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High-performance liquid chromatographic and capillary electrophoretic determination of free nicotinic acid in human plasma and separation of its metabolites by capillary electrophoresis.

Two methods are described based on high-performance liquid chromatography and capillary electrophoresis that provide the selective and sensitive determination of nicotinic acid in human plasma. Moreover, the capillary electrophoresis system was used for the separation of nicotinic acid, nicotinamide, nicotinamide N-oxide, N'-methylnicotinamide, 6-hydroxynicontinic acid, nicotinuric acid and barbital (internal standard). The extraction procedure is simple; no gradient elution or derivatization is required. Both methods can be useful for clinical and biomedical investigations.

Chromatography, High Pressure Liquid↗

Effects of dietary pyrazinamide, tryptophan, or nicotinic acid and gamma-ray irradiation on levels of NAD and NADP in various organs of mice.

The effects of large amounts of tryptophan, pyrazinamide, or nicotinic acid in diets on the contents of total NAD (NAD + NADH) and NADP (NADP + NADPH) of various organs were investigated in mice with or without gamma-irradiation. Female C3H/HeN mice were fed one of the following 4 kinds of experimental diets for one week: 1) control diet (20% casein diet containing 3 mg niacin per 100g diet); 2) diet supplemented by 0.5% L-tryptophan (T-diet); 3) diet supplemented by 0.5% L-tryptophan (T-diet); 4) diet supplemented by 0.1% nicotinic acid (NA-diet). Half of the mice in each group were subsequently irradiated with 8 Gy of gamma-ray (60 Co) after 4 h of fasting. Then, the contents of total NAD and NADP in thymus, spleen, kidney, liver, and blood were determined in all animals. The results indicated that NAD content of spleen was higher in PT-group (21.5%) and NA-group (23.2%) than in that of control group. In thymus, however, NAD content of only the PT-group was significantly greater (13.1%) than control. NAD level of kidney was also significantly higher (32.6%) in PT-group. By gamma-irradiation, NAD contents of thymus and spleen of all groups tended to be decreased, but those of kidney and liver were not always reduced. In the latter two organs, significant NAD reduction was shown only in kidney of PT-group and in liver of PT- and NA-groups. Even after irradiation, NAD levels of spleen and thymus in PT- and NA-groups tended to be kept higher than those in irradiated control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Severe hypertriglyceridaemia responding to insulin and nicotinic acid therapy.

A patient with unusually severe hypertriglyceridaemia (serum concentration initially 258 mmol/l or 22600 mg/dl) and hypercholesterolaemia is reported and discussed. The triglyceride elevation was found to reside within the very low density lipoprotein fraction and was probably attributable to the combination of diabetes mellitus and familial hypertriglyceridaemia. Treatment with insulin and restriction of dietary carbohydrate led to a 50% reduction in the triglyceride concentration, and the addition of nicotinic acid in modest doses led ultimately to a complete normalization of the patient's lipid values. A close correlation was noted between the falling triglyceride concentration and the rising serum sodium concentration during the course of successful therapy. Overall, it is felt likely that this patient's severe and reversible hypertriglyceridaemia was on the basis of excessively rapid lipolysis leading to high concentrations of very low density lipoprotein production. Combined therapy with insulin and nicotinic acid is recommended for other patients of this nature.

Diabetes Complications↗

[Nicotinic acid in the treatment of chronic circulatory failure in patients with ischemic heart disease].

Examined were 98 patients with chronic forms of ischemic heart disease, mainly atherosclerotic cardiosclerosis with different degrees of cardiac insufficiency. Two groups were distinguished. Patients of the first group received traditional treatment while patients of the second group received also nicotinic acid agents. It was found that inclusion of nicotinic acid in the complex treatment of patients with ischemic heart disease increased the therapeutic efficacy.

Aged↗

[Effect of large doses of nicotinic acid on certain metabolic processes and contractile function of an intact heart].

