect better guideline implementation rather than poor clinical practice.
Archives of Medical Science 10/2014; 10(5):920-32. DOI:10.5114/aoms.2014.46212 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dried blood spot (DBS) sampling represents a suitable method for pharmacokinetic studies in rats, particularly if serial sampling is needed. To study the pharmacokinetics of drugs in a rat heart failure (HF) model, we developed and validated a method for the simultaneous determination of bisoprolol, ramiprilat, propranolol and midazolam in DBS samples. Bisoprolol and ramipril are widely used in the treatment of HF, and midazolam and propranolol are markers of hepatic metabolism, which can be altered in HF. A 20 μL sample of rat blood was pipetted onto Whatman 903 Protein Saver Card and allowed to dry. The whole spot was excised and 300 μL of solvent (methanol with10% ultrapure water and 0.1% formic acid) was added. After mixing and incubating the sample in an ultrasonic bath, a mixture of isotopically labeled internal standards was added. After centrifugation, the extracts were cleaned on an Ostro™ plate and analyzed using liquid chromatography-tandem mass spectroscopy. The method was successfully validated. No significant interference was observed in the retention times of analytes or internal standards. The intraday and interday accuracy and precision were within a ±15% interval. The method was linear in the range 5–250 μg/L and the lower limit of quantification was 5 μg/L for all four analytes. The absolute matrix effect ranged from 98.7% for midazolam to 121% for ramiprilat. The recovery was lowest for ramiprilat and highest for propranolol. Samples were stable at all tested temperatures. The method has been used successfully in a real-time pharmacokinetic study in rats
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 05/2014; 958C. DOI:10.1016/j.jchromb.2014.03.009 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.
PLoS ONE 11/2013; 8(11):e79603. DOI:10.1371/journal.pone.0079603 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Rosiglitazone improves insulin sensitivity and promotes weight gain in patients with Diabetes Mellitus type 2, which could be useful in wasting and cachexia. However, its effects on cardiac function are controversial. We aimed to investigate the effects of rosiglitazone on body wasting, body composition, cardiac function and survival in a rat model of cancer cachexia.
Rats were injected Yoshida AH-130 hepatoma tumor cells and randomized to receive placebo or rosiglitazone 4 mg/kg/d. Treatment started one day after tumor inoculation and the rats were sacrificed 14 days thereafter. Body weight and body composition was measured at baseline and after the removal of the tumor. Echocardiography was performed at baseline and on day 11. At the end of the study, organs were weighed and the proteasome activity in gastrocnemius muscle was measured.
Survival analysis showed a significant benefit from treatment with rosiglitazone (hazard ratio = 0.38, 95% confidence interval: 0.15 – 0.86). Rosiglitazone reduced average daily weight loss (2.33 g/d rosiglitazone vs. 3.93 g/d placebo, p < 0.05) as a result of both fat and lean mass preservation. It decelerated white and brown tissue wasting, but had no effect on skeletal muscle mass and heart mass. However, peptidyl-glutamyl-protein-hydrolysing and trypsin-like activity in gastrocnemius muscle was significantly reduced by rosiglitazone. Finally, it increased left ventricular ejection fraction, fractional shortening and systolic volume and improved cardiac output in cachectic cancer rats.
Rosiglitazone prevents weight loss and improves survival in rat model of cancer cachexia. It exerts beneficial effects on cardiac function.
[Show abstract][Hide abstract] ABSTRACT: In lung cancer patients treated with chemotherapy, renal function is an important parameter to be monitored. Since measurement of renal function with either isotope or creatinine clearance is time consuming and expensive, we evaluated which of the following equations: Cockcroft-Gault (CG), Wright, modification of diet in renal disease equation (MDRD), MDRD adjusted for body surface area (BSA) and chronic kidney disease epidemiology collaboration (CKD-EPI) best resembles endogenous creatinine clearance (ECC) and could therefore replace its measurement in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Cachexia is an irreversible process that can develop in the course of chronic disease. It is characterized by the remodeling of the metabolic, inflammatory, and endocrine pathways. Insulin, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) are involved in glucose, protein, and fat metabolism, which regulates body composition. In body wasting and cachexia, their signaling is impaired and causes anabolic/catabolic imbalance. Important mechanisms include inflammatory cytokines and neurohormonal activation. Remodeled post-receptor insulin, GH, and IGF-1 pathways constitute a potential target for pharmacological treatment in the setting of body wasting and cachexia. Peroxisome proliferator-activated receptor gamma agonists, drugs inhibiting angiotensin II action (angiotensin II antagonists and inhibitors of angiotensin-converting enzyme), and testosterone, which interfere with post-receptor pathways of insulin, GH, and IGF-1, were investigated as pharmacological intervention targets and various clinically important implications were reported. There are several other potential targets, but their treatment feasibility and applicability is yet to be established.