New evidence for nicotinic acid treatment to reduce atherosclerosis

Nicotinic acid (at a daily dose of grams) has been shown to induce potent antiatherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that nicotinic acid treatment remarkably improves the plasma lipid profile. Large clinical studies showed that nicotinic acid improves clinical cardiovascular outcomes. Given the protective effects of niacin, basic research studies were designed to explore additional antiatherosclerotic pathways, such as those involved in cardiovascular inflammation. After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. Thus, further studies are needed to clarify this promising topic. Emerging evidence from clinical and basic research studies indicates that novel direct antiatherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Despite some limitations in its clinical use (mainly due to the incidence of adverse events, such as cutaneous flushing and hepatotoxicity), nicotinic acid should be considered as a very potent therapeutic approach to reduce atherosclerosis. Promising research developments are warranted in the near future.     

2-hydroxypropyl-beta-cyclodextrin increases aqueous solubility and photostability of all-trans-retinoic acid

BACKGROUND: All-trans-retinoic acid (ATRA, vitamin A acid or tretinoin) is effective in the treatment of acute promyelocytic leukaemia (APL). Unfortunately, the oral absorption of ATRA is highly variable. Its poor aqueous solubility also makes it difficult to be formulated into parenteral formulation. To date, there is no parenteral formulation of ATRA available commercially. OBJECTIVE: To undertake the preformulation work necessary for developing such a product. METHOD: We investigated the solubility and stability profile of ATRA in various formulations. RESULTS: The aqueous solubility of ATRA could be greatly increased by the inclusion of ATRA in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Adjusting the pH value further improved the water solubility of ATRA. The photostability of HP-beta-CD-based formulation of ATRA was evaluated and it was found that inclusion ATRA into HP-beta-CD did improve the photostability of ATRA. CONCLUSION: These results showed that it is possible to develop a parenteral formulation and/or an aqueous oral formulation of all-trans-retinoic acid by using 2-hydroxypropyl-beta-cyclodextrin. However, the biopharmaceutical properties of such a formulation would be necessary before its use.     

Dissociation between vascular and metabolic effects of nicotinic acid in Gilbert's syndrome

Summary. The relationship between the vasodilating and the hyperbilirubinaemic effect of low and high doses (50 and 300 mg i.v.) of nicotinic acid was studied in baseline conditions and after indomethacin pretreatment in healthy controls and patients with Gilbert's syndrome (a condition characterized by fluctuating, nonhaemolytic unconjugated hyperbilirubinaemia). The hyperbilirubinaemic effect of nicotinic acid was confirmed to be more pronounced in Gilbert's syndrome patients than in controls. The magnitude of hyperbilirubinaemia in the two groups was not dependent on the dose of nicotinic acid or indomethacin pretreatment. A dose-dependent vasodilation which was inhibited by indomethacin could be demonstrated in both controls and Gilbert's syndrome subjects. Vasodilating properties of nicotinic acid were therefore found to be dissociated from the effect on bilirubin.     

Effect of gemcitabine and retinoic acid loaded PAMAM dendrimer-coated magnetic nanoparticles on pancreatic cancer and stellate cell lines

Gemcitabine is an anticancer drug used in the treatment of different cancer types, including pancreatic ductal adenocarcinoma. The maximum tolerated dose in humans is restricted by its side effects on healty cells. Furthermore, the fibrotic stroma produced by the pancreatic stellate cells prevents effective delivery of chemotherapeutic agents providing a safe-haven for the cancer cells. This becomes more of a problem considering the short half-life of this drug. Magnetic nanoparticle-based targeted drug delivery systems are a promising alternative to overcome the limitations of classical chemotherapies. The aim of this study is to obtain an effective targeted delivery system for gemcitabine using magnetic nanoparticles (MNPs) and all-trans retinoic acid (ATRA). This dual approach targets the tumor cells and its infrastructure – stellate cells – simultaneously. Gemcitabine and ATRA were loaded onto the PAMAM dendrimer-coated magnetic nanoparticles (DcMNPs), which were synthesized and characterized previously. Drug loading and release characteristics, and stability of the nanoparticles were investigated. Gemcitabine and ATRA loaded MNPs are efficiently taken up by pancreatic cancer and stellate cells successfully targeting and eliminating both cells. Results of this study can provide new insights on pancreatic cancer therapy where tumor is seen as a system with its stroma insead of epithelial cells alone.     