Peroral administration of nicotinic acid to rabbits in amounts of 500 mg, twice a day for 7 days was attended by a reduced contractility of the myocardium, an increased content of catecholamines in the heart and deranged lipids metabolism in the heart muscle. It is assumed that the contractility of the heart is largely determined by the state of the lipids metabolism and their utilization in the generation of energy.

Administration, Oral↗

Simultaneous transport and metabolism of nicotinic acid derivatives in hairless mouse skin.

In vitro simultaneous transport and metabolism of three ester prodrugs of nicotinic acid (NA), methyl nicotinate (MN), ethyl nicotinate (EN) and butyl nicotinate (BN) were studied using excised skin from hairless mouse. Hydrolysis studies of these esters with and without skin homogenate were also done at 37 degrees C. Both the ester and NA were detected in all receiver solutions in permeation studies, and no chemical hydrolysis of the esters was found, indicating that the esters were hydrolyzed during the skin permeation process. The total (ester+NA) flux from a saturated solution of ester prodrugs was higher than that of NA and was highest for MN, followed by EN and BN, whereas the total permeability coefficient of ester prodrugs increased from MN to BN. A difference in the NA/total flux ratio was found among these prodrugs; thus, esterase activity was also dependent on the alkyl chain length of the esters. The total flux from each ester solution increased linearly with the donor concentration. NA flux from MN and EN solutions increased with an increase in the donor concentration and reached a plateau at the high concentration range, suggesting that metabolic saturation occurred. NA fluxes at the plateau were similar among ester prodrugs and corresponded to the Vmax estimated from the hydrolysis experiment. The order of donor concentration at which NA reached a plateau also corresponded to the order of Km. It was confirmed that a difference in alkyl chain length of the ester prodrugs affected not only permeability but also metabolism in the skin permeation process.

Alkylation↗

Discriminate analysis of roasted coffee varieties for trigonelline, nicotinic acid, and caffeine content.

Arabica and robusta roasted coffees from several geographical origins, in a total of 29 samples, were characterized for their contents in caffeine, trigonelline, and nicotinic acid by a recently developed HPLC/diode-array detector method. All samples were subjected to the same roasting procedure in order to eliminate the variations due to this process. Characterization was achieved by applying multivariate and nonparametric analysis to the chromatographic results. The two coffee varieties were clearly separated by their trigonelline and caffeine contents. Nicotinic acid could not be used as a variety discriminate factor. There was no association with the geographical origin of the samples.

Alkaloids↗

Acipimox, a nicotinic acid analog, stimulates growth hormone secretion in short healthy prepubertal children.

Recent studies in adult volunteers have demonstrated that the free fatty acid reduction induced by acipimox, a nicotinic acid analog, stimulated GH secretion per se and enhanced in an additive manner the GH secretion elicited by such different stimuli as pyridostigmine, GHRH and GHRP-6. In order to evaluate whether acipimox administration stimulates GH secretion in prepubertal children, we administered a single oral dose of acipimox (100 mg for children weighing <30 kg and 200 mg for those >30 kg) to 14 healthy prepubertal children with a mean age of 8.2 +/- 1.9 years, a mean bone age of 6.2 +/- 3.0 years, growing along the 5-10th percentiles, and with normal thyroid function and IGF-I levels. Acipimox administration elicited a sustained increase in GH from a mean baseline level of 0.6 +/- 0.4 to 6.7 +/- 2.4 microg/l at the end of the test (p<0.05), with a mean GH peak of 10.5 +/- 3.5 microg/l. GH release was delayed so that peak GH levels were achieved 180 minutes after acipimox administration. In order to determine whether acipimox was capable of enhancing the GH secretion elicited by levodopa (L-Dopa), we administered either oral L-Dopa (250 mg for children weighing <30 kg and 500 mg for those >30 kg) or oral acipimox plus L-Dopa to the same children on different days. GH concentrations increased in a similar fashion following either of these tests (from a baseline level of 1.2 +/- 0.4 and 0.7 +/- 0.4 microg/l to 8.4 +/- 2.7 and 9.3 +/- 2.9 microg/l at the end of the test (p<0.001), with peak GH concentrations of 13.1 +/- 4.1 and 11.8 +/- 3.3 microg/l after L-Dopa or acipimox plus L-Dopa, respectively). Although the peak GH concentrations obtained after the combined administration of acipimox plus L-Dopa were similar to those obtained after either acipimox or L-Dopa administration, a larger number of our patients reached a GH cut-off point of >7 microg/l following combined therapy than with either stimulus alone (13/14 patients with combined therapy and 10/14 with acipimox alone). No side effects other than mild facial flushing were noted after acipimox administration. These results indicate that: 1) following the administration of a single oral dose of acipimox, significant GH secretion was elicited in healthy short prepubertal children; 2) the combined administration of acipimox plus L-Dopa did not, however, enhance the GH secretion of this group of children; 3) acipimox was well tolerated with minimal side effects; and 4) further studies in both GH sufficient and GH deficient children are necessary to evaluate acipimox's usefulness in assessing GH reserve.

