Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
 6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this pilot study was to evaluate a potential skin test for schizophrenia based on the effect of aqueous methyl nicotinate (AMN) on the production of prostaglandin D2 (PGD2) from skin macrophages and the resultant cutaneous capillary vasodilatation. Four concentrations of AMN were applied topically to the forearm skin in patients and controls, and any resulting vasodilatation was rated as redness after 5 min. The test was carried out on 38 patients with schizophrenia diagnosed according to DSM-III-R criteria, and 22 normal control subjects. At all concentrations of AMN, the schizophrenics were highly significantly different from the controls. One concentration gave the greatest degree of differentiation: at this concentration at 5 min, 83% of schizophrenics but only 23% of controls had a zero or minimal response to AMN. The skin flushing seen after oral administration of nicotinic acid is due to the same reaction, and this has been normal in those with affective illness and neurosis; cyclo-oxygenase inhibitors, e.g., aspirin, give a false-positive result (failure of vasodilatation). This result is consistent with the concept of reduced membrane arachidonic acid levels in schizophrenia. This test may contribute to the reliable diagnosis of schizophrenia.
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PMID:Niacin skin flush in schizophrenia: a preliminary report. 951 68

Usual risk factors for coronary artery disease account for only 25-50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase-still within the so-called normal range-abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.
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PMID:Diabetic dyslipidemia. 991 65

Crystalline nicotinic acid (immediate-release niacin) is effective therapy for lipoprotein regulation and cardiovascular risk reduction. However, inconvenient regimens and unpleasant side effects decrease compliance. Sustained-release formulations designed to circumvent these difficulties increase hepatotoxicity. Niaspan, a new US Food and Drug Administration (FDA)-approved, once-daily, extended-release form, has been found effective and safe in short-term trials. The long-term efficacy and safety of Niaspan lipid monotherapy was studied in 517 patients (aged 21-75 years) for < or =96 weeks in dosages < or =3,000 mg/day. Primary efficacy endpoints were low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo B) changes from baseline; secondary efficacy endpoints were changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and total cholesterol/HDL-cholesterol ratio; safety data included adverse events and laboratory values over the 2-year study period. LDL-cholesterol levels decreased significantly: 18% at week 48 and 20% at week 96; apo B reduction was similar (16% decrease at week 48 and 19% at week 96). Large elevations in HDL cholesterol (26%, week 48; 28%, week 96) allowed only modest decreases in total cholesterol (12% and 13%, respectively), whereas total cholesterol/HDL-cholesterol ratio decreased by almost one third. Triglyceride and lipoprotein(a) levels were decreased by 27% and 30%, respectively (week 48), and by 28% and 40%, respectively (week 96). All changes from baseline were significant (p <0.001). Niaspan was generally well tolerated, although flushing was common (75%); however, there was a progressive decrease in flushing with time from 3.3 episodes in the first month to < or = 1 episode by week 48. Aspirin was used by one third of patients before Niaspan dosing to minimize flushing episodes. Although serious adverse events occurred in about 10% of patients, none were considered probably or definitely related to Niaspan. Adverse events in general varied widely, but their true relation to the study drug is difficult to ascertain without a placebo (control) group. No deaths occurred. There were statistically significant changes in hepatic transaminases, alkaline phosphatase, direct bilirubin, phosphorus, glucose, amylase, and uric acid. However, these changes were mostly small and are not likely to be biologically or clinically significant (the decrease in phosphorus is a new finding in niacin therapy). No myopathy was observed. Thus, this long-term study confirms the earlier short-term findings that Niaspan is safe and effective as monotherapy in plasma lipoprotein regulation.
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PMID:Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. 991 66

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.
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PMID:Hyperresponsivity to nicotinic acid challenge in generalized social phobia: a pilot study. 992 22

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.
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PMID:Acipimox, a nicotinic acid analog, stimulates growth hormone secretion in short healthy prepubertal children. 1108 90

This paper describes a new iodine-125 radioimmunoassay of 9alpha ,11beta-PGF2, and its use for the determination of urinary 9alpha,11beta-prostaglandin F2 after a selective one-step solid-phase extraction. The newly reported immunoassay is based on the use of 125I-tyrosyl methyl ester derivative of 9alpha,11beta-PGF2 and specific polyclonal antibody raised in rabbits. The assay detected as lowas 0.85 pg/tube 9alpha,11beta-PGF2, and the antibodyshowed lessthan 0.01 cross-reaction with PGF-ring metabolites (e.g., 8-iso-PGF2alpha, PGF2alpha 2,3-dinor-6-keto-PGF1alpha, and 5 more PGF-ring compounds). Both the intra-assay, and inter-assay CVs were lessthan 20% for internal controls containing low, medium and high concentrations of 9alpha,11beta-PGF2. Immuno-HPLC analysis showed a very low ratio of specific immunoreactivity in both non-extracted urine (6.5%), and in urine extracted on C18-silicacartridge (14.8%). By contrast, approximately 80% specific immunoreactivity could be achieved by using C2-silicaas the sorbent, acetonitrile: water (15:85, v/v) as wash solvent, and ethyl acetate as eluent of 9alpha,11beta-PGF2. This extraction procedure enabled a reasonably high extraction efficiency of 80.4 +/- 0.855 (mean +/- SEM, n=82), as determined by 3H-9alpha,11beta-PGF2. The new SPE/RIA method was applied for the determination of urinary 9alpha,11beta-PGF2 values in 50 healthy human volunteers. For the concentration and for the excretion rate 37.52 +/- 4.61 pg/ml (mean +/- SEM), and 3.50 + 0.35 ng/mmol creatinine (mean +/- SEM), respectively, was measured. The specificity of the SPE/RIA method was supported by the observed 69% decrease in 9alpha, 11beta-PGF2 excretion rate after acetylsalicylic acid treatment. The effect of nicotinic acid, a PGD2-stimulatory agent, was monitored by the urinary excretion of 9alpha ,11beta-PGF2 in 6 patients, by using the new SPE/RIA method. In patients responding with flushing symptoms nicotinic acid induced an increase of the urinary excretion of 9alpha,11beta-PGF2 in the range between 11% and 187%. In summary, the combination of the newly developed specific [125I] radioimmunoassay with solid-phase extraction on C2-silica cartridges enables the specific, sensitive, and reliable determination of 9alpha,11beta-PGF2 in human urine without the need for further laborious chromatographic purification before radioimmunoassay.
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PMID:Determination of 9alpha, 11beta prostaglandin F2 in human urine. combination of solid-phase extraction and radioimmunoassay. 1199 20