Combined treatment with cholestyramine and nicotinic acid in heterozygous familial hypercholesterolaemia: effects on biliary lipid composition

In ten patients with heterozygous familial hypercholesterolaemia, combination therapy with cholestyramine and nicotinic acid was instituted for a minimum of 2 months. During therapy, plasma low-density lipoprotein levels were reduced by 32%, and low-density lipoprotein to high-density lipoprotein ratios by 40%. The cholesterol saturation of fasting gall-bladder bile was reduced by 33% during treatment. We conclude that long-term combination therapy with cholestyramine and nicotinic acid is practically feasible in heterozygous familial hypercholesterolaemia, normalizes plasma cholesterol and low-density lipoprotein levels in many patients, and does not result in unwanted side-effects on biliary lipids. It should therefore be considered as the therapy of choice in this condition.     

Combination of fenofibrate plus low-dose nicotinic acid added to statin treatment in type 2 diabetes: An open-label, crossover study

Background:

Plasma lipid abnormalities commonly persist in patients with diabetic dyslipidemia in spite of statin monotherapy.

Objective:

The aim of this study was to determine whether fenofibrate plus low-dose nicotinic acid adequately improves the lipoprotein profile in patients with diabetic dyslipidemia who are being treated with a statin.

Methods:

In this open-label, crossover study, patients with type 2 diabetes mellitus who were receiving statin treatment were enrolled at the Lipid Clinic of the Veterans Affairs Medical Center, Dallas, Texas, and administered simvastatin 20 mg/d for 8 weeks. At the end of the 8-week period, fenofibrate 160 mg/d was added for 8 weeks, followed by the addition of extended-release nicotinic acid 1 g/d for an additional 8 weeks. The first subject was recruited on September 25, 2003, and the last subject was recruited on September 28, 2004. Liver function tests, creatine phosphokinase activity, and blood glucose levels were assessed every 4 weeks to assess tolerability. Levels of fasting plasma lipids and lipoprotein cholesterol were measured every 8 weeks on 3 consecutive days in each patient; C-reactive protein, lipoprotein pattern, and glycosylated hemoglobin levels were assessed once every 8 weeks. Plasma levels of total cholesterol, triglycerides, very-low-density lipoprotein plus intermediate-density lipoprotein cholesterol (VLDL+IDL-C), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B were also measured.

Results:

Twenty-six patients were enrolled in the study and 20 patients (18 men, 2 women; mean [SD] age, 58.8 [6.5] years) completed it. The mean plasma triglyceride level was significantly decreased (−29.2%; P= 0.004) and the mean HDL-C level was significantly increased (+13.5%; P < 0.001) with 3-drug treatment (simvastatin + fenofibrate + extended-release nicotinic acid) compared with simvastatin monotherapy. Significant reductions in plasma levels of VLDL+IDL-C (−35.7%; P = 0.001), VLDL+IDL-apolipoprotein B (−30%; P = 0.005), non-HDL-C (−12.9%; P = 0.001), and total-apolipoprotein B (−17.9%; P < 0.001) were seen with the 3-drug treatment compared with simvastatin alone. Compared with simvastatin monotherapy, simvastatin + fenofibrate-treated (2-drug treatment) patients had significantly lower plasma levels of triglycerides (−24.9%; P = 0.014) and significantly higher levels of HDL-C (+5.4%; P = 0.008). Significant reductions were also seen in levels of VLDL+IDL-C (−28.6%; P = 0.004), VLDL+IDL-apolipoprotein B (−26.7%; P < 0.001), non-HDL-C (−9.1 %; P= 0.004), and total-apolipoprotein B (−12.3%; P < 0.001) in the 2-drug treatment group compared with the simvastatin monotherapy group. The administration of 3-drug treatment was associated with improved responses in all lipoprotein fractions, although only the increase in HDL-C level was statistically significant (+7.7%; P = 0.008) compared with 2-drug treatment.