Body Height↗

Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family.

SMCT (sodium-coupled monocarboxylate transporter; slc5a8) is a Na+-coupled transporter for lactate, pyruvate and short-chain fatty acids. Similar to these already known substrates of SMCT, the water-soluble B-complex vitamin nicotinic acid also exists as a monocarboxylate anion (nicotinate) under physiological conditions. Therefore we evaluated the ability of SMCT to mediate the uptake of nicotinate. In mammalian cells, the cloned mouse SMCT (slc5a8) induced the uptake of nicotinate. The SMCT-induced uptake was Na+-dependent. The Michaelis constant for the uptake process was 296+/-88 microM. The Na+-activation kinetics indicated that at least two Na+ ions are involved in the process. Among the various structural analogues tested, nicotinate was the most effective substrate. Nicotinamide and methylnicotinate were not recognized by the transporter. 2-pyrazine carboxylate and isonicotinate interacted with the transporter to a moderate extent. SMCT-mediated uptake of nicotinate was inhibited by lactate and pyruvate. In the Xenopus laevis oocyte expression system, SMCT-mediated nicotinate transport was electrogenic, as evident from the nicotinate-induced inward currents under voltage-clamp conditions. Substrate-induced currents in this expression system corroborated the substrate specificity determined in the mammalian cell expression system. The kinetic parameters with regard to the affinity of the transporter for nicotinate and the Hill coefficient for Na+ activation, determined by using the oocyte expression system, were also similar to those obtained from the mammalian cell expression system. We conclude that SMCT functions not only as a Na+-coupled transporter for short-chain fatty acids and lactate but also as a Na+-coupled transporter for the water-soluble vitamin nicotinic acid.

Animals↗

[Prolonged treatment with slow release nicotinic acid in patients with type II hyperlipidemia].

The aim of the study was to compare efficacy and safety of one-year therapy with slow-release nicotinic acid (KN-SR) and with ordinary form of the acid (KN). The examination was performed in the group of 136 patients with hyperlipidemia-type II. KN-SR had satisfactory effectiveness and was much better tolerated than KN. During one-year treatment with KN-SR there were observed the decrease of total cholesterol (TC) by 18%, LDL-C by 22%, triglycerides by 36%, Lp(a) by 56%, and the increase of HDL-C by 12%. The percentage of skin unwanted signs differed significantly between KN-group (90.2%) and KN-SR group (24%). Hepatotoxic effects were not observed and antipyrine kinetics did not change during one-year treatment with slow-release nicotinic acid.

Adult↗

Differential effects of nicotinic acid in subjects with different LDL subclass patterns.

