Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00528 (Monit)
 35,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND: The role of nitric oxide (NO) in regulation of systemic blood pressure both in normotensives and in hypertensives remains unknown. OBJECTIVE: To investigate the influence of L-arginine (the substrate for generation of NO) on blood pressure in 30 men (aged 51.5 +/- 7.3 years) with established primary arterial hypertension that was not well controlled. METHODS: The antihypertensive therapy was not discontinued and the patients were administered beta-blockers and calcium antagonists only. On day '0' the patients were administered 250 ml 0.9% NaCl during 180 min intravenously. Then we infused 250 mg/kg L-arginine diluted in 250 ml 0.9% NaCl over 180 min into the antecubital vein for four consecutive days (days 'I'-'IV'). Conventional blood pressure and heart rate measurementws were performed before infusion and every 30 min during infusion. Twenty-four-hour ambulatory blood pressure monitoring (with a SpaceLabs 90207 device) with half-hourly recordings during the daytime and during the night-time was performed on the day of NaCl infusion ('0') and repeated on the day of L-arginine infusion ('II') for all patients. As indicators of generation of NO, blood level of cyclic GMP and urinary concentration of nitrite/nitrate were measured. RESULTS: On all days of L-arginine infusion we found significant falls in systolic and diastolic blood pressures (P < 0.0001) with an accompanying significant increase in heart rate (P < 0.001). The most potent hypertensive effect during infusion of L-arginine was observed on day 'I'. Mean systolic blood pressure decreawsed from 152.1 +/- 20.0 mmHg to a minimum of 123.3 +/- 16.2 mmHg after 60 min of the infusion (by about 19%). The maximal percentage fall in systolic blood pressure was consecutively lower on each day oif L-arginine infusion. It was 14.3% on day 'II', 11.9% on day 'III' and 10.1% on day 'IV'. Similarly, the greatest reduction of diastolic blood pressure was observed during infusion of L-arginine on day 'I'. Mean diastolic blood pressure decreased from 95.9 +/- 13.6 to 80 +/- 9.7 mmHg after 120 min of infusion (by about 17%). On the consecutive days maximal falls in diastolic blood pressure compared with its initial value were 13.5% on day 'II', 10.4% on day 'III' and 9.8% on day 'IV'. Twenty-four-hour ambulatory blood pressure monitoring revealed a significant decrease in diastolic blood pressure during infusion of L-arginine compared with day 0 when 0.9% NaCl was infused. Systolic and diastolic blood pressure variabilities were significantly decreased and the day-night differences in systolic and diastolic blood pressures were increased after infusion of L-arginine. We found a significant correlation between heart rate and systolic blood pressure both during the daytime and during night-time on the day of infusion of L-arginine. An increase in urinary concentration of nitrite/nitrate was observed after administration of L-arginine.CONCLUSION: The present results demonstrate that infusion of L-arginine can influence the systemic blood pressure in hypertensives through NO synthesis. By using ambulatory blood pressure monitoring we documented that the hypotensive effect of L-arginine seems to be limited to the infusion period itself. A decrease in blood pressure variability might imply an increase in sensitivity of baroreceptors or an improvement of autonomic functioning.
Blood Press Monit 1998 Apr
PMID:Blood pressure profile and variability in hypertensives treated with L-arginine infusion. 1021 36

During long-term prophylaxis of angina with oral nitrates, sustained high plasma nitrate concentrations produce partial or complete tolerance to both the haemodynamic and the clinical effects of the drug. There is substantial evidence that this can be prevented by an adequate nitrate-free or nitrate-low period during each 24 h dosing interval. However, a nitrate-free interval carries the risk of a rebound increase in myocardial ischaemia. Once-daily formulations of isosorbide mononitrate deliver high plasma nitrate concentrations that improve exercise tolerance in patients with angina for at least 12 h after dosing. During the remainder of the dosage interval, plasma nitrate concentrations fall but are sufficient to protect against coronary artery spasm overnight. Myocardial ischaemia has a marked circadian rhythm. All ischaemic events (total ischaemic burden, myocardial infarction and sudden cardiac death) are most frequent in the hours immediately after waking. Oral anti-ischaemic prophylaxis should ideally provide protection during this critical period, in order to minimize symptoms, maximize exercise capacity and perhaps also to reduce the risk of clinical events. The ideal long-acting nitrate formulation should therefore provide a rapid rise in plasma nitrate concentration as well as maintaining prolonged efficacy throughout the dosing interval. Elantan LA is a sustained-release capsule formulation of isosorbide mononitrate for once-daily dosing. This capsule contains pellets which release 30% of the dose immediately, while 70% is released slowly to maintain the therapeutic response. The pharmacokinetic profile of this formulation prevents the development of tolerance, while also conferring long-term anti-anginal efficacy. Patients reported an improvement in both severity of angina and quality of life indices when their therapy was changed from multiple daily dosing with isosorbide dinitrate to once-daily dosing with Elantan LA (50 mg). The anti-anginal effect of Elantan LA is attained rapidly after dosing. Within 30 min of ingestion, there are clinically significant improvements in exercise tolerance, comparable with the speed of onset after an immediate-release formulation of isosorbide mononitrate. Elantan LA is an effective once-daily prophylaxis for angina which also produces a rapid onset of therapeutic effect. The release profile of this formulation maximizes protection against the morning surge in myocardial ischaemia.
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PMID:Optimal nitrate therapy with a once-daily sustained-release formulation of isosorbide mononitrate. 1049 57