Conclusions:

Treatment with the 3-drug regimen was associated with a significant reduction in triglyceride levels compared with simvastatin monotherapy. However, there was not a significant incremental reduction in triglyceride levels when nicotinic acid was added to the 2-drug treatment, suggesting that the triglyceride-lowering effect of fenofibrate + nicotinic acid is not cumulative. To obtain clinically meaningful responses, particularly for the treatment of elevated HDL-C, higher doses of nicotinic acid might be required.     

The sources of plasma cyclic AMP: studies in the rat using isoprenaline, nicotinic acid and glucagon.

The effects of intravenous administration of isoprenaline, glucagon and nicotinic acid on plasma concentrations of cyclic AMP in rats are described. In order to determine the relative importance of the liver as a source of extracellular cyclic AMP, the effects of the hormones were investigated in intact and functionally hepatectomised rats. The results showed that hepatectomy did not prevent an isoprenaline-stimulated increase in plasma cyclic AMP concentrations, although glucagon was without effect on plasma nucleotide concentrations in this group of animals. It is suggested that the liver is essential for the action of glucagon but that isoprenaline can increase plasma cyclic AMP concentrations in hepatectomised animals by increasing extrahepatic release of the nucleotide. Since inhibition of adipose tissue lipolysis with nicotinic acid did not prevent an isoprenaline or glucagon-stimulated increase in plasma cyclic AMP concentrations, adipose tissue is discounted as a major source of plasma cyclic AMP.     

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.     

Differential identification of urine crystals with morphologic characteristics and solubility test

BackgroundUrinary crystals are the most diverse forms of urine sediments. Reference images for typical urinary crystals are common, however, but images for interpreting atypical urinary crystals are very rare. The authors reviewed various forms and solubility tests of urine crystals to interpret atypical crystals found in clinical specimens.MethodsWe reviewed textbooks on urinary crystals and articles published in PubMed. Some atypical crystals were confirmed using a solubility test.ResultsThe classification, shape, chemical structure, and solubility of the crystals were summarized. In the solubility test, some crystals showed different results; therefore, a new solubility test was proposed based on the literature review. We presented various types of calcium oxalates.ConclusionsThese review articles will be helpful in the examination of atypical crystals found in clinical specimens. The solubility test requires additional studies to discriminate the inconsistent results between the authors.     

Clinical evidence for use of acetyl salicylic acid in control of flushing related to nicotinic acid treatment

Nicotinic acid (NA) is highly effective and widely used in the management of dyslipidaemia. For many patients, the side effect of flushing of the face and upper body leads to discontinuation. Flushing with NA is mediated by prostaglandins, and as acetyl salicylic acid (ASA, 'aspirin') is a highly effective inhibitor of prostaglandin synthesis, there is a rationale for its use to prevent or reduce the severity of NA-related flushing. This literature survey identified four studies specifically exploring the utility of ASA in preventing NA-related flushing in healthy volunteers. Twenty-three NA studies, where ASA was mandatory or optional within the protocol, and four studies, where background ASA therapy was reported in most participants, were also identified. Although the incidence of flushing in studies using ASA was often high, discontinuation rates due to flushing were low (mean 7.7%). This figure compares favourably with discontinuation rates with NA commonly reported in the literature (up to approximately 40%). There is good supportive evidence for the use of ASA in reducing the severity of NA-related flushing.     

