[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 01/2013; 8(11):e79603. · 3.73 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.
218 lung cancer patients, who had their 24-h creatinine secretion in urine measured prior to the start of any chemotherapy, were included. Estimation of renal function was calculated and compared to ECC.
There were no major differences in the performance of the tested equations. Mean percentage error of more than 20% and general underestimation was common to all equations. Wright equation performed best although it describes only 43% of ECC variability. Mean measured ECC was 94 mL/min (95% confidence interval [CI]: 90-98 mL/min) and 90 mL/min for Wright equation (95% CI: 87-93 mL/min) (Supp. Fig. 3). MDRD and CKD-EPI equation performed poorest since they do not include any body size descriptor. Large deviations of differences were observed, with a median standard deviation of more than 20% and deviations from ECC exceeding 100%. Wright equation performed best, whereas, despite their leading role in the detection of renal diseases, the MDRD and CKD-EPI equation performed poorest since they do not include any body size descriptor. In the range of ECC<50 mL/(min×1.73 m(2)), the CG equation most often detected a contraindication for cisplatin use. Differences between ECC and calculated values correlated with patients' weight, BSA and body mass index when these were not included in the equation itself.
In evaluating the renal function of lung cancer patients, equations adjusted for body size descriptors should be preferred. Estimated renal function should be interpreted against the characteristics of patient's body size and special attention is needed when these are reaching the extremes.
Lung cancer (Amsterdam, Netherlands) 12/2011; 76(3):397-402. · 3.14 Impact Factor
[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.
Journal of cachexia, sarcopenia and muscle. 12/2011; 2(4):191-200.