Twenty-six subjects (20 male, 6 female) at high risk for CAD events were treated with moderate doses of nicotinic acid to investigate whether there was a differential lipoprotein response in patients with different LDL subclass patterns. Subjects were selected to have either pattern A (predominance of large LDL, peak particle diameter greater than 262 A, n = 9) or pattern B (predominance of small LDL, peak particle diameter less than 255 A, n = 17) as assessed by 2-16% gradient gel electrophoresis of plasma. Nicotinic acid dose was similar in pattern A (2111 +/- 651 mg/day) and pattern B subjects (1875 +/- 698 mg/day). Total cholesterol and LDL cholesterol decreased by similar amounts in pattern A (-41 +/- 26 mg/dl and -37 +/- 18 mg/dl) and pattern B (-51 +/- 44 mg/dl and -44 +/- 45 mg/dl) subjects. Triglycerides tended to be reduced more in pattern B subjects (-100 +/- 175 mg/dl) compared to pattern A subjects (-23 +/- 34 mg/dl) although this difference was not statistically significant (P = 0.08 for triglycerides log transformed). HDL cholesterol increased significantly more in the pattern B group (11.9 +/- 14.2 mg/dl) compared to pattern A subjects (0.7 +/- 8.5 mg/dl), (P less than 0.04). Similarly, LDL particle diameter increased significantly more in the pattern B subjects (9.8 +/- 6.9 A) compared to the pattern A subjects (3.6 +/- 3.0 A), (P less than 0.02). All pattern B subjects who achieved a plasma triglyceride less than 140 mg/dl converted to pattern A.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol↗

Hyperresponsivity to nicotinic acid challenge in generalized social phobia: a pilot study.

Although blushing is an almost pathognomonic feature of social phobia, little is known about the neurobiology of blushing in this disorder. Nicotinic acid (100 mg), a vasodilator that may induce flushing, was administered to six male patients with generalized social phobia and to six healthy male controls. Compared with controls, patients demonstrated increased flushing, anxiety, autonomic activity, and temperature after nicotinic acid administration. Further controlled research is necessary to confirm and extend these pilot findings.

Adult↗

Total and free tryptophan levels in serum of newborn infants. Relationships with the Serotonin and nicotinic acid pathways.

The levels of total and free serum tryptophan have been determined in a group of newborn babies at birth, one day later and five days after birth. Total and free tryptophan levels are very high in the umbilical cord at birth, decrease quickly and significantly 24 hours after birth and show a slight, but not significant increase five days after birth. The high tryptophan levels at birth and their decrease in the first day after birth recall previous data on tryptophan metabolism "via" serotonin and "via" nicotinic acid. Since the synthesis of cerebral serotonin depends on the availability of tryptophan, and is thus linked to the level of free tryptophan in blood, these data suggest that synthesis of serotonin as well may be elevated at birth and may reach the values of adult soon afterwards. With respect to the nicotinic acid pathway the high levels of tryptophan in blood may be related to the synthesis of tryptophan pyrrolase, which is present in the liver of newborn babies.

Female↗

Paradoxical effects of fenofibrate and nicotinic acid in apo E-deficient mice.

Atherosclerosis is a complex vascular disease initiated by abnormal accumulation of plasma lipoproteins in the subendothelial space. Elevated levels of plasma triglycerides (TG) and low-density lipoprotein (LDL)-cholesterol as well as low concentrations of high-density lipoprotein (HDL) play a causal role in the development and progression of atherosclerotic lesions. We have shown that apolipoprotein E-deficient (apo E-KO) mice have elevated triglyceride levels plus diminished HDL concentrations. Drugs such as fenofibrate and nicotinic acid are well known to reduce TG and increase HDL levels in humans. In this study, we investigated the beneficial effects of fenofibrate and niacin on lipid profile and atherogenesis in apo E-KO mice and their wild-type counterparts. Animals were fed with a cholesterol-enriched diet supplemented with fenofibrate (0.1% wt/wt, n = 8) or nicotinic acid (0.5% wt/wt, n = 8) for 14 weeks. Body weights were recorded weekly, and plasma lipid profiles were determined at 4-week intervals. The hearts and aortas were collected and fixed for histologic and morphometric evaluations of atherosclerotic lesions. Fenofibrate treatment in apo E-KO mice paradoxically increased total cholesterol and TG by 65% and 44%, respectively, and decreased HDL-cholesterol levels by 35% as compared with controls. Similar effects of fenofibrate on cholesterol levels, but not on TG concentrations, were observed in C57BL/6 mice. Fenofibrate-treated mice had lower body weight as compared with controls. Niacin had no effect on body weight gain but failed to decrease TG or to increase HDL levels in either apo E-KO mice or their wild-type counterparts. Neither fenofibrate nor niacin significantly influenced atherogenesis in apo E-KO mice as compared with controls. In conclusion, this study shows that neither niacin nor fenofibrate has beneficial lipid-modifying and antiatherosclerosis activities in mice. Identification of mechanisms underlying paradoxical effects of fenofibrate on lipoprotein metabolisms in apo E-KO mice merits further investigation.