Computational design and molecular modeling of the interaction of nicotinic acid hydrazide nickel-based complexes with H2S gas

The application of nickel complexes of nicotinic acid hydrazide ligand as a potential gas-sensor and adsorbent material for H₂S gas was examined using appropriate density functional theory (DFT) calculations with the ωB97XD/Gen/6-311++G(d,p)/LanL2DZ method. The FT-IR spectrum of the synthesized ligand exhibited a medium band at 3178 cm⁻¹ attributed to ν(NH) stretching vibrations and strong bands at 1657 and 1600 cm⁻¹ corresponding to the presence of ν(C O) and ν(C N) vibration modes. In the spectrum of the nickel(ii) complex, the ν(C O) and ν(C N) vibration bands experience negative shifts to 1605 cm⁻¹ and 1580 cm⁻¹, respectively, compared to the ligand. This indicates the coordination of the carbonyl oxygen and the azomethine nitrogen atoms to the Ni²⁺ ion. Thus, the sensing mechanism of the complexes indicated a short recovery time and that the work function value increases for all complexes, necessitating an excellent H₂S gas sensor material. Thus, a profound assertion was given that the complex sensor surfaces exhibited very dense stability with regards to their relevant binding energies corresponding to various existing studies.

We demonstrate the efficacy of nicotinic acid hydrazide as adsorbent/sensor materials for H₂S gas.     

烟酸治疗维持性血液透析伴高钙高磷血症的有效性及安全性

目的：观察烟酸治疗维持性血液透析同时伴发高钙血症及高磷血症的临床疗效及安全性。方法对经2周洗脱期后血清磷≥1.78 mmol·L-1、血清校正钙≥2.5 mmol·L-1的25例维持性血液透析患者在采用常规治疗基础上给予烟酸口服,观察治疗前及治疗4、8周后血清磷、血清校正钙、钙磷乘积、全段甲状旁腺激素（iPTH）和血碱性磷酸酶、血小板计数、血尿酸、血糖、总胆固醇、三酰甘油、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）的变化。结果与治疗前比较,治疗4周后血清磷及钙磷乘积明显下降（均P〈0.05）,而血清校正钙、血iPTH、血碱性磷酸酶、血小板计数、血尿酸、血糖及总胆固醇、三酰甘油、HDL-C及LDL-C水平无显著变化（均P〉0.05）;与治疗4周后比较,治疗8周后使血清磷及钙磷乘积进一步下降（均P〈0.01）,血iPTH、血碱性磷酸酶、血胆固醇、三酰甘油、LDL-C也显著降低（P〈0.05或P〈0.01）;相反,HDL-C则显著增加（P〈0.05）。血清校正钙、血小板计数、血尿酸及血糖未见显著变化（均P〉0.05）。结论烟酸可有效降低伴有高钙血症血透患者的血磷水平,改善血脂异常,安全性好。     

Identification and localization of the nicotinic acetylcholine receptor alpha3 mRNA in the brain of the honeybee,Apis mellifera

The nicotinic acetylcholine receptors are ligand-gated ion channels responsible for rapid neurotransmission and are target sites for pesticides in insects. In the honeybee Apis mellifera, pharmacological and electrophysiological studies have shown that different nicotinic acetylcholine receptor subtypes may exist in the brain. Here, we have identified a honeybee cDNA that encodes a 537 amino acid protein with features typical of nicotinic acetylcholine receptor alpha subunit, and sequence homology to human alpha3. In situ hybridization on cryosections shows that the Apisalpha3 mRNA is differently expressed in larvae and adult. In larvae, Apisalpha3 mRNA expression is restricted to the suboesophageal ganglia. In adult, it is further expressed in the optic lobes, the dorsal lobes, the antennal lobes and the calyces of mushroom bodies. Together our results suggest that Apisalpha3 shows a controlled expression pattern during development.     

