Distribution of lamivudine into lymph node HIV reservoir.

Efficient delivery of antiretroviral agents to lymph nodes is important to decrease the size of the HIV reservoir within the lymphatic system. Lamivudine (3TC) is used in first-line regimens for the treatment of HIV. As a highly hydrophilic small molecule, 3TC is not predicted to associate with chylomicrons and therefore should have negligible uptake into intestinal lymphatics following oral administration. Similarly, negligible amounts of 3TC are predicted to be transported into peripheral lymphatics following subcutaneous (SC) injection due to the faster flow rate of blood in comparison to lymph. In this work, we performed pharmacokinetic and biodistribution studies of 3TC in rats following oral lipid-based, oral lipid-free, SC, and intravenous (IV) administrations. In the oral administration studies, mesenteric lymph nodes (MLNs) had significantly higher 3TC concentrations compared to other lymph nodes, with mean tissue:serum ratios ranging from 1.4 to 2.9. However, cells and chylomicrons found in mesenteric lymph showed low-to-undetectable concentrations. In SC studies, administration-side (right) draining inguinal and popliteal lymph nodes had significantly higher concentrations (tissue:serum ratios as high as 3.2) than corresponding left-side nodes. In IV studies, lymph nodes had lower mean tissue:serum ratios ranging from 0.9 to 1.4. We hypothesize that following oral or SC administration, slower permeation of this hydrophilic molecule into blood capillaries may result in considerable passive 3TC penetration into lymphatic vessels. Further studies will be needed to clarify the mechanism of delivery of 3TC and similar antiretroviral drugs into the lymph nodes.

Evidence for changing lipid management strategy to focus on non-high density lipoprotein cholesterol.

Low-density lipoprotein cholesterol (LDL-C) has been recommended as the primary treatment target on lipid management in coronary heart disease (CHD) patients for past several decades. However, even by aggressive LDL-C lowering treatment, patients still present a significant residual risk of major adverse cardiovascular events (MACE). Non-high-density lipoprotein cholesterol (non-HDL-C) contained all the atherogenic lipoproteins, such as chylomicron, very-low density lipoprotein (VLDL), LDL, intermediate density lipoprotein (IDL). Many prospective observation studies have found that non-HDL-C was better than LDL-C in predicting risks of MACE. Since non-HDL-C appears to be superior for risk prediction beyond LDL-C, current guidelines have emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies and have flagged non-HDL-C as a co-primary therapeutic target. The goals of non-HDL-C were recommended as 30 mg/dl higher than the corresponding LDL-C goals, but the value seemed inappropriate. This review provide evidence for changing lipid management strategy to focus on non-HDL-C and appropriate values for adding to LDL-C goals would be proposed.

Hipocolesterolemia familiar en la infancia / Familiar hypocholesterolemia during childhood

Mientras los estados hiperlipémicos se manifestarán sintomáticamente en la edad adulta, los trastornos que cursan con hipocolesterolemia , pueden dar síntomas desde los primeros años de la vida.Los trastornos hipocolesterolémicos se dividen en: aquellos con valores reducidos de lipoproteínas de alta densidad (HDL), rara vez sintomáticos en la infancia; los hipocolesterolémicos secundarios a un déficit de lipoproteínas, como resultado de una enfermedad subyacente; y los hipocolesterolémicos que cursan con valores bajos de quilomicrones (QM), lipoproteínas de muy baja densidad (VLDL) y lipoproteínas de baja densidad (LDL). Estos últimos son el grupo de mayor interés en pediatría porque en él se engloban una serie de enfermedades hereditarias con manifestaciones ya desde la infancia. Todas ellas son consecuencia de un déficit de la apoproteína B (Apo-B) transportadora en el plasma de dichas lipoproteínas. Se presenta el caso de una familia con 4 hijos; en que el padre y 3 hermanos son portadores de hipobetalipoproteinemia forma heterocigota. La presentación de esta familia permite la revisión de todas las enfermedades hereditarias hipocolesterolémicas (AU)

Triglyceride-rich lipoproteins prevent septic death in rats.

Triglyceride-rich lipoproteins bind and inactive bacterial endotoxin in vitro and prevent death when given before a lethal dose of endotoxin in animals. However, lipoproteins have not yet been demonstrated to improve survival in polymicrobial gram-negative sepsis. We therefore tested the ability of triglyceride-rich lipoproteins to prevent death after cecal ligation and puncture (CLP) in rats. Animals were given bolus infusions of either chylomicrons (1 g triglyceride/kg per 4 h) or an equal volume of saline for 28 h after CLP. Chylomicron infusions significantly improved survival (measured at 96 h) compared with saline controls (80 vs 27%, P < or = 0.03). Chylomicron infusions also reduced serum levels of endotoxin, measured 90 min (26 +/- 3 vs 136 +/- 51 pg/ml, mean +/- SEM, P < or = 0.03) and 6 h (121 +/- 54 vs 1,026 +/- 459 pg/ml, P < or = 0.05) after CLP. The reduction in serum endotoxin correlated with a reduction in serum tumor necrosis factor, measured 6 h after CLP (0 +/- 0 vs 58 +/- 24 pg/ml, P < or = 0.03), suggesting that chylomicrons improve survival in this model by limiting macrophage exposure to endotoxin and thereby reducing secretion of inflammatory cytokines. Infusions of a synthetic triglyceride-rich lipid emulsion (Intralipid; KabiVitrum, Inc., Alameda, CA) (1 g triglyceride/kg) also significantly improved survival compared with saline controls (71 vs 27%, P < or = 0.03). These data demonstrate that triglyceride-rich lipoproteins can protect animals from lethal polymicrobial gram-negative sepsis.

Triglyceride-rich lipoproteins improve survival when given after endotoxin in rats.

BACKGROUND: Triglyceride-rich lipoproteins have been shown to bind bacterial endotoxin and inhibit its activity in vitro and to protect animals from death when administered before a lethal injection of endotoxin. We now demonstrate that triglyceride-rich lipoproteins can neutralize the toxic effects of endotoxin already in circulation. METHODS: Rats were infused with a lethal dose of endotoxin, followed at various time intervals by an infusion of either mesenteric lymph containing nascent chylomicrons (1 gm chylomicron triglyceride/kg) or an equal volume of normal saline solution. Survival was measured at 48 hours. The experiment was then repeated, substituting the synthetic triglyceride-rich lipid emulsion (1 gm/kg) for chylomicrons. We also measured the clearance and tissue distribution of radioiodinated endotoxin in rats treated subsequently with chylomicrons or saline solution. RESULTS: Chylomicron infusions significantly improved survival when given up to 30 minutes after a lethal dose of endotoxin (p < 0.05). Chylomicrons accelerated endotoxin clearance from the blood and increased endotoxin uptake by the liver. The synthetic triglyceride-rich lipid emulsion significantly improved survival when given up to 15 minutes after a lethal dose of endotoxin (p < 0.05). CONCLUSIONS: Triglyceride-rich lipoproteins and synthetic triglyceride-rich lipid emulsions significantly improve survival of rats when given after a lethal dose of endotoxin. Lipoprotein treatment accelerates endotoxin clearance to the liver, which may account for the observed protection. These data suggest a possible therapeutic role for triglyceride-rich lipoproteins or synthetic lipid emulsions in the treatment of the endotoxemia of gram-negative sepsis.