Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Current Understanding and Future Perspectives.

PURPOSE: To review current knowledge of elevated lipoprotein(a) [Lp(a)] levels in relation to atherosclerotic cardiovascular disease (ASCVD) and discuss their potential use as biomarkers and therapeutic approaches in clinical practice. METHODS: We summarized the current understanding and recent advances in the structure, metabolism, atherogenic mechanisms, standardized laboratory measurement, recommended screening populations, and prognostic value of Lp(a), with a special focus on the current potential treatment approaches for hyperlipoprotein(a)emia in patients with ASCVD. RESULTS: Lp(a) is composed of LDL-like particle and characteristic apolipoprotein(a) [apo(a)] connected by a disulfide bond. Substantial evidence shows that elevated plasma Lp(a) level is a heritable, independent, and possibly causal risk factor for ASCVD through its proatherogenic, proinflammatory, and potentially prothrombotic properties. Current guidelines recommend Lp(a) measurement for patients with an intermediate-high risk of ASCVD, familial hypercholesterolemia, a family history of early ASCVD or elevated Lp(a), and progressive ASCVD despite receiving optimal therapy. Traditional Lp(a)-lowering approaches such as niacin, PCSK9 inhibitors, mipomersen, lomitapide, and lipoprotein apheresis were associated with a non-specific and limited reduction of Lp(a), intolerable side effects, invasive procedure, and high expense. The phase 2 randomized controlled trial of antisense oligonucleotide against the apo(a) encoding gene LPA mRNA showed that IONIS-APO(a)-LRX could specifically reduce the level of Lp(a) by 90% with good tolerance, which may become a promising candidate for the prevention and treatment of ASCVD in the future. CONCLUSIONS: It is reasonable to measure Lp(a) levels to reclassify ASCVD risk and manage individuals with elevated Lp(a) to further reduce the residual risk of ASCVD, especially with IONIS-APO(a)-LRX.

Effect of three polyether ionophores on pharmacokinetics of florfenicol in male broilers.

Drug-drug interactions (DDIs) may adversely affect the prevention and cure of diseases. The effects of three polyether ionophore antibiotics, salinomycin (SAL), monensin (MON), and maduramycin (MAD) on the pharmacokinetics of florfenicol (FFC) were investigated in broilers. The chickens were fed rations with or without SAL (60 mg/kg feeds), MON (120 mg/kg feeds), or MAD (5 mg/kg feeds) for 14 consecutive days. FFC was given to the chickens either intravenously (i.v.) or orally (p.o.) at a single dose of 30 mg/kg body weight. Blood samples were taken from each chicken at 0-24 h postadministration of FFC. The plasma concentration of FFC was detected by high-performance liquid chromatography. The plasma concentration of FFC decreased with i.v. or p.o. co-administration of SAL, MON, or MAD in broilers, implying occurrence of DDIs during the co-administration of FFC with these ionophores. Our findings suggest that more attention should be given to the use of FFC to treat bacterial infections in chickens supplemented with polyether ionophore antibiotics.

Locus coeruleus stimulation modulates the nociceptive response in parafascicular neurons: an analysis of descending and ascending pathways.

The nociceptive responses in parafascicular neurons (PF) were recorded and studied following electrical stimulation of locus coeruleus (LC) combined with intrathecal (IT) or intracerebroventricular (ICV) administration of phentolamine (Ph), an alpha-adrenoceptor antagonist. The results revealed the following. (1) Three different PF neuronal populations were observed according to their response pattern following noxious stimulation: nociceptive-on, nociceptive-off, and nonresponsive units. Only the nociceptive-on units were studied further. (2) The nociceptive discharges in majority of PF neurons (66/87) were inhibited by electrical stimulation of the LC. (3) The inhibitory effect of LC stimulation was prevented and even reversed by pretreatment of IT Ph (40 nmol) in 22 units, or by dorsolateral funiculi transection in 24 units tested. (4) The inhibitory effect of LC stimulation was strengthened by preadministration of ICV Ph (40 nmol) in 17 units tested. (5) ICV administration of norepinephrine (NE 30 nmol) resulted in PF neurons a biphasic response to nociceptive stimulation: an early brief inhibition and a late long-lasting facilitation. (6) Pretreatment of ICV Ph (40 nmol) prior to NE injection prevented the NE-induced biphasic response. The results suggest that stimulation of LC modulates the nociceptive response of PF neurons through both ascending and descending routes. These two diverse routes exert two different effects: a predominantly inhibitory role on the nociceptive transmission at the spinal cord level by descending NE-ergic fibers, and a facilitatory role on the responsiveness of PF to noxious inputs by ascending fibers.

[Urine excretion of PGE2, PGF2 alpha in patients with deficiency-cold syndrome and deficiency-heat syndrome].

The 3 hours' urine excretion of PGE2 and PGF2 alpha in 32 patients and 19 healthy persons were determined by RIA. According to TCM, the patients were divided into two groups: 17 cases of deficiency-cold syndrome and 15 cases of deficiency-heat syndrome. The result showed that in patients with deficiency-cold syndrome, the excretion of urine PGE2 was lower than that of the normal control (P less than 0.05), while the excretion of urine PGF2 alpha higher than that of the normal control (P less than 0.01) and hence the PGE2/PGF2 alpha ratio was much lower (P less than 0.01); in those with deficiency-heat syndrome, the excretion of urine PGE2 was higher (P less than 0.01), the excretion of urine PGF2 alpha had no significant change (P greater than 0.05) from the normal, and the PGE2/PGF2 alpha ratio was higher (P less than 0.01). The above result indicates a close relationship between prostaglandins and the cold and heat nature of syndromes in TCM. In connection with our previous studies that showed decreased functioning of the sympathetic-adrenomedullary system and/or increased functioning of the parasympathetic nervous system with diminished catecholamines and reduced cAMP/cGMP ratio in deficiency-cold syndrome while increased functioning of the sympathetic-adrenomedullary system with augmented catecholamines and cAMP in deficiency-heat syndrome, the change of prostaglandins level can be considered as an intermediate link in the pathogenesis of syndromes different in cold and heat nature.