Selectivity of lynx proteins on insect nicotinic acetylcholine receptors in the brown planthopper,Nilaparvata lugens

Neuronal nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitter receptors in both vertebrates and invertebrates. Two lynx proteins (Nl‐lynx1 and Nl‐lynx2) have been identified in the brown planthopper, Nilaparvata lugens, which act as modulators on insect nAChRs. In the present study, two lynx proteins were found to act on the triplet receptor Nlα1/Nlα2/β2 expressed in Xenopus oocytes, increasing agonist‐evoked macroscopic currents, but not changing agonist sensitivity and desensitization properties. Nl‐lynx1 and Nl‐lynx2 increased I_max (maximum responses) of acetylcholine to 4.85‐fold and 2.40‐fold of that of Nlα1/Nlα2/β2 alone, and they also increased I_max of imidacloprid to 2.57‐fold and 1.25‐fold. Although, on another triplet nAChRs Nlα3/Nlα8/β2, Nl‐lynx2 increased I_max of acetylcholine and imidacloprid to 3.63‐fold and 2.16‐fold, Nl‐lynx1 had no effects on I_max of either acetylcholine or imidacloprid. The results demonstrate the selectivity of lynx proteins for different insect nAChR subtypes. This selectivity was also identified in native N. Lugens. Co‐immunoprecipitation was found between Nlα1/Nlα2‐containing receptors and both Nl‐lynx1 and Nl‐lynx2, but was only found between Nlα3/Nlα8‐containing receptors and Nl‐lynx2. When the previously identified Nlα1^Y151S and Nlα3^Y151S mutations were included (Nlα1^Y151S/Nlα2/β2 and Nlα3^Y151S/Nlα8/β2), the increase in I_max of imidacloprid, but not acetylcholine, caused by co‐expression of Nl‐lynx1 and Nl‐lynx2 was more noticeable than that of their wildtype counterparts. Taken together, these data suggest that two modulators, Nl‐lynx1 and Nl‐lynx2, might serve as an influencing factor in target site insensitivity in N. lugens, such as Y151S mutation.     

Reactions of kynurenic acid with hypobromous acid and hypochlorous acid

Kynurenic acid, a tryptophan metabolite, acts as antagonist or agonist of several receptors. Hypobromous acid (HOBr) and hypochlorous acid (HOCl) are generated by eosinophils and neutrophils. At inflammation sites, kynurenic acid may encounter HOBr and HOCl to generate products. When kynurenic acid was incubated with HOBr under neutral conditions, kynurenic acid generated a single product almost exclusively. This was identified as 3-bromokynurenic acid. Kynurenic acid reacted with HOCl, generating two products. The major product was identified as 3-chlorokynurenic acid with its oxidative decarboxylation product, 3-chloro-4-hydroxy-2(1H)-quinolinone as a by-product. Free amino acids suppressed the reactions of kynurenic acid with HOBr and HOCl. Taurine suppressed the HOCl reaction but not the HOBr reaction. An eosinophil peroxidase system containing H₂O₂, NaCl, and NaBr reacted with kynurenic acid, generating 3-bromokynurenic acid under mildly acidic conditions. Although a myeloperoxidase system containing H₂O₂ and NaCl reacted with kynurenic acid to generate 3-chlorokynurenic acid under mildly acidic conditions, the product was altered to 3-bromokynurenic acid by addition of NaBr to the system. These results suggest that 3-bromokynurenic acid and 3-chlorokynurenic acid may be generated from kynurenic acid at inflammation sites in humans, although their formation will be suppressed by coexistent amino acids.     

多不饱和脂肪酸摄入量与肿瘤的相关分析

目的研究膳食中影响ω-6和ω-3 PUFA摄入量及其比值的因素,探讨其与肿瘤发生的关系。方法通过膳食调查了解健康人和肿瘤病人膳食ω-6和ω-3 PUFA的摄入量、比值,比较两组人群在性别、年龄、教育程度、家庭经济收入等方面的差异。结果肿瘤病人ω-6/ω-3 PUFA比值高于健康人,差异有显著意义(P0.05)。家庭经济收入越高,ω-6和ω-3 PUFA的摄入量、比值也越高。结论肿瘤病人ω-6/ω-3 PUFA比值明显增高,提示与肿瘤发生有一定的相关性。家庭经济收入的增加是导致ω-6/ω-3 PUFA比值增高的主要原因。