We describe a packed-column supercritical fluid chromatographic method that can be used for the analysis of isosorbide-5-mononitrate (5-ISMN) bulk substance and the 5-ISMN content of Imdur tablets. The method is based on methanol-modified carbon dioxide as the mobile phase and porous graphitized carbon (PGC, Hypercarb) as column support at 40 degrees C and 100 bar back pressure. The method makes it possible to simultaneously determine 5-ISMN and related compounds. In order to elute NO(3)(-) with acceptable retention time a quarternary ammonium hydrogen sulfate salt is added to the methanol modifier. An almost linear increase of the retention time with increasing carbon content of the counter ion was found. Tetramethyl ammonium hydrogen sulfate 5 mM in methanol was used in the final method as polar modifier for the simultaneous determination of possible degradation products within 12 min. The present method can separate and detect related compounds such as isosorbide-2, 5-dinitrate, isomannidemononitrate and isosorbide-2-mononitrate at the 0.1% (w/w) level as required by regulatory guidelines. Nitrate can be detected down to about 0.02% (w/w). Repeated analyses of ground tablet powder gave an assay precision for isosorbide-5-mononitrate of 1.4% (R.S.D., eight samples and two injections of each). For related substances at an area percent of 0. 1 the precision was less than 10%.
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PMID:Packed-column supercritical fluid chromatography for the analysis of isosorbide-5-mononitrate and related compounds in bulk substance and tablets. 1086 72

In 22 patients with stable myocardial ischemia, we prospectively studied the short- and long-term effects of isosorbide-5-mononitrate (5-ISMN) on dipyridamole-induced myocardial ischemia, the ability of dipyridamole-stress echocardiography to evaluate nitrate tolerance, and the role of activation of the neurohumoral system in nitrate tolerance development, assessed by modifications of catecholamines plasma levels and heart rate variability. After brief treatment with 5-ISMN, dipyridamole-stress echocardiography was negative in 19 of 22 patients (p < 0.001 vs. placebo). During the sustained phase, dipyridamole-stress echocardiography was positive after both placebo and active drug (p = NS vs. placebo). Heart rate variability showed significantly higher values in power of the low frequency (LF) band and low- to high-frequency ratio (L/H), as well as significantly lower values of the power of the high-frequency (HF) band (all p < 0.001) during brief but not during sustained administration of 5-ISMN. Norepinephrine plasma levels were significantly higher (p < 0.001) during short-term 5-ISMN administration but not during the sustained phase. Our results indicate that short-term administration of 5-ISMN antagonizes dipyridamole-induced myocardial ischemia and show the loss of antiischemic efficacy in 95% of patients during sustained treatment, demonstrating that dipyridamole-stress echocardiography is a useful tool to assess the presence of nitrate tolerance. Spectral analysis of heart rate variability and norepinephrine values confirm that brief nitrate administration increases sympathetic activity, a possible crucial trigger event in the development of nitrate tolerance, whereas prolonged nitrate treatment is not associated with prolonged neurohumoral activation.
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PMID:Echo-dipyridamole stress test evaluation of isosorbide-5-mononitrate efficacy and tolerance in patients with coronary heart disease: interplay with sympathetic activity. 1089 60