Animals↗

The nicotinic acid test in the evaluation of unconjugated hyperbilirubinemia.

In 42 young adults with Gilbert's syndrome and in 9 patients with inactive, well-compensated liver cirrhosis the peroral nicotinic acid test was performed. Of the 13 parameters tested, the groups differed significantly in the sum of total and unconjugated serum bilirubin concentrations, respectively, during the test; in the difference between the maximal and initial concentrations of total and unconjugated bilirubin; in the retention of total bilirubin at the third, fourth and fifth hour of the test; and in the size of the area under the curve of unconjugated bilirubin increase. However, due to considerable overlap, no single parameter could reliably differentiate among all persons with Gilbert's syndrome and cirrhotics. The nicotinic acid test is neither necessary for the diagnosis of Gilbert's syndrome nor can it reliably differentiate between this condition and severe organic liver disease. Yet, it does supply valuable information about the readiness of the organism to develop or enhance hyperbilirubinemia following a defined stimulus.

Administration, Oral↗

Effects of glucose, insulin and nicotinic acid on adipose tissue blood flow in rats.

Adipose tissue blood flow (ATBF) was examined in rat parametrial fat by the 133-Xe elimination method. Intravenous infusion of glucose to fed rats resulting in blood glucose concentrations of 10-12 mmol X 1(-1) caused a significant reduction in ATBF (-37%). Similar infusions to 48 hour fasted rats had no consistant effect on ATBF. Glucose infusion caused a significant rise in plasma insulin concentrations in both fed and fasted animals, although the average concentration in fasted rats given glucose did not exceed the control value in fed animals. Insulin added to the glucose infusion caused a similar reduction in ATBF in fasted animals as that seen after glucose alone in fed animals (-38%). Guinea pig anti insulin serum administered intravenously to fed rats elicited an increase in blood glucose concentrations similar to that seen after glucose infusion, but was without effect on ATBF. These results suggest that the effect of glucose on ATBF is secondary to a release of insulin resulting in plasma levels above those found in fed control rats. Infusion of nicotinic acid also reduced ATBF without influencing blood glucose concentration and in spite of insulin concentrations lower than in fed control rats. Since both insulin and nicotinic acid inhibit the formation of c-AMP in adipocytes, it is hypothesized that both compounds decrease ATBF by decreasing the release of the vasodilator adenosine from the cells.

Adipose Tissue↗

Improved skin flap survival with nicotinic acid and nicotinamide in rats.

The effects of some components of the coenzyme nicotinamide adenine dinucleotide (NAD) on tissue viability were investigated in acute island skin flaps which were constructed to exceed the blood supply provided by a unilateral pedicle of inferior epigastric vessels. Control flaps undergo significant necrosis. Treatment with nicotinamide or nicotinic acid, precursors of NAD, prior to flap elevation significantly improved the area of viability in the random portion of the flap from 44 +/- 9% (mean +/- SD) to 67 +/- 12 and 65 +/- 5%, respectively. Similarly, NAD improved viability to 68 +/- 10% (P less than 0.001). Treatment with other components, adenosine diphosphoribose or quinolinic acid, had no effect on flap survival. The results suggest that nicotinic acid and nicotinamide deserve therapeutic consideration with regard to the treatment of ischemia/reperfusion injury in skin.

Animals↗