Thauany Martins Tavoni

Clinical experience with drug delivery systems as tools to decrease the toxicity of anticancer chemotherapeutic agents

ABSTRACT Introduction: The toxicity of chemotherapeutic agents, resulting from their low pharmacological index, introduces considerable discomfort and risk to cancer patients. Among several strategies to reduce the toxicity of chemotherapeutic agents, targeted drug delivery is the most promising one. Areas covered: Liposomes, micelles, albumin-based, polymeric, dendritic and lipid core nanoparticles have been used as carriers to concentrate anticancer drugs in neoplastic tissues, and clinical studies of those preparations are reviewed. In most clinical studies, drug delivery systems reduced drug toxicity. Lipid core nanoparticles (LDE) that bind to cell lipoprotein receptors have the ability to concentrate in neoplastic tissues and were the first artificial non-liposomal system shown in in vivo studies to possess targeting properties. The toxicity reduction achieved by LDE as vehicle of carmustine, etoposide and paclitaxel was singularly strong. Expert opinion: The reduced toxicity offered by drug delivery systems has expanded treatment population that may benefit from chemotherapy including feeble, overtreated and elderly patients that would otherwise be offered palliative therapy. Drug delivery systems may either prolong the duration of treatments or allow increases in drug dose.

Obstructive sleep apnea and effects of continuous positive airway pressure on triglyceride-rich lipoprotein metabolism

This study aimed to explore lipoprotein metabolism in obstructive sleep apnea (OSA) and the effects of continuous positive airway pressure (CPAP). We studied 15 men with severe OSA [apnea-hypopnea index (AHI) ≥30 events/hour] and 12 age-, BMI-, and waist circumference-matched volunteers without OSA (AHI <5 events/hour). Carotid intima-media thickness (CIMT) was determined by a blind examiner. After 12 h fasting, a triglyceride-rich chylomicron-like emulsion, labeled with [14C]cholesteryl oleate and [3H]triolein, was injected intravenously followed by blood sample collection at preestablished times. Fractional clearance rate (FCR) of the radiolabeled lipids was estimated by compartmental analysis of radioisotope decay curves. Compared with controls, patients with OSA showed a significant delay in both cholesteryl ester FCR (0.0126 ± 0.0187 vs. 0.0015 ± 0.0025 min−1; P = 0.0313) and triglycerides FCR (0.0334 ± 0.0390 vs. 0.0051 ± 0.0074 min−1; P = 0.0001). CIMT was higher in the OSA group: 620 ± 17 vs. 725 ± 29 µm; P = 0.004. Cholesteryl ester FCRs were inversely related to total sleep time <90% (r = −0.463; P = 0.029) and CIMT (r = −0.601; P = 0.022). The triglyceride FCR was inversely correlated with AHI (r = −0.537; P = 0.04). In a subgroup of patients treated with CPAP for 3 months (n = 7), triglyceride FCR increased 5-fold (P = 0.025), but the cholesteryl ester FCR was unchanged. In conclusion, severe OSA decreased lipolysis of triglyceride-rich lipoproteins and delayed removal of remnants. CPAP treatment may be effective to restore the lipolysis rates.

HDL acceptor capacities for cholesterol efflux from macrophages and lipid transfer are both acutely reduced after myocardial infarction

BACKGROUND The transport of lipids from the artery wall is one of the most essential anti-atherogenic functions of high-density lipoprotein (HDL). Recent reports of changes in the HDL composition, during myocardial infarction (MI), suggest that this function may be altered. METHODS Forty-one consecutive patients with ST-segment elevation MI enrolled at the Brasilia Heart Study were selected. The following HDL-related measures were determined upon admission (D1) and on the fifth day (D5) after MI: C-reactive protein, CETP and PLTP activity, HDL composition, efflux of cholesterol from J774 macrophages to HDL, and transfer of unesterified and esterified cholesterol, triglycerides and phospholipids from a donor nanoemulsion to HDL. RESULTS From D1 to D5, the activity of CETP decreased by 25%, but PLTP activity remained unchanged. Esterified cholesterol (-23%) and phospholipid (-9.5%) contents of HDL decreased. Transfer of triglycerides (-36.5%) and esterified cholesterol (-14.7%) to HDL from nanoemulsions was reduced, but other lipids transfers were unchanged. Cholesterol efflux to HDL was also diminished by 8.5% (p=0.04) on D5 compared to D1. It was more pronounced in patients above the 75th percentile of C-reactive protein. CONCLUSIONS After an MI, a simultaneous decrease in lipid transfer to HDL and in the capacity of HDL to efflux cholesterol from cells occurs. Thus, HDL with inferior atheroprotective properties may be generated in the acute post-MI period.