Since the first publication of isosorbide mononitrate 30% immediate-release 70% sustained-release (IR-SR) formulation in 1985, a considerable body of literature concerning its clinical efficacy and safety has become available. Theoretically, the formulation has the advantage over conventional isosorbide mononitrate or dinitrate (ISMN/ISDN) that it has a simpler and more predictable pharmacokinetic profile. The objectives of this paper are to review published data so far and to see whether the theoretical advantages translate into better clinical effectiveness. 1. After oral administration, isosorbide mononitrate IR-SR has a rapid onset of action (30 minutes), and effects are evident for up to 17 hours. 2. The antianginal effects of once-daily isosorbide mononitrate IR-SR increased with increasing dosages, were generally larger than those of either placebo or equipotent doses of conventional ISMN/ISDN, and were somewhat larger than those of the beta blocker bupranolol. The effects were generally similar to those of sustained release nifedipine. 3. Patients showed significantly greater improvement in some quality-of-life indices with once-daily isosorbide mononitrate IR-SR than with twice or three times daily regimens of conventional ISMN/ISDN. This was particularly so with mobility, psychological distress, and life satisfaction indices. 4. Tolerance did not develop after 13 months of once daily isosorbide dinitrate IR-SR. No rebound increase in incidence of ischemic episodes was observed after discontinuation of treatment. 5. Long-term efficacy data both of isosorbide mononitrate IR-SR and of conventional ISMN/ISDN are limited so far. Large studies in patients with angina pectoris and patients with heart failure addressing long-term effects are ongoing, and some of the data will be completed within the next months. Isosorbide mononitrate IR-SR has a rapid onset of action and has been shown to be clinically efficient and, in addition, to be more so than conventional ISMN / ISDN. Nitrate tolerance with continued use of the formulation has not yet been reported. Long-term effects on morbidity and mortality are currently being assessed.
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PMID:Isosorbide mononitrate 30% immediate-release 70% sustained-release formulation: a review. DUMQOL (DUtch Mononitrate Quality of Life) Study Group. 1095 15

Recent studies suggest that nitric oxide (NO) plays an important role in nitrate-induced headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs for NO and headache is a predominant adverse effect of nitrates but often disappears during continuous treatment. Insight into tolerance to headache could lead to insight into vascular headache mechanisms in general. The specific aim of the present study was therefore to characterize the headache and accompanying symptoms during continuous nitrate administration until a state of tolerance to headache had developed. 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily was administered orally for 7 days in 11 healthy subjects in a double-blind, randomized placebo controlled cross-over design. Wash-out between periods was 14 days or more. Haemodynamic data from the present study were compared to the observed changes of headache over time. Headache during 5-ISMN was longer lasting and more severe compared to placebo (P<0.004). In 10 subjects the headache fulfilled the pain sub-criteria for migraine and in five subjects all diagnostic criteria for migraine without aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate caused a milder headache and no migraine. The present results therefore suggest that NO may elicit a migraine attack in many healthy subjects if a high enough dose is given for several hours. A close temporal association between the disappearance of headache and the attenuation of the 5-ISMN induced dilatation of the superficial temporal artery was observed. In contrast, tolerance in the middle cerebral artery already appeared after 24 h, which was earlier than the development of tolerance to headache. If vasodilatation is the cause of headache the results point to extracerebral arteries. However, cytotoxic and pain modulating central nervous system effects of NO, the time courses of which are unknown, may also play a role, involving both intra- and extracranial arteries.
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PMID:Headache characteristics during the development of tolerance to nitrates: pathophysiological implications. 1103 39

1. The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. 2. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. 3. The vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.33+/-0.1, n=8), ISMN (1.61+/-0.07, n=7) and PETN (>10 microM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52+/-0.06, n=12), ISMN (3.66+/-0.08, n=10) and PETN (6.3+/-0.13, n=8) observed in coronary arteries. 4. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in -logM) was almost similar in basilar (7.76+/-0.05, n=7) and coronary arteries (7.59+/-0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. 5. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.84+/-0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor N(omega)-nitro-L-arginine (4.59+/-0.05, n=9, P<0.03). 6. These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.
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PMID:Impaired vasodilator response to organic nitrates in isolated basilar arteries. 1115 58