The use of the HDL-elevating drug nicotinic acid in the treatment and prevention of atherosclerotic disease is limited by the frequent induction of skin flushing. The therapeutic effects of nicotinic acid are attributed to inhibition of lipolysis in adipose tissue via a G protein-coupled receptor, whereas the mechanism of flush induction by release of prostaglandin D(2) from macrophages is not understood. In this study, we investigated if macrophages contain nicotinic acid receptors. Specific guanine nucleotide sensitive binding sites for [(3)H]nicotinic acid were detected in membranes from mouse RAW 264.7 macrophages. Nicotinic acid and related heterocycles stimulated activation of pertussis toxin-sensitive G proteins. The rank orders of potency in macrophage membranes were identical for inhibition of [(3)H]nicotinic acid binding and G protein activation, and were pharmacologically indistinguishable from that of the G protein-coupled nicotinic acid receptor in spleen membranes. These results indicate that the effects of nicotinic acid on macrophages, spleen and probably adipocytes are mediated via an identical, unique G protein-coupled receptor.
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PMID:G protein-coupled receptor for nicotinic acid in mouse macrophages. 1216 83

Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [(3)H]nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [(35)S]GTPgammaS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo[3,3,0(4,8)]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with K(i) values of approximately 0.15 microM and EC(50) values of approximately 6 microM, while their intrinsic activity was only approximately 50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a K(i) value of 0.072 microM, an EC(50) value of 4.12 microM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 microM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competitive mechanism of action.
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PMID:Pyrazole derivatives as partial agonists for the nicotinic acid receptor. 1293 Jan 55

Therapy with niacin (nicotinic acid) is unique in that it improves all lipoprotein abnormalities. It significantly reduces low-density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels, while increasing high-density lipoprotein cholesterol levels. This makes niacin ideal for treating a wide variety of lipid disorders, including the metabolic syndrome, diabetes mellitus, isolated low high-density lipoprotein cholesterol, and hypertriglyceridemia. Niacin-induced changes in serum lipid levels produce significant improvements in both coronary artery disease and clinical outcomes. Niacin is currently available in 3 formulations (immediate release, extended release, and long acting), which differ significantly with respect to their safety and efficacy profiles. Immediate-release niacin is generally taken 3 times a day and is associated with adverse flushing, gastrointestinal symptoms, and elevations in blood glucose levels. Long-acting niacin can be taken once daily and is associated with significantly reduced flushing, but its metabolism increases the risk of hepatotoxic effects. Extended-release niacin, also given once daily, has an absorption rate intermediate between the other formulations and is associated with fewer flushing and gastrointestinal symptoms without increasing hepatotoxic risk.
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PMID:New perspectives on the use of niacin in the treatment of lipid disorders. 1507 39

Niacin (nicotinic acid) favourably modifies all aspects of the lipoprotein profile; it raises high-density lipoprotein cholesterol (HDL-C) levels, lowers triglyceride, low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) levels and reduces atherogenic small, dense LDL particles. One large monotherapy trial and multiple trials of niacin in combination with other lipid-modifying drugs show remarkable consistency in the ability of niacin to improve angiographic and clinical outcomes. In practice, however, the use of regular, immediate-release niacin (niacin IR) has been limited by the side effect of flushing. Sustained-release (SR) formulations, developed in order to reduce flushing, were found to cause serious hepatotoxicity at varying frequencies. Extended-release niacin (niacin ER; Niaspan), Kos Pharmaceuticals, Inc.) is a prescription formulation of niacin, administered once-daily at bedtime. Niacin ER is as effective in modifying lipoprotein levels as an equal daily dose of niacin IR and it causes less flushing. In addition, niacin ER administered once-daily is not associated with the increased hepatotoxicity reported with SR formulations. Niacin ER has been studied extensively in combination therapy with statins, including lovastatin in a recently introduced combination tablet. Myopathy has not been a substantial problem in statin/niacin ER combination therapy. Finally, a study of niacin ER given to diabetic patients showed only mild trends towards increased glycosylated haemoglobin concentrations and a need for additional antidiabetic medication. Thus, niacin ER represents an effective and safe option in the management of low levels of HDL-C and other lipoprotein abnormalities in a variety of settings.
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PMID:Extended-release niacin for modifying the lipoprotein profile. 1516 82


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