Three atomic spectrometry techniques, namely sector field inductively coupled plasma mass spectroscopy, graphite furnace atomic absorption spectrometry and hydride generation atomic fluorescence spectroscopy (ICP-SMS, GF-AAS and HG-AFS, respectively), housed at separate independent laboratories, were used to analyse water and sediment samples collected from the Huon River Estuary, SE Tasmania (Australia) in the Austral spring 1998. A dithiocarbamate-chelation/back-extraction technique was used to separate and preconcentrate Co, Ni, Cu, Zn, Cd and Pb from eight collected water samples prior to analysis by ICP-SMS and GF-AAS. A number of other elements in the waters were analysed directly (Mn, Fe and Zn by GF-AAS; As by HG-AFS), or following sample dilution (1 + 19: V, Mn, Fe, As, Mo, Ba and U by ICP-SMS). Where possible, previously corroborated GF-AAS and HG-AFS techniques were used to verify obtained ICP-SMS results. From the analysis of four reference waters (SLEW-1 and -2, SLRS-3 and NASS-5), good agreement, to within +/- 10-20%, was typically found between certified (or information only values) and measured results (irrespective of analytical technique). Exceptions included Zn (and sometimes Fe) that could not be quantified by ICP-SMS due to elevated blank signals, and As which was found to lie below ICP-SMS detection limits. For Huon Estuary water samples, inter-method agreement was within +/- 10-20% (for those elements amenable to analysis by more than one technique). Nitric acid extracts of two certified reference materials (Buffalo River Sediment and BCSS-1) and six Huon Estuary sediments were analysed by ICP-SMS (for Al, Sc, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Cd and Pb) and HG-AFS (for As). Results from the certified reference materials indicated extraction efficiencies of 60 70% (for most elements). A close correlation between ICP-SMS and HG-AFS was obtained for leachable As in the sediments. In terms of potential inorganic contaminants, the Huon Estuary was found to be a relatively 'clean' water system. The elemental concentrations measured in water and sediment samples from this region were found to lie within current Australian guidelines for estuaries. In general, no one analytical technique was able to accurately determine all elements in all samples from this relatively pristine estuarine environment. A combination of all three analytical techniques was necessary for the successful analysis of the elements considered in this study.
J Environ Monit 2001 Feb
PMID:The application of ICP-SMS, GF-AAS and HG-AFS to the analysis of water and sediment samples from a temperate stratified estuary. 1125 3

The suitability of two different techniques (centrifugation and Rhizon sampler) for obtaining the interstitial pore water of soil (soil solution), integral to the ecotoxicity assessment of metal contaminated soil, were investigated by combining chemical analyses and a luminescence-based microbial biosensor. Two different techniques, centrifugation and Rhizon sampler, were used to extract the soil solution from Insch (a loamy sand) and Boyndie (a sandy loam) soils, which had been amended with different concentrations of Zn and Cd. The concentrations of dissolved organic carbon (DOC), major anions (F- , CI-, NO3, SO4(2-)) and major cations (K+, Mg2+, Ca2+) in the soil solutions varied depending on the extraction technique used. Overall, the concentrations of Zn and Cd were significantly higher in the soil solution extracted using the centrifugation technique compared with that extracted using the Rhizon sampler technique. Furthermore, the differences observed between the two extraction techniques depended on the type of soil from which the solution was being extracted. The luminescence-based biosensor Escherichia coli HB101 pUCD607 was shown to respond to the free metal concentrations in the soil solutions and showed that different toxicities were associated with each soil, depending on the technique used to extract the soil solution. This study highlights the need to characterise the type of extraction technique used to obtain the soil solution for ecotoxicity testing in order that a representative ecotoxicity assessment can be carried out.
J Environ Monit 2001 Feb
PMID:Soil solution extraction techniques for microbial ecotoxicity testing: a comparative evaluation. 1125 26

The aim of the present study was to analyse the data structure of a large data set from rainwater samples collected during a long-term interval (1990-1997) by the Austrian Precipitation Monitoring Network. Eleven sampling sites from the network were chosen as data sources (chemical concentrations of major ions only) covering various location characteristics (height above sea level, rural and urban sampling positions, Alpine rim and Alpine valley disposition, etc.). The analytical results were treated by the application of already classical environmetric approaches, such as linear regression analysis, time-series analysis and principal components analysis (PCA). For most of the sampling sites, a distinct trend of acidity decrease of the wet precipitation was observed. An overall decrease in sulfate concentration for the whole period and all sites of 3.9% year(-1) (2.0 muequiv. L(-1) year(-1)) was found. The free acidity decrease for most of the sites was between 3.5 and 10.9% year(-1). No significant linear trends were found for nitrate. Base cations either decreased (mean percentage decrease for calcium was 5.4% year(-1) and for magnesium 4.4% year(-1)) or did not show any significant change (sodium, potassium). The overall decrease in ammonium concentration was 2.3% year(-1). Further, some typical "rural" (summer minima and winter maxima) and "urban" (winter minima and spring maxima) seasonal behaviour for the majority of the sites in consideration could be defined, indicating the influence of local emission sources. Several latent factors, named "anthropogenic", "crustal" and "mixed salt", were revealed by the multivariate modelling procedure (PCA) possessing a similar structure for most of the sites. The unavoidable exceptions observed were indications of the influence of sporadic local events (construction and agricultural activities, secondary emission sources, etc.), and an effort was made to explain these exceptions.
J Environ Monit 2000 Oct
PMID:Trend, seasonal and multivariate modelling study of wet precipitation data from the Austrian Monitoring Network (1990-1997). 1125 44


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